Recommendations for Management of Chronic Hepatitis B and C in HIV Coinfected Patients ?

Approximately 33% of HIV patients worldwide have chronic hepatitis C virus (HCV) infection. However, greater than 75% of HIV positive individuals infected via contaminated needles or blood products, such as hemophiliacs and injection drug users, also are infected with hepatitis C.

In developed countries, complications from end-stage liver disease are now a prominent and increasing cause of hospitalization and death in HIV patients, who rarely experience opportunistic infections due to the benefits of HAART. In contrast to the decline in OIs in this population, liver complications from infection with hepatitis C or B are increasingly seen.

During the past few years, various expert guidelines and recommendations have appeared for the management of HIV patients coinfected with HCV [1-6]. Drs. Vincent Soriano, Pablo Barreiro and Marina Nunez of the Hospital Carlos III in Madrid, Spain have written a thoughtful review of these guidelines for the management of HIV-HCV and HIV-HBV coinfection, as well as offering some of their own recommendations. Following is a summary review of their article, which appears in the May 2006 issue of The Journal of Antimicrobial Chemotherapy [7].

Recommendations for Care of Patients Coinfected with HIV-HCV

Hepatitis C antibody testing should be mandatory for all individuals with HIV infection. HCV positive persons should undergo testing for serum HCV RNA. Approximately 15% of HCV positive individuals clear HCV spontaneously without any intervention. For those persons who do not experience spontaneous clearance of the virus, quantitative HCV RNA testing by assays with a lower limit of detection (10-50 IU/mL) and HCV genotyping should be performed prior to any decision about therapy.

The current standard of care is treatment with peginterferon alfa plus ribavirin. Unfortunately, this therapy is less effective and has a higher incidence of adverse side effects in HIV-HCV coinfected patients than in those with HCV-monoinfection [8, 9]. Fortunately, the results of recent studies suggest that increasing the ribavirin dose and using a 48 week course of therapy (regardless of genotype) and with good adherence, leads to significantly improved response rates, paralleling what is achieved in monoinfected patients [10-12]. However, even these approaches do not create an improved benefit for active injection drug users, alcoholics and those with low CD4 counts, according to the authors.

Following is the profile of coinfected patients who are the best responders:

The authors write, “It is time to design trials in coinfected patients in which therapy is tailored on the basis of individual characteristics. As an example, using variables such as baseline HCV RNA, genotype and week 4 virological clearance, patients could be allowed to complete different lengths of therapy in an attempt to balance efficacy and tolerance of the medication.”

For best results, early therapy should be considered in treatment-naïve coinfected patients whose HIV disease is stable. Antiretroviral experienced patients should avoid using didanosine (risk of pancreatitis or lactic acidosis and zidovudine (risk of anemia), and adherence to anti-HCV therapy should be emphasized.

Results of non invasive tests such as FibroScan or FibroTest or liver biopsy might be useful, but should not be regarded as a requirement prior to therapy.

Liver toxicity after starting HAART is more frequent and progression of fibrosis to cirrhosis and hepatocellular carcinoma is more rapid in HIV-HCV coinfected patients. As a result justification for therapy is based on virologic rather than on histologic findings in this population.

HCV therapy should be regarded as a priority in patients with advanced fibrosis. However, the authors emphasize “Patients with decompensated cirrhosis should not be treated with interferon, given the serious risk of liver failure.

On the other hand, in patients with CD4 counts <200 cells/mm³ and/or plasma HIV RNA >100 000 copies/mL, “it is advisable to suppress HIV replication and increase the CD4 counts before beginning HCV therapy, as the APRICOT trial showed that side effects of the HCV medication occurred more often in patients with lower CD4 counts” [13].

Patients with neuropsychiatric disorders should be evaluated by an experienced psychiatrist before being considered for therapy. The psychiatrist may have an opinion about the use of interferon and/or the use of antidepressants or other co-medication. It has been shown that those with mild depression who use antidepressants can derive a benefit from interferon/ribavirin.

On the other hand, patients who are heavy drinkers or who have drug addition should not be considered for treatment, according to the authors, and “medical efforts should concentrate on detoxification.”

Unlike anti-HIV drugs that must be taken lifelong by HIV patients, successful treatment for hepatitis C can be achieved with limited therapy duration. HIV-HCV coinfected patients should benefit from this situation.

In conclusion, the authors write, “Treatment for coinfected patients should not be discouraged or unnecessarily delayed unless there is a clear contraindication for therapy in these patients. Studies have shown that HIV patients who clear HCV with treatment demonstrate a lack of clinical progression of liver disease. They are cured of hepatitis C.” [14].

Recommendations for Care of Patients Coinfected with HIV-HBV 

Approximately 10% of the HIV-infected population worldwide also have chronic hepatitis B. This figure may approach 20% in Southeast Asia, whereas it is 5% in North America and Western Europe. Unlike with HCV, infection with HBV is not eradicable. As with HIV infection, the main goal of therapy is to suppress HBV replication as much as possible and for as long as possible.

This translates into histological and clinical benefit. Guidelines for the adequate management of chronic hepatitis B in HIV-coinfected individuals have recently been released, [2, 15,16] and several reviews [17] have updated the knowledge on this topic, providing useful information about how to manage HBV-HIV coinfected patients.

Four drugs have been approved so far for the treatment of chronic hepatitis B: standard interferon alfa (Intron A) and pegylated interferon alfa-2a (Pegasys), lamivudine (Epivir-HBV), adefovir (Hepsera) and, more recently, entecavir (Baraclude).

Other drugs with anti-HBV activity such as tenofovir and emtricitabine are FDA-approved for treatment of HIV infection and are frequently used in coinfected patients as anti-HBV agents. In ACTG A5127, the efficacy and safety of tenofovir and adefovir were prospectively compared in 52 HBV-HIV coinfected individuals, 75% of whom had already failed on lamivudine. [18] At 48 weeks, the mean reduction in serum HBV DNA was 3.2 logs in the adefovir arm and 4.4 logs in the tenofovir arm.

The study was powered only to show the non-inferiority of tenofovir with respect to adefovir, but the results support the general belief that tenofovir 300 mg/day is much more potent than adefovir 10 mg/day against HBV. The widespread use of tenofovir in HBV-HIV coinfected patients has demonstrated that HBV can become resistant to tenofovir, although this seems to occur very slowly.

The decision to treat chronic hepatitis B and the choice of drug(s) is controversial and is likely to vary in different situations. According to the authors, four main variables should guide the selection of patients to be treated for HBV and of the drug(s) of choice: transaminase levels, serum HBV DNA viral loads, presence of serum HBV e antigen (HBeAg) and liver fibrosis staging.

Given that chronic hepatitis B patients with elevated transaminase levels tend to have liver damage, they should generally be considered primary candidates for treatment (Figure 1), especially in the context of HIV coinfection, since HBV-related liver damage tends to progress faster in HIV-coinfected patients than in HBV-monoinfected patients.

While HBeAg-positive chronic hepatitis B patients tend to show better responses to interferon monotherapy provided for 6–12 months, HBeAg-negative individuals should preferentially be treated with nucleoside/nucleotide analogues (Figure 2). In HBV-HIV coinfected patients, a problem arises when no antiretroviral therapy is required but HBV therapy is considered necessary. Although some authors have favored the prescription of adefovir monotherapy in this situation, concern about the selection of the K65R resistance mutation in HIV has precluded this treatment in some cases. Recent data, however, suggest that this risk is negligible. [19]

Figure 2. Preferred anti-HBV agents in drug-naive HBV-HIV coinfected candidates for HBV therapy.

In this specific situation, drugs such as entecavir or in the future telbivudine or clevudine, which are potent anti-HBV agents lacking any HIV activity, will likely be the first choice. The 24-week results of the ETV-038 trial were presented at the 2005 Conference on Retroviruses and Opportunistic Infections. [20] This trial assessed prospectively the efficacy and safety of entecavir 1.0 mg/day against a placebo in 68 HBV/HIV-coinfected individuals, all of whom had failed prior lamivudine therapy. The virological response was significantly better in the entecavir arm. Even though entecavir acts in patients with lamivudine-resistant HBV, some cross-resistance between these two drugs exists, and therefore the greatest efficacy of entecavir will be obtained in patients without prior exposure to lamivudine.

In summary, significant progress has been made in the treatment of hepatitis B in HIV-positive individuals in recent years. This patient population, who usually experience more rapid and severe liver damage, now has expanded therapy options that are more convenient to use and have fewer adverse effects. The US FDA is expected to approve several promising new drug treatments for hepatitis B in the coming year.

The broad array of recently approved treatments as well as those in the pipeline will contribute to improved maintenance of HBV suppression and thus can be expected to prevent or significantly delay the onset of liver complications in most HBV-HIV coinfected patients.

04/18/06

Primary Source

V Soriano, P Barreiro and M Nunez. Management of chronic hepatitis B and C in HIV-coinfected patients. Journal of Antimicrobial Chemotherapy 57(5): 815-818. May 2006.

References

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7.      V Soriano, P Barreiro and M Nunez. Management of chronic hepatitis B and C in HIV-coinfected patients. Journal of Antimicrobial Chemotherapy 57(5): 815-818. May 2006.

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13.  Torriani F, Rodriguez-Torres M, Rockstroh J et al. Peginterferon Alfa-2a plus ribavirin for chronic hepatitis C virus infection in HIV-infected patients. N Engl J Med 2004; 351: 438–50.

14.  Soriano V, Maida I, Garcia-Samaniego J et al. Long-term follow-up of HIV-infected patients with chronic hepatitis C virus infection treated with interferon-based therapies. Antivir Ther 2004; 9: 987–92.

15.  Soriano V, Puoti M, Bonacini M et al. Care of patients with chronic hepatitis B and HIV co-infection: recommendations from an HIV-HBV international panel. AIDS 2005; 19: 221–40.

16.  Brook M, Gilson R, Wilkins E et al. BHIVA Guidelines on HIV and chronic hepatitis: coinfection with HIV and hepatitis B virus infection. HIV Med 2005; 6 Suppl 2: 84–95.

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18.  Peters M, Anderson J, Lynch P et al. Tenofovir disoproxil fumarate is not inferior to adefovir dipivoxil for the treatment of hepatitis B virus in subjects who are coinfected with HIV: results of ACTG A5127. Abstract 124. 12th Conference on Retroviruses and Opportunistic Infections, Boston, February 2005.

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