Pilar García-Gascó

Hepatotoxicity of Antiretroviral Drugs Is Reduced after Successful Treatment of Chronic Hepatitis C in HIV-Infected Patients

BACKGROUND The risk of liver toxicity during antiretroviral drug use in human immunodeficiency virus (HIV)-positive patients increases in the presence of chronic hepatitis C virus (HCV) infection. It is unknown whether sustained HCV clearance after interferon (IFN)-based therapy might reduce this complication. METHODS The incidence of severe elevations in liver enzyme levels during antiretroviral therapy was retrospectively analyzed in a group of HIV/HCV-coinfected patients after completion of a full course of IFN-based therapy. Hepatic events were recorded according to the achievement of a sustained virological response (SVR), and the presence of advanced liver fibrosis was assessed by transient elastometry. RESULTS A total of 132 HIV/HCV-coinfected patients were analyzed (66% men; mean age, 38 years). Overall, 33% achieved an SVR and 40% had advanced liver fibrosis after IFN therapy. A total of 49 episodes of liver toxicity occurred during a mean of 35 months of follow-up (9.7% per year) after IFN therapy. The yearly incidence of hepatic events was greater in patients who did not achieve an SVR than in those who did (12.9% vs. 3.1%; P<.001) and in patients with advanced liver fibrosis than in those without it (14.4% vs. 7.6%; P=.003). Drugs involved in hepatic events were dydeoxynucleoside analogues (namely, didanosine and stavudine; 40%) nevirapine (30%), efavirenz (11%), and protease inhibitors (PIs; 8%). In logistic regression analysis, lack of an SVR (odds ratio [OR], 6.13 [95% confidence interval {CI}, 1.83-37.45]; P=.003) and the use of dydeoxynucleosides (OR, 3.59 [95% CI, 1.23-10.42]; P=.02) were independent predictors of hepatotoxicity after IFN therapy. Conversely, regimens containing PIs (OR, 0.07 [95% CI, 0.02-0.30]; P<.01) or efavirenz (OR, 0.13 [95% CI, 0.04-0.44]; P=.001) were associated with a diminished risk of hepatic events. CONCLUSION Sustained HCV clearance after IFN-based therapy reduces the risk of liver toxicity during antiretroviral therapy, which should further encourage the treatment of chronic hepatitis C in HIV-coinfected patients. In this population, prescription of PIs or efavirenz decreases and use of dydeoxynucleoside analogues increases the risk of hepatotoxicity.

Liver cirrhosis in HIV-infected patients: prevalence, aetiology and clinical outcome

Summary.  Liver disease is frequently seen in HIV+ patients as a result of coinfection with hepatitis B (HBV) or C (HCV) viruses, alcohol abuse and/or exposure to hepatotoxic drugs. The aim of this study was to assess the prevalence of liver cirrhosis, its main causes and clinical presentation in HIV+ patients. Observational, cross‐sectional, retrospective study of all HIV+ individuals followed at one reference HIV outpatient clinic in Madrid. Liver fibrosis was measured in all cases using transient elastometry (FibroScan®). All 2168 HIV+ patients on regular follow‐up (76% males, 46% injecting drug users) were successfully examined by FibroScan® between October 2004 and August 2006. Liver cirrhosis was recognized in 181 (overall prevalence, 8.3%), and the main aetiologies were HCV, 82.3%; HBV, 1.6%; dual HBV/HCV, 2.8%; and triple HBV/HCV/ hepatitis delta virus (HDV) infection, 6.6%. The prevalence of cirrhosis differed among patients with distinct chronic viral hepatitis: HCV, 19.2%; HBV, 6.1%; HBV/HCV, 41.7%; and HBV/HCV/HDV, 66.7%. In 12 patients with cirrhosis (6.7%), no definite aetiology was recognized. Overall, cirrhotics had lower mean CD4 counts than noncirrhotics (408 vs 528 cells/μL respectively; P = 0.02), despite similar proportion of subjects with undetectable viraemia on highly active antiretroviral therapy. Clinical manifestations of liver cirrhosis were: splenomegaly, 61.5%; oesophageal varices, 59.8%; ascites, 22.6%; encephalopathy, 12.1%; and variceal bleeding, 6.1%. Liver cirrhosis and hepatic decompensation events are relatively frequent in HIV+ individuals. Chronic HCV and alcohol abuse, but not chronic HBV, play a major role. Transient elastometry may allow the identification of a significant number of HIV+ individuals with asymptomatic liver cirrhosis.

Liver fibrosis on account of chronic hepatitis C is more severe in HIV-positive than HIV-negative patients despite antiretroviral therapy

Summary.  The recent availability of non‐invasive tools to measure liver fibrosis has allowed examination of its extent and determination of predictors in all patients with chronic hepatitis C virus (HCV) infection. On the other hand, most information on hepatic fibrosis in HCV/human immunodeficiency virus (HIV)‐coinfected patients has been derived from liver biopsies taken before highly active antiretroviral therapy (HAART) was widely available. All consecutive HCV patients with elevated aminotransferases seen during the last 3 years were evaluated and liver fibrosis measured using transient elastography (FibroScan®) and biochemical indexes. Patients were split according to their HIV serostatus. A total of 656 (69.6%) HCV‐monoinfected and 287 (30.4%) HIV/HCV‐coinfected patients were assessed. Mean CD4 count of coinfected patients was 493 cells/μL and 88% were under HAART (mean time, 4.2 ± 2.4 years). Advanced liver fibrosis or cirrhosis was recognized in 39% of the coinfected and 18% of the monoinfected patients (P < 0.005). A good correlation was found between FibroScan® and biochemical indexes [AST to platelet ratio index (r = 0.405, P < 0.0001), FIB‐4 (r = 0.393, P < 0.0001) and Forns (r = 0.407, P < 0.0001)], regardless of the HIV status. In the multivariate analysis, age >45 years, body mass index (BMI) >25 kg/m2, and HIV infection were independently associated with advanced liver fibrosis or cirrhosis. HIV/HCV‐coinfected patients have more advanced liver fibrosis than HCV‐monoinfected patients despite the immunologic benefit of HAART.

Episodes of low-level viral rebound in HIV-infected patients on antiretroviral therapy: frequency, predictors and outcome

BACKGROUND The rate, predictors and outcome following episodes of low-level viral rebound (LLVR) in HIV patients on highly active antiretroviral therapy (HAART) are unknown. METHODS Retrospective assessment of all HIV patients who experienced LLVR episodes on HAART at one institution from January 1999 to December 2006. LLVR was defined as plasma HIV-RNA between 51 and 500 copies/mL after at least two consecutive undetectable plasma viral load measurements made during the last 6 months. Virological failure was defined as plasma HIV-RNA >500 copies/mL. RESULTS Out of 2720 HIV patients on successful HAART during the 8 year study period, 779 (28.6%) developed at least one LLVR episode. Only 655 patients who kept unchanged their HAART regimen following LLVR episodes were further examined. After 12 weeks, undetectable viraemia was regained in 458 (71%), which were considered as blips. In contrast, 66 (9%) LLVR episodes were followed by virological failure, and drug resistance mutations developed in most cases, mainly rtM184V (66%) and rtK103N (29.5%). Plasma HIV-RNA remained between 51 and 500 copies/mL at 12 weeks in the remaining 131 (20%) patients with LLVR episodes. In the multivariate analysis, only plasma HIV-RNA levels at the time of LLVR predicted subsequent virological failure. CONCLUSIONS Episodes of LLVR in HIV patients on successful HAART are relatively common and represent transient events (blips) in most cases (71%). Keeping the same treatment regimen, virological failure follows in <10% of the cases. Plasma HIV-RNA level at the time of LLVR is the best predictor of subsequent failure.

Evidence for different susceptibility to tipranavir and darunavir in patients infected with distinct Hiv-1 subtypes

Background:Tipranavir (TPV) and darunavir (DRV) are potent against protease inhibitor (PI)-resistant viruses. Efficacy of these compounds when confronting distinct HIV subtypes is not known. Methods:All clinical specimens from HIV-positive patients sent to our institution for drug resistance testing between 1999 and 2006 were analysed. The prevalence of TPV and DRV resistance mutations was assessed based on the latest International AIDS Society-USA panel list. Phenotypic susceptibility to DRV and TPV was examined in a subset of these samples using the PhenoSense assay. Results:A total of 1364 genotypes were analysed, including 1178 from individuals infected with clade B (285 drug naive) and 186 with non-B subtypes (137 drug naive). The mean number (±SD) of DRV resistance-associated mutations was higher in clade B than non-B (0.4 ± 0.9 versus 0.06 ± 0.3; P < 0.001), and more frequent among PI-experienced than drug-naive patients (0.6 ± 1.02 versus 0.02 ± 0.21; P < 0.001). In contrast, the mean number of TPV resistance-associated mutations was higher in non-B than B subtypes (2.7 ± 1 versus 1.2 ± 1.6; P < 0.001), regardless of PI experience. Susceptibility to TPV and DRV was examined in 29 drug-naive patients infected with non-B subtypes (1A, 3C, 2CRF01_AE, 9CRF02_AG, 1CRF12_BF, 3CRF14_BG, 3F and 7G). All showed susceptibility to DRV and 93% to TPV. Interestingly, two subtype F specimens showed reduced TPV susceptibility, with fold-changes of 2.7 and 2.1, respectively. Conclusions:Non-B subtypes show a greater number of TPV resistance-associated mutations than B viruses, regardless of PI exposure. While HIV clade has no influence on DRV susceptibility, some F subtypes may show reduced TPV susceptibility.

Switch from Ritonavir-Boosted to Unboosted Atazanavir Guided by Therapeutic Drug Monitoring

Plasma concentration of atazanavir (ATV) may be reduced when coadministered with tenofovir (TDF) or proton pump inhibitors. Boosting ATV exposure with ritonavir (r) may make it possible to overcome these drug interactions. However, jaundice and loss of the metabolic advantages of ATV are more frequent using ATV/r than ATV alone. Herein, we assessed whether therapeutic drug monitoring (TDM) could make it possible to identify the subset of patients in whom removal of ritonavir could be attempted without risk of suboptimal plasma ATV exposure and subsequent virological failure. A total of 56 patients with undetectable plasma HIV-RNA under a stable triple regimen containing ATV 300/100 mg qd were switched to ATV 400 mg qd. Plasma ATV concentrations were measured using a reliable high-performance liquid chromatography method. Median plasma ATV C(min) fell from 880 to 283 ng/ml (p = 0.03) after removal of ritonavir. While all patients on ATV/r showed ATV plasma concentrations within therapeutic values (IC(min) above 150 ng/ml) before switching, four patients (7%) fell below this threshold after switching to ATV 400 mg qd. However, only one of this group experienced virological failure at week 24 of follow-up. TDF was part of the antiretroviral regimen in all four cases. From a total of 29 (52%) patients on ATV/r showing grade 3-4 hyperbilirubinemia, only 7 (12%) remained on it upon switching to ATV 400 mg qd (p < 0.001). Patients with complete viral suppression under ATV/r 300/100 mg qd may benefit from switching to ATV 400 mg qd guided by TDM, which may make it possible to minimize adverse events without compromising antiviral efficacy in most cases.

Successful rescue therapy with darunabir (TMC114) in HIV-infected patients who have failed several ritonavir-boosted protease inhibitors

Darunabir, formerly TMC114, is a new protease inhibitor (PI) under clinical development designed to be active against HIV strains resistant to currently available PI. The virological and immunological response to ritonavir-boosted darunabir was assessed in four heavily antiretroviral-experienced patients who had failed enfuvirtide and two or more previous ritonavir-boosted PI regimens, including tipranavir in one instance. All four patients reached undetectable plasma HIV-RNA levels within 8 weeks of therapy and experienced significant CD4 cell count gains.

Value of the HLA-B*5701 Allele to Predict Abacavir Hypersensitivity in Spaniards

The use of abacavir (ABC) may be associated with a hypersensitivity reaction (HSR) that requires discontinuation of the drug. The HLA-B*5701 allele has been linked to this HSR. Information on the strength of this association across distinct geographic regions and ethnicities is scarce. We tested HLA-B*5701 in 53 Spaniards infected with HIV who received ABC treatment. The presence of HLA-B5701 had strong positive and negative predictive values for ABC HSR, 92% and 63%, respectively.

Predictors of severe hepatic steatosis using abdominal ultrasound in HIV-infected patients

Multiple factors may lead to hepatic steatosis (HS) in HIV‐positive patients. HS may result in severe liver damage on its own and/or by accelerating the progression of chronic viral hepatitis B or C.

Tipranavir: a new protease inhibitor for the treatment of antiretroviral-experienced HIV-infected patients

Tipranavir (TPV) is a novel non-peptidic protease inhibitor (PI). It binds strongly and selectively to the HIV-1 protease, is orally administered twice daily, boosted with low doses of ritonavir, and shows a favourable resistance profile. In the two registrational trials, named RESIST 1 and 2, TPV/ritonavir 500/200 mg b.i.d., along with an optimised antiretroviral backbone, provided better virologic responses than controls receiving standard of care ritonavir-boosted PI-based regimens. A total of 21 mutations at 16 protease codons have been shown to impact on TPV susceptibility and response rates. The TPV mutation score includes L10V, I13V, K20M/R/V, L33F, E35G, M36I, K43T, M46L, I47V, I54A/M/V, Q58E, H69K, T74P, V82L/T, N83D and I84V. Viruses containing eight or more of these mutations are generally resistant to the drug. TPV use is associated with an excess of grade 3/4 liver enzyme elevations compared with other ritonavir-boosted PIs, and the potential for drug–drug interactions is relevant and must be considered when prescribing TPV.