Hepatitis delta is a major determinant of liver decompensation events and death in HIV-infected patients.

BACKGROUND: Coinfection with hepatitis viruses is common in individuals infected with human immunodeficiency virus (HIV) and has become a leading cause of complications and death in those receiving antiretroviral therapy (ART). METHODS: We retrospectively examined the effect of coinfection with hepatitis B, C, and/or D viruses (HBV, HCV, HDV, respectively) on liver decompensation events (ascites, variceal bleeding, encephalopathy, and/or hepatocellular carcinoma) and liver-related mortality in HIV-positive patients on regular follow-up since the year 2004 at a reference HIV clinic in Madrid, Spain. RESULTS: A total of 1147 HIV-infected patients (mean age, 42 years; 81% males; 46% intravenous drug users, 85.4% on ART) were analyzed. Mean follow-up was 81.2 ± 17.8 months. At baseline, 521 patients (45.4%) were HCV-antibody positive, 85 (7.4%) were hepatitis B surface antigen positive, and 17 (1.5%) were anti-HDV positive. A total of 233 HIV/HCV-coinfected patients received antiviral therapy for HCV, of whom 106 (45%) achieved sustained virologic response (SVR). Overall, 15 patients died of liver-related complications and 26 developed hepatic decompensation events. Taking as controls the 524 HIV-monoinfected patients, HDV coinfection (adjusted hazard ratio [AHR], 7.5; 95% confidence interval [CI], 1.84-30.8; P = .005) and baseline liver stiffness (AHR, 1.1; 95% CI, 1.07-1.13; P < .0001) were associated with a higher rate of liver-related morbidity and mortality. In contrast, SVR following hepatitis C therapy in HIV/HCV-coinfected patients was protective (AHR, 0.11; 95% CI, .01-.86; P = .03). CONCLUSIONS: Hepatitis delta is associated with a high rate of death and liver decompensation events in HIV-infected patients on ART.

Spontaneous hepatitis C virus clearance in HIV patients with chronic hepatitis C bearing IL28B-CC alleles using antiretroviral therapy.

BACKGROUND: A quarter of individuals acutely infected with hepatitis C virus (HCV) clear the virus spontaneously. Once chronic infection is established, HCV elimination generally can only be achieved using specific antiviral therapy, such as peg-interferon-ribavirin. Herein, we report a group of chronically HIV/HCV-coinfected patients that cleared HCV spontaneously while being treated only with antiretrovirals. METHODS: Retrospective analysis of all HIV-infected individuals with positive HCV antibodies (HCV-Abs) and negative serum HCV-RNA seen during 2012 at a reference HIV clinic in Madrid. RESULTS: From a total of 2366 HIV-infected individuals, 618 (26%) were HCV-Ab+, of whom 387 (62%) were positive for serum HCV-RNA. Individuals HCV-Ab+/HCV-RNA-negative were grouped into two categories--those that had eliminated HCV following a course of antiviral treatment (n = 198, 86%) and those who had cleared the virus spontaneously (n = 33, 14%). Eight with spontaneous clearance were HBsAg+ and might have cleared HCV as a result of viral interference. However, six (24%) out of the remaining 25 did so after being serum HCV-RNA+ for longer than 6 months (median 5.6 years, range 1.3-12 years). All harbored alleles and had undetectable plasma HIV-RNA on HAART around the time of HCV clearance. CONCLUSION: Spontaneous HCV clearance may occur in a subset of chronically HIV/HCV-coinfected patients on HAART harboring IL28B-CC. Given that antiretrovirals do not display any direct anti-HCV activity, recovery of innate immune responses could be responsible for these late HCV clearance episodes. Thus, periodic testing of serum HCV-RNA may be warranted in chronically HIV/HCV-coinfected patients on HAART harboring IL28B-CC alleles.

X4 tropic viruses are on the rise in recent HIV-1 seroconverters in Spain.

BACKGROUND: Transmission of HIV-1 with drug resistance mutations (DRMs) in Spain remains stable around 13%. However, the profile of recent HIV-1 seroconverters has experienced significant changes. METHODS: Retrospective analyses of all individuals with HIV-1 infection acquired within the past 12 months recruited at a national registry since year 1997. RESULTS: A total of 1032 recent HIV-1 seroconverters were examined (92.2% men; median age 31 years; 84% homosexual men). At the moment of diagnosis, median plasma HIV-RNA and CD4 cell counts were 4.5  log copies/ml and 558 cells/µl, respectively. A total of 136 individuals (13.8%) carried non-B subtypes. Major primary DRMs were found in 13.4%, being 7.7% for nucleoside reverse transcriptase inhibitor (NRTI), 5.8% for nonnucleoside reverse transcriptase inhibitor (NNRTI) and 2.9% for protease inhibitor. NRTI DRM significantly declined from 23.7% in 1997-2000 to 5.7% in 2010-2012 (P<0.01). Overall, X4 viruses were found in 19.7% of HIV-1 seroconverters, increasing from 11.5% before 2001 to 23.3% since year 2010 (P=0.04). Interestingly, median CD4 cell counts were significantly lower in seroconverters diagnosed during the last period after adjusting for potential confounders. In multivariate analyses, X4 tropism, high HIV-RNA, foreigners and non-B subtypes were independent predictors of lower CD4 cell counts. CONCLUSION: Transmission of NRTI DRM has declined significantly in recent HIV-1 seroconverters in Spain. Conversely, X4 tropic viruses are on the rise and currently account for 23.3% of new HIV-1 infections. These individuals present with lower CD4 cell counts suggesting that circulating HIV-1 strains might have gained virulence.

Efficacy of prolonged tenofovir therapy on hepatitis delta in HIV-infected patients.

BACKGROUND: Hepatitis delta virus (HDV) produces the most severe form of chronic viral hepatitis. We explored whether prolonged tenofovir exposure might be beneficial on hepatitis delta in HIV-infected patients. METHODS: All HIV-infected patients with hepatitis delta followed at our institution since year 2000 were retrospectively examined. Serum HBV-DNA and HDV-RNA were quantified using commercial assays. Liver fibrosis was measured using elastometry. RESULTS: A total of 19 HIV/delta patients were identified. All were viremic for HDV and 11 for HBV. After a median tenofovir exposure of 58 months, all had undetectable HBV-DNA and 10 (53%) had undetectable HDV-RNA. The median drop in HDV-RNA in the remaining nine HDV viremic patients at the end of follow-up was 2.4 log copies/ml. A reduction above 30% in liver stiffness occurred in six out 10 (60%) patients who achieved undetectable HDV-RNA, whereas hepatic stiffness did not change in the remaining HDV viremic patients (P = 0.03). Serum HBsAg concentrations did not decline significantly, although HBsAg seroclearance occurred in three patients, all of whom became negative for HDV-RNA. CONCLUSION: Long-term exposure to tenofovir significantly reduced serum HDV-RNA apart from completely suppressing HBV-DNA in HIV-infected patients with hepatitis delta. This virological benefit is accompanied by significant improvements in liver fibrosis.

Progression to advanced liver fibrosis in HIV-HCV-coinfected patients and prioritization of new hepatitis C therapies.

BACKGROUND: Because of their high cost, the use of direct-acting antivirals (DAAs) is being restricted by many governments to chronic HCV-infected individuals with advanced liver fibrosis. However, response rates are lower and toxicities more frequent in this subset of patients. METHODS: All HIV-HCV-coinfected patients followed for at least 3 years at one reference clinic were identified. Liver fibrosis progression (LFP) was defined as a shift from Metavir F0-F2 to F3-F4 estimates (>9.5 KPa) using elastometry. RESULTS: A total of 527 HIV-HCV-coinfected patients were identified, of whom 344 had F0-F2 at baseline. Pegylated interferon/ribavirin therapy was given to 205 patients with null/mild fibrosis, of whom 92 (44.9%) achieved sustained virological response (SVR). After a mean follow-up of 53 months, LFP occurred in 5.4% SVR, 25.7% non-SVR and 18% untreated patients (P=0.005). In multivariate analysis, only achievement of SVR prevented LFP (adjusted hazard ratio 2.1; 95% CI 1.1, 4.1; P=0.01). In 139 untreated patients, only greater baseline elastometry values predicted LFP in multivariate analysis (adjusted hazard ratio 1.84; 95% CI 1.03, 3.3; P=0.03). The area under the receiver operating characteristic (AUROC) curve was 79%. A discriminant threshold of 7.1 kPa gave 68% sensitivity and 82% specificity. CONCLUSIONS: In the absence of successful treatment, more than 20% of HIV-HCV-coinfected patients with null/mild liver fibrosis progress to advanced fibrosis within 5 years. Patients with >7.1 kPa (Metavir F2) display the highest risk. Therefore, all coinfected patients with any significant liver fibrosis should be considered as candidates for new DAA-based therapies.

Influence of HIV infection on response to tenofovir in patients with chronic hepatitis B.

BACKGROUND: HIV worsens the natural history of chronic hepatitis B virus (HBV) infection. Suppression of HBV replication slows progression of liver damage. Information about the influence of HIV on response to tenofovir in HIV/HBV-coinfected patients is scarce. METHODS: All individuals with persistent HBsAg+ at four clinics in Spain were identified. Information from the subset that initiated tenofovir therapy was examined. RESULTS: A total of 176 patients with chronic hepatitis B were evaluated, of whom 138 (78.4%) were coinfected with HIV. Prior lamivudine exposure was extensive in both groups, and nearly half of HBV viremic patients harboured drug resistance mutations. Most patients took tenofovir coformulated along with emtricitabine (Truvada). Of 101 HBV viremic patients at the time of beginning tenofovir (78 with HIV coinfection and 33 with HBV alone), a similar proportion achieved undetectable HBV-DNA at weeks 24, 48 and 96 of tenofovir therapy. Interestingly, HIV/HBV-coinfected patients with positive HBeAg showed a lower response than HBeAg-negatives. In multivariate analysis, however, baseline serum HBV-DNA was the only predictor of virological response to tenofovir. CONCLUSION: The antiviral efficacy of tenofovir is similar in HIV/HBV-coinfected and HBV-monoinfected patients, achieving undetectable HBV-DNA nearly 90% of patients at week 96 of therapy. Baseline serum HBV-DNA is the major determinant of time-trends in virological response, with no significant influence of HBeAg, drug resistance mutations nor coinfection with hepatitis C or delta viruses.