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Treatment of Patients with HIV/HCV Coinfection: An Overview

By Ronald Baker, PhD

Approximately 30% of individuals living with HIV in the in the U.S. and Europe are also infected with hepatitis C virus (HCV). Seventeen years after the introduction of highly effective antiretroviral therapy (HAART), liver disease has emerged as an important cause of morbidity and mortality in HIV positive patients.

As survival time has increased, hepatitis C-related liver disease has become a leading cause of hospitalization and death in these patients. As a result, researchers have increasingly focused on HCV-related liver disease and treatment-associated issues in HIV-HCV coinfected individuals.

In an overview article published in the Journal of Viral Hepatitis (June 2007), researchers Mark Sulkowsky, MD, and Yves Benhamou, MD, review a variety of important issues related to the management of HIV-HCV coinfected patients, including disease progression, the effects of HAART, antiretroviral therapy for HIV, and treatment for HCV. Following is a summary of their review.

There are a variety of potential causes of liver damage in HIV-HCV coinfected patients. These include pre-existing liver disease (e.g. hepatitis B or hepatitis D), heavy alcohol use, HIV-related opportunistic infections (e.g., Mycobacterium avium complex), nonalcoholic steatohepatitis, hepatotoxicity related to drugs used to treat HIV and its complications, and AIDS cholangiopathy in patients with CD4 cell counts below 100 cells/mm3.

On the whole, studies indicate that HIV-HCV coinfected patients have higher HCV RNA loads and experience more rapid progression of liver fibrosis than those with HCV monoinfection. The mechanisms by which HCV may adversely affect HIV disease progression are not known, but some researchers have argued that HIV disease is accelerated by HCV-related immune activation and impairment in immune recovery after effective antiretroviral therapy. Others have theorized that HCV coinfection does not affect HIV disease progression or response to antiretroviral therapy.

Investigators observed no increase in the rate of progression to an AIDS-defining condition or death in a 6-year cohort study of 1995 coinfected patients [1]. In addition, they concluded that after adjusting for HIV treatment, HCV infection was not independently associated with death in the subsets of patients with CD4 counts of 50 to 200 cells/mm3. Further, mortality did not differ between HIV-infected and HIV-HCV coinfected patients receiving effective HAART. Finally, the authors noted no differences in increases in CD4 cell count or CD4 percentage during administration of HAART.

These data suggest that there are no major differences in HIV-related mortality between patients infected with both HIV and HCV and patients infected with HIV alone receiving HAART.

Compared with HIV negative individuals, coinfected patients have higher HCV RNA levels and more rapid progression of hepatic fibrosis [2]. There are preliminary findings that suggest effective HAART slows the rate of fibrosis in coinfected patients [3]. However, other studies show that HAART is associated with increased liver enzyme levels and hepatic steatosis in some patients, particularly those with hepatitis C.

Further research is needed to determine the long-term effect of HAART on the progression of liver disease in coinfected patients.

Hepatitis C Viremia and Progression to Cirrhosis and Hepatocellular Carcinoma

HIV-mediated immune suppression appears to stimulate HCV replication, impair immune-mediated HCV clearance or both. Studies have demonstrated that coinfected patients have significantly higher serum HCV titres than do patients infected with HCV alone [4,5]. This association is independent of HCV genotype.

In addition, compared with HCV infection alone, HIV-HCV coinfection is associated with an increased risk of cirrhosis, end-stage liver disease, and hepatocellular carcinoma (HCC) [6].

Risk of HAART-associated Hepatotoxicity

Although HAART should not be withheld from coinfected patients who require treatment for their HIV infection, chronic hepatitis C is associated with an increased risk of antiretroviral-related hepatotoxicity [7,8]. However, overall, HAART slows the progression of hepatic fibrosis in coinfected patients.

In a study of HIV-infected patients receiving HAART, HCV infection was associated with a 2.46-fold increased risk of liver enzyme (ALT, AST) elevations (5 x upper limit of normal) and an absolute increase of at least 100 U/L [9]. In a study of other HAART-associated risk factors, the following were also associated with increased risks for liver toxicity: excessive alcohol use (P= 0.01), HCV coinfection (P = 0.01), and older age (P = 0.001) [10].

Across several studies, the risk of liver injury appears to be particularly great with the use of nevirapine (Viramune) and full-dose ritonavir (Norvir). However, the administration of low-dose ritonavir (≥ 200 mg/day) has not been associated with a greater risk of hepatotoxicity.

The mechanisms underlying the association of HCV and hepatotoxicity have not been fully described.

Treating HCV in Coinfected Patients

The goal of therapy for chronic hepatitis C is eradication of the virus or sustained virological response (SVR), an outcome associated with improved histologic results and decreased risk of progression to cirrhosis, end-stage liver disease, and hepatocellular carcinoma.  

Candidates for HCV therapy should be patients in whom the potential benefits of treatment outweigh the potential risks. HIV disease status is a major consideration in this risk vs benefit assessment. HCV treatment may be considered for patients with relatively high CD4 cell counts (> 350 cells/mm3) for whom antiretroviral therapy may be deferred. Conversely, patients with low CD4 cell counts (< 200 cells/mm3) with untreated HIV infection should not receive anti-HCV therapy until HIV infection is treated effectively and HIV is suppressed.

Recommended HCV Therapy in Coinfected Patients

Published guidelines for anti-HCV therapy [11,12,13] indicate that the standard of care in coinfected patients is pegylated interferon alfa-2a (Pegasys) or -2b (Peg-Intron) plus ribavirin [14-20]. Efficacy and safety outcomes after treatment of HIV-HCV coinfection were published by investigators from APRICOT and from the French Randomized Controlled Trial of Pegylated Interferon alfa-2b plus Ribavirin vs Interferon alfa-2b plus Ribavirin for the Initial Treatment of Chronic Hepatitis C in HIV Co-Infected Patients (RIBAVIC) [19, 21]

Pegylated interferon plus ribavirin was significantly more effective than standard (conventional) interferon plus ribavirin in both APRICOT and RIBAVIC [19,21].

In coinfected patients, pegylated interferon is administered at either 180 microgram (pegylated interferon alfa-2a) or 1.5 microgram/kg (pegylated interferon alfa-2b). Although most clinical trials in this population have studied fixed doses of ribavirin (800 mg/day), data from studies of HIV negative patients indicate that higher weight-based doses of ribavirin (1000-1200 mg/day) are more effective than the lower fixed dose in persons infected with HCV genotype 1 [22,23,24].

[Editor’s Note: The recently-published results of the WIN-R trial [25,26,27] suggest that weight-based ribavirin is superior to the standard fixed dose in combination with pegylated interferon for treatment of genotype 1 hepatitis C]

Unresolved Issues in HCV Treatment

Unresolved issues include the duration of HCV therapy, optimal ribavirin dose for HCV genotype 1 [see WIN-R trial results—Ed] and the role of newer experimental directly targeted anti-HCV agents.

In clinical trials in HIV-HCV coinfected patients, the duration of therapy for all HCV genotypes was 48 weeks. Currently, the standard of care for HIV negative patients with HCV is 48 weeks for genotype 1 and 24 weeks for genotype 2 or 3.

Preliminary studies suggest that all coinfected patients should be treated for 48 weeks.

Treatment for 24 weeks in HIV-infected patients with HCV genotype 2 or 3 infection is associated with a high rate of relapse after the completion of therapy [28]. Recent data from HCV treatment in HIV negative patients indicate that the duration of HCV treatment should be determined by the viral response kinetics of the individual patient rather than a standard duration of therapy for all patients.

For example, pegylated interferon plus ribavirin for 24 weeks was as effective as 48 weeks among HCV genotype 1 patients who achieved an undetectable HCV RNA level after 4 weeks of treatment [29,30]. Conversely, the relapse rate was greater than 50% among HCV genotype 1 patients who achieved an undetectable HCV RNA level for the first time after 24 weeks of therapy, suggesting longer treatment may be needed [31].

Further research is needed to clarify the appropriate duration of HCV treatment in coinfected patients as well as the role of individual viral kinetics in determining the appropriate treatment course.

A number of newer therapeutic agents are in development, including cellular IMPDH or IMPDH inhibitors, viral key enzyme inhibitors (protease, helicase, and polymerase inhibitors), internal ribosomal entry site inhibitors, small and expressed interfering RNAs, ribozymes and several new types of interferon (interferon alfa-2b fused with albumin, consensus interferon, and interferon gamma). Several ribavirin-like molecules also in development may improve the outcomes compared with standard ribavirin.

Assessing Response to HCV Therapy

Early virological response (EVR) assessed after 12 weeks of anti-HCV therapy is an important indicator of virological failure. The failure to achieve an undetectable HCV RNA level or reductions in HCV RNA of at least 2 log10 by 12 weeks has a negative predictive value of 98-100% for treatment failure [32]. Therefore, HCV treatment should be discontinued if an adequate EVR is not achieved at 12 weeks. Patients should be made aware of the importance of strict adherence to dose and schedule during the first 3 months of combination therapy to increase the probability of achieving an EVR.

Similar to HCV RNA levels during treatment in monoinfected patients, levels in coinfected patients at 24 weeks should determine further therapy among those with detectable HCV RNA after 12 weeks of therapy; treatment should be discontinued in those with detectable HCV RNA after 24 weeks and continued in those without.

Some experts recommend the continuation of therapy in patients with marked hepatic fibrosis or cirrhosis, even if they experience virological failure, as a means to prevent liver disease progression. However, the benefits of this approach are currently unclear and cannot yet be incorporated into clinical practice.

Other Treatment-related Issues

CD4 cell threshold for treatment

Published guidelines do not provide a consensus CD4 cell threshold for treating hepatitis C in HIV-HCV coinfected patients. Whereas the American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA) do not specify a threshold, an International Expert Opinion Panel and the Centers for Disease Control recommend thresholds of 200 and 500 cells/mm3, respectively [11,12,13].

In the major randomized clinical trials of treatments for coinfected patients [i.e. RIBAVIC, APRICOT, and ACTG 5071], baseline CD4 cell count had no effect on SVR rates; however, eligible patients in these studies were required to have baseline counts ≥ 200 cells/mm3, with the exception of APRICOT, in which persons with CD4 counts of 100-200 cells/mm3 and HIV RNA levels > 5000 copies/mL were enrolled.

Effect of IFN on CD4 Cell Count

Soriano and others [33] reported marked decreases in the absolute CD4 cell counts in HIV-infected patients with chronic hepatitis C treated with interferon. A similar observation was made in the APRICOT, RIBAVIC, and ACTG studies, in which combination pegylated interferon plus ribavirin significantly lowered absolute CD4 cell counts in coinfected patients [34].

However, in each study, the CD4 cell percentage, representing the proportion of the total lymphocyte count, increased and the absolute CD4 cell count returned to baseline within 24 weeks after interferon-based therapy was stopped. Furthermore, in APRICOT, pegyalted interferon was associated with an approximate 0.7 log10 reduction in HIV RNA, confirming a modest antiretroviral effect of pegyalted interferon in some patients.

In addition, HIV-related opportunistic infections were rarely observed in the published studies. Thus, combination pegyalted interferon plus ribavirin does not appear to be detrimental to patients with HIV disease.

Treatment of Relapsed Patients

By definition, a relapsed patient has undetectable HCV RNA at the end of treatment and emerging HCV viremia after treatment is stopped. At present, no treatment strategies address relapse in HIV-HCV coinfected patients. However, possible strategies to produce an SVR in this population include extending the duration of interferon-based therapy, administering higher ribavrin doses, or deferring treatment until other classes of HCV therapy are introduced.

Liver Transplantation

Liver transplantation is the primary treatment option for eligible coinfected patients with Child–Pugh stage B or C liver disease. HAART has significantly improved short- and mid-term outcomes in HIV-infected patients undergoing liver transplantation.

The major issue in this HIV-HCV coinfected subpopulation is reinfection of the liver graft -- an outcome that may lead to rapid development of cirrhosis in the new liver. The best approach at this time appears to be pegylated interferon plus ribavirin combination therapy for the first 3 months after transplantation.

Recombinant Human Erythropoietin

Recombinant human erythropoietin (EPO) is used successfully to treat patients with ribavirin-associated anemia and does not adversely affect HCV clearance. In addition to maintaining the ribavirin dose, recombinant human EPO may increase adherence and improve health-related quality of life.

Other treatment-related challenges for coinfected individuals include mitochondrial toxicity, drug-drug interactions, and leukopenia. Thus, chronic hepatitis C should be treated in HIV-HCV coinfected patients, but steps must be taken to prevent and treat potential toxicities.

Conclusions

Because HIV infection can accelerate progression of HCV-related liver disease, treatment of chronic hepatitis C is generally recommended. Either virus can alter the outcomes associated with the other.

At this time, up to 40% of coinfected patients can achieve SVR with combination pegylated interferon plus ribavirin therapy. However, the ability to achieve SVR depends on adhering to the recommended doses of both drugs; thus, steps should be taken to prevent and treat potentially dose-limiting complications, such as hepatotoxicity, mitochondrial toxicity, anemia, fatigue, depression, and neutropenia.

New experimental agents -- including HCV protease and polymerase inhibtors now in trials of HCV monoinfected subjects -- have the potential to improve outcomes and should be studied in coinfected patients as well as in more traditional HCV-infected subgroups.

A 2007 consensus statement on the treatment of chronic hepatitis C in HIV-HCV coinfected patients addresses many of these issues. The guidelines were published in the May 31, 2007 issue of AIDS [35]..

10/19/07

Source

MS Sulkowski and Y Benhamou. Therapeutic issues in HIV/HCV-coinfected patients. Journal of Viral Hepatitis 14(6): 371-386. June 2007. 

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