V. Soriano

Impact of chronic liver disease due to hepatitis viruses as cause of hospital admission and death in HIV-infected drug users

The life expectancy of HIV-positive individuals has been prolonged in recent years, as a consequence of the wide use of antiretroviral drugs and primary prophylaxis for the most common opportunistic infections. In HIV-positive persons infected parenterally, chronic viral liver disease (CVLD), mainly that caused by hepatitis C virus (HCV), is frequently seen. Moreover, chronic hepatitis C seems to present a more accelerated course in HIV-infected patients, leading to cirrhosis and liver failure in a shorter period of time. The aim of the present study was to investigate the impact of CVLD on the morbidity and mortality of HIV-positive patients. A retrospective analysis of the causes of hospital admission during a 4.5-year period in a reference centre for AIDS situated in Madrid was performed. Decompensated liver disease (encephalopathy, ascites, jaundice), or complications directly related to it (gastrointestinal bleeding, hepatorenal syndrome, peritonitis) were diagnosed in 143 (8.6%) of 1670 hospital admissions. These episodes of CVLD corresponded to 105 different individuals, a quarter of whom had two or more re- admissions. HCV alone or in combination with other hepatotropic viruses was involved in 93 (88.6%) patients admitted for CVLD. Death directly associated with CVLD occurred in 15 individuals, which represented 4.8% of the total causes of inhospital mortality during the study period, and represented the fifth cause of death in hospital for HIV-infected patients. In conclusion, CVLD represents an important cause of hospital admission and death in HIV-infected drug users.

Discontinuation of secondary prophylaxis for opportunistic infections in HIV-infected patients receiving highly active antiretroviral therapy.

BackgroundImmune reconstitution following the introduction of highly active antiretroviral therapies (HAART) has lead to a remarkable reduction in the incidence of opportunistic infections (OI) in subjects with advanced HIV disease. Moreover, discontinuation of primary prophylaxis for some OI can be attempted without risk in patients experiencing a favourable response to treatment. However, data on the feasibility of discontinuing secondary prophylaxis are much more scarce, and restricted mainly to the withdrawal of maintenance treatment for cytomegalovirus (CMV) retinitis. Patients and methodsRetrospective review of the clinical outcome at 18 months in HIV-infected patients in whom discontinuation of secondary prophylaxis, for different OI, was recommended 3 months after the introduction of HAART, if both CD4 counts > 100 × 106 CD4 lymphocytes/l and plasma HIV-RNA < 500 copies/ml had been achieved. ResultsFifty-three subjects were analysed. Secondary chemoprophylaxis was discontinued for the following OI:Pneumocystis carinii pneumonia (PCP) (n = 29), cerebral toxoplasmosis (n = 9), disseminated Mycobacterium avium complex infection (n = 7), CMV retinitis (n = 5), recurrent oroesophageal candidiasis (n = 5), Visceral leishmaniasis (n = 2), recurrent herpes zoster (n = 2), and chronic mucocutaneous herpes simplex infection (n = 1). In six individuals, OI prophylaxis was discontinued for two or more entities. Only two episodes of OI were recorded in these individuals during 18 months of follow-up. One developed tuberculous lymphadenitis despite having a good response to treatment, and another suffered a new episode of PCP after voluntary treatment interruption for 6 weeks. ConclusionSecondary prophylaxis for OI can be attempted without major risk in HIV-infected patients experiencing a favourable response to HAART. The benefit of this intervention should reduce costs, drug side-effects and pharmacologic interactions, and indirectly will improve patients quality of life and adherence to antiretroviral treatment.

The Calculated Genetic Barrier for Antiretroviral Drug Resistance Substitutions Is Largely Similar for Different HIV-1 Subtypes

Background: The genetic barrier, defined as the number of mutations required to overcome drug-selective pressure, is an important factor for the development of HIV drug resistance. Because of high variability between subtypes, particular HIV-1 subtypes could have different genetic barriers for drug resistance substitutions. This study compared the genetic barrier between subtypes using some 2000 HIV-1 sequences (>600 of non-B subtype) isolated from anti-retroviral-naive patients in Europe. Methods: The genetic barrier was calculated as the sum of transitions (scored as 1) and/or transversions (2.5) required for evolution to any major drug resistance substitution. In addition, the number of minor protease substitutions was determined for every subtype. Results: Few dissimilarities were found. An increased genetic barrier was calculated for I82A (subtypes C and G), V108I (subtype G), V118I (subtype G), Q151M (subtypes D and F), L210W (subtypes C, F, G, and CRF02_AG), and P225H (subtype A) (P < 0.001 compared with subtype B). A decreased genetic barrier was found for I82T (subtypes C and G) and V106M (subtype C) (P < 0.001 vs subtype B). Conversely, minor protease substitutions differed extensively between subtypes. Conclusions: Based on the calculated genetic barrier, the rate of drug resistance development may be similar for different HIV-1 subtypes. Because of differences in minor protease substitutions, protease inhibitor resistance could be enhanced in particular subtypes once the relevant major substitutions are selected.

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.

Comparison of Three Different Commercial Methods for Measuring Plasma Viraemia in Patients Infected with Non-B HIV-1 Subtypes

Abstract In order to determine whether commercial assays presently in use for the quantification of plasma human immunodeficiency virus type 1 (HIV-1) RNA levels detect different genetic viral subtypes with the same reliability, a panel of 38 samples corresponding to 22 HIV-1-infected patients, representing non-B subtypes A–F, was examined. One to three plasma samples belonging to each individual were tested by the second-generation HIV-1 branched DNA (bDNA) assay (Chiron, Spain), the Nuclisens assay (Organon-Teknika, Spain), the Amplicor Monitor reverse transcriptase polymerase chain reaction assay (Roche, Spain), and the Ultradirect Monitor (Roche) using primers specifically designed to amplify non-B HIV-1 subtypes. Each of the different methods for measuring viral load showed a distinct sensitivity for non-B HIV-1 subtypes. Values higher than the assay detection limit were obtained in 22 (57.9%), 33 (86.8%), and 37 (93.3%) samples using the bDNA, Nuclisens, and Monitor assays, respectively. Significantly different values (>0.5 logs) were found in 55.3%, 81.6%, and 71.1% of specimens comparing results provided by bDNA and Nuclisens, bDNA and Monitor, and Nuclisens and Monitor, respectively. Quantitative values provided by the Ultradirect Monitor test using non-B primers were particularly discordant with the other tests. Overall, 44.7% of samples yielded higher viral load values with this assay than with the regular Monitor assay, reflecting its enhanced sensitivity for non-B subtypes; however, the reproducibility of this test was low. These results support the recommendation of always using the same assay when monitoring plasma viraemia.

Lack of hepatitis E virus infection in HIV patients with advanced immunodeficiency or idiopathic liver enzyme elevations.

Summary.  Hepatitis E virus (HEV) is an enterically transmissible RNA agent that causes self‐limited acute hepatitis. Recent reports have highlighted that organ‐transplant recipients may develop chronic hepatitis E and progress to cirrhosis. Similar cases could occur in HIV patients. We have investigated 50 HIV‐infected individuals with CD4 counts <200 cells/mm3 and 43 with cryptogenic hepatitis. None of them showed HEV viremia. Thus, HEV infection does not seem to be prevalent in the HIV population and accordingly universal HEV vaccination is not warranted in these patients.

HCV chronic hepatitis in patients with HIV: Clinical management issues

HIV-hepatitis C virus (HCV) coinfection is common and affects more than one-third of all HIV infected persons worldwide. Prevalence among risk categories varies according to shared risk factors for transmission, mainly intravenous drug use (IDU) and hemophiliacs. Chronic HCV infection seems to accelerate the course of HIV disease, resulting in a worsened clinical and immunological progression. At the same time, several studies suggest that HIV disease modifies the natural history of HCV infection, leading to a faster course of progression from active hepatitis to cirrhosis, to end stage liver disease and death. HCV infection mimics opportunistic diseases because its natural history is significantly accelerated in HIV patients. Since highly active antiretroviral therapy (HAART) has slowed the progression of HIV disease and decreased the rate of HIV associated mortality, the prognosis of HIV disease has been modified, and the need to treat HCV coinfection become a significant issue. Because of the poor response rate obtained by either interferon alone or interferon thrice weekly plus ribavirin, the combination of pegylated interferon and ribavirin will probably become the standard of care, although the clinicians should be aware of the overlapping toxicity of nucleoside analogues and ribavirin. Many selected categories of patients pose particular challenges to physicians treating HCV infection: nonresponders to interferon, cirrhotic patients, and patients infected with both HCV and HBV. Liver transplantation in HIV patients is currently under evaluation, but should become the rescue therapy for HIV patients with end stage liver disease.

First Case of HIV-1 Group O Infection in Spain

A 34‐year‐old woman born in Bilbao, a northern city in Spain, was first seen at our institution in April 1995. She had maintained a monogamous sexual relation in the preceding 6 years with a 35‐year‐old male, and previously has sex only sporadically with two other persons. She as well as her three partners were Spanish‐born, and had neither a history of transfusions, nor of injecting drugs, nor were they homosexual.

Lipid profiles for nevirapine vs. atazanavir/ritonavir, both combined with tenofovir disoproxil fumarate and emtricitabine over 48 weeks, in treatment-naïve HIV-1-infected patients (the ARTEN study).

Dyslipidaemic effects of antiretrovirals (ARVs) may contribute to increased cardiovascular risk (CR) in HIV‐1‐infected patients. The ARTEN (atazanavir/ritonavir on a background of tenofovir and emtricitabine vs. nevirapine on the same background, in naïve HIV‐1‐infected patients) study compared prospectively ritonavir‐boosted atazanavir (ATZ/r) 300 mg/100 mg once daily (qd) with immediate release nevirapine (NVP) 200 mg twice daily or 400 mg qd, each combined with fixed‐dose tenofovir 300 mg/emtricitabine 200 mg qd in 569 ARV‐naïve HIV‐1‐infected patients. Lipid profiles and CR from baseline to week 48 are reported.

Management of hepatitis C in HIV-infected persons.

The life expectancy of HIV-infected persons has extended significantly since the introduction of highly active antiretroviral therapies. Although classical opportunistic infections are now rarely seen, the toxicity of antiretroviral drugs as well as liver disease caused by hepatitis viruses represent an increasing cause of morbidity and mortality among HIV-positive persons. Since the rate of hepatitis C virus (HCV) infection is high among HIV carriers (up to 75% among intravenous drug users), HCV/HIV coinfection is widely prevalent. Predisposing liver damage favors a higher rate of hepatotoxicity of antiretroviral drugs, which can limit the benefit of HIV treatment in some individuals. Overall, severe hepatotoxicity appears in around 10% of subjects who began triple combinations including either protease inhibitors or non-nucleosides. The progression to cirrhosis seems to occur faster in the setting of HIV infection, and conversely recent data demonstrate that HCV infection can accelerate the progression to AIDS in HIV-positive persons. Although clinicians have been reluctant to treat hepatitis C in HIV-infected people, this therapeutic nihilism is unwarranted. The availability of new more successful regimens to treat hepatitis C, in particular using the new pegylated forms of interferon in combination with ribavirin, open new hopes for the care of HIV-HCV-coinfected persons.