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Date Posted: 20:57:06 02/28/02 Thu
Author: Anonymous
Subject: Management Issues in Patients Coinfected With Hepatitis C Virus and HIV

Management Issues in Patients Coinfected With Hepatitis C Virus and HIV

Maurizio Bonacini, MD

AIDS Read 12(1):19-26, 2002. © 2002 Cliggott Publishing, Division of SCP Communications
Abstract and Introduction
Abstract
Coinfection with HIV accelerates the progression of hepatitis C toward advanced liver disease. Low CD4+ cell counts may result in false-negative results on all diagnostic tests except hepatitis C virus (HCV) RNA assays, which are the gold standard for viral replication. First-line management of HIV-HCV-coinfected patients should be optimization of HAART, because low CD4+ cell counts have been associated with greater fibrosis. In addition, agents used to treat hepatitis C may lower CD4+ cell counts and hemoglobin levels. Long-acting interferons offer the promise of better sustained HCV response in HIV-HCV coinfection.

Introduction
At least a third of patients infected with HIV are also infected with hepatitis C virus (HCV), because of common routes of transmission. The natural progression of hepatic fibrosis due to hepatitis C is slow, but emerging evidence indicates that the disease progresses more rapidly in patients coinfected with HIV. Furthermore, several therapeutic agents for HIV infection have considerable potential for hepatotoxicity, which can complicate the course of hepatitis C.[1] This article explores the 3 main ways in which hepatitis C in HIV-positive patients differs from that in HIV-negative patients: diagnosis, natural history, and management.

Molecular Characteristics

* Structure. HCV is a single-stranded RNA virus, 9.4 kilobases long. It has at least 6 known genotypes based on analysis of the untranslated region. A hypervariable region (HVR-1) is located in the region of the virus that codes for the envelope protein (E2 coding region).[2] Hypervariability in this region makes it much more difficult for the immune system to mount an effective antibody response to the viral envelope. This, in turn, lessens the chances of development of a vaccine, because vaccines are based on the general principle of raising neutralizing antibodies against the viral envelope. Furthermore, the hypervariable region appears to be even more variable in patients coinfected with HIV.[2]

Because the virus consists of single-stranded RNA, it leads to the formation of a long polyprotein that requires a protease to produce functional molecules from which an infectious virion can result. In that regard, HCV is similar to HIV. This similarity fosters the hope that protease inhibitors active against HCV may be developed in the future.

* Genotypes. The 6 HCV genotypes described so far are clustered geographically. Genotype 1 is the most common, accounting for about 76% of cases in the United States and in Europe (Table 1). Genotype 1 is further subdivided into type a (45%) and type b (29%).[3]

Genotypes 2 and 3 are significantly more responsive to therapy but, unfortunately, much less common than genotype 1. Not only is the response much better for genotypes 2 and 3, but the duration of treatment required is much shorter: 24 weeks for genotypes 2 and 3, compared with 48 weeks for genotype 1.[4]

In the past, it was thought that genotype 1 caused the greatest illness -- more inflammation, more cirrhosis, more hepatocellular carcinoma (HCC), more recurrence after transplantation. Evidence now indicates that genotype 1 has probably existed longer than the others have; thus, the severity of disease is associated not as much with the genotype as with the duration of disease. In any chronic hepatitis, B or C, the longer the patient has the disease, the more likely it is to progress to an advanced stage or become complicated. The consensus now is that neither genotype nor viral load significantly alters the natural history of hepatitis C, but each has important treatment implications,[4,5] as will be discussed in more detail later.

Diagnosis
It is well established that the hepatitis C viral load is greater in HIV-positive patients than in HIV-negative patients.[1,6] In some HIV-positive patients with a negative anti-HCV enzyme-linked immunosorbent assay (ELISA)-2 result -- 5.5% in the University of Southern California (USC) experience but as high as 8% in some areas -- HCV RNA is detectable in serum by reverse transcriptase-polymerase chain reaction (RT-PCR).[6,7]

Here at USC, we recently compared the sensitivity of the ELISA-2, ELISA-3, recombinant immunoblot assay (RIBA), and HCV RNA (Roche Amplicor) tests. We found HCV RNA in the serum of 6 of 110 pa-tients who had negative results on anti-HCV ELISA-2.[6] The results of ELISA-3 were negative in 2, and RIBA was negative in 3 of these 6 patients. Therefore, an HCV RNA test, by qualitative or quantitative RT-PCR, is indicated in the HIV-positive patient who has elevated liver function test results and negative results on anti-HCV ELISA (2 or 3) or RIBA. Thus, the HCV RNA test is the diagnostic standard for viral replication.

We studied 259 patients with hepatitis C diagnosed by anti-HCV ELISA-2, of whom 112 were coinfected with HIV.[6] We sought to determine the prevalence of active HCV infection (defined as detectable viral replication) in HIV-positive versus HIV-negative patients. We further divided each group into those with elevated levels of alanine aminotransferase (ALT) (greater than 40 U/L) and those with normal levels (Table 2).

The majority of patients in both groups had elevated ALT levels. The groups differed, however, with respect to the percentage of patients with active infection (positive results on an HCV RNA test [Roche Amplicor]). Of the coinfected patients with normal ALT levels, 79% had positive results for HCV RNA. Of the HIV-negative patients with normal ALT levels, only 50% had positive results for HCV RNA.

Our policy, therefore, is to use an HCV RNA test in HIV-negative patients with hepatitis C who have normal ALT levels to determine whether they have active replication, because 50% do not. For those without active disease, we prescribe no treatment and follow up once a year for 2 to 3 years to see if the disease has indeed resolved spontaneously (ie, HCV RNA remains undetectable). On the other hand, HIV-positive patients with hepatitis C, even those with normal ALT levels, are far more likely to be HCV RNA-positive (Table 2).

We also compared hepatic tis-sue HCV RNA levels in frozen biopsy specimens and in serum from HIV-positive and HIV-negative patients with hepatitis C. Both serum and liver HCV RNA levels were significantly higher in HIV-positive patients than in those with HCV alone.[8] Clearly, HCV replication is significantly higher in HIV-positive patients.

Natural History
The main risk in patients with hepatitis C is the development of substantial fibrosis and ultimately cirrhosis in the liver. It is very difficult, however, to predict the course of the natural history in individual patients.[5]

One way to determine progression of liver disease is to perform 2 liver biopsies at an interval of 2 to 5 years. Poynard and associates,[5] however, have developed an equation based on 1 biopsy, which they validated by performing a second biopsy in a subset of patients. Their "fibrosis score" consists of values from 0 (no fibrosis or scarring at all) to 4 (established cirrhosis). The equation is:

Progression
(stages/year) = Fibrosis stage
____________________

Disease duration

Disease duration is estimated as the time elapsed since the most probable exposure, eg, the date of the first transfusion or the first year of parenteral drug use. For a patient who has stage 2 fibrosis and used intravenous drugs 20 years ago, for example, the equation would be 2/20, or 0.1 stage of fibrosis progression a year. HCV disease in such a patient could be estimated to progress to cirrhosis after 40 years (ie, stage 4/0.1 stage of fibrosis progression per year = 40 years). In this large cohort of more than 2000 patients, Poynard's group concluded that on average, cirrhosis would be reached after 30 years. Parameters associated with faster progression included alcohol consumption greater than 50 g/d (about 4 drinks daily), age at infection greater than 45 years, and male gender. Importantly, genotype and viremia did not affect progression in this study.

In a subsequent study, the same French group reported that alcohol consumption and HIV coinfection are independent risk factors for progression to fibrosis, each at about the same level of relative risk.[9] The investigators estimated that cirrhosis would develop in an HIV-positive patient who consumed more than 50 g/d of alcohol within 16 years, or in almost half the time needed in an HIV-negative patient who did not drink.

Data from approximately 4000 patients in the United Kingdom's hemophilia register show starkly the effect of HIV coinfection on the natural history of hepatitis C.[10] In patients with hemophilia, the risk of death due to chronic liver disease was 17-fold greater and the risk of death specifically due to HCC was 5- to 6-fold higher than the expected risk in the general population. Furthermore, the risk of death due to chronic liver disease was 5-fold higher in HIV-positive hemophiliac patients than in those who were HIV-negative.

We have recently summarized mortality data for our USC HIV cohort. In HIV-positive patients, most (71%) deaths were HIV-related. Of the 5 patients whose deaths were the result of liver disease, 3 had consumed more than 50 g/d of alcohol, 1 died of isoniazid hepatotoxicity, and 1 had HCC (unpublished data, January 2001). In the groups coinfected with either hepatitis B or C, deaths associated with liver disease were 30% to 40% of the total number of deaths. Thus, liver disease is a serious consideration in patients coinfected with HIV and hepatitis virus. We need to stress the importance of preventing liver damage through alcohol abstinence and through treatment of viral hepatitis before liver disease becomes advanced.

Viral hepatitis is not the only liver problem seen in patients with HIV infection. Opportunistic infections and neoplasms, such as lymphoma and Kaposi sarcoma, as well as biliary disease may be encountered, but these, fortunately, are less common now as a direct result of new antiretroviral therapeutic regimens.

Hepatotoxicity
Several factors are associated with the risk of drug-induced hepatotoxicity in HIV-positive patients: female gender, obesity, preexisting liver disease, age greater than 50 years, alcoholism, drug-drug interactions, and genetic predisposition. Unfortunately, the incidence of drug hepatotoxicity, seen early on with antibiotics such as sulfa drugs and oxacillin, appears to be even more common with many of the new antiretroviral agents.[11]

Several groups have studied the risk of HAART hepatotoxicity in patients with hepatitis B or C. Sulkowski and associates[12] assessed the incidence of hepatotoxicity during different HAART regimens in 298 patients, half of whom had hepatitis C. Hepatotoxicity developed in 10% of patients during HAART. Use of ritonavir was associated with a significantly higher incidence of toxicity (30%). Only in patients receiving regimens without ritonavir were the researchers able to document an association between hepatitis C and increased hepatotoxicity.

On the other hand, Saves and colleagues[13] found that hepatitis C was associated with an increased chance of hepatotoxicity for all HAART regimens, regardless of whether they included ritonavir. An Italian group found that hepatitis, either C or B, was associated with an increase in both hepatic and nonhepatic adverse events.[14] In addition, HAART has been blamed for inducing an "immune reconstitution" injury, whereby an elevation of transaminase levels occurs with improving CD4+ cell counts.[1] It seems safe to say that patients receiving HAART should be monitored with serum transaminase assays whenever they are seen by their HIV care provider.[1,11] In the long run, however, HAART has been shown to be beneficial in coinfected patients.[15,16]

Vaccination
The patient with underlying cirrhosis in whom acute hepatitis develops -- be it viral or drug-induced -- is at high risk for death from acute liver injury. Because acute hepatitis A or B may cause acute liver injury, vaccination has been recommended for patients with chronic hepatitis. In view of the frequency of liver involvement in HIV infection, this recommendation may need to be extended to all susceptible HIV-positive patients.

Hepatitis A vaccine prompts an antibody response in only about 75% of HIV-positive patients, compared with about 95% of the general population[17,18] ; however, that rate of response justifies vaccination. Hepatitis A antibody should be assayed before vaccination; if the result is positive, the patient has already acquired immunity to hepatitis A and will not benefit from vaccination.

Three doses of hepatitis B vaccine, on the other hand, prompt an antibody response in only about 50% of HIV-positive patients.[19] Half of nonresponders who receive 3 additional doses, however, mount an antibody response, so this vaccine is justified in patients without prior exposure. Again, hepatitis B antibody should be assayed before vaccination, particularly because most gay men and injection drug users have already been exposed to hepatitis B virus.

Management
The main controversy in the management of HIV-HCV-coinfected patients has been the question of which to treat first.[1] There is substantial evidence that CD4+ cell counts are inversely related to cirrhosis.[1] We have shown that patients with CD4+ cell counts below 500/mL have more rapid estimated progression of hepatic fibrosis.[20] In my view, there is therefore no doubt that we should first treat HIV infection. Doing so affords a chance to stabilize the patient's condition and optimize CD4+ cell counts. The latter may help stem progression of hepatitis C. On the other hand, interferon may theoretically decrease peripheral CD4+ cell counts.

nMonotherapy. In the beginning, interferon monotherapy was the only option for patients with HIV-HCV coinfection. A compilation of data from a number of studies (a total of 198 patients) showed that the sustained transaminase (ALT) response was about 24%, which was comparable with the rate of biochemical response in patients without HIV infection.[1] These studies, however, were not controlled trials, and the patients were most likely selected because of their better compliance and better prognosis. In fact, all the patients had CD4+ cell counts greater than 150/mL, and more than 90% were able to complete therapy.

nRibavirin and interferon alfa-2b. Treatment results have improved with the advent of combination therapy. Data on ribavirin and interferon alfa-2b (Rebetron) in HIV-positive patients, however, are scarce.

Two large studies of the effectiveness of interferon-ribavirin were reported in 2001 (Table 3).[21,22] The first, from Spain, compared induction versus no-induction interferon dosing. The second, from the United States, compared initial versus late ribavirin use. Both studies demonstrated lower virologic responses than historically reported in non-HIV-infected patients, despite the high percentage of favorable genotypes in the first study.[21] A sustained virologic response (SVR) is defined as lack of detectable HCV RNA 6 months after completion of therapy. Interestingly, Perez-Olmeda and colleagues[21] have shown that patients with an SVR demonstrate undetectable HCV RNA at 1 month. Those in whom results remain positive have a very low likelihood of SVR and may not benefit from prolonged administration. The low rate of treatment completion achieved in the US study underscores the importance of adherence in the success of anti-HCV therapy.[20]

There has been concern that ribavirin might interfere with the metabolism of zidovudine, but this has not been shown to occur. Most groups reported no significant changes in HIV viral load or CD4+ cell counts with combination interferon-ribavirin therapy.[19,20]

nPeginterferon alfa-2b . One pegylated interferon (peginterferon alfa-2b [Peg-Intron]) is now available for hepatitis C treatment. A second formulation (peginterferon alfa-2a [PEGASYS]) is expected to be available in the future. The addition of a "tail" of polyethylene glycol to the interferon molecule increased the half-life, so that the drug needs to be injected only once a week instead of 3 times a week.

Pockros and associates[23] demonstrated that the SVR rate with the older interferon formulation was 17% in patients with minimal fibrosis, compared with 6% in those with cirrhosis. The SVR rate with peginterferon alfa-2a was 35% in patients with minimal fibrosis and 30% in those with cirrhosis. Peginterferon alfa-2a was therefore superior to regular interferon for all patients, including those with more advanced disease. These data have changed the paradigm for treating patients with compensated cirrhosis, who are now good candidates for therapy.

Manns and associates[24] randomized 1530 interferon-naive patients with chronic hepatitis C to 3 regimens: interferon alfa-2b (3 million IU SC 3 times a week) plus ribavirin (1000 to 1200 mg/d PO); peginterferon alfa-2b (1.5 mg/kg once a week) plus ribavirin (800 mg/d); or peginterferon alfa-2b (1.5 mg/kg once a week for 4 weeks, then 0.5 mg/kg once a week) plus ribavirin (1000 to 1200 mg/d) for 48 weeks. The SVR was significantly higher in the higher-dose peginterferon alfa-2b group (274 [54%] of 511 patients) than in the lower-dose peginterferon group (244 [47%] of 514 patients) or the interferon group (235 [47%] of 505 patients). The rate of SVR among patients with genotype 2 or 3 in all groups was around 80%, but even in patients with genotype 1, the rate of SVR was impressive: 42%, 34%, and 33%, respectively, for the 3 groups.

The drawback of peginterferon alfa-2b is increased neutropenia. In this study by Manns' group,[24] neutropenia was far more frequent in group 2, the higher-dose peginterferon alfa-2b group: 22% compared with 9% in group 1 (interferon alfa-2b) and 15% in group 3 (moderate-dose peginterferon). One further implication of this study is that the optimal dosage of ribavirin is greater than 10.6 mg/kg/d, rather than the current standard dosage of 1000 to 1200 mg/d. Ribavirin also decreases hemoglobin levels by 2 to 3 g/dL, leading to anemia that may not be tolerated in HIV-positive patients. This effect often prompts decreases in ribavirin dose.

To address the latter problem, Wasserman and associates[25] recently conducted a randomized controlled trial in 37 patients with hepatitis C, giving 21 patients erythropoietin (EPO), 40,000 units weekly, in addition to ribavirin in an attempt to ameliorate anemia. Hemoglobin levels dropped to an average of 11.2 g/dL by 24 weeks. In the EPO group, the hemoglobin rose to nearly 14 g/dL by 6 weeks, while in the control patients it remained depressed. Furthermore, the average ribavirin dose was reduced by only 17 mg/d in the EPO group, compared with a dose reduction of almost 300 mg/d in the control group. This could make the difference between successful and unsuccessful HCV therapy.

Summary
Coinfection with HIV alters the natural history of hepatitis C, accelerating the progression of liver disease. New diagnostic methods facilitate identification of hepatitis C in HIV-positive patients. Preventive measures aimed at minimizing the impact of liver disease on survival include elimination of alcohol consumption and vaccination for hepatitis A and B. Treatment should focus on HIV first, then HCV. Finally, new medications (pegylated interferons) and new regimens (18 versus 12 months of therapy) offer the hope of sustained virologic response for greater numbers of patients.

(TABLES REMOVED)


References

1. Bonacini M, Puoti M. Hepatitis C in patients with human immunodeficiency virus infection: diagnosis, natural history, meta-analysis of sexual and vertical transmission, and therapeutic issues. Arch Intern Med. 2000;160:3365-3373.
2. Sherman KE, Andreatta C, O'Brien J, et al. Hepatitis C in human immunodeficiency virus-coinfected patients: increased variability in the hypervariable envelope coding domain. Hepatology. 1996;23:688-694.
3. Lau JY, Davis GL, Prescott LE, et al. Distribution of hepatitis C virus genotypes determined by line probe assay in patients with chronic hepatitis C seenat tertiary referral centers in the United States. Hepatitis Interventional Therapy Group. Ann InternMed. 1996;124:868-876.
4. Liang TJ. Combination therapy for hepatitis C infection. N Engl J Med. 1998;339:1549-1550.
5. Poynard T, Bedossa P, Opolon P. Natural history of liver fibrosis progression in patients with chronic hepatitis C. Lancet. 1997;349:825-832.
6. Bonacini M, Lin HJ, Hollinger FB. Effect of coexisting HIV-1 infection on the diagnosis and evaluation of hepatitis C virus. J Acquir Immune Defic Syndr. 2001;26:340-344.
7. Dieterich DT, Purow JM, Rajapaksa R. Activity of combination therapy with interferon alfa-2b plus ribavirin in chronic hepatitis C patients co-infected with HIV. Semin Liver Dis. 1999;19(suppl 1):87-94.
8. Bonacini M, Govindarajan S, Blatt LM, et al. Patients co-infected with human immunodeficiency virus and hepatitis C virus demonstrate higher levels of hepatic HCV RNA. J Viral Hepat. 1999;5:203-208.
9. Pol S, Lamorthe B, Thi NT, et al. Retrospective analysis of the impact of HIV infection and alcohol use on chronic hepatitis C in a large cohort of drug users. J Hepatol. 1998;28:945-950.
10. Darby SC, Ewart DW, Giangrande PL, et al. Mortality from liver cancer and liver disease in haemophilic men and boys in UK given blood products contaminated with hepatitis C. UK Haemophilia Centre Directors' Organisation. Lancet. 1997;350:1425-1431.
11. Nunez M, Lana R, Mendoza JL, et al. Risk factors for severe hepatic injury after introduction of highly active antiretroviral therapy. J AcquirImmune Defic Syndr. 2001;27:426-431.
12. Sulkowski MS, Thomas DL, Chaisson RE, Moore RD. Hepatotoxicity associated with antiretroviral therapy in adults infected with human immunodeficiency virus and the role of hepatitis C or B virus infection. JAMA. 2000;283:2526-2527.
13. Saves M, Vandentorren S, Daucourt V, et al. Severe hepatic cytolysis: incidence and risk factors in patients treated by antiretroviral combinations. Aquitaine cohort, France, 1996-1998. AIDS. 1999;13:F115-F121.
14. Bonfanti P, Valsecchi L, Parazzini F, et al. Incidence of adverse reactions in HIV patients treated with protease inhibitors: a cohort study. Coordinamento Italiano Studio Allergia e Infezione da HIV (CISAI) Group. J Acquir Immune Defic Syndr. 2000;23:236-245.
15. Benhamou Y, Dimartino V, Bochet M, et al. Factors affecting liver fibrosis in human immunodeficiency virus and hepatitis C virus-coinfected patients: impact of protease inhibitor therapy. Hepatology. 2001;34:283-287.
16. Qurishi N, Kreuzberg C, Voigt E, et al. Effect of HAART on liver related mortality in HIV/HCV coinfected patients [abstract]. Hepatology. 2001;34:1027A. Abstract 1027.
17. Kemper C, Haubrich R, Frank I, et al. The safety and immunogenicity of hepatitis A vaccine (Havrix) in HIV+ patients: a double-blind, randomized, placebo-controlled trial. In: Program and abstracts of the 8th Conference on Retroviruses and Opportunistic Infections; February 4-8, 2001; Chicago. Abstract 558.
18. Daly P. Hepatitis C and the British Columbia experience with hepatitis A vaccination. J Viral Hepat. 2000;7(suppl 1):23-25.
19. Bonacini M. Hepatobiliary complications in patients with human immunodeficiency virus infection. Am J Med. 1992;92:404-411.
20. Puoti M, Bonacini M, Spinetti A, et al. Liver fibrosis progression is related to CD4 cell depletion in patients coinfected with hepatitis C virus and human immunodeficiency virus. J Infect Dis. 2001;183:134-137.
21. Perez-Olmeda M, Romero M, Asensi V, et al. Efficacy and safety of combination therapy with interferon plus ribavirin in HIV-infected patients with chronic hepatitis [abstract]. Hepatology. 2001;34:332A. Abstract 641.
22. Kostman J, Smith J, Giffen C, et al. Interferon alfa-2b/ribavirin combination therapy in HIV/HCV co-infected persons: results of a multicenter randomized double-blind controlled trial [abstract]. Hepatology. 2001;34:330A. Abstract 634.
23. Pockros P, Heathcote J, Schiffman ML, et al. Efficacy of pegylated interferon alfa-2a (PEGASYS) in randomized trials of patients with chronic hepatitis C, with and without cirrhosis: correlation of virological responses with baseline histology and genotype [abstract]. Hepatology. 2000;32:442A. Abstract 1131.
24. Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet. 2001;358:958-965.
25. Wasserman R, Brau N, Hassanein TA, et al. Once weekly epoietin alfa increases hemoglobin and decreases RBV discontinuation among HCV patients who develop anemia on RBV/INF therapy [abstract]. Hepatology. 2000;32:368A. Abstract 833.

Editorial Comment
Douglas T. Dieterich, MD , Chief of Gastroenterology and Hepatology, Cabrini Medical Center, Associate Professor of Medicine, New York University School of Medicine, New York

Hepatitis C Management in HIV Infection -- Where Is the Controversy?The summary article by Dr Bonacini is a good example of the state of the art in hepatitis treatment in the world of HIV today. For many years, controversy swirled around this issue. No one treated hepatitis C in HIV patients before the age of protease inhibitors (PIs), because survival with HIV was so dismal. Then, no one would treat hepatitis C in HIV patients for fear of toxicity of interferon and its impact on quality of life and its poor response rate. The next fear was of ribavirin toxicity, a theoretic fear that it might interfere with the metabolism of zidovudine and stavudine.

All of these fears were rational ones propounded by rational people that led most HIV clinicians away from treating hepatitis C in their HIV patients. However, the evidence began to mount that hepatitis C was taking its toll on our patients. Articles in the medical literature began to pile up, showing increased mortality due to liver disease and hepatitis C in HIV-infected patients.[1] It became clear and no longer controversial that hepatitis C runs an accelerated course in patients with HIV infection. In fact, the US Public Health Service and the Infectious Diseases Society of America got together in 1999 and declared hepatitis C to be an opportunistic infection.[2]

The next controversy concerned the effect of infection with hepatitis C virus (HCV) on the course of HIV infection. There has been considerable discussion in small studies of this effect, and the most favored response has been that there was no effect, so why treat? Last year's report from the Swiss Cohort Study investigators settled the question conclusively. This study examined more than 3000 HIV-infected patients, more than 1000 of whom were coinfected with HCV. The statistics were clear: progression to AIDS or death was significantly faster in the HCV-HIV-infected patients compared with progression in HIV-infected patients without hepatitis C. In addition, the CD4+ cell counts of the HCV-HIV-infected patients remained a full 50/mL lower, even 36 months after initiation of antiretroviral therapy.[3] This report now clearly ends the controversy of the effect of HCV on HIV infection, because of the massive number of patients it involved: hepatitis C accelerates the course of HIV infection.

The final controversy is, does hepatitis C cause more liver toxicity, prompting discontinuation of a patient's HAART? The answer here is also very clear: hepatitis C clearly causes more liver toxicity among those receiving HAART. In a recently reported study of 222 HIV-infected patients receiving HAART, predictors of hepatotoxicity were evaluated in subgroups of those coinfected with HCV, hepatitis B virus (HBV), or hepatitis D virus. In this analysis, the overall toxicity rate was 9% for nonnucleoside reverse transcriptase inhibitor (NNRTI)-based regimens and 10% for PI-based regimens.[4] Independent predictors of liver toxicity were found to be infection with HCV, older age, and alcohol abuse.

Hepatitis C clearly contributes to liver toxicity. The complexity of this situation is magnified by the liver toxicities that are associated with all 3 classes of anti-HIV medications and occur by different mechanisms. The nucleoside reverse transcriptase inhibitors (NRTIs) cause liver toxicity mostly by mitochondrial toxicity, which can lead to hyperlactatemia and lactic acidosis. This toxicity appears to be caused more frequently by stavudine, with and without didanosine, than by zidovudine-based regimens.[5] However, all nucleosides are capable of causing mitochondrial toxicity . The liver is the major organ that metabolizes lactate, and I strongly believe that patients with compromised liver function from hepatitis C are much more vulnerable to hyperlactatemia and lactic acidosis. This is something to consider when observing HIV-infected patients with rising alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, whether or not they also have hepatitis C. Particularly in patients coinfected with HIV-HCV, one should not be lulled into a false sense of security by assuming all rises in ALT and AST levels are from HCV. Elevated ALT and AST levels are hallmarks of mitochondrial toxicity and lactic acidosis. The answer for the NRTIs is undoubtedly yes; hepatitis C can cause more potential for toxicity.

There does not seem to be much controversy about PIs. They can all cause liver toxicity, but ritonavir seems to be the biggest offender, probably because of its propensity to inhibit the P-450 system.[6] This may be exacerbated by hepatitis C, and I believe that liver toxicity is likely to be caused by higher drug levels in hepatitis C patients, something that has yet to be proved but clearly needs to be studied with therapeutic drug monitoring.

There is even more controversy about the NNRTIs and liver toxicity. A recent study from Africa showed considerably more liver toxicity with nevirapine than with efavirenz.[7] This study was primarily in black African women with CD4+ cell counts above 350/mL -- the group in which nevirapine-related liver toxicity is most likely to develop. In another study in an urban HIV clinic in Baltimore, with about 50% African American patients and about 50% of patients coinfected with HCV, there was more hepatotoxicity among patients receiving a nevirapine-containing regimen than among those receiving an efavirenz-based regimen.[8] On the other hand, in more than 10,000 patients in a recently reported large retrospective analysis of 21 adult AIDS Clinical Trials Groups, use of nevirapine and use of efavirenz were associated with similar rates of hepatotoxicity and subsequent discontinuation.[9]

Another investigation into the hepatotoxic effects of nevirapine found that several risk factors -- including baseline CD4+ cell counts of at least 350/mL, elevated baseline ALT/AST levels and, notably, coinfection with HBV or HCV -- contribute to the observed rates of hepatic events in clinical trials.[10] Furthermore, another recent report found that duration of antiretroviral therapy (also found to be associated with mitochondrial toxicity of NRTIs, lipodystrophy, and lipoatrophy), HCV infection, and elevated ALT level at baseline were associated with nevirapine hepatotoxicity during the course of 9 months.[11] This study also revealed in a univariate analysis that factors associated with liver toxicity were the use of stavudine (relative hazard [RH], 2.29) and use of zidovudine (RH, 0.4). Together, these data imply that long-term nevirapine toxicity may be more likely related to the mitochondrial toxicity seen with stavudine than to nevirapine per se. Another trial from Europe including more than 1000 patients revealed a relatively low incidence (7.9%) of liver toxicity. Independent risk factors for liver toxicity were elevated baseline AST and ALT levels and presence of hepatitis B or C. In this analysis, liver toxicity was less likely to develop in patients receiving stavudine-containing regimens than in those receiving zidovudine.[12]

The types of long-term toxicity characterized above for nevirapine should be distinguished from the clear hypersensitivity-type reaction that occurs in the first 6 to 8 weeks after starting nevirapine therapy. Notably, long-term toxicity, if it is related to NNRTIs, would be exacerbated by the presence of HCV infection, while the hypersensitivity reaction likely would not. It has always been clear that the liver toxicity of efavirenz is at least twice as likely to occur in HCV-infected patients. Finally, a recent comparison from our group in New York of all 3 available NNRTIs showed that there was more liver toxicity in HBV- or HCV-infected patients but there was no difference in the incidence of liver toxicities among patients receiving nevirapine, efavirenz, or delavirdine.[13]

Where does this leave us? The first conclusion is that hepatitis C, and B for that matter, increases the risk for liver toxicity with all anti-HIV medications. It would follow from that conclusion that treating hepatitis C is likely to help avoid liver toxicity. Second, the NNRTIs are generally equal in their risk of causing liver toxicity, with some nuances that need consideration when making a decision about anti-HIV treatment. There may be a future role for therapeutic drug monitoring of NNRTIs and PIs, particularly in the patient with liver disease.

The recent availability of peginterferon alfa-2b plus ribavirin is making the decision to treat easier, because it is more effective and has many fewer side effects. There are not a great many data yet in HIV patients, although a trial of peginterferon alfa-2b for resistant HIV infection is beginning soon. The other pegylated product -- peginterferon alfa-2a -- should be approved in the United States sometime in 2002. There are more than 1000 patients coinfected with HIV and HCV now in clinical trials with peginterferon alfa-2a, and the HIV and HCV treatment data that will come out of those trials will be extraordinary. We eagerly await the conclusion of those trials.

Two controversies remain. The first is not really whether to treat hepatitis C in HIV-infected patients but, rather, will treating hepatitis C decrease the liver toxicity of anti-HIV medications? That is something that clearly needs to be studied; in the meantime, I firmly believe that it will. The second controversy is who will treat patients coinfected with HCV. Hepatitis treatment has long been in the hands of the GI/liver specialists. Most hepatologists have only a passing acquaintance with HIV infection and are not at all familiar with the toxicity of all 16 approved antiretroviral medications. I believe that HIV caregivers who are willing to learn about hepatitis C treatment and stay current should be the ones responsible for the day-to-day care of these patients. HIV care providers should have consulting hepatologists who can help out with serious liver disease questions -- and perhaps perform an occasional biopsy or endoscopy -- but who are not involved in the daily treatment decisions. The HIV treater is much better prepared than the hepatologist to manage the complications in the HIV-infected population, for example, using erythropoietin and filgrastim to treat the cytopenias that are likely to be encountered -- factors, particularly in the HIV patient, that are likely to be important to the success of treatment. The bottom line is that hepatitis C is not only a treatable opportunistic infection in HIV but also a curable one. Its treatment is likely to lead to better outcomes for HIV-infected patients as well as for those infected with HCV.

References

1. Bica I, McGovern B, Dhar R. Increasing mortality due to end-stage liver disease in patients with human immunodeficiency virus infection. Clin Infect Dis. 2001;32:492-497.
2. Centers for Disease Control and Prevention. 1999 USPHS/IDSA guidelines for the prevention of opportunistic infections in persons infected with human immunodeficiency virus. MMWR. 1999;48(RR10):1-59.
3. Greub G, Ledergerber B, Battegay M, et al. Clinical progression, survival, and immune recovery during antiretroviral therapy in patients with HIV-1 and hepatitis C virus coinfection: the Swiss Cohort Study. Lancet. 2000;356:1800-1805.
4. Núñez M, Lana R, Mendoza JL, et al. Risk factors for severe hepatic injury after introduction of highly active antiretroviral therapy. J Acquir Immune Defic Syndr. 2001;27:426-431.
5. Boubaker K, Flepp M, Sudre P, et al. Hyperlactatemia and antiretroviral therapy: the Swiss HIV Cohort Study. Clin Infect Dis. 2001;33:1931-1937.
6. Sulkowski MS, Thomas DL, Chaisson RE, Moore RD. Hepatotoxicity associated with antiretroviral therapy in adults infected with human immunodeficiency virus and the role of hepatitis C or B virus infection. JAMA. 2000;283:74-80.
7. Bartlett J. Severe liver toxicity in patients receiving two nucleoside analogues and a NNRTI. In: Program and abstracts of the 8th Conference on Retroviruses and Opportunistic Infections; February 4-8, 2001; Chicago. Abstract 19.
8. Sulkowski M, Mehta S, Thomas D, Moore R. Hepatotoxicity associated with NNRTI use: role of drugs and chronic viral hepatitis. In: Program and abstracts of the 8th Conference on Retroviruses and Opportunistic Infections; February 4-8, 2001; Chicago. Abstract 618.
9. Reisler R, Liou S, Servoss J, et al. Incidence of hepatotoxicity and mortality in 21 adult antiretroviral treatment trials. In: Program and abstracts of the 1st International AIDS Society Conference on HIV Pathogenesis and Treatment; July 8-11, 2001; Buenos Aires. Abstract 43.
10. Dieterich D, Stern J, Robinson P, et al. Analyses of four key clinical trials to assess the risk of hepatotoxicity with nevirapine: correlation with CD4+ levels, hepatitis B & C seropositivity, and baseline liver functions tests. In: Program and abstracts of the 1st International AIDS Society Conference on HIV Pathogenesis and Treatment; July 8-11, 2001; Buenos Aires. Abstract 44.
11. Martinez E, Blanco JL, Arnaiz JA, et al. Hepatotoxicity in HIV-1-infected patients receiving nevirapine-containing antiretroviral therapy. AIDS. 2001;15:1261-1268.
12. Monforte A, Bugarini R, Pezzotti P, et al. Low frequency of severe hepatoxicity and association with HCV coinfection in HIV-positive patients treated with HAART. J Acquir Immune Defic Syndr. 2001;28:114-123.
13. Palmon R, Koo BCA, Shoultz D, Dieterich D. Lack of hepatotoxicity associated with nonnuceloside transcriptase inhibitors. J Acquir Immune Defic Syndr. In press.

Drugs Mentioned in This Article
Delavirdine Rescriptor
Didanosine Videx
Efavirenz Sustiva
Erythropoietin Epogen, Procrit
Filgrastim Neupogen
Hepatitis A vaccine Havrix, Vaqta
Hepatitis B vaccine Engerix-B, Recombivax HB
Interferon alfa-2b Intron A
Isoniazid Nydrazid, generic
Nevirapine Viramune
Oxacillin Bactocill, generic
Peginterferon alfa-2a PEGASYS
Peginterferon alfa-2b PEG-Intron
Ribavirin Virazole
Ribavirin and interferon alfa-2b Rebetron
Ribavirin and peginterferon alfa-2b Rebetol
Ritonavir Norvir
Stavudine Zerit
Zidovudine Retrovir



Dr. Bonacini is associate professor of clinical medicine, division of gastroenterology and liver diseases, Keck School of Medicine, University of Southern California, Los Angeles.

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