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Early Initiation of Antiretroviral Therapy:
The Current Best Way to Reduce Liver-Related Deaths in HIV/Hepatitis C
Virus-Coinfected Patients
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JAIDS Early online publication Jan 11, 2007
Stephen D. Shafran, MD
From the Division of Infectious Diseases, Department of Medicine, University
of Alberta, Edmonton, Alberta, Canada.
Summary: Approximately 25% to 35% of HIV-infected persons in developed countries are coinfected with hepatitis C virus (HCV). HCV liver disease is accelerated by HIV coinfection, especially at low CD4 cell counts. Highly active antiretroviral therapy (HAART) dramatically reduces HIV-related mortality, and liver disease has emerged as a major cause of death in HIV/HCV-coinfected persons. Anti-HCV therapy with pegylated interferon plus ribavirin can cure HCV infection in up to 40% of coinfected patients; however, only approximately 10% of coinfected patients are considered candidates. Hence, HCV therapy cures approximately 4% of coinfected patients. Eleven cohort studies have shown that HAART is associated with a reduced rate of progression of HCV liver disease, and 4 of these studies have demonstrated a reduction in liver-related mortality. Although offering HCV therapy to the few eligible HIV/HCV-coinfected patients is important, early initiation of HAART in coinfected patients has a greater public health impact in reducing liver-related mortality than in curing HCV infection in approximately 4% of these patients.....
.....it is highly unlikely that significant advances in anti-HCV therapy for HIV/HCV coinfected patients are going to be available for several years.....
....Several groups of investigators have demonstrated that low CD4 cell counts are associated with more advanced hepatic fibrosis......
.....This observation raises the hypothesis that correcting (or significantly reducing) the immunodeficiency of HIV infection with HAART might slow the rate of hepatic fibrosis in HIV-negative/ HCV-coinfected individuals.....
....No study has been conducted in which HIV/HCV-coinfected subjects have been randomized to earlier versus later initiation of ART.....
.....There are 11 cohort studies that demonstrate decreased liver disease progression associated with ART,67-70,77,79,80,84-87 however, 4 of which demonstrate reductions in advanced liver-related disease,70,80,84,86 including reduced liver-related mortality.70,84 Seven of these studies used liver biopsy graded hepatic fibrosis as the hepatic disease outcome.67-69,77,79,85,87 Six of these 7 studies found that HAART was associated with a reduced rate of hepatic fibrosis.67,69,77,79,85,87......
[NOTE from Jules Levin: although I agree that earlier HAART should be considered in coinfection, HAART is a 2-edged sword at once improving immunodeficiency but also risking hepatoxicity in a significant percent of patients. Regarding this the author says, and I agree with this statement but coinfected patients starting HAART can accelerate liver disease due to hepatoxicity, which may or may not be detected or may be underestimated.]
.....It is well recognized that HIV/HCV-coinfected patients are more prone to develop hepatotoxicity attributed to HAART than are HIV-monoinfected subjects.91 There is no evidence to suggest that this risk is reduced by initiating HAART later, however. Indeed, the risk may actually be increased, because the incidence of HAART-associated hepatotoxicity in HIV/HCV-coinfected subjects is higher In patients with more advanced hepatic fibrosis.94....
....The issue of when to initiate ART in nonpregnant HIV-infected adults remains a major unresolved question. Current and past recommendations regarding initiation of HAART are thus also based on cohort studies, because randomized trials have not been conducted. In the absence of definitive data, a variety of ''soft'' criteria are used to influence this decision, including patient preference and whether the patient is in an HIV-discordant sexual relationship. HCV coinfection is another factor that should be considered in making this important decision. Although a definitive answer from randomized clinical trials is not presently available, and may never be available, the current evidence, imperfect as it is, argues in favor of earlier initiation of ART in HIV/HCVcoinfected patients, especially in those who are not candidates for anti-HCV therapy.....
Article text
As a result of common routes of transmission of HIV and hepatitis C virus (HCV), a substantial proportion of HIV-infected persons in the developed world are coinfected with both viruses. Coinfection rates are relatively low at 8% in The Netherlands1 and 13% in Australia,2 but they are 33% in the EuroSIDA study,3 38% among US military veterans receiving antiretroviral therapy (ART),4 45% in patients attending the Johns Hopkins Hospital HIV Clinic,5 46% in the Italian Cohort of Patients Naive from Antiretrovirals (ICONA) study,6 and 51% in persons receiving ART in British Columbia.7 It is interesting to note that the prevalence of HCV infection in participants in the 2 major US HIV clinical trials organizations, the AIDS Clinical Trials Group (ACTG) and Community Programs for Clinical Research on AIDS (CPCRA), is only 16%8 and 17%,9 respectively, suggesting that the clinical trials populations are not broadly representative of the HIV-infected population in the United States. Highly active antiretroviral therapy (HAART) has revolutionized the outcome of HIV infection, resulting in a marked reduction in mortality,10 hospitalization,11 and opportunistic infections.12,13 As HIV-related mortality has decreased dramatically, an increasing proportion of the diminishing number of deaths in HIV-infected persons is attributable to non-HIV related causes, with liver disease emerging as an important cause of death,14-17 mostly in the HIV/HCV-coinfected population.
HIV exerts multiple adverse effects on HCV infection. First, spontaneous clearance of HCV infection is less frequent among those first infected with HIV.18 Second, the HCV viral load is higher in coinfected persons,19-26 which likely explains the higher rate of sexual27 and mother-to-child transmission28 from HIV/HCV-coinfected persons compared with those with HCV monoinfection. Third, the rate of hepatic fibrosis is accelerated by HIV coinfection.29,30 Fourth, the time to hepatic decompensation is shorter in coinfection.30 Fifth, the time from hepatic decompensation to death is also accelerated in coinfected patients.31 Sixth, anti-HCV therapy with pegylated interferon plus ribavirin is less successful in HIV-coinfected patients32-35 than in HCV-monoinfected patients.36-39 Furthermore, if end-stage liver disease (ESLD) develops, many liver transplant programs do not accept HIV-infected subjects. The ''obvious solutionh is to treat HCV infection in HIV/HCV-coinfected patients with anti-HCV therapy, which, unlike antiviral therapy for HIV infection, is given for a finite duration with curative intent; indeed, this approach is widely recommended.40 42 This solution is not nearly as satisfactory as it may seem, however. The major problem with currently available anti-HCV therapy (pegylated interferon plus ribavirin) is that most HCV-infected persons, whether monoinfected or coinfected with HIV, are not being treated. Among the HCV monoinfected, only 28% of 293 patients were treated in a referral liver clinic in Cleveland43 and only 11.8% of 114,005 patients in the US Veterans Administration system were treated.44 In the United Kingdom, only 49% of those who tested anti-HCV-positive were referred for specialist assessment and only 10% began antiviral treatment.45 Furthermore, sustained virologic response (SVR) rates in HCV-monoinfected
patients are approximately 55% to 60%,36-38 such that the impact of anti-HCV therapy is further reduced by another 40% to 45%. The major reasons why few patients are being treated for HCV infection are that they have contraindications to treatment, such as active drug and alcohol abuse, active mental illness, unreliable attendance at medical appointments, and decompensated liver disease.43,44
Among HIV/HCV-coinfected persons, only 3% to 17% are initiated on anti-HCV therapy,44,46-52 and the overall SVR rate is only approximately 40%.32-35 If one assumes that approximately 10% of HIV/HCV-coinfected patients are treated with pegylated interferon plus ribavirin and that 40% of these are cured (achieve an SVR), this means that only 4% of this population is being cured of HCV infection, whereas 96% remains infected. Hence, the impact of current anti-HCV therapy on liver disease in HIV/HCV-coinfected persons at the population level is regrettably minimal.
It is possible that those who receive interferon-based therapies for HCV but fail to achieve an SVR may still derive some benefit. Data from HCV-monoinfected individuals indicate that approximately 40% of nonresponders to interferon therapy had a reduced rate of histologic progression after up to 48 weeks of therapy.51-57 This observation led to a randomized pilot study of 53 nonresponders after 6 months of interferon therapy, 27 of whom were randomized to 24 additional months of therapy, which revealed histologic benefit compared with the 26 nonresponders randomized to receive no additional interferon.58 This study, in turn, has led to the initiation of much larger studies that are currently ongoing to determine if this strategy actually results in clinical benefits on liver disease-related outcomes.59 Data regarding the potential benefit of noncurative anti-HCV therapy in HIV-coinfected patients are limited. In the ACTG A5071 study, nonresponders at week 24 were supposed to have a liver biopsy performed,32 although only 70% (26 of 37) of nonresponders who received pegylated interferon plus ribavirin actually had a biopsy. Of those, 35% had histologic benefit.32 Because the studies of pegylated interferon plus ribavirin in coinfected patients have demonstrated that the week 12 virologic response has a negative predictive value greater than 98%,32-34 however, most nonresponders receive only 12 to 14 weeks of therapy (until the week 12 HCV RNA result is obtained), and it seems doubtful that such a short duration of anti HCV therapy in nonresponders would impart a clinically significant benefit. A long-term study of low-dose pegylated interferon in HIV/HCV-coinfected patients with cirrhosis has recently been announced,60 but the study has not yet started and this approach cannot currently be recommended.
Although preliminary studies of HCV protease inhibitors in HCV-monoinfected subjects are encouraging61,62 and HCV polymerase inhibitors are also being developed63,64 and entering clinical trials in the HCV monoinfected, it is too early to know if these novel agents are likely to be proven safe and effective in an HCV-monoinfected population. Furthermore, these new antiviral agents are not going to be studied in HIV/HCV-coinfected persons until safety and efficacy in HCV-monoinfected persons is established and drug-drug interactions with antiretroviral agents are undertaken. Hence, it is highly unlikely that significant advances in anti-HCV therapy for HIV/HCV-coinfected patients are going to be available for several years.
So, recognizing that anti-HCV therapy is practical and effective in such a low proportion of patients, what can one do to benefit the liver in most HIV/HCV infected patients in 2007? First, it is important to counsel against alcohol intake because this clearly accelerates progression of HCV liver disease,65,66 including that in HIV-coinfected persons.16,29,67-70 Second, those who are serologically susceptible to hepatitis A virus (HAV) or hepatitis B virus (HBV) should be offered vaccine,42,71 recognizing that HAV and HBV vaccines are of reduced immunogenicity in HIV-infected persons.72-74 Third, those who are obese (admittedly uncommon in HIV-infected persons) should be encouraged to reduce their weight, because obesity contributes to steatosis, which can also accelerate hepatic fibrosis in HCV-infected persons75 and reduce the likelihood of responding to anti-HCV therapy. Fourth, efforts should be made to overcome barriers to anti-HCV therapy by treating mental illness and addiction and improving patients' social circumstances. Even doubling the proportion of HIV/HCV-coinfected patients who are cured of HCV infection from approximately 4% to approximately 8%, which would be an ambitious goal, is not likely to have a major public health impact on HCV-related liver disease in this population. Fifth, although not addressed in current guidelines, early initiation of ART should be seriously considered, and this is discussed below in this article.
Several groups of investigators have demonstrated that low CD4 cell counts are associated with more advanced hepatic fibrosis.65,76-80 Indeed, this seems to be immunologically analogous to liver transplantation for ESLD attributable to HCV infection, wherein HCV reinfection of the transplanted liver is universal and the rate of hepatic fibrosis after transplantation is much more rapid than that occurring with HCV infection in the original host liver.81-83 The accelerated rate of hepatic fibrosis after liver transplantation for HCV is presumed to be mediated by the significant impairment in cellmediated immunity caused by antirejection therapy. The fact that the spectrum of opportunistic infections seen in HIV-infected subjects with low CD4 cell counts is remarkably similar to that seen in liver transplant patients suggests that these 2 conditions are immunologically similar. This observation raises the hypothesis that correcting (or significantly reducing) the immunodeficiency of HIV infection with HAART might slow the rate of hepatic fibrosis in HIV-negative/ HCV-coinfected individuals.
No study has been conducted in which HIV/HCV-coinfected subjects have been randomized to earlier versus later initiation of ART. There are 11 cohort studies that demonstrate decreased liver disease progression associated with ART,67-70,77,79,80,84-87 however, 4 of which demonstrate reductions in advanced liver-related disease,70,80,84,86 including reduced liver-related mortality.70,84 Seven of these studies used liver biopsy-graded hepatic fibrosis as the hepatic disease outcome.67-69,77,79,85,87 Six of these 7 studies found that HAART was associated with a reduced rate of hepatic fibrosis.67,69,77,79,85,87 The single study in which HAART was not associated with reduced fibrosis did find that HAART was associated with reduced necroinflammatory activity.68 Two of these studies compared HIV/HCV-coinfected patients with HCV-monoinfected controls.69,79 Verma et al69 reported that HCV/HIV-coinfected patients whose primary HIV treatment was HAART had liver fibrosis rates no different from HCV-monoinfected controls, in contrast to HIV/HCV-coinfected patients who received no ART, nucleoside analogues, or nucleoside analogues followed by HAART, who had more rapid hepatic fibrosis rates. Similarly, Brau et al79 reported that HIV/HCV-coinfected subjects whose plasma HIV RNA level was suppressed to <400 copies/mL on HAART had hepatic fibrosis rates comparable to those of HCV-monoinfected subjects, in contrast to those with detectable HIV viremia, who had increased hepatic fibrosis rates compared with those of HCV-monoinfected patients.
Four studies have reported on the effect of HAART on clinical liver disease outcomes, all of which demonstrated benefit.70,80,84,86 Stuver et al80 evaluated 231 HIV/HCVcoinfected injection drug users in Boston and demonstrated that ART with HIV RNA levels less than 75 copies/mL reduced liver-related events, defined as clinical progression of, or death from, liver disease. Schillo et al86 evaluated 157 HCV-infected hemophiliacs from western Pennsylvania, 85 of whom were coinfected with HIV. ESLD-free survival was significantly shorter in the HIV-coinfected men. By contrast, ESLD-free survival among HIV-coinfected men receiving HAART was significantly longer than in HIV-infected men not treated with HAART (30.3 vs 20.0 years; P = 0.043; hazard ratio = 3.14 [95% confidence interval (CI): 1.27 to 7.08) but was similar to that in HCV-monoinfected men (P =0.13; hazard ratio = 2.20 [95% CI: 0.76 to 2.35]). Qurishi et al84 reported on 285 HIV/HCV-coinfected subjects followed in Bonn, 81% of whom were hemophiliacs. They reported that subjects receiving HAART had a substantial reduction in liver-related mortality (P = 0.018). This study has been criticized as having a survivor bias, because hemophiliacs were infected with HIV early in the HIV epidemic and those who survived to the availability of HAART may be slower HIV progressors.88 Reanalysis of the data restricted to those who survived until the availability of HAART did not alter the survival benefit of HAART, however.89 Bonacini et al70 reported on 472 HIV-infected subjects from Los Angeles, of whom 126 were HIV monoinfected; 256 were coinfected with HIV and HCV; 72 were coinfected with HIV and HBV; and 18 were triply infected with HIV, HCV, and HBV. When the 346 subjects with HCV- or HBV-infection were considered as a group, those who received HAART had significantly lower liver-related mortality (P = 0.004).
Because the 11 studies noted previously are cohort studies in which patients were not randomized to receive ART or a particular ART regimen, some biases may exist. One of the 11 studies consisted entirely of hemophiliacs,86 and another consisted of 81% hemophiliacs,84 and it is possible that the finding of these 2 studies may not be applicable to nonhemophiliacs. Furthermore, several of the cohort studies were cross-sectional rather than longitudinal, and it is acknowledged that cross-sectional studies are more likely to be subject to bias. It is also possible that patients who received no ART are those who refuse all medical interventions or have extremely chaotic lifestyles that do not lead clinicians to prescribe ART.
Data from the EuroSIDA study provide confusing results.90 This large cohort study demonstrated that patients receiving ART had a significantly lower death rate from liver-related disease than those who did not start ART (2.8 vs. 6.2 deaths per 1000 person-years of follow-up; P <0.0001). After adjustment for other variables, however, including CD4 lymphocyte counts, the death rate from liver disease increased by 12% per year among those receiving ART for >2 years. It should be noted that HCV status was unknown in 47% of the EuroSIDA study population. The conclusions of the EuroSIDA study contrast with those of Tural et al,67 who reported that time on ART was associated with decreased hepatic fibrosis.
In the absence of randomized trials evaluating the effect of ART on liver-related outcomes, treatment decisions have to be made on the basis of lower levels of evidence, which consist mainly of cohort studies. The cohort studies noted previously, which were conducted in 4 different countries (France,77,87 Spain,67,85 Germany,84 and the United States68-70,79,80,86), are remarkably consistent in their conclusion, a conclusion that is also biologically plausible.
In a recent editorial, Jade Ghosn91 wrote ''because the major goal for persons treating HIV/AIDS coinfected patients is to slow or interrupt liver fibrosis, the best way to achieve this goal is to treat HCV infection with pegylated IFN and ribavirin.'' Although I agree with the first point that Ghosn makes, I respectfully disagree on the latter point for the reasons outlined previously. Whereas curing any patient of HCV infection is a laudable goal that should be pursued whenever possible, the reality is that this is achieved in far <10% of HIV/HCV-coinfected patients. In contrast, ART can be given to most HIV/HCV-coinfected subjects, including those with severe mental illness, decompensated liver disease, autoimmune disease, severe cardiopulmonary disease, and pregnancy, none of whom can be treated with pegylated interferon plus ribavirin. Indeed, even most of those who continue to use injection drugs can adhere to HAART,92,93 whereas they are not candidates for currently available anti-HCV therapy. It is well recognized that HIV/HCV-coinfected patients are more prone to develop hepatotoxicity attributed to HAART than are HIV-monoinfected subjects.91 There is no evidence to suggest that this risk is reduced by initiating HAART later, however. Indeed, the risk may actually be increased, because the incidence of HAART-associated hepatotoxicity in HIV/HCV-coinfected subjects is higher in patients with more advanced hepatic fibrosis.94
The issue of when to initiate ART in nonpregnant HIVinfected adults remains a major unresolved question. Current and past recommendations regarding initiation of HAART are thus also based on cohort studies, because randomized trials have not been conducted. In the absence of definitive data, a variety of ''soft'' criteria are used to influence this decision, including patient preference and whether the patient is in an HIV-discordant sexual relationship. HCV coinfection is another factor that should be considered in making this important decision. Although a definitive answer from randomized clinical trials is not presently available, and may never be available, the current evidence, imperfect as it is, argues in favor of earlier initiation of ART in HIV/HCV-coinfected patients, especially in those who are not candidates for anti-HCV therapy.
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