A program of Legacy Community Health Services
P.O. Box 66308, Houston, TX 77266-6308
• Starting Treatment at Higher CD4 Count Cuts HIV Transmission Risk 4
• Impact of Starting CD4 Count and Virologic Failure on CD4 Gains 6
• Years of Antiretroviral Therapy Do Not Raise Risk of non-AIDS Death 9
• Preventable Causes of Death Not Rare in Seattle-Area HIV Group 12
• Higher non-AIDS Illness Rate With 350+ CD4s But Detectable Viral Load 15
• Better HIV Appointment Keeping Linked to Lower Viral Loads 18
• Heart Disease Signals Get Worse With Time in Adults With HIV 20
• Colon Exam Finds Possible Trouble Spots in 60% With HIV 24
• Higher Bone Fracture Risk in People With HIV or With HIV and HCV 26
• Sex Hormones May Play Role in Diabetes Among HIV-Positive Gay Men 30
• Need for Cataract Surgery Greater in People With Than Without HIV 34
• Low Testing Rates for Gonorrhea and Chlamydia in US HIV Group 37
• How Feelings About Aging Affect Emotions in HIV-Positive Adults 40
Definitions
42
Board and staff
44
ISSN 1535-2048
Articles
APRIL 2012 A publication of
The Center for AIDS Information & Advocacy
MISSION
The Center for AIDS Information & Advocacy empowers people living with
HIV to make informed decisions about their health care by providing the
latest research and treatment information and by advocating for accessible,
affordable, and effective treatment options until there’s a cure.
About HIV Treatment Alerts!
HIV Treatment Alerts! is a publication of The Center for AIDS Information & Advocacy (The CFA).
This newsletter is intended for those affected by HIV and their caregivers. The statements and
opinions expressed in this newsletter do not impy recommendations or endorsement. Always consult your doctor before altering a prescribed drug regimen or taking any drug or supplement.
HIV Treatment Alerts! is published twice a year. The print version of the newsletter is available
for free at the L. Joel Martinez Information Center at Legacy Montrose Clinic, 1415 California
Street, Houston, TX 77006. Access to the newsletter is available online from The CFA website
(www.centerforaids.org).
The CFA also publishes Research Initiative/Treatment Action! (RITA!), a literature-review
journal that covers issues in HIV research and policy. This and other publications are available
on The CFA website (www.centerforaids.org).
HIV Teatment ALERTS! thanks Jason Baker, Stephen Berry, Christoph Boesecke,
Susan Buskin, Myron Cohen, Carmina Fumaz, Ann-Brit Hansen, Rachel Hughes,
Justyna Kowalska, Alexandra Mangili, Marybeth McCauley, Anne Monroe,
Michael Mugavero, Line Dahlerup Rasmussen, and Joanne Reekie for reviewing
the reports on their research.
The Center for AIDS Information & Advocacy
Editor
A program of Legacy Community Health Services
Mark Mascolini
P.O. Box 66308, Houston, TX 77266-6308
1415 California Street, Houston, TX 77006
Graphics Teresa Southwell
Phone 713.527.8219
Fax 713.521.3679
Website http://www.centerforaids.org
2
HIVTreatmentAlerts
Article 1
Starting Antiretrovirals at Higher CD4 Count Cuts Risk of HIV Transmission
In couples with one HIV-positive partner and one HIVnegative partner, the risk of HIV transmission dropped
96% if the positive partner started antiretroviral therapy at a CD4 count* between 350 to 550 rather than
waiting until the count fell to 250 or less.1 Results of this
important trial, called HPTN 052, strongly support the
idea that standard antiretroviral therapy can limit the
spread of HIV by lowering viral load in genital fluids
of people with HIV.
Previous research showed that effective antiretroviral
therapy decreases viral load in blood and genital fluids, including semen and vaginal fluids.2,3 Studies in
large groups of couples with one HIV-positive partner
found a lower risk of HIV transmission between sex
partners when the HIV-positive partner had a lower
viral load. Other studies showed a decreased risk of
HIV transmission when the positive partner was taking antiretroviral therapy.
positive partners had taken antiretrovirals (except for
brief periods to prevent mother-to-child transmission
of HIV), and all couples had three or more episodes of
vaginal or anal sex in the past 3 months.
Study participants came from nine countries: Botswana,
Kenya, Malawi, South Africa, Zimbabwe, Brazil, India,
Thailand, and the United States.
The HIV-positive person in each couple was randomly assigned to start antiretroviral therapy immediately
(when the CD4 count was still above 350) or to wait until two consecutive CD4 counts between 200 and 250 or
an AIDS disease developed. The study drugs—provided
for free by six companies—included antiretrovirals often used in the United States and throughout the world.
The study team specifically chose those drugs based on
research showing that they reached high levels in the
genital tract and lowered viral load in the genital tract.
All of these studies are called “observational,” meaning
the researchers simply observed groups of people with
HIV—the researchers didn’t ask these people to do one
thing or another. There had been no randomized trial
comparing HIV transmission risk in people taking antiretroviral therapy versus those not taking antiretrovirals.
In a randomized trial, researchers do ask study participants to do one thing or another. A randomized trial offers the strongest evidence for antiretroviral treatment
planning because such a trial greatly lowers the possibility that chance, bias, or behavior change will affect the results. HPTN 052 investigators planned this international
trial to examine the impact of early versus delayed antiretroviral therapy on HIV transmission in stable couples
with one HIV-positive partner and one negative partner.
All study participants—positive and negative—got
counseled on HIV risk reduction and received condoms at regular study visits. Participants got checked
regularly for sexually transmitted infections (which can
raise the risk of HIV transmission), and everyone received care for any sexually transmitted infection and
for other illnesses.
The researchers also planned the trial to address another critical question in HIV care—whether starting antiretroviral therapy at a higher CD4 count lowers the risk
of disease and death. Some studies of large HIV groups
found evidence that starting therapy at a higher CD4
count has disease-related benefits.4-6 But these studies
were not randomized trials.
■ What the study found. The trial involved 1763 couples
in which about half of the HIV-positive partners started
antiretroviral therapy as soon as they joined the study.
The other half of the HIV-positive partners delayed
treatment until their CD4 count fell to 250 or they had
an AIDS illness. CD4 counts and viral loads were similar in the early-therapy group and the delayed-therapy
group when people entered the trial.
■ How the study worked. HPTN 052 researchers recruited couples with one HIV-positive partner whose
CD4 count lay between 350 and 550. None of the HIV-
If an HIV-negative partner became infected with HIV,
researchers compared the genetic makeup of the newly
infected person’s HIV with the positive partner’s HIV to
see if the negative person had been infected by the study
partner or by someone else. The researchers developed
new procedures to make sure these HIV matches between partners were virtually foolproof.
Almost all couples, 97%, were heterosexual, 94% were
married, and 61% were 26 to 40 years old. Half of the
*Words in bold are defined in the Technical Word List at the end of this issue of HIV Treatment Alerts!
HIVTreatmentAlerts
3
HIV-positive partners were men and half were women.
A little more than half of study participants, 56%, were
from Africa, 30% were from Asia, and 16% were from
North or South America.
The two study groups were similar in education, sexual
behavior, and rates of sexually transmitted infections
and condom use. More than 90% in each study group
reported 100% condom use during the study. The early-antiretroviral group included a higher proportion
of men who had been circumcised (19% versus 14%).
(Circumcision lowers the risk that a heterosexual man
will become infected with HIV during sex with an HIVpositive woman.)
An independent panel recommended releasing study
results earlier than planned because findings heavily favored the early-antiretroviral group. During the study
period, 39 HIV-negative people became infected, including 35 in the delayed-antiretroviral group and 4 in
the early-antiretroviral group. Genetic analysis of the
HIV in newly infected partners showed that 28 of the
39 newly infected people were infected by their regular
partner, not by someone else. Of those 28 new infections,
27 were in the delayed-antiretroviral group and 1 in the
early-antiretroviral group.
Statistical analysis determined that starting antiretrovirals at a CD4 count between 350 and 550 lowered
the risk of HIV transmission by 96% compared with
starting antiretrovirals at a CD4 count of 250 or lower
(Figure 1).
Every 10-times higher viral load when the study began
almost tripled the risk of HIV transmission (Figure 1).
Couples who reported 100% condom use when they entered the study had a 67% lower risk of HIV transmission than couples who reported less than 100% condom
use. Transmission risk did not depend on whether the
infected partner was a man or a woman.
During the study 105 participants had a serious HIVrelated illness or died. Sixty-five of these 105 events
(62%) occurred in the delayed-antiretroviral group
and 40 (38%) in the early-antiretroviral group. Statistical analysis that considered other AIDS or death risk
factors determined that early therapy lowered the risk
of AIDS or death by 41%. The death rate alone did not
differ significantly between the two groups.
HIV transmission risk in steady couples
with one HIV-positive partner
Figure 1. Statistical analysis that considered several factors that may
raise HIV transmission risk from a positive partner to a negative partner found several factors that affected the risk independently, including
(1) starting antiretroviral therapy at a CD4 count between 350 and 550
rather than waiting for a count of 250 or lower, (2) 100% condom use
when entering the study versus less than 100% condom use, and (3)
every 10-times higher viral load when entering the study. (1, odds ratio
[OR] 0.04, 95% confidence interval [CI] 0.01 to 0.28; 2, OR 0.33, 95%
CI 0.12 to 0.91; 3, OR 2.85, 95% CI 1.51 to 5.41).
4
In an analysis that excluded the clinical
endpoints just discussed, the rate of severe
or life-threatening adverse events was
14% in both the early-antiretroviral group
and the delayed-antiretroviral group. The
early group had a higher rate of serious
lab abnormalities than the delayed group
(27% versus 18%).
■ What the results mean for you. This
large trial shows that HIV-positive people
who start antiretroviral therapy at a CD4
count between 350 and 550 are much
less likely to infect a regular sex partner with HIV than are people who do
not start therapy until their CD4 count
falls to 250.1 The researchers believe the
most likely explanation of this result is
that effective antiretroviral therapy can
make viral loads undetectable in genital
secretions—such as semen and vaginal
fluids.2,3 Since HIV in semen or vaginal
fluids can pass from an HIV-positive person to an HIV-negative person during
sex, people with high viral loads in these
fluids are more likely to transmit the virus to their partner during sex.
HIVTreatmentAlerts
Because of this study result, people with HIV can be
more confident that they will not infect a sex partner if
they are taking antiretrovirals and have an undetectable
viral load in blood. For some people, this finding may be
another reason to consider starting antiretrovirals at a
high CD4 count.
But the study does not mean antiretroviral-treated
people can stop using condoms or completely stop
worrying about infecting a sex partner. Viral loads can
jump suddenly in antiretroviral-treated people for a
number of reasons, including (1) forgetting to take antiretrovirals regularly, (2) getting another illness such
as a sexually transmitted infection, and (3) getting a
routine vaccination.
The study found clear evidence that 100% condom use
greatly lowers the risk of HIV transmission to sex partners. And these researchers regularly encouraged study
participants to practice safer sex. Antiretroviral-treated
people should not abandon everything they’ve learned
about safer sex.
Almost all study participants (97%) were heterosexual,
most (54%) were African, and most HIV transmissions
(82%) occurred in Africa. So do these findings apply to
gay and bisexual men, and do they apply to heterosexual
couples outside of Africa? Although the researchers do
not address this question, the answer is probably yes.
Antiretroviral therapy lowers viral loads in semen and
vaginal fluids regardless of whether the treated person
is gay or straight, or whether that person is African or
American. Factors that affect the risk of HIV transmission do differ from region to region, and they differ between gay men and heterosexual men and women. But
all of these groups can reach an undetectable viral load
with antiretroviral therapy.
This study also provides evidence that starting antiretroviral therapy at a higher CD4 count lowers the risk
of AIDS illnesses. In this study the biggest difference in
new AIDS diseases between the early-therapy group and
the delayed-therapy group involved tuberculosis (TB)
outside the lung: This kind of TB developed in 17 people in the delayed-antiretroviral group and in only 3 in
the early-antiretroviral group, and most of these people
lived in India. TB is much rarer in the United States and
Europe than in India or Africa. Still, the protective effect
of early antiretroviral therapy in this study was similar to
the effect seen in large HIV group studies in the United
States and Europe.
The researchers conclude that their findings “support
the use of antiretroviral treatment as a part of a public
health strategy to reduce the spread of HIV-1 infection.”
References
1. Cohen MS, Chen YQ, McCauley M, et al. Prevention of HIV-1 infection with early antiretroviral therapy. N Engl J Med. 2011;365:493-503.
2. Graham SM, Holte SE, Peshi NM, et al. Initiation of antiretroviral therapy leads to a rapid decline in cervical and vaginal HIV1 shedding. AIDS. 2007;21:501-507.
3. Vernazza PL, Troiani L, Flepp MJ, et al. Potent antiretroviral treatment of HIV infection results in suppression of the seminal
shedding of HIV. AIDS. 2000;14:117-521.
4. Kitahata MM, Gange SJ, Abraham AG, et al. Effect of early versus deferred antiretroviral therapy for HIV on survival.
N Engl J Med. 2009;360:1815-1826.
5. Sterne JA, May M, Costagliola D, et al. Timing of initiation of antiretroviral therapy in AIDS-free HIV-1-infected patients:
a collaborative analysis of 18 HIV cohort studies. Lancet. 2009;373:1352-1363.
6. Cain LE, Logan R, Robins JM, et al. When to initiate combined antiretroviral therapy to reduce mortality and AIDS-defining illness in HIV-infected persons in developed countries: an observational study. Ann Intern Med. 2011;154:509-515.
HIVTreatmentAlerts
5
Article 2
Impact of Starting CD4 Count, Virologic Failure,
and Treatment Interruption on CD4 Gains
A large study of people starting their first antiretroviral combination made several new and important findings on CD4 cell gains during treatment. First, people
who reached and maintained an undetectable viral
load while on treatment continued to gain CD4 cells 4
to 8 years after starting therapy, regardless of their starting CD4 count. But CD4 counts in people who started
treatment with a lower CD4 count never “caught up”
with CD4 counts in people who started treatment with a
higher CD4 count. Also, having a virologic failure after
reaching an undetectable viral load had a negative impact on CD4 gains, especially if the viral load rose above
10,000 copies during that failure.
HIV-positive people starting their first antiretroviral
combination usually reach an undetectable viral load
(meaning HIV cannot be measured in their blood) and
gain CD4 cells (which are necessary to fight infections).
But studies on CD4 gains during treatment have not
always produced similar results. And research has not
determined whether people reach normal CD4 counts if
they start antiretrovirals with fewer than 200 CD4s and
then achieve and maintain an undetectable viral load.
Researchers in the United Kingdom (Great Britain)
set out to address these issues with two specific goals
in mind:
1.To see how the CD4 count before treatment begins
affects CD4 gains during treatment.
2.To see how virologic failure during treatment or
treatment interruption affects CD4 gains.
■ How the study worked. The study involved a large
group of HIV-positive people who get care at some of
the largest centers in the United Kingdom. Clinicians at
those centers regularly measure and record important
health signals—like CD4 count and viral load—in all
these people. Later, researchers can use these records to
analyze specific changes in different patient groups. The
overall patient group is called UK CHIC.
In this study, researchers focused on people older than
15 who started their first antiretroviral combination after
1997. Everyone had a CD4 count before starting therapy
or in the first few days of therapy. And everyone had
CD4 counts and viral loads measured at specific times
that the researchers picked before the study.
6
The researchers considered findings up to December
2009. They defined virologic failure as a viral load above
1000 copies for any reason, regardless of whether a person interrupted treatment. They defined treatment interruption as at least 1 day when a person was not taking
three or more antiretrovirals more than 6 months before
death.
The researchers divided study participants into seven
groups according to their CD4 count before antiretroviral therapy began: under 25, 25 to 49, 50 to 99, 100 to
199, 200 to 349, 350 to 499, and 500 or higher.
■ What the study found. The study involved 7069 people
starting their first antiretroviral combination after 1997.
More than two thirds of study participants were men,
and about half were gay or bisexual. About half of these
people were white, while most of the rest were black Africans living in the United Kingdom.
Median follow-up time for each of the starting CD4count groups was 35 months or more, and 2880 people
(41%) had more than 4 years of follow-up. As a result,
the researchers could see CD4 changes over periods of 3
years or more for most study participants.
In the whole study group, CD4 counts continued to
rise through 8 years of treatment at about the same rate
in each of the starting-CD4 brackets (under 25, 25 to
49, and so on), except for people with a pretreatment
CD4 count at or above 350. People who began treatment with a CD4 count between 350 to 500 gained CD4
cells through the first 2 years of treatment then tended
to gain no more. This analysis showed that people who
began treatment with very low CD4 counts did not have
a limit in how many CD4 cells they could gain. But even
after 8 years of treatment, CD4 counts in people who
started with the lowest counts did not catch up with CD4
counts in people who started with higher counts.
Among the 7069 study participants, 1980 (28%) had
at least one virologic failure after the first 6 months of
therapy. In the 5089 people who never had a virologic failure, CD4 counts rose steadily through 8 years of
treatment, with little difference between the initial-CD4
groups. But that was not true in people with at least one
virologic failure 6 months after starting treatment. In
HIVTreatmentAlerts
people with one or more virologic failures after starting
treatment with fewer than 200 CD4 cells, CD4 counts
rose at a slower rate than in people with no virologic
failure. In people with one or more virologic failures after starting treatment with 200 or more CD4 cells, CD4
counts fell.
Among people with no virologic failures, after 8 years
of treatment average CD4 counts ranged from 415 in
people who began treatment with a CD4 count under 25
to 897 in people who began with more than 500 CD4s
(Figure 1). In contrast, after 8 years of treatment, average CD4-cell gains in people who had one or more
virologic failures were about half as high as counts in
people who never had a virologic failure (Figure 1). Virologic failure with a viral load above 10,000 copies had
a greater negative impact on CD4-cell gains than failure
with 1000 to 10,000 copies.
Geometric mean CD4 count in 8 years
with or without virologic failure
Among people who began treatment with a CD4 count
of 500 or higher and had at least one virologic failure,
average CD4 counts dropped about 14% between 4 and
8 years of treatment. Average CD4 count did not drop in
people who started treatment with more than 500 CD4
cells and never had a virologic failure. The researchers
suggest a possible explanation for this difference is that
some people stop antiretroviral therapy if their CD4
count reaches a high level. For example, the investigators think that may be true of women with a high CD4
count who start antiretroviral therapy to avoid transmitting HIV during pregnancy or delivery.
■ What the results mean for you. This large study of HIVpositive people who started antiretroviral therapy made
several important findings on CD4 count changes up to
8 years after treatment began.
First, average CD4 counts rose regardless of how low the CD4 count was when
therapy began. For example, people who
started antiretroviral therapy with a CD4
count under 25 and never had a virologic
failure had an average count of 350 after 4 years of treatment and an average
count of 415 after 8 years (Figure 1). As
a result, these people had a much lower
risk of developing an AIDS disease after
4 years of treatment and had a stronger
infection-fighting system.
A second key finding is that people
who started antiretroviral therapy with
a higher CD4 count ended up with a
higher count after 8 years of treatment
than did people who started with a lower
CD4 count. For example, people who began therapy with a CD4 count of 350 to
499 and always kept their viral load beFigure 1. CD4 counts rose higher in 7069 people starting antiretro- low 1000 copies had an average count of
748 after 8 years of therapy. In contrast,
viral therapy and never having a virologic failure (defined as a viral load
people who started treatment with a CD4
above 1000 copies) than in 1980 people who had at least one virologic
count of 50 to 99 and always kept their vifailure after the first 6 months of therapy.
ral load under 1000 had an average count
of 482 after 8 years. For the full 8 years
of this study, people who began treatment with a CD4
Treatment interruptions were linked to lower CD4
count in one of the lower brackets never caught up with
counts after the interruption. This negative impact on
people who started treatment in a higher CD4 bracket—
CD4-cell gains was greatest up to 44 days after the treateven if they always had a viral load below 1000 copies.
ment interruption. However, the negative impact of
virologic failure on current CD4 count lasted for more
This finding adds to earlier work showing that starting
than 1 year after the failure if the viral load rose above
antiretroviral therapy at a CD4 count above 350 has
10,000 copies.
HIVTreatmentAlerts
7
benefits over the long term.2,3 But it’s encouraging that
people who start antiretroviral therapy with a low CD4
count keep gaining CD4 cells throughout treatment.
A third important finding is that people who had a virologic failure—going from an undetectable viral load
to a load over 1000 copies—did not gain as many CD4
cells in the 4 to 8 years after treatment began as did people who always kept their viral load under 1000 copies.
For example, people who started treatment with a CD4
count between 200 and 349 and always had a viral load
below 1000 copies had an average CD4 count of 565 after 4 years of treatment and an average count of 656
after 8 years. In contrast, people who started therapy
with a CD4 count between 200 and 349 and had one
or more viral loads above 1000 copies after 6 months of
therapy had average CD4 counts of 371 after 4 years of
treatment and 360 after 8 years.
This difference in 4- and 8-year CD4 gains between
people with and without virologic failure underlines the
importance of reaching and keeping an undetectable viral load once antiretroviral therapy begins. Taking your
antiretrovirals inconsistently—especially missing several
days—poses a risk that an undetectable viral load will
become detectable. As this study shows, when the viral
load become detectable, you may stop gaining CD4 cells
and you may lose CD4 cells if your viral load stays detectable long enough.
This study also found that CD4 counts fall during treatment interruptions, with the greatest drops seen in the
weeks immediately after the interruption and only modest drops after that. That’s good to know if your provider recommends interrupting antiretroviral therapy
briefly for some reason, such as the need to treat another
disease. But you should never interrupt treatment unless your provider tells you to. Interrupting treatment
on your own will make your viral load rise and could
result in development of resistance to the antiretrovirals
you’re taking. Resistance makes treating HIV infection
more difficult.
The researchers believe their findings “support hopes
that, given continuing virological suppression, many patients will ultimately be able to attain normal or nearnormal CD4 cell counts regardless of their baseline [initial] CD4 cell count.”
References
1. Hughes RA, Sterne JAC, Walsh J, et al. Long-term trends in CD4 cell counts and impact of viral failure in individuals starting antiretroviral therapy: UK Collaborative HIV Cohort (CHIC) study. HIV Med. 2011;12:583-593.
2. Kitahata MM, Gange SJ, Abraham AG, et al; NA-ACCORD investigators. Effect of early versus deferred antiretroviral therapy for HIV on survival. N Engl J Med. 2009;360:1815-1826.
3. When To Start Consortium, Sterne JA, May M, Costagliola D, et al. Timing of initiation of antiretroviral therapy in AIDS-free HIV-1-infected patients: a collaborative analysis of 18 HIV cohort studies. Lancet. 2009;373:1352-1363.
8
HIVTreatmentAlerts
Article 3
Years of Antiretroviral Therapy Do Not Raise
Risk of non-AIDS Death
Taking combination antiretroviral therapy for many
years does not raise the risk of death from non-AIDS
causes, according to results of a 12,000-person study in
which half of the participants took antiretroviral combinations for more than 4.4 years.1 In fact, this study’s results suggest that every year of treatment may lower the
risk of non-AIDS death. The study produced solid evidence that every year of antiretroviral therapy cuts the
risk of death from any cause. These new findings ease
fears that taking antiretroviral combinations for many
years will cause side effects severe enough to damage
organs like the heart and liver and cause death.
Antiretrovirals do cause side effects that may involve
the heart, liver, kidneys, and other organs and systems
critical to health. Since the mid-1990s, when triple-antiretroviral combinations lowered the risk of death from
AIDS, the proportion of HIV-positive people dying
from non-AIDS diseases (like heart disease and cancer)
rose. For these reasons, some feared that many years
of treatment with antiretrovirals would raise the risk of
non-AIDS deaths.
Because of these fears, researchers planned studies in
which some people took antiretrovirals continuously
while others took planned breaks from antiretroviral
therapy. These studies found that people taking steady
antiretroviral therapy had a lower risk of AIDS, serious
non-AIDS diseases, and death than people taking treatment breaks.2-4
Still, the impact of long-term antiretroviral therapy on
risk of non-AIDS death outside of clinical trials2-4 remained unknown. Therefore, researchers in the EuroSIDA study group planned this analysis of people taking antiretrovirals for several years.
■ How the study worked. EuroSIDA is an ongoing
study involving more than 16,000 HIV-positive people
across Europe and in Israel and Argentina. Healthrelated findings and other information (such as age
and how people got infected with HIV) are collected
regularly on all EuroSIDA participants and sent to a
central databank. Later, researchers can analyze specific sets of findings on EuroSIDA participants in different patient groups. This type of study is called “observational” because the researchers observe findings
from regular day-to-day care—the researchers do not
HIVTreatmentAlerts
specify certain treatments or strategies that study participants must follow.
This study involved everyone who joined EuroSIDA
since January 1, 1996 and started combination antiretroviral therapy at some point. Everyone had at least
one CD4 count before or when treatment began. Follow-up for this study continued until 6 months after the
last EuroSIDA visit or death, whichever happened first.
EuroSIDA researchers defined duration of combination antiretroviral therapy as the total time a person
was actually taking antiretrovirals. The EuroSIDA team
broke down treatment duration into five periods: under 2 years, 2 to 3.99 years, 4 to 5.99 years, 6 to 7.99
years, and 8 or more years. The researchers determined how many people died over the study period,
and they divided deaths into those caused by AIDS and
those caused by specific non-AIDS diseases, such as liver failure, non-AIDS cancers, and heart disease.
The EuroSIDA investigators used standard statistical
methods to measure changes in rates of AIDS deaths,
non-AIDS deaths, and death from any cause. They also
figured the impact of antiretroviral treatment duration
on risk of death from AIDS, non-AIDS illnesses, or any
cause.
■ What the study found. This analysis involved 12,069
people taking combination antiretroviral therapy for
a median of 4.4 years. Three quarters of study participants were men, 89% were white, 41% became infected with HIV during sex between men, 29% became
infected during sex between men and women, and 22%
became infected while injecting drugs. Median age of
the study group was 38.2 years, and median follow-up
was 5.4 years.
During the study period, 1297 people died. The researchers determined that non-AIDS illnesses caused
884 deaths (68%) while AIDS caused 413 deaths (32%).
Among non-AIDS causes of death, liver-related problems caused 182 deaths (14%), non-AIDS cancers
caused 125 (10%), heart disease caused 122 (9%), nonAIDS infections caused 121 (9%), violent deaths including suicide caused 90 (7%), and other or unknown
causes explained the remaining deaths.
9
Statistical analysis that considered pretreatment CD4cell count and viral load, time on antiretroviral therapy, and other factors figured a 5% decrease in the risk
of death from any cause and a 14% decrease in the risk
of death from AIDS for each additional year of antiretroviral therapy after the second year of treatment
(Figure 1).
for more than 4.4 years, this study found no evidence
that each year of antiretroviral therapy (after the first 2
years) leads to a higher risk of death from non-AIDS infections, liver disease (such as hepatitis), heart disease,
violent causes (including suicide), other causes, or unknown causes that are known to be non-AIDS causes.
Change in risk of non-AIDS death
with each added year of antiretroviral therapy
Figure 1. After the first 2 years of combination antiretroviral therapy, each additional year of treatment lowered the risk
of death from all causes, AIDS, all non-AIDS causes, violence
(including suicide), liver disease, and unknown causes that are
known to be non-AIDS causes. The lowered death risks from all
causes, AIDS, and violence were statistically significant (meaning
it was highly unlikely that chance could explain these results).
The lowered death risks from the other causes approached statistical significance (meaning there was a small possibility that
chance could explain these results).
In fact, every year of antiretroviral therapy
lowered the risk of death from any cause,
the risk of violent death, and the risk of
death from liver disease (Figure 1). Also,
every year of antiretroviral therapy sharply lowered the risk of death from AIDS.
The researchers believe the results should
reassure people with HIV that several
years of antiretroviral therapy does not
seem to be raising the risk of non-AIDS
deaths. In other words, taking three or
more antiretrovirals for a long time does
not appear to cause problems that make
death from non-AIDS diseases more likely.
However, the researchers noted, because
combination antiretroviral therapy protects
against development of many non-AIDS illnesses by controlling HIV and raising CD4
counts, they expected an even greater drop
in the risk of non-AIDS death.
The EuroSIDA team suggests that the
lower risk of violent death with longer antiretroviral therapy may reflect the better
overall health that comes with treatment,
lifestyle changes, or improvements in the
financial security of people who stay in
care. They propose that the lower risk of
dying from unknown causes suggests that
people who keep taking antiretrovirals
and stay in care for many years have betThe risk of non-AIDS death dropped 3% for each ter and more predictable health outcomes.
additional year of treatment after the second year of
therapy, but this finding did not quite reach statistical The study found some evidence that the risk of death
significance (meaning there was a small chance that this from non-AIDS cancers (such as lung cancer and anal
result could be explained by chance). After the first 2 cancer) may increase with longer antiretroviral therayears of antiretroviral therapy, each additional year of py. That trend was not statistically significant, meaning
treatment also lowered the risk of liver-related death that chance could explain this result. The researchers
suggest that aging itself may explain a higher cancer
and violent death.
death risk in people with HIV, since older age raises
■ What the results mean for you. The main result of the cancer risk in people with and without HIV. When
this large study is that prolonged treatment with com- the researchers performed a statistical analysis that facbination antiretroviral therapy does not raise the risk tored in the impact of aging, longer antiretroviral treatof death from non-AIDS causes. With half of the 12,069 ment no longer appeared to raise the cancer risk.
study participants taking three or more antiretrovirals
10
HIVTreatmentAlerts
The researchers believe that “death due to accumulating treatment toxicities [side effects] is a very uncommon event” and thus remains difficult to study. It is also
clear that all antiretrovirals cause side effects, which
vary from one antiretroviral to the next and may affect each person differently. But as HIV providers grow
more familiar with these side effects, and as more antiretrovirals become available, it gets easier to select
antiretroviral combinations that work well for each
individual without causing severe side effects. Still,
the EuroSIDA team believes the long-term impact of
treatment side effects should remain a focus of future
research that observes aging HIV-positive people over
longer periods.
It is important to realize that serious non-AIDS illnesses, like cancer and heart disease, do affect many people
with HIV infection. And as people live longer because
of antiretroviral therapy, these illnesses will occur more
often, as they do in aging people without HIV. So it’s
important to avoid the many non-HIV risk factors for
these diseases, like smoking, physical inactivity, and an
unhealthy diet.
References
1. Kowalska JD, Reekie J, Mocroft A, et al. Long-term exposure to combination antiretroviral therapy and risk of death from specific causes: no evidence for any previously unidentified increased risk due to antiretroviral therapy. AIDS. 2012;26: 315-323.
2. Strategies for Management of Antiretroviral Therapy (SMART) Study Group, El-Sadr WM, Lundgren JD, Neaton JD, et al. CD4+ count-guided interruption of antiretroviral treatment. N Engl J Med. 2006;355:2283-2296.
3. Ananworanich J, Gayet-Ageron A, Le Braz M, et al; Staccato Study Group; Swiss HIV Cohort Study. CD4-guided scheduled
treatment interruptions compared with continuous therapy for patients infected with HIV-1: results of the Staccato
randomised trial. Lancet. 2006;368:459-465.
4. Danel C, Moh R, Minga A, et al. CD4-guided structured antiretroviral treatment interruption strategy in HIV-infected adults in west Africa (Trivacan ANRS 1269 trial): a randomised trial. Lancet. 2006;367:1981-1989.
HIVTreatmentAlerts
11
Article 4
Preventable Causes of Death
Not Rare in Seattle-Area HIV Group
Researchers in Seattle planned this study to
determine recent causes of death in people with
HIV and to identify conditions and behaviors
that can be changed to lower the risk of death.
Downtown Seattle view from Kerry park
Photo/Chris Vlachos
Certain behaviors and non-AIDS illnesses—many of
which can be changed or treated—raised the risk of
death in a study of more than 6000 HIV-positive people
in Seattle/King County in Washington State.1 Use of illegal drugs, cocaine, or tobacco were each independently
linked to a higher death risk. High blood pressure and
untreated depression also made death more likely in this
study. More than 20% of people in this HIV group declined to take antiretrovirals at some point in the year
before they died.
Survival with HIV infection rose dramatically when
people began taking combination antiretroviral therapy
in the mid-1990s. But people with HIV still do not survive as long as HIV-negative people the same age. AIDS
remains among the most frequent causes of death in
people with HIV. At the same time, non-AIDS causes of
death, such as heart disease and non-AIDS cancers, account for growing proportions of deaths among people
with HIV.
Researchers in Seattle planned this study to determine
recent causes of death in people with HIV and to identify conditions and behaviors that can be changed to lower
the risk of death.
■ How the study worked. Researchers examined data
from three sources: (1) the Seattle/King County HIV database for deaths from 2008 through 2010, (2) in-depth
medical record reviews and healthcare provider inter12
views for deaths in 2009, and (3) the 2009 Medical Monitoring Project of people living with HIV in the Seattle/
King County area.
Including both Seattle and Bellevue, King County has a
population of 1.9 million people and ranks 14th in population among US counties.
The researchers analyzed factors that may cause death
in people who died during the study period compared
with HIV-positive people who did not die. They counted
numbers of deaths caused by AIDS and non-AIDS illnesses. And they used standard statistical methods to calculate the impact of various factors on the risk of death.
■ What the study found. The study involved 6193 HIVpositive people, 240 of whom (4%) died during the 20082010 study period. Men made up 88% of the group that
died and 89% of the group that did not die. But gay/
bisexual men made up only 52% of the group that died
versus 69% of the group that did not die. People who injected drugs made up 17% of the group that died versus
5% of the group that did not die. Race did not appear to
affect chances of dying.
Compared with people who did not die during the study
period, those who died were older (median 52 versus
46 years), had been diagnosed with HIV infection longer (median 12 versus 10 years), had lower CD4 counts
(59% versus 10% under 200), had higher viral loads
HIVTreatmentAlerts
Factors that raised the risk of death in
Seattle-area HIV-positives in 2009
Figure 1. Having high blood pressure or
untreated depression, smoking cigarettes, using cocaine or crack cocaine, using any illegal
drug, or making 0 or 1 medical visit in the past
year versus 2 or more raised the risk of death
among HIV-positive people in Seattle/King
County in 2009.
(50% versus 75% undetectable), and were more likely to
have an AIDS illness diagnosed within 6 months of testing positive for HIV (43% versus 28%).
Certain factors that raised the risk of death were not
surprising. For example, a recent CD4 count below 200
increased the risk of dying more than 7 times, having
an AIDS illness at some point almost tripled the risk of
death, having a detectable viral load doubled the risk of
death, and being an injection drug user almost doubled
the risk of death.
In-depth analysis of 87 HIV-positive people who died
in 2009 determined that AIDS was the single most frequent cause of death (in 29%), followed by non-AIDS
cancers (23%), pneumonia or other lung disease (10%),
self-harm, including suicides and drug overdoses (10%),
heart disease (8%), liver disease (6%), and cerebrovascular disease such as stroke (3%). Among these 87 people
who died, 18 (21%) had refused antiretroviral therapy at
some point in the past year.
In the analysis of people who died in 2009, providers diagnosed depression in 55% of people in the year before
they died. But only 57% of those with a depression diagnosis got prescriptions for antidepressant drugs. Among
people who did not die during that period, 45% had a
diagnosis of depression, and 78% of these people were
prescribed antidepressant drugs.
Among people who died in 2009, 47% had hypertension
(high blood pressure) and 78% were prescribed antihypertensive drugs. Among the people who did not die in
HIVTreatmentAlerts
2009, 23% had hypertension and 74% were prescribed
antihypertensive drugs.
Statistical analysis found several medical and behavioral characteristics significantly associated with an
increased risk of death. These included hypertension
and untreated depression, which both tripled the risk of
death (Figure 1).
Among people who died in 2009, 56% of those who died
smoked, compared with 39% of those who did not die.
Rates of illegal drug use were 33% among people who
died and 15% among people who did not die. Use of any
illegal drug, use of cocaine or crack cocaine, and smoking each raised the risk of death (Figure 1). Compared
with people who made 2 or more clinic visits in the past
year, those who made 0 or 1 visit had a 5 times higher
risk of death.
■ What the results mean for you. This large study of
people with HIV in the current antiretroviral treatment
era made several important findings. First, despite the
availability of strong antiretroviral combinations, AIDS
was the cause of death in almost one third of people who
died. Analysis of people who died in 2009 suggests one
reason for this high AIDS death rate: 1 in 5 people who
died had recently declined antiretroviral therapy.
Taking antiretrovirals consistently is essential to avoid
AIDS illnesses. Research also shows that steady antiretroviral therapy lowers rates of serious non-AIDS illnesses
such as heart disease and liver disease.2 Other research
found evidence that waiting until the CD4 count fell be13
low 500 rather than starting above 500 doubled the risk
of death.3 US antiretroviral guidelines for adults and
adolescents recommend starting treatment in all HIVpositive adolescents and adults regardless of CD4 count.4
The Seattle/King County study found strong evidence
that smoking, using cocaine, or using any illegal drug
raised the risk of death. Smoking can cause death
from heart disease, lung disease, and several cancers.
Of the six main non-AIDS causes of death found in
this study, four can be caused by smoking: non-AIDS
cancers, lung disease, heart disease, and stroke. If you
smoke, you should talk to your provider about findings ways to stop. The US National Heart Lung and
Blood Institute has practical advice about quitting
smoking at the link below.5
This study also made important findings about two specific illnesses and the risk of death—depression and high
blood pressure. Both of these illnesses can be treated by
drugs and in other ways. About half of the people who
died in 2009 had depression and about half had high
blood pressure. But only 57% of people with depression who died were taking antidepressant drugs, while
78% of people with high blood pressure who died had
taken antihypertensive drugs. Drug therapy may not be
necessary for everyone with depression or high blood
pressure, but these numbers suggest that many people
who needed drug therapy were not getting it. Depression—feeling sad or hopeless much of the time—is not
“a mood.” It’s a serious illness that can be treated. Talk
to your provider if you feel depressed. High blood pressure, which has no symptoms, can lead to heart disease
and other serious diseases. It’s easy to detect and should
be treated.
Considering all their findings, these researchers
conclude that “premature mortality [early death]
may be reduced with more aggressive HIV diagnosis and treatment.”
References
1. Buskin S, Kent J, Barash E, Aboulafia D, Golden M. Inevitable vs preventable deaths among HIV+ people in King County:
Washington, 2008-2010. 19th Conference on Retroviruses and Opportunistic Infections. March 5-8, 2012. Seattle. Abstract
1128. http://www.retroconference.org/2012b/PDFs/1128.pdf.
2. Strategies for Management of Antiretroviral Therapy (SMART) Study Group, El-Sadr WM, Lundgren JD, Neaton JD, et al.
CD4+ count-guided interruption of antiretroviral treatment. N Engl J Med. 2006;355:2283-2296. http://www.nejm.org/doi/
full/10.1056/NEJMoa062360.
3. Kitahata MM, Gange SJ, Abraham AG, et al. Effect of early versus deferred antiretroviral therapy for HIV on survival. N Engl J Med. 2009;360:1815-1826. http://www.nejm.org/doi/full/10.1056/NEJMoa0807252.
4. HHS Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-
infected adults and adolescents. March 27, 2012. http://aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-treatment-guidelines/0/
5. National Heart Lung and Blood Institute. Strategies to quit smoking. http://www.nhlbi.nih.gov/health/health-topics/topics/smo/s
trategies.html.
14
HIVTreatmentAlerts
Article 5
Higher Rates of New AIDS and Non-AIDS Illnesses
With CD4s Above 350 but a Detectable Viral Load
Compared with HIV-positive people with a CD4 count
above 350 and a viral load below 500 copies, people
with a CD4 count above 350 and a viral load above 500
copies had over a 60% higher risk of a new non-AIDS illnesses.1 Having a viral load between 500 and 9999 copies
versus under 500 raised the risk of a new AIDS illness
more than 40% in these people with a CD4 count above
350. And having a viral load of 10,000 copies or more
made a new AIDS illness almost 4 times more likely, despite having a CD4 count above 350.
This large study adds to evidence that uncontrolled HIV
infection—or poorly controlled infection—raises the risk
of both AIDS and non-AIDS diseases. These results are
particularly important because this study focuses on people with a relatively high CD4 count.
HIV physicians and other providers have known for a
long time that AIDS diseases are more likely to develop
in people with a high viral load. Often, though, people
with a high viral load also have a low CD4 count. No one
had studied the impact of a high viral load on risk of
AIDS only in people with a CD4 count over 350.
Even less was known about how a high viral load with
a high CD4 count affected the risk of non-AIDS illnesses, like heart disease and non-AIDS cancers. A few trials have randomly assigned HIV-positive people to take
steady antiretroviral therapy or to interrupt treatment
when they had a CD4 count above 350.2-4 In these studies serious non-AIDS diseases developed more often in
people who interrupted treatment. But these findings
did not explain whether non-AIDS diseases developed
because of a high viral load, a low CD4 count, or both.
To help providers and people with HIV understand
these issues better, researchers involved with the EuroSIDA group planned this study. Their goal was to compare
rates of new fatal or nonfatal AIDS illnesses—and rates
of new fatal or nonfatal non-AIDS illnesses—in people
with a CD4 count above 350 but either a detectable or an
undetectable viral load.
■ How the study worked. EuroSIDA is an ongoing
study of more than 16,000 HIV-positive adults in Europe, Israel, and Argentina. Every 6 months health-
HIVTreatmentAlerts
related information (like CD4 count, viral load, and
antiretroviral therapy) on each study participant is
sent to a central databank. Information stored there
can later be analyzed to help answer specific questions—such as the impact of a detectable viral load
on new AIDS and non-AIDS diseases. Since January
2001, EuroSIDA researchers began collecting information on serious non-AIDS diseases (like heart,
liver, and kidney disease).
This viral-load study involved people with a CD4
count above 350 measured in the past 6 months and
a viral load measured in that time. Individuals fell out
of the study if they did not have a CD4 count or a viral load in any 6-month period, or if their CD4 count
dropped below 350; but those people could rejoin the
study later if their CD4 count later rose above 350. For
each 6-month period, researchers divided EuroSIDA
participants into three groups, according to their viral load in that period: under 500 copies, 500 to 9999
copies, and 10,000 copies or more.
The researchers counted all new AIDS diseases and
non-AIDS diseases that developed during the study
period. They used accepted statistical methods to
compare the risk of new AIDS and non-AIDS diseases in the three viral load groups. These calculations
considered the impact of many factors, including
age, gender, ethnic origin, latest CD4 count, latest
viral load, and whether a person was taking antiretroviral therapy.
■ What the study found. The study involved 11,492
people assessed for a new AIDS disease and 10,869
assessed for a new non-AIDS disease. Most people in
the AIDS analysis (90%) and in the non-AIDS analysis
(85%) had a viral load below 500 copies. In both the
AIDS analysis and the non-AIDS analysis, about three
quarters of study participants were men and 85% to
90% were white.
During the study period 354 new AIDS diseases and
572 new non-AIDS diseases developed. The most frequent non-AIDS illnesses were heart disease (36% of
572), non-AIDS cancers (36%), liver disease (6%), pancreatitis (an inflamed pancreas) (6%), and kidney dis-
15
Proportions of new non-AIDS diseases in people
with a CD4 count above 350
Figure 1. Among 572 new non-AIDS diseases in people with a CD4 count above
350, heart disease accounted for about one third and a non-AIDS cancer accounted
for another third. Seventy-two of these people (13%) died.
ease (3%) (Figure 1). There were 72 deaths from nonAIDS causes (13% of 572).
Statistical analysis that accounted for several factors that
may affect development of AIDS figured that a new
AIDS disease was 1.44 times (44%) more likely in people
with a viral load of 500 to 9999 copies than in those with
a viral load below 500 copies. A new AIDS disease was
almost 4 times more likely in people with a viral load of
10,000 copies or more compared with those who had a
viral load under 500 copies (Figure 2).
Compared with people who had a viral load under 500
copies, those with 500 to 9999 copies had a 1.61 times
(61%) higher risk of a new non-AIDS illness (Figure 2),
even though everyone had a CD4 count above 350. People with a viral load of 10,000 copies or more had a 1.66
times (66%) higher risk of a new non-AIDS disease than
people with a viral load below 500 copies. Compared
with people whose viral load lay below 500 copies, those
with 500 to 9999 copies had a 1.65 times (65%) higher
risk of heart disease.
Increased risk of AIDS or non-AIDS disease with
a CD4 count over 350 and a detedtable viral load
Figure 2. In people with a CD4
count above 350, having a viral load
above 500 copies (versus under 500)
raised the risk of AIDS, non-AIDS disease, and heart disease.
16
HIVTreatmentAlerts
Viral load did not affect risk of non-AIDS cancers, liver
disease, or pancreas disease. But the numbers of people
with these other diseases may have been too small in this
study to allow the researchers to find a link between viral
load and development of these diseases.
a detectable viral load hikes the risk of AIDS and nonAIDS illnesses despite a relatively good CD4 count underlines the importance of reaching and keeping an undetectable viral load. The aim of antiretroviral therapy is
always to push the viral load below 50 copies.
■ What the results mean for you. This large study made
important new findings on the risk of AIDS and nonAIDS diseases in people with a CD4 count above 350.
Despite this relatively high CD4 count, a detectable viral load greatly raised the risk of a new AIDS disease
and moderately raised the risk of a non-AIDS disease
(Figure 2).
In this study people with a viral load above 500 copies
despite a high CD4 count fell into three groups: (1) people who had not started taking antiretroviral therapy, (2)
people who had stopped taking antiretroviral therapy,
or (3) people whose antiretroviral combination was failing. The newest US guidelines on antiretroviral therapy
say all adults and adolescents with HIV infection should
start therapy, whatever their CD4 count.
Rates of death from AIDS dropped sharply in the mid1990s when people began taking antiretroviral combinations including at least three drugs. Some research
showed that rates of non-AIDS deaths also fell when
people started taking triple antiretroviral therapy at
this time.5,6 Those studies suggested that uncontrolled
HIV boosts the risk of non-AIDS diseases as well as
AIDS diseases.
But this new study is the first in which researchers looked
only at people with a CD4 count above 350 to figure out
the impact of a detectable viral load.1 The finding that
Once treatment begins and the viral load falls below 50
copies, it is very important to keep the viral load undetectable. As this study shows, people who stopped
therapy or whose antiretroviral combination failed had
a detectable viral load and ran a higher risk of AIDS,
heart disease, and other non-AIDS illnesses. Taking your
antiretrovirals regularly—according to your provider’s
instructions—is essential to keeping an undetectable viral load. Never stop treatment unless your provider tells
you to.
References
1. Reekie J, Gatell JM, Yust I, et al. Fatal and nonfatal AIDS and non-AIDS events in HIV-1-positive individuals with high CD4
cell counts according to viral load strata. AIDS. 2011;25:2259-2268.
2. E
l-Sadr WM, Lundgren JD, Neaton JD, et al. CD4 count-guided interruption of antiretroviral treatment. N Engl J Med.
2006;355:2283-2296.
3. Lundgren JD, Babiker A, El-Sadr W, et al. Inferior clinical outcome of the CD4-cell count-guided antiretroviral treatment interruption strategy in the SMART study: role of CD4-cell counts and HIV RNA levels during follow-up. J Infect Dis.
2008;197:1145-1155.
4. Danel C, Moh R, Minga A, et al. CD4-guided structured antiretroviral treatment interruption strategy in HIV-infected adults
in west Africa (Trivacan ANRS 1269 trial): a randomised trial. Lancet. 2006;367:1981-1989.
5. Mocroft A, Brettle R, Kirk O, et al. Changes in the cause of death among HIV positive subjects across Europe: results from the
EuroSIDA study. AIDS. 2002;16:1663-1671.
6. Grabar S, Lanoy E, Allavena C, et al. Causes of the first AIDS-defining illness and subsequent survival before and after the
advent of combined antiretroviral therapy. HIV Med. 2008;9:246-256.
HIVTreatmentAlerts
17
Article 6
Better HIV Appointment Keeping Linked
to Lower Viral Loads
HIV-positive people with a better record of keeping
medical appointments reached an undetectable viral
load faster after starting antiretroviral therapy. And
good appointment keepers had a lower total viral load
measured over the first 2 years of HIV care. These encouraging findings come from a study of 676 HIV-positive people cared for at the University of Alabama at Birmingham and the University of Washington in Seattle.
Effective treatment of HIV infection depends on getting
prompt care, keeping medical appointments once in
care, and taking antiretrovirals every day, once you and
your provider agree that treatment should begin. All of
these steps are necessary to reach and keep an undetectable viral load (no HIV copies detected in blood). An
undetectable viral load is the main goal of treatment not
only because it will restore your health, but also because
it greatly lowers the chance that you will pass HIV to a
sex partner.
To get a better understanding of how many people starting care for HIV stay in care and how staying in care
affects viral load, researchers planned this study. Specifically, they wanted to learn if missing HIV care visits
would delay the time to reaching an undetectable viral
load, and whether poor appointment keeping would affect a 2-year measure of viral load called viremia copyyears (explained below).
The researchers measured HIV clinic appointment
keeping in two ways: (1) number of missed visits and
(2) proportion of scheduled visits attended over the first
2 years of care. Missed visits did not include visits that
HIV-positive people cancelled in advance or visits cancelled by the clinic.
The study used standard statistical techniques to determine (1) how the number of missed visits affected time to
reaching an undetectable viral load and (2) how the proportion of scheduled visits kept affected viremia copyyears in the first 2 years of care. These analyses factored
in patient age, gender, race or ethnicity, health insurance, and CD4 count and viral load before antiretroviral
therapy began.
■ What the study found. The 676 study participants averaged 36 years in age. While 44% were nonwhite men,
38% were white men, 13% were nonwhite women, and
5% were white women. A little more than one third of
these people (36%) had no insurance, and 27% had public insurance (such as Medicaid). One third of the study
group (33%) had a CD4 count under 200 when they
started care for HIV, 24% had a CD4 count between 200
and 350, and 43% had a CD4 count above 350.
■ How the study worked. The study involved people just
starting care for HIV infection at one clinic in Birmingham, Alabama and one in Seattle, Washington between
January 2007 and September 2010. The study did not
include people who had earlier HIV care at other clinics.
Of the 676 people studied, 169 (25%) missed 2 or more
clinic visits, 536 (79%) started antiretroviral therapy,
and 425 (63%) got their viral load below 50 copies. Two
groups took a significantly longer time to reach a viral
load below 50 copies—people who started treatment
with a higher viral load, and people with who missed
more visits. Chances of reaching a viral load below 50
copies fell 17% with each additional missed visit.
Researchers kept track of two viral load goals for each
person: (1) the time it took to reach a viral load below
50 copies, and (2) total viral load measured as viremia
copy-years in the 2 years immediately after a person began HIV care. The research team defined viremia copyyears as the number of HIV copies in each milliliter of
blood plasma over time. For example:
Analysis of 2-year total viral load (measured as viremia copy-years) involved 258 people seen for at least 2
years after starting care for HIV infection. Almost half
of this group, 48%, missed two or more visits. The appointment-keeping rate averaged 84% overall, with the
following numbers and percentages of people in three
appointment-keeping brackets:
10,000 copy-years = 10,000 copies per milliliter for 1
year (10,000 × 1 = 10,000)
• Kept 0% to 79% of appointments: 83 people, 32%
or
• Kept 100% of appointments: 80 people, 31%
• Kept 80% to 99% of appointments: 95 people, 37%
10,000 copy-years = 1000 copies per milliliter for 10
years (1000 × 10 = 10,000)
18
HIVTreatmentAlerts
Viremia copy-years through 2 years of care averaged
about 20,415 copies. Average viremia copy-years were
lower with better appointment keeping (Figure 1).
makes poor health—and even death—more likely.2-4 In
a study of 2027 people starting antiretroviral therapy,
every 10-times higher viremia copy-year level independently raised the risk of death 44%.4
Impact of appointment keeping on 2-year total viral load
It’s easy to understand why missing HIV
clinic visits has a negative impact on viral
load. Health care providers are reluctant
to start antiretroviral therapy with people
who tend to miss visits, and HIV cannot be controlled without antiretrovirals.
People who start therapy then start missing visits are more likely to forget to take
their antiretrovirals and may even run
out of pills. Viral loads go up in people
who don’t take their antiretrovirals daily.
About one third of the people in this
study group kept fewer than 80% of their
HIV clinic visits. The first 2 years of HIV
care can be particularly difficult for several reasons: (1) It takes time to adjust to
the news that you have HIV infection. (2)
Figure 1. Total viral load measured over the first 2 years of HIV care Some people find it difficult to get into
was lower in people who kept a higher percentage of appointments in
the habit of keeping the regular clinic
that time.
appointments needed for HIV care. (3)
Other people have a hard time getting
used to taking one or more antiretroviral
pills—and perhaps other medicines—every day.
Every 10% lower appointment-keeping rate was associated with a higher 2-year total viral load independently
If you experience these difficulties or similar problems,
of other risk factors, such as pretreatment viral load and
talk to someone about it—either your HIV care propretreatment CD4 count.
vider, a nurse or assistant in your provider’s office, or
perhaps the case worker or adviser who first talked to
■ What the results mean for you. This study of 676 people
you about HIV when you tested positive. There may be
in two parts of the United States showed the importance
a person in your HIV care clinic who is specially trained
of keeping clinic appointments when a person starts HIV
to help HIV-positive people with problems like these. If
care. People who missed more visits (1) took a longer time
you can’t keep an appointment for a good reason, call
to reach an undetectable viral load and (2) had a higher
your provider’s office as soon as possible to schedule an2-year total viral load (Figure 1). Previous studies found
other appointment.
that having a higher total viral load over a given period
References
1. Mugavero MJ, Amico KR, Westfall AO, et al. Early retention in HIV care and viral load suppression: implications for a test and
treat approach to HIV prevention. J Acquir Immune Defic Syndr. 2012;59:86-93.
2. Cole SR, Napravnik S, Mugavero MJ, et al. Copy-years viremia as a measure of cumulative human immunodeficiency virus viral burden. Am J Epidemiol. 2010;171:198-205.
3. Marconi VC, Grandits G, Okulicz JF, et al. Cumulative viral load and virologic decay patterns after antiretroviral therapy in
HIV-infected subjects influence CD4 recovery and AIDS. PLoS One. 2011;6:e17956.
4. Mugavero MJ, Napravnik S, Cole SR, et al. Viremia copy-years predicts mortality among treatment-naive HIV-infected patients
initiating antiretroviral therapy. Clin Infect Dis. 2011;53:927-935.
HIVTreatmentAlerts
19
Article 7
Heart Disease Signals Get Worse
With Time in Adults With HIV
Two often-used signals of heart disease grew worse in a
2-year study and a 3-year study of HIV-positive adults.1,2
In the Centers for Disease Control SUN Study,1 keeping
the viral load undetectable with antiretroviral therapy
slowed worsening of one of these heart disease signals.
In the Tufts University CARE Study,2 traditional heart
disease risk factors explained the worsening heart disease signals—and most of these factors can be changed
by drug therapy or lifestyle changes.
As HIV-positive people live longer because of antiretroviral therapy, they run an increased risk of heart disease.
Older age explains part of this risk, but HIV infection
and antiretroviral therapy also contribute to the risk.
Traditional heart disease risk factors—like smoking, high
blood pressure, and high lipids (cholesterol and triglycerides)—add to the growing risk as people with HIV age.
Understanding the impact of all these risk factors is
important to help HIV providers identify people with
a high risk of heart disease and to change or eliminate
those risk factors that can be modified. It is also important to understand how HIV-related risk factors versus
non-HIV risk factors affect chances of heart disease.
To help define these risks, researchers often use two signals of undetected heart disease—carotid artery intimamedia thickness (cIMT) and coronary artery calcium
(CAC). Changes in these signals can predict a higher
risk of heart disease and tell physicians when to manage
risk factors more aggressively to prevent heart disease
and stroke. cIMT measures the thickness of the inner
two layers of the carotid artery—the intima and the media (Figure 1). The carotid arteries run along the side
of the neck to the brain. Calcium build-ups in heart
arteries can narrow those arteries and boost the risk of
a heart attack.
Both the SUN Study and the CARE Study measured
these heart disease signals at two points so the researchers could learn how these signals change over time in
people with HIV.
■ How the SUN Study worked. In the ongoing Centers for Disease Control SUN Study, researchers record
health markers (like CD4 count and viral load) and other information every 6 months in HIV-positive people
in four cities—Denver, Minneapolis, Providence, and St.
Louis.1 Study participants also complete a computer-assisted questionnaire asking about health-related lifestyle
factors, like alcohol and tobacco use.
Everyone in this heart risk analysis1 had ultrasound imaging to measure cIMT in the common carotid artery
when they entered the SUN Study and about 2 years
later. Researchers compared cIMT thickness at those
two times in the overall study group and in different
subgroups. Then they used standard statistical methods
to identify factors that affected cIMT thickness. As cIMT
gets thicker, heart disease risk becomes greater.
■ What the SUN Study found. This SUN Study analysis involved 389 people, including 300 men (77%) and
89 women (23%).1 Ages in the study group ranged from
36 to 47; 60% of these people were non-Hispanic white,
38% smoked when they entered SUN, and 33% had hypertension. Most people did not have high cholesterol or
triglyceride levels.
Figure 1. Carotid intima-media thickness (cIMT)
measures the two inner layers of the carotid artery, the
intima and the media. cIMT can predict heart and blood
vessel disease.
(Illustration from Servier Medical Art, www.servier.com/)
20
HIVTreatmentAlerts
Median CD4 count when people entered SUN was 485,
303 people (78%) were taking combination antiretroviral therapy at that point, and 266 people (88% of
those taking antiretrovirals) had an undetectable viral
load. During the study period, 184 of these 266 people
kept their viral load undetectable. Similar proportions
of treated people were taking a protease inhibitor or a
nonnucleoside.
Statistical analysis that considered the impact of traditional heart risk factors found that an undetectable viral
load when people entered SUN and keeping an undetectable viral load through the study were independently linked to a smaller cIMT increase (Figure 3): In other
words, these viral load factors accounted for a smaller
cIMT increase regardless of what other heart risk factors
a person had.
Median cIMT for the whole study group increased by
0.016 mm over the course of 2 years. cIMT increased
less in people taking antiretrovirals than in untreated
people (0.014 versus 0.019 mm), less in people with an
undetectable viral load when they entered the study than
in those with a detectable viral load (0.013 versus 0.021
mm), less in people who kept their viral load undetectable throughout the study period than in those who did
not (0.015 versus 0.019 mm), and less in people taking
a nonnucleoside than in those taking a protease inhibitor (0.011 versus 0.019 mm) (Figure 2). The last two of
these four differences are statistically significant, meaning that chance could not account for the difference.
A separate statistical analysis that considered other heart
risk factors focused on 302 people taking combination
antiretrovirals when they entered SUN. In this analysis,
taking a nonnucleoside rather than a protease inhibitor when entering SUN accounted for a lower cIMT increase regardless of other heart risk factors.
Increasing carotid artery wall thickness
(cIMT) in people with HIV
Figure 3. The SUN Study linked three HIV-related
Figure 2. Carotid artery intima-media thickness
(cIMT), a signal of heart disease, increased more (got
worse) over 2 years in (1) people not taking antiretroviral therapy (ART) versus those taking ART, (2) people
with a viral load above 400 copies when they entered the
study versus those with a viral load below 400 copies, (3)
people who did not keep their viral load below 400 copies throughout the study versus those who did, and (4)
people taking a protease inhibitor (PI, light cone) versus
a nonnucleoside reverse transcriptase inhibitor (NNRTI,
dark cone).
HIVTreatmentAlerts
factors to a smaller cIMT increase—a viral load below
400 copies when people entered SUN, keeping the viral load below 400 copies throughout the study period,
and treatment with a nonnucleoside (NNRTI) rather
than a protease inhibitor (PI).1 The CARE Study identified several well-known heart risk factors that made
greater cIMT and/or CAC increases more likely—older age, higher triglycerides, current smoking, taking
drugs for diabetes, and insulin resistance (which can
lead to diabetes).2
■ How the CARE Study worked. The CARE Study involved 255 HIV-positive people in Boston and Providence who were assessed for heart risk factors.2 Everyone had a regular health check-up every 6 months that
included HIV-related factors like CD4 count, viral load,
and antiretroviral therapy. All study participants had
cIMT and CAC measured when they entered the study
(in 2002-2003) and again a few years later (in 2005-
21
2007). Researchers used ultrasound imaging to measure
cIMT in the common and internal carotid arteries. They
used carotid ultrasound to measure cIMT and computed tomography (CT) imaging to measure CAC.
The study did not include people who already had diabetes or uncontrolled high blood pressure, or who had a
myocardial infarction (heart attack) or stroke in the past
6 months.
Researchers used accepted statistical methods to identify factors that raised or lowered the risk of worsening
cIMT or CAC. These analyses considered several factors
that may affect heart disease risk, including age, gender,
race, smoking, triglycerides, cholesterol, and glucose.
(Uncontrolled glucose can lead to diabetes.)
■ What the CARE Study found. There were 234 people
in the CARE Study cIMT analysis and 255 in the CAC
analysis.2 Seventy-one of 255 study participants (28%)
were women, 119 (47%) were nonwhite, 111 (44%)
smoked at the time of the study, and 187 (74%) were taking combination antiretroviral therapy. Only 2 people
were injection drug users.
When these people entered the CARE Study, their age
averaged 45 years, their CD4 count averaged 491, and
their viral load averaged 1000 copies. While 111 people (44%) were taking a protease inhibitor when they
joined the study, 92 (36%) were taking a nonnucleoside
reverse transcriptase inhibitor (NNRTI). CARE Study
participants had few heart risk factors when they entered the study.
Follow-up time averaged 3.4 years and ranged from 2.2
to 5.9 years for the cIMT analysis. For the CAC analysis,
follow-up time averaged 3.4 years and ranged from 1.9
to 6.0.
Every year, cIMT increased significantly more in CARE
Study men than in CARE Study women. cIMT thickening did not differ greatly between people taking a nonnucleoside and those taking a protease inhibitor. Having an undetectable viral load or a CD4 count above or
below 500 when entering the CARE Study did not affect
cIMT changes.
Statistical analysis that considered numerous factors
that may affect heart disease risk identified five that independently raised the risk of cIMT thickening—older
age, higher triglycerides, insulin resistance (which can
lead to diabetes), taking drugs for diabetes, and smoking
(Figure 3).
Among CARE Study participants, 28% overall had worsening CAC during the study period. Among people with
no detectable CAC when they entered the CARE Study,
33% had detectable CAC during follow-up. Among people with detectable CAC when they entered the study,
27% still had detectable CAC 3 years later. Thus overall
rates of detectable CAC were about the same when first
measured (55%) and when measured 3 years later (57%).
However, the number of people with a CAC score above
100 rose 40% during these 3 years.
In the general population, a CAC worsening rate of 15%
or more yearly raises the risk of heart disease. In the
CARE Study group, yearly CAC worsening was 28%.
One third of CARE Study participants (32%) whose CAC
got worse during the study were older than 50, while
18% whose CAC did not get worse were over 50. Insulin resistance independently raised the risk of worsening
CAC in the CARE Study.
In healthy people without HIV, cIMT increases 0.015
mm yearly. In people who have had heart disease, the
yearly increase is 0.017 mm year. The CARE group averaged a yearly increase of 0.016 mm in the common carotid artery and 0.020 mm in the internal carotid artery.
■ What the SUN and CARE Study results mean for you.
Measuring heart disease signals in hundreds of HIVpositive people for 2 to 3 years, both of these studies
found evidence of increasing heart disease risk. The
SUN Study, which tracked 300 men and 89 women for 2
years, found worsening cIMT (thickening of the carotid
artery wall).1 The CARE Study, which tracked 184 men
and 71 women for 3 years, found worsening cIMT and
worsening CAC (coronary artery calcium).2
About 13% of age-matched healthy people have a cIMT
above the 75th percentile (that is, a cIMT in the top
25% of cIMTs measured). In contrast, 23% of the CARE
group had a cIMT above the 75th percentile when they
entered the study. Three years later, 38% had a common
carotid cIMT above the 75th percentile and 30% had an
internal carotid cIMT above the 75th percentile.
cIMT increased by an average 0.016 mm over 2 years
in the SUN Study and by the same amount every year
in the 3-year CARE Study. The CARE study found that
heart disease risk factors similar to those in the general
population (like smoking, high triglycerides, and insulin resistance) raised the risk of increasing cIMT. In the
SUN Study, people with a viral load below 400 copies
22
HIVTreatmentAlerts
when they entered the study and people who kept their
viral load under 400 copies throughout the study had
slower cIMT increases. The CARE Study also found that
another heart disease signal—CAC—got worse during
the study’s 3 years.
Both cIMT and CAC increases in these studies were
greater than average increases seen in the general population. That finding is especially troubling since SUN
and CARE study participants were middle-aged (averaging 42 in SUN and 45 in CARE), and most of these
people had few or no heart disease risk factors when
they entered the studies. cIMT increases in SUN participants, who were 36 to 47 years old, were similar to
increases seen in general-population groups from 45 to
64 years old.3,4
The CARE researchers believe their study “strongly
suggests that the progression of carotid and coronary
atherosclerosis [artery hardening] is accelerated in HIVinfected persons” compared with HIV-negative people.2
In the SUN Study, cIMT increased less during 2 years
in (1) people taking combination antiretrovirals versus
untreated people, (2) people with a viral load below 400
copies when they entered the study versus those with a
higher viral load, and (3) people who kept their viral
load below 400 copies throughout the study versus those
who did not. These findings, the researchers say, support the idea that taking antiretrovirals and keeping an
undetectable viral load cut the risk of heart disease in
people with HIV.
The CARE study also found evidence that treating conditions that lead to heart disease lowered the risk of worsening cIMT and CAC in study participants. These conditions include high triglycerides and cholesterol, high
blood pressure, and high glucose or diabetes. Both drug
therapy and lifestyle changes (losing weight, exercising,
quitting smoking) can help control these conditions.
Both SUN and CARE found that heart disease risk factors often identified in people without HIV also raised
the risk of increasing cIMT and CAC in these studies.
These findings are important because many of these
risk factors can be prevented or reversed (Figure 3).
Smoking is probably the most important heart disease
risk factor in people with HIV. Besides raising the risk
of heart disease, smoking can also cause lung disease
and many cancers. If you smoke, finding a way to stop
is one of the most important things you can do to improve your health.
References
1. Baker JV, Henry WK, Patel P, et al; Study to Understand the Natural History of HIV/AIDS in the Era of Effective Therapy Investigators. Progression of carotid intima-media thickness in a contemporary human immunodeficiency virus cohort. Clin Infect
Dis. 2011;53:826-835.
2. Mangili A, Polak JF, Skinner SC, et al. HIV infection and progression of carotid and coronary atherosclerosis: the CARE study.
J Acquir Immune Defic Syndr. 2011;58:148-153.
3. Howard G, Sharrett AR, Heiss G, et al. Carotid artery intimal-medial thickness distribution in general populations as evaluated
by B-mode ultrasound. ARIC Investigators. Stroke. 1993;24:1297-1304.
4. Chambless LE, Folsom AR, Davis V, et al. Risk factors for progression of common carotid atherosclerosis: the Atherosclerosis
Risk in Communities Study, 1987-1998. Am J Epidemiol. 2002;155:38-47.
HIVTreatmentAlerts
23
Article 8
Colon Exam Finds Possible Trouble Spots
in 60% With HIV
Colonoscopy, a routine exam looking inside the colon,
detected colon tissue abnormalities in more than half
of 96 HIV-positive people who had the procedure at a
large HIV clinic.1 Four people who underwent colonoscopy had early anal, rectal, or colon cancer.
Precancerous polyp detected by colonoscopy
Some but not all studies of colon cancer in people with
HIV found a higher risk of colon cancer at an earlier
age in people with HIV than in the general population.2 Colon cancer develops slowly from precancerous
stages (Figure 1) that can be seen during colonoscopy,
a procedure in which a camera at the end of a flexible
tube is inserted into the colon via the anus. This procedure is done under sedation and is painless.
During colonoscopy, a specialist can (1) see changes in
the colon lining that may be early signs of cancer, (2)
see any cancer that is already developing, (3) clip small
pieces of colon lining that can be tested later to see if
the cells are cancerous or precancerous, and (4) remove
any dangerous growths. In the United States, in Germany (where this study took place), and in many other
countries, health authorities recommend colonoscopy
for everyone 50 and older. How often colonoscopy is
repeated depends on what the procedure finds.
To assess colonoscopy rates in HIV-positive people and
what those colonoscopies showed, a group of clinicians
in Bonn, Germany planned this study.
■ How the study worked. The researchers focused on
159 HIV-positive people older than 50 who were offered colonoscopy during a routine visit to the HIV
outpatient clinic over a 12-month period. The investigators recorded the number of patients who decided
not to have a colonoscopy and the number who did.
Among people who had a colonoscopy during the study
or had one recently, the researchers recorded abnormal findings. The clinician performing the colonoscopy
snipped out tissue samples from any colon lining areas
that looked like they might be precancerous or cancerous. Those snipped-out samples were sent to a lab for
evaluation. Finally, the researchers compared people
with abnormal versus normal colonoscopy results to see
if they could identify predictors of abnormal findings.
24
Figure 1. Colonoscopy can detect and remove colon polyps that cause no symptoms, like this one in a
57-year-old man. (Provided by Steven J. Morris, MD,
and the Centers for Disease Control and Prevention
Public Health Image Library [PHIL].)
■ What the study found. Of the 941 HIV-positive people in the clinic study group, 159 (17%) were older than
50 and were offered colonoscopy. Of those 159, 15%
decided not to have a colonoscopy, 10% asked for more
time to think about it, and the rest had a recent colonoscopy or had a new colonoscopy.
Of the 96 patients who had a new or recent colonoscopy, 85% were men and median age was 58. Almost
all of these 96 people (96%) were taking combination
antiretroviral therapy. Median CD4 count at the time
of the study was 499, and median viral load was 40
copies. Colon cancer risk factor rates were moderate
or low in these 96 people: 38.5% had cardiovascular
disease, 20% smoked, 16% had an immediate relative
with colon cancer, 13.5% had diabetes, 10% were obese,
6% abused alcohol, and 1% had chronic inflammatory
bowel disease.
HIVTreatmentAlerts
Fifty-eight of the 96 people (60.4%) who had a new
or recent colonoscopy had abnormalities. Lab assessment of tissue samples found early colon cancer in 1
person, early rectal cancer in 1, and early anal cancer
in 2. About one quarter of the others with lab testing
of samples had adenomas—noncancerous tumors that
may become cancerous.
The 58 people with abnormal colonoscopy results did
not differ much from those with normal results in age,
HIV transmission risk group, years of antiretroviral
therapy, CD4 count, proportion with a viral load under
40 copies, or any other factor assessed. Notably, more
years of successful antiretroviral therapy did not protect people from abnormal colonoscopy results. Also,
15% to 20% of people in this study took regular aspirin
or statins (cholesterol-lowering drugs). Although aspirin and statins help control inflammation, they did not
protect people who took them from abnormal colonoscopy findings.
The 24 people with abnormal colon cell results in lab
studies did not differ from those with normal colon cell
results in gender, age, HIV transmission risk, years of
antiretroviral therapy, CD4 count, number of colonoscopies, colon cancer in an immediate family member, or
any other factor assessed.
■ What the results mean for you. This study of people
older than 50 in a large HIV clinic found that most
agreed to have a colonoscopy or had a recent colonoscopy.1 While 60% of people who had a new or recent
colonoscopy had abnormalities that might be the first
signs of colon cancer, 4% actually had early cancer.
A recent US comparison of 50-and-older people with
versus without HIV found almost exactly the same rate
of abnormal results in 136 people with HIV (62.5%)3 as
in the German study.1 In the US study 272 HIV-negative people matched to the HIV group in age, gender,
and family colorectal cancer had a significantly lower
rate of abnormal results (41%).3
Together these studies1,3 indicate that HIV-positive
people 50 and older have higher rates of abnormal
colonoscopy results than HIV-negative people the
same age. That finding probably means 50-and-older
HIV-positive people can protect themselves from colon
cancer by having regular colonoscopies. Because colon
cancer develops slowly, precancerous tissue can be removed during the colonoscopy to prevent colon cancer
from developing.
A recent US study focused on 2602 people in the general population who had adenomas (precancerous
growths) removed during colonoscopy.4 These people
had more than a 50% lower risk of death from colorectal cancer than would be expected in the United States.
The researchers believe that result supports the idea
that removing adenomas during colonoscopy prevents
death from colorectal cancer.
Colonoscopy is a painless procedure because the patient
is sedated first. Preparing for a colonoscopy requires
fasting and drinking lots of fluid to clean out the colon.
That can be unpleasant, but it is not difficult. And it is far
simpler than getting treated for colon cancer.
The researchers who performed this study1 believe the
high rate of abnormal findings and the high colonoscopy acceptance rate in HIV-positive people justify
regular use of preventive colonoscopy in HIV-positive
people 50 and older.
References
1. Boesecke C, Kasapovic A, Wasmuth JC, et al. High rates of endoscopic findings and histologic abnormalities in routine colonoscopy of HIV patients: German HIV cohort. 19th Conference on Retroviruses and Opportunistic Infections. March 5-8, 2012.
Seattle. Abstract 890. http://www.retroconference.org/2012b/PDFs/890.pdf.
2. Ford RM, McMahon MM, Wehbi MA. HIV/AIDS and colorectal cancer: a review in the era of antiretrovirals. Gastroenterol
Hepatol (NY). 2008;4:274-278. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3093732/?tool=pubmed.
3. Bini EJ, Green B, Poles MA. Screening colonoscopy for the detection of neoplastic lesions in asymptomatic HIV-infected
subjects. Gut. 2009;58:1129-1134. http://www.ncbi.nlm.nih.gov/pubmed/19293177.
4. Zauber AG, Winawer SJ, O’Brien MJ, et al. Colonoscopic polypectomy and long-term prevention of colorectal-cancer deaths.
N Engl J Med. 2012;366:687-696. http://www.nejm.org/doi/full/10.1056/NEJMoa1100370.
HIVTreatmentAlerts
25
Article 9
Higher Bone Fracture Risk in People With HIV or
With HIV and HCV
HIV-positive people had a 50% higher risk of fracture (a
broken bone) than the general population in Denmark,
according to results of a nationwide study.1 People with
both HIV and hepatitis C virus (HCV) infection had a 3
times higher fracture risk than the general population.
Starting antiretroviral therapy raised the fracture risk
somewhat, but the impact of antiretrovirals appeared to
level off after a few years.
Many studies have linked HIV infection and antiretroviral therapy to higher-than-normal loss of bone density,
which can result in osteoporosis (severe bone density
loss) and fractures. Antiretroviral therapy appears to
speed up bone loss in the first 6 to 12 months of treatment.2-4 But after that bone density loss generally levels
off in people who continue taking antiretrovirals.5,6
Several studies comparing HIV-positive people with the
general population show a higher fracture rate in the
HIV group.7-10 One study of US women who had not
passed the menopause did not find that HIV-positive
women had a higher fracture risk than HIV-negative
women.11
The impact of antiretroviral therapy on bone loss, bone
disease, and fractures remains poorly understood. Two
US studies found no link between antiretroviral therapy
and risk of fracture.9,11 To get a better understanding of
how HIV infection—and antiretroviral therapy—affect
fracture risk, researchers in Denmark planned a nationwide study.
26
■ How the study worked. The study involved everyone
in Denmark who was 16 or older and had their first positive HIV test while living in Denmark. For each person
with HIV, researchers found 5 people in a nationwide
database who matched the HIV-positive person by gender and by month and year of age.
Then the researchers used standard statistical methods
to compare the HIV-positive group with the generalpopulation group to determine differences in (1) time
to first fracture of any bone, (2) time to first low-energy
fracture, and (3) time to first high-energy fracture. The
investigators defined low-energy fracture as one possibly caused by osteoporosis (severe bone density loss),
usually resulting from relatively minor (“low-energy”)
impact. They defined high-energy fracture as one
probably not caused by osteoporosis, usually resulting
from relatively greater (“high-energy”) impact. The
researchers measured time to fracture from January
1, 1995 or from the date of HIV diagnosis, whichever
came later.
The study considered low-energy and high-energy
fracture rates in people only with HIV and in people
with HIV and HCV. In Denmark, HCV infection usually occurs in people who inject illegal drugs, and those
people tend to have more fracture risk factors than
people infected only with HIV. The study also considered fracture rates before and after people started antiretroviral therapy.
HIVTreatmentAlerts
■ What the study found. This analysis included 5306
HIV-positive adults, who were compared with 26,530
people from Denmark’s general population. Women
made up about 25% of the study group, and the median
age was 37. Almost two thirds of the HIV group (62%)
learned they had HIV infection after January 1, 1995,
and about three quarters (78%) started antiretroviral
therapy during the study period. Among people with
HIV, 851 (16%) also had HCV infection.
High-energy fractures—the kind probably caused by
high impact trauma, not by low bone density—occurred
at rates of 9.5 per 1000 person-years in people infected
only with HIV, similar to the rate of 8.7 per 1000 personyears in the general population. In contrast, the highenergy fracture rate in people with HIV and HCV was
22.7 per 1000 person-years. People with both HIV and
HCV had a 2.4 time higher risk of high-energy fractures
than the general population.
During the 1995-2009 study period, there were 806
fractures in the HIV-positive group. Fracture incidence
(the new fracture rate) was 21 fractures per 1000 person-years. There were 3312 fractures in the generalpopulation group, for an incidence of 13.5 fractures per
1000 person-years. Compared with the general population, HIV-positive people had a 1.5 times higher risk of
fracture (a 50% higher risk) (Figure 1).
Low-energy fractures—the kind that probably result
from low bone density—occurred at rates of 7.4 per 1000
person-years in people with HIV only and 17.8 per 1000
person-years in people with HIV and HCV. In contrast,
low-energy fractures occurred at a rate of only 4.8 per
1000 person-years in the general population. Compared
with the general population, people with HIV had a 1.6
times higher risk of low-energy fractures, and people
with HIV and HCV had a 3.8 times higher risk.
Fracture risk in HIV-positive people
compared with the general population
The low-energy fracture rate did not differ greatly between the general population and HIV-positive people
who had never taken antiretrovirals. But the low-energy fracture rate was 1.8 times higher in antiretroviraltreated HIV-positive people than in the general population. After the researchers accounted for the effect of
non-HIV illnesses, the low-energy fracture rate was 1.6
times higher in antiretroviral-treated people than in the
general population.
Figure 1. Compared with the general population in
Denmark, people with HIV had a 1.5 times (50%) higher risk of breaking a bone from 1995 through 2009. The
relative risk was higher in HIV-positive people taking
antiretroviral therapy (ART) than in those not on ART,
and higher in people infected with both HIV and hepatitis C virus (HCV) than in those infected only with HIV.
Compared with the general population, the fracture
risk was 1.4 times higher in people who had never taken
antiretrovirals and 1.6 times higher in people who had
taken antiretrovirals. People infected with HIV (but not
HCV) had a 1.3 times higher fracture risk than the general population (Figure 1). People infected with both
HIV and HCV had a 2.9 times higher fracture risk than
the general population.
HIVTreatmentAlerts
Among people infected with HIV (but not HCV), the
risk of low-impact fracture was higher in whites than
in blacks, in older people, and in people with a higher
rate of other illnesses besides HIV. Next the researchers focused on people they knew to be smokers or nonsmokers. This analysis found that antiretroviral-treated
smokers had a twice higher fracture risk than antiretroviral-treated nonsmokers. Treatment with Viread (tenofovir), Sustiva (efavirenz), or Ziagen (abacavir) did not
affect fracture risk.
Finally, the researchers determined that in people infected only with HIV, the rate of low-energy fractures
increased from 3.5 per 1000 person-years in 1995-1996
(when triple-drug antiretroviral combinations first came
into use) to 8.3 per 1000 in 1997-2003 (Figure 2). After
that, the low-energy fracture rate fell slightly to 7.5 per
1000 in 2004-2009. Among people infected with HIV
and HCV, low-energy fracture rates were steady over
those three periods, at 16.7 in 1996-1997, 17.9 in 19972003, and 17.8 in 2004-2009.
27
Yearly fracture incidence with HIV
and with HIV plus HCV
population. This is the first study to show a higher rate
of low-energy fractures (those that probably indicate decreasing bone density) in antiretroviral-treated people
with HIV than in the general population. In contrast,
HIV-positive people who had not started antiretrovirals
did not have a higher rate of low-energy fractures than
the general population.
These findings do not necessarily mean that antiretrovirals cause low-energy fractures. In fact, treatment with
Viread (tenofovir), Ziagen (abacavir), or Sustiva (efavirenz) did not make fractures more likely. Perhaps people
taking antiretrovirals in this study group were those who
had HIV infection for a longer time or those with more
advanced HIV infection. People with HIV infection for
a longer time would probably be older, and this study—
like many other studies—found that older age raised the
fracture risk. Smoking also made fractures more likely.
Figure 2. The rate of low-energy fractures (those
probably indicating decreased bone density) rose
among people in Denmark infected only with HIV
(not HCV) as use of combination antiretroviral therapy
grew (from 1995-1996 to 1997-2003). Then that rate
leveled off (from 1997-2003 to 2004-2009). Among
people infected with both HIV and HCV, the low-energy fracture rate remained high and consistent over the
three study periods.
■ What the results mean for you. This large and wellrun study made several important findings about fractures in people with HIV compared with the general
The Danish researchers stress that the fracture risk seen
with combination antiretroviral was moderate and did
not increase over time after 1997 (Figure 2).
The researchers did not have information on several
well-known risk factors for low bone density and fractures, such as low weight and use of steroid drugs. Experts on bone disease in people with HIV list several
other lifestyle choices, habits, or conditions that may
raise the risk of decreasing bone density and fracture
in HIV-positive people (Table 1).12 All of the lifestyle
choices or habits listed are things that can be changed
or avoided.
Table 1. Conditions that may raise risk of osteoporosis or fracture with HIV
Lifestyle choices or habits
More than 3 alcohol drinks daily, low dietary calcium, methadone/opiates, physical inactivity, tobacco use, low weight
Hypogonadal states
Early menopause, premenopausal infrequent menstruation,
low testosterone in men
Other endocrine disorders
Adrenal insufficiency
Blood disorders
Hemophilia, sickle-cell disease
Lung diseases
Emphysema
Medications
Antiretrovirals, glitazones, glucocorticoids, proton pump inhibitors,
excess thyroxine
Other
Chronic metabolic acidosis, chronic infection, chronic kidney disease,
depression, vitamin D deficiency
Source: McComsey et al.12
28
HIVTreatmentAlerts
The Danish study also found that—compared with the
general population—the fracture risk in people infected
with both HIV and HCV was even higher than it was
among people infected with HIV but not HCV. That
makes sense, the researchers say, because HCV infection
often indicates injection drug use in Denmark, as it does
in the United States and other countries. Injection drug
users tend of have more fracture risk factors than people
who do not inject drugs, such as regular alcohol drinking, smoking, depression, and the dietary problems listed in Table 1.
Besides avoiding or correcting the fracture risk factors in Table 1, some HIV-positive people may benefit
from having a DEXA scan to detect bone density loss.
US experts recommend DEXA scanning for (1) all
HIV-positive men 50 years old or older, (2) all HIVpositive women past the menopause, and (3) possibly
HIV-positive people who have had a broken bone.12
References
1. Hansen ABE, Gerstoft J, Gitte Kronborg G, et al. Incidence of low- and high-energy fractures in persons with and without
HIV-infection: a Danish population-based cohort study. AIDS. 2011;25:285-293.
2. Gallant JE, Staszewski S, Pozniak AL, et al. Efficacy and safety of tenofovir DF vs stavudine in combination therapy in antiretroviral-naive patients: a 3-year randomized trial. JAMA. 2004;292:191-201.
3. Hansen AB, Obel N, Nielsen H, Pedersen C, Gerstoft J. Bone mineral density changes in protease inhibitor-sparing vs.
nucleoside reverse transcriptase inhibitor-sparing highly active antiretroviral therapy: data from a randomized trial. HIV Med.
2011;12:157-165.
4. McComsey GA, Kitch D, Daar ES, et al. Bone mineral density and fractures in antiretroviral-naive persons randomized to
receive abacavir-lamivudine or tenofovir disoproxil fumarate-emtricitabine along with efavirenz or atazanavir-ritonavir: AIDS
Clinical Trials Group A5224s, a substudy of ACTG A5202. J Infect Dis. 2011;203:1791-1801.
5. Bolland MJ, Grey AB, Horne AM, et al. Bone mineral density remains stable in HAART-treated HIV-infected men over 2 years
1. Clin Endocrinol (Oxf). 2007;67:270-275.
6. Nolan D, Upton R, McKinnon E, John M, James I, Adler B, et al. Stable or increasing bone mineral density in HIV-infected
patients treated with nelfinavir or indinavir. AIDS. 2001;15:1275-1280.
7. Triant VA, Brown TT, Lee H, Grinspoon SK. Fracture prevalence among human immunodeficiency virus (HIV)-infected versus non-HIV-infected patients in a large U.S. healthcare system. J Clin Endocrinol Metab. 2008;93:3499-3504.
8. Womack JA, Goulet JL, Gibert C, et al. Increased risk of fragility fractures among HIV infected compared to uninfected male
veterans. PLoS One. 2011;6:e17217.
9. Young B, Dao CN, Buchacz K, Baker R, Brooks JT. Increased rates of bone fracture among HIV-infected persons in the HIV
Outpatient Study (HOPS) compared with the US general population, 2000-2006. Clin Infect Dis. 2011;52:1061-1068.
10. Arnsten JH, Freeman R, Howard AA, Floris-Moore M, Lo Y, Klein RS. Decreased bone mineral density and increased fracture
risk in aging men with or at risk for HIV infection. AIDS. 2007;21:617-623.
11. Yin MT, Shi Q, Hoover DR, et al. Fracture incidence in HIV-infected women: results from the Women’s Interagency HIV
Study. AIDS. 2010;24:2679-2686.
12. McComsey GA, Tebas P, Shane E, et al. Bone disease in HIV infection: a practical review and recommendations for HIV care
providers. Clin Infect Dis. 2010;51:937-946.
HIVTreatmentAlerts
29
Article 10 Sex Hormones May Play Role in Diabetes
Among HIV-Positive Gay Men
Two sex hormones, testosterone and sex hormone-binding globulin (SHBG), influenced development of insulin resistance or diabetes in gay men with or without
HIV in the Multicenter AIDS Cohort Study (MACS).1
Compared with HIV-negative men in this group, HIVpositive men had a 2 times higher risk of diabetes.
Diabetes—a lifelong disease marked by high sugar levels in blood—affects many people with HIV. It can be
caused by too little insulin (a hormone that controls
blood sugar), or resistance to insulin (Figure 1), or
both. Diabetes raises the risk of sickness and death from
heart disease and kidney disease and has many other
serious consequences. Risk factors for diabetes, including being overweight and physically inactive, are common in many HIV-positive men and women.
An earlier MACS study found higher rates of diabetes in HIV-positive men taking antiretrovirals than
in HIV-negative men.2 Another study found a link between longer treatment with nucleoside antiretrovirals
and diabetes in HIV-positive women.3
Identifying diabetes risk factors can help HIV providers
and people with HIV avoid or reverse those
risks and thus avoid or control insulin resistance and diabetes. A person’s testosterone
level is a possible diabetes risk factor that
has not been studied in people with HIV.
Studies in the general population linked
low testosterone to higher diabetes rates.4,5
Low testosterone levels are not rare in people with HIV, and testosterone may be low
even in people taking effective antiretroviral therapy.6
SHBG binds testosterone in the blood, leaving only a small proportion of unbound or
“free” testosterone to perform its functions
in the body. Previous studies in the general
population found that low SHBG makes diabetes more likely. But the potential impact
of SHBG on insulin resistance and diabetes
had not been studied in people with HIV.
■ How the study worked. The Multicenter
AIDS Cohort Study—called MACS for
short—is an ongoing study of almost 7000
30
HIV-positive gay men and gay men with a high risk of
HIV infection. The men live in or near Baltimore, Chicago, Los Angeles, Pittsburgh, and Washington, DC.
They visit the MACS center twice a year for check-ups
and to give samples for testing.
In this study researchers measured free testosterone,
SHBG, glucose (sugar in blood), and other values in
samples collected at a single MACS study visit. They
calculated insulin resistance with a standard method
called HOMA-IR. The researchers defined diabetes as
(1) a blood glucose at or above 126 mg/dL in a sample
collected after fasting or (2) self-reported diabetes and
use of diabetes medications.
This analysis involved men at least 40 years old who weighed under 300 pounds. No one had prior heart disease.
The researchers used accepted statistical methods to
determine (1) insulin resistance and diabetes rates in
men with HIV versus men without HIV and (2) factors
that affected risk of insulin resistance and diabetes, including SHBG and free testosterone (that is, testosterone not bound by SHBG).
How type 2 diabetes develops
Figure 1. Insulin is a hormone produced by the pancreas to control blood sugar (glucose). When the body cannot use insulin properly, a person has insulin resistance. Diabetes results when insulin resistance causes glucose to build up to high levels. (Stomach and
pancreas from Servier Medical Art, www.servier.com/)
HIVTreatmentAlerts
nmol/L). SHBG increased with age in men with HIV
but decreased with age in men without HIV.
In the entire study group—including men with and
without HIV—free testosterone was inversely associated with insulin resistance: In other words, the lower
the testosterone level, the higher the insulin resistance.
SHBG was inversely associated with both insulin resistance and diabetes: The lower the SHBG, the higher
the insulin resistance and the diabetes rate.
Looking only at men with HIV, the researchers found
that free testosterone was inversely associated with diabetes (the lower the testosterone, the higher the diabetes rate), but only when testosterone was measured in
a sample collected in the morning. (Testosterone levels are normally higher in the morning, then decline
throughout the day.) HIV-positive men who also had
HCV infection had higher insulin resistance.
■ What the study found. The study included 534 gay
men with HIV and 322 gay men without HIV. HIVpositive men were less likely to be white (60.7% versus
73.6%) and more likely to have hepatitis C virus (HCV)
infection (17.4% versus 8.7%). HIV-negative men were
older (average 52.6 versus 48.9 years) and had higher
weight, measured as body mass index (26.0 versus 25.1
kg/m2). (A body mass index of 18.5 to 24.9 is considered
normal, 25 to 29.9 is considered overweight, and 30 or
higher is considered obese.)
Almost all HIV-positive men (97%) were taking antiretrovirals at the time of the study visit. Median CD4
count was 510 in men with HIV, and one third of them
had a viral load above 400 copies.
Insulin resistance (measured as HOMA-IR) was higher in men with HIV than in men without HIV (1.30
versus 1.06). Statistical analysis considering many factors that may affect insulin resistance determined that
insulin resistance was 22.3% higher in men with HIV
than in men without HIV. A higher proportion of men
with HIV than without HIV had diabetes (11.4% versus
8.0%). Statistical analysis that considered several diabetes risk factors figured that men with HIV had a 2 times
higher risk of diabetes than men without HIV.
Average free testosterone was lower in men with HIV
than in men without HIV (88.9 versus 100.9 pg/mL).
Average SHBG, on the other hand, was higher in men
with HIV than in HIV-negative men (53.4 versus 46.5
HIVTreatmentAlerts
Statistical analysis that considered multiple diabetes
risk factors found only one that made diabetes more
likely regardless of what other risk factors a person
had: Ever taking Zerit (stavudine, d4T) raised the diabetes risk 4 times.
■ What the results mean for you. This large study of
US gay men made several important findings:
•HIV-positive gay men had higher insulin resistance
(which can lead to diabetes) and a higher rate of
diabetes itself than HIV-negative gay men.
•HIV-positive men had a 2 times higher risk of diabetes than HIV-negative men.
•Free testosterone was lower in HIV-positive men
than HIV-negative men.
•SHBG was higher in HIV-positive men than HIVnegative men.
•In all men studied, lower free testosterone meant
higher insulin resistance.
•When free testosterone was measured in the morning in men with HIV, lower free testosterone meant
a higher risk of diabetes.
The higher insulin resistance and diabetes rates in HIVpositive men than in HIV-negative men are cause for
concern. Diabetes is a serious and complicated disease
that damages nerves and blood vessels and can lead to
heart disease, stroke, blindness, kidney disease, nerve
problems, gum infections, and the need to amputate
limbs.7 Table 1 lists risk factors for insulin resistance
and diabetes. Almost all of these risk factors can be prevented or reversed.
31
Table 1. Risk factors of insulin resistance and diabetes
Being age 45 or older
Being overweight or obese
Being physically inactive
Having a parent, brother, or sister with diabetes
Being African American, Alaskan Native, American Indian, Asian American, Hispanic/Latino, or
Pacific Islander
Giving birth to a baby weighing more than 9 pounds or being diagnosed with gestational diabetes
(diabetes first found during pregnancy)
Having high blood pressure (140/90 or above) or being treated for high blood pressure
Having an HDL (“good”) cholesterol below 35 mg/dL or a triglyceride level above 250 mg/dL
Having heart disease
Having impaired fasting glucose or impaired glucose tolerance
Having other conditions linked to insulin resistance, such as severe obesity or acanthosis nigricans
(darker, thick, velvety skin in body folds and creases)
Having polycystic ovary syndrome (also called PCOS)
Source: National Institute of Diabetes and Digestive and Kidney Disease. Insulin resistance and pre-diabetes.
http://diabetes.niddk.nih.gov/dm/pubs/insulinresistance/#what
In addition to the risk factors listed in Table 1, this study
found evidence that lower testosterone in gay men with
and without HIV raises the risk of insulin resistance.
And low testosterone in the morning (when testosterone
levels are normally highest) raised the risk of diabetes in
men with HIV. These findings may not apply to HIVpositive gay men not taking antiretrovirals, because almost all men in this study were taking antiretrovirals.
HIV found improved insulin sensitivity and others did
not. In one study of men with HIV and low testosterone, testosterone supplements did not lower central
fat—the type of fat linked to insulin resistance.8 Ongoing research in the Multicenter AIDS Cohort Study
is assessing the impact of testosterone supplementation. Testosterone therapy has side effects that must be
weighed against potential advantages.
The researchers note that several factors may contribute to low testosterone: poor diet, more advanced
HIV infection, use of drugs including opiates, Megace
(megestrol acetate), and steroids, HCV infection, illegal drug use, and poor pituitary gland function. Many
people with HIV infection have body fat abnormalities
including increased central fat. And increased central
fat lowers testosterone and increases insulin resistance.
These researchers stress that “weight loss would certainly improve both insulin sensitivity and testosterone levels.”
It is unclear whether taking testosterone supplements
will help control blood sugar in people with HIV. Some
studies of testosterone supplements in people without
32
US guidelines for HIV care suggest that providers
measure blood glucose levels (after fasting) when people begin care and 3 to 6 months after starting antiretroviral therapy depending on whether levels are
normal.9 After that, they suggest measuring glucose
every 6 to 12 months. If glucose levels are high or if
people have diabetes risk factors, glucose should be
measured more often.
HIVTreatmentAlerts
Illustration by Isaac Yonemoto
Online Advice on Diabetes
The National Institute of Diabetes and Digestive and Kidney Diseases
has many easy-to-read handbooks on diabetes in English and en Español
at http://diabetes.niddk.nih.gov/dm/ez.aspx?control=Pubs.
References
1. Monroe AK, Dobs AS, Xu X, et al. Sex hormones, insulin resistance, and diabetes mellitus among men with or at risk for HIV
infection. J Acquir Immune Defic Syndr. 2011;58:173-180.
2. Brown TT, Cole SR, Li X, et al. Antiretroviral therapy and the prevalence and incidence of diabetes mellitus in the Multicenter
AIDS Cohort Study. Arch Intern Med. 2005;165:1179-1184.
3. Tien PC, Schneider MF, Cole SR, et al. Antiretroviral therapy exposure and incidence of diabetes mellitus in the Women’s
Interagency HIV Study. AIDS. 2007;21:1739-1745.
4. Selvin E, Feinleib M, Zhang L, et al. Androgens and diabetes in men: results from the third National Health and Nutrition
Examination Survey (NHANES III). Diabetes Care. 2007;30:234-238.
5. Ding EL, Song Y, Malik VS, et al. Sex differences of endogenous sex hormones and risk of type 2 diabetes: a systematic review
and metaanalysis. JAMA. 2006;295:1288-1299.
6. Wunder DM, Bersinger NA, Fux CA, et al. Hypogonadism in HIV-1-infected men is common and does not resolve during
antiretroviral therapy. Antivir Ther. 2007;12:261-265.
7. National Institute of Diabetes and Digestive and Kidney Diseases. Am I at risk for type 2 diabetes?
http://diabetes.niddk.nih.gov/dm/pubs/riskfortype2/index.aspx.
8. Bhasin S, Parker RA, Sattler F, et al. Effects of testosterone supplementation on whole body and regional fat mass and distribution in human immunodeficiency virus-infected men with abdominal obesity. J Clin Endocrinol Metab. 2007;92:1049-1057.
9. US Department of Health and Human Services Health Resources and Services Administration. Guide for HIV/AIDS clinical
care. January 2011. http://hab.hrsa.gov/deliverhivaidscare/clinicalguide11/.
HIVTreatmentAlerts
33
Article 11 Need for Cataract Surgery Greater in People
With Than Without HIV
HIV-positive people in Denmark had almost a 2 times
higher need for cataract surgery than people of the
same age in the general population, according to results of a nationwide study.1 Having a CD4 count under
200 raised the need for cataract surgery even more.
A cataract is clouding of the lens in the eye (Figure
1). Like a camera lens, the lens in the eye helps focus an image. So clouding makes vision blurry.2 Older
age, smoking, drinking too much alcohol, prolonged
exposure to sunlight, and diseases like diabetes can
raise the risk of cataracts.2 Blurred vision caused by
cataracts can be corrected by surgery in which the affected lens is removed and an artificial lens is inserted.
Cataracts cloud the lens of the eye
cells may cause uveitis or vitritis—eye inflammation.
This kind of inflammation can impair vision and may
lead to cataracts.
To see whether HIV-positive people have a higher
risk of cataract surgery than people without HIV, researchers in Denmark planned this study involving all
HIV-positive adults in the country and a comparison
group from the general population. The researchers
designed the study so that they could identify factors
that raise the risk of cataracts.
■ How the study worked. Researchers focused on people in the Danish HIV Cohort Study, which includes
all HIV-positive people cared for in Denmark since January 1, 1995. Everyone in
the cataract surgery analysis was 16 or
older when diagnosed with HIV. They
were included in the study at the date
of their HIV diagnosis, the date they arrived in Denmark from another country,
or on January 1, 1995, whichever date
was the most recent. The researchers
called this the index date, and they did
not include people who had cataract surgery before the index date.
(Source: Eye illustration from Servier Medical Art, www.servier.com/.)
Figure 1. The lens of the eye focuses an image on the retina at the
back of the eye. Cataracts cloud the lens and make the image fuzzy.
Thanks to antiretroviral therapy, people with HIV
are not getting AIDS diseases as often and are living
longer. But HIV-positive people have higher rates of
some age-related non-AIDS diseases than do people
without HIV, like heart, liver, and kidney disease, and
some non-AIDS cancers. Because cataracts are an agerelated problem, it seems possible that cataracts may
also develop more often in people with HIV than in
HIV-negative people.
When people with a low CD4 count start combination antiretroviral therapy, the rapid gain in CD4
34
For every HIV-positive person, the research team selected 10 people from the
general population. These 10 people
matched the HIV-positive person by age
and gender, and none of them had cataract surgery before the index date.
For all study participants, the researchers checked hospital admission records
for the first date of any earlier eye disease or eye surgery that may raise the risk of cataracts. They used
standard statistical techniques to figure an incidence
rate ratio that compared the risk of needing cataract
surgery in HIV-positive people with the risk in the
general population. The statistical analysis considered
the impact of age, gender, and calendar year on risk
of cataract surgery.
The investigators also analyzed the possible impact of
Ziagen (abacavir), Viread (tenofovir), and any protease inhibitor or nonnucleoside on risk of cataract sur-
HIVTreatmentAlerts
gery. Medical care including antiretroviral therapy is
free in Denmark. Cataract surgery is also free in all
government hospitals and many private clinics.
eye disease that may cause cataracts could not explain
the higher risk of cataract surgery in the HIV group.
■ What the study found. The researchers compared
5315 HIV-positive people with 53,150 people in the general population. Median age of the study group was 37
years and 76% were men. Most people in the HIV group
(80.5%) were white, and similar proportions got infected
with HIV during sex between men (45%) and during sex
between men and women (36%). Median follow-up time
for this analysis was 7.9 years for people with HIV and
11.4 years for the general population.
Further analysis showed that a lower CD4 count and
taking antiretroviral therapy raised the risk of cataract
surgery compared with the risk in the general population (Figure 2). Specifically, (1) having a CD4 count
of 200 or lower before starting antiretroviral therapy
tripled the risk of cataract surgery, (2) having a CD4
count of 200 or lower after starting antiretroviral therapy raised the risk of cataract surgery almost 5 times,
and (3) having a CD4 count above 200 while taking
antiretroviral therapy almost doubled the risk of cataract surgery.
Ninety HIV-positive people (1.7%) had cataract surgery, compared with 718 people (1.4%) in the general
population. Eye disease that could make cataracts more
likely affected 252 people (4.7%) in the HIV group
and 494 (0.9%) in the general-population group.
Treatment with Ziagen, Viread, a protease inhibitor,
or a nonnucleoside did not affect the risk of cataract
surgery.
■ What the results mean for you. This large study included all adults in Denmark receiving care for HIV
over the past several years. Compared with people in
the general population who were the same age and
gender, HIV-positive people had almost
a 2 times higher risk of needing cataract surgery. HIV-positive people had a
Risk of cataract surgery in HIV-positive people
3 times higher risk of cataract surgery if
compared with general population
they had a CD4 count of 200 or lower before starting antiretroviral therapy. The
HIV group had almost a 5 times higher
risk of cataract surgery if they had a CD4
count that low during antiretroviral therapy, and they had almost a twice higher risk
if they had a CD4 count above 200 during
antiretroviral therapy.
Compared with people in the general population,
people with HIV had almost a 2 times higher risk of
needing cataract surgery (Figure 2). By itself, having
Figure 2. Compared with the general population (HIV-), HIVpositive people (HIV+) had a 1.87 times higher risk of cataract
surgery. Before study participants had any eye disease that may
make cataracts more likely, HIV-positive people had a 1.6 times
higher risk of cataract surgery than the general population. A
lower CD4 count and antiretroviral therapy (ART) also raised the
risk of cataract surgery in HIV-positive people compared with the
general population.
HIVTreatmentAlerts
These findings do not mean antiretroviral
therapy should be avoided or delayed because of the higher risk of cataracts with
antiretroviral treatment. The many benefits of antiretroviral therapy in preventing
AIDS and promoting overall health far
outweigh any cataract risk. With regular
eye exams, cataracts can be detected early
and treated effectively.
The link between antiretroviral therapy
and cataract risk may just mean people
taking antiretrovirals have more advanced
HIV infection—and more advanced infection makes cataracts more likely: People
with a CD4 count of 200 or lower had a
higher risk of cataract surgery whether or
35
not they were taking antiretrovirals. It is also possible
that rapid gains in CD4 cells with antiretroviral therapy caused uveitis—a type of eye inflammation—and
that uveitis sometimes resulted in cataracts.
Compared with the general population, people with
HIV had higher rates of other eye diseases that make
cataracts more likely. But statistical analysis showed
that the higher rate of other eye diseases did not explain the higher cataract risk in people with HIV. This
study could not assess the possible impact of other factors that may raise the risk of cataracts, such as smoking and diabetes.
Despite the higher cataract risk in this HIV group,
the researchers do not believe their results mean HIVpositive people should get eye exams for cataracts
more often than they do now or that antiretroviral
strategies should change.
The United States National Eye Institute lists several
factors that raise the risk of cataracts: smoking, alcohol
use, diabetes, steroid drugs, and prolonged exposure
to sunlight.2 The Eye Institute suggests that wearing
sunglasses or a hat with a brim to block sunlight may
delay cataracts. “If you smoke, stop,” the Eye Institute
says. They add that a diet that includes green leafy
vegetables, fruit, or other foods with antioxidants may
delay or prevent cataracts.
The Eye Institute recommends that everyone 60 or
older should have an eye exam by an ophthalmologist (an eye specialist) at least once every 2 years.2 US
guidelines for people with HIV say “routine eye examinations should be part of the patient’s primary care.”3
HIV-positive people with a CD4 count below 50 should
be examined by an ophthalmologist when they start
care for HIV and then every 6 months.3 If your vision
is becoming blurry, tell your HIV provider.
References
1. Rasmussen LD, Kessel L, Molander LD, et al. Risk of cataract surgery in HIV-infected individuals: a Danish nationwide
population-based cohort study. Clin Infect Dis. 2011;53:1156-1163.
2. National Eye Institute. Facts about cataracts. http://www.nei.nih.gov/health/cataract/cataract_facts.asp.
3. US Department of Health and Human Services Health Resources and Services Administration. Guide for HIV/AIDS clinical
care. January 2011. http://hab.hrsa.gov/deliverhivaidscare/clinicalguide11/.
36
HIVTreatmentAlerts
Article 12 Low Testing Rates for Gonorrhea and Chlamydia
in Large US HIV Group
Rates of testing for gonorrhea and chlamydia infection
rose slowly among HIV-positive men and women in the
United States from 2004 through 2010.1 But testing
rates for these common infections remained far below
rates for syphilis testing and for cholesterol monitoring
in this study group.
US guidelines recommend at least annual gonorrhea
and chlamydia testing for sexually active people with
HIV. Testing for these sexually transmitted infections
(STIs) is important because they may have no symptoms. As a result, gonorrhea and chlamydia can be
overlooked without testing.
Untreated gonorrhea and chlamydia raise the risk that
an HIV-positive person will pass HIV to a sex partner;
they also raise the risk of pelvic inflammatory disease, a
serious condition that can prevent women from becoming pregnant or cause abnormal pregnancies.2
HIV Research Network investigators planned this
study to compare testing rates for gonorrhea and chlamydia with rates of testing for syphilis and high cholesterol or high triglycerides.
■ How the study worked. Researchers checked medical
records at seven HIV clinics across the United States
to determine how many HIV-positive people got tested
for gonorrhea, chlamydia, syphilis, and cholesterol or
triglyceride levels. The study period lasted from 2004
through 2010.
The investigators calculated testing rates for all clinic
attendees and separately for gay/bisexual men, heterosexual men, and women. They used standard statistical
methods to identify factors that affected chances of getting tested for gonorrhea, chlamydia, or syphilis.
■ What the study found. The study involved 19,323
HIV-positive people seen at the seven clinics. Numbers
of people seen in 2004, 2007, and 2010 were 8947,
9288, and 10,945. Median ages for those three years
were 43, 45, and 47. About 30% of these people were
women, 46% black, 27% white, and 24% Hispanic.
A little more than one third of study participants became infected with HIV during sex between men, one
HIVTreatmentAlerts
third became infected during sex between men and
women, and about 12% had injection drug use as their
only HIV risk factor. Proportions of people who took
combination antiretroviral therapy rose over the
study period, from 73% in 2004 to 88% in 2010.
Among all people studied, more than 60% got tested
for cholesterol or triglycerides every year throughout
the 2004-2010 study period. Yearly syphilis testing
rates rose steadily from just below 60% in 2004 to about
70% in 2009 and 2010. In contrast, overall testing rates
for gonorrhea and chlamydia were about 20% in 2004
and 2005 and were still below 40% in 2009 and 2010.
Gonorrhea and chlamydia testing rates were higher
among women than men but remained around 40%
yearly for women throughout the 2004-2010 study
period. Gonorrhea and chlamydia testing rates were
lower for gay and bisexual men, starting under 20%
yearly in 2004 and reaching only about 40% in 2010.
Testing rates were lowest for heterosexual men, starting below 10% yearly in 2004 and reaching only about
20% in 2010.
Despite the relatively low gonorrhea and chlamydia
testing rates, the odds of being tested did increase yearly from 2004 through 2010, 6% yearly for women, 34%
yearly for heterosexual men, and 42% yearly for gay/
bisexual men. Younger age substantially raised chances
of gonorrhea and chlamydia testing for women, heterosexual men, and gay men (Table 1).
Compared with whites, black women had a 44% higher
odds of being tested for gonorrhea and chlamydia and
Hispanic women had 35% higher odds. Compared with
whites, black gay/bisexual men had 21% higher odds of
getting tested for gonorrhea and chlamydia and Hispanic gay/bisexual men had 19% higher odds. Among
heterosexual men, blacks had 30% higher odds of getting tested than whites, but Hispanics were not more
likely to get tested than whites.
Making more clinic visits and having a higher CD4
count also raised odds of getting tested for gonorrhea
and chlamydia (Table 1), but a higher or lower viral
load did not affect testing chances.
37
Table 1. Impact of age, clinic visits, and CD4 count on chance of getting tested for gonorrhea and chlamydia
5413 Women
6066 Nongay men
7884 Gay men
Compared with 50 years or older
Age under 30
2.13 × higher odds
2.17 × higher odds
2.41 × higher odds
Age 30 to 39
1.94 × higher odds
1.62 × higher odds
1.89 × higher odds
Age 40 to 49
1.53 × higher odds
1.37 × higher odds
1.37 × higher odds
Compared with 3 or fewer clinic visits yearly
4 to 6 visits yearly
1.76 × higher odds
1.63 × higher odds
1.72 × higher odds
7 or more visits yearly
2.69 × higher odds
2.19 × higher odds
2.45 × higher odds
Compared with CD4 count at or below 200
201 to 350 CD4s
1.14 × higher odds
1.18 × higher odds
1.24 × higher odds
351 or more CD4s
1.32 × higher odds
1.35 × higher odds
1.33 × higher odds
The odds of getting tested for syphilis also rose each
year for women (10% yearly), heterosexual men (11%
yearly), and gay/bisexual men (21% yearly). Compared
with being white, being black raised chances of syphilis
testing in men and tended to raise chances in women.
Compared with whites, gay/bisexual Hispanics were
more likely to get tested for syphilis, while nongay Hispanic men and women tended to get tested for syphilis
more than whites.
■ What the results mean for you. Gonorrhea, chlamydia, and syphilis occur frequently in people with
HIV because, like HIV, they can be transmitted during
sex. More than 700,000 people in the United States
get gonorrhea every year,3 chlamydia is the most frequently reported sexually transmitted infection in the
United States,4 and syphilis rates are rising, especially
among gay and bisexual men.5 (Click on the links for
references 2 to 5 below for more information on these
three sexually transmitted infections and on pelvic inflammatory disease, a serious complication of gonorrhea or chlamydia.)
Gonorrhea, chlamydia, and syphilis can usually be
cured with antibiotics. But because these infections may
have no symptoms, they often remain hidden unless
sexually active people get tested regularly. Besides causing possibly dangerous complications, these infections
raise the risk that an HIV-positive person will transmit
38
HIV to sex partners or get infected with other sexually
transmitted diseases. In the United States health authorities recommend at least annual testing for all three
infections in sexually active people with HIV.
This study of more than 19,000 HIV-positive people
across the United States found that testing rates for
gonorrhea, chlamydia, and syphilis have risen steadily
from 2004 through 2010. But testing rates for gonorrhea and chlamydia are still far below testing rates for
syphilis or for high cholesterol. This difference in testing rates is greatest for heterosexual men with HIV.
The researchers suggest that people may get tested for
gonorrhea and chlamydia less often than for syphilis
because testing for the first two infections takes a little
more time because it requires genital, rectal, and/or
oral samples, whereas syphilis testing can be done with
blood samples. (Sometimes gonorrhea and chlamydia
can be diagnosed in urine samples.)
People who visited their HIV clinic 4 or more times a
year were more likely to get tested than people who had
3 or fewer visits yearly. Keeping all medical appointments is important not only to ensure regular testing
for sexually transmitted infections, but also for proper
care of HIV infection and other illnesses you may have.
If you have HIV and are sexually active, be sure to
get tested for gonorrhea, chlamydia, and syphilis evHIVTreatmentAlerts
ery year. Recent HIV guidelines recommend syphilis testing every 3 to 6 months for people with more
than one sex partner, people who have sex without
condoms, and people who use illegal drugs including
methamphetamine.6 These experts suggest that how
often you get tested for gonorrhea and chlamydia depends on sexual behavior including anal sex, whether you or your sex partners have another sexually
transmitted infection, and sexually transmitted infection rates in the community.
References
1. Berry S, Korthuis T, Mathews C, et al. Gonorrhea and chlamydia testing increasing, but not on par with syphilis and lipid testing in a consortium of HIV clinics. 19th Conference on Retroviruses and Opportunistic Infections. March 5-8, 2012. Seattle.
Abstract 891. http://www.retroconference.org/2012b/PDFs/891.pdf.
2. Centers for Disease Control and Prevention. Pelvic inflammatory disease (PID)—CDC fact sheet.
http://www.cdc.gov/std/pid/stdfact-pid.htm.
3. Centers for Disease Control and Prevention. Sexually transmitted diseases (STDs): Gonorrhea—CDC fact sheet.
http://www.cdc.gov/std/gonorrhea/stdfact-gonorrhea.htm.
4. Centers for Disease Control and Prevention. Sexually transmitted diseases (STDs): Chlamydia.
http://www.cdc.gov/std/chlamydia/default.htm.
5. Centers for Disease Control and Prevention. Sexually transmitted diseases (STDs): Syphilis.
http://www.cdc.gov/std/syphilis/default.htm.
6. Aberg JA, Kaplan JE, Libman H, et al. Primary care guidelines for the management of persons infected with human immunodeficiency virus: 2009 update by the HIV Medicine Association of the Infectious Diseases Society of America. Clin Infect Dis.
2009;49:651-681. http://www.uphs.upenn.edu/bugdrug/antibiotic_manual/idsahivprimarycare2009.pdf.
HIVTreatmentAlerts
39
Article 12 How Feelings About Aging Affect Emotions in
HIV-Positive Adults
Almost half of an HIV-positive group studied in Spain
believed they were aging faster than normal.1 More than
half of this group thought aging limited their day-to-day
living, their work, and their relations with others. People
who felt they were aging rapidly felt more depressed
than others. Women expressed these concerns more
than men in this 100-person study.
Several factors related to aging may affect the emotional
life of people with and without HIV, including declining
physical function, lower income, and changes in social
activity and relationships. Previous research found that
people with HIV may have depression (feeling sad or
unmotivated much of the time) more than people without HIV.2,3 Aging and problems that occur with aging
also raise the risk of depression.
Researchers at a large HIV clinic in Spain planned this
study to see how many people have depression after
many years of HIV care. The study also aimed to determine how feelings about aging affected depression and
day-to-day functioning in these people.
■ How the study worked. When HIV-positive adults
came to the clinic for a regular visit between April 1 and
July 1, 2010, researchers invited them to participate in
the study of feelings about aging and depression. Everyone had HIV infection for at least 15 years. No one had
a recorded psychiatric illness (like anxiety or depression)
and no one was getting treated for such an illness. No
one was getting treated for hepatitis C virus infection,
and no one injected illegal drugs at the time of the study.
The researchers gathered details from medical records
of these people, who completed a standard 15-question
survey to assess symptoms of depression. A score of 0 to
4 meant no symptoms, 5 to 8 indicated mild depression,
8 to 11 indicated moderate depression, and 12 or higher
meant severe depression.
Study participants were asked whether they felt they
were aging faster than HIV-negative people of a similar
age. They answered questions about whether limitations
related to aging affected (1) daily life functioning, (2)
interpersonal relations, and (3) work. The researchers
used standard statistical methods to determine whether
feelings about more rapid aging and other factors affected depression scores.
40
■ What the study found. Researchers invited 124 HIVpositive people to enter the study, and 100 agreed, including 60 men and 40 women. These people had a
median age of 47 years and knew they had HIV infection for a median of 18 years. The group’s median CD4
count stood at 543, and 80% had an undetectable viral
load. While 37% of the study group got infected with
HIV while injecting drugs, 32% got infected during sex
between men. More than half of the study group (62%)
had a job, and 58% had a stable partner. Men and women were similar in all these ways, except that more men
than women worked.
Median depression score was 6, indicating mild depression for the group as a whole. The median depression
score was moderately higher in women than men (7 versus 5). Eighteen people (18%) had severe depression that
had not been detected before the study began and was
not being treated.
Forty-three study participants (43%) believed they were
aging faster than normal, including 80% of women and
18% of men. High proportions of people thought aging:
1.Limited their daily functioning: 74% overall, 71% of
men, 77% of women
2.Affected their interpersonal relations: 61% overall,
63% of men, 82% of women
3.Affected their work activity: 61% overall, 53% of
men, 77% of women
Six factors made a higher depression score more likely—
a feeling of early aging, feeling older than HIV-negative
people of a similar age, limitations in daily life functioning, limitations in interpersonal relations, limitations in
work activity, and more symptoms of aging (Figure 1).
■ What the results mean for you. This study of middleaged people who had been receiving care for HIV for
more than 10 years found that nearly half of them (43%)
believed they were aging faster than normal. People who
had this feeling were more likely to be depressed, as
were people who said they had problems in daily functioning, interpersonal relations, and work.
Almost 20% of the study group had severe depression
detected by a standard test, and none of these people
were taking drugs or getting counseling to treat their
HIVTreatmentAlerts
Factors that raised risk of
higher depression score
Figure 1. Six factors related to aging, daily life functions, personal relationships, and work raised the risk of
a higher (worse) depression score in a study of 100 adults
with long-term HIV infection.
depression. Most people with depression in this group
had mild depression. Mild depression is often ignored by
people with HIV and their providers, so it usually goes
untreated and can get worse.
Women reported more symptoms of depression than
men, and a higher proportion of women believed they
were aging faster than normal. These findings may have
several explanations. For example, women often feel under more pressure than men to look young and fit, so
they may feel they are aging faster because society holds
them to a higher physical standard. Also, women often
speak more freely about their emotions than men, so
they may have worse scores on tests for depression and
similar tests. On the other hand, if men are less willing
than women to say they’re depressed, they will be less
likely to benefit from effective treatments.
Both women and men should realize that depression is
not a sign of weakness—it’s an illness that can be treated
with drugs, with professional counseling, or with both.
The difficulties caused by HIV infection raise the risk of
depression. If you think you’re depressed—feeling sad,
tired, or unmotivated much of the time—you should
discuss these feelings with your HIV provider or with
someone you trust in your provider’s office. Getting on
top of depression can have a big positive impact on many
aspects of your life.
The National Institute of Mental Health has an online
video explaining depression and its treatment (http://
www.youtube.com/watch?v=mlNCavst2EU&feature=p
layer_embedded). An online booklet discusses depression (http://www.nimh.nih.gov/health/publications/depression/index.shtml), and another booklet focuses on
depression in women (http://www.nimh.nih.gov/health/
publications/women-and-depression-discovering-hope/
index.shtml).
There has been much recent discussion about aging in
people with HIV. Many reports refer to “accelerated aging” or “premature aging” with HIV, creating the impression that HIV makes you older faster. But this is
a complicated issue still being studied and debated by
experts. Certain diseases and conditions do appear to
occur earlier in some people with HIV than in people
without HIV. Examples are heart disease and loss of
bone density.
But many factors besides HIV contribute to those conditions. For example, smoking, physical activity, and diet
all affect both the heart and the bones. So instead of worrying that HIV is making you older faster, it makes more
sense to worry about the individual conditions that contribute to aging. Then you can fight “aging” by focusing
on factors you can control—like smoking, physical activity, and diet. Taking a positive approach to controlling
your own health is also one way to fight depression.
References
1. Fumaz CR, Muñoz-Moreno JA, Ferrer MJ, et al. Emotional impact of premature aging symptoms in long-term treated HIVinfected subjects. J Acquir Immune Defic Syndr. 2012;59:e5-e8.
2. Sueoka K, Goulet JL, Fiellin DA, et al. Depression symptoms and treatment among HIV-infected and uninfected veterans.
AIDS Behav. 2010;14:272-279.
3. Lopes M, Olfson M, Rabkin J, et al. Gender, HIV status, and psychiatric disorders: results from the National Epidemiologic
Survey on Alcohol and Related Conditions. J Clin Psychiatry. 2011 Oct 18. Epub ahead of print.
HIVTreatmentAlerts
41
Technical word list
Adenomas are noncancerous tumors that may become cancerous.
Antiretrovirals are drugs used to treat HIV infection.
CD4 cells are one type of cell necessary to fight infection. HIV attacks CD4
cells, so CD4 counts fall when a person is not taking antiretrovirals to control
HIV or when treatment fails.
CD4 count measures the number of CD4 cells in a cubic millimeter of blood.
People with CD4 counts below 500 have a harder time controlling infections.
The risk of uncontrolled infection gets higher as the CD4 count gets lower.
Diabetes is a lifelong disease in which there are high levels of sugar in the
blood. Diabetes can be caused by too little insulin, resistance to insulin, or both.
Insulin is a hormone produced by the pancreas to control blood sugar.
Insulin resistance is the inability of the body to use insulin properly.
Insulin resistance raises the risk of diabetes.
A median is the number above which half of all the numbers recorded lie,
and below which half of all the numbers recorded lie. The median number
differs from the average (or mean) number. For example, in the series 1, 3, 8,
9, and 14, the median is 8 because half of the other numbers lie above it and
the remaining half lie below. But the average of 1, 3, 8, 9, and 14 is 7.
A person-year is a measure of time used in medical studies. A single
person-year is 1 year lived by 1 person.
Viral load is the number of HIV particles in a milliliter of blood or
another body fluid, such as semen or cerebrospinal fluid.
Viremia copy-years are the number of HIV copies in each milliliter
of blood over a given period of time.
42
HIVTreatmentAlerts
HIVTreatmentAlerts
43
Ray Purser, Chairperson
Jeri Brooks, Vice-Chairperson
Lydia Baehr, Secretary
Richard L. Davidson, Treasurer
Robert Hilliard, Jr. M.D., At-Large/Exec. Committee
Beth Apollo
Glenn Bauguss
Ramiro Fonseca
David L. Fox, Ph.D.
Cyndy Garza-Roberts
Bryan Hlavinka
Alton LaDay
Jani C. Lopez
Executive Director
Katy Caldwell
Chief Medical Officer
Richard Beech, M.D.
Nichole L. Moore
Trudy Nix
John C. Sheptor
James A. Reeder, Jr.
Ann Reid
Ian Rosenberg
Len Zwelling, M.D.
Chief Financial Officer
Ben Glisan
Chief Development Officer
Chree Boydstun
Chief Operating Officer
Jo Carcedo
Chief Marketing &
Communications Officer
Kimberly Paulus