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Hepatitis C Virus

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Currently Under Revision – March 2003

Currently under revision

A. Introduction

As overall mortality declines and life expectancy increases for people infected with HIV, end-stage liver disease has emerged as an increasingly common cause of death in people with HIV. A large proportion of the liver pathology in patients with HIV can be traced to chronic co-infection with hepatitis C virus (HCV). In a retrospective study of hospitalized HIV-infected patients in Madrid, Spain, end-stage liver disease was found in 8.6% of patients, and 88.6% of these patients had HCV. End-stage liver disease was the fifth most common cause of in-hospital mortality.1 In another study from New York City, liver failure was the second leading cause of death in HIV-infected individuals after AIDS-defining opportunistic infections. Finally, one study showed that end-stage liver disease was the cause of death in 50% of hospitalized HIV-infected patients treated during the HAART era.2 Because chronic hepatitis C infection is common in people with HIV, is a source of substantial morbidity and mortality, and may be amenable to treatment, early identification and treatment of HCV co-infection have become increasingly important elements in the management of HIV infection.

Both HCV and HIV are RNA viruses, but their life cycles are quite different. The single-stranded HIV genome is transcribed into a double-stranded DNA copy that is integrated irreversibly into the host-cell genome. The single-stranded RNA genome of HCV is never transcribed to DNA or integrated into the host cell genome. Rather, it reproduces in the cytoplasm of the hepatocyte. HCV is therefore able to be eradicated and cured. Similar to HIV, HCV mutates frequently, establishing a genetically diverse population of viral quasi-species within each infected host. This genetic diversity is at least partly responsible for the ability of HCV to evade the body’s immune defenses and establish chronic infection.

B. Epidemiology And Prevention

Recommendations:

Clinicians should perform HIV testing and counseling in patients with HCV infection who are not already known to be HIV-infected.

Regardless of a patient’s HIV or HCV infection, clinicians should counsel patients to avoid practices that transmit both HIV and HCV, including high-risk sexual practices and needle-sharing behaviors among injection drug users.

Clinicians should counsel active injection drug users to use new sterile equipment at all times, dispose of their syringes after one use, and clean their injection sites carefully with clean alcohol swabs. These patients should be urged to undergo treatment to reduce drug use.

Clinicians should encourage all patients with HCV and all patients with HIV who are sexually active to use condoms.

Clinicians should advise household contacts of persons chronically infected with HCV to avoid sharing items that may be contaminated with blood such as toothbrushes and razors.

Clinicians should encourage uninfected, long-term sexual partners of persons co-infected with HCV and HIV to continue to use safe-sex practices to prevent transmission of HIV and HCV.

HCV was discovered in 1989 and accounts for approximately 85% of what was formerly called "non-A non-B hepatitis" in the United States. Approximately 4 million (1.8%) Americans have been infected with HCV, and an estimated 10,000 Americans die of HCV-related liver disease each year. The infection is more prevalent in minority populations (6.1% of African Americans and 2.1% of Mexican Americans) than in non-Hispanic whites (1.5%).

HCV is primarily transmitted via the parenteral route. Transmission through transfusion of blood or blood products was once a major source of HCV but has been almost eliminated in the United States over the past decade due to screening of blood donations. Injection drug use is now the major route of HCV transmission, accounting for at least 60% of all new infections in the United States. In some populations of injection drug users, >80% have been infected with HCV; however, lower prevalence has been found in other populations, particularly among young users.3 Cleansing shared needles with bleach and water in between users may be useful to prevent HCV transmission.4

Less frequent sources of HCV infection in the United States include nosocomial exposures (particularly hemodialysis), high-risk sexual behaviors, perinatal transmission, and occupational exposure. HCV is not easily transmitted sexually, but sexual transmission is estimated to account for approximately 10% to 15% of HCV cases in the United States. HIV infection may facilitate sexual transmission of HCV. The risk of HCV transmission is increased among those with large numbers of sexual partners, by failure to use a condom, and among those with a history of sexually transmitted diseases (STDs). Transmission of HCV between non-sexual household contacts has been known to occur, probably through inadvertent or inapparent exposure to blood or infectious body fluids. In studies from other countries, prevalence of HCV among non-sexual household contacts of infected persons with no other apparent risk factors was 4%; however, other unreported risk factors may have contributed to this total. Non-sexual household transmission is thought to be uncommon in the United States. Maternal-fetal transmission in HIV/HCV co-infected women is approximately 4%.5 The risk of HCV infection from injury with an HCV-contaminated needle is approximately 3%.

Co-infection with HIV and hepatitis C is common, particularly in areas where injection drug use is a major route of transmission of HIV. Nationally, 30% of people with HIV are estimated to be co-infected with HCV. In New York City, the co-infection rate is estimated to be approximately 40%, and the rate is presumably much higher among patients infected with HIV through injection drug use (~70%-90%).

HCV exists in 6 known clades and over 11 genotypes, each of which is divided into several subtypes. Approximately 70% of patients with HCV in the United States are infected with genotype 1 and 4, with subtype 1a being more common than subtype 1b. Although there are no known differences in clinical course among the various genotypes and subtypes, genotypes 1 and 4 are known to have a poorer response to interferon-based therapy than other genotypes.

C. Natural History

Acute HCV disease is usually asymptomatic, but 25% to 35% of patients develop some constitutional symptoms or jaundice. Serum alanine aminotransferase (ALT, SGPT) levels frequently rise, fluctuate, and fall again, suggesting recovery from the acute phase.

Following acute infection, however, HCV is not easily cleared by the immune system. Approximately 60% to 85% of acute HCV infections become chronic, with persistent or intermittent HCV viremia. Acute HCV infection is cleared in only 5% to 10% of HIV-infected persons.6 Two-thirds of patients with chronic infection develop persistent or fluctuating serum ALT elevations indicative of active liver inflammation. Because serum ALT levels may normalize intermittently, a single normal serum ALT level is not sufficient to indicate that liver damage is absent. Co-infected patients with persistently normal serum liver enzyme levels may also have significant liver disease.

Chronic hepatitis C progresses slowly, if at all, with most patients remaining asymptomatic for 20 to 30 years after the onset of infection. However, even in patients who remain free of symptoms and whose serum liver enzymes remain normal, histologic damage can often be demonstrated. Chronic HCV infection can cause inflammatory infiltration, particularly of the portal tracts, as well as both focal liver cell necrosis and fibrosis that bridge between portal tracts. Approximately 10% to 20% of patients progress to cirrhosis after 20 to 30 years of infection. Hepatocellular carcinoma occurs in approximately 1% to 5% of patients after 20 years of infection, and, once cirrhosis develops, the rate of hepatocellular carcinoma increases to approximately 1% to 4% per year. Progression to cirrhosis seems to occur more quickly in men, in patients who use alcohol, and in those who acquire HCV after 40 years of age. Liver biopsies showing portal or bridging fibrosis, or at least moderate inflammation or necrosis, are the best predictors of eventual cirrhosis. HCV viral load, serum transaminase levels (e.g., serum ALT), and genotype (HCV) do not accurately predict the extent of liver damage or the likelihood of future progressive liver disease.

Patients co-infected with HIV and HCV seem to be at significantly greater risk of progression to cirrhosis than patients infected with HCV alone. Fibrosis is more severe, cirrhosis is more common, and mortality due to end-stage liver disease is greater in co-infected patients than in patients with HCV alone. HCV viral loads are generally higher with concomitant HIV infection, which may account for the more rapid clinical progression of HCV in co-infected patients.

Although the hepatotoxic effects of antiretroviral (ARV) agents or a hyperactive immune response precipitated by HAART might accelerate HCV-induced liver damage, HAART is not contraindicated in HCV-infected patients and such patients should be treated with HAART as indicated by current HIV treatment guidelines. In fact, the Swiss HIV Cohort Study showed that patients with HCV co-infection had an increased risk of progression to a new AIDS-defining event or death, which supports the potential benefit of HAART for this group.7

D. Screening And Diagnostic Tests

Recommendations:

Clinicians should screen all HIV-infected patients for anti-HCV antibodies as part of the initial evaluation (see Figure 3).

Patients who are currently under care for HIV infection but have never been tested for anti-HCV antibodies should be tested for antibodies, even if they have no evidence of liver disease. If an ELISA for HCV antibodies is reactive in a patient who does not have known risk factors or evidence of liver disease, HCV infection should be confirmed with a qualitative PCR assay.

A negative HCV ELISA antibody test in HIV-infected patients, particularly those who are severely immunosuppressed (CD4 <100 cells/mm3), may not exclude HCV and should be followed by a qualitative PCR assay if serum liver enzymes are elevated and the individual has risk factors for HCV exposure.

A number of tests are available for diagnosis of HCV infection. The most readily available and inexpensive test is the ELISA for anti-HCV antibodies. These antibodies are not protective but rather serve as a marker of present or past disease. The ELISA test is highly sensitive but relatively non-specific, resulting in a low positive predictive value in low-prevalence populations. Seroconversion with the ELISA antibody test occurs in 50% of patients within 9 weeks of exposure, in 80% of patients within 15 weeks of exposure, and in at least 97% of patients within 6 months of exposure. Positive HCV ELISA antibody test results require confirmation by a qualitative HCV PCR when serum liver enzymes are not elevated. There is a small but measurable false-negative rate for antibody testing in patients who are severely immunosuppressed (CD4 <100 cells/mm3). When there is a strong clinical suspicion of HCV in a severely immunosuppressed individual, the PCR assay may be more sensitive than an ELISA antibody test.

HCV can be diagnosed definitively through qualitative assays for viral RNA using gene amplification techniques. With qualitative HCV RNA assays, HCV RNA is usually detectable within 1 to 2 weeks after exposure to the virus. However, because HCV RNA may be only intermittently detectable in chronically infected patients, a single negative qualitative HCV RNA assay does not exclude chronic HCV infection. Quantitative assays for HCV RNA (HCV viral load assays) are less sensitive than the qualitative assays, are not well standardized, and are generally not recommended for diagnostic purposes. Although they are in common use, quantitative HCV RNA assays are not currently approved by the Food and Drug Administration (FDA). Notably, the level of HCV RNA does not correlate with the severity of liver injury or fibrosis.

Click here to view Figure 3: Hepatitis C Virus Testing Algorithm

E. Evaluating The Patient Co-Infected With HIV And HCV

Recommendations:

Clinicians should obtain a substance use and alcohol history for HIV/HCV co-infected patients.

Clinicians should advise HIV/HCV co-infected patients and patients infected with HCV alone to discontinue intake of alcohol.

Clinicians should perform diagnostic testing to determine the presence of HCV viremia and the extent of liver pathology as early as possible for HIV/HCV co-infected patients.

Baseline evaluation of the HIV/HCV co-infected patient should include a clinical assessment for signs and symptoms of liver disease and baseline laboratory measurements, including serum AST and ALT, prothrombin time, and serum albumin. Quantitative HCV RNA assay and HCV genotype should be performed for those who are candidates for treatment.

For HIV/HCV co-infected patients who are candidates for treatment and have HCV genotypes 1 and 4, clinicians should obtain a liver biopsy; however, for genotypes 2 and 3, a biopsy may not always be necessary due to higher rates of treatment response.

Clinicians should screen HIV/HCV co-infected patients and patients infected with either virus alone for immunity to hepatitis A and B. If patients are found to be susceptible to either or both of these viruses, the clinician should vaccinate the patient against hepatitis A and hepatitis B accordingly. Patients who are at increased risk for and non-immune to hepatitis A and hepatitis B infection may be given the combined hepatitis A and B vaccine in a total of three doses at 0, 1, and 6 months.

Clinicians should refer patients with HCV viremia who are potential candidates for treatment to a specialist with experience in treating hepatitis C in patients with HIV infection or to a clinical trial.

Evaluation of the HIV/HCV co-infected patient is extremely important. Both laboratory and histologic evaluations can be performed. Usually clinicians begin the assessment with laboratory tests, including serum AST and ALT, prothrombin time, serum albumin, quantitative HCV RNA, and HCV genotype; however, these laboratory tests may not reliably reflect the degree of histologic damage caused by chronic HCV infection (especially in the setting of HIV co-infection). Given that there is laboratory-to-laboratory variability in quantitative HCV RNA test results, the same laboratory should be used for subsequent testing.

Liver biopsy is the most specific test for defining the extent of liver pathology induced by HCV infection and defining long-term prognosis. The histopathological changes in the liver involve two distinct processes: inflammation (piecemeal, lobular, and/or portal) and fibrosis. Several indices have been developed and validated to describe inflammation and fibrosis. The Ishak or Metavir scoring system should be used to grade liver biopsy results. These are based on a visual assessment of cellular inflammation of hepatocytes and fibrosis.

A healthcare provider with experience in HCV treatment or a gastrointestinal specialist should evaluate patients with inflammation and fibrosis more severe than Grade 2 or 3 before treating with pegylated interferon plus ribavirin. For patients with genotype 2 or 3, it may not always be necessary to obtain the liver biopsy based on the potentially more favorable response to interferon/ ribavirin treatment.

Acute infection with hepatitis A virus, normally a relatively benign and self-limited disease, is more likely to result in fulminant hepatic necrosis in the presence of HCV. Hepatitis A vaccine is safe for HIV-infected patients; more than two-thirds of HIV-infected patients immunized with hepatitis A vaccine develop protective antibody responses. The National Institutes of Health 2002 consensus statement recommends both hepatitis A and B vaccination for all non-immune HCV-infected persons. The epidemiologic risk for hepatitis B is similar to that for hepatitis C, and thus it is prudent to immunize susceptible patients with both hepatitis A and B vaccine.

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F. Selecting Patients For Treatment Of HCV

Recommendations:

Patients at greatest risk for progression to cirrhosis should be considered candidates for anti-HCV therapy (see Table 5).

The decision to treat should be individualized based on the patient’s desire to be treated, his/her immune status, extent of liver damage, HCV and HIV viral loads, risk of adverse effects of treatment, current ARV therapy, and absence of contraindications to therapy (see Table 6). ARV therapy may need to be modified, delayed, or interrupted to complete an adequate course of therapy for HCV.

HIV-infected patients with active HCV infection and/or evidence of chronic liver disease who are potential candidates for treatment should be referred to a specialist with experience in treating hepatitis C in patients with HIV infection for evaluation and guidance regarding possible treatment.

Clinicians should monitor liver pathology in HIV/HCV co-infected patients in whom treatment may be deferred by performing periodic ALT assays; clinicians should consider obtaining a liver biopsy every 3 to 5 years to reassess disease severity in this population.

Click here to view Table 6: Contraindications for Treating Patients With HIV/HCV Co-Infections

Click here to view Table 7: Childs-Pugh Classification

Given the current status of therapies for HCV, not all patients with HCV should receive treatment. Factors to be considered in the selection of patients for treatment include the likelihood of progression to cirrhosis in the absence of treatment, the likelihood of a favorable response to therapy, the patient’s commitment to therapy, and the risk of adverse effects of treatment (see Table 5).

Patients who are most likely to progress to cirrhosis include those with persistently elevated serum ALT, persistently positive HCV RNA assay, and a liver biopsy that shows either portal or bridging fibrosis and at least moderate inflammation and necrosis. Such patients should be considered potential candidates for treatment. Current National Institutes of Health recommendations for patients who do not meet these criteria are outlined in Table 8. Potential contraindications to treatment include cytopenias, uncontrolled thyroid disease, autoimmune disease, and organ transplantation. In addition, because of the significant risk of exacerbation of concomitant psychiatric disease, treatment with interferon is relatively contraindicated in patients with serious psychiatric diagnoses, such as bipolar disorder. Patients with other psychiatric disorders, such as schizophrenia, may be carefully selected for treatment if they are co-managed with a mental healthcare provider.

Patient motivation, age, duration of infection, viral genotype, and HCV RNA may be used in the decision to treat patients with normal ALT, although consensus guidelines do not currently recommend therapy for this group.

There is an inverse relationship between daily amount of alcohol consumed and the likelihood of response to therapy; heavy drinkers are unlikely to achieve sustained virologic response. Active substance use may interfere with adherence; however, several studies have shown that active and recent users can be treated successfully. Methadone is not a contraindication to treatment.

G. Treatment Of Hepatitis C Infection

Recommendations:

Treatment for HCV should be considered for all patients co-infected with HIV and HCV.

Given the available data, pegylated interferon alfa plus ribavirin is the treatment of choice (see Figure 4).

Clinicians should exercise caution when using interferon/ribavirin combination therapy in patients with cirrhosis or patients receiving HAART.

The combined use of didanosine and ribavirin is contraindicated.

Clinicians should obtain baseline studies to assess liver chemistry and measure complete blood counts, thyroid-stimulating hormone, glucose, quantitative HCV RNA in serum, HCV genotype, and -fetoprotein (only if cirrhotic) before initiating anti-HCV therapy. If the patient is female, the clinician should perform a pregnancy test due to potential teratogenic effects of HCV treatment.

Co-infected patients should be referred to a specialist with experience in treating hepatitis C in patients with HIV infection. This specialist should obtain a liver biopsy to assess the extent of liver damage. Based on the results of laboratory tests and the liver biopsy, the specialist should offer guidance and recommendations regarding treatment.

Click here to view Table 8: Current Treatment Guidelines

The most advanced new treatment modality for HCV infection is pegylated interferon. This form of interferon has covalently bound molecules of polyethylene glycol, which inhibit the metabolism of interferon. Therefore, pegylated interferon is metabolized slowly, permitting a weekly dosing schedule, increased serum levels of interferon, and improved anti-HCV activity. There are now two approved forms of pegylated interferon: alfa-2a and alfa-2b. Although the manner in which they are pegylated differs, clinical outcome is similar. See Table 9 for dosing recommendations.

Click here to view Figure 4: HCV Therapy for Treatment-Naïve Patients

Click here to view Table 9: Comparison Dosing With Interferon alfa-2a and -2b

The primary goal of HCV therapy for chronic hepatitis C is eradication of HCV from the serum as determined by undetectable HCV RNA. A secondary goal is reduction of hepatic inflammation/ necrosis with the expectation of decreased disease progression and subsequent reduction in hepatocellular carcinoma. Clinicians should consider the factors listed in Table 5 when determining the need for treatment in a particular patient. Treatment of hepatitis C has evolved over the last few years. Three to five years ago, the primary treatment of hepatitis C was monotherapy with interferon, which had poor sustained viral suppression rates (12% to 18%). The current treatment of choice for chronic HCV is a combination of pegylated interferon alfa-2b 1.5 µg/kg or pegylated interferon alfa-2a 180 µg given subcutaneously once per week + ribavirin 800 to 1200 mg/day depending on the genotype, weight, and type of pegylated interferon prescribed for 48 weeks. Some clinicians now recommend that the dose of ribavirin be based solely on the patient’s body weight (see Table 10). This combination anti-HCV treatment given to those with HCV alone yields sustained virologic suppression of approximately 55%. However, if one examines the response rate based on the HCV genotype, patients with type 1 achieve a sustained virologic response of approximately 45%, whereas those with non-type 1 HCV achieve sustained virologic responses of approximately 75%. Ongoing clinical trials in those with HIV/HCV co-infection will determine the tolerability and efficacy of pegylated interferon plus ribavirin in this group. Despite the lack of long-term data, pegylated interferon therapy with ribavirin (800-1200 mg/day) is currently the recommended treatment of choice for co-infected patients.

Click here to view Table 10: Ribavirin Weight-Based Dosing

The duration of treatment is determined by change in HCV RNA at week 24 of treatment (see Figure 4).

Patients who fail to respond to a first course of combination therapy rarely respond to a second course. Patients with persistent serum ALT elevations and viremia after 24 weeks of treatment are not likely to respond to the remainder of the standard course of therapy and are generally advised to discontinue treatment.

Ribavirin can cause hemolytic anemia, which may require dose reduction and/or the use of epoetin alfa (40,000 U SC weekly). Ribavirin is also teratogenic; male patients should prevent impregnating women while receiving treatment, and female patients should prevent pregnancy during therapy and for 6 months afterward. During treatment and for 6 months after treatment, both female and male patients receiving ribavirin should use two forms of effective contraception with one being a condom, even if their partner is already pregnant. Table 11 lists possible side effects.

Until recently, trials of HCV therapies have excluded patients co-infected with HIV. Many of the early studies of co-infected patients have been small with inconsistent outcomes. Most early interferon alfa monotherapy trials resulted in similar end-of-treatment responses but lower rates of sustained virologic response in patients who are co-infected with HIV compared with patients with HCV alone. In contrast, other studies have suggested that sustained virologic responses are equivalent among HIV/HCV co-infected patients and patients with HCV alone, but that patients with lower CD4 counts are likely to have poorer long-term response rates than patients with competent immune systems regardless of whether they are receiving HAART. A clearer picture should emerge in early 2004 when the results from several large randomized controlled HCV treatment trials in HIV-infected patients are expected to be reported.

In vivo studies of potential drug interactions between ribavirin and other HIV medications have not been conducted with the exception of didanosine. The combination of ribavirin and didanosine is known to raise didanosine levels. In several ongoing clinical trials, an increased risk of pancreatitis, lactic acidosis, and hepatic decompensation and death in patients with cirrhosis has been identified. Therefore, the combination of didanosine and ribavirin is contraindicated.

Recently, data from clinical trials have shown efficacy of pegylated interferon alone and as part of combination therapy with ribavirin 600-1200 mg/day in HIV/HCV co-infected patients. Following is a summary of recent findings:

  • Pegylated interferon-based therapy is the preferred treatment option. Pegylated interferon + ribavirin is more effective than pegylated interferon alone or standard interferon plus ribavirin.8
  • Decisions regarding treatment of HIV/HCV co-infected patients should be individualized. Patients with the greatest risk for progression/advanced liver disease should be considered for treatment despite limited data from clinical trials. These data include the following:
  1. Co-infected patients may achieve a sustained viral response to anti-HCV therapy.
  2. Levels of adverse events in co-infected patients are comparable with those seen in patients with HCV alone.
  3. HIV accelerates HCV progression/cirrhosis.
  4. Hepatitis C is a leading cause of death in the HIV-infected population.
  5. There may be an increased potential for liver cancer in the co-infected patient.
  6. Interferon may improve histological abnormalities.9
  • Data from ACTG 5071 show that 44% of HIV/HCV co-infected patients treated with pegylated interferon alfa-2a (180 µg) + ribavirin had an undetectable HCV RNA after 24 weeks of treatment compared with 15% of patients treated with interferon alfa + ribavirin. Also, data are available that show that even patients who did not respond to pegylated interferon demonstrated improvement in liver histology, suggesting a possible benefit of treatment even without viral eradication.10
  • 48-week end-of-treatment data from the RIBAVIC study was presented in mid-2002. This study compared ribavirin combined with either standard or pegylated interferon in co-infected patients. Among those who completed 48 weeks of treatment (n=195), 51% achieved an undetectable HCV viral load with pegylated interferon/ribavirin compared with 31% with interferon/ribavirin.11
Further studies of HCV treatment are ongoing that are intended to clarify optimal duration of treatment, correlation of sustained virologic response with improved survival, the role of maintenance interferon for non-responders, and re-treatment options for non-responders.

1. Non-Responders to Anti-HCV Treatment

Patients who were treated with interferon (with or without ribavirin) and did not achieve an end-of-treatment response or sustained virologic response are considered to be "non-responders." The following factors may predict failure to achieve a sustained virologic response:

  • Genotype 1
  • Advanced fibrosis
  • High baseline HCV viral load
  • Age >40 years
  • Longer duration of disease
  • Monotherapy versus combination therapy
  • Short duration of treatment
  • African American race
Maintenance interferon/ribavirin therapy for non-responders may have some benefit by decreasing the degree of fibrosis and delaying progression of hepatocellular carcinoma. None of the currently available treatments are FDA indicated for maintenance therapy. Preliminary results suggest that 15% to 20% of non-responders initially treated with standard interferon/ribavirin achieve a sustained virologic response upon re-treatment with pegylated interferon plus ribavirin. Patients with genotypes 2 or 3 have better response rates upon re-treatment than those with genotype 1. However, re-treatment is only FDA indicated for those who did not respond to previous interferon monotherapy.

Recent preliminary results of the HALT-C study, which gives a course of pegylated interferon plus ribavirin to previous non-responders with HCV infection alone, showed the following response rates: 37% achieved negative HCV RNA at week 20; 33% achieved negative HCV RNA at week 48; and 18% achieved negative HCV RNA at week 72. This study suggests that non-responders can be successfully treated with pegylated interferon plus ribavirin therapy. Patients with genotypes 2 or 3 responded more favorably than those with genotype 1. The following factors are also associated with a favorable response:
  • Low HCV viral load <1.5 million IU/mL
  • Virologic response at 12 weeks
  • Maintenance of full-dose ribavirin during treatment
  • Prior interferon monotherapy
Studies are ongoing to better define treatment strategies using pegylated interferon plus ribavirin in non-responders to improve sustained virologic responses. It is important to recognize that most studies completed to date have been performed in patients with HCV infection alone. Additional clinical trial results in co-infected patients are expected in early 2004.

2. Anti-HCV Treatment and HAART

Because HIV/HCV co-infection may predispose HIV-infected patients to hepatotoxicity from HAART, some experts suggest that there may be benefit in treating HCV infection before initiating ARV therapy. In fact, in some cases, it may be necessary to treat HCV before the patient is able to tolerate HIV therapy.

The combination of anti-HCV treatment and HAART in co-infected patients may lead to an increased incidence of metabolic complications and/or adverse drug interactions due to synergistic toxicity profiles. Lactic acidosis, pancreatitis, and hepatic decompensation have been reported in patients receiving didanosine-containing regimens in combination with interferon/ ribavirin. This may be due to the increased phosphorylation of didanosine by ribavirin and/or additive mitochondrial toxicity of these nucleoside analogues.12 As such, didanosine should not be used when simultaneously treating HCV with combination therapy.

3. Transplantation

Recommendation:

HIV Specialists should collaborate with transplantation programs to offer transplant as an option for HIV/HCV co-infected patients.

Transplantation offers patients another treatment option for HCV monoinfection or HIV/HCV co-infection. However, the availability of live donors and cadaveric liver allografts is a major obstacle. In addition, hepatitis C re-infection of the new liver continues to be an obstacle. Despite these issues, new advances in immunosuppressive agents, surgical techniques, and peri- and post-operative management have resulted in survival rates of ~90% after transplantation for chronic viral hepatitis. Outcome of transplantation may be influenced by multiple factors: pre-transplantation viremia, HLA compatibility, degree of immunosuppression, and the integrity of cellular immune responses.

Although all evaluations are individualized, in one program the criteria for liver transplant in HIV-infected persons include meeting standard requirements for liver transplantation (at least moderate liver disease, no advanced heart/lung disease, no moderate to advanced kidney failure, not on life support, and no liver cancer more advanced than Stage III disease) in addition to the anticipated ability to maintain HIV suppression even if their current serum liver enzymes do not allow for HAART.

The present data concerning transplant outcomes for HIV/viral hepatitis co-infection are limited. One study describes 10 HIV-infected liver recipients who had no history of opportunistic infections, CD4 counts >100 cells/mm3 (median, 375 cells/mm3), and undetectable HIV RNA at baseline.13 In this group, there was one death due to HCV-related cirrhosis 14.5 months post-transplantation. The same patient who died also developed CMV esophagitis and required re-transplantation. All other grafts remained viable, with median follow-up CD4 counts of 283 cells/mm3. Five of six successful orthotopic liver transplantations also were recently reported at 24-month follow-up in HIV-infected patients who received transplants.14 Therefore, HIV Specialists and transplantation programs should begin to collaborate to offer transplantation as a possible treatment option in the appropriately screened patient.

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H. Side Effects Of HCV Treatment

Interferon alfa has significant potential side effects (see Table 11), including flu-like symptoms, fatigue, alopecia, bone marrow suppression, and neuropsychiatric effects, including apathy, cognitive changes, irritability, and depression (see Mental Health Committee chapter Depression and Mania in Patients With HIV/AIDS). It is important to recognize that some of these adverse effects may be treatable with antidepressants and colony-stimulating factors for bone marrow toxicity. Side effects are severe enough to require dose reductions in 10% to 40% of patients and discontinuation of treatment in 5% to 10%. Patients treated with interferon may also develop a paradoxical worsening of liver disease, probably due to autoimmune processes, and fatal liver failure has occurred; however, this is a rare event and only occurs in patients with already decompensated liver disease. Therefore, patients with a Childs-Pugh classification of B or C must not be treated. Rising serum ALT levels during treatment may be an indication for discontinuation of treatment.

Click here to view Table 11: Possible Side Effects of Treatment for Hepatitis C

The most common toxicity of ribavirin is hemolytic anemia, which can be effectively treated with recombinant erythropoietin. Use of erythropoietin to maintain ribavirin dosing is preferential to reducing the dose of ribavirin. In addition, ribavirin is teratogenic and should be used with caution in women of child-bearing age. A monthly pregnancy test should be performed. Also, sexually active men and women taking ribavirin should use two forms of contraception.

I. Monitoring And Follow-Up Of The HIV/HCV Co-Infected Patient

Recommendations:

Clinicians should obtain a complete blood count and monitor serum ALT at 2- to 4-week intervals in patients receiving anti-HCV therapy (see Table 12).

A quantitative HCV RNA assay should be obtained after 24 weeks of treatment to determine whether the patient is responding to therapy.

If HCV RNA is undetectable or has decreased ≥2 log10 (100-fold) at 24 weeks, treatment should be continued for another 24 weeks (see Figure 4). If HCV RNA is detectable with <2 log10 reduction with persistently elevated serum liver enzymes, therapy should be discontinued; if serum liver enzymes have normalized, completing the course of therapy should be considered (see Figure 4).

Clinicians should perform a quantitative HCV RNA assay at the completion of therapy and again 24 weeks later to assess end-of-therapy response and sustained treatment response, respectively.

A repeat liver biopsy after eradication of HCV infection is not indicated.

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REFERENCES

1. Soriano V, Rodriguez-Rosado R, Garcia-Samaniego J. Management of chronic hepatitis C in HIV-infected patients. AIDS 1999;13:539-546.

2. Bica I, McGovern B, Dhar R, et al. Increasing mortality due to end-stage liver disease in HIV infection. Clin Infect Dis 2001;32:492-497.

3. Thorpe LE, Ouellet LJ, Levy JR, et al. Hepatitis C virus infection: Prevalence, risk factors, and prevention opportunities among young injection drug users in Chicago, 1997-1999. J Infect Dis 2000;182:1588-1594.

4. Kapadia F, Vlahov D, DesJarlais DC, et al. Does bleach disinfection of syringes protect against hepatitis C infection among young adult injection drug users? Epidemiology 2002;13:738-741.

5. Maggiolo F, et al. 43rd ICAAC, Chicago, September 2003, # V-774.

6. Sulkowsi MS, Thomas DL. Hepatitis C in the HIV-infected person. Ann Intern Med 2003;138:197-207.

7. 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 co-infection: The Swiss HIV Cohort study. Lancet 2000;356:1800-1805.

8. National Institutes of Health HCV Consensus Conference. Consensus Development Conference Statement. Management of hepatitis C. June 2002. Available at: http://consensus.nih.gov/cons/116/116cdc_intro.htm

9. Chung R, Andersen J, Alston M, et al. A randomized, controlled trial of pegylated interferon alpha-2a with ribavirin vs. interferon alpha-2a with ribavirin for the treatment of chronic HCV in HIV co-infection: ACTG A5071. 9th Conference on Retroviruses and Opportunistic Infections; Seattle, Washington; February 2002. Available at: http://www.retroconference.org/2002/Abstract/14102.htm

10. Sherman, et al. HCV RNA kinetic response to PEG-interferon and ribavirin in HIV-co-infected patients. ACTG 5071. 9th Conference on Retroviruses and Opportunistic Infections; Seattle, Washington; February 2002. Available at: http://www.retroconference.org/2002/Abstract/13849.htm

11. Perronne C, et al. RIBAVIC trial (ANRS HC02): A controlled randomized trial of pegylated-interferon alfa-2b plus ribavirin vs interferon alfa-2b plus ribavirin for the initial treatment of chronic hepatitis C in HIV co-infected patients: preliminary results. Fourteenth International AIDS Conference; Barcelona, Spain; July 2002; Abstract LbOr16, 2002.

12. Quereda C. 4th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV; San Diego, California; September 2001; Abstract 103.

13. Roland M, Stock P, Carlson L, et al. Liver and kidney transplantation in HIV-infected patients: A preliminary multi-site experience. 9th Conference on Retroviruses and Opportunistic Infections; Seattle, Washington; February 2002. Available at: http://www.retroconference.org/2002/Abstract/13851.htm

14. Neff G, Jayaweera D, Hung O, et al. Solid organ transplantation in patients with human immunodeficiency syndrome: A successful case series. 41st Interscience Conference on Antimicrobial Agents and Chemotherapy; Chicago, Illinois; December 2001. Abstract I-203. Available at: http://www.natap.org/2001/ICAAC/day28.htm