Viral Hepatitis Co-Infection in HIV

Hopkins HIV Report 2007 Mar; 19(2):7-9

Kelly Gebo, M.D. M.P.H. and Lucy Wilson M.D., Sc.M.
Johns Hopkins

The 14th CROI demonstrated the increasing importance of viral hepatitis in the management of chronic HIV infection. There were numerous abstracts presented as posters and two oral sessions devoted to the management of viral hepatitis. Some of the most interesting findings of the meeting were the discussion of the utility of liver biopsy and other markers in the staging and management of hepatic disease, appropriate vaccination of patients against hepatitis B virus (HBV), the low treatment rates of hepatitis C virus (HCV) infection among injection drug users (IDUs), and the potential dangers of using entecavir in patients co-infected with HIV and HBV who are not on HAART.

Alternative Markers for Fibrosis

David Thomas commented on assessment of liver fibrosis among those chronically infected with HIV and HCV [Abstract 161]. He postulated that the gold standard, the liver biopsy, is inherently limited in accuracy due to sampling error, heterogeneity of the diseased liver, and inter- and intra-observer variability among pathologists. However, other noninvasive markers of liver fibrosis, including transient hepatic elastography and serum markers of inflammation and collagen deposition are also limited. Given the inherent inaccuracy of the liver biopsy, it is difficult to accurately predict the true sensitivity and specificity of the noninvasive markers. Thomas proposed that, given current data, it may be safer and as informative to use an optimal panel of noninvasive markers to evaluate liver fibrosis, especially if HCV/HIV co-infected patients are followed longitudinally and the tests repeated serially.

There were 10 posters addressing the noninvasive assessment of liver damage among patients co-infected with HIV and either hepatitis B or C [Abstracts 908-917]. Many abstracts compared various predictive models of liver fibrosis and disease using serum markers. Abstracts 912 through 914 compared multiple markers and validated specific markers, such as FIB-4, FORNS, APRI, or hyaluronic acid, as good predictors of severe fibrosis, but inaccurate as markers of more moderate disease that would indicate clinically significant fibrosis still requiring initiation of HCV or HBV treatment. Suzman and colleagues generated a predictive model of fibrosis among HCV-infected patients using various serum markers. The investigators found that α2 macroglobulin and haptoglobin combined with 2 genes (alanyl amino peptidase and mitogen activated protein) to be most predictive of Ishak fibrosis score F3 or above (area under receiver operator curve, or AUROC, 0.92) in HIV/HCV coinfected patients [Abstract 908]. Cacoub and colleagues evaluated non-invasive liver fibrosis biomarkers in 274 treatment-naïve French patients and found that the various markers (Fibrometer, Hepascore and Fibrotest) can only correctly classify patients with severe fibrosis (≥F3, accuracy 74 to 97%) [Abstract 909]. They found Fibrometer to be most accurate for F2 or F3 and above, while Fibrotest was most accurate for F1 or less. Nunes and colleagues evaluated numerous noninvasive markers for predicting end-stage liver disease (ESLD) events in HCV-infected patients [Abstract 916]. In this study, the best marker was hyaluronic acid with AUROC of 0.92 and APRI score, with an AUROC of 0.90.

Two abstracts assessed transient hepatic elastography, a measurement of liver stiffness. Vergara and coworkers used Fibroscan to distinguish clinically significant fibrosis in HCV/HIV co-infected persons [Abstract 910]. Liver biopsies were paired with elastography among HCV-untreated subjects. Using the standard Fibroscan cutoff of 7.2 kPa, 19% of those with METAVIR fibrosis scores (a score based on basic pathological features) greater than F1 were misclassified. The AUROC for Fibroscan >7.2 KPa for F4 was 0.95, for F3 0.93 and for F2 0.87, all considered good predictors. Miailhes and colleagues assessed those on treatment for both HBV and HIV infection, with Fibroscan versus liver biopsy for concordance [Abstract 911]. AUROC for METAVIR F0-F2 vs. F3-F4 was 0.73 and for F0-F1 vs. F2-F4 was 0.79. Duration of therapy and suppression of HBV were not reported.

Two other abstracts looked at novel predictors of fibrosis due to HCV infection. Shuart established that soluble TNF receptor II levels may be increased as a result of HIV infection, and this elevation may accelerate liver fibrosis [Abstract 915]. Salmon and colleagues demonstrated that insulin resistance among those with HCV/HIV co-infection independently predicts liver fibrosis, although this abstract did not indicate which patients were on antiretroviral therapy [Abstract 917]. A group from England suggested that steatosis in HCV/HIV co-infected patients is independently associated with advanced liver fibrosis [Mohsen A, et al., Abstract 926]. Finally, several groups showed that progression from fibrosis to cirrhosis or death is faster among those infected with HIV and HCV (plus or minus HBV) than in those with HIV and HBV, perhaps because of HBV suppression with antiretrovirals such as tenofovir (TDF), lamivudine (3TC), and/or emtricitabine (FTC) [Abstracts 931-933].

Vaccinations

HIV-infected patients are less likely to respond to HBV vaccination than the general population. Several groups evaluated different regimens for HBV vaccination to achieve higher rates of seroconversion. Vries-Slujis and colleagues revaccinated all patients who did not seroconvert after one HBV series with high dose recombinant vaccination at monthly intervals (0, 1, 2 months) [Abstract 883]. Of 144 patients revaccinated, 51% demonstrated a response. Responders were more likely to be female and younger than non-responders. In a similar abstract from Ireland, Low found that double-dosing patients increased response rates in non-responders; 87% of non-responders seroconverted after the double dosing regimen [Abstract 884]. Of note, all of those with CD4 counts >500 cells/mm³ seroconverted, suggesting that vaccinating before the CD4 count falls below 500 or waiting until HAART has boosted the CD4 count may improve response rates.

Treatment

Sulkowski and colleagues evaluated treatment rates among treatment eligible IDUs with and without HIV infection followed in the Johns Hopkins Moore clinic [Abstract 947]. He found that while 80% of HCV mono-infected patients were eligible for treatment, only 50% of HIVHCV co-infected patients were eligible for HCV treatment. The most common reasons for exclusion were severe depression, life expectancy less than 2 years, and hematologic abnormalities. Even after the removal of financial and geographic barriers, only 40% of eligible IDUs obtained HCV treatment, suggesting that better strategies for engaging and retaining HCV infected IDUs in care are essential.

Standard management with pegylated interferon/ribavirin (PEG-IFN/RBV) in the HCV/HIV co-infected patient involves monitoring HCV RNA response at week 12 of therapy to determine the rapid virological response (RVR); this helps determine the utility of continuating therapy for the full 24 or 48 weeks. Two abstracts assessed whether evaluation of HCV RNA response at 4 weeks (early RVR) was equally predictive of sustained virological response (SVR) as the traditional 12 week evaluation. Mira and coinvestigators evaluated 101 HCV/HIV co-infected patients treated with PEG-IFN/ RBV [Abstract 891]. Ninety seven percent of patients with RVR (undetectable HCV RNA) had SVR, for a positive predictive value (PPV) of 97%. Those with HCV genotype 3 treated for 24 weeks had a PPV=100% for SVR with early RVR checked at 4 weeks. The highest negative predictive value (NPV=96%) was found when the HCV RNA failed to decrease by more than 0.6 log₁₀ at 4 weeks, where failure of SVR could have been predicted in 24% of patients and treatment thus discontinued at 4 weeks. The authors point out that the use of these 2 cutoffs could predict the SVR after 4 weeks in 60% of HIV/HCV coinfected patients on HCV therapy. Likewise, O’Shea and colleagues evaluated early RVR at week 4 in 55 HCV/HIV coinfected and 77 HCV mono-infected patients undergoing HCV treatment [Abstract 894]. Sixty-seven percent of HCV/HIV co-infected patients achieved early RVR (HCV RNA decline >2 log₁₀ or undetectable), with a PPV of 92% and NPV of 88%. Similar predictive values were seen for HCV mono-infected patients as well. Separate analyses by HCV genotype were not reported. These data could have substantial clinical utility, as those with early RVR at 4 weeks would have strong motivation to continue therapy, while those without early RVR would be less likely to respond, and could avoid treatment-related side effects and costly therapy.

Treatment of Hepatitis B Co-Infection

Chloe Thio provided a comprehensive overview of the management of hepatitis B infection [Abstract 48]. She summarized some of the most important treatment developments over the past 5 years, including the appropriate treatment of HBV/HIV co-infected patients who need HAART (TDF plus either FTC), who do not need HAART (IFN, adefovir dipivoxil, or telbivudine), and who are 3TCexperienced, indicating that they probably have 3TC resistance (add tenofovir). She explained the limitations for each of the available options for treating patients who do not have an indication for starting HAART. She also cautioned against cross- resistance that can develop between lamivudine, telbivudine, and entecavir, but less commonly between these drugs and adefovir/tenofovir. In addition, she presented a patient with HBV/HIV co-infection treated with entecavir for HBV who did not have documented M184V mutation prior to entecavir treatment [Abstract 136LB], although he had previously received a lamivudine-containing antiretroviral regimen. Despite previous data suggesting that entecavir has no inherent anti-HIV activity, the patient developed a 1 log drop in HIV RNA after initiation of treatment, and the M184V mutation emerged suggesting that entecavir does have antiretroviral activity against HIV and that it can select for M184V. The implications of this study are that patients co-infected with HBV and HIV should not be treated with entecavir monotherapy without careful consideration of other options, and that treatment for both infections should be considered whenever possible.

Findings presented at the 14th CROI demonstrated that viral hepatitis is an increasing cause of morbidity and mortality, that successful vaccination of HIV infected patients may require additional vaccines beyond the traditional 3 shot series, questioned the accuracy of liver biopsy and suggested that alternative non-invasive measures of liver fibrosis may be beneficial in the management and treatment of hepatitis co-infection in HIV infected patients.

2007-01-10
HHR-2007-03-03

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