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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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MCNELIS C INFECTION IN 10.1177/0897190005284096 HIV HEPATITIS

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.

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

I

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 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-

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-

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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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Table 1 Overview of Treatment Guidelines for Hepatitis C Virus and HIV Coinfected Adults AASLD/IDSA Practice 12 Guideline (Strader et al ) Yes Yes Yes Yes Yes, especially in genotype 1 Yes Yes CDC/NIH/HIVMA/ IDSA OI Guidelines European Consensus Guidelines Yes Yes Yes International Consensus 34 Panel (Soriano et al ) Yes Yes Yes Yes Yes ETOH; consider treatment in recovering IVDU Yes Yes Consider No No Yes Yes Yes if CD4 >100 cells/mm3 and HIV RNA <200 copies/mL No CD4 >350 cells/mm3 HIV PCR <50000 copies/mL Yes No No No Avoid didanosine; use zidovudine with caution No Avoid didanosine; use zidovudine and stavudine with caution Yes No No Not required Consider starting therapy before CD4 <500 cells/mm3 Yes No No No Avoid didanosine Yes Yes Consider; outcomes poor Not mandatory “Stable” disease not defined Yes No Contraindicated

Group

Recommends universal screening for HCV in HIV-infected patients Endorses hepatitis A and B vaccination Urges discontinuation ETOH/IVDU

Treatment: peginterferon + ribavirin No response by 12 wk predicts failure Endorses liver transplantation

Endorses liver biopsy CD4 count threshold for treatment

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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

Use of zidovudine and/or didanosine

Encourage doses >800 mg/d Avoid didanosine, zidovudine, stavudine

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.

HEPATITIS C INFECTION IN HIV

be avoided, although studies in the HIV-negative, HCVpositive population vary widely in the definition of significant intake.37,38 As a general rule, patients should be counseled to discontinue alcohol intake and, if necessary, enter an alcohol treatment or relapse-prevention program.9 Coinfected patients who are considering treatment of HCV should also report a full medication history to the treatment team, including prescription medications from all health care providers and the use of vitamins, natural products, or herbal products that could prove to be hepatotoxic. Coinfected patients are at risk for developing fulminant hepatitis if they contract hepatitis B infection, hepatitis A infection, or both, unless previously exposed or vaccinated. Therefore, these patients should be tested for immunity and vaccinated for hepatitis A and hepatitis B if necessary, despite documented decreased efficacy of these vaccines in immunocompromised patients.39-41 Hepatitis A antibodies can be measured and if not present, the vaccine series can be administered. Hepatitis B core antibody can be measured and if positive, testing for hepatitis B surface antigen and DNA can be pursued. Treatment Goals Previously, because of a lack of clinical trial data in coinfected patients, treatment strategies in this population were based on established clinical data in HCVmonoinfected patients. However, 4 recent clinical trials in the coinfected population have been published and will be reviewed in this article. Treatment goals in the coinfected population should be to eradicate HCV as measured by an undetectable end-of-treatment viral load, called end-of-treatment response; then again, 6 months after treatment completion, HCV RNA should remain undetectable, termed sustained virologic response (SVR).3,12,34 Current guidelines note that a 2log10 response at week 12 of treatment, called early virologic response (EVR), is a predictor of reaching SVR. Because of the complexity and toxicity of treatment in this patient population, if a >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] <10 000 copies/mL) or CD4 >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 <60 IU/mL. Those who had virologic response at week 24 continued therapy and finished at week 48. HCV RNA levels were assessed at baseline and at weeks 4, 8, 12, 36, and 60. Peginterferon plus ribavirin was associated with a significantly higher rate of SVR than was interferon and ribavirin, 27% versus 12% (P = .03), respectively. Also, SVR in patients with genotype 1 occurred less frequently than in those with genotype 2/3, 14% versus 73%, respectively. Those who did best in this trial received peginterferon and ribavirin, had no history of IVDU, and had genotype 2/ 3. It is important to note that patients who continued treatment through week 24 had CD4 cell count drops averaging 103 cells/mm3; this is not surprising since interferon can suppress white blood cells (although CD4 percentage can increase during the same time period).

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Table 2 Overview of Clinical Studies of Peginterferon alfa-2a or alfa-2b and Ribavirin APRICOT (Torriani et al43) Barcelona Study Group (Laguno et al45) RIBAVAC (Carrat et al46) ACTG 5071 42 (Chung et al ) 95 412 French, 71 site, grant funded, Prospective, single center, randomized, open label, parallel randomized, open-label trial, 48 wk of therapy for genotype 1 group, stratified, 48 wks of therapy Weight-based PEG-IFN 2b SQ + 1.5 mg/kg PEG-IFN 2b SQ weekly ribavirin vs 3 million IU IFN 2b (n = 205) vs 3 million IU IFN 2b SQ 3 times a wk (n = 207) 3 times a wk + ribavirin 133 868 International, 95-site, drugUS, 21 site, prospective NIH funded, randomized, controlled, company sponsored (Roche), randomized, stratified, 48 wk stratified, 48 wk of therapy of therapy 180 mg PEG-IFN 2a weekly 180 mg PEG-IFN 2a weekly (n = 289 ribavirin and n = 290 (n = 66) vs 6 million IU IFN 2a placebo) vs 3 million IU IFN 2a 3 times a wk ´ 12 wks, then 3 3 times a wk with ribavirin million IU IFN 2a 3 times a wk (n = 289) thereafter (n = 67) Stepped dosing 600 mg/d ´ 4 wk, 800 mg/d or placebo 800 mg/d ´ 4 wk 1000 mg/d ´ 4 wk 82 81 <60 kg = 800 mg/d; 60-75 kg = 800 mg/d 1000 mg/d; >75 kg = 1200 mg/d 68 74 93 NA NA 482 67 (<400 copies/mL) 83 57 27 20 48 33 19 474 60 86 46 27 12 84 61 40 12 79 11 10 530 60 NA NA NA 560 NA; mean viral load 199 copies/ mL 88 74 44 21

Study

Number of patients Type of study

Dose peginterferon (PEG-IFN) or interferon (IFN)

Dose ribavirin

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Male, % Race, % White Black Other Mean CD4 count, no./mm3 HIV-1 RNA <50 copies/mL, %

HAART, % HCV therapy finished, % SVR, % peginterferon + ribavirin SVR, % standard interferon + ribavirin

Source: Modified from Manns et al.47 Note: NIH = National Institutes of Health; SQ = subcutaneous; NA = not available; HAART = highly active antiretroviral therapy; HCV = hepatitis C virus; SVR = sustained virologic response.

HEPATITIS C INFECTION IN HIV

HIV RNA levels changed minimally through week 24 of treatment, and no clinical progression to AIDS was seen during this trial. All values returned to baseline 24 weeks after stopping therapy. Although adherence to HCV treatment regimen was not measured during this trial, it is an important measure that should be reviewed as a factor influencing SVR. Dose escalation of ribavirin in this study design was done to decrease hematologic toxicity and retain participants. ACTG 5071 documented a 12% premature discontinuation rate despite incorporating this strategy into the trial. Torriani and colleagues,43 with the AIDS Pegasys Ribavirin International Coinfection Trial (APRICOT) study group, compared 3 regimens: peginterferon alfa2a and ribavirin, peginterferon alfa-2a and placebo, and interferon alfa-2a and ribavirin. The clinical end point of this trial was an HCV RNA <50 IU/mL 72 weeks after starting therapy (SVR), 48 weeks on therapy, and at 24 weeks of follow-up. Patients were stratified by HCV genotype, presence of cirrhosis, baseline ALT divided by the upper limit of normal (ALT quotient), geographic region, CD4 cell count <200 or ³200 cells/mm3, antiretroviral therapy, and histologic activity index score. This score was calculated based on liver biopsy findings to stage hepatic inflammation and fibrosis. All patients received liver biopsies in this trial. Virologic response was defined as an HCV RNA <50 IU/mL at the end of study follow-up and was measured at weeks 4, 12, 24, 36, and 48 of treatment and at weeks 12 and 24 during the study follow-up period. The overall SVR, regardless of HCV genotype, was dramatically different in the peginterferon and ribavirin group versus interferon and ribavirin or peginterferon and placebo: 40%, 12%, and 20%, respectively (P < .001). In genotype 1, the SVR rates were 29% for peginterferon and ribavirin, 14% for peginterferon and placebo, and 7% for interferon and ribavirin. As expected, those with HCV genotypes 2/3 had significantly better response rates than did participants with genotype 1 (62% vs 29% achieved SVR, respectively). As with the ACTG 5071 trial, mean CD4 cell counts decreased in all groups and CD4 percentages increased, with little to no change in HIV RNA levels. The APRICOT trial had 10 AIDS-defining events distributed evenly between the 3 study groups. The impressive size of this trial provides significant results. It is interesting to note that the peginterferon and placebo group had better SVR rates than the interferon and ribavirin group did, which may be important in cases in which patients may not be able to tolerate ribavirin, although the current standard of care is peginterferon and ribavirin combination therapy. It is

important to note for all of the clinical trials reviewed here that higher doses of ribavirin in HCVmonoinfected patients, 1000 to 1200 mg/d, demonstrated improved SVR.44 Consideration should be given to comparing SVR rates of this study and ACTG 5071. The latter trial had lower SVR rates, with a particularly large difference between those with genotype 1 infection. It is difficult to compare these trials, but perhaps the stepped ribavirin-dosing approach used by Chung and colleagues42 negatively affected SVR outcomes. Laguno and colleagues,45 for the Barcelona Study Group, compared peginterferon alfa-2b plus ribavirin with interferon alfa-2b plus ribavirin for the treatment of HCV in coinfected patients. The primary clinical end point of the trial was the number of patients with undetectable HCV PCR at 48 and 72 weeks (<500 copies/ml). If patients were not undetectable at 24 weeks, they were considered treatment failures and therapy was discontinued. Secondary clinical end points included EVR at 48 weeks, sustained biochemical response (SBR) defined as normal ALT levels at the end of 24 weeks, and relapses in patients who had EVR but did not maintain SVR. Patients were divided into 1 of 2 treatment arms. Peginterferon was dosed at 100 mg for patients weighing less than 75 kg and 150 mg for patients weighing more than 75 kg. The ribavirin dosing was weight based and is reviewed in Table 1. Patients who received interferon received 3 million units subcutaneously 3 times a week with weight-based ribavirin. HCV RNA was measured at weeks 4, 24, 36, 48 (end of therapy), 60, and 72. Liver biopsy was performed on all patients prior to randomization and was graded by one pathologist at the institution. Most of the study participants were men on antiretroviral therapy who had a previous history of IVDU. Sixty-three percent of the study population was genotype 1 or 4. Patients who were genotype 2 or 3 received 24 weeks of therapy if their HCV RNA was <800000 IU/mL at baseline. Dose adjustments could be made in peginterferon, interferon, or ribavirin based on adverse events as an attempt to keep patients in the study and on medication. Overall, 34% of all participants achieved an SVR, 44% in the peginterferon group versus 21% in the interferon group (P = .17). Of those with genotype 1 or 4, 24% had SVR at 48 weeks versus 50% of those with genotype 2 or 3, regardless of treatment group. Patients with lower baseline HCV PCR, genotype 2 or 3, and a lower degree of fibrosis had increased rates of SVR.45 CD4 count, not percentage or HIV RNA, decreased slightly in study participants. In short, therapy was well tolerated, and the peginterferon plus ribavirin group had statistically significant increased rates of SVR when compared to interferon plus ribavirin in all
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MCNELIS

study participants. The authors recognized that 20% of patients obtaining SVR had increased ALT levels at the end of the study, noting that SBR is not a good marker of virologic response to treatment and should not be used as such. The last important clinical trial to be discussed is from Carrat and colleagues for the ANRS HCO2 RIBAVIC Study Team.46,47 This study compared peginterferon alfa-2b administered weekly plus 800 mg of ribavirin daily to 3 million IU interferon alfa-2b administered 3 times a week plus 800 mg of ribavirin daily for 48 weeks. As with the other trials reviewed here, the primary clinical end point for this study was SVR < 50 IU/mL at week 72, although HCV RNA levels were reviewed at weeks 4, 12, 24, 48, and 72. The secondary end point for this trial was histological improvement determined by review of pre- and posttreatment biopsy results. Liver tissue inflammation and fibrosis were evaluated using previously validated scoring systems.35,36 A decrease of 1 point or more between the Metavir and/or Ishak scores pre- and posttreatment was considered histologic improvement. Patients were stratified by HCV genotype, severity of HIV infection, baseline HCV RNA, antiretroviral history, and mode of acquiring HCV infection. All patients received liver biopsy before and after treatment. This study included a stepwise reduction in peginterferon and interferon as well as in ribavirin dosing, with the goal of keeping patients on therapy while decreasing the rates of adverse events. A total of 412 patients was included in data analysis with the following clinical outcomes: 27% of patients in the peginterferon and 20% of patients in the standard interferon group had an SVR at week 72. If patients did not have an undetectable HCV RNA at week 12 in either group, 99% to 100% of them were unable to obtain an SVR at week 72, demonstrating that early virologic response to treatment is essential for SVR once therapy is completed. Those with genotype 1 or 4 had poorer SVR rates compared to those with genotypes 2, 3, or 5: 17% versus 44%, respectively. However, in genotype 1 or 4, those who received peginterferon/ribavirin had better rates of SVR than did those who received interferon/ ribavirin: 17% versus 8% (P = .006), respectively. The authors did not report any CD4 cell or HIV RNA changes during this trial. There was 1 study death that was attributed to peginterferon and ribavirin therapy. This patient developed decompensated cirrhosis, severe thrombocytopenia, sepsis, and liver failure and died at study week 32. In addition, it is important to note that 11 patients receiving didanosine containing HAART developed symptomatic mitochondrial toxic-

ity. The manufacturers of didanosine added a warning to the prescribing information that coadministration of didanosine and ribavirin is contraindicated.48,49 The ribavirin dose-reduction component of this study did not appear to keep more patients on HCV therapy. This important clinical trial demonstrated that HCV genotype is the most important predictor of disease response followed by younger age and a lower HCV RNA level. Drug Therapy The pegylated formulations of interferon provide a longer half-life, easier dosing, and higher serum concentrations than do standard interferon preparations.48,49 The addition of polyethyleneglycol (PEG) to interferon produces a molecule that is active against HCV and cleared more slowly from the body.48-50 These preparations combined with ribavirin have become the standard of care for the HCV-monoinfected population because of better clinical outcome data and increased rates of SVR.6 Combination therapy with pegylated interferon and ribavirin has not been FDA approved in the coinfected population because of a lack of clinical trial data. However, multiple interferon alfa-2b and interferon alfa-2a products are FDA approved for the treatment of HCV infection in the non-HIV-infected patient population.3 Currently, 2 pegylated interferon products are commercially available in the United States. PEG-Intron, peginterferon alfa-2b, is manufactured and marketed by the Schering Corporation. This product is available as a Redipen for direct reconstitution and injection and also as a vial of powder requiring reconstitution with sterile water. The polyethylene glycol (PEG) molecule in PEG-Intron is covalently attached to interferon alfa2b. The addition of this large molecule, 12 000 d, extends the half-life of interferon. The peginterferon product has a 10-fold greater Cmax and 50-fold greater area under the curve (AUC) than does Schering’s standard interferon product. It is not known whether peginterferon has any effect on drugs metabolized by the cytochrome P450 enzyme system. Table 3 reviews dosing and drug discontinuation guidelines.48 Roche Laboratories makes PEGASYS, peginterferon alfa-2a. This product is marketed with COPEGUS, ribavirin, and has a molecular weight of 20 000 d. PEGASYS is available in an injectable solution as well as in prefilled syringes. Maximum serum concentrations of this product occur 72 to 96 hours after dosing, and the drug clears at a significantly slower rate than

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Table 3 Combination Dosing Guidelines for Hepatitis C Treatment Products: Pegylated Interferon Alfa-2b (PEG-Intron) and Ribavirin (Rebetol) Therapy PEG-Intron Dosing Recommendations PEG-Intron Vial Strength 50 mg/0.5 mL 80 mg/0.5 mL 120 mg/0.5 mL 150 mg/0.5 mL Rebetol Dosing Recommendations for Weight-Based Dosing Body Weight, kg <40 40-64 65-85 86-105 >105 PEG-Intron and Rebetol Dose Modifications, Hematologic Toxicity Laboratory Value Permanently discontinue PEG-Intron Rebetol 600 800 1000 1200 1400 Amount of Rebetol to Administer (Twice-Daily Dose), mg/d 50 64 80 96 120 150 0.5 0.4 0.5 0.4 0.5 0.5 Amount of PEG-Intron to Administer, mg Volume of PEG-Intron to Administer, mL

Body Weight, kg

<40 40-50 51-60 61-75 76-85 >85

Hemoglobin level, g/dL

White blood cell count

Decrease by 200 mg/d Permanently discontinue Permanently discontinue Permanently discontinue Permanently discontinue

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Neutrophils

Platelets

<10 <8.5 <1.5 ´ 109/L <1.0 ´ 109/L <0.75 ´ 109/L <0.5 ´ 109/L <80 ´ 109/L <50 ´ 109/L

Reduce dose by 50% Permanently discontinue Reduce dose by 50% Permanently discontinue Reduce dose by 50% Permanently discontinue PEG-Intron and Rebetol Dose Modifications, Depression

Initial Management Dose Modification No change ¯ PEG-Intron to 50% Visit Schedule Evaluation once weekly Evaluate every wk or every other wk Remains Stable Continue weekly visits Consider psychiatric consultation; continue reduced dosing Obtain immediate psychiatric evaluation Psychiatric therapy necessary

Depression Improves Resume normal schedule Worsens

Depression Severity

Mild

Moderate

See moderate or severe status See severe depression

Severe

Discontinue both drugs permanently

If symptoms improve and are stable for 4 wks, resume normal schedule; consider ­ to normal dose Psychiatric therapy necessary

Psychiatric therapy necessary

45

Note: For patients with stable cardiac disease who experience a drop in hemoglobin levels of >2 g/dL in a 4-week period, PEG-Intron dose should be decreased by half and Rebetol should be decreased by 200 mg/d. If hemoglobin levels drop below 12 g/dL after this dose reduction, both agents should be discontinued.

MCNELIS

interferon alfa-2a does in healthy subjects. Table 4 reviews dosage and drug discontinuation guidelines.49 Both products are contraindicated in patients with hypersensitivity to any component of the product, autoimmune hepatitis, decompensated liver disease, pregnant women or men whose female partners are pregnant (ribavirin is pregnancy category X), patients with hemoglobinopathies, and patients with a creatinine clearance <50 mL/min. Both forms of the drug are subcutaneously injected once weekly.48,49 Ribavirin is a nucleoside analog that should be used only in combination with peginterferon or interferon for the treatment of HCV. Ribavirin is manufactured by several companies and is available in a generic formulation. It is manufactured in a 200-mg capsule or 40mg/mL solution. The AUC and Cmax of ribavirin is positively affected by food, and patients should be instructed to administer doses with meals.48,49 Ribavirin can cause dose-related hemolytic anemia, which can be managed with the use of epoetin alfa or dose reductions. However, higher doses of ribavirin have demonstrated improved clinical outcomes in several studies.42,43,45 Cesario and colleagues51 compared SVR data in HCV-monoinfected obese (body mass index [BMI] >30 kg/m2) and nonobese (BMI <30 kg/m2) patients. Both groups had a similar SVR when treated with weightbased dosing of pegylated interferon and ribavirin. The obese group was more likely to have steatosis, and fewer of the obese study participants achieved SVR on standard interferon and ribavirin. A larger, randomized clinical trial is needed to explore these interesting findings.51 Screening Patients for HCV Therapy Before initiating HCV treatment, patients must be assessed physically and psychosocially for the difficult and lengthy treatment course. More data are accumulating on the treatment of the coinfected patient, but treatment standards are based on the HCVmonoinfected patient. Currently available guidelines4,33,34 suggest that treatment should be initiated before development of severe fibrosis or cirrhosis and that all HIV-infected patients with active HCV disease should be considered candidates for treatment. Also, it is important to note that higher response rates to HCV treatment are seen in patients with well-controlled HIV disease defined as CD4 >500 cells/mm3.12,34 The European Consensus Conference reports that the need for HAART and higher CD4 cell counts is not an absolute, and treatment could be initiated whether or not these factors are present.33 All guidelines support the need
46 • JOURNAL OF PHARMACY PRACTICE 2006(19.1)

for patients to be alcohol and drug free. In addition, patients should be assessed for concomitant opportunistic infections, psychiatric conditions, and cardiopulmonary and/or kidney disease.3,48,49 Since drug therapy is extremely expensive, in addition to laboratory testing and monitoring, insurance status and patient ability to afford insurance copayments are essential. Schering-Plough, the manufacturer of PegIntron, offers an informal indigent drug program, Commitment to Care,52 for uninsured patients (information is available by calling 1-800-521-7157). Roche Pharmaceuticals, makers of PEGASYS, offers the Pegassist Program53 for uninsured patients (information is available by calling 1-877-PEGASYS). Both manufacturers also offer patient support programs, health care provider information, and teaching kits.52,53 HCV treatment involves weekly peginterferon injections, and patients should be assessed for their ability to self-inject or attend weekly medical visits for health care providers to inject the drug. For assessment of depression, our program uses the validated Center for Epidemiologic Studies–Depression tool.54,55 For evaluation of alcohol use or abuse, the CAGE (Cut Down, Annoyed, Guilty, and Eye Opener) tool can be used.56 Availability of psychiatric services and drug and alcohol counseling services is an extremely important part of the planning process to assist patients with therapy. In addition, because of the teratogenicity of the agents used to treat HCV infection, strict birth control must be practiced by both men and women while on therapy for the duration of treatment and for 6 months thereafter. Laboratory Monitoring and Screening Considering the initiation of treatment in an HCVinfected patient begins with a positive antibody test to HCV, followed by a quantitative HCV RNA test to determine hepatitis C viral load and whether the patient has cleared HCV infection. Once these test results are obtained, baseline screening tests can be ordered. Determination of HCV genotype is of primary importance in planning treatment. In addition, the following laboratory tests are recommended at baseline3,57: complete blood count, liver enzyme tests, chemistry and metabolic panel, prothrombin time/international normalized ratio, ferritin, iron, total iron-binding capacity, thyroid-stimulating hormone (TSH), pregnancy test in women, hepatitis A virus total antibody to evaluate the need for hepatitis A vaccination, and determination of hepatitis B antibody status. Suggestions for follow-up laboratory screening are listed in the appendix. Tables 3 and 4 review manufacturer dosing guidelines as well as recommended dose adjustments (Roche, Schering).

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Table 4 Dosing Guidelines for Hepatitis C Treatment Products: Pegylated Interferon Alfa-2a (PEGASYS) and Ribavirin (COPEGUS) Therapy PEGASYS and COPEGUS Dosing Recommendations PEGASYS Dose, mg COPEGUS Dose 180 180 PEGASYS Dose Modifications, Hematologic Toxicity PEGASYS Dose Reduction 135 mg 90 mg COPEGUS Dose Modification, Hematologic Toxicity Reduce COPEGUS Dose to 600 mg/d if: <10 g/dL ³2 g/dL ¯ in hemoglobin level during any 4-wk treatment period PEGASYS Dose Modifications, Depression Initial Management (4-8 wk) Dose Modification No change ¯ PEGASYS to 135 mg or 90 mg depending on severity Discontinue PEGASYS permanently Evaluate every wk or every other wk Evaluation once weekly Visit Schedule Remains Stable Continue weekly visits Consider psychiatric consultation; continue reduced dosing Psychiatric therapy necessary Depression Improves Resume normal schedule Worsens Discontinue COPEGUS if: <8.5 g/dL <12 g/dL despite 4 wk at reduced dose Discontinue PEGASYS if: ANC £500/mm3 until ANC values >1000 mm3 3 Platelets <25 000/mm Duration, wk

Genotype

1,4

2,3

<75 kg = 1000 mg ³75 kg = 1200 mg 800 mg

48 48 24

Laboratory Value

ANC £750/mm3 3 Platelets <50 000/mm

Laboratory Value

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Hemoglobin levels in patients with no cardiac disease Hemoglobin levels in patients with history of stable cardiac disease

Depression Severity

Mild

Moderate

See moderate or severe status See severe depression

Severe

Obtain immediate psychiatric evaluation

If symptoms improve and are stable for 4 wk, resume normal schedule; consider ­ to normal dose Psychiatric therapy necessary

Psychiatric therapy necessary

Note: ANC = absolute neutrophil count.

47

MCNELIS

In addition, an excellent treatment algorithm is available from the Hepatitis C Resource Network at http:// www.h-r-n.org. It is important to closely monitor complete blood count and platelets, metabolic panel, and depression on a monthly or bimonthly schedule to assess for adverse events caused by peginterferon and/ or ribavirin. Adverse Events Peginterferon and ribavirin are associated with multiple adverse events.48,49 If monitored closely and with vigilance, patients are able to tolerate these medications well and avoid severe toxicities. Most commonly, patients experience flulike side effects from peginterferon. Fatigue, irritability, malaise, weight loss, and skin rash are some of the most commonly reported side effects.42,43,45,46,48,49 Administration of the injection at bedtime and supportive symptomatic care provide some practical approaches to management of these issues. The most dangerous side effects caused by peginterferon are the neuropsychiatric adverse events. The rate of these side effects, particularly any reported depression, ranges from 25% to 60% depending on the study.3,42,43,45,46 In the APRICOT trial, Torriani and colleagues43 reported 1 suicide, possibly related to treatment with peginterferon and ribavirin. Regular monitoring of depression can prevent any further progression, and use of antidepressants is helpful in most patients. Thyroid dysfunction can occur in a small percentage of patients receiving peginterferon, and TSH levels should be followed during the drug therapy period.48,49 Complete blood counts should be followed closely because of peginterferon-induced cytopenias. These side effects are dose related and usually reversible. In addition, patients with preexisting cardiac disease could have a worsening of these conditions by peginterferon- or ribavirin-induced anemia.48,49 Growth factors can be used to support patients on drug therapy, and epoetin alfa has been demonstrated to be particularly helpful in improving quality of life in anemic patients on HCV therapy.58-60 Leukopenia, as well as a decrease in absolute number of CD4 cells, has been seen in clinical trials; however, no significant risk of infection has been demonstrated.42,43,45,46 Rarely, peginterferon has been shown to cause worsening of autoimmune disorders, hypersensitivity reactions, pancreatitis, and decrease or change in visual acuity. A baseline ophthalmologic examination should be considered, and those patients with significant preexisting disorders should be monitored more frequently.48,49

Ribavirin commonly causes anemia that is seen soon after treatment initiation.48,49 The teratogenicity of ribavirin was discussed earlier, and cases of maternal and fetal outcomes of pregnant women exposed to peginterferon and ribavirin during pregnancy should be reported to the COPEGUS Pregnancy Registry by calling 1-800-593-2214.49 Drug Interactions Ribavirin is a guanosine nucleoside analog that inhibits reverse transcriptase. In vitro, ribavirin inhibits the antiretroviral activity of the dideoxynucleosides, zidovudine, stavudine, and zalcitabine, by inhibiting their intracellular phosphorylation. In addition, ribavirin increases the intracellular concentrations of didanosine, which can lead to increased risk of toxicity, particularly mitochondrial toxicity.48,49,61 Ribavirin, peginterferon, and zidovudine have similar side effect profiles and can cause additive toxicity on the bone marrow. Alvarez and colleagues demonstrated the concomitant use of zidovudine with ribavirin resulted in a 3.13-g/dL drop in hemoglobin level compared with a 1.96-g/dL drop in nonzidovudine users (P < .0001) after 4 weeks of therapy on HCV treatment and HAART. This group concluded that close monitoring is necessary when zidovudine and ribavirin are used.62 Currently, coadministration of didanosine with ribavirin is contraindicated; however, because of limited information, recommendations on the use of other NRTIs with ribavirin do not exist. This clinical significance of a documented drug interaction between pegylated interferon and methadone is not known. Pegylated interferon can increase the AUC of methadone from 10% to 16%, in some cases causing the methadone AUC to be doubled.48,49 In most cases, decreasing the dose of methadone is not recommended. For patients on theophylline, peginterferon may inhibit the metabolism of this agent, causing a 25% increase in theophylline AUC. Theophylline serum concentrations should be monitored and dose adjustments made as necessary.49 For patients receiving any agent that causes bone marrow toxicity, a complete blood count should be routinely monitored to prevent overlapping toxicity. LIVER TRANSPLANTATION Because of the risk of hepatic decompensation, peginterferon and ribavirin are contraindicated in patients with cirrhosis and decompensated liver disease.48,49 In cases in which treatment cannot be admin-

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HEPATITIS C INFECTION IN HIV

istered, multiple centers are currently looking at liver transplantation in coinfected patients. Limited data are available, and this is an area for additional and ongoing research. PREVENTING TRANSMISSION OF HCV People who are HIV/HCV coinfected should be educated on prevention of the spread of both viruses to others. Similar to HIV infection, HCV is spread through contact with blood and body fluids. This message is particularly important for IVDUs because percutaneous exposure is the most efficient way to transmit the virus. IVDUs need to be educated about proper hand-washing techniques as well as not using or sharing injection drug paraphernalia with others. The use of methadone treatment programs, riskmodifying education programs, and needle exchange programs, as well as attempting to ensure access to clean needles, offers opportunities for people to decrease risk. It is important to note that HCV genotype has no effect on the rate or risk of transmission.6,12 There are multiple patient counseling and education opportunities to prevent the spread of HCV. Coinfected patients should avoid sharing dental or shaving equipment and cover any bleeding wound. These patients should be advised to not donate body organs, blood, other tissues, or semen. Safer sex practices and the use of condoms should be strongly encouraged, especially in the setting of multiple sexual partners. Injection drug use should be discouraged and substance-abuse treatment programs encouraged, especially when reusing or sharing needles, syringes, cotton swabs, or other drug paraphernalia. Injection sites should be cleaned with a new alcohol swab and disinfected, and new con-

tainers and filters should be used to prepare drugs. Syringes and needles should be disposed properly after 1 use.12 In addition, patients should be educated about the HCV transmission risk as well as the risk of acquiring other blood-borne infections from tattooing or body piercing. Proper infection control should be used for these procedures.4 CONCLUSION Hepatitis C in the HIV-infected population is a significant cause of morbidity and mortality. While clinical management and patient tolerability is challenging, previously sparse data about this important treatable opportunistic infection is growing. The medical management of HCV infection is complicated by HIV-related immunosuppression, treatment side effects and monitoring, patient tolerance of the regimen, and length of treatment. A multidisciplinary team approach to care monitoring toxicities, drug interactions, and psychiatric interventions can assist and support patients in addressing this important disease challenge. Future research should be focused on prevention of HCV, clinical treatment options with fewer side effects, identifying noninvasive markers of liver disease, treatment options for nonresponders, and options for liver transplantation in coinfected patients. Acknowledgments The author greatly appreciates the critical review of this article by Christopher James, PharmD; Susan Szabo, MD; and Mary Matsumoto RN, ACRN, CCRN, as well as the work of Mary Kay Steinhaus, APN.

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50
Baseline Week 2 Week 4 Week 8 Week 12 Week 16 Week 20 Week 24 Week 28 Week 32 Week 36 Week 40 Week 44 Week 48

Appendix Christiana Care Health Services HIV Community Program: Hepatitis C Laboratory Protocol Schedule

Date

X X X X X X X X X X X X X X X X X X X X X
Date/Dose Date/Dose

X X X X X X X X X X X X X X X

X

X

X

X

X

X

X

X

X

X

X

X X X X

X

X

X

X

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X

Complete blood count with platelets Chemistry and metabolic panel Thyroid-stimulating hormone Antinuclear antibody Alpha 1 fetoprotein Ferritin/iron/total iron-binding capacity Prothrombin time/ international normalized ratio Hepatitis C virus genotype Hepatitis C virus RNA quantitative test a Pregnancy test b Hepatitis A IgG Imaging study HIV RNA quantitative test/ultra CD4 cell count c Depression screen c CAGE/alcohol screen d Liver biopsy X X X X
Date/Dose

X X

X X
Date/Dose

X X
Date/Dose

X X

Dose Changes

Peginterferon Ribavirin Epoetin Alfa Filgrastim HCV RNA quantitative test, IU/mL Baseline Week 12 (EVR) Week 24Week 48 Week 72 (SVR)

Note: EVR = early virologic response; SVR = sustained virologic response. a. Female patients. b. If negative, hepatitis A vaccine series. c. May do monthly. d. Preferred.

HEPATITIS C INFECTION IN HIV
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