First-line Antiretroviral Therapy Research Articles

Late presentation for HIV impairs immunological but not virological response to antiretroviral treatment.

The aim of this study was to examine the impact of late presentation (CD4+ cell count <350 cells/μl or an AIDS-defining event) on effectiveness and safety of initial antiretroviral therapy (ART) and to evaluate whether treatment response depends on first-line ART regimen in late presenters. ART-naive adults from the Cohort of the Spanish HIV/AIDS Research Network (CoRIS) starting triple ART between 2010 and 2018. We used multivariable models to assess differences in viral suppression (viral load <50 copies/ml), immunological response (change in CD4+ cell count, CD4% (>29%) and CD4/CD8 normalization (>0.4 and >1) multiple T-cell marker recovery (MTMR): CD4+ cell count more than 500 cells/μl and CD4% >29% and CD4/CD8 >1), and treatment discontinuation due to adverse events (TDAE) at 48 weeks from ART initiation. Out of 8002 participants, 48.7% were late presenters. Of them, 45.8% initiated ART with a NNRTI- (mostly TDF/FTC/EFV), 33.9% with a protease inhibitor (mostly TDF/FTC+boosted DRV) and 20.3% with an INI-based regimen (mostly ABC/3TC/DTG). At 48 weeks, late presenters had similar viral suppression, but worse immunological response, than non-late presenters with no difference on TDAE. Late presenters initiating with NNRTI-based regimens were more likely to achieve viral suppression than those starting with INI-based, due to the higher chance of achieving viral suppression observed with TDF/FTC/RPV compared to ABC/3TC/DTG. Initial treatment with NNRTI or protease inhibitor based showed similar immunological response than the INI-based regimens, which showed lower rates of TDAE than NNRTI- and protease inhibitor based regimens. Despite safety and effectiveness of initial ART in terms of viral suppression, late presenters may not experience complete immunological response. In late presenters, effectiveness and safety depends on both the class and the specific first-line ART regimen.

The relationship between T-CD4 recovery and HIV disclosure status among HIV-infected patients on first-line antiretroviral therapy at the Hospital for Tropical Diseases in Ho Chi Minh City

Objective: Establishes a relationship between T-CD4 recovery and patient’s HIV disclosure status. Methods: Cross-section and clinical record review study on 151 HIV-infected patients who were 18 years old or above on first-line antiretroviral therapy (1) for 18 to 36 months at the Hospital for Tropical Diseases in Ho Chi Minh city (HCMC) in 2019. Participants are selected by convenient method. Research conducted face-to-face interviewing participants by structured questionnaire and collected data directly from each participant's respective medical record, including duration of ART, number of T-CD4 at the beginning of ART, number of current T-CD4. Results: The results showed that within patients who revealed HIV infection to other people, the patients who revealed to their brothers and sisters recovered T-CD4 were 1.45 times more effective (95% CI: 1.09 – 1.93) compared with patients who did not disclose to siblings (p = 0.010). Conclusion: Family members, especially siblings need to care and share so that HIV-infected patients can disclose their status. In particular, wife, husband or partners need to help and motivate patients more to make the patient's treatment better. Keywords: ART, T-CD4, recovery, HIV, disclosure.

Clinical and Public Health Implications of HIV- Genetic Diversity and Drug Resistance Mutations in Angola: A Systematic Review.

HIV-1 genetic diversity and drug resistance mutations (DRMs) remain a public health concern mainly in low- and middle-income countries. In this review, we estimated the HIV-1 molecular evolution over the past 40 years (1980-2019) in Angola to help guide affordable strategies for HIV-1 epidemic surveillance. We searched for studies written in English or Portuguese on HIV-1 diversity and DRMs carried out in Angola and published between 1980 and 2019. This review yielded eight studies describing a total of 493 samples. No HIV-1 Group N, O, and P were identified, whereas a ll non-B subtypes f rom Group M were identified. About 66% of HIV-1 subtypes were pure subtype and 34% recombinant strains. The frequency of recombinant strains increases from 1980 to 2019 (23.6%-41.4%, p<0.001). The subtypes C, F1, CRF02_AG, and the recombinant U/H were the most frequent. One DRM in the PIs was found (I54 M), 22 in the nucleoside reverse transcriptase inhibitors (NRTIs), and 18 in the non-nucleoside reverse transcriptase inhibitors (NNRTIs). The major DRM in the NRTIs was the M184V, whereas the G190A, K103N, and Y181C were the major DRMs in the NNRTIs. Over the past 40 years, the frequency of the DRM M184V (50-64.3%, p=0.363), G190A (17.2-46.2%, p=0.021), and K103N (34.5-42.3%, p=0.551) increased, while the frequency of Y181C (17.2-7.7%, p=0.289) decreased. The current review shows an increase in HIV-1 genetic complexity and DRMs in Angola. Our findings suggest the need to include PIs or integrase strand transfer inhibitors in the first-line antiretroviral therapy regimens in Angola.

Addressing Pediatric HIV Pretreatment Drug Resistance and Virologic Failure in Sub-Saharan Africa: A Cost-Effectiveness Analysis of Diagnostic-Based Strategies in Children ≥3 Years Old.

Improvement of antiretroviral therapy (ART) regimen switching practices and implementation of pretreatment drug resistance (PDR) testing are two potential approaches to improve health outcomes for children living with HIV. We developed a microsimulation model of disease progression and treatment focused on children with perinatally acquired HIV in sub-Saharan Africa who initiate ART at 3 years of age. We evaluated the cost-effectiveness of diagnostic-based strategies (improved switching and PDR testing), over a 10-year time horizon, in settings without and with pediatric dolutegravir (DTG) availability as first-line ART. The improved switching strategy increases the probability of switching to second-line ART when virologic failure is diagnosed through viral load testing. The PDR testing strategy involves a one-time PDR test prior to ART initiation to guide choice of initial regimen. When DTG is not available, PDR testing is dominated by the improved switching strategy, which has an incremental cost-effectiveness ratio (ICER) of USD 579/life-year gained (LY), relative to the status quo. If DTG is available, improved switching has a similar ICER (USD 591/LY) relative to the DTG status quo. Even when substantial financial investment is needed to achieve improved regimen switching practices, the improved switching strategy still has the potential to be cost-effective in a wide range of sub-Saharan African countries. Our analysis highlights the importance of strengthening existing laboratory monitoring systems to improve the health of children living with HIV.

Gender disparities operate in opposite directions for hospitalizations and mortality among individuals receiving long-term ART in rural Uganda.

We conducted an analysis to determine if differences in health-seeking behaviour can explain gender disparities in mortality among long-term survivors receiving antiretroviral therapy (ART) in rural Uganda. From June 2012 to January 2014, we enrolled patients receiving a first-line ART regimen for at least 4 years without previous viral load (VL) testing in Jinja, Uganda. We measured HIV VL at study entry. We switched participants to second-line therapy, if VL was≥1000 copies/mL on two measurements, and followed participants for 3 years. We collected clinical and behavioural data at enrolment and every 6 months after that. We used Poisson regression to examine factors associated with hospitalizations and Cox proportional hazards modelling to assess mortality to September 2016. We enrolled 616 participants (75.3% female), with a median age of 44years and a median duration of ART use of 6years. Of these, 113 (18.3%) had VLs≥1000 copies/mL. Hospitalizations occurred in 101 participants (7% of men vs. 20% of women; P<0.001). A total of 22 (3.6%) deaths occurred, 9% of men vs. 2% of women (P<0.001). Multivariate modelling revealed that mortality was associated with age [adjusted hazard ratio (AHR)=1.07 per year increase; 95% confidence interval (CI): 1.01-1.13], male gender (AHR=2.57; 95% CI 1.06-6.23) and time-updated CD4 counts (AHR=0.67 per 100 cell increment; 95% CI: 0.52-0.88). Virological failure was not associated with mortality (P=0.762). Female patients receiving ART in rural Uganda were three times more likely to be hospitalized than men, but male mortality was nearly four times higher. Facilitating care for acute medical problems may help to improve survival among male ART patients.

Neurocognitive Trajectories After 72 Weeks of First-Line Anti-retroviral Therapy in Vietnamese Adults With HIV-HCV Co-infection.

Background: Long-term neurocognitive outcomes following first-line suppressive anti-retroviral therapy (ART) remain uncertain for individuals with HIV and hepatitis C (HCV) co-infection. The study examined neurocognitive performance before and after 72 weeks of ART using repeated multivariate analyses and latent trajectory models.Methods: One hundred and sixty adults with chronic, untreated HIV infection (n = 80 with HCV co-infection and n = 80 HIV mono-infected) and 80 demographically similar healthy controls were recruited from the Hospital for Tropical Diseases in Ho Chi Minh City and the surrounding community, respectively. Neurocognitive measures (adapted for use in Vietnam) and liver enzyme tests were compared across groups at baseline. Repeated multivariate and group-based trajectory analyses (GBTA) examined neurocognitive subgroup profiles of the co-infected individuals after 72 weeks of de novo efavirenz- (n = 41) or raltegravir-based (n = 39) ART.Results: Baseline analyses revealed worse motor function in HIV-HCV co-infected individuals compared to both comparison groups. Longitudinal analyses revealed improved neurocognitive performance by week 48 for most participants regardless of treatment arm. GBTA identified a subgroup (35% of HIV-HCV sample) with persistent motor impairment despite otherwise successful ART. Higher HIV viral load and lower CD4+ T cell count at baseline predicted persistent motor dysfunction. Liver indices and ART regimen did not predict neurocognitive outcomes in HIV-HCV co-infected individuals.Conclusions: Most HIV-HCV co-infected individuals achieve normative neurocognitive performance after 48 weeks of de novo suppressive ART. However, individuals with more severe HIV disease prior to ART exhibited motor impairment at baseline and 72 weeks after otherwise successful treatment. Interventions aimed at improving motor symptoms at the time of HIV treatment onset may improve long-term clinical outcomes in HIV-HCV co-infected adults.

Survival, CD4 T lymphocyte count recovery and immune reconstitution pattern during the first-line combination antiretroviral therapy in patients with HIV-1 infection in Mongolia.

Mongolia has a low incidence of human immunodeficiency virus (HIV) infection, with 281 cases reported at the end of 2019 and an estimated incidence rate of <0.01 cases per 1000 population.However, no study has analyzed the association between antiretroviral therapy (ART) outcomes and pretreatment characteristics of patients with HIV/acquired immunodeficiency syndrome (AIDS) in Mongolia. This retrospective study aimed to determine the survival, CD4 T cell recovery, and immune reconstitution pattern during ART in HIV patients and to determine baseline patient characteristics associated with ART outcomes. Based on three different World Health Organization (WHO) guidelines, we analyzed the 3-year observation data of 166 patients with HIV/AIDS who received treatment between 2010 and 2017. An increase of >50 cells/μL indicated CD4 T cell count recovery, and a cell count of ≥500 cells/μL in patients with a baseline cell count of <500 cells/μL indicated immune reconstitution. In this study, the 3- and 1-year mortality rates were 5.4% (survival rate: 94.6%) and 3.6%, respectively. A total of 83% of deaths that occurred in the observation time occurred within the first 3 months. The CD4 T cell count recovery rates at 3, 12, and 36 months were 62.7%, 80.7%, and 89.2%, respectively. The CD4 T cell count increased to >500 cells/μL in 95 of 145 (65.5%) patients with a baseline cell count of <500 cells/μL after 36 months of ART. The baseline CD4 T cell count was found to be a sensitive indicator for immune reconstitution. An advanced pretreatment clinical stage of HIV infection (as classified by the WHO classification), a low CD4 T cell count in the peripheral blood, and a high viral load before the initiation of the first-line ART accurately predicted survival, CD4 T cell count recovery, and immune reconstitution in Mongolian patients with HIV/AIDS.

High virological failure rates in HIV-1 perinatally infected children in South Africa: A retrospective cohort study.

Large cohorts of HIV-1 perinatally infected children with long-term follow-up in developing countries are limited. To explore rates and predictors of virological failure in a paediatric cohort. A 10-year retrospective study was conducted from January 2004 to December 2013 to determine the incidence of and factors associated with virological failure among 1 659 HIV perinatally infected children in a public sector setting in South Africa (SA). Children aged &lt;17 years who initiated first-line antiretroviral therapy between 1 January 2004 and 31 December 2013 and had at least 5 years of HIV viral load measurements were eligible. The 1 659 children contributed 7 075 person-years of follow-up (PYFU). In the initial cohort of 2024 children, 51.0% were male and 62.0% were aged &lt;5 years. The incidence of virological failure was 18.7 per 100 PYFU. Virological failure was associated with male gender, death of the mother, concurrent tuberculosis treatment and World Health Organization stage IV disease. Of the 320 HIV isolates successfully amplified, 249 (77.8%) had drug resistance mutations. We observed high rates of virological failure and emergence of HIV drug resistance mutations. Despite gains made by SA in the treatment of HIV, such results challenge the country's ability to meet global targets of 90% viral suppression by 2020.

Standard versus double dose dolutegravir in patients with HIV-associated tuberculosis: a phase 2 non-comparative randomised controlled (RADIANT-TB) trial

Dolutegravir, a second-generation integrase strand transfer inhibitor (InSTI), is replacing efavirenz as first-line antiretroviral therapy (ART) in low middle-income countries (LMICs). Tuberculosis remains the leading cause of HIV-related morbidity and mortality in LMICs. Rifampicin is a key agent in the treatment of tuberculosis but induces genes involved in dolutegravir metabolism and efflux. The resulting drug-drug interaction (DDI) reduces the exposure of dolutegravir. However, this can be overcome by supplying a supplemental dose of 50 mg dolutegravir 12 hours after the standard daily dose, which is difficult to implement in LMICs. Four lines of evidence suggest that the supplemental dose may not be necessary: 1) a phase 2 study showed 10 mg of dolutegravir as effective as 50 mg; 2) the prolonged dissociative half-life of dolutegravir after binding to its receptor; 3) a DDI study reported dolutegravir trough concentrations were maintained above its minimum effective concentration when using 50 mg dolutegravir with rifampicin; and 4) virologic outcomes were similar between standard and double dose of raltegravir (a first-generation InSTI) in participants with HIV-associated tuberculosis treated with rifampicin. We hypothesise that virologic outcomes with standard dose dolutegravir-based ART will be acceptable in patients on rifampicin-based antituberculosis therapy. Here we outline the protocol for a phase 2, non-comparative, randomised, double-blind, placebo-controlled trial of standard versus double dose dolutegravir among adults living with HIV (ART naïve or first-line interrupted) on rifampicin-based antituberculosis therapy. A total of 108 participants will be enrolled from Khayelitsha in Cape Town, South Africa. Follow up will occur over 48 weeks. The primary objective is to assess proportion virological suppression at 24 weeks between groups analysed by modified intention to treat. Participant safety and the emergence of antiretroviral resistance mutations among those with virologic failure will be assessed throughout. Trial registrations: clinicaltrials.gov NCT03851588 (22/02/2019), SANCTR DOH-27-072020-8159 (03/07/2020).

Detection of Drug Resistance Mutations in the Reverse Transcriptase Gene of HIV-1-Infected North Indian Population Failing First-Line Antiretroviral Therapy "A Follow-Up Cohort Study".

We aim to characterize the drug resistance mutations in reverse transcriptase gene of HIV-1 subtype C-infected North Indian population in those who are failing first-line antiretroviral therapy (ART) and if these mutations are associated with mortality. We also attempted the assessment of switch over to second-line antiretroviral therapy in these patients. Based on the immunological marker CD4 count (<350 cubic/mm), 192 HIV/AIDS patients were selected and viral load was estimated in those who were enrolled from December 2009 to November 2016. Based on viral load, genotyping was carried out in 57 HIV-1 isolates (VL ≥1,000 copies/mL) by sequencing and drug resistance mutations were examined through the Stanford HIV Drug Resistance Database, USA. Among them, 21 (36.84%) first-line ART failure patients were shifted to second-line ART. These patients were followed for a period wide ranging from 10 months to 11 years. Drug resistance mutation M184V (ATG to GTA) (63.15%) associated with lamivudine and abacavir and K103N (AAG or AAA to AAU) (36.84%) associated with efavirenz and nevirapine were predominantly identified in first-line ART failure patients. During follow-up, it was observed that 3 out of 21 who were in second-line ART died, whereas 9 out of 36 died who were in the first-line ART. No mutation could be associated with mortality although TAM-2 mutations were absent in patients who died. This study indorses the need for a facility for viral load estimation and resistance monitoring in each treatment failure patient and availability of appropriate antiretroviral therapies.

Pre-treatment integrase inhibitor resistance is uncommon in antiretroviral therapy-naive individuals with HIV-1 subtype A1 and D infections in Uganda.

Dolutegravir (DTG) is now a preferred component of first-line antiretroviral therapy (ART). However, prevalence data on natural resistance to integrase inhibitors [integrase strand transfer inhibitors (INSTIs)] in circulating non-subtype B HIV-1 in sub-Saharan Africa is scarce. Our objective is to report prevalence of pre-treatment integrase polymorphisms associated with resistance to INSTIs in an ART-naive cohort with diverse HIV-1 subtypes. We retrospectively examined HIV-1 integrase sequences from Uganda. Plasma samples were derived from the Uganda AIDS Rural Treatment Outcomes (UARTO) cohort, reflecting enrollment from 2002 to 2010, prior to initiation of ART. HIV-1 integrase was amplified using nested-PCR and Sanger-sequenced (HXB2 4230-5093). Stanford HIVdb v8.8 was used to infer clinically significant INSTI-associated mutations. Human leukocyte antigen (HLA) typing was performed for all study participants. Plasma samples from 511 ART-naive individuals (subtype: 48% A1, 39% D) yielded HIV-1 integrase genotyping results. Six out of 511 participants (1.2%) had any major INSTI-associated mutations. Of these, two had E138T (subtype A1), three had E138E/K (subtype D), and one had T66T/I (subtype D). No participants had mutations traditionally associated with high levels of INSTI resistance. HLA genotypes A∗02:01/05/14, B∗44:15, and C∗04:07 predicted the presence of L74I, a mutation recently observed in association with long-acting INSTI cabotegravir virologic failure. We detected no HIV-1 polymorphisms associated with high levels of DTG resistance in Uganda in the pre-DTG era. Our results support widespread implementation of DTG but careful monitoring of patients on INSTI with virologic failure is warranted to determine if unique mutations predict failure for non-B subtypes of HIV-1.

The Impact of Same-Day Antiretroviral Therapy Initiation Under the World Health Organization Treat-All Policy.

Rapid initiation of antiretroviral therapy (ART) is recommended for people living with human immunodeficiency virus (HIV), with the option to start treatment on the day of diagnosis (same-day ART). However, the effect of same-day ART remains unknown in realistic public sector settings. We established a cohort of ≥16-year-old patients who initiated first-line ART under a treat-all policy in Nhlangano (Eswatini) during 2014–2016, either on the day of HIV care enrollment (same-day ART) or 1–14 days thereafter (early ART). Directed acyclic graphs, flexible parametric survival analysis, and targeted maximum likelihood estimation (TMLE) were used to estimate the effect of same-day-ART initiation on a composite unfavorable treatment outcome (loss to follow-up, death, viral failure, treatment switch). Of 1,328 patients, 839 (63.2%) initiated same-day ART. The adjusted hazard ratio of the unfavorable outcome was higher, 1.48 (95% confidence interval: 1.16, 1.89), for same-day ART compared with early ART. TMLE suggested that after 1 year, 28.9% of patients would experience the unfavorable outcome under same-day ART compared with 21.2% under early ART (difference: 7.7%; 1.3%–14.1%). This estimate was driven by loss to follow-up and varied over time, with a higher hazard during the first year after HIV care enrollment and a similar hazard thereafter. We found an increased risk with same-day ART. A limitation was that possible silent transfers that were not captured.

Pretreatment HIV Drug Resistance Among Adults Initiating or Re-Initiating First-Line Antiretroviral Therapy in Zimbabwe: Fast-Tracking the Transition to Dolutegravir-Based First-Line Regimens?

Pretreatment drug resistance (PDR) can compromise antiretroviral therapy (ART) efficacy and undermine the WHO targets to end the AIDS epidemic as a public health threat by 2030. Thus, we examined the level of PDR in Harare, Zimbabwe. Eligible study participants were adults who were ART naive or individuals with previous ART exposure reinitiating treatment, recruited between October 2018 and February 2020 in a HIV ART treatment clinic, in Harare. HIV drug resistance tests were performed for all specimens with viral load ≥400 copies/mL and interpreted using the Stanford HIVDB Algorithm. Chi-square test or Fisher's exact test was used for comparison of proportions of PDR across ART-naive or prior ART-exposed participants. All statistical analyses were performed using Stata version 14. Overall, 120 samples were genotyped of whom 104 were ART naive and 16 reported previous ART exposure. The overall PDR frequency among all participants was 31% [95% confidence interval (CI): 22.5-39.6]. PDR to any non-nucleotide reverse transcriptase inhibitor (NNRTI) was reported in 29% (95% CI: 21.0-37.9). PDR to nucleotide reverse transcriptase inhibitors (NRTIs) and protease inhibitors were low, found in 3% (95% CI: 0.9-8.2) and 1% (95% CI: 0.02-4.52), respectively. PDR to NNRTIs [efavirenz/nevirapine (EFV/NVP)] was found in 17% (95% CI: 10.5-24.6) and was more than six times higher among people with previous ART exposure than ART-naive people: 63% versus 10%, p < .001. Our study shows that PDR to NNRTIs in Zimbabwe has remarkably increased from the 10.9% prevalence reported in the 2016 WHO survey. Addressing PDR at a national level is a critical need and will be facilitated by fast-tracking the transition to dolutegravir in first-line ART regimens.

Assessment of atherosclerotic cardiovascular disease risks between people living with HIV receiving first-line and second-line antiretroviral therapy in a resource-limited setting.

Cardiovascular disease has become an important health problem in people living with HIV (PLHIV) who receive antiretroviral therapy (ART). Atherosclerotic cardiovascular disease (ASCVD) risk score is a non-invasive tool to estimate the 10-year risk for ASCVD. A cross-sectional study was conducted among PLHIV receiving ART in a resource-limited setting, in order to assess the 10-year ASCVD risk between PLHIV receiving first-line and second-line ART. Of 460 participants with a mean age of 51.2years, 262 (57.0%) were men. The mean duration of HIV infection was 14.7years and the mean CD4 cell count was 509cells/μL. Of all, 345 participants were receiving first-line ART and 115 were receiving second-line ART. The median 10-year ASCVD risk was 3.0% and 5.1% in the first-line and second-line ART groups, respectively (p = 0.029). The prevalence of a high 10-year ASCVD risk (≥20%) was significantly higher in the second-line ART group (3.5% vs 0.9%, p = 0.048). In multivariate analysis, receiving second-line ART was significantly associated with intermediate to high 10-year ASCVD risk (OR = 2.952; 95% CI, 1.656-6.997; p = 0.015). Atherosclerotic cardiovascular disease risk should be assessed in PLHIV, particularly those who receive second-line ART.

Drivers of HIV-1 Drug Resistance to Non-Nucleoside Reverse-Transcriptase Inhibitors (NNRTIs) in Nine African Countries: A Modelling Study

Background: The rise of HIV-1 drug resistance to non-nucleoside reverse-transcriptase inhibitors (NNRTI) threatens antiretroviral therapy (ART) programmes' long-term success. NNRTIs will likely remain an essential drug for the management of HIV-1 due to the adverse effects and safety concerns associated with integrase inhibitors. Mathematical models can contribute to a better understanding of the mechanisms that shape the HIV-1 epidemic and the rise of NNRTI pretreatment resistance in a country. We fitted a dynamic transmission model to data 2000-2018 from nine countries of southern Africa. Methods: We included data on HIV-1 prevalence, ART coverage, HIV-related mortality, and survey data on NNRTI pretreatment drug resistance from Botswana, Eswatini, Lesotho, Malawi, Mozambique, Namibia, South Africa, Zambia, and Zimbabwe, from a systematic review, UNAIDS and the World Bank. Using a Bayesian hierarchical framework, we developed a dynamic transmission model linking the country-specific data on the HIV-1 epidemic to survey data on NNRTI drug resistance in each country. We estimated the proportion of resistance attributable to unregulated, off-programme use of ART. We examined the vulnerability of national ART programmes to NNRTI resistance by defining a fragility index: the ratio of the rate of NNRTI resistance emergence during first-line ART over the rate of switching to second-line ART. We explored associations between national ART programme's fragility and the characteristics of health systems and countries. Findings: The model reliably described the dynamics of the HIV-1 epidemic and NNRTI resistance in each country. Predicted levels of resistance in 2018 ranged between 3.3% (95% credible interval [CrI] 1.9 to 7.1%) in Mozambique and 25.3% (17.9 to 33.8%) in Eswatini. The proportion of NNRTI pretreatment drug resistance attributable to unregulated antiretroviral use ranged from 6% (95%CrI 2-14) in Eswatini to 64% (95%CrI 26-85) in Mozambique. The fragility index was low in Botswana (0.01; 95%CrI 0.0-0.11) but high in Namibia (0.48; 95% CrI 0.16-10.17), Eswatini (0.64; 95%CrI 0.23-11.8) and South Africa to 1.21 (95%CrI 0.83-9.84). The combination of high fragility of ART programmes and high levels of ART coverage was associated with a sharp increase in NNRTI pretreatment drug resistance. Interpretation: This comparison of nine countries shows that NNRTI pretreatment drug resistance can be controlled despite high ART coverage levels, as in Botswana, Mozambique, or Zambia, most likely because of better HIV care delivery, including rapid switching to second-line ART of patients failing first-line ART. Funding Statement: National Institute of Allergy and Infectious Diseases (grant 5U01-AI069924-05) and Swiss National Science Foundation (grant 174281). Declaration of Interests: We declare no conflict of interest.

Protocol for a randomised feasibility study of Point-Of-care HIV viral load testing to Enhance Re-suppression in South Africa: the POwER study

IntroductionAccess to HIV viral load testing remains difficult for many people on antiretroviral therapy (ART) in low-income and middle-income countries. Weak laboratory and clinic systems often delay the detection and...

Pharmacovigilance of Antiretroviral Drugs at B.P. Koirala Institute of Health sciences.

Antiretroviral drugs are lifeline for patients living with HIV. Adverse drug reactions can compromise the compliance to antiretroviral therapy. The objectives of the study were to estimate the prevalence of adverse drug reactions and to assess its risk factors in patients living with HIV and receiving antiretroviral therapy. A prospective cohort study was conducted among 496 patients living with HIV at B.P. Koirala Institute of Health Sciences for a period of one year. Adverse drug reactions were evaluated based upon clinical history, clinical examination and investigations. Majority of patients were of 31-45 year age group (58.1%) and on first-line antiretroviral therapy regimen (94.3%). Total of 240 adverse drug reactions were documented. Prevalence of adverse drug reaction was 34.7%. Skin rash, anemia and nausea and vomiting were the three most common adverse drug reactions. The adverse drug reactions were more common in patients having non-communicable diseases, chronic co-infections, taking more than 3 non-HIV drugs, second and third-line antiretroviral regimen and it was statistically significant (P-value < 0.05). Prevalence of adverse drug reaction was high in the patients living with HIV. Age, gender, co-infections, non-communicable diseases, taking more than three non-HIV drugs and second and third-line antiretroviral regimen were identified as possible risk factor for occurrence of adverse drug reactions and their prior identification is important to optimize the best suited antiretroviral regimen.

Dynamics of HIV-1 quasispecies diversity of participants on long-term antiretroviral therapy based on intrahost single-nucleotide variations

ObjectivesHuman immunodeficiency virus (HIV) quasispecies diversity presents a large barrier to the eradication of HIV. The aim of this study was to investigate intrahost HIV quasispecies diversity and evolutionary patterns underpinning the mechanisms of viral pathogenesis during antiretroviral therapy (ART). MethodsForty-five participants with HIV-1 infection were enrolled in a follow-up cohort for >84 months in 2004, and received a lamivudine-based first-line ART regimen. Blood samples were collected every 6 months to measure viral load and CD4+ cell count. Ultra-deep sequencing and phylogenetic analysis were used to characterize the dynamics governing quasispecies diversity of HIV-1 circulating between plasma RNA and cellular DNA of participants with treatment failure (TF, n = 20) or virologic suppression (VS, n = 25). ResultsAnalysis of the distribution of intrahost single-nucleotide variations (iSNVs) and their mutated allele frequencies revealed that approximately 65% of the quasispecies co-occurred in plasma HIV RNA and cellular DNA either before or after ART. The number and frequency of iSNVs are more representative of intrahost HIV diversity, and have better generalizability than phylogenetic inference by measurement of phylogenetic associations. Furthermore, drug-resistance-associated mutations (DRAMs) accumulated to high levels, dramatically increasing the DRAM-to-total-mutation ratio for TF patients. Linear regression analysis revealed that emergent mutations accumulated faster in TF patients compared with VS patients, at a rate of 0.02 mutations/day/kb. ConclusionsBased on iSNV analysis, the results demonstrate the dynamics of intrahost HIV quasispecies diversity in patients on ART, and provide a novel insight into the persistence of HIV and development of DRAMs.

Standard versus double dose dolutegravir in patients with HIV-associated tuberculosis: a phase 2 non-comparative randomised controlled (RADIANT-TB) trial.

Dolutegravir, a second-generation integrase strand transfer inhibitor (InSTI), is replacing efavirenz as first-line antiretroviral therapy (ART) in low middle-income countries (LMICs). Tuberculosis remains the leading cause of HIV-related morbidity and mortality in LMICs. Rifampicin is a key agent in the treatment of tuberculosis but induces genes involved in dolutegravir metabolism and efflux. The resulting drug-drug interaction (DDI) reduces the exposure of dolutegravir. However, this can be overcome by supplying a supplemental dose of 50 mg dolutegravir 12 hours after the standard daily dose, which is difficult to implement in LMICs. Four lines of evidence suggest that the supplemental dose may not be necessary: 1) a phase 2 study showed 10 mg of dolutegravir as effective as 50 mg; 2) the prolonged dissociative half-life of dolutegravir after binding to its receptor; 3) a DDI study reported dolutegravir trough concentrations were maintained above its minimum effective concentration when using 50 mg dolutegravir with rifampicin; and 4) virologic outcomes were similar between standard and double dose of raltegravir (a first-generation InSTI) in participants with HIV-associated tuberculosis treated with rifampicin. We hypothesise that virologic outcomes with standard dose dolutegravir-based ART will be acceptable in patients on rifampicin-based antituberculosis therapy. Here we outline the protocol for a phase 2, non-comparative, randomised, double-blind, placebo-controlled trial of standard versus double dose dolutegravir among adults living with HIV (ART naïve or first-line interrupted) on rifampicin-based antituberculosis therapy. A total of 108 participants will be enrolled from Khayelitsha in Cape Town, South Africa. Follow up will occur over 48 weeks. The primary objective is to assess proportion virological suppression at 24 weeks between groups analysed by modified intention to treat. Participant safety and the emergence of antiretroviral resistance mutations among those with virologic failure will be assessed throughout. Trial registrations: clinicaltrials.gov NCT03851588 (22/02/2019), SANCTR DOH-27-072020-8159 (03/07/2020).

Non-communicable Diseases in Pregnant and Postpartum Women Living with HIV: Implications for Health Throughout the Life Course.

The development of non-communicable diseases (NCDs) in pregnant women living with HIV can be a harbinger of future NCD-related morbidity and mortality. This review focuses on the NCDs that complicate pregnancy and the postpartum period, including hypertensive complications, hyperglycemic disorders, excessive gestational weight gain, and bone mineral density losses. For each disease process, we explore the role of HIV as a possible driver of excess risk, the immediate consequences of these complications on pregnancy outcomes and maternal and infant health, and possible implications for long-term women's health. Countries with the highest burden of HIV also shoulder a high burden of NCDs that complicate pregnancy, including hypertensive disorders, hyperglycemic disorders, weight gain, and osteopenia. This double burden of disease is a significant public health threat for reproductive-age women, with the potential for serious short- and long-term consequences for both women and their infants. Additionally, as the global first-line antiretroviral therapy regimens increasingly include integrase inhibitors, unhealthy weight gain associated with this drug class poses additional risk for NCD-related pregnancy complications and their persistence postpartum. Further research is needed to better define prevalence of NCD complications in pregnancy, elucidate HIV-specific and traditional factors associated with poor outcomes, and to develop interventions to reduce risk and avoid downstream complications in those at highest risk.