Estimating the benefit of an HIV-1
vaccine which reduces viral load
set point
Swati Gupta, DrPH, MPH
Merck Research Laboratories
Epidemiology Department
DIMACS Workshop on Facing the Challenge of Infectious
Disease in Africa
September 25-27th, 2006
Adults and children estimated to be living
with HIV, 2005
Eastern Europe
Western &
& Central Asia
Central Europe
1.5 million
720 000
North America
[1.0
– 2.3 million]
[550 000 – 950 000]
1.3 million
East Asia
[770 000 – 2.1 million]
680,000
North Africa & Middle East
[420 000 – 1.1 million]
Caribbean
440 000
330 000
[250 000 – 720 000]
South & South-East Asia
[240 000 – 420 000]
7.6 million
[5.1 – 11.7 million]
Sub-Saharan Africa
24.5 million
Latin America
Oceania
[21.6 – 27.4 million]
1.6 million
78 000
[1.2 – 2.4 million]
[48 000 – 170 000]
Total: 38.6 (33.4 – 46.0) million
Global estimates for adults and children, 2005
• People living with HIV
38.6 million
[33.4 – 46.0 million]
• New HIV infections in 2005
4.1 million
[3.4 – 6.2 million]
• Deaths due to AIDS in 2005
2.8 million
[2.4 – 3.3 million]
Source: UNAIDS, 2006 Report on the Global AIDS Epidemic
Over 11,000 new HIV infections a day in 2005
•
More than 95% are in low and middle income
countries
•
About 1,500 are in children under 15 years of age
•
About 10,000 are in adults aged 15 years and
older of whom:
— Almost 50% are among women
— Over 40% are among young people (15-24)
Source: UNAIDS, 2006 Report on the Global AIDS Epidemic
Estimated number of people living with HIV
globally, 1985–2005
Estimated number of people living with HIV, millions
50
40
30
20
10
0
1985
1990
1995
Year
Source: UNAIDS, 2006 Report on the Global AIDS Epidemic
2000
2005
Estimated number of people living with HIV
in sub-Saharan Africa, 1985–2005
30
25
20
15
10
5
0
1985
1990
1995
Year
Source: UNAIDS, 2006 Report on the Global AIDS Epidemic
2000
2005
Estimated number of adults and children
living with HIV by region, 1985–2005
Estimated number of people living with HIV by region, millions
45
40
35
30
25
20
15
10
5
0
1985
1990
1995
2000
Year
Oceania
North Africa & Middle East
Eastern Europe & Central Asia
Latin America and Caribbean
Source: UNAIDS, 2006 Report on the Global AIDS Epidemic
North America and Western Europe
Asia
Sub-Saharan Africa
2005
A global view of HIV infection
38.6 million people [33.4‒46.0 million] living with HIV, 2005
Source: UNAIDS, 2006 Report on the Global AIDS Epidemic
HIV prevalence in adults in Asia, 1990−2005
Source: UNAIDS, 2006 Report on the Global AIDS Epidemic
HIV prevalence in adults in Latin America
and the Caribbean, 1990−2005
Source: UNAIDS, 2006 Report on the Global AIDS Epidemic
HIV prevalence in adults
in sub-Saharan Africa, 1990−2005
Source: UNAIDS, 2006 Report on the Global AIDS Epidemic
Comparison of 2003 and 2005 data
Coverage of antiretroviral
therapy
Access to mother-to-child
prevention services (all
pregnant women)
Coverage of HIV-infected mothers
who received antiretroviral
prophylaxis
Percent
25
Percent
25
Percent
25
20
20
20
15
15
15
10
10
20.0
7.0
9.0
7.6
5
5
5
0
0
0
2003
2005
2003
2005
9.2
10
3.3
2003
2005
Sources: WHO/UNAIDS (2006). Progress on global access to HIV antiretroviral therapy: a report on “3 by 5” and beyond; USAID et al. (2006).
Coverage of selected services for HIV/AIDS prevention, care and support in low and middle income countries in 2003 and 2005.
Comparison of 2003 and 2005 data (cont.)
Coverage of HIV-infected mothers
who received antiretroviral prophylaxis
Coverage of antiretroviral therapy
60
60
56.0
50
50
40
40
35.0
30
30
25.0
19.7
20
20
12.0
9.3
6.3
10
10
3.0
7.0
4.6
1.0
0.0
0
0
Kenya
Namibia
Sources: Individual country reports (2005).
Uganda
Kenya
2003
2005
Namibia
Uganda
15–24 year olds reporting condom use during sexual
intercourse with a non-regular partner, Sub-Saharan Africa,
2001–2005
Female
Male
Countries with date of survey indicated, percent
Benin 2001
Botswana 2001
Burkina Faso 2003
Cameroon 2004
Chad 2004
Ghana 2003
Guinea 2005
Kenya 2003
Lesotho 2004
Madagascar 2003
Malawi 2004
Mali 2001
Mozambique 2003
Nigeria 2003
Rwanda 2004
Senegal 2005
United Republic of Tanzania 2003
Uganda 2004
Zambia 2003
0
10
20
30
Sources: Demographic Health Surveys; HIV/AIDS Indicator Surveys (2001-2005).
40
50
60
70
80
90
100
Median percentage of most-at-risk populations
reached with prevention programs and those
who received HIV testing in the last 12 months
and who knew their results
50
42% (n=13)
40
38% (n=9)
30
28% (n=10)
23% (n=10)
%
20
19% (n=10)
17% (n=10)
10
0
Percentage who received HIV
Percentage reached with
testing and who knew their results
prevention programs
Sex workers
Men who have sex with men Injecting drug users
Source: UNAIDS, 2006 Report on the Global AIDS Epidemic
25 years of AIDS
50
1 First cases of unusual immune deficiency are identified
among gay men in USA, and a new deadly disease
noticed
45
2 Acquired Immune Deficiency Syndrome (AIDS) is
defined for the first time
40
3 The Human Immune Deficiency Virus (HIV) is
identified as the cause of AIDS
35
Million
30
25
20
15
10
5
People
living
with
HIV
15
16
14
4 In Africa, a heterosexual AIDS epidemic is
revealed
5 The first HIV antibody test becomes
available
11 Scientists develop the first
treatment regimen to reduce motherto-child transmission of HIV
11
10
9
12
8 The first therapy for AIDS –
zidovudine, or AZT -- is
approved for use in the USA
7 8
6
5
2 3 4
1
In 1991-1993, HIV prevalence in
young pregnant women in Uganda
and in young men in Thailand
begins to decrease, the first major
downturns in the epidemic in
developing countries
10 Highly Active Antiretroviral
Treatment launched
13
6 Global Network of People living with
HIV/AIDS (GNP+) (then International
Steering Committee of People Living
with HIV/AIDS) founded
7 The World Health Organisation
launches the Global Programme on
AIDS
9
Children
orphaned
by AIDS in
subSaharan
Africa
12 UNAIDS is created
13 Brazil becomes the first developing
country to provide antiretroviral
therapy through its public health
system
14 The UN General Assembly Special
Session on HIV/AIDS. Global Fund
to fight AIDS, Tuberculosis and
Malaria launched
15 WHO and UNAIDS launch the "3 x 5"
initiative with the goal of reaching 3
million people in developing world
with ART by 2005
16 Global Coalition on Women and
AIDS launched
0
1980
1985
1990
Source: UNAIDS, 2006 Report on the Global AIDS Epidemic
1995
2000
2005
Background
•
The continued rapid spread of HIV-1 globally highlights the
need for urgent new preventive measures
•
A safe and effective prophylactic vaccine for human
immunodeficiency virus (HIV) is now widely thought to be
critical in controlling the pandemic, especially in developing
countries
•
To understand why there is still no effective HIV vaccine 25
years after the first case of AIDS was diagnosed requires
understanding a bit of background about the virus and how
our immune systems interact with the virus
Background (continued)

Innate immunity
• “non-specific” or “non-adaptive” responses

Acquired immunity
• Humoral immunity

Coordinated by B cell/antibody responses which have
receptors on their surface that allow them to connect with
and capture pathogens as they circulate freely in the blood

Examples of vaccines which lead to the production of
neutralizing antibodies: measles, polio, and hepatitis B
vaccines

Unfortunately, the induction of neutralizing antibodies against
HIV is a difficult task

Results of first large scale Phase III efficacy trial
Background
(continued)
Background (continued)

Acquired immunity
• Humoral immunity
• Cellular immunity

Coordinated by CD4+ T cells and CD8+ “killer” T cells that
identify and kill pathogen infected cells

Vast majority of AIDS vaccines in clinical trials have been
designed to induce cellular immune responses

Implications of cell mediated immunity (CMI)-based
responses to HIV infection in the context of vaccine
development
Background (continued)
•
Cell mediated immunity (CMI)-based HIV vaccines
– Current CMI-based vaccines are expected to either
prevent infection or contain post-infection viral load setpoint in people who become infected despite vaccination
Viral load set point after infection
Background (continued)

Natural history of HIV Infection in the context of
CMI-based HIV vaccines
Variable
<3 years
(19)
Time-to-AIDS category (n)
3-7 years
>7 years
AIDS-free >9
(67)
(37)
years (50)
Level at FP visit
HIV RNA
4.91
4.52
4.39
3.89
CD4 cell count
640
670
768
785
Slope per year
HIV RNA
0.18
0.09
-0.01
-0.05
CD4 cell count
-249
-89
-87
-73
Note. Data are medians. To exclude significant antiretroviral use, only visits before 1
January 1990 were considered.
Lyles et al.; JID 2000;181:872-880
Background (continued)
•
Natural history of HIV Infection in the context of
CMI-based HIV vaccines
– Current cell mediated immunity (CMI)-based vaccines
are expected to either prevent infection or contain postinfection viral load set-point in people who become
infected despite vaccination
– The time to events in the course of HIV disease
progression could be extended
– Magnitude of the potential clinical benefit of a vaccine
which reduces viral load setpoint is largely unknown
Background (continued)
•
Candidate vaccines designed to induce cell-mediated
immune responses against human immunodeficiency
virus-1 (HIV-1) are currently being developed
•
These vaccines are expected to provide either
“complete” or “partial protection” from HIV-1 infection.
–
–
•
“Complete protection” refers to preventing establishment of
HIV-1 infection
“Partial protection” refers to an attenuation of the course of
HIV-1 infection due to suppression of viral replication
Vaccines which provide “partial protection” are likely to
be associated with reduced viral set points after
infection
Background (continued)
•
Plasma viral load measured up to 18 months after
seroconversion strongly predicts the risk of disease
progression
•
Therefore, a vaccine capable of reducing viral load set
point could provide important clinical benefit such as
delaying the onset of AIDS or the need for antiretroviral
therapy
• Using data collected from a cohort study on the natural
history of HIV-1 infection, we modeled the potential
impact of a vaccine which would reduce viral set point
after infection.
Methods

Study Population
• Multicenter AIDS Cohort Study (MACS)

On-going (initiated in 1983), prospective cohort
study of HIV infection in men who have sex with
men
• 5622 participants enrolled before 2001
• 4 sites in Baltimore/Washington, Chicago, Los Angeles and
Pittsburgh



Participants were either HIV-1 seronegative or HIV-1
seropositive but without a clinical AIDS diagnosis at
enrollment
Participants seen every 6 months
Study visits include the following:
• Behavioral and medical history
• Physical Exam
• Blood collection
Methods (continued)
Role of MACS in describing the epidemiology of
HIV infection

• Incidence and risk factors of HIV infection
• Natural history of HIV infection
 Time to AIDS and death (survival times)
• Prognostic value viral load characterized
• Efficacy of combination/HAART therapies on individual and
population levels
• Adverse events / toxicities of therapies
• Role of genetic markers on infection and disease
progression
Source: UNAIDS, 2006 Report on the Global AIDS Epidemic
Methods (continued)

Inclusion Criteria for analyses
– HIV-1 seronegative at enrollment into the MACS and
seroconverted during the follow-up period
– One year or less between their last HIV-1 seronegative
(LN) and first HIV-1 seropositive (FP) visits
(seroconversion dates were calculated as the midpoint
between the LN and FP visits)
– HIV-1 RNA measurement available at 3, 9 or 15 months
post-seroconversion
– Early HIV-1 RNA measurement was required to
precede the initiation of any antiretroviral therapy
Methods (continued)

Data Analysis
• Early HIV-1 RNA measurements were examined to
determine if there were in any trends in viral load
soon after seroconversion.
• Lognormal parametric regression models were used
to investigate the relationship between viral load set
point and time to the following outcome variables:




Clinical AIDS (defined as an opportunistic illness)
CD4 cell count level (<350 cells/mm3, <200 cells/mm3)
Loss of virological control ( HIV-1 RNA >=55,000 copies/mL)
Clinical indication for initiation of antiretroviral therapy (HIV-1 RNA
>=55,000 copies/mL or CD4+ T-cell count <350 cells/mm3 or
diagnosis of an OI)
• Relative times to events of interest were estimated for
those with viral load set points of 30,000 copies/mL
(reference group) vs. those with lower viral set points.
Results
TABLE 1. Viral RNA and CD4+ T-cell count measurements
following seroconversion
CD4+ T-cell count (cells/mm3)
HIV-1 RNA (copies/mL)
Months post
seroconversion (PSC)
n
Median (IQR)
Geometric
mean (SD)*
n
Median (IQR)
Mean (SD)
~3 months PSC
340
28,832 (7,887,
90,441)
22,387 (6.8)
324
738 (548, 944)
780 (332.6)
~9 months PSC
311
27,986 (7,903,
63,861)
19,815 (5.9)
298
639 (460, 847)
681 (291.1)
~15 months PSC
275
25,495 (9,238,
58,478)
20,797 (4.9)
271
587 (450, 792)
643 (289.4)
* The standard deviation of the geometric mean represents 10 to the x, where x is the standard deviation of the log 10 HIV RNA
Results (continued)
TABLE 2. Demographic statistics for 311 seroconverters
with HIV RNA available at 9 months postseroconversion
Median year of seroconversion
1986 (IQR*: 1985-1989)
Median age at seroconversion
34 (IQR*: 29-38)
Race
White, non Hispanic
n (%)
269 (86.5)
White, Hispanic
19 (6.1)
Black, non-Hispanic
22 (7.1)
Other
Median Follow-up time (years)
* IQR = Interquartile range
1 (0.3)
5.5 (IQR*: 3.1-6.9)
TABLE 3. Median and relative time (RT)* to clinical events for cohort
participants with HIV-1 RNA of 30,000 copies/mL compared with a
0.50, 0.75, 1.00 and 1.25 log reduction in HIV-1 RNA at 9 months
post-seroconversion, using Log-Normal Models (n=311)
0.50-log reduction:
HIV-1 RNA = 9,487
0.75-log reduction:
HIV-1 RNA = 5,335
No. free of
event at set
point, No.
of, events
Median time
to event
(years)
Reference
group HIV-1
RNA=30,000
Median
Time to
event
(years)
Median
Time to
event
(years)
AIDS (defined as
diagnosis of an OI)
(310, 93)
8.4
11.9
1.4 (1.3, 1.6)
14.2
1.7 (1.5, 2.0)
16.9
2.0 (1.6, 2.5)
20.2
2.4 (1.9, 3.2)
CD4+ T-cell count
< 200 cells/mm3
(298, 95)
6.1
8.1
1.3 (1.2, 1.5)
9.2
1.5 (1.3, 1.8)
10.6
1.7 (1.4, 2.1)
12.1
2.0 (1.5, 2.6)
CD4+ T-cell count
< 350 cells/mm3
(263, 133)
3.4
4.5
1.3 (1.2, 1.5)
5.2
1.5 (1.3, 1.8)
5.9
1.7 (1.4, 2.1)
6.8
2.0 (1.6, 2.6)
HIV-1 RNA > 55,000
copies/mL
(149, 59)
2.4
4.3
1.8 (1.4, 2.2)
5.7
2.4 (1.6, 3.4)
7.6
3.1 (1.9, 5.0)
10.1
4.1 (2.3, 7.5)
Clinical indication
for initiation of antiretroviral therapy**
(137, 76)
1.9
2.7
1.4 (1.2, 1.7)
3.3
1.7 (1.3, 2.2)
3.9
2.0 (1.5, 2.9)
4.7
2.4 (1.6, 3.7)
Event
Relative
time
(95% CI)
Relative
time
(95% CI)
1-log reduction:
HIV-1 RNA = 3,000
Median
Time to
event
(years)
Relative
time
(95% CI)
1.25-log reduction:
HIV-1 RNA = 1,687
Median
Time to
event
(years)
Relative
time
(95% CI)
• Relative time is a calculated as the ratio of time to each event for the comparison HIV-1 RNA categories (9487, 5335, 3000, 1687 copies/mL) and
reference group category of 30,000 copies/mL.
** Clinical indication for initiation of antiretroviral therapy defined as HIV-1 RNA > 55,000 copies/mL or CD4+ T-cell count < 350 cells/mm3 or OI
Conclusions

The time to key clinical events in the course of HIV-1
disease progression was significantly extended for those
with initial HIV-1 RNA 0.5-1.25 log10 copies/mL lower
than the reference group

For those with an initial viral load measurement of 3,000
vs. 30,000 copies/mL, the relative time to study
endpoints was approximately double or higher
• This applies to those events which occur earlier in
HIV disease progression, such as a CD4 cell count
below 350 cells/mm3

A viral set point of no more than approximately 10,000
copies/mL is still associated with at least a 30%
extension in the time to clinical events in HIV disease
progression compared to the reference group
Conclusions (continued)

This analysis, based upon natural history data, provides
a context for understanding the expected long term
clinical value of a reduction in viral set point

These findings may be useful in predicting the clinical
benefit of HIV-1 vaccines that are currently in clinical
trials
Limitations

The MACS does not include women.
• Additional analyses should be conducted to determine if relative
times to events of interest are similar in men and women

The MACS participants are predominantly infected with
clade B HIV-1.
• Since the natural history of HIV-1 infection may differ by
infecting clade, it will be important to conduct similar analyses in
populations infected with non-clade B subtypes.

A number of studies have shown the association
between specific HLA alleles and disease resistance or
progression.
• Future analyses of the effect of viral load set point on time to
events in HIV disease progression could account for individual
HLA types.
Acknowledgments

Data in this poster were collected by the Multicenter AIDS
Cohort Study (MACS) with centers (Principal Investigators) at
The Johns Hopkins University Bloomberg School of Public
Health (Joseph B. Margolick, Lisa Jacobson), Howard Brown
Health Center and Northwestern University Medical School
(John Phair), University of California, Los Angeles (Roger
Detels), and University of Pittsburgh (Charles Rinaldo).

The MACS is funded by the National Institute of Allergy and
Infectious Diseases, with additional supplemental funding
from the National Cancer Institute and the National Heart,
Lung and Blood Institute. UO1-AI-35042, 5-MO1-RR-00722
(GCRC), UO1-AI-35043, UO1-AI-37984, UO1-AI-35039,
UO1-AI-35040, UO1-AI-37613, UO1-AI-35041.
Discussion

HIV-1 RNA measurements were relatively similar at 3, 9,
and 15 months after seroconversion (range of geometric
means: 19,815-22,387).

Compared with a viral set point of 30,000 copies/mL, a
viral set point of 3,000 copies/mL was associated with an
additional 2.5 years before CD4 count fell to 350
cells/mm3 - a common threshold for initiating antiretroviral
therapy.

The median time to HIV-1 RNA >= 55,000 copies/mL,
commonly defined as the loss of virological control, was
three times longer for those with viral load set points of
3,000 compared to those with viral load set points of
30,000 copies/mL.
Discussion (continued)

Compared to those with an HIV RNA of 30,000 copies/mL
at set point, an HIV RNA of 10,471 (4.02 log10) would be
required to significantly reduce the hazard of progressing
to a clinical indication to initiate antiretroviral therapy
within 3 years by 25%.
People in sub-Saharan Africa on
antiretroviral treatment as percentage of
those in need, 2002–2005
2002
2003
2004
Source: WHO/UNAIDS (2005). Progress on global access to HIV antiretroviral therapy: An update on “3 by 5.”
2005
Impact of AIDS on life expectancy in five
African countries, 1970–2010
70
65
Botswana
60
55
South Africa
Life
50
expectancy
45
at birth
40
(years)
Swaziland
Zambia
35
30
Zimbabwe
25
20
1970–1975
1980–1985
1990–1995
2000–2005
1975–1980
1985–1990
1995–2000
2005–2010
Source: United Nations Population Division (2004). World Population Prospects: The 2004 Revision, database.
Impact of three scenarios on HIV infection
in sub-Saharan Africa, 2003–2020
5.0
4.0
Number
3.0
of new HIV
infections
2.0
(millions)
1.0
0.0
2003 2005
2010
2015
2020
Year
Baseline
Treatment-centered
Prevention-centered
Comprehensive response
Source: Salomon JA et al. (2005). Integrating HIV prevention and treatment: from slogans to impact
Figure 3. Percentage of Adenovirus 5
neutralizing antibody titers by country
50
45
40
35
Negative
30
18 - 200
25
201-1000
20
> 1000
15
10
5
0
Brazil
Cameroon
Malawi
S. Africa
Thailand
Dominican International
Republic
Sites
US
Worldwide Distribution of HIV-1 Clades (Subtypes)*
A, B, AB, Other
B, Other
B
G
F A
B, Other
B
B, AE
B, BC
G, Other
B, O
B, Other
B, G, Other
C
C
O
A, Other
A
AG
G, Other
Legend
AE, B, Other
All
A,C,D
B, F, Other
C
B
B dominant + Another
B
C, Other
C
B, F
O
A
B, AE
B, C
All
Other
Note:
B, AE, Other
*Dominant clades are bolded above; All regions have multiple clades in their populations
Figure 4. Frequencies of subjects who were
responders on ELISPOT assays in 340 HIVpositive subjects
100
90
80
70
60
50
40
30
20
10
0
Gag
US (n=16)
South Africa (n=48)
Cameroon (n=51)
Nef
Pol1
Pol2
Brazil (n=50)
Malawi (n=40)
Dominican Republic (n=15)
Rev
Tat
Thailand (=77)
Botswana n=43)
Table 1. Ratios of cellular immune response against HIV-1 Gag and Nef proteins, for
heterologous clades versus homologous clades, among 363 HIV-1infected participants.
Immune response ratio, geometric mean (95% CI)
Country, clade comparison
Gag
Nef
New countries
Botswanaa (n = 48)
A vs C
0.51 (0.370.71)
1.04 (0.851.26)
B vs C
0.81 (0.710.93)
1.08 (0.831.40)
b
Cameroon (n = 40)
B vs A
0.84 (0.661.06)
1.18 (1.051.31)
C vs A
0.92 (0.721.19)
0.90 (0.741.11)
Previously reported countries with updated datac
Brazild (n = 57)
A vs B
0.76 (0.640.90)
0.90 (0.751.09)
C vs B
0.82 (0.680.97)
0.95 (0.791.14)
Malawia (n = 54)
A vs C
0.52 (0.420.63)
0.74 (0.590.92)
B vs C
0.69 (0.580.82)
1.00 (0.831.21)
South Africaa (n = 50)
A vs C
0.49 (0.410.58)
0.84 (0.641.09)
B vs C
0.53 (0.420.66)
0.98 (0.841.15)
e
Thailand (n = 77)
B vs A
0.65 (0.510.82)
0.73 (0.590.92)
C vs A
0.54 (0.440.66)
0.92 (0.721.17)
United Statesf (n = 37)
A vs B
0.63 (0.480.81)
0.89 (0.701.12)
C vs B
0.65 (0.540.77)
0.63 (0.420.95)