55th Annual Meeting of the American Association for the Study of Liver Diseases
Viral Liver Disease CME
October 29, 2004 - November 2, 2004, Boston, Massachusetts
This activity is not sanctioned by, nor a part of, the American Association for the Study of Liver Diseases.
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Developments in the Management of Hepatitis B
Disclosures
Daniel Pratt, MD
Introduction
Hepatitis B virus (HBV) is a major healthcare problem around the world. It is estimated that 350-400 million people are
chronically infected.[1,2] Patients with chronic hepatitis B are at increased risk for progression to cirrhosis and end-stage liver
disease and for the development of hepatocellular carcinoma (HCC), including patients who are asymptomatic. Interferon has
been used to treat hepatitis B since the mid-1980s with limited results. The efficacy of pegylated interferon is now being actively
investigated. The development and availability of nucleoside and nucleotide analogues has greatly altered the management of
patients with chronic hepatitis B. Unfortunately, the increased use of these drugs, particularly when used as monotherapy, has
produced mutations that confer viral resistance, much as what was seen in the management of HIV. Investigators have sought
to define these mutations and to examine the role of combination therapy to improve virologic response and reduce viral
resistance.
This report reviews some of the most clinically interesting HBV-related research presented during this year's meeting of the
American Association for the Study of Liver Diseases.
Hepatitis B and the Risk of Developing HCC
It is known that patients with chronic hepatitis B who are hepatitis B e antigen (HBeAg)-positive are at greatest risk for both the
progression of liver disease and the development of HCC.[3] What this implies, but what hasn't been clearly shown, is that the
HBV viral load also correlates with disease progression and the risk of HCC. Chen and colleagues [4] looked at this issue in their
10-year, prospective cohort study of 3464 patients found to be hepatitis B surface antigen (HBsAg)-positive at screening
between 1992 and 1993. Ten years later, 2354 of these patients had either sufficient baseline serum samples or adequate
follow-up information to allow them to be included in a mortality analysis; 1681 patients had both sufficient baseline serum
samples and were willing to undergo rescreening with physical examination, laboratory tests, and liver ultrasound. All of the
patients were placed in 1 of 3 viral load categories on the basis of their viral loads at the time of entry: undetected (< 1.6 x 103
copies/mL), low titer (< 105 copies/mL but >/= 1.6 x 103 copies/mL), and high titer (>/= 105 copies/mL). Liver disease was
characterized as normal, mild, moderate, or severe on the basis of adapted Dionysos criteria. HCC was diagnosed by the
presence of a > 2-cm mass on ultrasound and an alpha-fetoprotein level > 400 ng/mL.
The patients in the high-titer virus group at entry were found to be at a statistically significant greater risk for mortality from
progressive liver disease or HCC than patients with low or undetectable viral loads. Although it did not reach statistical
significance, low viral load also appeared to be associated with an increased risk of mortality from progressive liver disease or
HCC when compared with patients with an undetectable viral load.
This study has potentially significant implications for the management of patients with chronic hepatitis B. There is controversy
regarding whether patients in the immunotolerant stage of HBV infection (patients with high levels of HBV DNA, normal
aminotransferases, and little to no necroinflammatory activity on liver biopsy) should be treated. This study by Chen and
colleagues[4] provides additional weight to the argument that perhaps these patients would benefit from being treated and
highlights the need for a trial to be designed to look at this specific question. The end points of such a study, the progression of
liver disease and the development of HCC, would take many years to assess and will require the enrollment of large numbers of
patients. In addition, the study would need to use multiple anti-HBV agents to prevent the development of viral resistance.
Hopefully, studies, such as this one by Chen and colleagues,[4] will provide the impetus for such future investigation.
Prevention of Hepatitis B
The use of passive and active immunity to reduce the risk of vertical transmission of hepatitis B is well accepted in clinical
practice.[5] Hepatitis B immunoglobulin (HBIg), given at the time of birth in combination with 3 doses of the recombinant hepatitis
B vaccine given over the first 6 months of life, has proven to be as much as 95% effective in preventing vertical transmission.[6]
However, the risk of vertical transmission of hepatitis B increases as the mother's viral load increases. In one series of mothers
with high viral loads (defined as HBV DNA >/= 1.2 x 109 copies/mL), this risk was as high as 28%.[7] It stands to reason that if the
mother's viral load could be reduced at the time of birth, the risk of vertical transmission could also be reduced. This is exactly
what Xu and colleagues[8] examined with a well-structured, multicenter, randomized, double-blind, placebo-controlled study
carried out at centers in China and the Philippines.
Mothers chronically infected with hepatitis B (HBsAg-positive) and with high HBV viral loads (defined as a serum HBV DNA >
1000 mEq/mL) were enrolled. One hundred fourteen mothers completed the study; 56 mothers received lamivudine, 100 mg a
day, beginning at the 32nd week of gestation and continuing until 4 weeks post partum. The control group of mothers (n = 59)
received placebo. All of the infants received standard prophylaxis (HBIg within 24 hours of birth and vaccination with the
recombinant HBV vaccine; 3 injections over the first 6 months of life). The primary end point of the study was HBsAg positivity in
the infants at 1 year. Secondary end points were hepatitis B surface antibody (HBsAb) positivity and HBV DNA positivity in the
infants at 1 year.
Not surprisingly, the mothers treated with lamivudine were more likely (98%) to have a reduction in their viral loads to < 1000
mEq/mL than the controls (31%). This reduction in viral load translated into improved outcomes for the infants of mothers
receiving lamivudine. They had a lower likelihood of being HBsAg-positive at 1 year of age (18% vs 39%; P = .014) or to be
viremic (20% vs 46%; P = .003). Infants also had a greater chance of being HBsAb-positive at 1 year of age (84% vs 61%; P =
.008). There was no difference seen in adverse events between the treatment and control groups in either the mothers or the
infants.
Although this study had some issues with patient dropout, it nonetheless strongly suggests that the use of lamivudine in the third
trimester of pregnancy in mothers with high HBV viral loads is effective in reducing the risk of vertical transmission beyond what
can be achieved with passive and active immunization. In addition, this therapy is safe for both the mother and the infant. While
we await additional trials, lamivudine* should be considered for use in the third trimester in those mothers infected with chronic
hepatitis B at greatest risk for passing the infection on to their infants -- ie, those with high viral loads.
New and Old Therapies for Hepatitis B
Entecavir, a carbocyclic analogue of 2'-deoxyguanosine, is a potent and selective inhibitor of HBV polymerase. Rosmawati and
colleagues[9] reported the results of a phase 3 trial comparing entecavir, .5 mg a day, with lamivudine, 100 mg a day, for 48
weeks in patients with HBeAg-positive chronic hepatitis B. The investigators chose to pay particular attention to those patients
with low-baseline alanine aminotransferase (ALT) levels, defined as < 2.6 times the upper limit of normal. The reason for this
focus was a previously completed phase 2 trial that suggested that entecavir may be as effective in patients with low-baseline
ALT as in those with more elevated ALT. This was of interest because patients with normal or near-normal ALT levels at
baseline respond less well to interferon or lamivudine than do patients with elevated ALT. The investigators did not explain why
the threshold value of 2.6 times the upper limit of normal was chosen for this particular analysis. The results showed that in
those patients with a baseline ALT < 2.6 times the upper limit of normal, entecavir produced a mean log reduction in the HBV
DNA of 6.79 at 48 weeks compared with a 4.85 log reduction for lamivudine (P < .0001). In those patients with a baseline ALT of
>/= 2.6 times the upper limit of normal, entecavir produced a mean log reduction in the HBV DNA of 7.18 at 48 weeks compared
with a 6.15 log reduction for lamivudine (P < .0001). Entecavir was much more likely to suppress the HBV DNA to < 400
copies/mL by polymerase chain reaction at week 48. No data were provided on HBeAg loss or seroconversion.
In a phase 1/2 clinical trial, clevudine, an L-nucleoside, was shown to have potent anti-HBV activity over a 12-week period. Lee
and colleagues[10] examined the safety and antiviral activity of clevudine, 30 mg a day, in 21 patients with HBeAg-positive
chronic hepatitis B over 24 weeks at 7 sites in South Korea. The results shown in Table 1 suggest that clevudine has excellent
anti-HBV activity with increased benefit at 24 weeks compared with 12 weeks. There was no viral breakthrough reported.
Table 1. Viral Suppression and Normalization of ALT
End Point
Week 12 Week 24
Log reduction in HBV DNA
4.05
4.64
HBV DNA < 4700 copies/mL
59%
82%
HBV DNA < 400 copies/mL
24%
59%
Normalization of ALT
47%
76%
HBeAg loss
12%
24%
ALT = alanine aminotransferase; HBeAg = hepatitis B e antigen
Marcellin and colleagues[11] reported the 144-week data in a long-term study of adefovir, 10 mg a day, in patients with HBeAgpositive chronic hepatitis B. Eighty-four patients were followed through the 144 weeks. These patients enjoyed increasing rates
of HBeAg seroconversion (12% at 48 weeks, 29% at 96 weeks, and 43% at 144 weeks), HBV DNA suppression defined as <
1000 copies/mL (28% at 48 weeks, 45% at 96 weeks, and 56% at 144 weeks), and normalization of ALT.
Other important findings included the low resistance rate at 144 weeks (3.1%) and the absence of any renal dysfunction in
patients followed through the 144 weeks. This study shows that adefovir can be used safely for an extended period of time with
increasing efficacy. The most desired end point of any treatment for HBeAg-positive chronic hepatitis B is e-antigen
seroconversion. Treatment with any noninterferon therapy should be continued until this occurs. This study shows that although
the rate of seroconversion at 48 weeks is only 12%, the rate increases over time at a rate of 12% to 15% per year of therapy. It
is conceivable that all of the treated patients might eventually achieve seroconversion, assuming that resistance has not
developed. This is further support for the use of multidrug regimens to prevent resistance while awaiting the development of
seroconversion.
Combination Therapies for Chronic Hepatitis B
Up until this point, combination therapies for HBV have not been shown to improve virologic response. Specific therapies that
have been examined include lamivudine + LdT (telbivudine) and adefovir + lamivudine. However, in a study presented during
this year's meeting, Lau and colleagues[12] evaluated the efficacy of adefovir + emtricitabine. Thirty treatment-naive, HBeAgpositive patients with serum ALT > 1.3 times the upper limit of normal were randomized to either adefovir (10 mg a day) plus
emtricitabine (200 mg a day) or adefovir (10 mg a day) plus placebo for 48 weeks. Combination therapy produced a median
log10 reduction of 3.14 vs 2.16 for adefovir alone (P = .004) at 24 weeks and 3.48 vs 2.22 (P = .036) at 48 weeks. There was no
difference in HBeAg seroconversion between the groups. Larger studies will be required to determine whether there is a
difference in seroconversion. This was the first time that a combination therapy regimen showed improved virologic response
over monotherapy. It is important to keep in mind that the primary benefit of combination therapy will likely not be an improved
virologic response, but rather a decreased rate of viral resistance.
There were a number of studies looking at the combination of pegylated interferon* and lamivudine. Piratvisuth and
colleagues[13] reported the results from a study comparing pegylated interferon alfa-2a, 180 mcg/week, plus lamivudine, 100
mg/day (n = 179), with pegylated interferon plus placebo (n = 177), and lamivudine alone (n = 181) in HBeAg-negative chronic
hepatitis B. All groups received 48 weeks of treatment and were followed for an additional 24 weeks. The results are shown in
Table 2.
Table 2. Pegylated Interferon Alfa-2a ± Lamivudine vs Lamivudine Alone in HBeAg-Negative Chronic Hepatitis B
Week 72
Peg IFN + Peg IFN +
P Value (Peg IFN vs LAM/
Placebo
LAM
LAM Peg IFN + LAM vs LAM)
ALT normalization
59%
60%
44%
.004/.003
HBV DNA < 20,000 copies/mL
43%
44%
29%
.007/.003
4.00%
2.80%
0%
.007
3%
2%
0%
.029
HBsAg loss
HBsAg seroconversion
ALT = alanine aminotransferase; HBV = hepatitis B virus; HBeAg = hepatitis B e antigen; Peg IFN = pegylated interferon; LAM =
lamivudine; HBsAg = hepatitis B surface antigen
Patients receiving pegylated interferon alfa-2a, with or without lamivudine, had statistically better results for each of the
measured end points than those receiving lamivudine alone. The investigators also noted that the use of pegylated interferon
alfa-2a, with or without lamivudine, had on-therapy ALT elevations and that there was a significant association between a
marked on-therapy elevation of the ALT (defined as an ALT level > 10 times the upper limit of normal) and a sustained ALT
normalization. These ALT elevations were not associated with serious safety issues in the majority of patients -- no patients
experienced hepatic decompensation and no patient was withdrawn from therapy. These data suggest that pegylated interferon
alfa-2a has efficacy in patients with HBeAg-negative chronic hepatitis B and that the addition of lamivudine adds little benefit. No
resistance data were provided to indicate whether the combination therapy protected against the development of lamivudine
resistance.
The same study group examined predictors of response in these patients (HBeAg-negative chronic hepatitis B).[14] They found
that a low-baseline HBV DNA and a high-baseline ALT level were predictive of response -- the exact positive predictors
described in patients with HBeAg-positive chronic hepatitis. It was also found that patients with genotype D disease did better
with the combination of pegylated interferon alfa-2a and lamivudine than with pegylated interferon alfa-2a alone -- a finding not
seen with genotypes B or C. However, the investigators cautioned that the small numbers of subjects involved (with genotype D)
make it necessary to confirm these data.
Lau and colleagues[15] compared the efficacy of pegylated interferon alfa-2a 180 mcg/week plus lamivudine 100 mg/day (n =
271); pegylated interferon alfa-2a (180 mcg/week) + placebo (n = 271); and lamivudine 100 mg/day (n = 272), in patients with
HBeAg-positive chronic hepatitis B. The duration of therapy was 48 weeks with a 24-week follow-up. The results are shown in
Table 3.
Table 3. Pegylated Interferon Alfa-2a ± Lamivudine vs Lamivudine in HBeAg-Positive Chronic Hepatitis B
End Points
Peg-IFN + Peg-IFN +
P Value (Peg-IFN + LAM vs LAM/
LAM
Placebo LAM
Peg-IFN vs LAM)
ALT normalization
39%
41%
28%
.006/.002
HBV DNA <
100,000 copies/mL
34%
32%
22%
.003/.012
HBeAg seroconversion
27%
32%
19%
.023/< .001
ALT = alanine aminotransferase; HBV = hepatitis B virus; HBeAg = hepatitis B e antigen; Peg-IFN = pegylated interferon; LAM =
lamivudine
The use of pegylated interferon for 48 weeks provided excellent results in this group of HBeAg-positive chronic hepatitis B
patients, and was well tolerated. The 48-week duration is longer than the 16- to 24-week duration typically used with standard
interferon alfa-2a and -2b. Lamivudine added no additional benefit. No resistance data were provided.
Janssen and colleagues[16] studied the combination of pegylated interferon alfa-2b (100 mcg/week for 32 weeks, then 50
mcg/week for 20 weeks) in combination with lamivudine 100 mg/day (n = 130) or placebo (n = 136) in HBeAg-positive chronic
hepatitis B. Patients were followed for an additional 26 weeks of treatment. Seven percent of patients treated with pegylated
interferon, with or without lamivudine, were HBsAg-negative at the end of follow-up. Patients with genotype A disease were
most likely to have HBsAg loss (14%), whereas those who were genotype D were least likely to achieve HBsAg loss (2%). None
of the patients, including those with viral genotype D, seemed to derive any benefit from the combination of pegylated interferon
and ribavirin. No resistance data were provided.
On the basis of these studies, pegylated interferon looks promising in both HBeAg-positive and HBeAg-negative chronic
hepatitis B, particularly for those patients with low-baseline HBV DNA and high-baseline ALT levels. The optimal duration of
treatment appears to be at least 1 year, particularly in the HBeAg-negative patients. Lamivudine appears to add no benefit,
except perhaps in the subset of patients with genotype D disease -- but this finding will require confirmation.
Drug Resistance in Hepatitis B
HBV resistance to lamivudine occurs at a rate of 15% to 20% per year of use. There are 4 well-described, major mutational
patterns that confer resistance: L180M + M240V (seen in about 60% of patients), V173L + L180M + M204V, M204I, and L180M
+ M204I.[17] All of these patterns include either M240V or M204I, the mutations that affect the YMDD site. All confer high levels of
resistance to lamivudine.
Delaney and colleagues[17] aimed to look at the cross-resistance profiles of various anti-HBV agents against each of the 4
lamivudine-resistant mutational patterns. The investigators did this by producing cell lines that expressed wild-type or
lamivudine-resistant HBV variants. The anti-HBV compounds tested included the L-nucleosides (lamivudine, emtricitabine,*
telbivudine,* L-dC,* L-dA,* and clevudine*), the acyclic phosphonate nucleotides (adefovir, tenofovir,* and alamifovir*),
entecavir,* and DXG* (dioxolane guanosine). All of the patterns of lamivudine resistance conferred a high degree of resistance
to all of the L-nucleosides. The acyclic phosphonate nucleotides all maintained efficacy against all of the mutational patterns.
Entecavir and DXG fell in between, with varying levels of resistance. This study suggests that in the presence of lamivudine
resistance, none of the L-nucleosides will be effective in suppressing viremia. The acyclic phosphonate nucleotides will maintain
their efficacy in the presence of lamivudine resistance. Entecavir is an interesting story. Although the lamivudine mutations all
had resistance to entecavir in vitro, entecavir effectively suppressed viremia in a phase 3 study of this drug in lamivudine
refractory, HBeAg-positive patients.[18]
Compared with lamivudine, adefovir resistance occurs in only a small percentage of patients (about 3% to 4% at 3 years). Two
mutations have been identified in the reverse transcriptase of patients with adefovir resistance -- A181V and N236T.[19] Locarnini
and colleagues[20] aimed to further characterize the effects of these mutations with an in vitro assay. Using site-directed
mutagenesis, they produced mutant HBV constructs with the A181V and N236T mutations in both wild-type HBV and in precore
mutant HBV, transduced into HepG2 cells, and then exposed them to different concentrations of lamivudine, adefovir, and
tenofovir to assess their resistance profiles. The investigators found that the mutations that conferred resistance to adefovir
caused only small decreases in drug sensitivity. Unlike the rapid and complete breakthrough seen with lamivudine, there is a
slow rise in the HBV DNA in patients who develop adefovir resistance, something described nicely by Dr. Locarnini during the
presentation of this study as "virologic creep." The reason for the "creep" is explained by the small decreases in drug sensitivity
to adefovir seen with either of the described mutations, in contrast to the dramatic decrease in sensitivity seen with the YMDD
mutants in lamivudine-resistant patients. It is important and reassuring to note that mutants associated with adefovir resistance
remain relatively sensitive to lamivudine (and presumably all L-nucleosides) and tenofovir.
Entecavir has demonstrated efficacy in the treatment of "naive HBV" and in lamivudine-refractory HBV. In a phase 2 trial of
entecavir, 2 patients developed virologic rebound. Two groups studied these patients to better understand the mutations
involved.[21,22] Two classes of entecavir resistance were seen: M250V and T184G + S202I. Of interest, the entecavir resistance
only developed in patients with pre-existing lamivudine-resistant mutations. During his presentation of his study results, Dr.
Tenney[22] reported that a small percentage of patients previously naive to all therapies and on entecavir preselected for the
lamivudine-resistant mutations, even in the absence of prior treatment with lamivudine.
What are we to make of these findings? Resistance has been reported with every new HBV therapy except pegylated interferon.
The lesson to be learned is that monotherapy with any of the noninterferon agents runs the risk of producing viral resistance,
particularly in those patients who will require long-term therapy. If a single agent will be used, it should not be lamivudine, given
the high likelihood of resistance developing rapidly and the possibility that lamivudine resistance may predispose to the
development of entecavir resistance.
Concluding Remarks
The management of hepatitis B will continue to be a challenge. The risk of disease progression and HCC can be tied to the
serum viral load, making it easy to identify those patients at greatest risk. What should be done for these patients remains a
point of controversy. The availability of newer agents (lamivudine) has made it possible to decrease the risk of perinatal
transmission of HBV in those women at greatest risk for passing on the disease. Newer agents that are moving through the
evaluation pipeline (entecavir and clevudine) will be welcome additions to our growing anti-HBV armamentarium. The long-term
data on adefovir are quite promising: There is increasing efficacy with low resistance and good safety data. Pegylated interferon,
both alfa-2a and alfa-2b, are proving to be more effective therapies for hepatitis B than their nonpegylated predecessors, and
there is no risk of developing viral resistance. They appear most beneficial in patients with a baseline elevated ALT and low
HBV DNA. The duration of treatment should be at least 1 year in both HBeAg-positive and HBeAg-negative patients.
Lamivudine has not been shown to provide any additive benefit to pegylated interferon. Viral resistance is a growing problem,
and the specific mutations that have been reported have been fully categorized. We now need to find a way to prevent
resistance from developing. The role of combination therapy, even at the onset of treatment, needs to be further investigated.
*The US Food and Drug Administration has not approved this medication for this use.
This program was supported by an independent educational grant from Gilead.
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Hepatitis C -- Current State of the Art and Future Directions
Disclosures
David Bernstein, MD
Introduction
Hepatitis C, a common blood-borne infection and a frequent reason for visitation to a physician's office, was a major topic of
discussion at the recent annual meeting of the American Association for the Study of Liver Diseases (AASLD), held in Boston,
Massachusetts, October 30-November 2, 2004.
The current state-of-the-art treatment for previously untreated patients with chronic hepatitis C infection is a once-weekly
injection of pegylated interferon in combination with oral ribavirin. Although initially thought to be an asymptomatic disease,
numerous studies have now shown that hepatitis C adversely affects patients' quality of life.
The topics of discussion regarding hepatitis C presented at this year's meeting concerned the prevalence and natural history of
this viral infection, the treatment of acute hepatitis C, the treatment of African-American populations infected with hepatitis C, the
appropriate treatment duration for infection, the treatment of the patient infected with genotype 2 and 3 disease, the re-treatment
of nonresponders to standard interferon therapy, and new therapies for the treatment of hepatitis C infection.
This report addresses key highlights in these topical issues, with an emphasis on implications for the treating physician.
Prevalence and Natural History
Trends in Hepatitis C Prevalence in the United States
The Centers for Disease Control and Prevention (CDC)[1] reported on the prevalence of hepatitis C infection derived from data in
the National Health and Nutrition Examination Survey (NHANES), which was conducted during 1999-2002 in 15,079
noninstitutionalized, nonmilitary personnel. The results were then compared with those from a similar survey performed 10 years
ago.
They found the prevalence of anti-hepatitis C virus (HCV) antibody to be 1.6%, corresponding to 3.8 million people. The
prevalence was 2.1% in men and 1.1% in women. Black individuals had an anti-HCV prevalence rate of 3.0%, which was higher
than the rates seen in white individuals (1.5%) and Mexican-American individuals (1.3%). Of all individuals infected with HCV,
69.9% were between the ages of 35 and 54 years. Prevalence was highest among those aged 45-49 years, with 7.1% of men
and 2.3% of women infected in this group. Black men aged 45-49 years had an astounding prevalence rate (anti-HCV-positive)
of 17.9%. Individuals with a history of injection drug use had a disease prevalence rate of 57.3%.
The study authors compared these data with data from the NHANES III survey performed 10 years ago. They found that the
overall incidence of hepatitis C antibody prevalence has not changed over the past 10 years, but that the peak age-specific
disease prevalence has increased from the group aged 35-39 years as found a decade ago, to 45-49 years in the current
NHANES. These data are consistent with a past epidemic of acute hepatitis C that affected a large cohort of people. One of the
major shortcomings of this study is that it reports on the prevalence of the hepatitis C antibody, which may indicate previous
exposure or active disease. This study does not report on disease prevalence, as prevalence of hepatitis C infection is defined
by the presence of hepatitis C viral RNA in serum. Only 148 of the 15,079 participants had serum available for hepatitis C viral
RNA testing, making any statements regarding disease prevalence, and not potential exposure to the disease, invalid.
HCV Prevalence Among Liver Transplant Surgeons
The prevalence of hepatitis C among physicians remains undetermined. Because hepatitis C is the most common indication for
liver transplantation, it seems reasonable to assume that liver transplant surgeons would be expected to be at high risk for
acquiring the disease.
Thorburn and colleagues,[2] in an anonymous survey of 117 liver transplant surgeons who attended the 9th Congress of the
International Liver Transplantation Society Meeting in Barcelona, Spain, in June 2003, determined that the incidence of hepatitis
C infection in this group was 0.8%. The reported prevalence of hepatitis C infection among the transplant recipients in this group
was 31% to 40%. Based on these findings, the risk of hepatitis C transmission to transplant surgeons is reassuringly low,
despite the particular risks associated with their occupation.
Natural History of Chronic Hepatitis C Among Plasma Donors
The natural history of hepatitis C infection is difficult to assess because of the inability to determine the initial exposure to the
disease. Ferenci and colleagues[3] reported on the Austrian experience following several outbreaks of hepatitis C infection in
plasmapheresis centers in Austria in the 1970s and 1980s; 435 individuals have been identified as having contracted hepatitis C
at these centers. All patients were infected with genotype 1 disease; 39 are women and 396 are men. The mean age of infection
was 22 years. The mean follow-up in this study was 27 years. Nine of the 435 individuals (2.1%) have died of liver disease,
including 1 following a liver transplantation. Fifteen subjects (3.4%) developed hepatocellular carcinoma; 22 subjects (5.1%)
underwent liver transplantation; and 93 individuals (21.4%) have compensated cirrhosis. A total of 110 (25.3%) noncirrhotic
patients were nonresponders to antiviral therapy. Thirty-one subjects (9%) cleared the virus either spontaneously (3 people) or
with antiviral therapy (28 people). The study authors concluded that within 27 years of exposure, 29.7% of the plasma donors
developed advanced liver disease, with an overall mortality rate of 2.1%. These data underscore the progressive nature of this
disease.
HCV Genotype 3a
The origin and worldwide spread of disease is always fascinating to those in the medical field. Morice and colleagues [4] reported
on the worldwide spread of HCV genotype 3a disease, using nucleotide sequencing of the nonstructural 5B component of the
hepatitis C genome. It is believed that genotype 3a probably originated in the Indian subcontinent and/or Southeast Asia, and
has spread to the rest of the world among intravenous drug users. This study evaluated samples from 93 patients infected with
genotype 3a from around the globe.
These investigators found that the phylogenetic tree topologies showed no specific clustering according to the continent or area
of origin, suggesting a homogeneous spread of genotype 3a infection, and small, noninclusive clusters of viral sequences from
South America, California, or Australia were noted. These data are consistent with the concept that genotype 3a infection had a
common origin and that genetic diversification may occur among local areas of infection.
Impact of Marijuana on Fibrosis Progression in Hepatitis C
Most hepatitis C experts agree that factors such as alcohol intake, coinfection with either hepatitis B or the human
immunodeficiency virus, and age at infection may lead to the development of significant fibrosis. Other factors remain elusive
and not proven. Of particular interest is the effect of Cannabis sativa, or marijuana, on disease progression. Many patients use
marijuana for pleasure or to combat complaints of nausea associated with antiviral therapy. Marijuana is known to exert its
effects via the CB1 and CB2 receptors. An upregulation of CB1 receptors has been found to be present in cirrhosis.
Hezode and colleagues[5] investigated the effects of marijuana use on the development of fibrosis in 211 consecutive untreated
patients with chronic hepatitis C infection. Forty-nine percent of patients admitted to marijuana use. For purposes of the study,
marijuana cigarette use was classified into the following 3 categories: (1) nonsmokers; (2) occasional smokers (< 1 cigarette per
day); and (3) daily smokers (at least 1 daily marijuana cigarette).
By both univariate and multivariate analyses, daily marijuana smoking was found to be associated with the development of
significant hepatic fibrosis. Thus, this study reports a strong association between daily marijuana use and fibrosis progression;
the underlying mechanism needs to be further determined, although current data would suggest a role in the upregulation of the
CB1 receptor. These findings should encourage physicians to advise their patients with hepatitis C infection to avoid marijuana
use. Further studies regarding this important and controversial topic need to be addressed.
Hepatitis C and Sleep Disorders
Hepatitis C has been previously shown to adversely affect patients' quality of life. The prevalence of sleep disorders and fatigue
in 59 patients with chronic hepatitis C was addressed by Carlson and colleagues. [6]
Patients with hepatitis C were found to have an increased incidence of fatigue vs normal historical controls. The majority of
patients with hepatitis C (64%) were found to be "poor sleepers," as defined by a Pittsburgh Sleep Quality Index score of greater
than 5. With respect to the presence of sleep disorders and fatigue, no difference was noted between men and women or
between patients with and without cirrhosis. However, weekly use of sleeping medications was reported in 33% of patients
without cirrhosis and in 9.7% of those with cirrhosis.
The study authors concluded that patients with chronic hepatitis C infection suffer from poor quality of sleep, regardless of their
disease stage, and that fatigue is significantly correlated to poor sleep quality.
Acute Hepatitis C
Acute hepatitis C is not commonly seen in clinical practice; therefore, there is a paucity of well-designed, randomized, controlled
trials for the treatment of this patient group. Approximately 15% to 30% of patients with acute hepatitis C will spontaneously
clear the infection, whereas the remainder of patients will develop chronic disease. Although most clinicians agree that acute
hepatitis C should be treated, when therapy should be initiated, how long it should be given, and which therapy to use remain
unclear. Two studies presented during this year's AASLD meeting evaluated 3-month regimens of pegylated interferon for the
treatment of acute hepatitis C.
Kamal and colleagues[7] compared the use of once-weekly pegylated interferon alfa-2b vs 3 times weekly interferon alfa-2b plus
ribavirin in 68 patients acutely infected with either hepatitis C genotype 1 or 4. Treatment was randomized to begin 8 weeks, 12
weeks, or 20 weeks after presumed disease exposure. Patients were treated for an initial 12 weeks of therapy, and if a virologic
response was not achieved at this point, therapy was continued for an additional 12 weeks. The primary end point of therapy
was an undetectable HCV-RNA at 24 weeks after the end of therapy; this was termed a sustained viral response. Seven
patients (10%) had a spontaneous clearance of virus without treatment. The sustained viral response rates for the groups
receiving pegylated interferon monotherapy initiated at 8, 12, or 20 weeks were 90%, 90%, and 80%, respectively. The
sustained viral response rates for the groups receiving combination interferon and ribavirin 3 times per week were 63%, 70%,
and 60%, respectively. The study authors concluded that in patients with acute hepatitis C infection, once-weekly pegylated
interferon alfa-2b was better than standard combination interferon plus ribavirin therapy, and that the pegylated interferon was
safer and more cost effective. There appears to be a trend toward higher sustained viral response rates when pegylated
interferon is started earlier after disease exposure, although this difference was not statistically significant. It also appears from
this study that patients with genotype 1 disease require 24 weeks of therapy, whereas those with genotype 4 require only 12
weeks of treatment.
In the second of these studies, Calleri and colleagues[8] evaluated the use of pegylated interferon alfa-2b at a dose of 1.5
mcg/kg weekly for 3 months in 43 patients with acute hepatitis C. Overall, 30 of 43 (69.8%) subjects had a sustained viral
response. When evaluated by genotype, 10 of 16 (62%) patients with genotype 1 and 4 disease had a sustained viral response,
and 11 of 14 (79%) genotype 2 and 3 patients had a sustained viral response. There was a trend toward higher response rates
in men, non-intravenous-drug users, and patients with low levels of virus, although none of these factors were independently
predictive of response. Hepatitis C viral persistence at 4 weeks of therapy was predictive of nonresponse to therapy.
Persistence of Virus Following Successful Therapy
Sustained viral response to hepatitis C therapy is defined as an undetectable serum HCV-RNA 6 months after stopping
treatment, regardless of the therapy used. This definition has become the cornerstone of hepatitis C treatment because its
attainment has a significant impact upon both the patient and the treating physician.
An important study was presented by Radkowski and colleagues[9] during these meeting proceedings that places into question
our definition of response. They evaluated for the presence of hepatitis C viral RNA in either stimulated lymphocytes, cultured
macrophages, or posttreatment liver biopsy samples from 17 sustained viral responders to combination interferon and ribavirin
therapy. HCV-RNA was detectable in the macrophages of 11 (65%) patients and in the lymphocytes of 7 (41%) patients. Three
patients had HCV-RNA detectable in liver tissue. Overall, only 2 of the 17 (12%) sustained viral responders were negative for
the presence of HCV-RNA in all analyzed specimens.
These findings are important because they bring into question the current definition of sustained viral response. These findings
need to be further evaluated in larger series because the persistence of virus may have significant implications on future
disease progression, disease activation, disease transmission, and the development or persistence of hepatic fibrosis.
Treatment of Hepatitis C
Comparison of Pegylated Interferons
The current standard of care for the treatment of chronic hepatitis C infection is a combination of pegylated interferon and
ribavirin. Two types of pegylated interferon, pegylated interferon alfa-2a and pegylated interferon alfa-2b, are approved for use
in the United States. Many investigators have publicly compared these 2 compounds, but to date, all of these comparisons have
been based on opinion, without the benefit of unbiased comparative data. This lack of data renders all comparisons as being
without true scientific merit.
In an effort to compare these 2 interferons, Silva and colleagues [10] compared the pharmacokinetic and pharmacodynamic
properties of pegylated interferon alfa-2a and pegylated interferon alfa-2b in 36 genotype 1 patients during the first 4 weeks of
therapy. (Author's note: The study was presented by Dr. Mark Laughlin, an employee of Schering-Plough, the manufacturer of
pegylated interferon alfa-2b.). Laughlin reported that this study found a significantly greater viral load reduction in the first 4
weeks of therapy in those patients treated with pegylated interferon alfa-2b. While this finding is intriguing, this finding was not
related by the investigators to clinical efficacy, side effects, or quality of life while on therapy. Because pegylated interferon
monotherapy is not used as the standard of care for the treatment of chronic hepatitis C infection, this report offers no statement
regarding the clinical efficacy of either pegylated interferon and should not influence drug selection. A head-to-head comparison
of the 2 pegylated interferons in combination with a controlled ribavirin dose is required to appropriately compare these
medications. Such a trial is underway.
African-American Population
The prevalence of hepatitis C in the African-American population in the United States, is roughly 2-3 times that seen in the white
population in this country. Despite this finding, African-American patients have been underrepresented in the numerous large
published hepatitis C treatment trials. Initial reports indicate that response rates to interferon and ribavirin-based therapies are
lower in African-American individuals than in white or Asian individuals. The factors, such as the high prevalence of genotype 1
disease in this population, behind these differences are uncertain.
Jacobson and colleagues[11] reported on the use of weight-based ribavirin vs flat-dose ribavirin in combination with pegylated
interferon alfa-2b in 387 African-American patients infected with hepatitis C genotype 1. All patients received pegylated
interferon alfa-2b 1.5 mcg/kg weekly. Patients were randomized to either a fixed dose of 800 mg of ribavirin or a weight-based
dosing regimen.* In the weight-based dosing regimen, patients received 800 mg per day if they weighed < 65 kg, 1000 mg of
ribavirin if they weighed between 65 kg and 85 kg, 1200 mg of ribavirin if they weighed between 86 kg and 104 kg, and 1400 mg
of ribavirin if they weighed between 105 kg and 124 kg. Because of the higher dosages of ribavirin, both dose reductions and
hematopoietic growth factors were allowed. In an analysis of patients who had received at least 1 dose of medication, a
sustained viral response was seen in 21% of those in the weight-based dose arm and in 10% of those in the fixed-dose arm.
Anemia, defined as a hemoglobin drop to below 11 g, occurred in 47% of patients in the weight-based dose arm and in 29% of
those in the fixed-dose arm. Dose reductions and growth factor use were greater in the group receiving weight-based dose
ribavirin. While dose reductions and anemia were more common in the group receiving weight-based ribavirin dosing, dose
discontinuation rates were similar in both groups.
The results of this study are very important and support the use of weight-based dosing over fixed dosing of ribavirin in AfricanAmerican patients infected with genotype 1 disease. This study is equally important because it is one of the largest cohorts of
African-American patients studied to date with hepatitis C infection.
Treatment Duration
The current approved treatment for hepatitis C is pegylated interferon plus ribavirin for a total of 48 weeks. Some studies have
suggested that a longer treatment period may be warranted in those patients who have a late documented viral clearance while
on therapy. Currently, a 12-week time point is used to determine the presence of an early viral response; however, many studies
indicate that a 4-week point may also be useful in predicting a response to 48 weeks of therapy.
The TeraVIC-4 study[12] evaluated the treatment of patients whose 4-week on-treatment HCV-RNA was positive, for a total
course of either 48 weeks or 72 weeks of continued therapy.* All patients were treated with pegylated interferon alfa-2a at a
dose of 180 mcg per week plus ribavirin 800 mg per day; 327 patients were included in the analysis, and 90% were genotype 1.
The end-of-treatment response in the group receiving 48 weeks vs the group receiving 72 weeks of therapy, was 61% and 52%,
respectively. The sustained viral response rate in the group receiving 48 weeks vs 72 weeks of therapy was 32% and 46%,
respectively. The relapse rate in the group receiving 48 weeks vs 72 weeks of therapy was 48% and 13%, respectively.
The study authors concluded that the increased duration of therapy in this select population resulted in an increase in sustained
viral response rate and a decrease in the relapse rate. Although this study is interesting and supports longer duration of therapy
in this group of patients, one cannot help but wonder if the ribavirin dose used in this study was too low. Because higher ribavirin
dosages have been shown to decrease relapse rates, perhaps the same effect may have been achieved with higher ribavirin
doses for a treatment period of 48 weeks. Although there were no increased adverse events noted in the group treated for 72
weeks, the investigators do not comment upon the quality of life of these patients during this treatment period.
Berg and colleagues[13] also looked at relapse rates in patients treated for 48 vs 72 weeks with pegylated interferon alfa-2a 180
mcg/week plus ribavirin 800 mg per day. This study focused on the late virologic responder, which was defined as those
patients whose serum HCV-RNA was positive at 12 weeks but became negative at 24 weeks. In this particular population, there
was a significant reduction in relapse rates when treatment was extended to 72 weeks. This study supports a longer duration of
therapy in this patient population. However, as in the TeraVIC-4 study,[12] one cannot help but wonder why a higher dose of
ribavirin was not chosen as the baseline dosage.
Genotype 2 and 3 Disease
Patients infected with HCV genotype 2 and 3 have been shown to have better responses to pegylated interferon and ribavirinbased regimens than those infected with genotype 1. (The response rates of these 2 genotypes are usually reported together.)
Efficacy of treatment. Rizzetto and colleagues[14] reported the results of a subanalysis of 2 previously published studies
assessing the efficacy of pegylated interferon alfa-2a plus ribavirin in the treatment of patients with genotype 2 and 3 infection;
258 patients with genotype 2 disease and 374 patients with genotype 3 disease were included in the analysis. Sustained viral
response rates were found to be higher in genotype 2 patients than in those with genotype 3 disease. The response rates for
genotype 2 patients treated with pegylated interferon alfa-2a 180 mcg weekly plus ribavirin 800 mg per day for 24 weeks with
low and high viral levels were 100% and 84%, respectively. The response rates for genotype 2 patients treated with pegylated
interferon alfa-2a 180 mcg weekly plus ribavirin 1000-1200 mg per day for 24 weeks with low and high viral levels were 82%
and 86%, respectively. The response rates for genotype 2 patients treated with pegylated interferon alfa-2a 180 mcg weekly
plus ribavirin 800 mg per day for 48 weeks with low and high viral levels were 93% and 84%, respectively. The response rates
for genotype 2 patients treated with pegylated interferon alfa-2a 180 mcg weekly plus ribavirin 1000-1200 mg per day for 48
weeks with low and high viral levels were 75% and 77%, respectively.
The response rates for genotype 3 patients treated with pegylated interferon alfa-2a 180 mcg weekly plus ribavirin 800 mg per
day for 24 weeks with low and high viral levels were 75% and 84%, respectively. The response rates for genotype 3 patients
treated with pegylated interferon alfa-2a 180 mcg weekly plus ribavirin 1000-1200 mg per day for 24 weeks with low and high
viral levels were 83% and 76%, respectively. The response rates for genotype 3 patients treated with pegylated interferon alfa2a 180 mcg weekly plus ribavirin 800 mg per day for 48 weeks with low and high viral levels were 83% and 66%, respectively.
The response rates for genotype 3 patients treated with pegylated interferon alfa-2a 180 mcg weekly plus ribavirin 1000-1200
mg per day for 48 weeks with low and high viral levels were 78% and 75%, respectively.
Based on these findings, the study authors concluded that patients with genotype 2 infection responded better than those with
genotype 3. The study authors also concluded that in all groups of patients with genotype 3 disease, a treatment course of lowdose ribavirin plus pegylated interferon for 24 weeks is sufficient. This is a very provocative report because there does appear to
be a difference in response rates between genotype 2 and 3 patients. Further studies need to be performed that include
variables such as viral load, the presence of steatosis, and the presence of fibrosis to better evaluate the response rates of each
individual genotype. This represents an important clinical area in which new information should be obtained.
Duration of treatment. The duration of treatment for patients with genotype 2 and 3 infection also needs to be addressed.
Although most physicians use a treatment duration of 24 weeks in this population, studies are being performed to determine the
ideal length of treatment.
Dalgard and colleagues[15] studied the efficacy of 14-week treatment duration in patients infected with hepatitis C genotypes 2
and 3; 122 previously untreated patients were treated with pegylated interferon alfa-2b 1.5 mcg/kg once weekly plus weightbased ribavirin dosing at 800-1400 mg per day.* Patients who achieved an undetectable HCV-RNA level at weeks 4 and 8 were
continued for a total course of 14 weeks. Those patients who were positive at 8 weeks were treated for a total of 24 weeks; 95
(78%) patients were treated for 14 weeks and the remaining 27 were treated for 24 weeks. The sustained viral response rate
was 90% in the group treated for 14 weeks and 56% in the group treated for 24 weeks. The overall sustained viral response rate
was 82%. The study authors concluded that 14 weeks of therapy is sufficient for those patients with genotype 2 and 3 infection
who have had an early viral response at 4 and 8 weeks.
This finding has wide-reaching implications because it questions both our current accepted time point for early viral response of
12 weeks and our current recommended duration of therapy for genotype 2 and 3 disease. Additional studies in this area must
be performed to validate these findings. As we postulate that there may be a difference in response rates between genotype 2
and 3 infection, it would be nice to learn from these investigators the individual sustained viral response rates of those patients
infected with genotype 2 and 3 disease.
Nonresponders
Re-treatment of patients unresponsive to standard interferon plus ribavirin therapy has been disappointing.
Re-treatment with pegylated interferon-based therapy. Poynard and colleagues[16] reported preliminary results of the EPIC
(Early viral response with Peg-intron/rebetol weight based dosing in previous Interferon/ribavirin HCV treatment failures) trial's
attempts to address the issue of re-treatment of patients previously unresponsive to standard interferon and ribavirin, with
pegylated interferon and ribavirin-based therapy. In this trial, patients are treated with pegylated interferon alfa-2b 1.5 mcg/kg
per week plus a weight-based ribavirin regimen of 800-1400 mg per day.* Data were presented on the early virologic response
in more than 1400 patients enrolled in the trial. Early virologic response was defined as a decrease in HCV-RNA level by greater
than 2 logs from baseline or an undetectable HCV-RNA at 12 weeks of therapy. Based on these criteria, 65% of treated patients
have achieved an early virologic response. The early virologic response in genotype 2/3 patients and genotype 1 patients was
88% and 49%, respectively. Even more interesting is that 40% of patients were HCV-RNA negative at week 12 of therapy.
These data are very preliminary, and we eagerly await the sustained viral response data from this trial.
Re-treatment with consensus interferon. Daily consensus interferon plus ribavirin is another regimen currently being
evaluated for the treatment of patients who have failed to respond to combination interferon and ribavirin therapy.
Kaiser and colleagues[17] reported preliminary data comparing the use of either consensus interferon 18 mcg per day for 4 weeks
followed by 9 mcg per day for 8 weeks, vs the use of consensus interferon 27 mcg per day for 4 weeks followed by 18 mcg per
day for 8 weeks. After this initial 12-week treatment course, all patients received consensus interferon 9 mcg per day plus
weight-based dosing of ribavirin for another 36 weeks.* A total of 120 patients were evaluated; 91% had genotype 1 infection
and 28% had either bridging fibrosis or cirrhosis. The end-of-treatment viral response rates in the group receiving the higherdose consensus interferon vs the lower-dose consensus interferon were 66% and 59%, respectively. The sustained viral
response rates in the group receiving the higher dose consensus interferon vs the lower dose consensus interferon were 44%
and 39%, respectively. Consensus interferon had to be dose reduced in 17% of patients and discontinued in 6%. The most
common reason for dose reduction was thrombocytopenia. There was no difference in the drop-out rates between the 2
treatment arms.
This trial reports the highest sustained viral response rates yet in patients previously unresponsive to interferon and ribavirinbased therapy. Relapse rates in this group, however, still continue to be significant.
Future Therapies
The current standard of care for the treatment of previously untreated hepatitis C infection is once-weekly pegylated interferon
plus ribavirin. These therapies have overall sustained response rates of between 52% and 54%, meaning that approximately
50% of patients do not respond to therapy. Because of these response rates, many new therapies are being evaluated to treat
hepatitis C infection. This year, phase 1/2 data were reported for a new polymerase inhibitor named NM283* and a recombinant
alfa interferon genetically fused to human serum albumin.*[18,19] While preclinical data suggest antiviral synergy for NM283 and
interferon, and phase 1/2 data with the recombinant alfa interferon show a favorable safety profile and biphasic viral decline,
both compounds are early in development and expanded clinical testing is warranted.
Concluding Remarks
The annual meeting of the AASLD brought some interesting topics regarding hepatitis C to the forefront. The CDC NHANES
data showed that the prevalence of the antibody for hepatitis C has remained constant over the past decade, while the cohort of
people with the disease has aged. New advances have also been made in understanding the natural history of the disease.
Although response rates to therapy have improved, we continue to refine our approach to patients with HCV genotypes 2 and 3.
The issue of longer duration of therapy has also been discussed for those patients who do not demonstrate an early virologic
response. Lastly, although many new therapies are being evaluated, they remain in early clinical development. Therefore, the
best approach to maximizing current therapies appears to be improved familiarity with pegylated interferon and ribavirin and
improved management of the adverse events associated with this combination therapy.
*The US Food and Drug Administration has not approved this medication for this use.
Supported by an independent educational grant from Gilead.
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Coinfection With HIV and Hepatitis C or Hepatitis B
Disclosures
Adrian M. Di Bisceglie, MD, FACP
Introduction
Both the hepatitis C virus (HCV) and the human immunodeficiency virus (HIV) are blood-borne viruses; therefore, it is not
unexpected that individuals at risk may become infected with both viral agents. It has been estimated that 10 million individuals
are coinfected with HCV and HIV worldwide (including 300,000 in the United States). The most frequent common source of
infection is through injection drug use. HCV is less readily transmitted by sexual contact than HIV, and both viral agents have
been virtually eliminated from the blood supply in the United States.
It appears that coinfection has significant clinical implications for patients. Because HIV has become more treatable with highly
active antiretroviral therapy (HAART), the mortality due to opportunistic infections and malignancies has decreased markedly.
Recent evidence suggests that progressive liver disease is now the most common cause of death among patients infected with
HIV.[1] Additionally, there is now convincing evidence that HIV infection is associated with significantly more rapidly progressive
liver disease due to hepatitis C.[2] Finally, hepatotoxicity associated with the antiviral agents used in HAART may be more likely
to occur in patients infected with HCV, and may also lead to significant diagnostic confusion.[3]
Epidemiology
Although national and even international estimates have been made regarding the frequency of coinfection (see above), the
precise features of at-risk groups are not clear. Thus, the survey conducted by Ross and colleagues[4] is of considerable interest
in this setting.
During this year's meeting of the American Association for the Study of Liver Diseases (AASLD), these investigators reported on
a survey of 531 individuals admitted over a 1-year period to a residential substance abuse treatment facility in New York City. All
patients admitted to this facility underwent testing for HCV and HIV. The mean age of patients was 32.7 years, and 69% were
men; most were black (59%). Fully 14% of patients were seropositive for anti-HCV, 9.4% for anti-HIV, and 3.6% were
coinfected.
These findings illustrate the importance of routinely testing active injection drug users for both HCV and HIV infection.
Natural History
Impact of HIV on Disease Course in Hepatitis C
The precise impact of HIV infection on disease course in hepatitis is not known, although it has been the focus of many studies
over the last several years. In part, this is because most of the assessments have been cross-sectional in nature rather than
longitudinal. That is, many studies have examined the liver disease status of a group of patients infected with HCV alone, and
compared them with a coinfected group, rather than following events in such patients over a period of time to assess the
outcome.
Between 1997 and 2003, a cohort of several hundred injection drug users was assembled in San Francisco from methadone,
HIV, and liver clinics at 2 inner city hospitals. This cohort has now been followed for several years, and results were reported in
several abstracts presented during this year's meeting proceedings.
The question of whether HIV infection results in more rapid progression of HCV-related liver disease continues to remain
uncertain. A study reported by Monto and colleagues[5] suggests that HIV-HCV coinfected patients have similar rates of death or
cirrhosis compared with HCV monoinfected patients when followed over a period of approximately 4 years. Thus, the rates of
end-stage liver disease were 5% in a cohort of 123 coinfected patients compared with 3% in 105 patients with HCV
monoinfection over a mean follow-up period of 4.2 years. This same cohort of patients was examined with regard to serum
levels of HCV and, indeed, those with coinfection were found to have significantly greater viral levels. [6] Although this
observation has been made previously, this detailed evaluation found that the HCV viral load did not correlate with factors such
as CD4+ lymphocyte count, HIV RNA levels, or the status of therapy for HIV. Instead, viral load was correlated later with
duration of infection (ie, longer duration, higher viral load) in multivariate analysis.
Additional studies conducted in the same cohort of injection drug users evaluated persistence of HCV-RNA on follow-up.[7]
Although HCV-RNA-positive patients in this cohort were not necessarily defined as having acute or chronic HCV infection, some
were initially HCV-RNA-positive but then became HCV-RNA-negative, suggesting the type of viral clearance associated with
acute hepatitis C. Among a cohort of 354 injection drug users (including 186 individuals who were HIV-positive), 25 cleared HCV
RNA. A multivariate analysis was then performed on a number of viral and host factors that might be associated with viral
clearance. It was interesting to note that, again, viral clearance did not seem to be affected by seropositivity for anti-HIV, by the
level of HIV RNA, degree of alcohol consumption, or antiretroviral therapy for HIV. Instead, only younger age at infection and
female sex were identified as predictive factors for viral clearance.
Hepatocellular Carcinoma in HIV-Infected Patients
One complication of advanced liver disease due to HCV infection is development of hepatocellular carcinoma (HCC). It has
been estimated that the lifetime risk of developing HCC from HCV infection is approximately 4%. Furthermore, the annual risk of
developing HCC among patients with cirrhosis due to hepatitis C infection is approximately 1% to 4%. Until now, there has been
very little information on the occurrence of HCC in HCV-HIV coinfected individuals.
Brau and colleagues[8] conducted a retrospective survey of consecutive HCC cases in HIV-seropositive individuals. Between
1999 and 2003, the centers identified 26 patients with HCC. The investigators compared these patients with 70 HIV-negative
controls. The HIV-positive patients were significantly younger (mean age, 53 years vs 62 years) and were more likely to be
infected with hepatitis B virus ([HBV]; 27% vs 4%). It is interesting to note that the proportion of patients infected with HCV was
the same in both groups and that, furthermore, 50% of those with HIV had a history of excessive alcohol consumption compared
with 80% of patients who were HIV-negative. The proportion of patients with potentially curable tumors was similar in both
groups.
Liver-Related Mortality in HIV-Infected Patients
A survey of 59 departments of internal medicine and infectious diseases in France was conducted to study consequences of
HIV-HCV coinfection.[9] Nearly 21,000 HIV-positive patients (in the GERMIVIC cohort study) were included in this survey by
2003. Of this group of patients, 215 died, including 27 deaths associated with end-stage liver disease. Of note, no cases of HCC
were noted in this survey. Further study of these deaths suggested that the patients who died were all injection drug users, were
predominantly male, and that many had consumed alcohol in excess.
Treatment of Hepatitis C
Antiviral therapy for hepatitis C has become well established and commonly used among other healthy patients. Until recently,
however, there has been uncertainty regarding the role of antiviral therapy with pegylated interferon and ribavirin in coinfected
patients. Three large multicenter trials have recently been completed, and their results have now become available. These
investigations include the AACTG 5071 trial and the APRICOT (AIDS PEGASYS Ribavirin International Co-infection Trial )
study.[10,11] With respect to these 2 studies, coinfected patients treated with combination pegylated interferon alfa-2a and
ribavirin* had overall sustained virologic response rates of 27% and 40%, respectively -- lower than that found in monoinfected
patients. It is interesting to note that patients infected with HCV genotypes 2 or 3 had quite high response rates (60% to 70%),
but it was among those patients with HCV genotype 1 infection that response rates were particularly disappointing (15% and
29%, respectively). Clearly, the use of combination pegylated interferon and ribavirin therapy appears to be relatively safe in this
population.
In contrast, a study from Spain presented during this year's AASLD meeting found surprisingly high rates of on-treatment
response among coinfected patients. Camino and colleagues[12] enrolled 366 HIV-positive patients with chronic hepatitis C and
CD4+ counts > 300 cells/mm3 into a single-arm treatment study using pegylated interferon alfa-2a and ribavirin (1000-1200 mg
per day based on body weight).* Overall, they found that 83% of patients achieved an early virologic response (defined as viral
clearance or a reduction of at least 2 logs in serum HCV-RNA by week 12). This response was very much genotype dependent,
and early virologic response rates were 42% for genotype 1 disease, 46% for genotype 4, and 90% for genotypes 2 and 3
together. Ultimately, the rate of sustained virologic response needs to be determined in these patients, but it appears that
complete response rates are possible in coinfected patients, provided they are still immunologically preserved.
The explanation for the lower rates of response for HCV to antiviral therapy in coinfected patients is not completely clear.
Blackard and coworkers[13] studied the presence of HCV replication in peripheral white blood cells of coinfected and
monoinfected patients and found that HCV replication (as assessed by the negative strand of HCV-RNA) was more prevalent in
HIV-infected individuals, suggesting that peripheral blood cells may represent a reservoir of HCV infection that is difficult to
eliminate.
HBV/HIV Coinfection
Just as coinfection with HCV and HIV is relatively common, coinfection with HBV and HIV is a significant clinical and public
health issue as well. The latter may be particularly true in sub-Saharan Africa and in parts of Asia, where HBV is still endemic.
The frequent use of antiviral agents for HIV that have activity against HBV has focused attention on the inadvertent risks of
developing viral resistance. In the United States, several licensed drugs have activity against both HIV and HBV -- lamivudine,
emtricitabine, tenofovir, and adefovir (has activity against HIV only at high doses).* More recently, a drug combination with
tenofovir and emtricitabine has been marketed for HIV.
Sene and colleagues[14] from France examined the impact of HIV infection on HBV by comparing disease characteristics among
a group of 205 coinfected patients with 184 HBV-monoinfected patients. The coinfected group was more frequently seropositive
for hepatitis B e antigen (53% vs 27%), seropositive for antibody to hepatitis delta virus (15.3% vs 5.7%), and more frequently
seropositive for anti-HCV (19.7% vs 3.3%). However, it was interesting to note that the proportion of patients with cirrhosis was
greater in the monoinfected group (17.5% vs 8.5%). Thus, it is not clear at all that coinfection with HIV exacerbates liver disease
due to hepatitis B.
In another study,[15] a group of investigators from Dallas reviewed their experience in treating HBV-HIV coinfected patients and
found that simultaneous administration of tenofovir and lamivudine* appeared to be associated with a greater drop in serum
levels of HBV-DNA than treatment with lamivudine alone.
More studies are needed with larger numbers of patients to fully evaluate the optimal use of these new drugs for HBV in
coinfected patients.
Concluding Remarks
It is evident that a great deal remains to be learned about coinfection with HCV or HBV and HIV; clearly, coinfection represents
a significant public health problem. Clinicians now have a better idea about the epidemiology of coinfection. On balance, it
seems that HIV infection is associated with slightly more severe liver disease due to HCV and perhaps even HBV. What is
certain is that coinfection poses difficulties and complexities for treatment. We have begun the long and arduous process of
establishing a clear role for antiviral therapy against HCV and HBV in patients with HIV infection.
*The US Food and Drug Administration has not approved this medication for this use.
Supported by an independent educational grant from Gilead.
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