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Hepatitis C in HIV-infected Individuals
Michael A Poles MD and Douglas T Dieterich MD
Division of Digestive Diseases, 375 Charles E Young Drive South, UCLA School of Medicine, Los Angeles, CA, 90095, USA
232 East 20th Street, Cabrini Medical Center, New York, NY, 10003, USA

Current Treatment Options in Infectious Diseases 2001, 3:137-146

http://www.biomedcentral.com/1523-3820/3/137

The presence of hepatitis C virus (HCV) infection increases morbidity and mortality of HIV-infected patients and increases the risk of hepatotoxicity secondary to anti-retroviral medications. HCV, the newest opportunistic infection, should be treated with the hope of decreasing these adverse outcomes. As in immunocompetent patients, interferon-α monotherapy appears to be less effective than combination therapy in achieving a complete virologic response and should be abandoned for newer modalities. At present, though data is scarce, combination therapy using -interferon-α with ribavirin appears to be the most efficacious approach to treat this population. Patients are usually treated for 12 months with interferon/ribavirin combination therapy, though 18 months of therapy may be given to patients at greater risk of treatment failure. Erythropoietin is used successfully to treat the most common hematologic toxicity of ribavirin, anemia. Pegylated interferon or the combination of pegylated interferon with ribavirin may be found to be equally acceptable alternatives. It is likely that future approaches to treatment of -HIV-HCV co-infected patients will involve combinations of antiviral medications with immunomodulatory therapy.

The response of a patient to anti-HCV therapy may correlate with the patient's degree of immunosuppression. In general, patients with greater than 200 CD4 cells will respond similarly to immunocompetent patients, but patients with more severe immunosuppression may not respond as well. Still, treatment of the more immuno-suppressed patient potentially carries other benefits, such as reducing hepatic fibrosis and therefore cirrhosis, as well as perhaps reducing the risk of hepatoma development. One approach to improve response to anti-HCV therapy in the more immunosuppressed HIV patient would be to optimize highly active antiretroviral therapy (HAART) prior to initiating anti-HCV therapy. It is always preferable to treat HCV in patients on stable HAART because it clarifies the etiology of adverse medication effects on anti-HCV therapy. If a patient has severe HCV-induced histologic changes on biopsy, then it may be necessary to treat HCV before HAART is stabilized. If an immuno-suppressed patient's liver biopsy is of mild or moderate severity, then it may be preferable to HAART to raise the CD4 cell count above 200 before initiating anti-HCV therapy.

Introduction

Since the use of highly active antiviral therapy (HAART) has extended the healthy lifespan of HIV-infected patients, greater attention will need to be focused on the recognition and management of potentially severe concurrent illnesses that may increase their mid- to long-range morbidity and mortality. Infection with hepatitis C virus (HCV) is many times more prevalent than that of HIV, and due to shared epidemiologic risks is common among HIV-infected patients. HCV may not only impact upon the health status of HIV-infected patients, but also may decrease their quality of life and increase health care costs. Chronic liver disease, especially that due to hepatotropic viruses, is also a common cause of death in HIV patients [1,2]. Physicians caring for patients with HIV require up-to-date information to make rational decisions regarding hepatitis C virus co-infection to ensure that morbidity and mortality are minimized and quality of life and medical care costs are optimized.

Immunosuppression due to HIV appears to accel-erate the natural history of HCV infection. The decline in CD4 cells associated with progressive HIV infection appears to permit greater HCV replication, with more hepatic spread of HCV and therefore vast hepatocyte injury. While there is not a direct correlation between the plasma titers of HCV RNA and disease course, --co-infected patients harbor greater amounts of HCV than immunocompetent patients, both in their plasma [3,4] and in their liver [5•]. When compared with -HIV-negative patients, co-infected patients have a greater degree of piecemeal necrosis, portal inflammation, as well as fibrosis, the most important prognostic factor for liver disease [6•,7]. HCV-HIV co-infected patients more commonly and more rapidly progress to cirrhosis [8•,9•]. These patients also have a significantly greater risk of hepatic decompensation and liver failure [10,11•]. Orthotopic liver transplantation has been performed in HIV-positive patients but is still experimental.

HIV protease inhibitors have not been found to inhibit HCV replication [12]. Instead, initiation of HAART may transiently increase the level of trans-aminases and even the HCV viral load for the first 3 to 4 months of treatment [13]. Many antiretroviral drugs are hepatotoxic; according to the Physicians Desk Reference;the risk of hepatotoxicity of anti-retroviral drugs is between 3% to 12%, and associates depending on the therapeutic agent. In a large study, Sulkowski [14••] showed that transaminase elevations are almost universal during HAART, though severe hepatotoxicity (transaminase levels over five times the upper limit of normal) was present in only 10% of patients with the highest incidence occurring in patients given ritonavir (30%). The incidence of hepatotoxicity of any grade was greater in patients infected with HCV (54% vs 39%). Overall, in patients receiving antiretrovirals (excluding ritonavir), severe hepatotoxicity was seen in 9.4% of patients with chronic viral hepa-titis, compared with 2.7% without viral hepatitis. The incidence of severe hyperbilirubinemia, most commonly seen with indinavir, was also elevated in patients with HCV co-infection.

Clinicians may be reluctant to prescribe antiretro-viral medications in the presence of chronic viral hepa-titis, with or without elevations in liver-associated enzymes. Therefore, the presence of HCV infection limits our ability to care for the HIV-infected patients. It is logical to infer that normalizing alanine amino-transferase levels and/or reducing HCV titer through anti-HCV treatment might increase the tolerance of -co--infected patients to antiretroviral therapy. Given the effect that HIV has on the natural history of HCV disease, the United States Public Health Service and Infectious Diseases Society of America declared it to be our newest opportunistic disease, in August of 1999 [15••]. It is widely believed that HIV coinfected patients respond poorly to anti-HCV therapy, given the higher HCV viral titers in these patients. Several studies, however, have shown that the biologic and histologic benefit of such therapy in co-infected patients is not significantly different from that noted in HIV--negative patients [16,17].

Treatment

Pharmacologic treatment

Interferon-α

Standard dosage

3 MU subcutaneously or intramuscularly three times a week for 12 months was the previous standard. Biochemical response (normalization of transaminase levels) is usually seen in the first 3 months. Therapy may be halted if no response is seen over this duration, though in the HIV-coinfected population, other causes of elevated transaminase levels may be present. If, after 12 months, the response to interferon is incomplete or relapse occurs, the patient may be considered for retreatment for an additional 6 to 12 months or treatment using other modalities.

Contraindications

Known hypersensitivity to interferon-α.

Main drug interactions

Interferon may reduce clearance of theophylline and other drugs that are metabolized through the activity of hepatic microsomal cytochrome enzymes of the p450 system. The risks of renal failure from interleukin-2 therapy may be potentiated by interferon, as may be the neurotoxic, hematotoxic, or cardiotoxic effects of other concurrently administered drugs.

Main side effects

Flu-like symptoms (fever, headache, myalgias, fatigue, chills/rigors, arthralgias, asthenia) are seen in approximately half of all treated patients, and occur 2-8 hours after injection. These side effects are usually worse in the first month of therapy. Due to these effects, interferon should be used with caution in patients with severe concurrent medical conditions, such as cardiovascular disease, chronic obstructive pulmonary disease, and patients with diabetes mellitus who are prone to ketoacidosis. Gastrointestinal effects include diarrhea, anorexia, and nausea in 13% to 19% of patients. Reversible bone marrow suppression may be seen in 7% to 19% of patients, while severe leukopenia is seen in less than 1% of patients. Thrombocytopenia and leukopenia associated with this medication necessitate monitoring of blood cell counts, but are generally reversible, and granulocyte -colony-stimulating factor may be used as prophylaxis for neutropenia. Bacterial infection associated with the immunosuppression induced by interferon therapy is among one of the most worrisome effects of therapy. Urinary tract infections, sinusitis, and bronchitis are seen with increased frequency in patients receiving this drug. More serious infections have also been noted; thus, any sign of fever should be promptly evaluated. Interferon may induce or aggravate psychiatric disturbancessuch that depression or irritability are seen in around 12% of patients. In rare instances suicidal ideation and behavior has been reported among patients receiving interferon; therefore, patients with a history of severe psychiatric conditions, including suicidal behavior, should not receive interferon. Antidepressant medications are commonly used successfully to treat depression associated with interferon use. Thyroid dysfunction (hypo- or hyperthyroidism) isseen in approximately 5% of patients and is usually reversible. Hepatotoxicity, including fatalities, has been reported in interferon-treated patients, so inter-----feron should not be used in patients with decompensated liver disease. At the typical dosage of 3 MU three times a week, 5% of patients require drug discon-tinuation and 9% require dose reductions due to the above-mentioned adverse effects. Despite the high incidence of adverse effects associated with the use of this agent, there does not seem to be an increase in the incidence of intolerance among the patients who are HIV infected. There may also be some antiretroviral activity of interferon-α.

Special points

The first multicenter trial of interferon-α monotherapy for HIV-negative, -- HCV---positive patients performed in the United States was published in 1989 and showed that use of 3 MU three times a week for 6 months resulted in an initial biochemical response of 54%. It has since become apparent that about half of the patients who respond to an initial 6-month course of interferon -monotherapy will suffer a relapse of their disease. Similarly, about 65% to 70% of patients with a virologic response after 6 months will relapse. Extending the duration of therapy to 12 months does not affect the number of initial responders but improves the sustained response rate. Overall, a sustained virologic response is seen in less than 25% of all interferon monotherapy-treated patients. A sustained virologic response appears to indicate long-term efficacy. Several studies, however, have shown that the biologic and histologic benefit of interferon-α therapy in HIV-HCV co-infected patients is not significantly different from that noted in HIV-negative patients [16,17].

Cost effectiveness

Increasing attention is being paid to the cost effectiveness of treating human disease. The cost effectiveness of treating patients with chronic HCV infection has come under increasing scrutiny, since interferon-α is expensive and is not highly effective. The cost of interferon monotherapy is approximately $7000 per year and $10,000 for 18 months, not including costs of laboratory monitoring. The cost effectiveness of treatment using interferon-α has been evaluated by a number of authors, though never in HIV-infected patients. Using Markov modeling, Shiell [18] showed that treatment with interferon results in a discounted cost per life-year gained of $33,230 in patients with cirrhosis and $71,950 in patients without advanced liver disease. In an excellent computer simulation model, Wong [19•] showed that treating patients with histologically mild chronic hepatitis C for 6 months with interferon results in a $400 reduction in lifetime cost of care and a 1.5-year increase in life expectancy due to prevention of cirrhosis and hepato-cellular carcinoma. Bennett and colleagues [20•], using meta-analysis of five prospective trials and cost-effectiveness analysis, estimated that interferon treatment should increase life expectancy by 3.1 years if given at 20 years of age, by 1.5 years if given at 35 years of age, and by 22 days if given at 70 years of age. Davis and colleagues [21] compared the cost effectiveness of standard 12 months of therapy (as well as prolonged [24-month] therapy) of interferon with no treatment and with shorter term (6-month) therapy. They found that the incremental marginal cost per life-year gained by longer treatment at age 20 to 50 years ranged from $938 to $9957. Longer treatment always showed a survival benefit. Another study by Kim et al. [22•] suggested that, although 6 months of interferon-α therapy was less efficacious than 12 months of therapy, it was more cost effective. Nonetheless, in this study, treatment of patients younger than 60 years of age with either 6 or 12 months of interferon compared favorably with other established medical inter-ventions, such as screening mammography and cholesterol reduction programs. Based on the data presented in these studies it appears that interferon mono-therapy should result in improved life expectancy and decreased health care costs.

Interferon-α/ribavirin combination

Standard dosage

Combination therapy using standard interferon-α 3 MU with ribavirin given orally has become the new standard in HCV therapy. Ribavirin is dosed according to the patient's weight. Patients who weigh less than 75 kg should take two 200-mg tablets in the morning and three 200-mg tablets in the evening, while patients weighing over 75 kg should take three 200-mg tablets twice a day.

Contraindications

Use of ribavirin is absolutely contraindicated in women who are or may become pregnant, due to significant teratogenic or embryocidal potential. Women should not consider getting pregnant for 6 months after taking ribavirin and men should be cautioned against impregnating women for 6 months after taking ribavirin. Use of interferon/ribavirin combination is also contraindicated in patients with autoimmune liver disease, since treatment may cause exacerbation. Treatment is also contraindicated in patients with a known hypersensitivity to either interferon or ribavirin.

Main drug interactions

The main drug interactions of interferon were described above. Maximum ribavirin plasma concentrations may be increased up to 70% by concurrent administration with a high fat meal. Absorption may be decreased by concurrent administration with antacids containing magnesium, aluminum, or simethicone. There has been some concern about using ribavirin in HIV-infected individuals because of the potential inhibition of the phosphorylation of azidothymidine (AZT) and d4T [23], although phosphorylation of dideoxyinosine (DDI) increases [24]. In all of the studies to date, combination therapy did not have a significant effect on the patient's HIV viral load or CD4 cell count.

Main side effects

The main adverse effects of interferon were described above. The primary toxicity of ribavirin is dose-related hemolysis and anemia that typically occurs in the first 2 weeks of therapy. The anemia, which may be severe, has been reported to result in exacerbation of cardiovascular disease. Anemia has been reported in 21% of combination-treated HIV-HCV-infected patients, but can be successfully treated with erythropoietin [25]. Prolonged use of ribavirin can result in pruritis, nasal congestion, and cough. The plasma concentrations of ribavirin are increased in patients with renal impairment, so use of ribavirin in patients with renal dysfunction is not recommended.

Special points

Ribavirin, a guanosine analogue, is a broad-spectrum antiviral agent that targets both DNA and RNA viruses. When used alone, ribavirin will reduce alanine amino-transferase levels and improve histologic findings without significantly changing viral HCV-RNA levels, suggesting that it does not have major effects on viral replication. However, when used in combination with interferon-α, ribavirin reduces the rate of hepatitis relapse, suggesting an enhancement of interferon-α's antiviral activity, though the mechanism of action of ribavirin is still not well understood.

Combination ribavirin with interferon may raise the sustained response rate to closer to 50%, compared with less than 25% for interferon monotherapy [26••,27••,28]. The effect of interferon and ribavirin combination therapy has been encouraging to date in small series of HIV patients. In a recent report, Dieterich and associates [29] reported on 24 patients who were treated with combined interferon and ribavirin. They showed that after only 3 months patients receiving combination therapy had decreased HCV RNA from a median of 350,000 to 600 copies per mL. By 6 months the median HCV viral load remained at 600 and had become undetectable in five of eight (62.5%) of combination-treated patients. Landau and colleagues [30] reported that combination interferon---ribavirin rendered HCV RNA undetectable in 50% of 20 patients after 6 months. In the majority of these patients, HCV RNA was undetectable by 3 months of treatment. In a Spanish study, Sauleda and colleagues [31] also showed a complete virologic response in 50% of HIV-positive patients treated with combination therapy. In a study of 37 patients with HIV, eight of whom had cirrhosis, Sulkowski [32] showed that combination interferon-ribavirin resulted in 50% HCV RNA less than 100 copies at 12 weeks with only seven dropouts for adverse events.

Cost effectiveness

Interferon/ribavirin combination is more costly than interferon monotherapy; thecost of a 1-year supply of medication is approximately $20,000. Similar to treatment with interferon monotherapy, the cost effectiveness of combination interferon-ribavirin treatment of patients with chronic HCV has been debated, but in comparison, has been scantly studied, and never in an HIV-infected population. In one analysis, using the Markov model, Younossi and associates [33•] studied six treatment strategies for previously untreated chronic hepatitis C patients and compared them on the basis of incremental cost per additional quality-adjusted life years. They showed that using interferon with ribavirin as the initial therapy for all patients was associated with a cost of $34,792 and 15.31 quality-adjusted life years, and was more cost effective than use of interferon monotherapy initially. They also found that using viral geno-typing first and then adjusting the duration of combination therapy based on genotype was associated with a cost of $37,263 and 15.89 quality-adjusted life years, and was the most effective approach, with an incremental cost-effectiveness ratio of $7500 per quality-adjusted life years. The cost effectiveness of combination therapy has also been studied in patients who have relapsed following an initial treatment with interferon. Wong and colleagues [34•] showed that combination therapy should prolong life expectancy by about 2 discounted quality-adjusted life years (3 life years, undiscounted), while increasing costs modestly.

Pegylated interferon

Standard dosage

The standard dosage for pegylated interferon-α 2a is 180 g per week. The standard dosage for pegylated interferon-α 2b is 1.5 mg/kg per week.

Contraindications

Known hypersensitivity to interferon-α.

Main drug interactions

The drug interactions are identical for those of regular interferon-α.

Main side effects

Pegylated interferon achieves higher plasma concentrations without the significant peaks and troughs as seen with unmodified interferon. Therefore, the side effects of pegylated interferon are identical to regular interferon-α, except that all adverse effects, excluding neutropenia, occur at a lower incidence.

Special points

Modification of interferon-α, by attachment of a 40-kD or a 12-kD branched polyethylene glycol (PEG) moiety, has resulted in pegylated interferon, which has a more sustained delivery and reduced clearance. Pegylated interferon, therefore, has a half-life of approximately 54 to 100 hours, compared with 8 hours for routine interferon-α, and may be administered once weekly. At the time of this writing, pegylated inter--feron is not approved by the US Food and Drug Administration. One early study suggested that in HIV-seronegative patients, pegylated interferon's safety profile was similar to routine interferon and appears to have an efficacy equivalent to, or slightly superior to, routine interferon monotherapy [35]. Further controlled studies of this antiviral agent will be needed before further conclusions can be drawn, but with regard to HIV, the potential inhibition of AZT and D4T phosphoryl-a--tion by ribavirin makes the use of pegylated interferon monotherapy very appealing. While studies of pegylated interferon have not been completed in an HIV-positive population, research is currently underway in the form of a phase III prospective multicenter trial examining pegylated interferon alone against pegylated interferon plus ribavirin and interferon plus ribavirin.

Cost effectiveness

There are no data examining the cost effectiveness of this preparation in the treatment of patients with chronic hepatitis C infection.

Procedures

Liver biopsy

Liver biopsies are used in the care of HCV-infected patients. Prior to initiation of therapy, a liver biopsy is often obtained to assess the degree of hepatic damage (fibrosis and inflammation), and is thus important for prognostication. In addition, liver biopsy may be used to confirm the diagnosis of HCV and rule out concomitant liver processes. Lastly, many clinicians may decide not to treat patients who exhibit little or no inflammation or fibrosis on biopsy. It is not necessary to perform a liver biopsy to determine the effectiveness of therapy, given that virologic and biochemical markers of response are excellent surrogate markers of histologic response.

Abdominal ultrasound

Hepatic ultrasound plays less of a role than liver biopsy. The primary reason to perform a hepatic ultrasound is to rule out the presence of hepatocellular carcinoma. However, in comparison with hepatitis B virus infection, HCV-related hepatocellular carcinoma does not occur in the absence of cirrhosis, which would have been evaluated by the screening liver biopsy. Some cautious practitioners also choose to obtain an ultrasound prior to or during the liver biopsy to decrease the risk of adverse procedural events.

Hepatitis C virus viral load

Quantification of HCV RNA levels by polymerase chain reaction is commonly used to gauge response in clinical trials but its standard use in clinical practice is more controversial. Those who do use this expensive tool state that by following the RNA levels every 3 to 6 months, the slope of the curve can give a feel for the likelihood of positive response. At this time, HCV viral load testing cannot be considered standard of care.

Surgery

While orthotopic liver transplantation has been performed in HIV patients with HCV-related cirrhosis [36], its use clinically must still be considered experimental.

Lifestyle factors and prevention

Hepatitis C virus infections occur primarily through the parenteral route; the majority of patients are infected by intravenous inoculation (intravenous drug use or transfusion of infected blood products). Transmission through a damaged mucosa, as in sexual or perinatal transmission, occurs with far lower efficiency. Given the predominant route of transmission, the most effective preventive measures involve interventions designed to decrease intravenous drug use and to screen blood products. The effectiveness of blood-product screening is apparent by the fact that the risk of transmission by transfusion is as low as one in every 125,000 units transfused [37]. Worldwide though, stringent screening techniques are not uniformly used and therefore transmission by blood products will continue. Increased HCV seropositivity in hemodialysis patients suggests that transmission through use of contaminated dialysis machines and tubing is likely, but use of universal precautions and segregation of HCV-positive patients can effectively decrease the risk [38]. Social programs, such as needle exchange programs for intravenous drug users, may also have a significant effect on HCV transmission.

Since the risk of sexual transmission of HCV is low, few precautions are recommended for infected patients with regard to close contacts. The patient need not use condoms for transmission prevention unless he or she has multiple partners. Nonsexual transmission among family members is even lower, so while objects that could be blood contaminated, such as razors, toothbrushes, and nail clippers, should not be shared, it is not necessary to avoid sharing eating utensils.

The development of a hepatitis C vaccine is not imminent. The ineffectiveness of current vaccine approaches likely relates to the virus' high mutation rate in the hypervariable region resulting in poor neutralizing activity of the host humoral immune response [39•]. Several approaches are currently being evaluated for HCV vaccine development, including using live -attenu-ated strains, recombinant HCV envelope subunit vaccines, or use of HCV gene construct vaccines.

Other treatments

Iron reduction therapy

Some studies have suggested a correlation between the plasma and liver concentrations of iron and the degree of progression of, and hepatic damage due to, HCV [40,41]. Phlebotomy may reduce transaminase levels but has no effect on HCV RNA levels. Many studies are presently underway evaluating various forms of iron reduction therapy as an adjunct to interferon-based therapies in the treatment of HCV-infected patients.

Amantidine/rimantidine

The efficacy of antiviral medications, such as amantidine and rimantidine, against other viral pathogens, such as influenza, has led some investigators to examine their effectiveness against HCV. The results of such studies have been equivocal, with some showing decreases in transaminase levels and HCV RNA, and others showing no improvements in any of the traditional markers of success in anti-HCV therapy [42,43]. Studies are currently being performed to further evaluate these agents as monotherapy and in combination with interferon and - inter--feron-ribavirin.

Thymosin α-1

Thymosin α is a thymus-derived immunomodulatory medication that is believed to act by upregulating major histocompatibility complex class I expression on the surface of virally infected cells, making them more susceptible to cyto--toxic T---cell--mediated destruction. Due to its putative antiviral mechanism, it has been used in the treatment of HCV-infected patients both as monotherapy and in combina-tion with interferon. The results have been mixed, with combination studies suggesting a treatment benefit [44,45].

Ursodeoxycholic acid

This hydrophilic bile salt has been shown to improve transaminase levels in a variety of chronic liver diseases; it has shown to do the same in hepatitis C infection.Still, it does not appear to improve virologic responses [46,47]

Emerging therapies

Despite the advances in interferon-based therapy, other unique therapeutic modalities are sorely needed. In one interesting recent study, Schlaak and colleagues [48] showed that when two of seven (28.6%) HIV and HCV -co-infected patients were treated with interleukin-2, they cleared their HCV RNA for 6 and 11 months. While the proinflammatory effects of interleukin-2 therapy may theoretically have upregulated anti-HCV immune responses in these patients, large studies will be necessary to determine whether other immuno----modulatory therapies, in addition to interferon, should be considered in the treatment of HCV infection.

Interleukin-10 has been shown to reduce fibrosis in preliminary studies, but may downregulate TH1 cytokines and may not be the best choice in HIV-infected individuals.

Other new approaches that will soon be tested include antisense techno-logy, ribozymes, HCV-specific protease inhibitors, and helicase inhibitors. It is likely that future anti-HCV therapy will entail multiple combinations of medications with interferon-α similar to the multiple drug regimens used in HIV therapy today. The future is bright for antiviral and immunologic therapy of hepatitis C both with and without co-infection with HIV, and much of the technology that has moved the field forward has been and continues to be translated from the field of HIV.

References

Papers of particular interest have been highlighted as:
• of special interest
•• of outstanding interest