To the Editor:
Because of shared routes of transmission, coinfection with hepatitis B virus (HBV) and hepatitis C virus (HCV) is common among HIV-infected people.1-3 Over the past few years, HBV and HCV have emerged as significant causes of morbidity and mortality in HIV-infected patients in developed countries, where classic opportunistic infections have declined as a result of the widespread use of potent antiretroviral therapies.2,4 Although increasing attention has been paid to HIV/HBV and HIV/HCV coinfections,5,6 there are few data on HIV/HBV/HCV triple infection.1,7-9
This retrospective study aimed to estimate the prevalence of chronic coinfection with HBV and HCV in a large cohort of HIV-infected persons and to investigate the replicative patterns of both viruses in such patients.
In September 2006, we reviewed the charts of all HIV-positive patients being followed at our outpatient clinic. On the basis of prior medical records data, subjects with chronic HBV and/or HCV coinfection were identified. Chronic HBV and HCV infections were defined by the presence of, respectively, the hepatitis B surface antigen (HbsAg) and the antibody to HCV (anti-HCV) in serum for at least 6 months. Demographic, laboratory, and treatment data (gender, age, HIV risk factor, duration of HIV infection, AIDS diagnosis, CD4 cell count, plasma HIV RNA level, alanine aminotransferase [ALT] level, current alcohol abuse, diagnosis of chronic liver disease, previous or current interferon-α therapy, and current antiretroviral treatment) on patients with HIV/HBV/HCV triple infection who had been visited at least once in the past 6 months were collected; they refer to the last checkup before the beginning of the study. To evaluate viral activity, we tested each of these patients for HBV and HCV viremia levels. Serum HBV DNA was measured by means of the Versant HBV-DNA 3.0 Assay (branched DNA [bDNA]; Bayer Diagnostics, Tarrytown, NY), with a detection limit of 2000 copies/mL, whereas serum HCV RNA was detected using the Cobas Amplicor HCV Test 2.0 (Roche Diagnostics, Branchburg, NJ), with a sensitivity limit of 50 IU/mL. In HCV RNA-positive cases, viremia was quantified by the Versant HCV-RNA 3.0 Assay (Bayer Diagnostics), with a detection limit of 615 IU/mL. Active HBV infection was defined on the basis of an HBV viremia level greater than 105 copies/mL, whereas active HCV infection was defined by the presence of detectable HCV viremia. Data were analyzed using the SPSS (Chicago, IL) 13.0 for Windows XP software package.
The charts of 1656 HIV-1-infected outpatients attending our clinic were examined. We found that 548 patients (33%) were anti-HCV-positive, 47 (3%) were HbsAg-positive, and 21 (1%) were HbsAg- and anti-HCV-positive. Among the 21 HIV-HBV-HCV-coinfected patients, 13 (62%) were considered evaluable for the purpose of our study. Their characteristics were as follows: 10 (77%) male and 3 (23%) female; median age of 43 years (range: 36-56 years); HIV risk factors represented by 10 (77%) injecting drug users, 2 (15%) homosexuals, and 1 (8%) heterosexual; median duration of HIV infection of 14 years (range: 7-21 years); 3 (23%) with AIDS and 10 (77%) without AIDS; median CD4 count of 378 cells/μL (range: 58-1052 cells/μL); median HIV RNA level of 184 copies/mL (range: 49-33,582 copies/mL); median alanine aminotransferase level of 51 IU/L (range: 16-482 IU/L); 1 (8%) with current alcohol abuse and 12 (92%) without current alcohol abuse; and 7 (54%) with chronic liver disease and 6 (46%) without chronic liver disease. Two patients (15%) had been treated with peginterferon α-2b plus ribavirin for HCV, with a sustained virologic response in 1, but neither of them was currently on HCV treatment. All patients except 1 (92%) were on combination antiretroviral therapy, including at least 1 drug also active against HBV, such as tenofovir disoproxil fumarate (TDF), lamivudine (3TC), or emtricitabine (FTC).
After testing for HBV and HCV viremia levels, we found active HBV and HCV infection in no patients, inactive infection by both viruses in 5 (39%), active HBV and inactive HCV in 2 (15%), and inactive HBV and active HCV in 6 (46%). Table 1 shows the detailed findings of the exposure to TDF, 3TC, and FTC as well as the replicative patterns of HBV and HCV in the study population. The 2 patients with active HBV infection had HBV DNA levels greater than 107 copies/mL, although they were both on TDF and FTC. Among the patients with active HCV infection, the median HCV RNA level was 222,159 IU/mL (range: 2722-772,549 IU/mL). The HCV genotype was 3 in all patients except 1, who exhibited genotype 4. Among the 8 patients with active HBV or HCV infection, 7 (88%) had evidence of chronic liver disease; specifically, chronic hepatitis was found in 3 cases and cirrhosis in the other 4 (2 with active HBV and 2 with active HCV). Among the patients with chronic hepatitis, 1 also had a history of current alcohol abuse and 2 presented with serum antibody to hepatitis D virus, although they were HDV RNA-negative. Because the small number of individuals with triple infection did not allow us to achieve adequate statistical power, we performed only a descriptive analysis. We found that active HBV infection was associated with a lower CD4 cell count, higher HIV RNA level, and more advanced liver disease, whereas active HCV infection was associated with a longer duration of HIV infection, higher CD4 cell count, and lower HIV RNA level.
Dual chronic infection by HBV and HCV in HIV-positive patients is associated with a high risk of accelerated progression to cirrhosis and hepatocellular carcinoma.2,10 Furthermore, it has important implications for hepatitis treatment, choice of antiretroviral regimen, and antiretroviral-associated hepatotoxicity.7,11 Several studies in HIV-uninfected patients have shown an interplay between HBV and HCV in cases of dual infection, with a subsequent inhibition of the replication of 1 or both viruses and a prevalent negative influence of HCV on HBV activity. Moreover, they have also demonstrated that HBV/HCV coinfection is not a stable condition but that it may present with dynamic virologic profiles characterized by wide fluctuations of HBV and HCV viremia levels over time, with both viruses demonstrating alternating phases of active and suppressed replication.12-14
Our study shows that a wide spectrum of virologic patterns may also occur in HIV-positive patients with HBV/HCV coinfection. Nevertheless, some considerations should be made. First, in some cases, lack of detection of HBV DNA might be attributable to 3TC, FTC, or TDF use as part of antiretroviral regimens, although baseline HBV viremia levels were not available in most patients. Second, undetectable levels of HCV RNA might indicate a resolved infection. Finally, our single time point evaluation of HBV and HCV viremia levels might reflect only a temporary virologic status, which might change over time. Therefore, a longitudinal evaluation of HBV and HCV should be recommended in HIV-infected patients who are HbsAg- and anti-HCV-positive to assess their current virologic status and tailor the most proper therapeutic approach.
Salvatore Sollima, MD
Ilaria Caramma, MD
Barbara Menzaghi, MD
Benedetta Massetto, MD
Veronica Acquaviva, MD
Giuseppe Giuliani, MD
Mauro Moroni, MD
Spinello Antinori, MD
Istituto di Malattie Infettive e Tropicali, Università di Milano, Ospedale L. Sacco Milan, Italy
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