Antiretroviral-naive Participants Research Articles

Tenofovir and emtricitabine resistance among antiretroviral-naive patients in the Canadian Observational Cohort Collaboration: implications for PrEP.

The real-world effectiveness of pre-exposure prophylaxis (PrEP) may be influenced by circulating HIV strains resistant to either tenofovir or emtricitabine. Yet, few studies have examined rates of resistance to these drugs in clinical settings. We conducted a retrospective cohort study of antiretroviral-naive participants in the Canadian Observational Cohort collaboration who initiated antiretroviral therapy between 2006 and 2014. In separate analyses, we determined the prevalence of pretherapy resistance and cumulative incidence of follow-up resistance to tenofovir and emtricitabine. We used multivariable proportional hazards models to examine associations between baseline variables and the development of resistance. We studied 6,622 antiretroviral-naive participants initiating therapy, of whom 5,428 (82.0%) had a baseline resistance test. Baseline resistance to tenofovir and emtricitabine was observed in 83 (1.5%) and 21 (0.4%) patients, respectively. Among patients without baseline resistance, the cumulative incidence of resistance to tenofovir and emtricitabine 5 years following treatment initiation was 0.0070 (95% CI 0.0046, 0.0095) and 0.033 (95% CI 0.028, 0.038), respectively. Following multivariable analysis, a baseline viral load ≥100,000 copies/ml was associated with emergence of tenofovir (hazard ratio [HR] 2.88; 95% CI 1.35, 6.15) and emtricitabine (HR 2.27; 95% CI 1.64, 3.15) resistance. Initiating an integrase inhibitor-based regimen and CD4+ T-cell count below 200 cells/mm3 were also associated with resistance to each drug. We observed a low prevalence of baseline resistance and a low incidence of emergence of resistance to tenofovir and emtricitabine among antiretroviral-naive patients in routine clinical care.

Cognitive Function Among Antiretroviral Treatment-Naive Individuals Infected With Human Immunodeficiency Virus Type 1 Subtype G Versus CRF02_AG in Nigeria.

Human immunodeficiency virus type 1 (HIV-1) subtype has been shown to be associated with disease progression. We compared cognitive function between individuals infected with HIV-1 subtype G and CRF02_AG in Nigeria. For this cross-sectional study, samples were analyzed from 146 antiretroviral-naive participants. Genotypic analysis of plasma HIV RNA was performed by nested polymerase chain reaction of protease and reverse transcriptase genes, and sequences were aligned with curated HIV-1 subtype references. Cognitive status was determined using demographically adjusted T scores and global deficit score (GDS) obtained from a comprehensive neuropsychological test battery. A total of 76 (52.1%) participants were infected with CRF02_AG, 48 (32.8%) with subtype G, and 22 (15.1%) with other HIV-1 strains. In a multivariable linear regression adjusting for plasma HIV RNA, CD4 count, and depression score, mean global T score was lower among subtype G-infected compared with CRF02_AG-infected participants (mean difference, -3.0 [95% confidence interval {CI}, -5.2, to -.7]; P = .011). Also, T scores were significantly lower among subtype G- than CRF02_AG-infected participants for the speed of information processing, executive function, and verbal fluency ability domains. Adjusting for similar variables in a logistic regression, the odds of global cognitive impairment (GDS ≥0.5) were 2.2 times higher among subtype G compared with CRF02_AG-infected participants (odds ratio, 2.2 [95% CI, .9-5.4]; P = .078). Cognitive performance was significantly worse among antiretroviral-naive individuals with HIV-1 subtype G vs CRF02_AG infection. Further studies are required to characterize the mechanistic basis for these differences.

IMMUNOGENS DESIGNED FOR TARGETING NEUTRALIZING EPITOPES OF HIV-1 ENVELOPE GLYCOPROTEIN

BackgroundDue to its unique challenge of establishing lifelong reservoirs a successful HIV-1 vaccine must elicit protective antibodies responses at the portals of entry. Broadly neutralising antibodies (bnAb) have been demonstrated...

HIV-1 subtype B/B' and baseline drug resistance mutation are associated with virologic failure: a multicenter cohort study in China.

Distribution of HIV-1 subtypes, transmitted drug resistance (TDR)/drug resistance mutation (DRM), and their impact on response to combination antiretroviral therapy remain poorly understood in China. We analyzed data from our multicenter cohort study with 444 antiretroviral-naive participants recruited between 2008 and 2010. HIV-1 subtype and tropism were determined by V3 sequencing, and TDR/DRM was determined by Pol sequencing. Virologic and immunologic responses were monitored over 96 weeks of follow-up. The initial combination antiretroviral therapy regimen for all patients was nevirapine + lamivudine + zidovudine or stavudine. Analysis 1 included patients who finished 96 weeks of follow-up (n = 379), and analysis 2 included all 444 patients. Subtype B/B' was associated with higher prevalence of TDR/DRM to nucleoside reverse transcriptase inhibitors and nonnucleoside reverse transcriptase inhibitors. Median time to HIV-1 suppression was 18 weeks in all 3 subtype groups. In Cox proportional models for viral suppression, neither viral tropism nor HIV-1 subtypes had any impact on viral suppression; however, subtypes CRF01_AE and C/CRF07_BC/CRF08_BC were associated with lower risk of virologic failure compared with subtype B/B', with adjusted hazard ratio of 0.11 (P = 0.032) and 0.06 (P = 0.036), respectively in analysis 1, 0.42 (P = 0.047) and 0.22 (P = 0.008), respectively in analysis 2. This association was attenuated by adding DRM profiles to multivariate regression models. Neither subtype nor HIV-1 tropism affected immunologic response. HIV-1 subtype tended to be associated with virologic but not immunologic response; this effect could be ascribed to baseline DRM.

Association Between Efavirenz as Initial Therapy for HIV-1 Infection and Increased Risk for Suicidal Ideation or Attempted or Completed Suicide

This article has been corrected. The original version (PDF) is appended to this article as a Supplement. Background: The relationship between efavirenz use and suicidality is not well-defined. Objective: To compare time to suicidality with efavirenz-containing versus efavirenz-free antiretroviral regimens for initial treatment of HIV. Design: Participant-level data were analyzed from 4 AIDS Clinical Trials Group, antiretroviral-naive studies conducted from 2001 to 2010. Within each study, participants were randomly assigned to an efavirenz-containing (n = 3241) or efavirenz-free (n = 2091) regimen. (ClinicalTrials.gov: NCT00013520 [A5095], NCT00050895 [A5142], NCT00084136 [A5175], and NCT00118898 [A5202]) Setting: AIDS Clinical Trials Group sites; 74% of participants enrolled in the United States. Patients: Antiretroviral-naive participants. Intervention: Efavirenz versus efavirenz-free regimens. Measurements: Suicidality was defined as suicidal ideation or attempted or completed suicide. Groups were compared with a hazard ratio and 95% CI estimated from a Cox model, stratified by study. Results: Seventy-three percent of participants were men, the median age was 37 years, and 32% had documented psychiatric history or received psychoactive medication within 30 days before entering the study. Median follow-up was 96 weeks. Suicidality incidence per 1000 person-years was 8.08 (47 events) in the efavirenz group and 3.66 (15 events) in the efavirenz-free group (hazard ratio, 2.28 [95% CI, 1.27 to 4.10]; P = 0.006). Incidence of attempted or completed suicide was 2.90 (17 events) and 1.22 (5 events) in the efavirenz and efavirenz-free groups, respectively (hazard ratio, 2.58 [CI, 0.94 to 7.06]; P = 0.065). Eight suicides in the efavirenz group and 1 in the efavirenz-free group were reported. Limitation: There was not a standardized questionnaire about suicidal ideation or attempt. Efavirenz was open-label in 3 of 4 studies. Conclusion: Initial treatment with an efavirenz-containing antiretroviral regimen was associated with a 2-fold increased hazard of suicidality compared with a regimen without efavirenz. Primary Funding Source: National Institutes of Health.

Factors associated with remaining on initial randomized efavirenz-containing regimens

Efavirenz (EFV) along with two nucleoside reverse transcriptase inhibitors (NRTIs) is a recommended initial antiretroviral regimen. Understanding characteristics related to EFV success is clinically useful. Data from 2220 antiretroviral-naive participants randomized to EFV and two to three NRTIs in four ACTG trials as well as a long-term cohort were analysed. Logistic regression, using inverse probability of censoring weighting to address selective-follow-up bias, was used to identify factors associated with EFV success (no treatment interruptions of >30 days, HIV RNA < 200 copies/ml) 1 year post initiation and at years 2-5 if successful at year 1. Pretreatment characteristics were median age 38 years, 82% male, 40% white, 10% history of IDU (HxIDU), median CD4+ T-lymphocyte 227 cells/μl and 33% HIV RNA more than 100 ,000 copies/ml. In a multivariable model, factors associated with year 1 EFV success were race [white odds ratio (OR) 1.5; P < 0.001; Hispanic OR 1.5; P = 0.003 vs. black], no pretreatment sign/symptom grade 3 or higher (OR 1.7; P = 0.008) and no HxIDU (OR 1.7; P = 0.001). Predictors of EFV success at years 2-5 were no HxIDU (years 2-5; ORs 1.9-2.2); self-reported complete (4 days prior to study visit) adherence during year 1 (years 2-4; ORs 1.6-1.9); fewer missed visits during year 1 (years 2, 4, 5; ORs 0.92-0.98/1% increase); HIV RNA less than 50 copies/ml at year 1 (years 2, 3; ORs 1.9-2.2); and older age (>50 vs. ≤30 years) (years 2-4: ORs 2.3-3.7). Characteristics predictive of EFV success in the short-term and longer term differed except for HxIDU. Behaviours occurring during year 1 were associated with EFV success over 5 years.

Immunological and virological responses to combined antiretroviral therapy in HIV/hepatitis B virus-coinfected patients from a multicenter cohort

To evaluate the influence of hepatitis B virus (HBV) coinfection on immunological, virological and clinical responses to lamivudine (3TC)-based combined antiretroviral therapy (cART) in Chinese patients. This prospective, multicenter cohort study recruited 529 antiretroviral-naive participants (aged 18–65 years, both sexes) between 2008 and 2010.They were grouped by HBV serostatus. Virological and immunological responses were monitored at baseline and week 4, 8, 12, 24, 36 and 48. cART for all patients was nevirapine, 3TC with either zidovudine or stavudine. First, HIV/HBV coinfection rate in our cohort was 14.6%. Second, among 508 patients with complete baseline information, median CD4 level was significantly lower in the chronic HBV-infected (CHB) group and isolated core group. In the CHB group,hepatitis B e antigen positivity rather than HBV DNA level was associated with lower CD4 cell count. Third, in the isolated core group, occult infection rate was 9.5%.Fourth, at week 48, rate of HIV suppression below 40 copies/ml was 74.2%. Median increase in the CD4 cell count at week 48 was 127 cells/ml. Of note, HBV serostatus did not influence virological and immunological response to cART at each follow-up time point. Although HBV serostatus was associated with different alanine aminotransferase levels during follow-up, hepatitis and hyperbilirubinemia rates were not significantly different. Fifth, the 3TC-based regimen was efficacious against HBV replication, with median decrease in HBV DNA of 2.87 log copies/ml. However, hepatitis B e antigen positivity was associated with poorer HBV DNA suppression. In our cohort, CHB infection and isolated hepatitis B core antibody positivity were related to faster HIV progression. Despite of this, virological and immunological responses were not affected by HBV serostatus.

Antiretroviral medication adherence and class-specific resistance in a large prospective clinical trial

To assess the association between adherence to antiretroviral therapy and the presence of class-specific antiretroviral medication resistance. Secondary analysis of prospective clinical trial data. Participants randomized to the protease inhibitor or nonnucleoside reverse transcriptase inhibitor (NNRTI) strategies of the Community Programs for Clinical Research on AIDS (CPCRA) Flexible Initial Retrovirus Suppressive Therapies (FIRST) Study were included. Adherence was measured by 7-day self-report. Virological failure was defined as an HIV-RNA more than 1000 at or after 4 months. The association between cumulative adherence and the development of class-specific genotypic resistance was assessed by Cox regression analysis. Included were 457 and 446 antiretroviral-naive participants on the protease inhibitor and NNRTI strategies, respectively. The median time to initial virological failure in the protease inhibitor strategy was 1.2 years; 135 (30%) individuals failed with resistance. The median time to initial virological failure in the NNRTI strategy was 3.0 years; 127 (28%) failed with resistance. No association was found between cumulative adherence and protease inhibitor resistance [hazard ratio 1.1, 95% confidence interval (CI) 0.9-1.4 per 10% lower adherence]. However, lower cumulative adherence was associated with an increased risk of NNRTI resistance at initial virological failure (hazard ratio 1.2, 95% CI 1.1-1.3 per 10% lower adherence). In both strategies, lower cumulative adherence was associated with an increased risk of nucleoside reverse transcriptase inhibitor (NRTI) resistance at initial virological failure. Adherence-resistance relationships are class-specific. For NRTIs and NNRTIs, initial virological failure with resistance is more likely at lower levels of cumulative adherence.

Long-Term Body Fat Outcomes in Antiretroviral-Naive Participants Randomized to Nelfinavir or Efavirenz or Both Plus Dual Nucleosides

Long-term regional body fat outcomes have not been well described in randomized antiretroviral drug trials. Dual x-ray absorptiometry (DXA) scans were performed every 16 weeks on a subset of 157 antiretroviral-naive participants who were randomized to receive nelfinavir, efavirenz, or both, combined with zidovudine and lamivudine or stavudine and didanosine, in a multicenter trial. Participants with any available data after baseline up to week 144 contributed to this as-treated analysis. Limb fat increased similarly in all groups during the first 32 weeks. After week 32, limb fat changed by - 1.7% per year for zidovudine-lamivudine and by -19.0% per year for didanosine-stavudine (mixed model analysis of variance [MMANOVA], P < 0.0001). Adjusting for nucleoside backbone, there was an additional decrease in limb fat of -8.7% per year for the combined nelfinavir and nelfinavir + efavirenz group compared with the efavirenz group (MMANOVA, P = 0.03). Among participants receiving zidovudine-lamivudine, after week 32, limb fat changed by +2.7% per year with efavirenz and by -7.9% per year for the combined nelfinavir and nelfinavir + efavirenz group (MMANOVA, P = 0.03). Over 144 weeks, zidovudine-lamivudine was superior to didanosine-stavudine with regard to limb fat loss. The combination of zidovudine, lamivudine, and efavirenz showed no overall pattern suggesting limb fat loss over time and was significantly superior to the pooled zidovudine-lamivudine-nelfinavir (with and without efavirenz) arms.

Stavudine, lamivudine and nevirapine combination therapy for treatment of HIV infection and AIDS in adults.

A favourable regimen for people infected with HIV/AIDS is one that provides optimal efficacy, durability of antiretroviral activity, tolerability, and has low adverse effects and drug-drug interactions. The combination of the non-nucleoside reverse transcriptase inhibitor nevirapine (NVP), and two nucleoside reverse transcriptase inhibitors, stavudine (d4T) and lamivudine (3TC), is widely used as first-line therapy, especially in low-resource countries. Analysis of the efficacy, durability and tolerability of the regimen is thus important to clinicians, consumers and policy-makers living in both rich and poor countries. To examine the efficacy of the stavudine, lamivudine and nevirapine regimen for the treatment of HIV infection and AIDS in adults. We used the comprehensive search strategy developed specifically by the Cochrane HIV/AIDS Review Group to identify HIV/AIDS randomised controlled trials, and searched the following electronic databases: MEDLINE (searched July 2004); Embase (searched October 2004); and CENTRAL (July 2004). This search was supplemented with a search of AIDSearch (April 2005) to identify relevant conference abstracts, as well as searching reference lists of all eligible articles. The search was not limited by language or publication status. Randomised controlled trials of the stavudine, lamivudine and nevirapine regimen, compared with any other regimens for treating HIV/AIDS, in antiretroviral treatment-naive or antiretroviral treatment-experienced adults. Two reviewers independently assessed the methodological quality of the trials and extracted data. Our search resulted in 1,148 records, of which two studies described trials that met our inclusion criteria. One trial was a small single-centre Australian trial of 70 antiretroviral-naive participants, while the other trial was a large, multicentre trial, conducted in 14 countries, of 1,216 antiretroviral-naive participants. In both trials over 60% of participants were male. As the therapeutic combinations compared in both trials were not identical, it was not possible to conduct a meta-analysis to increase the power of the results. The main findings, therefore, are from the much larger trial, which was of a high quality. This trial found that there was no statistically significant difference in the efficacy (measured by treatment failure) between nevirapine and efavirenz (EFZ), when used in combination with 3TC and d4T (RR = 1.16; 95%CI: 0.95, 1.41). There was no statistically significant difference between once daily or twice-daily dosing of NVP, when used in combination with 3TC and d4T (RR = 1.00; 95%CI: 0.83; 1.21). It also showed that, compared with NVP plus EFZ, 3TC and d4T, a once-daily dosing of NVP, in combination with 3TC and d4T, performs better in averting treatment failure (RR = 0.82; 95%CI: 0.67, 1.00) than does twice-daily dosing of NVP with 3TC and d4T (RR = 0.82; 95%CI: 0.69; 0.97). Frequency of toxicity was higher in participants receiving NVP, compared with EFZ. The combination of nevirapine, 3TC and d4T is as efficacious as a combination of efavirenz, 3TC and d4T. Once-daily NVP with twice-daily 3TC and d4T is as efficacious as twice-daily NVP, 3TC and d4T. However, toxicity may be increased in the once-daily NVP regime. Additional trials of sufficient duration are required to provide better evidence for the use of this combination as a first line therapy. Ideally, trials should use standardised assessment measures especially with respect to measuring viral load, so that results can be compared and combined in meta-analyses.

Efficacy of Nevirapine-Based HAART in HIV-1-Infected, Treatment-Naive Persons with High and Low Baseline Viral Loads

Purpose: The objective of this analysis was to assess the efficacy of nonnucleoside reverse transcriptase inhibitor (NNRTI)-containing, protease inhibitor (PI)-sparing, three-drug highly active antiretroviral therapy (HAART) in HIV- 1-infected, treatment-naive patients with high and low baseline viral loads. Method: A composite analysis was performed of clinical studies including the NNRTI nevirapine that were presented at international conferences between 1998 and October 2000. In all of the studies, nevirapine was administered in combination with two nucleoside reverse transcriptase inhibitors (NRTIs). For a study to be included in the analysis, more than 25% of participants must have had baseline viral loads >100,000 copies/mL, and more than 25% of participants must have had viral loads <100,000 copies/mL. Results: After 6 months, 139 of 156 (89%) and 82 of 99 (83% ) patients in the low and high baseline viral load groups, respectively, had on-treatment viral loads <200 to 500 copies/mL (depending on assay used). After 12 months, 95 of 124 patients (77%) with lower baseline viral loads and 63 of 76 patients (83%) with high baseline viral loads had on-treatment viral loads below the limit of quantification. Conclusion: Baseline viral load does not affect virologic outcome in HIV-1-infected, antiretroviral-naive participants treated with nevirapine-containing, PI-sparing HAART.