Enrique Ortega

Consensus conference on chronic viral hepatitis and HIV infection: updated Spanish recommendations

Summary.  Chronic hepatitis B and C represent a leading cause of morbidity and mortality among human immunodeficiency virus (HIV)‐infected patients worldwide. New treatment options against both hepatitis B (HBV) and C (HCV) viruses have prompted us to update previous recommendations for the management of coinfected individuals. Fifteen topics (nine related to HCV, five to HBV and one to both viruses) were selected for this purpose. A panel of Spanish experts in the field was invited to review these areas and propose specific recommendations, which were scored according to the Infectious Disease Society of America (IDSA) grading system. These guidelines represent a comprehensive and updated overview on the management of hepatitis B and C in HIV‐infected patients.

Increasing Incidence of Hepatocellular Carcinoma in HIV-Infected Patients in Spain

BACKGROUND To report the clinical and epidemiological characteristics of hepatocellular carcinoma (HCC) diagnosed in a cohort of human immunodeficiency virus (HIV)-infected patients in Spain. METHODS All HIV-infected patients diagnosed of HCC in 18 hospitals in Spain before 31 December 2010 were included. The main characteristics of HCC cases are described and comparisons between cases according to the year of diagnosis are presented. RESULTS Eighty-two cases of HCC in HIV-infected patients were included, all of them related to viral hepatitis coinfection: hepatitis C virus (HCV) in 66 (81%), hepatitis B virus (HBV) in 6 (7%), and HBV/HCV in 10 (12%). From 1999, when the first case of HCC was diagnosed, a progressive increment in the incidence of HCC in the cohort has occurred. In patients coinfected with HIV/HCV-coinfected patients, the incidence HCC increased from 0.2 to 2.8 cases per 1000 person-years between 2000 and 2009. Death occurred in 65 patients (79%), with a median survival of 91 days (interquartile range, 31-227 days). Three of 11 patients (28%) who received potentially curative therapy died, compared with 62 of 71 patients (87%) who did not receive curative therapy (P = .0001). Compared with cases of HCC diagnosed before 2005, cases diagnosed later did not show a higher survival rate. CONCLUSIONS HCC is an emerging complication of cirrhosis in HIV-infected patients. A sharp increase in its incidence has occurred in those also infected by HCV in the recent years. Unfortunately, HCC is frequently diagnosed at an advanced stage, and mortality continues to be very high, with no significant changes in recent years. Earlier diagnosis, which may allow potentially curative therapy, is necessary.

Management of chronic viral hepatitis in HIV-infected patients: Spanish Consensus Conference

Abstract Co-infection by human immunodeficiency virus and hepatitis B and C viruses is quite common because they share similar routes of transmission. The introduction of highly active antiretroviral therapy has significantly improved the life expectancy of HIV-infected patients in the last few years. However, chronic viral hepatitis represents an emerging cause of morbidity and mortality in this population, either as a result of end-stage liver disease or as a consequence of hepatotoxicity induced by antiretroviral drugs. The main goal of the Consensus Conference was to establish specific recommendations for the management of chronic viral hepatitis B and C in HIV-infected patients. The role of orthotopic liver transplantation for co-infected individuals with end-stage liver disease was also assessed.

Noninvasive diagnosis of liver fibrosis in patients with HIV infection and HCV/HBV co-infection

Summary.  The measurement of fibrosis stage critically affects the identification of the progression of liver disease, the establishment of a prognosis and therapeutic decision making. Liver biopsy has been the single, most useful method to determine the degree of liver fibrosis (LF), but with recognized limitations, mainly associated with its invasiveness. In recent years, alternative noninvasive methods have been developed, including imaging methods, such as transient elastometry, and assays based on serum biomarkers. This article reviews the available studies evaluating the value of various noninvasive methods for the assessment of LF in patients with HIV‐infection and HBV/HCV co‐infection, and makes recommendations on how to best use and combine them in clinical practice.

Hepatic steatosis and steatohepatitis in human immunodeficiency virus/hepatitis C virus-coinfected patients.

Hepatic steatosis (HS) is frequent in human immunodeficiency virus (HIV)‐ and hepatitis C virus (HCV)‐coinfected patients. Antiretroviral therapy (ART) and metabolic alterations could induce HS. However, a protective effect of ART has been reported in a paired biopsy study. Thus, our aim was to examine the changes and predictors of HS progression among HIV/HCV‐coinfected patients with sequential biopsies. We also evaluated the rates of steatohepatitis and factors associated thereof. HIV‐infected patients with detectable serum HCV RNA, who underwent two biopsies, separated at least by 1 year, were included in this retrospective study. HS progression was defined as increase in one or more HS grades. The median (interquartile range) time between biopsies was 3.3 (2.0‐5.2) years. Among 146 individuals, HS at baseline was observed in 86 (60%) patients and in 113 (77%) in the follow‐up biopsy (P < 0.001). Progression of HS was observed in 60 (40%) patients. HS regressed in 11 (8%) patients. Factors associated with HS progression were changes in fasting plasma glucose (FPG) between biopsies (per 10 mg/dL increase; odds ratio [OR] [95% confidence interval; CI] = 1.4 [1.04‐1.8]; P = 0.024) and cumulative use of dideoxynucleoside analogs (per year; OR [95% CI] = 1.5 [1.2‐1.8]; P = 0.001). Persistent steatohepatitis or progression to steatohepatitis between biopsies was observed in 27 (18%) patients. Persistence of or progression to steatohepatitis was associated with progression ≥1 fibrosis stages between biopsies (OR [95% CI] = 2.4 [1.01‐5.7]; P = 0.047). Conclusions: HS progresses frequently and regression is rarely observed in HIV/HCV‐coinfected patients, including in those on ART. Cumulative exposure to dideoxynucleoside analogs and increases in FPG are related with HS progression. Stetatohepatitis is frequently observed in these patients and is linked to fibrosis progression. (HEPATOLOGY 2012)

Clinical effects of viral relapse after interferon plus ribavirin in patients co-infected with human immunodeficiency virus and hepatitis C virus

BACKGROUND & AIMS Sustained viral response (SVR) after therapy with interferon-ribavirin (IF-RB) reduces liver-related (LR) complications and mortality in HIV/HCV-co-infected patients. Here, we assess the impact of end-of-treatment response with subsequent relapse (REL) on LR events (LR death, liver decompensation, hepatocellular carcinoma, or liver transplantation), and liver stiffness (LS) by transient elastography. METHODS We analyzed the GESIDA 3603 Cohort (HIV/HCV-co-infected patients treated with IF-RB in 19 centers in Spain). Response to IF-RB was categorized as SVR, REL, and no response (NR). The study started when IF-RB was stopped and ended at death or the last follow-up visit. Multivariate regression analyses were adjusted for age, sex, HIV category of transmission, CDC clinical category, nadir CD4+ cell count, HCV genotype, HCV-RNA viral load, and liver fibrosis. RESULTS Of 1599 patients included, response was categorized as NR in 765, REL in 250 and SVR in 584. Median follow-up was more than 4 years in each group. Taking the group of patients with NR as reference, we found that the adjusted hazard ratios (95% confidence interval) of liver-related events (liver-related death, liver decompensation, hepatocellular carcinoma, liver transplantation) for patients with REL and for patients with SVR were 0.17 (0.05; 0.50) and 0.03 (0; 0.20), respectively. We also found that SVR was followed by less liver stiffness than both REL and NR. However, REL was associated with less liver stiffness than NR. CONCLUSIONS Best outcomes were achieved with an SVR. However, REL was associated with less LR mortality, decompensation, and liver stiffness than NR.

Prevalence and factors associated with significant liver fibrosis assessed by transient elastometry in HIV/hepatitis C virus-coinfected patients.

Summary.  Transient elastometry (TE) could provide a more accurate evaluation of the frequency and risk factors of liver fibrosis in hepatitis C virus (HCV) infection than that based on biopsy. The aim of this study was to assess the prevalence of and factors associated with significant liver fibrosis in a large population of HIV/HCV‐coinfected patients. HIV/HCV‐coinfected patients, who had participated in a cross‐sectional, multicenter, retrospective study of liver fibrosis using noninvasive markers and in whom a determination of liver stiffness (LS) by TE was available, were included in this analysis. Factors potentially associated with significant fibrosis (LS ≥ 9 kPa) were analyzed. One thousand three hundred and ten patients fulfilled the inclusion criteria, 526 (40%) of them showed LS ≥ 9 kPa and 316 (24%) cirrhosis (LS ≥ 14 kPa). The factors independently associated with significant fibrosis [adjusted odds ratio (95% confidence interval, P value) were the following: older age [1.04 (1.01–1.07), 0.002], daily alcohol intake > 50 g/day [1.58 (1.10–2.27), 0.013] and the length of HCV infection [1.03 (1.00–1.06), 0.023]]. A CD4 cell count lower than < 200 per mm3 [1.67 (0.99–2.81), 0.053] and HCV genotype 4 [0.66 (0.42–1.02), 0.066] were marginally associated with LS ≥ 9 kPa. In conclusion, the prevalence of cirrhosis in HIV/HCV‐coinfected patients seems to be higher than previously reported in studies based on liver biopsy. Older age, alcohol consumption and lower CD4 cell counts are related with significant fibrosis. The latter association supports an earlier starting of antiretroviral therapy in this setting.

Analysis of hepatitis B precore region in serum and liver of chronic hepatitis B virus carriers

Using an oligonucleotide hybridization assay we studied the prevalence of wild-type and the predominant pre-core mutant hepatitis B virus in serum and liver of 49 antibody to hepatitis B e antigen carriers and three hepatitis B e antigen positive patients. Of the 45 serum samples from the anti-HBe carriers analyzed (no serum sample was available in four patients), 36 (80%) had hepatitis B virus DNA. In 26 of these 36 patients (72%) a mixed population was detected, wild-type genome alone was found in six patients (16%), the single mutant (nucleotide position 1896), in three cases (8%) and in one patient (2%) the viral DNA had the two nucleotide mutation (1896 and 1899). Of the liver biopsies from the 36 anti-HBe patients studied (no liver biopsy was available in 13 patients), 33 (92%) had hepatitis B virus DNA. A mixed viral population was detected in 23 patients (69%), only wild-type virus or a single mutation was found in eight (34%) and two patients (8%), respectively. In all cases, wild-type was the predominant genome. In serum and liver samples from the same patient, we found a concordance of the presence of wild-type HBV and the pre-core mutants studied in 23/26 (88%) of the patients. Alanine aminotransferase levels were higher (p < 0.01) and the duration of hepatitis B surface antigen carrier lower (p < 0.02) in patients with a predominance of precore mutant in comparison to wild-type.(ABSTRACT TRUNCATED AT 250 WORDS)

Recomendaciones de GEAM/SPNS sobre el tratamiento de las alteraciones metabólicas y morfológicas en el paciente con infección por VIH*

Objetivo Efectuar una puesta al dia de las alteraciones metabolicas y morfologicas presentes en los pacientes con infeccion por virus de la inmunodeficiencia humana (VIH), ahondando en su manejo clinico y tratamiento. Metodos Estas recomendaciones han sido consensuadas por un comite de expertos en alteraciones metabolicas y en la atencion al paciente con VIH, bajo los auspicios de la Secretaria del Plan Nacional sobre el Sida (PNS). Para ello se han revisado los ultimos avances clinicos, epidemiologicos y fisiopatologicos resenados en estudios publicados en las revistas medicas y/o presentados en los congresos. Resultados Las alteraciones metabolicas que con mayor frecuencia aparecen en los pacientes con infeccion por VIH y en tratamiento antirretroviral (TAR) son la dislipidemia con perfil aterogenico y las alteraciones del metabolismo hidrocarbonado/resistencia a la insulina. Se ha descrito una elevada prevalencia de factores de riesgo cardiovascular, especialmente el tabaquismo. Para su manejo se han utilizado los mismos criterios que para la poblacion general, con matices especificos. La dieta y el ejercicio deben ser la primera recomendacion terapeutica. En los pacientes con dislipidemia y necesidad de tratamiento farmacologico, estarian indicadas las estatinas y/o los fibratos. En el tratamiento de la resistencia a la insulina las glitazonas han demostrado su eficacia. El abordaje del reparto anomalo de la grasa sigue siendo controvertido. El cambio de TAR, la cirugia reparadora, el soporte psicologico y los cambios de estilo de vida son las bases para abordar este problema en el momento actual. La acidosis lactica es una complicacion infrecuente pero muy grave, siendo la primera actitud terapeutica la retirada del TAR. En cuanto a las alteraciones del metabolismo oseo son fundamentales la prevencion y la deteccion precoz, especialmente en mujeres perimenopausicas y ninos. La disfuncion sexual es un problema frecuente tanto en varones como en mujeres; la diversidad de causas obliga a un tratamiento individualizado. Conclusiones La prevalencia de alteraciones metabolicas y morfologicas ha aumentado desde la introduccion del tratamiento antirretroviral de gran actividad (TARGA). Es fundamental el conocimiento de los diversos aspectos relacionados con su diagnostico y tratamiento para una correcta atencion de los pacientes con infeccion por VIH.

Liver toxicity of initial antiretroviral drug regimens including two nucleoside analogs plus one non-nucleoside analog or one ritonavir-boosted protease inhibitor in HIV/HCV-coinfected patients.

Abstract Objective: To evaluate the incidence and risk factors for grade 3 or 4 ALT or AST elevations (TE) and grade 4 total bilirubin elevations (TBE) among HIV/HCV- coinfected treatment-naïve patients with an initial regimen including 2 nucleoside analogs plus efavirenz (EFV), nevirapine (NVP), or a ritonavir-boosted protease inhibitor (PI/r).Patients and Methods: This was a retrospective multicenter observational cohort study that recruited 745 HIV-infected drug-naïve patients with detectable plasma HCV RNA who started a regimen including EFV, NVP, or PI/r.Results: EFV was prescribed in 323 (43%), NVP in 126 (17%), and a PI/r in 296 (40%) patients. Grade 3 or 4 TE were observed in 19 (5.9%) individuals receiving EFV compared with 14 (11%) on NVP (P = .056) and 31 (10.5%) on PI/r (P = .036). Grade 4 TBE were identified in 7 (2.2%) patients on EFV, 1 (0.8%) on NVP, and 11 (3.7%) on PI/r (P = .19). Therapy was discontinued due to liver toxicity in 13 (4%) patients on EFV, 16 (13%) on NVP, and 17 (6%) on PI/r (P = .003).Conclusions: Regimens including EFV, NVP, or PI/r are generally safe in treatment-naïve HIV/HCV-coinfected patients. Grade 3-4 TE are less commonly seen with EFV than with PI/r. Discontinuations due to hepatotoxicity were less frequent for patients receiving EFV than for those treated with NVP.