Non-nucleoside Transcriptase Inhibitors Research Articles

Central arterial stiffness in young adults with perinatal HIV exposure & infection.

To compare arterial stiffness between young adults with perinatally acquired HIV (YAPHIV) and young adults perinatally HIV exposed but uninfected (YAPHEU). Cross-sectional analysis of pulse wave velocity (PWV) measures among participants with echocardiography in the PHACS Cardiac Toxicity Substudy. A total of 150 participants (95 YAPHIV, 55 YAPHEU, mean 23.4 years, 60% female, 72% Black, 24% Hispanic) had echocardiography and PWV measured. We compared PWV between groups. Among YAPHIV, we fit linear regression models to evaluate the association of measures of HIV disease severity and antiretroviral treatment (ART) with PWV. We computed correlations between PWV and measures of left ventricular structure and function. Mean PWV did not differ by group (YAPHIV 5.63 vs YAPHEU 5.39 m/s; P = 0.50). HIV control was good (82% with viral load <400 copies/ml); 91% used combination ART. Mean PWV was normal, but 3 of 95 YAPHIV (3%) had values above 11.8 m/s (level associated with cardiovascular events in adults). Weak correlations (<0.20) were observed between PWV and echocardiographic measures. Among YAPHIV, current and historical HIV severity measures were not associated with PWV. YAPHIV on protease inhibitor (PI)-based ART had higher mean PWV than those on integrase strand inhibitors (1.68 m/s higher, 95% CI -0.36, 3.72) or nonnucleoside transcriptase inhibitors (1.58 m/s higher, 95% CI -0.94, 4.11). Our data shows no difference in PWV between those perinatally exposed to and perinatally infected with HIV. Therefore, CV risk reduction guidelines should be followed to prevent CV disease in all young adults.

Recycling Tenofovir in Second-line Antiretroviral Treatment With Dolutegravir: Outcomes and Viral Load Trajectories to 72 weeks.

Recycling tenofovir and lamivudine/emtricitabine with dolutegravir (TLD) after failure of non-nucleoside transcriptase inhibitor first-line antiretroviral therapy is more tolerable and scalable than dolutegravir plus optimized nucleoside reverse transcriptase inhibitors. Studies have demonstrated TLD's efficacy as second line, but long-term follow-up is limited. ARTIST is a single arm, prospective, interventional study conducted in Khayelitsha, South Africa, which switched 62 adults with 2 viral loads >1000 copies/mL from tenofovir, lamivudine/emtricitabine, and an non-nucleoside transcriptase inhibitor to TLD. We report efficacy to 72 weeks and, in a post hoc analysis, evaluated viral load trajectories of individuals with viremic episodes. Virologic suppression was 86% [95% confidence interval (CI) 74 to 93], 74% (95% CI: 61 to 84), and 75% (95% CI: 63 to 86) <50 copies/mL and 95%, 84%, and 77% <400 copies/mL at week 24, 48, and 72, respectively, with 89% (50/56) resistant (Stanford score ≥15) to tenofovir and/or lamivudine preswitch. No participants developed integrase-inhibitor resistance. Of the 20 participants not suppressed at week 24 and/or 48, 2 developed virologic failure, 1 switched regimen (adverse event), 2 were lost to follow-up, 1 missed the visit, 1 transferred out, 9 resuppressed <50 copies/mL with enhanced adherence counseling, and 4 remained viremic (3 with <200 copies/mL) at week 72. Recycling NRTIs with dolutegravir was effective for most participants to 72 weeks. Most with viremia did not develop virologic failure and subsequently suppressed with enhanced adherence counseling or continued to have low-level viremia. No integrase-inhibitor resistance was detected despite low-level viremia in a minority of participants.

Derangement in Enzymatic and Non-Enzymatic Markers of Liver Function in Human Immunodeficiency Virus (HIV) Infected Patients in Makurdi, North Central Nigeria

Liver disease has emerged as a critical issue in the management of human immunodeficiency virus (HIV) victims. This study was carried out to investigate the derangement in indices of liver function in HIV-infected patients in Makurdi, North Central Nigeria. One hundred and fifty males and females adults within the age range of 21- 50 years were enrolled for this study. One hundred of these participants were confirmed HIV positive, out of which fifty were on various antiretroviral drugs including the nucleoside / nucleotide reverse transcriptase inhibitors and the non-nucleoside transcriptase inhibitors classes of antiretroviral drugs. The remaining fifty persons who were HIV- negative served as the control group. Blood samples from the studied persons were analysed for alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, total protein, albumin, total bilirubin and conjugated bilirubin using automated clinical chemistry analyser, Hitachi 902 (Roche Diagnostic GMBH, Germany). The HIV- patients with or without antiretroviral drugs had their serum levels of alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase significantly raised (p&lt; 0.05) compared with the control subjects. A significant rise (p&lt; 0.05) was observed in serum level of total protein in the HIV patients who were yet to commence antiretroviral drugs when compared to the control subjects. However, the albumin levels of the HIV patients on the antiretroviral drugs and those who were yet to commence the antiretroviral drugs decreased significantly (p&lt; 0.05) when compared with that of the control. The total bilirubin level of the HIV patients on antiretroviral drugs showed significant increase (p&lt; 0.05) compared with the control subjects and the HIV patients who were not on antiretroviral drugs. This study reveals that both HIV infection itself and the antiretroviral drugs cause hepatic malfunction

From the Editor’s desk…: May 2019

From the Editor’s desk…: May 2019

Computational drug design strategies applied to the modelling of human immunodeficiency virus-1 reverse transcriptase inhibitors.

Reverse transcriptase (RT) is a multifunctional enzyme in the human immunodeficiency virus (HIV)-1 life cycle and represents a primary target for drug discovery efforts against HIV-1 infection. Two classes of RT inhibitors, the nucleoside RT inhibitors (NRTIs) and the nonnucleoside transcriptase inhibitors are prominently used in the highly active antiretroviral therapy in combination with other anti-HIV drugs. However, the rapid emergence of drug-resistant viral strains has limited the successful rate of the anti-HIV agents. Computational methods are a significant part of the drug design process and indispensable to study drug resistance. In this review, recent advances in computer-aided drug design for the rational design of new compounds against HIV-1 RT using methods such as molecular docking, molecular dynamics, free energy calculations, quantitative structure-activity relationships, pharmacophore modelling and absorption, distribution, metabolism, excretion and toxicity prediction are discussed. Successful applications of these methodologies are also highlighted.

Quality of life in patients treated with first-line antiretroviral therapy containing nevirapine or efavirenz in Uganda: a prospective non-randomized study.

BackgroundThe goal of antiretroviral therapy (ART) is to suppress viral replication, reduce morbidity and mortality, and improve quality of life (QoL). For resource-limited settings, the World Health Organization recommends a first-line regimen of two-nucleoside reverse-transcriptase inhibitors and one non-nucleoside transcriptase inhibitor (nevirapine (NVP) or efavirenz (EFV)). There are few data comparing the QoL impact of NVP versus EFV. This study assessed the change in QoL and factors associated with QoL among HIV patients receiving ART regimens based on EFV or NVP.MethodsWe enrolled 640 people with HIV eligible for ART who received regimens including either NVP or EFV. QoL was assessed at baseline, three months and six months using Physical Health Summary (PHS) and Mental Health Summary (MHS) scores and the Global Person Generated Index (GPGI). Data were analyzed using generalized estimating equations, with ART regimen as the primary exposure, to identify associations between patient and disease factors and QoL.ResultsQoL increased on ART. The mean QoL scores did not differ significantly for regimens based on NVP versus EFV during follow-up for MHS and GPGI regardless of CD4 stratum and for PHS among patients with a CD4 count >250 cells/μL. The PHS-adjusted β coefficients for ART regimens based on EFV versus NVP by CD4 count strata were as follows: −1.61 (95 % CI −2.74, −0.49) for CD4 count <100 cells/μL; 0.82 (0.22, 1.43) for CD4 count 101–250 cells/μL; and −1.33 (−5.66, 3.00) for CD4 count >250 cells/μL. The corresponding MHS-adjusted β coefficients were as follows: −0.39 (−1.40, 0.62) for CD4 < 100 cells/μL; 0.16 (−0.66, 0.98) for CD4 count 101–250 cells/μL; and −0.75 (−2.01, 0.51) for CD4 count >250 cells/μL. The GPGI-adjusted odds ratios for EFV versus NVP were 0.51 (0.25, 1.04) for CD4 count <100 cells/μL, 0.98 (0.60, 1.58) for CD4 count 101–250 cells/μL, 1.39 (0.66, 2.90) for CD4 > 250 cells/μL. QoL improved among patients on EFV over the 6-month follow-up period (MHS p < 0.001; PHS p = 0.04, p = 0.028). Overall, patients with depression (PHS p < 0.001; GPGI p < 0.001) had lower scores and women had lower MHS (on NVP, p = 0.001). Other factors associated with lower QoL included alcohol use, low education level and advanced HIV disease.ConclusionsART improves QoL. The results support use of either NVP or EFV. Patients initiating ART should be assessed for depression and managed appropriately. Women may require extra support to improve their QoL.

Factors associated with suboptimal adherence to antiretroviral therapy in Asia.

IntroductionAdherence to antiretroviral therapy (ART) plays an important role in treatment outcomes. It is crucial to identify factors influencing adherence in order to optimize treatment responses. The aim of this study was to assess the rates of, and factors associated with, suboptimal adherence (SubAdh) in the first 24 months of ART in an Asian HIV cohort.MethodsAs part of a prospective resistance monitoring study, the TREAT Asia Studies to Evaluate Resistance Monitoring Study (TASER-M) collected patients’ adherence based on the World Health Organization-validated Adherence Visual Analogue Scale. SubAdh was defined in two ways: (i) <100% and (ii) <95%. Follow-up time started from ART initiation and was censored at 24 months, loss to follow-up, death, treatment switch, or treatment cessation for >14 days. Time was divided into four intervals: 0–6, 6–12, 12–18 and 18–24 months. Factors associated with SubAdh were analysed using generalized estimating equations.ResultsOut of 1316 patients, 32% ever reported <100% adherence and 17% ever reported <95%. Defining the outcome as SubAdh <100%, the rates of SubAdh for the four time intervals were 26%, 17%, 12% and 10%. Sites with an average of >2 assessments per patient per year had an odds ratio (OR)=0.7 (95% confidence interval (CI) (0.55 to 0.90), p=0.006), compared to sites with ≤2 assessments per patient per year. Compared to heterosexual exposure, SubAdh was higher in injecting drug users (IDUs) (OR=1.92, 95% CI (1.23 to 3.00), p=0.004) and lower in homosexual exposure (OR=0.52, 95% CI (0.38 to 0.71), p<0.001). Patients taking a nucleoside transcriptase inhibitor and protease inhibitor (NRTI+PI) combination were less likely to report adherence <100% (OR=0.36, 95% CI (0.20 to 0.67), p=0.001) compared to patients taking an NRTI and non-nucleoside transcriptase inhibitor (NRTI+NNRTI) combination. SubAdh decreased with increasing time on ART (all p<0.001). Similar associations were found with adherence <95% as the outcome.ConclusionsWe found that SubAdh, defined as either <100% and <95%, was associated with mode of HIV exposure, ART regimen, time on ART and frequency of adherence measurement. The more frequently sites assessed patients, the lower the SubAdh, possibly reflecting site resourcing for patient counselling. Although social desirability bias could not be excluded, a greater emphasis on more frequent adherence counselling immediately following ART initiation and through the first six months may be valuable in promoting treatment and programme retention.

Role of Mitochondria in HIV Infection and Associated Metabolic Disorders: Focus on Nonalcoholic Fatty Liver Disease and Lipodystrophy Syndrome

Highly active antiretroviral therapy (HAART) has considerably improved the prognosis of HIV-infected patients. However, prolonged use of HAART has been related to long-term adverse events that can compromise patient health such as HIV-associated lipodystrophy syndrome (HALS) and nonalcoholic fatty liver disease (NAFLD). There is consistent evidence for a central role of mitochondrial dysfunction in these pathologies. Nucleotide reverse transcriptase inhibitors (NRTIs) have been described to be mainly responsible for mitochondrial dysfunction in adipose tissue and liver although nonnucleoside transcriptase inhibitors (NNRTIs) or protease inhibitors (PIs) have also showed mitochondrial toxicity, which is a major concern for the selection and the long-term adherence to a particular therapy. Several mechanisms explain these deleterious effects of HAART on mitochondria, and evidence points to other mechanisms beyond the “Pol-γ hypothesis.” HIV infection has also direct effects on mitochondria. In addition to the negative effects described for HIV itself and/or HAART on mitochondria, HIV-infected patients are more prone to develop a premature aging and, therefore, to present an increased oxidative state that could lead to the development of these metabolic disturbances observed in HIV-infected patients.

Assessing subtype and drug-resistance-associated mutations among antiretroviral-treated HIV-infected patients

Several studies have reported an increasing number of therapeutic failures with antiretroviral drugs in HIV-infected patients. The emergence of viral-resistant strains is a major problem for the medical management of infected individuals. The aim of this study is to determine viral subtypes and drug-resistance mutations among antiretroviral-treated HIV-infected patients. A total of 42 antiretroviral-treated but still viremic HIV-infected patients were enrolled. The HIV pol regions were amplified and sequenced to determine subtypes and antiretroviral-resistant mutations. The subtype distribution was 48% A/D recombinants, 43% subtype B, 5% subtype A and 5% CRF01-AE recombinants. Drug-resistant mutations were most common in subtype B (53%) and A/D recombinant strains (44%). Virus samples from 19% of participants had no drug-resistant mutations; 2, 2 and 76% of samples carried one, two and at least three drug-resistant mutations, respectively. The prevalence of nucleoside transcriptase inhibitor mutations was 76%, with M184V and L74V present in 60 and 38% of samples, respectively. The prevalence of nonnucleoside transcriptase inhibitor mutations was 74%, with P225H present in 55% of study specimens. The prevalence of protease inhibitor mutations was 45%, with major mutation L90M seen in 33% and minor mutation A71V in 36% of samples. Of note, the P225H and A71V are 'minor' drug-resistance mutations conferring only minimal drug-resistance phenotypes in the absence of major mutations. Our study found a high prevalence of drug-resistant mutations in Iranian HIV-infected patients. Our data support the need for continued surveillance of resistance patterns to help guide therapeutic approaches and limit transmission of these variants.

Genotyping and NNRTI mutations: where do we go from here as HIV populations get older? A perspective

As genotyping procedures have increasingly become more sensitive and complex, HIV scientists and physicians are finding new clinical approaches to treat compromised patient populations on non-nucleoside transcriptase inhibitor (NNRTI) classes of drugs. Further, as age demographics play a vital role in older populations affected with HIV, understanding phenotype/resistance panels for regimen changes is paramount. Key words: HIV/AIDS, gerontology and geriatrics, micro biology.

The nephrologist in the HAART era

The nephrologist in the HAART era

Antiretrovirals: simultaneous determination of five protease inhibitors and three nonnucleoside transcriptase inhibitors in human plasma by a rapid high-performance liquid chromatography--mass spectrometry assay.

An analytical technique using liquid chromatography (LC) coupled with electrospray-mass spectrometry (ESI--MS) has been developed for the simultaneous determination of five protease inhibitors (PIs): saquinavir, indinavir, ritonavir, nelfinavir, and amprenavir; and three non-nucleoside reverse transcriptase inhibitors (NNRTIs): nevirapine, delavirdine, and efavirenz, in human plasma. This assay allows the elution and identification of these drugs in a single run (10 minutes) using a linear gradient with water and acetonitrile. The procedure involves liquid--liquid extraction. High-performance liquid chromatography (HPLC) separation was achieved on a C18 reversed-phase column, with a linear gradient elution followed by mass spectrometry detection. The calibration curves, obtained by automatic process peak area integration, show a good linearity in a range of concentrations between 20 and 10,000 ng/mL (40--10,000 ng/mL for efavirenz). The limit of detection was approximately 10 ng/mL for seven drugs (25 ng/mL for efavirenz). The coefficients of variation (CV) were always less than 15% for both intraday and interday precision for each compound. The recovery of the eight drugs ranged from 88.5% to 100%. This novel LC/ESI--MS assay provides an excellent method for simultaneous quantitative monitoring of different components of the highly active antiretroviral treatments (HAARTs) in patients treated simultaneously with PIs and NNRTIs, and it has been successfully applied to therapeutic drug monitoring and pharmacokinetic studies.