Treatment of HIV-1 infection in sub-Saharan Africa has many challenges. In this report, the safety and efficacy of three different regimens are assessed in HIV-1–infected persons in South Africa: ...tenofovir alafenamide fumarate (TAF)–emtricitabine (FTC)–dolutegravir (DTG), tenofovir disoproxil fumarate (TDF)–FTC–DTG, and the local standard-of-care regimen (TDF–FTC–efavirenz).
Abstract
Rapid advances in the potency, safety, and availability of modern HIV antiretroviral therapy (ART) have yielded a near-normal life expectancy for most people living with HIV (PLWH). ...Ironically, considering the history of HIV/AIDS (initially called “slim disease” because of associated weight loss), the latest dilemma faced by many people starting HIV therapy is weight gain and obesity, particularly Black people, women, and those who commenced treatment with advanced immunodeficiency. We review the pathophysiology and implications of weight gain among PLWH on ART and discuss why this phenomenon was recognized only recently, despite the availability of effective therapy for nearly 30 years. We comprehensively explore the theories of the causes, from initial speculation that weight gain was simply a return to health for people recovering from wasting to comparative effects of newer regimens vs prior toxic agents, to direct effects of agents on mitochondrial function. We then discuss the implications of weight gain on modern ART, particularly concomitant effects on lipids, glucose metabolism, and inflammatory markers. Finally, we discuss intervention options for PLWH and obesity, from the limitations of switching ART regimens or specific agents within regimens, weight-gain mitigation strategies, and potential hope in access to emerging antiobesity agents, which are yet to be evaluated in this population.
Long-acting antiretroviral drugs have emerged as exciting treatment and preexposure prophylaxis (PrEP) options for people with HIV and at risk of HIV. Long-acting regimens may improve dosing ...convenience, tolerability and cost compared with current daily-based oral therapy. They can also circumvent stigma associated with oral therapy for both treatment and PrEP, thereby improving adherence and outcomes. Yet, multiple challenges remain, many specific to low-income and middle-income countries (LMICs), where the epidemic is most concentrated and HIV prevention and treatment options are limited. To optimize the use of long-acting formulations, key outstanding questions must be addressed. Uncertain costing, scale-up manufacturing, complex delivery systems and implementation challenges are potential barriers when considering the scalability of long-acting ARVs for global use.
Excessive weight gain affects some HIV-positive individuals prescribed dolutegravir-containing regimens. Mechanisms underlying such weight gain are unknown.
Data and DNA from antiretroviral ...therapy-naïve participants who were randomized to initiate dolutegravir with emtricitabine plus either tenofovir alafenamide (TAF) or tenofovir disoproxil fumarate (TDF) in the ADVANCE study (NCT03122262) were used to characterize associations between human genetic polymorphisms and magnitude of weight gain.
Associations with percent weight gain from baseline to week 48 were assessed using multivariable linear regression models. Primary analyses a priori considered 59 polymorphisms and 10 genes of potential relevance to dolutegravir, TAF, or TDF pharmacokinetics. We also explored genome-wide associations.
Among the 314 (92%) of 340 dolutegravir recipients who were successfully genotyped, 160 (47%) and 154 (45%) were randomized to TAF/emtricitabine and TDF/emtricitabine, respectively. In target gene analyses, the lowest P-values for the dolutegravir and tenofovir groups were ABCG2 rs4148149 (P = 7.0 × 10-4) and ABCC10 rs67861980 (P = 1.0 × 10-2), respectively, which were not significant after correction for multiple testing. In genome-wide analyses, the lowest P-values were rs7590091 in TMEM163 (P = 3.7 × 10-8) for dolutegravir, rs17137701 in LOC105379130 (P = 6.4 × 10-8) for TAF, and rs76771105 in LOC105371716 (P = 9.7 × 10-8) for TDF.
Among South African participants in a randomized clinical trial of dolutegravir plus either TAF/emtricitabine or TDF/emtricitabine, we identified several potential genetic associations with weight gain. Only TMEM163 rs7590091 withstood correction for multiple testing. These associations warrant replication in other cohorts.
OBJECTIVE:Dolutegravir exposure at conception was associated with a preliminary signal of increased infant neural tube defect (NTD) risk. As low maternal folate levels are linked with NTDs, we aimed ...to assess serum folate concentrations in women starting dolutegravir.
DESIGN:We analysed serum folate concentrations from stored plasma among women enrolled in the South African ADVANCE trial.
METHODS:We compared changes in mean serum folate and occurrence of low serum folate (<14.0 nmol/L) at weeks 0, 12 and 24 across study arms. In ADVANCE, 1,053 treatment-naïve participants were randomised to initiate tenofovir-alafenamide/emtricitabine + dolutegravir (TAF/FTC+DTG), tenofovir-disoproxil-fumarate (TDF)/FTC+DTG, or TDF/FTC/efavirenz (EFV).
RESULTS:Analysis includes 406 females, mean age 31.5 years and baseline CD4 count 356 cells/mm. At baseline, folate concentrations were similar across treatment arms. However, serum folate increased over 12 weeks in the TAF/FTC+DTG arm (+4.0 ± 8.1 nmol/L), while folate concentrations decreased slightly in the TDF/FTC+DTG arm (-1.8 ± 8.9 nmol/L) and decreased in the TDF/FTC/EFV arm (-5.9 ± 8.1 nmol/L). Women taking TDF/FTC/EFV had low folate concentrations at both 12 and 24 weeks compared with the other arms (p < 0.001). Of 26 women who became pregnant on study before week 24, folate concentrations increased between baseline and 12 weeks by a mean 2.4 ± 7.1 nmol/L in the TAF/FTC+DTG arm and 2.3 ± 8.4 nmol/L in the TDF/FTC+DTG arm, but decreased by -3.3 ± 8.1 with TDF/FTC/EFV arm.
CONCLUSIONS:Unexpectedly, no declines were noted in the dolutegravir-containing arms, and concentrations were considerably higher than in the efavirenz arm. The possibility that dolutegravir may block cellular uptake of folate warrants investigation.
Syphilis, 'the great imitator', caused by
infection, remains a complex and multifaceted disease with a rich history of clinical diversity. This guideline aims to be a comprehensive guide for ...healthcare workers in Southern Africa, offering practical insights into the epidemiology, pathogenesis, clinical manifestations, diagnostic testing, therapeutic principles, and public health responses to syphilis. Although the syphilis burden has declined over the years, recent data indicate a troubling resurgence, particularly among pregnant women and neonates. This guideline highlights the diagnostic challenges posed by syphilis, stemming from the absence of a single high-sensitivity and -specificity test. While treatment with penicillin remains the cornerstone of treatment, alternative regimens may be used for specific scenarios. We highlight the importance of thorough patient follow-up and management of sex partners to ensure optimal care of syphilis cases. In the context of public health, we emphasise the need for concerted efforts to combat the increasing burden of syphilis, especially within high-risk populations, including people living with HIV.
Repeated COVID-19 waves and corresponding mitigation measures have impacted health systems globally with exceptional challenges. In response to the pandemic, researchers, regulators, and funders ...rapidly pivoted to COVID-19 research activities. However, many clinical drug studies were not completed, due to often complex and rapidly evolving research conditions.
We outline our experience of planning and managing a randomised, adaptive, open-label, phase 2 clinical trial to evaluate the safety and efficacy of four repurposed drug regimens versus standard-of-care (SOC) in outpatients with 'mild to moderate' COVID-19 in Johannesburg, South Africa, in the context of a partnership with multiple stakeholders. The study was conducted between 3 September 2020 and 23 August 2021 during changing COVID-19 restrictions, significant morbidity and mortality waves, and allied supply line, economic, and political instability.
Our clinical study design was pragmatic, including low-risk patients who were treated open label. There was built-in flexibility, including provision for some sample size adjustment and a range of secondary efficacy outcomes. Barriers to recruitment included the timing of waves, staff shortages due to illness, late presentation of patients, COVID-19 misinformation, and political unrest. Mitigations were the use of community health workers, deployment of mobile clinical units, and simplification of screening. Trial management required a radical reorganisation of logistics and processes to accommodate COVID-19 restrictions. These included the delivery of staff training and monitoring remotely, electronic consent, patient training and support to collect samples and report data at home, and the introduction of tele-medicine. These measures were successful for data collection, safe, and well received by patients.
Completing a COVID-19 trial in outpatients during the height of the pandemic required multiple innovations in nearly every aspect of clinical trial management, a high commitment level from study staff and patients, and support from study sponsors. Our experience has generated a more robust clinical research infrastructure, building in efficiencies to clinical trial management beyond the pandemic.
Dolutegravir, a component of the preferred first-line antiretroviral therapy regimen, has been associated with increased weight gain. South Africa has a high prevalence of obesity, especially among ...women. Understanding dolutegravir exposure in patients with obesity is important for dose optimisation.
We compared the pharmacokinetic parameters of dolutegravir in Southern African adults living with HIV with and without obesity.
Blood samples were collected at various time points over a 24 h-period for dolutegravir assays. Non-compartmental analysis was conducted and geometric mean ratios (GMRs), with 90% confidence intervals (CIs), were generated to compare dolutegravir pharmacokinetic parameters between the groups. Regression analyses to assess predictors of dolutegravir exposure were done.
Forty participants were enrolled, 26 were women and 10 had obesity. Dolutegravir area under the concentration-time curve to 24-h and the maximum concentrations were not statistically significantly lower in participants with obesity: GMR 0.91 (90% CI: 0.71-1.16) and GMR 0.86 (90% CI: 0.68-1.07), respectively. In a multivariate linear regression analysis adjusting for age, gender, body mass index, creatinine clearance and randomisation arm (tenofovir alafenamide or tenofovir disoproxil fumarate), a unit increase in body mass index was associated with 1.2% lower dolutegravir area under the concentration-time curve to 24-h (
= 0.035).
Dolutegravir exposure was marginally lower in participants with obesity, but this is not clinically significant. Our findings suggest that there is no need to dose adjust dolutegravir in people with obesity.
The Consortium for Advanced Research Training in Africa (CARTA) aims to transform higher education in Africa. One of its main thrusts is supporting promising university faculty (fellows) to obtain ...high quality doctoral training. CARTA offers fellows robust support which includes funding of their attendance at Joint Advanced Seminars (JASes) throughout the doctoral training period. An evaluation is critical in improving program outcomes. In this study; we, CARTA fellows who attended the fourth JAS in 2018, appraised the CARTA program from our perspective, specifically focusing on the organization of the program and its influence on the fellows' individual and institutional development.
Exploratory Qualitative Study Design was used and data was obtained from three focus group discussions among the fellows in March 2018. The data were analyzed using thematic approach within the framework of good practice elements in doctoral training-Formal Research Training, Activities Driven by Doctoral Candidates, Career Development as well as Concepts and Structures.
In all, 21 fellows from six African countries participated and all had been in the CARTA program for at least three years. The fellowship has increased fellows research skills and expanded our research capacities. This tremendously improved the quality of our doctoral research and it was also evident in our research outputs, including the number of peer-reviewed publications. The CARTA experience inculcated a multidisciplinary approach to our research and enabled significant improvement in our organizational, teaching, and leadership skills. All these were achieved through the well-organized structures of CARTA and these have transformed us to change agents who are already taking on research and administrative responsibilities in our various home institutions. Unfortunately, during the long break between the second and the third JAS, there was a gap in communication between CARTA and her fellows, which resulted in some transient loss of focus by a few fellows.
The CARTA model which builds the research capacity of doctoral fellows through robust support, including intermittent strategic Joint Advanced Seminars has had effective and transformative impacts on our doctoral odyssey. However, there is a need to maintain the momentum through continuous communication between CARTA and the fellows all through this journey.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
PDF
