Advances in the Management of Viral Hepatitis B and Hepatitis C Infection in HIV-Coinfected Patients - CROI 2007 CME

[Guest guest]



Selection from: CROI 2007 - Key Challenges in HIV: Metabolic Complications and Adverse Effects; HIV/Hepatitis Coinfection; and Clinical Pharmacology

Advances in the Management of Viral Hepatitis B and Hepatitis C Infection in HIV-Coinfected Patients - CROI 2007 CME

V. Soriano, MD, PhD Disclosures

Introduction

This year's Conference on Retroviruses and Opportunistic Infections (CROI) convened in Los Angeles, California, and drew nearly 4000 attendees, 45% of whom were from abroad. The opening ceremony coincided with the Academy Awards ceremony in Hollywood. In light of the number of abstracts on viral hepatitis infection in people with HIV coinfection -- 75 out of 1100 abstracts in total -- there is no doubt that HIV-viral hepatitis coinfection should have merited at least 1 at CROI.

Hepatitis B Virus Infection

The HBV Genome

The hepatitis B virus (HBV) genome is composed of 4 overlapping genes that encode a number of complex and multifunctional proteins. Of interest, part of the polymerase gene overlaps the gene that encodes the HBV surface antigen (HBsAg) protein. It is not surprising that long-term antiretroviral therapy directed against HBV reverse transcriptase (RT) can lead to the selection of drug resistance mutations that may affect the antigenicity of the overlapping HBsAg protein (Figure 1). In the other direction, HBV vaccination or the use of hepatitis B immunoglobulin as prophylaxis may select for envelope mutations that affect the polymerase (Figure 2).

Characteristics of Drug-Resistant HBV

Spanish and Australian researchers examined 71 individuals with chronic hepatitis B infection who were exposed to anti-HBV agents for longer than 12 months and who were currently experiencing virologic failure.[1] Fifty-two of these individuals were coinfected with HIV. The study investigators found a significant segregation of HBV genotypes. Genotype A was more prevalent in HBV/HIV-coinfected patients (38/52), whereas genotype D was the most common in HBV-monoinfected persons (10/19) (P < .01). Of interest, lamivudine-associated resistance mutations in HBV were present in more than half of all patients and were more common in HBV/HIV-coinfected than in HBV-monoinfected individuals. In the multivariate analysis, this observation was mainly driven by the characteristic genotype distribution.

Remarkably, 3 coinfected patients harbored HBV strains with the RT triple mutant V173L + L180M + M204V, which results in diminished HBsAg antibody binding.[2] The public health implications of these findings suggest that the selection of certain HBV drug-resistance mutations may result in altered HBsAg, thereby creating HBV strains that can evade or escape from the immune responses generated by vaccines and/or failure to be recognized by serologic tests for HBsAg, explaining the phenomenon of "occult" hepatitis B.

Possible Anti-HIV Activity of Entecavir?

Entecavir is one of the antiviral agents most recently approved for treating HBV. The drug label specifically states that it lacks anti-HIV activity at the approved recommended doses. In a rather surprising late-breaker presentation, researchers from s Hopkins University reported on 3 HBV/HIV-coinfected individuals who were exposed to entecavir in the absence of antiretroviral therapy.[3] All showed about a 1-log10 decline in plasma HIV-RNA and 1 developed the M184V mutation in HIV, suggesting that entecavir has activity against HIV. The study investigators also reported that in vitro experiments provided additional support that entecavir shows anti-HIV activity, although the data were somewhat controversial and virologists from the company that markets the drug replied that their data do not support the investigators' findings.[4] It is intriguing that HIV drug resistance information was not reported for the other 2 HBV/HIV-coinfected patients exposed to entecavir and that the 1 individual who harbored the M184V mutation in HIV had been exposed in the past to lamivudine. Clearly, further data are needed before it can be concluded that entecavir is not appropriate for the treatment of HBV in HIV-infected individuals who do not require antiretroviral therapy, as is recommended in current guidelines (Figure 3)[5,6]

Hepatitis C Virus

Factors Contributing to the Spread of HCV Among Those With HIV Infection

Hepatitis C virus (HCV) has not been thought to be efficiently transmitted through sexual contact. However, recent reports of outbreaks of acute hepatitis C among men who have sex with men (MSM) have changed this view. British researchers examined 7223 MSM who attended a single clinic in Brighton, United Kingdom, since 2000.[7] The study investigators reported that highly risky sexual practices along with multiple sex partners explained the increase in episodes of acute HCV infection in this population. Other sexually transmitted diseases, such as syphilis and gonorrhea, were also common among those with acute HCV infection. This phenomenon was not restricted to HIV-infected MSM, although compared with HIV-uninfected MSM, those with HIV infection seemed to be particularly prone to spreading and acquiring HCV infection, most likely due to high levels of HCV viremia and impaired immune responses, respectively. In view of these findings, MSM who engage in risky sexual behaviors should be screened periodically for HCV as well as for HIV antibodies, and preventive measures and counseling must be reinforced in this population.

In a totally different scenario, a study performed in St. sburg, Russia, examined the rates of HCV and HIV infections among intravenous drug users.[8] HCV genotype 3 and HIV subtype A were the predominant variants rapidly spreading in this community. Most new infections seemed to derive from people who were themselves recently infected, most likely as a consequence of high levels of HCV and/or HIV viremia and the fact that most individuals who transmitted viruses were unaware of their HCV and/or HIV infection status.

The Use of Liver Biopsy in HCV/HIV-Coinfected Patients

The use of liver biopsy in HCV/HIV-coinfected patients was elegantly discussed by , MD, s Hopkins, Baltimore, land.[9] He began his presentation by acknowledging that the extent of hepatic fibrosis is the best prognostic factor of liver disease progression in patients with chronic HCV infection. Therefore, it is worth considering the degree of hepatic fibrosis before initiating HCV therapy. Liver biopsy has for many years been the only tool for assessing hepatic fibrosis. This method has the advantage of providing additional information on other relevant histologic findings, such as necroinflammation and steatosis. However, several limitations of the procedure, including: (1) its invasive nature with occasional serious and even life-threatening complications; (2) the possibility of sampling error due to a relatively small biopsy size, the fragmentation of examined tissue, and/or the inherent heterogeneity of hepatic fibrosis[10,11]; (3) low acceptance by most patients; and (4) its relatively elevated cost; have prompted the development of noninvasive tools for staging hepatic fibrosis.

Noninvasive procedures for assessing liver fibrosis are currently split into 2 major categories: imaging techniques, such as elastometry (FibroScan),[12] and serum biochemical marker tests (eg, Fibrotest, APRI, SHASTA, FIB-4, Forns, serum hyaluronic acid).[12] These tools are generally accurate in discriminating between a lack of fibrosis and advanced fibrosis, but they are less precise at distinguishing between intermediate fibrosis stages. The predictive value of these tests is particularly good for advanced hepatic fibrosis and cirrhosis. Liver fibrosis staging using elastometry seems to be particularly reliable. Elastometric measurements can be made in 10 minutes, can be repeated periodically, are inexpensive, and have a positive predictive value greater than 90% for advanced fibrosis.[12]

Dr. concluded that when the diagnosis of hepatic disease is clear by other means, such as the detection of serum HCV RNA indicative of chronic HCV infection, the need for a liver biopsy to stage hepatic fibrosis and guide the treatment decision is no longer justified in most instances.[9] The relatively high response to pegylated interferon plus ribavirin, the faster progression of HCV-related liver disease in the HIV-coinfected population, and the opportunity for assessing the HCV response at earlier time points to identify who will and will not respond to therapy all favor initiating anti-HCV therapy without the need for a liver biopsy in most cases.

Chung, MD, from the Massachusetts General Hospital in Boston, provided an excellent overview of the current treatment of chronic hepatitis C in HIV-infected individuals.[13] After reviewing the data from the pivotal prospective, randomized clinical trials of HCV treatment in the setting of HIV coinfection -- APRICOT, RIBAVIC, and ACTG 5071[14-16] -- he addressed which strategies improved the response rates in the coinfected populations. Dr. Chung mentioned that the results from the PRESCO trial[17] suggest that the use of high ribavirin doses (1000-1200 mg/day) -- much higher than doses used in prior studies (800 mg/day) -- may provide a significant benefit (Table 1). Moreover, the appropriate selection of candidates for anti-HCV therapy (eg, excluding individuals concomitantly using zidovudine and didanosine or patients with low CD4+ cell counts) may allow for improved sustained virologic response rates in the coinfected population, as was discussed in another presentation.[18] According to these criteria, the rate of premature treatment discontinuations due to side effects in PRESCO was only 8.2% -- a rate quite similar to that seen in HCV-monoinfected individuals.[17]

Table 1. Comparison of Large Trials Using Pegylated Interferon and Ribavirin in HCV/HIV-Coinfected Patients

Baseline, Treatment, and Outcomes

APRICOT[14](n = 289)

RIBAVIC[15](n = 205)

ACTG 5071[16](n = 66)

PRESCO[17](n = 389)

Type of pegIFN

Alfa-2a

Alfa-2b

Alfa-2a

Alfa-2a

RBV dose

800 mg/d

800 mg/d

Escalating 600→ 1000 mg/d

1000-1200 mg/d(if weight is< or > 75 kg)

IDU (% of patients)

62%

81%

80%

89.5%

Liver cirrhosis (% of patients)

15%

18%

11%

8.7%

HCV genotypes 1 or 4 (% of patients)

67%

69%

77%

61%

Median CD4+ cell count (cells/mcL)

520

525

492

546

On ART

84%

82%

85%

74%

Premature treatment discontinuation (% of patients)

25%

36%

12%

27.8%

ETR (ITT) (% of patients)

49%

36%

41%

67.3%

SVR (ITT) (% of patients)

40%

27%

27%

49.6%

ART = antiretroviral therapy; ETR = end-of-treatment response; HCV = hepatitis C virus; IDU = injection drug use; ITT = intention to treat; pegIFN = pegylated interferon; RBV = ribavirin; SVR = sustained virologic response.

A number of studies presented at this meeting provided new and interesting information that may help to optimize the treatment of chronic hepatitis C in HIV-infected individuals. A substudy of the RIBAVIC trial acknowledged that the concomitant use of abacavir and ribavirin could be deleterious, given that response rates were lower in this subset of patients compared with the rest of the study participants.[19] The basis for this negative interaction may have to do with the fact that both nucleoside analogues are guanosine derivatives and may compete in the same phosphorylation pathways within cells.

Another intriguing observation came from a substudy of the PRESCO trial, which showed that virologic relapse following undetectable HCV RNA at the end of pegylated interferon plus ribavirin therapy did not diminish with extended treatment.[20] The rates of virologic failure were comparable whether individuals with HCV genotypes 2 or 3 received 24 or 48 weeks of treatment or whether individuals with HCV genotype 1 or 4 received 8 or 72 weeks of treatment (Figure 4).

Another interesting report examined the potential of transcription-mediated amplification (TMA), a very sensitive tool that has a lower limit of HCV RNA detection of 5 IU/mL, for detecting serum HCV RNA at the end of a course of anti-HCV therapy and predicting subsequent relapse.[21] The positive and negative predictive values of relapse were above 80% using this assay.

Finally, one study compared the proportion of patients with advanced liver fibrosis (Metavir scores of F3 or F4) in HCV/HIV-coinfected patients with repeated normal liver enzyme levels vs a matched control group of patients with elevated liver enzymes.[22] The study investigators used elastometry (FibroScan) to measure liver fibrosis. The main results are summarized in Table 2. Nearly 15% of coinfected patients with persistently normal alanine aminotransferase (PNALT) levels showed advanced liver fibrosis (Metavir estimates F3 to F4), and this finding was more frequent in women and in individuals infected with HCV genotype 4. Thus, coinfected patients with normal liver enzyme levels should not be excluded from anti-HCV therapy, as liver disease progression may occur in a significant proportion of these patients in a silent manner.

Table 2. Liver Fibrosis Staging in HCV/HIV-Coinfected Patients With Elevated and Persistently Normal ALT (PNALT)

ALT

Liver Fibrosis

MildMetavir F0 to F2;FibroScan < 9.5 kPa

ModerateMetavir F3;FibroScan 9.5-13.9 kPa

SevereMetavir F4;FibroScan > 14 kPa

Elevated ALT(n = 133)

65 (49%)

22 (16%)

46 (35%)

PNALT(n = 87)

76 (86%)

9 (10%)

3 (4%)

Adapted from -Carbonero et al.[22]ALT=alanine amino transferase; kPa = kilopascals; PNALT = persistently normal ALT.

Supported by an independent educational grant from Bristol-Myers Squibb

http://www.medscape.com/viewarticle/554156?src=mp