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Journal of Pharmacy Practice http://jpp.sagepub.com/

Management of Hepatitis C Infection in the HIV-Infected Patient Kelly McNelis Journal of Pharmacy Practice 2006 19: 37 DOI: 10.1177/0897190005284096 The online version of this article can be found at: http://jpp.sagepub.com/content/19/1/37

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New York State Council of Health-system Pharmacists

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M 10.1177/0897190005284096 HEPATITIS CNELIS C INFECTION IN HIV

Management of Hepatitis C Infection in the HIV-Infected Patient Kelly McNelis, BS, PharmD

Morbidity and mortality associated with HIV infection have rapidly decreased with the introduction of highly active antiretroviral therapy. Of recent concern is the increase of unusual opportunistic infections, particularly hepatitis C virus in this population. Because of the shared route of transmission, a significant number of HIV-infected patients are also coinfected with hepatitis C virus. HIV infection has been

demonstrated to increase the rate of hepatitis C virus disease progression. New data on the use of pegylated interferon plus ribavirin indicate that while cure of hepatitis C virus in the coinfected patient is a clinical challenge, it is possible. Aggressive management of anemia, drug-induced depression, and drug interactions increase the opportunity for clinical response and positive patient outcomes.

KEY WORDS: Pegylated interferon, ribavirin, hepatitis C virus, liver biopsy, fibrosis.

I

N THE UNITED STATES, highly active antiretroviral therapy (HAART) has led to a significant decrease in HIV- and AIDS-related morbidity and mortality.1,2 HAART has also decreased morbidity and mortality from common opportunistic infections experienced by this patient population.3,4 Because of the shared routes of transmission, hepatitis C virus (HCV) coinfection in HIV-infected individuals has emerged as a significant and somewhat common opportunistic infection. HCV can be transmitted from intravenous drug use (IVDU), from mother to infant, via needle-stick injury, or through unprotected sexual contact. HCV has become the most important cause of chronic liver disease and ultimately death from cirrhosis and hepatocellular carcinoma.5,6 In the United States, the number of HIV and HCV coinfected persons is estimated to be 150 000 to 300 000.3,6 In HIV-infected patients with a history of IVDU, several studies have documented a 50% to 90% coinfection rate.7-9 The management of HCV in the setting of HIV is complicated but safe and in most cases well tolerated. Newer data on the use of combination therapy with pegylated interferon and ribavirin in coinfected patients indicates improved outcomes. Pharmacists as members of HIV and HCV treatment teams can positively affect patient care. EPIDEMIOLOGY HCV is a single-stranded RNA virus of the Flaviviridae family, within the Hepacivirus genus. The

virus was discovered in 1989 and has since been recognized as a significant cause of hepatocellular carcinoma, chronic hepatitis, and liver fibrosis.10 There are approximately 50 subtypes but only 6 genotypes. In the United States, genotype 1 is most commonly seen, accounting for approximately 70% to 75% of all infections. Genotype 1 also has the lowest response rate to treatment. Genotypes 2, 3, and, to a lesser extent 4, 5, and 6, account for the remaining number of cases.4,6 Because genotypes 2 and 3 respond more favorably to treatment, genotyping patients before treatment is extremely important. In the United States, approximately 2% of the general population or about 2.7 million people are HCV infected.11,12 The efficiency of transmitting HCV varies depending on the route of transmission. Heterosexual transmission of HIV is more common than is the transmission of HCV. Sexual transmission of HCV, while uncommon, may be increased in the setting of HIV/HCV coinfection.13 HCV is approximately 10

To whom correspondence should be addressed: Kelly McNelis, BS, PharmD, Christiana Care Health Services–Wilmington Hospital Annex, HIV Community Program Room 221, PO Box 1668, Wilmington, DE 19899-1668; e-mail: [email protected]. Kelly McNelis, BS, PharmD, clinical pharmacy specialist–HIV Community Program, Christiana Care Health Services, Wilmington Hospital Annex, Wilmington, Delaware. JOURNAL OF PHARMACY PRACTICE 2006. 19;1:37–52 © 2006 Sage Publications DOI: 10.1177/0897190005284096

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MCNELIS

times more infectious than HIV is from percutaneous exposure and in hemophiliacs, with a transmission rate of 1.5% to 3% versus 0.3%, respectively.4,14 Perinatal transmission of HCV is estimated to be 5%, but the presence of HIV infection increases transmission rates to 17%.4,15 Accidental percutaneous exposures to HCV in health care workers resulted in a seroconversion rate of approximately 1.8%,16-18 while documented transmission of HIV in this setting is substantially lower at an estimated rate of 0.3%.16,19 NATURAL HISTORY The natural history of HCV has been difficult to review and assess because patients are usually asymptomatic in early disease. Long-term complications from HCV, as well as hepatocellular carcinoma and fibrosis, take years to develop. Time between initial infection and long-term complications can range from 20 to 30 years.20,21 After acute infection, approximately 15% to 20% of patients are able to clear the virus from their blood without developing chronic HCV infection. However, in the HIV coinfected population, HCV clearance occurs at a lesser rate of 5% to 10%, especially in those patients with lower CD4 counts.22,23 The remaining 80% to 85% of persons will go on to develop chronic HCV infection and ongoing viremia. These patients may or may not have elevated alanine aminotransferase (ALT) levels. Because there are no reliable markers of disease progression, predicting how quickly the disease will advance or how soon a chronically infected patient will develop fibrosis, liver failure, or hepatocellular carcinoma is difficult. After 20 years of HCV infection, there is a 5% to 25% chance of developing cirrhosis, depending on the population studied.21 EFFECT OF HIV ON HCV HCV disease progression appears to be dramatically affected by HIV coinfection. Multiple studies have documented that HCV RNA levels are higher in patients with HIV disease.24-26 HIV may shorten the time course to development of liver failure. In short, HCV, in the setting of HAART, has become a significant, and potentially fatal, opportunistic infection. Hospital admissions and deaths due to HCV in HIV coinfected patients have increased.27 The mechanism for accelerated HCV progression could be due to the decrease in cell-mediated immunity associated with HIV infection or possibly even di-

rect cytotoxic activity of HIV on the hepatocyte.20,28 The presence of HIV infection increases the chance of HCV transmission and increases the probability of chronic HCV viremia. 28-31 The increased incidence of hepatotoxicity from HAART will be discussed later, as will the decreased efficacy of HCV treatment modalities in HIV/HCV-infected individuals. EFFECT OF HCV ON HIV While significant data exist to support the direct effect of HIV infection on HCV, the reverse is not necessarily true. Conflicting data point to both no impact on HIV progression and worsened immune reconstitution due to HCV. Dorrucci and colleagues29 studied 1052 HIV-positive patients over 9.7 years in both the preHAART (June 1991-May 1996) and post-HAART (June 1996-June 2001) eras to determine whether HAART and HCV had any effect on progression to AIDS. In the pre-HAART time period, HCV/HIV coinfection did not affect the progression to AIDS. However, in the postHAART time period, coinfection appeared to increase progression to AIDS (P = .009).29 This study is contrasted by previous work that indicates no dramatic change in HIV disease and progression to AIDS in an HIV/HCV-infected cohort. The presence of HCV, while controversial, appears to have little impact on progression to AIDS over time.30,31 HAART-ASSOCIATED HEPATOTOXICTY Overall, available information suggests that HCV can be safely treated in the setting of HIV, as long as liver enzyme tests are routinely followed. Of the 4 classes of commercially available agents to treat HIV and AIDS, the protease inhibitors (PIs), because of hepatic metabolism, appeared to be of greatest concern. As many as 50% of patients on PIs can develop asymptomatic increases in liver enzymes. This is particularly true with ritonavir.32 The use of lower dose ritonavir in “dose-boosting” regimens has decreased these enzyme changes. However, newer data on the hepatotoxicity of the nonnucleoside reverse transcriptase inhibitors, particularly nevirapine, also raise apprehension. Nevirapine can cause a hypersensitivity reaction with elevated liver enzymes, rash, fever, and eosinophilia. The drug should be discontinued immediately if this reaction occurs.32 As a class, the nucleoside reverse transcriptase inhibitors (NRTIs) are well known for causing mitochondrial toxicity, including lactic acidosis, hepatic steatosis, pancreatitis, and increased creatine kinase, and can lead to hepatic fail-

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HEPATITIS C INFECTION IN HIV ure.32 HAART should not be discontinued in patients on HCV treatment; however, close monitoring and careful choice of an antiretroviral regimen is vitally important to treatment success. NRTIs with the highest affinity for the enzyme DNA polymerase g, which puts patients at increased risk for mitochondrial toxicity (didanosine, stavudine, and zalcitabine), should be avoided, and zidovudine, lamivudine, abacavir, and tenofovir can be substituted depending on genotypic profile.32 It is important to note that the impact of HAART is so significant that the risk outweighs the benefit, and antiretroviral treatment should not be withheld. A cautious approach to monitoring side effects and laboratory values is the key to success. DIAGNOSIS According to the currently published HIV/HCV treatment guidelines, any patient diagnosed with HIV infection should be screened for HCV infection because of the shared modes of transmission.4,12,33,34 In addition, those who have risk factors for HCV—IVDUs, hemophiliacs, underserved patient populations, patients who are on dialysis, those with unexplained increases in ALT levels, recipients of transfusions before 1992, children of HCV-positive mothers, health care professionals exposed to blood or body fluids through a needle-stick or mucosal exposure, and, although the prevalence is low, current sexual partners of HCV-infected people—should be tested.4,33 HCV antibodies (anti-HCV) can be measured easily in serum or plasma. The HCV RNA quantitative test will then document the range of HCV viremia, or lack thereof. If the HCV RNA test is negative in the presence of a positive anti-HCV test, it is likely that the patient resolved his or her HCV infection. It is important to note that a negative HCV RNA test may also indicate sporadic or lowlevel but present viremia or a false-positive anti-HCV. The American Association for the Study of Liver Diseases (AASLD) guidelines document the commercially available quantitative HCV RNA assays and their specifications.12 In immunocompromised patients, it is also important to remember that the routine serologic assay, anti-HCV, may not detect antibodies to HCV. HCV RNA may be used to clarify a suspected case of decreased antibody production. Another important function of the HCV RNA quantitative test is to measure response to treatment. The same quantitative test should be used initially and then while on treatment to determine response. As mentioned earlier, there are 6 major HCV genotypes. Since genotypes 2 and 3 respond better to treat-

ment and genotypes 1 and 4 are more challenging to treat, it is important to determine the patient’s genotype before initiating drug therapy. Genotype can be determined by 2 commercially available, but not yet approved by the Food and Drug Administration (FDA), clinical test kits.4,12 The role and utility of liver biopsy have been debated in all available guidelines.4,12,33,34 Table 1 reviews important topics covered in these guidelines. Biopsy can provide important information on urgency of treatment by documenting staging of disease and fibrosis. Two popular grading systems, Metavir and Ishak, grade the degree of hepatic inflammation as well as the staging of fibrosis.35,36 A Metavir fibrosis score of ³2 or an Ishak score of ³3 indicates the need for treatment of HCV.4 However, fibrosis score is only 1 consideration of many to begin this complicated therapy. The European Consensus Conference Guidelines33 recommend biopsy as the gold standard but suggest patient acceptance and importance of information gathered for treatment decisions be considered before deciding on a biopsy. The AASLD guidelines,12 with moderate medical evidence, support getting a liver biopsy if results will influence whether treatment is recommended. These guidelines do not recommend biopsy for starting HCV therapy. The International Consensus Panel also does not recommend deferring HCV therapy based on the lack of liver biopsy.34 Liver biopsy is recommended by the Opportunistic Infection Treatment Guidelines, although the authors note that many specialists would begin treatment without a biopsy.4 Because of the important histology revealed by liver biopsy, for patients who do not undergo treatment of HCV, it has been suggested that biopsy be considered every 2 to 5 years to follow disease progression. 3 However, current guidelines clearly state that liver biopsy is not required to proceed with HCV treatment in the coinfected patient. TREATMENT After screening all HIV and HCV coinfected patients, evaluation for treatment can begin. To prevent further liver damage, nonpharmacologic interventions can be instituted while evaluation for HCV treatment continues. Patients should be educated on discontinuation of alcohol intake. Alcohol has been assessed as an independent risk factor for HCV disease progression in coinfected patients.37,38 In one study, more than 50 g/d of alcohol (approximately equal to 3 drinks per day) resulted in increased fibrosis progression.38 In general, alcohol consumption in HIV/HCV coinfection should

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No

No

Avoid didanosine; use zidovudine and stavudine with caution

Avoid didanosine

No

Not required Consider starting therapy before CD4 800 mg/d Avoid didanosine, zidovudine, stavudine

Yes No Contraindicated

Yes Yes Consider; outcomes poor Not mandatory “Stable” disease not defined

Yes Yes

Yes

European Consensus Guidelines

Note: AASLD = American Association for the Study of Liver Diseases; IDSA = Infectious Diseases Society of America; CDC = Centers for Disease Control and Prevention; NIH = National Institutes of Health; HIVMA = HIV Medical Association; OI = opportunistic infection; ETOH = alcohol; IVDU = intravenous drug user; PCR = polymerase chain reaction.

Use of zidovudine and/or didanosine

Avoid didanosine; use zidovudine with caution

Yes No No

No No

Yes No No

Endorses liver biopsy CD4 count threshold for treatment

Duration of treatment 48 wk Suggest plan to manage nonresponders Recommend treatment in the setting of ongoing ETOH and drug use Recommend ribavirin dosing scheme

Yes Yes ETOH; consider treatment in recovering IVDU Yes Yes Consider

Yes Yes Yes Yes Yes if CD4 >100 cells/mm3 and HIV RNA 350 cells/mm3 HIV PCR 2log10 change in HCV RNA is not seen at 12 weeks, treatment should be discontinued.4,12,33,34 A second treatment goal is to reduce the risk of hepatocellular carcinoma and liver failure. Patients whose HCV RNA levels are decreased by >2log10 but never become undetectable are known as partial responders and may have improvement in histologic findings. However, continuation of HCV treatment in this subset of patients is controversial. It is important to

note that in HIV-infected patients, the HIV RNA correlates directly to disease improvement and clinical outcomes. In HCV treatment, the goal is eradication of virus, and clinical outcomes are not directly correlated with changes in HCV RNA quantitative measures. Clinical Trial Data Clinical trial data regarding the treatment of HCV in the HIV-infected patient population have been lacking until recently. Four important original articles have recently been published and are reviewed in detail in Table 2. Chung and colleagues,42 for the AIDS Clinical Trials Group A5071 Study Team, compared peginterferon alfa-2a plus ribavirin (n = 66) to standard interferon alfa-2a plus ribavirin in a coinfected population (n = 67) for 48 weeks of treatment. Ribavirin was dose escalated in this trial to avoid treatment-induced anemia. Clinical end points included virologic response, which will be discussed below, and safety at week 24, EVR at 12 weeks on therapy, and SVR 24 weeks after stopping HCV treatment, in addition to any change in HIV RNA, CD4 cell count, or development of an AIDS-defining illness. Patients were stratified by history of antiretroviral therapy as stable on HAART for greater than 12 weeks (CD4 >100 cells/mm3 with HIV polymerase chain reaction [PCR] 300 cells/mm3 and no need for HAART during the trial. Patients were also stratified based on HCV genotype: genotype 1 versus genotype 2/3. Patients possibly endured 1 or more of 3 biopsies during the trial, 1 at baseline, 1 in those who had no virologic response after 12 weeks looking for possible histologic response, and 1 biopsy at week 24 for patients with virologic response. Virologic response was defined in this trial as HCV RNA