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Clinical and genetic factors associated with increased risk of severe liver toxicity in a monocentric cohort of HIV positive patients receiving nevirapine-based antiretroviral therapy.

ABSTRACT: BACKGROUND:Nevirapine has been used as antiretroviral agent since early '90. Although nevirapine is not currently recommended in initial anti-HIV regimens, its use remains consistent in a certain number of HIV-1-positive subjects. Thus, our aim was to determine clinical and genetic factors involved in the development of severe nevirapine induced liver toxicity. METHODS:We retrospectively analyzed all HIV positive patients who were followed at the Infectious Diseases Unit, DIBIC Luigi Sacco, University of Milan from May 2011 to December 2015. All patients treated with nevirapine who underwent a genotyping for the functional variants mapping into ABCB1, CYP2B6, CYP3A4 and CYP3A5 genes were included in the analysis. Severe hepatotoxicity was defined as ACTG grade 3-4 AST/ALT increase during the first three months of nevirapine treatment. The causality assessment between NVP exposure and drug-induced liver injury was performed by using the updated Roussel Uclaf Causality Assessment Methods. Hardy Weinberg equilibrium was tested by ?2 test. A multivariable logistic regression model was constructed using a backward elimination method. RESULTS:Three hundred and sixty-two patients were included in the analysis, of which 8 (2.2%) experienced a severe liver toxicity. We observed no differences between patients with and without liver toxicity as regards gender, ethnicity, age and immune-virological status. A higher prevalence of HCV coinfection (75.0% vs 30.2%; p?=?.0013) and higher baseline AST (58 IU/L vs 26 IU/L; p?=?0.041) and ALT (82 IU/L vs 27 IU/L; p?=?0.047) median levels were observed in patients with liver toxicity vs those without toxicity. The genotypes CT/TT at ABCB1 rs1045642 single nucleotide polymorphism (SNP), showed a protective effect for liver toxicity when compared with genotype CC (OR?=?0.18, 95%CI 0.04-0.76; p?=?0.020) in univariate analysis. In the multivariate model, HCV coinfection was independently associated with higher risk of developing liver toxicity (aOR?=?8.00, 95%CI 1.27-50.29; p?=?0.027), whereas ABCB1 rs1045642 CT/TT genotypes (aOR?=?0.10, 95%CI 0.02-0.47; p?=?0.004) was associated with a lower risk. CONCLUSIONS:According to our findings HCV coinfection and ABCB1 rs1045642 SNP represent independent determinants of severe liver toxicity related to nevirapine. This genetic evaluation could be included as toxicity assessment in HIV-1-positive subjects treated with nevirapine.

SUBMITTER: Giacomelli A

PROVIDER: S-EPMC6233541 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Clinical and genetic factors associated with increased risk of severe liver toxicity in a monocentric cohort of HIV positive patients receiving nevirapine-based antiretroviral therapy.

Giacomelli Andrea A Riva Agostino A Falvella Felicia Stefania FS Oreni Maria Letizia ML Cattaneo Dario D Cheli Stefania S Renisi Giulia G Di Cristo Valentina V Lupo Angelica A Clementi Emilio E Rusconi Stefano S Galli Massimo M Ridolfo Anna Lisa AL

BMC infectious diseases 20181112 1

<h4>Background</h4>Nevirapine has been used as antiretroviral agent since early '90. Although nevirapine is not currently recommended in initial anti-HIV regimens, its use remains consistent in a certain number of HIV-1-positive subjects. Thus, our aim was to determine clinical and genetic factors involved in the development of severe nevirapine induced liver toxicity.<h4>Methods</h4>We retrospectively analyzed all HIV positive patients who were followed at the Infectious Diseases Unit, DIBIC Lu ...[more]

PMID: 30419834

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Project description:This is a substudy of the Agence Nationale de Recherches sur le Sida et les Hépatites Virales (ANRS) Comparison of Nevirapine and Efavirenz for the Treatment of HIV-TB Co-infected Patients (ANRS 12146-CARINEMO) trial, which assessed the pharmacokinetics of rifampin or isoniazid with or without the coadministration of nonnucleoside reverse transcriptase inhibitor-based HIV antiretroviral therapy in HIV-tuberculosis-coinfected patients in Mozambique. Thirty-eight patients on antituberculosis therapy based on rifampin and isoniazid participated in the substudy (57.9% males; median age, 33 years; median weight, 51.9 kg; median CD4(+) T cell count, 104 cells/μl; median HIV-1 RNA load, 5.5 log copies/ml). The daily doses of rifampin and isoniazid were 10 and 5 mg/kg of body weight, respectively. Twenty-one patients received 200 mg of nevirapine twice a day (b.i.d.), and 17 patients received 600 mg of efavirenz once a day (q.d.) in combination with lamivudine and stavudine from day 1 until the end of the study. Blood samples were collected at regular time-dosing intervals after morning administration of a fixed-dose combination of rifampin and isoniazid. When rifampin was administered alone, the median maximum concentration of drug in serum (Cmax) and the area under the concentration-time curve (AUC) at steady state were 6.59 mg/liter (range, 2.70 to 14.07 mg/liter) and 27.69 mg · h/liter (range, 11.41 to 109.75 mg · h/liter), respectively. Concentrations remained unchanged when rifampin was coadministered with nevirapine or efavirenz. When isoniazid was administered alone, the median isoniazid Cmax and AUC at steady state were 5.08 mg/liter (range, 1.26 to 11.51 mg/liter) and 20.92 mg · h/liter (range, 7.73 to 56.95 mg · h/liter), respectively. Concentrations remained unchanged when isoniazid was coadministered with nevirapine; however, a 29% decrease in the isoniazid AUC was observed when isoniazid was combined with efavirenz. The pharmacokinetic parameters of rifampin and isoniazid when coadministered with nevirapine or efavirenz were not altered to a clinically significant extent in these severely immunosuppressed HIV-infected patients. Patients experienced favorable clinical outcomes. (This study has been registered at ClinicalTrials.gov under registration no. NCT00495326.).

Project description:BackgroundIndia has among the highest rates of infant malnutrition. Few studies investigating the growth patterns of HIV-exposed infants in India or the impact of timing of HIV infection on growth in settings such as India exist.MethodsWe used data from the Six Week Extended Nevirapine (SWEN) trial to compare the growth patterns of HIV-infected and HIV-exposed but uninfected infants accounting for timing of HIV infection, and to identify risk factors for stunting, underweight and wasting. Growth and timing of HIV infection were assessed at weeks 1, 2, 4, 6, 10, 14 weeks and 6, 9, 12 months of life. Random effects multivariable logistic regression method was used to assess factors associated with stunting, underweight and wasting.ResultsAmong 737 HIV-exposed infants, 93 (13%) were HIV-infected by 12 months of age. Among HIV-infected and uninfected infants, baseline prevalence of stunting (48% vs. 46%), underweight (27% vs. 26%) and wasting (7% vs. 11%) was similar (p>0.29), but by 12 months stunting and underweight, but not wasting, were significantly higher in HIV-infected infants (80% vs. 56%, 52% vs. 29%, p< 0.0001; 5% vs. 6%, p=0.65, respectively). These differences rapidly manifested within 4-6 weeks of birth. Infants infected in utero had the worst growth outcomes during the follow-up period. SWEN was associated with non-significant reductions in stunting and underweight among HIV-infected infants and significantly less wasting in HIV-uninfected infants. In multivariate analysis, maternal CD4 < 250, infant HIV status, less breastfeeding, low birth weight, non-vaginal delivery, and infant gestational age were significant risk factors for underweight and stunting.ConclusionBaseline stunting and underweight was high in both HIV-infected and uninfected infants; growth indices diverged early and were impacted by timing of infection and SWEN prophylaxis. Early growth monitoring of all HIV-exposed infants is an important low-cost strategy for improving health and survival outcomes of these infants.Trial registrationNCT00061321.

Project description:BackgroundSwaziland has the highest adult HIV prevalence and second highest rate of TB/HIV coinfection globally. Recently, the Ministry of Health and partners have increased integration and co-location of TB/HIV services, but the timing of antiretroviral therapy (ART) relative to TB treatment-a marker of program quality and predictor of outcomes-is unknown.MethodsWe conducted a retrospective analysis of programmatic data from 11 purposefully-sampled facilities to evaluate timely ART provision for HIV-positive TB patients enrolled on TB treatment between July-November 2014. Timely ART was defined as within two weeks of TB treatment initiation for patients with CD4<50/μL or missing, and within eight weeks otherwise. Descriptive statistics were estimated and logistic regression used to assess factors independently associated with timely ART.ResultsOf 466 HIV-positive TB patients, 51.5% were male, median age was 35 (interquartile range [IQR]: 29-42), and median CD4 was 137/μL (IQR: 58-268). 189 (40.6%) were on ART prior to, and five (1.8%) did not receive ART within six months of TB treatment initiation. Median time to ART after TB treatment initiation was 15 days (IQR: 14-28). Almost 90% started ART within eight weeks, and 45.5% of those with CD4<50/μL started within two weeks. Using thresholds for "timely ART" according to baseline CD4 count, 73.3% of patients overall received timely ART after TB treatment initiation. Patients with CD4 50-200/μL or ≥200/μL had significantly higher odds of timely ART than patients with CD4<50/μL, with adjusted odds ratios of 11.5 (95% confidence interval [CI]: 5.0-26.6) and 9.6 (95% CI: 4.6-19.9), respectively. TB cure or treatment completion was achieved by 71.1% of patients at six months, but this was not associated with timely ART.ConclusionsThis study demonstrates the relative success of integrated and co-located TB/HIV services in Swaziland, and shows that timely ART uptake for HIV-positive TB patients can be achieved in resource-limited, but integrated settings. Gaps remain in getting patients with CD4<50/μL to receive ART within the recommended two weeks post TB treatment initiation.

Dataset Information

Clinical and genetic factors associated with increased risk of severe liver toxicity in a monocentric cohort of HIV positive patients receiving nevirapine-based antiretroviral therapy.

Publications

Clinical and genetic factors associated with increased risk of severe liver toxicity in a monocentric cohort of HIV positive patients receiving nevirapine-based antiretroviral therapy.

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