Upskilling nursing students and nurse practitioners to initiate and manage patients on ART: An outcome evaluation of the UKZN NIMART course

Background. Currently, there is a need in South Africa to implement strategies to upskill nurses in the clinical management of HIV and AIDS, for effective and efficient management of people living with HIV. One such strategy is the nurse-initiated management of antiretroviral therapy (NIMART) course.Objectives. To evaluate the effectiveness of the NIMART course in increasing the knowledge of trainees in select clinical competencies, to assess whether perceived knowledge gain varied according to individual-level characteristics of trainees, and to determine trainee perceptions of the value and delivery of the course.Methods. A 5-day training course focusing on various areas of HIV was developed and delivered by experts in the field of HIV to multiple cohorts of fourth-year nursing students at the University of KwaZulu-Natal, and to post-basic nursing practitioners, over a 5-year period. A single-group pre- and post-quasi-experimental design was used to assess knowledge change and perceptions about the course among 1 369 trainees who had benefitted from the course during the implementation period.Results. Post-workshop test scores were significantly higher than pre-workshop scores (p<0.0001), based on both pooled and cohort-specific data. For pooled analysis, the pre-test median score was 67% (interquartile range (IQR) = 60% - 73%) and the post-test median score was 77% (IQR = 70% - 80%), with p<0.0001. The knowledge gain was the highest in respect of HIV prevention, followed by prevention of mother-to-child transmission, then HIV treatment and lastly, general knowledge of HIV. The vast majority were very satisfied with the content of the training, although 31.3% strongly disagreedthat they were ready to apply the knowledge they had learned in their workplace.Conclusion. The training was generally well received, and improved the knowledge of participants in HIV and its management. However, this outcome represents short-term benefits of the programme, and there is a need for on-the-job mentorship and support in order to maximise on clinical outcomes related to HIV

Serum Albumin as a Prognostic Marker for Serious Non-AIDS Endpoints in the Strategic Timing of Antiretroviral Treatment (START) Study

Background: Serum albumin may be used to stratify human immunodeficiency virus (HIV)-infected persons with high CD4 count according to their risk of serious non-AIDS endpoints. Methods: Cox proportional hazards models were used to analyze the risk of serious non-AIDS events in the Strategic Timing of Antiretroviral Treatment (START) study (NCT00867048) with serum albumin as a fixed and time-updated predictor. Models with exclusion of events during initial follow-up years were built to assess the ability of serum albumin to predict beyond shorter periods of time. Secondarily, we considered hospitalizations and AIDS events. Results: Among 4576 participants, 71 developed a serious non-AIDS event, 788 were hospitalized, and 63 experienced an AIDS event. After adjusting for a range of variables associated with hypoalbuminemia, higher baseline serum albumin (per 1 g/dL) was associated with a decreased risk of serious non-AIDS events (hazard ratio, 0.37 [95% confidence interval, .20-.71]; P = .002). Similar results were obtained in a time-updated model, after controlling for interleukin 6, and after excluding initial follow-up years. Serum albumin was independently associated with hospitalization but not with risk of AIDS. Conclusions: A low serum albumin level is a predictor for short- and long-term serious non-AIDS events, and may be a useful marker of risk of noncommunicable diseases, particularly in resource-limited settings

Antiretroviral initiation at ≥800 CD4+ cells/ mm 3 associated with lower HIV reservoir size.

BACKGROUND: Identifying factors that determine the frequency of latently infected CD4+ T-cells on antiretroviral therapy (ART) may inform strategies for HIV cure. We investigated the role of CD4 count at ART initiation for HIV persistence on ART. METHODS: Among participants of the Strategic Timing of Antiretroviral Treatment (START) Study, we enrolled people with HIV (PWH) who initiated ART with CD4+ T-cell counts of 500-599, 600-799 or ≥800 cells/mm 3. After 36-44 months on ART, we quantified levels of total HIV-DNA, cell-associated unspliced HIV-RNA (CA-US HIV-RNA) and 2-long terminal repeat HIV-DNA in CD4+ T-cells and measured plasma HIV-RNA by single-copy assay. We measured T-cell expression of HLA-DR, programmed death-1, phosphorylated signal transducer and activator of transcription-5 (pSTAT5). Virological and immunological measures were compared across CD4+ strata. RESULTS: We enrolled 146 PWH, 36 in the 500-599, 60 in the 600-799 and 50 in the ≥800 CD4 strata. After 36-44 months of ART, total HIV-DNA, plasma HIV-RNA and HLA-DR expression were significantly lower in PWH with CD4+ T-cell count ≥800 cells/mm 3 at ART initiation compared to 600-799 or 500-599 cells/mm 3. The median level of HIV-DNA after 36-44 months of ART was lower by 75% in participants initiating ART with ≥800 vs. 500-599 cells/mm 3 [median (IQR): 16.3 (7.0-117.6) vs. 68.4 (13.7-213.1) copies/million cells, respectively). Higher pSTAT5 expression significantly correlated with lower levels of HIV-DNA and CA-US HIV-RNA. Virological measures were significantly lower in females.. CONCLUSION: Initiating ART with a CD4+ count ≥800 cells/mm 3 compared to 600-799 or 500-599 cells/mm 3 was associated with achieving a substantially smaller HIV reservoir on ART

Dolutegravir twice-daily dosing in children with HIV-associated tuberculosis: a pharmacokinetic and safety study within the open-label, multicentre, randomised, non-inferiority ODYSSEY trial

Background: Children with HIV-associated tuberculosis (TB) have few antiretroviral therapy (ART) options. We aimed to evaluate the safety and pharmacokinetics of dolutegravir twice-daily dosing in children receiving rifampicin for HIV-associated TB. Methods: We nested a two-period, fixed-order pharmacokinetic substudy within the open-label, multicentre, randomised, controlled, non-inferiority ODYSSEY trial at research centres in South Africa, Uganda, and Zimbabwe. Children (aged 4 weeks to <18 years) with HIV-associated TB who were receiving rifampicin and twice-daily dolutegravir were eligible for inclusion. We did a 12-h pharmacokinetic profile on rifampicin and twice-daily dolutegravir and a 24-h profile on once-daily dolutegravir. Geometric mean ratios for trough plasma concentration (Ctrough), area under the plasma concentration time curve from 0 h to 24 h after dosing (AUC0–24 h), and maximum plasma concentration (Cmax) were used to compare dolutegravir concentrations between substudy days. We assessed rifampicin Cmax on the first substudy day. All children within ODYSSEY with HIV-associated TB who received rifampicin and twice-daily dolutegravir were included in the safety analysis. We described adverse events reported from starting twice-daily dolutegravir to 30 days after returning to once-daily dolutegravir. This trial is registered with ClinicalTrials.gov (NCT02259127), EudraCT (2014–002632-14), and the ISRCTN registry (ISRCTN91737921). Findings: Between Sept 20, 2016, and June 28, 2021, 37 children with HIV-associated TB (median age 11·9 years [range 0·4–17·6], 19 [51%] were female and 18 [49%] were male, 36 [97%] in Africa and one [3%] in Thailand) received rifampicin with twice-daily dolutegravir and were included in the safety analysis. 20 (54%) of 37 children enrolled in the pharmacokinetic substudy, 14 of whom contributed at least one evaluable pharmacokinetic curve for dolutegravir, including 12 who had within-participant comparisons. Geometric mean ratios for rifampicin and twice-daily dolutegravir versus once-daily dolutegravir were 1·51 (90% CI 1·08–2·11) for Ctrough, 1·23 (0·99–1·53) for AUC0–24 h, and 0·94 (0·76–1·16) for Cmax. Individual dolutegravir Ctrough concentrations were higher than the 90% effective concentration (ie, 0·32 mg/L) in all children receiving rifampicin and twice-daily dolutegravir. Of 18 children with evaluable rifampicin concentrations, 15 (83%) had a Cmax of less than the optimal target concentration of 8 mg/L. Rifampicin geometric mean Cmax was 5·1 mg/L (coefficient of variation 71%). During a median follow-up of 31 weeks (IQR 30–40), 15 grade 3 or higher adverse events occurred among 11 (30%) of 37 children, ten serious adverse events occurred among eight (22%) children, including two deaths (one tuberculosis-related death, one death due to traumatic injury); no adverse events, including deaths, were considered related to dolutegravir. Interpretation: Twice-daily dolutegravir was shown to be safe and sufficient to overcome the rifampicin enzyme-inducing effect in children, and could provide a practical ART option for children with HIV-associated TB

Neuropsychiatric manifestations and sleep disturbances with dolutegravir-based antiretroviral therapy versus standard of care in children and adolescents: a secondary analysis of the ODYSSEY trial

BACKGROUND: Cohort studies in adults with HIV showed that dolutegravir was associated with neuropsychiatric adverse events and sleep problems, yet data are scarce in children and adolescents. We aimed to evaluate neuropsychiatric manifestations in children and adolescents treated with dolutegravir-based treatment versus alternative antiretroviral therapy. METHODS: This is a secondary analysis of ODYSSEY, an open-label, multicentre, randomised, non-inferiority trial, in which adolescents and children initiating first-line or second-line antiretroviral therapy were randomly assigned 1:1 to dolutegravir-based treatment or standard-of-care treatment. We assessed neuropsychiatric adverse events (reported by clinicians) and responses to the mood and sleep questionnaires (reported by the participant or their carer) in both groups. We compared the proportions of patients with neuropsychiatric adverse events (neurological, psychiatric, and total), time to first neuropsychiatric adverse event, and participant-reported responses to questionnaires capturing issues with mood, suicidal thoughts, and sleep problems. FINDINGS: Between Sept 20, 2016, and June 22, 2018, 707 participants were enrolled, of whom 345 (49%) were female and 362 (51%) were male, and 623 (88%) were Black-African. Of 707 participants, 350 (50%) were randomly assigned to dolutegravir-based antiretroviral therapy and 357 (50%) to non-dolutegravir-based standard-of-care. 311 (44%) of 707 participants started first-line antiretroviral therapy (ODYSSEY-A; 145 [92%] of 157 participants had efavirenz-based therapy in the standard-of-care group), and 396 (56%) of 707 started second-line therapy (ODYSSEY-B; 195 [98%] of 200 had protease inhibitor-based therapy in the standard-of-care group). During follow-up (median 142 weeks, IQR 124–159), 23 participants had 31 neuropsychiatric adverse events (15 in the dolutegravir group and eight in the standard-of-care group; difference in proportion of participants with ≥1 event p=0·13). 11 participants had one or more neurological events (six and five; p=0·74) and 14 participants had one or more psychiatric events (ten and four; p=0·097). Among 14 participants with psychiatric events, eight participants in the dolutegravir group and four in standard-of-care group had suicidal ideation or behaviour. More participants in the dolutegravir group than the standard-of-care group reported symptoms of self-harm (eight vs one; p=0·025), life not worth living (17 vs five; p=0·0091), or suicidal thoughts (13 vs none; p=0·0006) at one or more follow-up visits. Most reports were transient. There were no differences by treatment group in low mood or feeling sad, problems concentrating, feeling worried or feeling angry or aggressive, sleep problems, or sleep quality. INTERPRETATION: The numbers of neuropsychiatric adverse events and reported neuropsychiatric symptoms were low. However, numerically more participants had psychiatric events and reported suicidality ideation in the dolutegravir group than the standard-of-care group. These differences should be interpreted with caution in an open-label trial. Clinicians and policy makers should consider including suicidality screening of children or adolescents receiving dolutegravir

Efficacy and Safety of Three Antiretroviral Regimens for Initial Treatment of HIV-1: A Randomized Clinical Trial in Diverse Multinational Settings

Background:Antiretroviral regimens with simplified dosing and better safety are needed to maximize the efficiency of antiretroviral delivery in resource-limited settings. We investigated the efficacy and safety of antiretroviral regimens with once-daily compared to twice-daily dosing in diverse areas of the world.Methods and Findings:1,571 HIV-1-infected persons (47% women) from nine countries in four continents were assigned with equal probability to open-label antiretroviral therapy with efavirenz plus lamivudine-zidovudine (EFV+3TC-ZDV), atazanavir plus didanosine-EC plus emtricitabine (ATV+DDI+FTC), or efavirenz plus emtricitabine-tenofovir-disoproxil fumarate (DF) (EFV+FTC-TDF). ATV+DDI+FTC and EFV+FTC-TDF were hypothesized to be non-inferior to EFV+3TC-ZDV if the upper one-sided 95% confidence bound for the hazard ratio (HR) was ≤1.35 when 30% of participants had treatment failure.An independent monitoring board recommended stopping study follow-up prior to accumulation of 472 treatment failures. Comparing EFV+FTC-TDF to EFV+3TC-ZDV, during a median 184 wk of follow-up there were 95 treatment failures (18%) among 526 participants versus 98 failures among 519 participants (19%; HR 0.95, 95% CI 0.72-1.27; p = 0.74). Safety endpoints occurred in 243 (46%) participants assigned to EFV+FTC-TDF versus 313 (60%) assigned to EFV+3TC-ZDV (HR 0.64, CI 0.54-0.76; p<0.001) and there was a significant interaction between sex and regimen safety (HR 0.50, CI 0.39-0.64 for women; HR 0.79, CI 0.62-1.00 for men; p = 0.01). Comparing ATV+DDI+FTC to EFV+3TC-ZDV, during a median follow-up of 81 wk there were 108 failures (21%) among 526 participants assigned to ATV+DDI+FTC and 76 (15%) among 519 participants assigned to EFV+3TC-ZDV (HR 1.51, CI 1.12-2.04; p = 0.007).Conclusion: EFV+FTC-TDF had similar high efficacy compared to EFV+3TC-ZDV in this trial population, recruited in diverse multinational settings. Superior safety, especially in HIV-1-infected women, and once-daily dosing of EFV+FTC-TDF are advantageous for use of this regimen for initial treatment of HIV-1 infection in resource-limited countries. ATV+DDI+FTC had inferior efficacy and is not recommended as an initial antiretroviral regimen.Trial Registration:http://www.ClinicalTrials.gov NCT00084136

Incidence and Predictors of Pregnancy in Women Enrolled in Large Multi-National HIV Treatment Trials of the AIDS Clinical Trials Group

Objectives: Women are under-represented in clinical trials and must often commit to using contraception to enroll. We sought to determine the incidence and predictors of pregnancy in women participating in HIV treatment trials. Design: Individual participant data meta-analysis. Methods: We included data from multi-country HIV treatment trials conducted 2005-2019 by the AIDS Clinical Trials Group (ACTG) that included females with HIV who were of reproductive potential, did not intend to become pregnant, and agreed to use effective contraception during study treatment. We extracted data from all female participants of age 18-55 years, including occurrence and dates of pregnancy on-study however, only a few incident pregnancy predictor variables were available for analysis. Results: 1,626 women from four trials were included. Over a median of 28 months (6,461 person-years) of follow-up, 143 (9%) women became pregnant, for an overall incidence of 2.2 pregnancies/100 person-years (range 0.5–3/100 person-years, by study). In multivariable analysis including baseline age, type of regimen and country as predictor variables, younger age remained the strongest predictor of incident pregnancy (p&lt;0.0001 adjusted for country and ART regimen). CD4 and HIV-1 RNA were not associated with pregnancy incidence. Conclusion: Pregnancy incidence was 2.2/100 person-years in female participants of HIV treatment trials. Rather than leading to exclusion of young women from trials, this finding should prompt appropriate adaptations in study design and analysis for earlier generation of pregnancy safety information for drugs

A Randomized Comparison of Anthropomorphic Changes With Preferred and Alternative Efavirenz-Based Antiretroviral Regimens in Diverse Multinational Settings

Background. Existing data on anthropomorphic changes in resource-limited settings primarily come from observational or cross-sectional studies. Data from randomized clinical trials are needed to inform treatment decisions in these areas of the world. Methods. The AIDS Clinical Trials Group Prospective Evaluation of Antiretrovirals in Resource-Limited Settings (PEARLS) study was a prospective, randomized evaluation of the efficacy of emtricitabine/tenofovir + efavirenz (FTC/TDF + EFV) vs lamivudine/zidovudine + efavirenz (3TC/ZDV + EFV) for the initial treatment of human immunodeficiency virus (HIV)-1-infected individuals from resource-diverse settings. Changes in anthropomorphic measures were analyzed using mixed-effect models for repeated measurements, using all available measurements at weeks 48, 96, and 144. Intent-to-treat results are presented; as-treated results were similar. Results. Five hundred twenty-six participants were randomized to FTC/TDF + EFV, and 519 participants were randomized to 3TC/ZDV + EFV. Significantly greater increases from baseline to week 144 were seen among those randomized to FTC/TDF + EFV vs 3TC/ZDV + EFV in all measures except waist-to-hip ratio, with the following mean changes: weight, 4.8 vs 3.0 kg; body mass index, 1.8 vs 1.1 kg/m2; mid-arm, 1.7 vs 0.7 cm; waist, 5.2 vs 4.3 cm; hip, 3.8 vs 1.4 cm; and mid-thigh circumference, 3.1 vs 0.9 cm. There were 7 clinical diagnoses of lipoatrophy in the 3TC/ZDV + EFV arm compared with none in the FTC/TDF + EFV arm. The proportion of overweight or obese participants increased from 25% (week 0) to 42% (week 144) for FTC/TDF + EFV and from 26% to 38% for 3TC/ZDV + EFV. Conclusions. Our findings support first-line use of FTC/TDF + EFV in resource-limited settings and emphasize the need for interventions to limit weight gain among overweight or obese HIV-infected participants in all settings