Paula Tuma

Risk factors for advanced liver fibrosis in HIV‐infected individuals: role of antiretroviral drugs and insulin resistance

Summary.  Liver damage may result from multiple factors in HIV‐infected patients. The availability of reliable noninvasive tools to measure liver fibrosis has permitted the screening of large patient populations. Cross‐sectional study of all consecutive HIV outpatients who underwent examination by transient elastometry (FibroScan) at one HIV reference clinic during 2007. Advanced liver fibrosis (ALF) was defined as hepatic stiffness >9.5 kilopascals, which corresponds to Metavir stages F3‐F4 in the liver biopsy. A total of 681 consecutive HIV‐infected patients (64% injecting drug users; mean age 43; 78% male; 98% on antiretroviral therapy) had at least one valid FibroScan evaluation. ALF was diagnosed in 215 (32%) of them. In the univariate analysis, ALF was significantly associated with older age, low CD4 counts, chronic hepatitis C, past alcohol abuse, elevated ALT, high triglycerides, low cholesterol, high homeostasis model assessment (HOMA) index and exposure to didanosine and/or stavudine. In a multivariate model (OR, 95% CI), chronic hepatitis C (2.83, 1.57–5.08), past alcohol abuse (2.26, 1.37–3.74), exposure to didanosine and/or stavudine (1.85, 1.14–3.01), high HOMA index (1.25, 1.04–1.51), older age (1.09, 1.05–1.14) and elevated ALT (1.04, 1.03–1.06) remained as independently associated with ALF. Therefore, in addition to chronic hepatitis C and alcohol abuse, insulin resistance and/or exposure to dideoxy‐nucleosides may contribute to ALF in HIV‐infected patients.

Emerging drugs for hepatitis C.

Background: Chronic hepatitis C virus (HCV) infection remains a global health threat with approximately 200 million carriers worldwide. Current treatment consists of the use of peginterferon (pegIFN)/ribavirin (RBV) for 24 or 48 weeks depending on HCV genotype. Serious side effects and the fact that less than half of patients infected with HCV genotypes 1 and 4 (which are the most common) accomplish sustained virological response with this medication warrant the need for novel anti-HCV therapies. Objective: Description of specifically targeted antiviral therapies for hepatitis C (STAT-C) designed to inhibit the serine protease and the RNA-dependent HCV-RNA polymerase. Methods: Review of available data reported in peer-reviewed journals and medical conferences. Results/conclusions: Early preclinical studies using these compounds produced encouraging results, but the initial enthusiasm has been hampered by toxicity issues and rapid selection of resistance. Therefore, combination therapy with a backbone of pegIFN/RBV, or perhaps in the future using several of these small molecules, preferably having distinct modes of action and resistance profiles, will be required.

Incidence of liver cirrhosis in HIV-infected patients with chronic hepatitis B or C in the era of highly active antiretroviral therapy.

BACKGROUND Longitudinal assessment of liver fibrosis with transient elastometry (TE) in patients with chronic viral hepatitis is becoming routine clinical practice in many clinics, as this procedure is non-invasive, easy to perform and relatively inexpensive, allowing early detection of cirrhosis. Herein, we examine the incidence of cirrhosis, using TE assessment, in HIV-infected individuals with chronic hepatitis B or C receiving highly active antiretroviral therapy (HAART). METHODS A longitudinal study was performed on a cohort of HIV-infected patients with chronic hepatitis B or C who were followed since 2004 at Hospital Carlos III (Madrid, Spain) with periodic TE assessments. The primary outcome was the development of cirrhosis, defined as liver stiffness >12.5 KPa. RESULTS A total of 508 HIV-infected patients were examined, of whom 54 developed liver cirrhosis during a mean ±(SD) follow-up of 2.6 ±1.0 years (overall incidence was 41.13 cases per 1,000 person-years). The risk of developing cirrhosis was significantly higher in 297 HCV-RNA-positive patients (either untreated or non-responders to hepatitis C therapy) compared with 55 patients who had cleared HCV with therapy (odds ratio 3.73, 95% confidence interval 1.06-13.17; P=0.04). By contrast, the risk of developing cirrhosis was low and similar in 24 HIV-HBV-coinfected patients under long-term suppressive HBV therapy (mainly tenofovir disoproxil fumarate), 132 HIV-infected patients without chronic liver disease and those who had cleared HCV with therapy. CONCLUSIONS Development of liver cirrhosis in HIV-infected individuals in the HAART era is mainly associated with active HCV coinfection. The risk of developing cirrhosis is negligible in patients who cleared HCV with therapy, as well as in HIV-HBV-coinfected patients on long-term suppressive tenofovir disoproxil fumarate therapy.

Survival of HIV-infected patients with compensated liver cirrhosis.

Introduction:Since the advent of HAART, liver-related mortality has become the leading cause of non-AIDS deaths in HIV-infected patients in western countries, complications of end-stage liver disease due to chronic hepatitis B, chronic hepatitis C or both being mainly responsible. Methods:The incidence and predictors of mortality were examined in HIV-infected patients with compensated liver cirrhosis. The accuracy of three different methods (elastometry, Child–Pugh and Model for End-Stage Liver Disease scores) to predict mortality was further examined. Cirrhosis was defined for hepatic elastometry values above 14.5 kPa. Results:A total of 194 (11.4%) out of 1706 HIV-positive individuals were cirrhotic and were prospectively followed since October 2004 until December 2008. Overall, 89% of cirrhotic individuals had chronic hepatitis C, 10.3% chronic hepatitis B, 4.6% hepatitis delta and 4.1% liver disease of other causes or unknown cause. The overall mortality rate was 5.8 deaths per 100 patient-years. Multivariate analyses showed that age of at least 50 years (hazard ratio 4.76, 95% confidence interval 1.66–13.59, P = 0.004), CD4 cell counts below 200 cells/μl (hazard ratio 3.01, 95% confidence interval 1.26–7.23, P = 0.03) and detectable plasma HIV-RNA (hazard ratio 3.97, 95% CI, 1.53–10.27, P = 0.005) were associated with mortality. A baseline Model for End-stage Liver Disease score of at least 11 (P = 0.03) and hepatic elastometry values above 28.75 kPa (P = 0.001) were independent predictors of mortality. Conclusion:The death rate in HIV-infected patients with compensated liver cirrhosis in the HAART era is 5.8% yearly, higher than mortality previously reported for either HIV-uninfected individuals with cirrhosis or noncirrhotic HIV-positive patients. Factors associated with mortality were older age, low CD4 cell counts and detectable plasma HIV-RNA. Both Model for End-Stage Liver Disease and especially hepatic elastometry accurately predicted mortality in this population.

Rate and Timing of Hepatitis C Virus Relapse after a Successful Course of Pegylated Interferon plus Ribavirin

Information on the rate and timing of hepatitis C virus (HCV) relapse after treatment with pegylated interferon plus ribavirin is scarce. Among 604 patients treated for chronic hepatitis C, the 386 who were human immunodeficiency virus (HIV) positive attained an end-of-treatment response less frequently and experienced relapse more often than did the 218 who were HIV negative. However, episodes of HCV relapse occurred before week 12 in most cases, regardless of HIV status.

Hepatitis C virus (HCV) treatment uptake and changes in the prevalence of HCV genotypes in HIV/HCV-coinfected patients.

Summary.  The efficacy of current hepatitis C therapy in HIV/HCV‐coinfected patients is largely dependent on HCV genotype. The annual prevalence of HCV genotypes/subtypes and their influence on HCV clearance with antiviral treatment were examined in a dynamic cohort of HIV/HCV‐coinfected patients followed up in Madrid since 2000. Patients entered the cohort at first visit and left the cohort when HCV clearance was achieved with HCV therapy or when follow‐up was interrupted for any reason, including death. A total of 672 HIV/HCV‐coinfected patients constituted the cohort. The mean follow‐up time was 5.5 years, corresponding to 4108 patient‐years. Mean age at entry was 37 years, and 73% were men and 86% were intravenous drug users. Overall distribution of HCV genotypes was as follows: 57.1% HCV‐1 (1a: 29.2%, 1b: 20.4%, unknown: 7.6%), 1.3% HCV‐2, 25.4% HCV‐3 and 15.9% HCV‐4. A total of 274 (40.8%) patients were treated with peginterferon–ribavirin, of whom 116 (42.3%) achieved HCV clearance following 1–3 courses of therapy. The proportion of HCV‐1/4 rose from 71.7% in 2000 to 76.8% in 2008, whereas the proportion of HCV‐2/3 fell from 28.1% in 2000 to 23.2% in 2008. The yearly prevalence increased for HCV‐1 (R2: 0.92, b: 0.59, P < 0.001) and HCV‐4 (R2: 0.77, b: 0.33, P < 0.005) and conversely diminished for HCV‐3 (R2: 0.94, b: −0.82, P < 0.001). In summary, the prevalence of HCV‐1 and HCV‐4 has increased over the last decade in HIV/HCV‐coinfected patients, whereas conversely it has declined for HCV‐3, in association with the wider use of HCV therapy (41%) in this population.

Rate and predictors of success in the retreatment of chronic hepatitis C virus in HIV/hepatitis C Virus coinfected patients with prior nonresponse or relapse.

Background:In hepatitis C virus (HCV)/HIV-coinfected patients who failed a course of suboptimal hepatitis C therapy, retreatment with adequate doses and duration of pegylated interferon (pegIFN) plus ribavirin (RBV) is advisable in the presence of compensated advanced liver fibrosis. Methods:The efficacy and safety of pegIFN-α2a (180 μg/wk) plus RBV (<75 kg: 1000 mg/d; ≥75 kg: 1200 mg/d) given for 12 months was prospectively assessed in HIV/HCV patients with nonresponse or relapse to a prior course of suboptimal hepatitis C therapy. The main endpoint was the achievement of sustained virological response (SVR). Results:A total of 52 patients were enrolled in the study (78% HCV genotypes 1 or 4; 56% with advanced liver fibrosis). Prior suboptimal regimens were IFN monotherapy (20%), IFN plus RBV (29%), and pegIFN plus RBV 800 mg/d (51%). Overall, 61% were nonresponders and 39% relapsers. Retreatment provided SVR in 30.8% of patients (19.5% for genotypes 1/4 vs. 72.7% for genotypes 2/3; P = 0.002). In multivariate analysis, HCV genotypes 2/3 [OR 22.2, 95% confidence interval (CI), 2.9-166.7, P = 0.003] and RBV plasma trough concentrations at week 4 [OR 3.9 (95% CI, 1.3-11.8), P = 0.01] were the only independent predictors of SVR. Conclusions:Retreatment with pegIFN-α2a plus weight-based RBV for 12 months permits to achieve HCV clearance in nearly one-third of HIV/HCV-coinfected patients who failed a prior suboptimal course of hepatitis C therapy. Patients with HCV genotypes 2/3 and those with RBV plasma trough levels above 2.07 μg/mL show the highest chances of SVR.

Short Communication: Transmission of Hepatitis B Viruses with Lamivudine Resistance Mutations in Newly Diagnosed HIV Individuals

From 1519 newly diagnosed HIV individuals seen in Madrid between the years 2000 and 2008, 65 (4.3%) were HBsAg(+). Two HIV/HBV-coinfected patients showed the lamivudine resistance mutation M204V in HBV while no drug resistance mutations were recognized in HIV. None of them admitted prior exposure to antiretroviral drugs. Thus, HIV/HBV-coinfected patients might benefit from baseline drug resistance testing for both HIV and HBV to optimize the selection of anti-HBV active antiviral therapy.

Papel de tenofovir en la coinfección por el virus de la inmunodeficiencia humana y el virus de la hepatitis C

Chronic hepatitis C virus (HCV) infection is common in HIV-infected individuals, especially if the route of infection is intravenous (e.g. intravenous drug use or blood transfusion). Prognosis is poorer in patients with HCV and HIV coinfection than in those with HCV monoinfection, mainly due to the immunodepression caused by HIV infection and probably also to a direct effect of HIV on the liver. Moreover, although antiretroviral therapy can cause liver damage, there is little doubt about the net benefits obtained with triple therapy in coinfected individuals, since suppression of HIV replication and immune recovery help to halt liver damage. However, not all antiretroviral agents are equal and those with the lowest hepatotoxicity and best metabolic profile should be used in coinfected patients, since hepatic steatosis accelerates progression of hepatic fibrosis and insulin resistance hampers the success of treatment with interferon and ribavirin. Tenofovir is currently one of the safest nucleos(t)ide analogues, due to its low hepatotoxicity and its lack of negative interference on treatment of HCV infection.La hepatitis cronica C es frecuente en personas infectadas por el virus de la inmunodeficiencia humana (VIH), particularmente si se han infectado por via parenteral (p. ej., consumo de drogas intravenosas o transfusion de hemoderivados). Tiene peor pronostico en el paciente coinfectado por VIH y virus de la hepatitis C (VHC) que en el monoinfectado por VHC, fundamentalmente por la inmunodepresion que provoca el VIH y probablemente por una accion directa del VIH en el higado. Aunque los antirretrovirales pueden provocar dano hepatico, quedan pocas dudas acerca del beneficio neto que se obtiene con la terapia triple en el coinfectado, pues la supresion de la replicacion del VIH y la recuperacion inmune contribuyen a frenar el dano hepatico. Sin embargo, no todos los antirretrovirales son iguales, y en el paciente coinfectado deben priorizarse los farmacos con menor hepatotoxicidad y mejor perfil metabolico, puesto que la esteatosis hepatica acelera la progresion de la fibrosis hepatica y la resistencia a la insulina dificulta el exito del tratamiento con interferon y ribavirina. De los analogos de nucleospidos, el tenofovir es actualmente uno de los mas seguros por tener escasa hepatotoxicidad y no interferir negativamente con el tratamiento de la hepatitis C.

Treatment of chronic hepatitis C in HIV-infected patients with compensated liver cirrhosis.

Summary.  The greatest benefit of hepatitis C virus (HCV) therapy is seen in cirrhotics attaining sustained virological response (SVR). However, concerns about toxicity and poorer responses often discourage treatment of cirrhotics. This may be particularly relevant in HIV–HCV‐coinfected patients, in whom progression of liver fibrosis is faster and treatment responses lower. This is a retrospective analysis of HIV–HCV‐coinfected patients who had received peginterferon–ribavirin therapy at our institution. Individuals naïve for interferon in whom liver fibrosis had been assessed using elastometry within the year before being treated were chosen. Response rates and toxicities were compared in cirrhotics (>14.5 KPa) and noncirrhotics. Patients with previous liver decompensation were excluded. Overall, 41 cirrhotics and 190 noncirrhotics entered the study. Groups were similar in age, gender, HCV genotypes and baseline serum HCV‐RNA. SVR occurred at similar rates in cirrhotic and noncirrhotics, either considered by intention‐to‐treat (39%vs 45%; P = 0.4) or as treated (50%vs 52%, P = 0.8). In multivariate analysis (odds ratio, 95% CI, P), SVR was associated with HCV genotypes 2–3 (5, 2.9–11, <0.01) and lower serum HCV‐RNA (2, 1.4–3.03 for every log decrease, <0.01) but not with cirrhosis (1.2, 0.4–3.6, 0.6). Treatment discontinuations because of adverse events tended to be more common in cirrhotics than in noncirrhotics (17%vs 12%; P = 0.2), but only severe thrombocytopenia was more frequent in cirrhotics than in non‐cirrhotics (20%vs 3% at week 24; P < 0.01). Response to peginterferon–ribavirin therapy is similar in HIV–HCV coinfected patients with and without liver cirrhosis. Therefore, treatment must be encouraged in all compensated cirrhotic patients, although closer monitoring and management of side effects, mainly thrombocytopenia, may be warranted.