HCV-induced liver disease can be progressive, with cirrhosis developing in 20-30% of individuals over a follow-up of 10-20 years.(3) HIV coinfection has been associated with a more rapid progression of liver disease as well as a higher prevalence of cirrhosis.(7,26-28) In individuals with parenterally acquired HCV infection (blood transfusion recipients or IDUs), there is a higher incidence of cirrhosis within the first 15 years of follow-up (15-25% vs 2.6-6.5%, respectively; p < .05) in HIV-positive individuals compared with those who are HIV negative.(29,30) Additionally, the estimated interval from HCV infection to cirrhosis may be significantly shorter in the HIV-infected individuals (7 vs 23 years; p < .001).(29) A recent study compared a cohort of 122 HIV/HCV-coinfected individuals with 122 HIV-negative, HCV-infected patients. HIV seropositivity (p < .0001), alcohol consumption of >50 grams/day (p = .0002), age at infection >25 years (p < .0001), and CD4 lymphocyte counts <200 cells/µL (p <.0001) were associated with an increased rate of liver fibrosis progression.(28) Among the coinfected individuals, alcohol consumption, low CD4 counts, and higher age at HCV infection were independent predictors of fibrosis progression.(28) Although HIV/HCV coinfection results in a more rapid progression of liver disease, its effect on mortality requires further assessment. Some studies have found a higher rate of mortality from liver-related diseases in the coinfected patients,(31,32) yet others have not shown any effect on survival.(33,34)

HCV replication is enhanced in the presence of HIV, resulting in higher serum and liver HCV RNA levels.(30,35-41) Some studies have shown a further increase in HCV RNA levels as immunodeficiency progresses,(37,40,41) yet others have failed to find a correlation between CD4 count and hepatitis C viral load.(36,38,39,42) Similarly, although a decrease in HCV viremia has been reported with successful antiretroviral therapy (ART) and immune restoration,(43) other investigators have noted either no change or a transient increase in HCV replication in this setting.(44,45) Therefore, there are discrepancies in the literature regarding the influence of immunodeficiency on HCV replication. HIV coinfection also may affect hepatitis C viral heterogeneity. In one study, patients with CD4 counts <50 cells/µL demonstrated a marked decrease in HCV nucleotide diversity, despite the lack of a decrease in the number of the HCV quasispecies clones.(46) This observation suggests that, within each quasispecies, clones that replicate efficiently may become predominant when immunological selection is impaired, resulting in faster progression of HCV in some cases.

Treatment of HIV with ART may result in severe hepatotoxicity in a proportion of coinfected patients.(47,48) In a cohort of 141 HIV-positive patients, use of ritonavir and saquinavir resulted in >5-fold increase in serum transaminases in 10% of cases. The risk of hepatotoxicity was associated with pretreatment abnormal liver enzymes as well as coinfection with chronic HCV or HBV (relative risk [RR] 5.0; confidence interval [CI] 1.5-16.9).(47) Similarly, in a recent prospective cohort of 298 patients, the incidence of severe hepatotoxicity was approximately 10%, but this toxicity occurred more frequently with ritonavir compared with other protease inhibitors such as indinavir and nelfinavir.(49) Therefore, ART should be administered cautiously and liver function tests must be followed in all patients, especially those coinfected with HCV or HBV.

Patients with adequately controlled HIV disease (CD4 counts >150-200 cells/µL), compensated liver disease, and chronic hepatitis C on liver biopsy should be evaluated for HCV treatment. Liver biopsy will aid in establishing the diagnosis of chronic HCV as well as identifying individuals at risk of progression of liver disease. These individuals must have no evidence of active opportunistic infection and must be stable on ART.

There is limited information available on the treatment of hepatitis in coinfected individuals. The studies assessing the role of interferon monotherapy in HIV/HCV coinfection are predominantly nonrandomized and uncontrolled (see Table 2). In these studies, the dose of standard interferon has ranged from 1 million units 3 times weekly to 9 million units daily as induction therapy for 6-18 months. The end-of-therapy and sustained (6 months following end of therapy) biochemical and/or virologic response rates are similar to those of treated individuals with chronic HCV alone (23-55% and 0-29%, respectively) (see Table 2).

In a controlled study of 80 coinfected individuals and 27 patients with HCV alone, the rates of sustained response to standard interferon were similar at 22% and 26%, respectively, without any increase in adverse events.(53) Factors associated with interferon response include higher CD4 counts, lower HCV viremia, and genotype 3a.(35,53) Although a decrease in CD4 counts during interferon therapy has been observed, HIV RNA levels remain unchanged.(35) This decline in CD4 counts, however, has occurred in only a small proportion (5%) of individuals in the largest published series.(54) Currently, the combination of interferon and ribavirin is the standard of care for the treatment of chronic HCV. The overall sustained hepatitis C virologic response to combination therapy is approximately 40%.(55) There are only limited reports on the use of interferon and ribavirin combination therapy in patients with HIV coinfection. Studies of this combination to date in subjects who are either interferon naive or who have relapsed or failed to respond to interferon alone have shown 28-31% end-of-treatment and 14-19% sustained virologic response rates.(56,57)

Conjugation of interferon with polyethylene glycol ("pegylation") delays the clearance of the drug, permitting once-weekly dosing. Studies with pegylated interferon ("peginterferon") in individuals with HCV infection alone have been encouraging. A sustained loss of HCV RNA at 6 months following discontinuation of therapy was observed in 39% with pegylated interferon (180 micrograms once weekly) compared with 19% with interferon (6 million units 3 times weekly) following 12 months of therapy.(58) The frequency of adverse events has been similar for both types of interferon. The U.S. Food and Drug Administration (FDA) has approved the use of pegylated interferon alfa-2b (PEG-Intron) or pegylated interferon alfa-2a (Pegasys) with ribavirin as combination therapy for management of HCV. In patients with HCV infection alone, the combination of peginterferon and ribavirin has resulted in a higher overall sustained virologic response (defined as loss of HCV RNA at 24 weeks following cessation of therapy) of 54-56%.(59,60) The final results of several large randomized studies assessing the role of pegylated interferon therapy alone or in combination with ribavirin in coinfected individuals have become available recently. In a nationwide trial of 154 patients in the United States, peginterferon alfa-2a alone resulted in either the loss of HCV RNA or a drop in HCV RNA levels of at least 2 log₁₀ copies/mL in 38% of coinfected patients at 3 months of therapy, and 36% of those who responded at 3 months also had a sustained virologic response assessed by undetectable HCV RNA at 6 months following completion of therapy.(61) The results from a trial evaluating 133 patients revealed that peginterferon alfa-2a and ribavirin combination therapy resulted in a higher sustained virologic response (defined as undetectable HCV RNA at 6 months following discontinuation of therapy) compared with standard interferon and ribavirin combination therapy (27% vs 12%; p = .03).(62) The independent predictors of sustained virologic response included use of peginterferon and ribavirin, an HCV genotype other than type 1, the absence of prior injection drug use, and a detectable level of HIV RNA at entry.(62) Among virologic nonresponders, liver biopsies at week 24 of treatment showed a 36% histologic response.(62) Although severe adverse events were observed more frequently in the peginterferon group, the rates of treatment discontinuation were similar in the 2 groups.(62) Similarly, in the AIDS Pegasys Ribavirin International Coinfection Trial (APRICOT) study of 868 patients, the combination of peginterferon alfa-2a and ribavirin was superior to standard interferon and ribavirin combination therapy (40% vs 12% sustained virologic response rate; p < .0001).(63) As expected, coinfected patients with genotype 1 had lower sustained virologic responses: 29% with peginterferon alfa-2a plus ribavirin, 14% with peginterferon alfa-2a plus placebo, and 7% with interferon alfa-2a plus ribavirin.(63) Based on these results, peginterferon and ribavirin combination therapy should be the first-line treatment in HCV/HIV-coinfected individuals, but overall, the responses are lower than those observed in the HCV-monoinfected population. Given the evolving data, treating HCV in the setting of HIV coinfection should be considered on a case-by-case basis.(64)

Hepatitis A virus (HAV) vaccination is effective and well tolerated. There are conflicting data regarding the course of HAV infection in patients with chronic HCV. Acute liver failure secondary to HAV is uncommon, but can lead to significant mortality and morbidity in the elderly and in patients with chronic liver disease.(65) Vaccination of all average-risk North American patients with chronic HCV may not be cost effective.(65,66) In subgroups of individuals with high prevalence of HAV immunity, such as adults >50 years of age and IDUs, testing for the presence of HAV antibodies prior to vaccination may be more cost effective.(67) The HAV vaccine is efficacious in the HIV-infected population but appears to be more effective early in the course of HIV when CD4 counts are high.(68) The USPHS/IDSA guidelines recommend HAV vaccination of patients with chronic HCV in the setting of HIV coinfection because HAV vaccine is safe in the HIV-infected population; the risk of fulminant hepatitis associated with HAV appears increased in HCV-coinfected patients; and, although immunogenicity is decreased in patients with advanced HIV, two thirds develop a protective antibody response.(21) Additionally, prevaccination testing against HAV antibody is cost effective and is recommended when the prevalence of HAV antibody is expected to exceed 30% (eg, in populations >40 years of age).(21)

HIV coinfection may result in poor response to standard interferon due to high levels of HBV DNA, low transaminase levels, and HIV-induced immunosuppression.(85) Only a few studies with a small sample size have assessed long-term follow-up of patients with HIV/HBV coinfection. In one study, 2 of 5 patients had a sustained response to standard interferon therapy and another 2 patients had a sustained response to an additional course of standard interferon.(86) Therefore, standard interferon therapy in coinfected individuals can be effective, but higher response rates are likely with nucleoside analogues such as lamivudine.

Use of pegylated interferon for treatment of chronic HBV recently was approved by the FDA. In HBV-monoinfected, HBeAg-positive individuals, pegylated interferon is more effective than standard interferon therapy with combined response (HBeAg loss, HBV DNA suppression, and ALT normalization) twice that achieved with standard interferon.(87,88) Pegylated interferon therapy also is more effective in HBeAg-positive and HBeAg-negative patients compared with lamivudine.(89) The addition of lamivudine to pegylated interferon does not seem to improve HBV response rates.(89) Although the results of HBV therapy with pegylated interferon in the HIV/HBV-coinfected population are not yet known, pegylated interferon may be used in individuals not requiring ART.(90)

Lamivudine inhibits both RNA- and DNA-dependent DNA polymerase activities of both HBV and HIV reverse transcriptase.(91) In HBV-infected individuals, a 1-year course of lamivudine results in a 16-18% rate of HBeAg seroconversion (loss of HBeAg with detection of HBe antibody), an efficacy that is similar to that of a 4-month course of nonpegylated interferon.(92) HBV replication is inhibited by lamivudine in up to 87% of HIV/HBV-coinfected patients.(93) Although the antiviral response is durable in most patients, very few patients actually clear HBsAg and most have detectable serum HBV DNA by PCR.(92) Lamivudine therapy can result in drug-resistant HBV mutants (tyrosine-methionine-aspartate-aspartate [YMDD] motif mutation) leading to an increase in serum ALT and HBV DNA levels in about 15-25% of cases after 1 year of therapy and in about 49% after 3 years of treatment.(92) In the HIV-coinfected population, the development of lamivudine resistance may be more frequent (approximately 90% after 4 years of therapy) and can be associated with hepatitis flares.(94,95,96) Additionally, severe hepatitis flares have been observed with the discontinuation of lamivudine.(94)

Adefovir, a nucleotide analogue and potent inhibitor of HBV infection, also has been approved by the FDA for treatment of chronic HBV. Adverse effects associated with use of adefovir include renal failure and acute worsening of HBV after discontinuation of therapy. Adefovir may be effective for the treatment of lamivudine-resistant HBV in individuals coinfected with HIV. In a cohort of 35 HIV/HBV-coinfected patients receiving lamivudine as part of their antiretroviral regimen who added adefovir at a dosage of 10 mg daily, adefovir therapy decreased HBV DNA levels, and 2 of 31 patients who completed 48 weeks of therapy underwent HBeAg seroconversion. Adefovir was well tolerated but resulted in a transient increase in ALT levels in 15 patients.(97) These results are similar to those achieved in HBV-monoinfected individuals. The incidence of adefovir resistance is low and an N-to-T mutation at codon rt236 is selected in approximately 2% of HBV-infected individuals after 2 years of adefovir therapy.(90) In a different study, resistance mutations rtN236T and rtA181V were identified in 5.9% of HBeAg-negative monoinfected patients after 2 years of adefovir therapy.(98) In a recent study of 43 HBV-monoinfected individuals, patients with adefovir resistance were more likely to have been switched from lamivudine to adefovir monotherapy, to be older, and to be infected with HBV genotype D.(99) Adefovir-resistant HBV is sensitive to lamivudine, emtricitabine, and entecavir (ETV).(90)

Tenofovir disoproxil fumarate (TDF) is an acyclic nucleotide reverse transcriptase inhibitor that is effective against wild-type and most nucleoside-resistant HIV. Additionally, TDF has shown activity against wild-type and lamivudine-resistant HBV.(100-102) An ongoing randomized, double-blind study is designed to compare the safety and efficacy of an antiretroviral regimen containing both TDF and lamivudine (with efavirenz) vs a regimen containing lamivudine (with stavudine and efavirenz) in 600 HIV/HBV-coinfected, treatment-naive patients. A preliminary report from this study compared 5 HBV-coinfected patients receiving both TDF and lamivudine with 6 patients receiving lamivudine alone.(103) Patients receiving TDF and lamivudine combination therapy had a greater decrease in HBV DNA levels compared with those receiving lamivudine alone (the mean change in log₁₀ HBV DNA levels was 4.70 copies/mL vs 2.95 copies/mL, respectively), but the analysis of this small group did not show statistical significance. Combination of TDF with lamivudine also appeared to be more effective in suppressing development of lamivudine resistance. Additionally, simultaneous administration of lamivudine and TDF in HBV/HIV coinfected patients appears to be associated with a decrease in HBV DNA viral load of greater magnitudes than those observed with lamivudine alone or with lamivudine followed by lamivudine and TDF in combination.(104) In a randomized controlled noninferiority trial comparing TDF with adefovir, the mean log₁₀ HBV DNA change from baseline to week 48 was -4.44 copies/mL on TDF and -3.21 copies/mL on adefovir.(105) However, further results are required in order to evaluate the efficacy and safety of TDF in patients with HBV/HIV coinfection.

ETV, a purine-derived nucleoside analogue, received FDA approval in 2005 for the treatment of chronic HBV. ETV currently is the most potent anti-HBV agent. In HBV-monoinfected, lamivudine-naive patients, ETV has resulted in about 7 log₁₀ copies/mL drop in HBV DNA levels after 48 weeks of therapy. In addition, there have been no observed mutations associated with ETV resistance in that population at 48 weeks of therapy.(106) In a randomized controlled study of 709 HBeAg-positive patients treated with ETV 0.5 mg daily vs lamivudine 100 mg daily, 96 weeks of treatment with ETV resulted in undetectable HBV DNA levels in 80% vs 39% of patients on lamivudine (p < .0001) with a safety profile comparable to that of lamivudine.(107) Preliminary results have shown ETV to be effective in reduction of HBV DNA levels in HIV-coinfected patients with lamivudine-resistant HBV.(108) Because ETV has no anti-HIV activity, it also can be a potential alternative in the treatment of HIV/HBV-coinfected individuals not requiring ART.