Evaluation of Phylogenetic Methods for Inferring the Direction of Human Immunodeficiency Virus (HIV) Transmission: HIV Prevention Trials Network (HPTN) 052.

BACKGROUND: Phylogenetic analysis can be used to assess human immunodeficiency virus (HIV) transmission in populations. We inferred the direction of HIV transmission using whole-genome HIV sequences from couples with known linked infection and known transmission direction. METHODS: Complete next-generation sequencing (NGS) data were obtained for 105 unique index-partner sample pairs from 32 couples enrolled in the HIV Prevention Trials Network (HPTN) 052 study (up to 2 samples/person). Index samples were obtained up to 5.5 years before partner infection; partner samples were obtained near the time of seroconversion. The bioinformatics method, phyloscanner, was used to infer transmission direction. Analyses were performed using samples from individual sample pairs, samples from all couples (1 sample/person; group analysis), and all available samples (multisample group analysis). Analysis was also performed using NGS data from defined regions of the HIV genome (gag, pol, env). RESULTS: Using whole-genome NGS data, transmission direction was inferred correctly (index to partner) for 98 of 105 (93.3%) of the individual sample pairs, 99 of 105 (94.3%) sample pairs using group analysis, and 31 of the 32 couples (96.9%) using multisample group analysis. There were no cases where the incorrect transmission direction (partner to index) was inferred. The accuracy of the method was higher with greater time between index and partner sample collection. Pol region sequences performed better than env or gag sequences for inferring transmission direction. CONCLUSIONS: We demonstrate the potential of a phylogenetic method to infer the direction of HIV transmission between 2 individuals using whole-genome and pol NGS data.

The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Epidemic in Zimbabwe: Quo Vadis?

The trajectory and impact of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic in sub-Saharan Africa are unclear, but they are seemingly varied between different countries, with most reporting low numbers. We use the situation in Zimbabwe to build an argument that the epidemic is likely to be attenuated in some countries with similar socioeconomic and cultural structures. However, even an attenuated epidemic may overwhelm weak health systems, emphasizing the importance of prevention. These prevention strategies should be tailored to the unique social and cultural networks of individual countries, which may facilitate the spread of SARS-CoV-2. It is also equally important to maintain services for the major infectious diseases in the region, such as tuberculosis and malaria. A breakdown of treatment and prevention services for these conditions may even overshadow the projected morbidity and mortality from coronavirus disease 2019 (COVID-19).

Phylogenetic Methods Inconsistently Predict the Direction of HIV Transmission Among Heterosexual Pairs in the HPTN 052 Cohort.

BACKGROUND: We evaluated use of phylogenetic methods to predict the direction of human immunodeficiency virus (HIV) transmission. METHODS: For 33 pairs of HIV-infected patients (hereafter, "index patients") and their partners who acquired genetically linked HIV infection during the study, samples were collected from partners and index patients close to the time when the partner seroconverted (hereafter, "SC samples"); for 31 pairs, samples collected from the index patient at an earlier time point (hereafter, "early index samples") were also available. Phylogenies were inferred using env next-generation sequences (1 tree per pair/subtype). The direction of transmission (DoT) predicted from each tree was classified as correct or incorrect on the basis of which sequences (those from the index patient or the partner) were closest to the root. DoT was also assessed using maximum parsimony to infer ancestral node states for 100 bootstrap trees. RESULTS: DoT was predicted correctly for both single-pair and subtype-specific trees in 22 pairs (67%) by using SC samples and in 23 pairs (74%) by using early index samples. DoT was predicted incorrectly for 4 pairs (15%) by using SC or early index samples. In the bootstrap analysis, DoT was predicted correctly for 18 pairs (55%) by using SC samples and for 24 pairs (73%) by using early index samples. DoT was predicted incorrectly for 7 pairs (21%) by using SC samples and for 4 pairs (13%) by using early index samples. CONCLUSIONS: Phylogenetic methods based solely on the tree topology of HIV env sequences, particularly without consideration of phylogenetic uncertainty, may be insufficient for determining DoT.

Antiretroviral Therapy for the Prevention of HIV-1 Transmission.

BACKGROUND: An interim analysis of data from the HIV Prevention Trials Network (HPTN) 052 trial showed that antiretroviral therapy (ART) prevented more than 96% of genetically linked infections caused by human immunodeficiency virus type 1 (HIV-1) in serodiscordant couples. ART was then offered to all patients with HIV-1 infection (index participants). The study included more than 5 years of follow-up to assess the durability of such therapy for the prevention of HIV-1 transmission. METHODS: We randomly assigned 1763 index participants to receive either early or delayed ART. In the early-ART group, 886 participants started therapy at enrollment (CD4+ count, 350 to 550 cells per cubic millimeter). In the delayed-ART group, 877 participants started therapy after two consecutive CD4+ counts fell below 250 cells per cubic millimeter or if an illness indicative of the acquired immunodeficiency syndrome (i.e., an AIDS-defining illness) developed. The primary study end point was the diagnosis of genetically linked HIV-1 infection in the previously HIV-1-negative partner in an intention-to-treat analysis. RESULTS: Index participants were followed for 10,031 person-years; partners were followed for 8509 person-years. Among partners, 78 HIV-1 infections were observed during the trial (annual incidence, 0.9%; 95% confidence interval [CI], 0.7 to 1.1). Viral-linkage status was determined for 72 (92%) of the partner infections. Of these infections, 46 were linked (3 in the early-ART group and 43 in the delayed-ART group; incidence, 0.5%; 95% CI, 0.4 to 0.7) and 26 were unlinked (14 in the early-ART group and 12 in the delayed-ART group; incidence, 0.3%; 95% CI, 0.2 to 0.4). Early ART was associated with a 93% lower risk of linked partner infection than was delayed ART (hazard ratio, 0.07; 95% CI, 0.02 to 0.22). No linked infections were observed when HIV-1 infection was stably suppressed by ART in the index participant. CONCLUSIONS: The early initiation of ART led to a sustained decrease in genetically linked HIV-1 infections in sexual partners. (Funded by the National Institute of Allergy and Infectious Diseases; HPTN 052 ClinicalTrials.gov number, NCT00074581 .).

"Well, not me, but other women do not register because..."- Barriers to seeking antenatal care in the context of prevention of mother-to-child transmission of HIV among Zimbabwean women: a mixed-methods study.

BACKGROUND: While barriers to uptake of antenatal care (ANC) among pregnant women have been explored, much less is known about how integrating prevention of mother-to-child transmission (PMTCT) programmes within ANC services affects uptake. We explored barriers to uptake of integrated ANC services in a poor Zimbabwean community. METHODS: A cross-sectional survey was conducted among post-natal women at Mbare Clinic, Harare, between September 2010 and February 2011. Collected data included participant characteristics and ANC uptake. Logistic regression was conducted to determine factors associated with ANC registration. In-depth interviews were held with the first 21 survey participants who either did not register or registered after twenty-four weeks gestation to explore barriers. Interviews were analysed thematically. RESULTS: Two hundred and ninety-nine participants (mean age 26.1 years) were surveyed. They came from ultra-poor households, with mean household income of US$181. Only 229 (76.6%) had registered for ANC, at a mean gestation of 29.5 weeks. In multivariable analysis, household income was positively associated with ANC registration, odds ratio (OR) for a $10-increase in household income 1.02 (95% confidence interval, CI, 1.0-1.04), as was education which interacted with having planned the pregnancy (OR for planned pregnancy with completed ordinary level education 3.27 (95%CI 1.55-6.70). Divorced women were less likely to register than married women, OR 0.20 (95%CI 0.07-0.58). In the qualitative study, barriers to either ANC or PMTCT services limited uptake of integrated services. Women understood the importance of integrated services for PMTCT purposes and theirs and the babies' health and appeared unable to admit to barriers which they deemed "stupid/irresponsible", namely fear of HIV testing and disrespectful treatment by nurses. They represented these commonly recurring barriers as challenges that "other women" faced. The major proffered personal barrier was unaffordability of user fees, which was sometimes compounded by unsupportive husbands who were the breadwinners. CONCLUSION: Women who delayed/did not register were aware of the importance of ANC and PMTCT but were either unable to afford or afraid to register. Addressing the identified challenges will not only be important for integrated PMTCT/ANC services but will also provide a model for dealing with challenges as countries scale up 'treat all' approaches.

Hematological and biochemical laboratory reference intervals for Zimbabwean adolescents.

BACKGROUND: Reference intervals are used as an aid in the interpretation of laboratory results. Most developing countries do not have reference intervals specific to adolescents. This study was aimed at establishing hematological and biochemical reference intervals for adolescents aged ≥ 12 years to < 18 years. METHODS: A community based, cross sectional study was conducted using the multistage sampling technique. Participants were enrolled from the UZ-UCSF research study catchment areas of Harare, Chitungwiza, and Mutoko. Samples were transported for analysis at the UZ-UCSF Central Laboratory under recommended conditions. The data analysis presented in this paper is for 302 adolescents aged ≥ 12 to < 18. Non-parametric statistical methods were used to estimate the 95% reference limits for the hematological and biochemical parameters, with the lower limit defined as the 2.5 percentile and the upper limit defined as the 97.5 percentile of the distribution. RESULTS: A total of 302 adolescents were included. Results show significant differences between males and females in hematological parameters except platelets, eosinophils, basophils, and red cell distribution width. The biochemical parameters which showed significant differences between males and females were phosphate, ALP, ALT, AST, GGT, and lipase. CONCLUSIONS: Hematological indices and liver function tests differ significantly by gender and this should be considered when defining normal intervals.

Manuscript title: Facilitators and barriers to cotrimoxazole prophylaxis among HIV exposed babies: a qualitative study from Harare, Zimbabwe.

BACKGROUND: Implementation of cotrimoxazole prophylaxis (CTX-p) among HIV-exposed infants (HEI) is poor in southern Africa. We conducted a study to investigate barriers to delivery of CTX-p to HEI in Zimbabwe at each step of the care cascade. Here we report findings of the qualitative component designed to investigate issues related to adherence conducted among women identified as HIV positive whose babies were started on CTX-p postnatally. Of note, Zimbabwe also provided nevirapine prophylaxis for HIV exposed babies, so the majority were giving nevirapine and CTX-p to their babies. METHODS: Between Feb-Dec 2011, the first 20 HIV infected mothers identified were invited for in-depth interview 4-5months postnatally. Interviews were recorded, transcribed, translated and analysed thematically. RESULTS: All women desired their baby's health above all else, and were determined to do all they could to ensure their wellbeing. They did not report problems remembering to give drugs. The baby's apparent good health was a huge motivator for continued adherence. However, most women reported that their husbands were less engaged in HIV care, refusing to be HIV tested and in some cases stealing drugs prescribed for their wives for themselves. In two instances the man stopped the woman from giving CTX-p to the baby either because of fear of side effects or not appreciating its importance. Stigma continues to be an important issue. Mothers reported being reluctant to disclose their HIV status to other people so found it difficult to collect prescription refills from the HIV clinic for fear of being seen by friends/relatives. Some women reported that it was hard to administer the drugs if there were people around at home. Other challenges faced were stock-outs of CTX-p at the clinic, which occurred three times in 2011. The baby would then go without CTX-p if the woman could not afford buying at a private pharmacy. CONCLUSIONS: The study highlights that adherence knowledge and desire alone is insufficient to overcome the familial and structural barriers to maintaining CTX-p. Improving adherence to CTX-p among HEI will require interventions to improve male involvement, reduce HIV stigma in communities and ensure adequate supply of drugs.

Prevention of HIV-1 infection with early antiretroviral therapy.

BACKGROUND: Antiretroviral therapy that reduces viral replication could limit the transmission of human immunodeficiency virus type 1 (HIV-1) in serodiscordant couples. METHODS: In nine countries, we enrolled 1763 couples in which one partner was HIV-1-positive and the other was HIV-1-negative; 54% of the subjects were from Africa, and 50% of infected partners were men. HIV-1-infected subjects with CD4 counts between 350 and 550 cells per cubic millimeter were randomly assigned in a 1:1 ratio to receive antiretroviral therapy either immediately (early therapy) or after a decline in the CD4 count or the onset of HIV-1-related symptoms (delayed therapy). The primary prevention end point was linked HIV-1 transmission in HIV-1-negative partners. The primary clinical end point was the earliest occurrence of pulmonary tuberculosis, severe bacterial infection, a World Health Organization stage 4 event, or death. RESULTS: As of February 21, 2011, a total of 39 HIV-1 transmissions were observed (incidence rate, 1.2 per 100 person-years; 95% confidence interval [CI], 0.9 to 1.7); of these, 28 were virologically linked to the infected partner (incidence rate, 0.9 per 100 person-years, 95% CI, 0.6 to 1.3). Of the 28 linked transmissions, only 1 occurred in the early-therapy group (hazard ratio, 0.04; 95% CI, 0.01 to 0.27; P<0.001). Subjects receiving early therapy had fewer treatment end points (hazard ratio, 0.59; 95% CI, 0.40 to 0.88; P=0.01). CONCLUSIONS: The early initiation of antiretroviral therapy reduced rates of sexual transmission of HIV-1 and clinical events, indicating both personal and public health benefits from such therapy. (Funded by the National Institute of Allergy and Infectious Diseases and others; HPTN 052 ClinicalTrials.gov number, NCT00074581.).

Impact of second-line antiretroviral regimens on lipid profiles in an African setting: the DART trial sub-study.

BACKGROUND: Increasing numbers of HIV-infected patients in sub-Saharan Africa are exposed to antiretroviral therapy (ART), but there are few data on lipid changes on first-line ART, and even fewer on second-line. METHODS: DART was a randomized trial comparing monitoring strategies in Ugandan/Zimbabwean adults initiating first-line ART and switching to second-line at clinical/immunological failure. We evaluated fasting lipid profiles at second-line initiation and ≥48 weeks subsequently in stored samples from Zimbabwean patients switching before 18 September 2006. RESULTS: Of 91 patients switched to second-line ART, 65(73%) had fasting samples at switch and ≥48 weeks, 14(15%) died or were lost <48 weeks, 10(11%) interrupted ART for >14 days and 2(2%) had no samples available. 56/65(86%) received ZDV/d4T + 3TC + TDF first-line, 6(9%) ZDV/d4T + 3TC + NVP and 3(5%) ZDV + 3TC with TDF and NVP. Initial second-line regimens were LPV/r + NNRTI in 27(41%), LPV/r + NNRTI + ddI in 33(50%) and LPV/r + TDF + ddI/3TC/ZDV in 6(9%). At second-line initiation median (IQR) TC, LDL-C, HDL-C and TG (mmol/L) were 3.3(2.8-4.0), 1.7(1.3-2.2), 0.7(0.6-0.9) and 1.1(0.8-1.9) respectively. Levels were significantly increased 48 weeks later, by mean (SE) +2.0(0.1), +1.1(0.1), +0.5(0.05) and +0.4(0.2) respectively (p < 0.001; TG p = 0.01). 3% at switch vs 25% 48 weeks later had TC >5.2 mmol/L; 3% vs 25% LDL-C >3.4 mmol/L and 91% vs 41% HDL-C <1.1 mmol/L (p < 0.001). Similar proportions had TG >1.8 mmol/L (0 vs 3%) and TC/HDL-C ≥5 (40% vs 33%) (p > 0.15). CONCLUSION: Modest lipid elevations were observed in African patients on predominantly LPV/r + NNRTI-based second-line regimens. Routine lipid monitoring during second-line ART regimens may not be warranted in this setting but individual cardiovascular risk assessment should guide practice.

Feasibility and sustainability of an interactive team-based learning method for medical education during a severe faculty shortage in Zimbabwe.

BACKGROUND: In 2010, in the midst of the human immunodeficiency virus (HIV) epidemic in Zimbabwe, 69% of faculty positions in the Department of Medicine of the University of Zimbabwe College of Health Sciences (UZ-CHS) were vacant. To address the ongoing need to train highly skilled HIV clinicians with only a limited number of faculty, we developed and implemented a course for final-year medical students focused on HIV care using team-based learning (TBL) methods. METHODS: A competency-based HIV curriculum was developed and delivered to final-year medical students in 10 TBL sessions as part of a 12 week clinical medicine attachment. A questionnaire was administered to the students after completion of the course to assess their perception of TBL and self-perceived knowledge gained in HIV care. Two cohorts of students completed the survey in separate academic years, 2011 and 2012. Descriptive analysis of survey results was performed. RESULTS: Ninety-six of 120 students (80%) completed surveys. One hundred percent of respondents agreed that TBL was an effective way to learn about HIV and 66% strongly agreed. The majority of respondents agreed that TBL was more stimulating than a lecture course (94%), fostered enthusiasm for the course material (91%), and improved teamwork (96%). Students perceived improvements in knowledge gained across all of the HIV subjects covered, especially in challenging applied clinical topics, such as management of HIV antiretroviral failure (88% with at least a "large improvement") and HIV-tuberculosis co-infection (80% with at least a "large improvement"). CONCLUSIONS: TBL is feasible as part of medical education in an African setting. TBL is a promising way to teach challenging clinical topics in a stimulating and interactive learning environment in a low-income country setting with a high ratio of students to teachers.

Undisclosed antiretroviral drug use in a multinational clinical trial (HIV Prevention Trials Network 052).

The HIV Prevention Trials Network 052 study enrolled serodiscordant couples. Index participants infected with human immunodeficiency virus reported no prior antiretroviral (ARV) treatment at enrollment. ARV drug testing was performed retrospectively using enrollment samples from a subset of index participants. ARV drugs were detected in 45 of 96 participants (46.9%) with an undetectable viral load, 2 of 48 (4.2%) with a low viral load, and 1 of 65 (1.5%) with a high viral load (P < .0001); they were also detected in follow-up samples from participants who were not receiving study-administered treatment. ARV drug testing may be useful in addition to self-report of ARV drug use in some clinical trial settings.

Analysis of genetic linkage of HIV from couples enrolled in the HIV Prevention Trials Network 052 trial.

BACKGROUND: The HIV Prevention Trials Network (HPTN) 052 trial demonstrated that early initiation of antiretroviral therapy (ART) reduces human immunodeficiency virus (HIV) transmission from HIV-infected adults (index participants) to their HIV-uninfected sexual partners. We analyzed HIV from 38 index-partner pairs and 80 unrelated index participants (controls) to assess the linkage of seroconversion events. METHODS: Linkage was assessed using phylogenetic analysis of HIV pol sequences and Bayesian analysis of genetic distances between pol sequences from index-partner pairs and controls. Selected samples were also analyzed using next-generation sequencing (env region). RESULTS: In 29 of the 38 (76.3%) cases analyzed, the index was the likely source of the partner's HIV infection (linked). In 7 cases (18.4%), the partner was most likely infected from a source other than the index participant (unlinked). In 2 cases (5.3%), linkage status could not be definitively established. CONCLUSIONS: Nearly one-fifth of the seroconversion events in HPTN 052 were unlinked. The association of early ART and reduced HIV transmission was stronger when the analysis included only linked events. This underscores the importance of assessing the genetic linkage of HIV seroconversion events in HIV prevention studies involving serodiscordant couples.

Does trimethoprim-sulfamethoxazole prophylaxis for HIV induce bacterial resistance to other antibiotic classes? Results of a systematic review.

BACKGROUND: Trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis has long been recommended for immunosuppressed HIV-infected adults and children born to HIV-infected women. Despite this, many resource-limited countries have not implemented this recommendation, partly because of fear of widespread antimicrobial resistance not only to TMP-SMX, but also to other antibiotics. We aimed to determine whether TMP-SMX prophylaxis in HIV-infected and/or exposed individuals increases bacterial resistance to antibiotics other than TMP-SMX. METHODS: A literature search was conducted in Medline, Global Health, Embase, Web of Science, ELDIS, and ID21. RESULTS: A total of 501 studies were identified, and 17 met the inclusion criteria. Only 8 studies were of high quality, of which only 2 had been specifically designed to answer this question. Studies were classified as (1) studies in which all participants were infected and/or colonized and in which rates of bacterial resistance were compared between those taking or not taking TMP-SMX and (2) studies comparing those who had a resistant infection with those who were not infected. Type 1 studies showed weak evidence that TMP-SMX protects against resistance. Type 2 studies provided more convincing evidence that TMP-SMX protects against infection. CONCLUSION: There was some evidence that TMP-SMX prophylaxis protects against resistance to other antibiotics. However, more carefully designed studies are needed to answer the question conclusively.

HIV prevention in southern Africa: why we must reassess our strategies?

Southern Africa continues to shoulder a disproportionate burden of the HIV epidemic with the number of new infections outstripping treatment initiation two- to threefold. Current prevention strategies have had a limited impact on the trajectory of the epidemic so far. The history of HIV prevention research is dominated by failed approaches, but recent developments have provided reason for hope. These include the successful male circumcision outcomes in trials in South Africa, Kenya and Uganda, the recent protective outcome of a tenofovir vaginal gel trial in South Africa and the proof that pre-exposure prophylaxis with oral combination tenofovir/emtricitabine can work in men. The latter positive outcome has however been shattered by the early closure of FEM-PrEP for futility. The challenge now is on how to best integrate emerging prevention methods with established strategies, recognising that some of the older methods have never been scaled up to saturation level.

Prevalence and risk of residual viremia after ART in low- and middle-income countries: A cross-sectional study.

ABSTRACT: In order to design effective strategies to eradicate the HIV, an understanding of persistent viral reservoirs is needed. Many studies have demonstrated HIV residual viremia prevalence in high income countries, data from low- and middle-income countries (LMIC) are limited. We assessed the prevalence, and factors associated with residual viremia in people with HIV (PWH), who were virally-suppressed on antiretroviral therapy (ART) in LMIC. We also compared residual viremia prevalence between the LMIC and US.This is a cross-sectional, retrospective study that utilized stored specimen samples from the AIDS clinical trials group (ACTG) studies A5175 and A5208. The last available sample among participants with plasma HIV RNA < 400 copies/mL for ≥3 years were tested by the HIV molecular and monitoring core gag (HMMCgag) single copy assay (SCA). Residual viremia was defined as detectable if ≥1 copy/mL. Spearman's correlation and multivariable stepwise logistic regression were used to assess associations of various factors with SCA.A total of 320 participants, 246 (77%) from LMIC and 74 (23%) from US, were analyzed. Median (IQR) age was 33 (2840) years; baseline CD4 166 (88,230) cells/mm3; HIV RNA 5.0 (4.5, 5.3) log10 copies/mL; duration of viral suppression 3.4 (3.1, 4.0) years and 48% were male. In 85 participants with information available, 53% were subtype C, 42% subtype B and 5% other subtypes. Overall prevalence of residual viremia was 57% [95% CI, 52-63] with 51% [40-63] in US and 59% [53-65] in LMIC. Among participants with detectable SCA, the median (IQR) HIV RNA was 3.8 (2.2, 8.1) copies/mL. The multivariable model conducted in LMIC participants showed that higher baseline HIV RNA was associated with detectable residual RNA (OR 2.9, 95% CI 1.8, 4.6 for every log10 increase, P < .001). After including both US and LMIC in the final model, baseline HIV RNA remained significant. No difference in SCA detestability was found between US and LMIC sites (OR 1.1 [0.6, 2.0], P = .72) after adjusting for baseline RNA and parent study.The prevalence of residual viremia between both groups were not different and more than half of the participants had detectable viremia. Higher baseline HIV RNA was independently associated with residual viremia.

Early versus delayed initiation of antiretroviral therapy for concurrent HIV infection and cryptococcal meningitis in sub-saharan Africa.

BACKGROUND. Cryptococcal meningitis (CM) remains a leading cause of acquired immunodeficiency syndrome-related death in sub-Saharan Africa. The timing of the initiation of antiretroviral therapy (ART) for human immunodeficiency virus (HIV)-associated CM remains uncertain. The study aimed to determine the optimal timing for initiation of ART in HIV-positive individuals with CM. METHODS. A prospective, open-label, randomized clinical trial was conducted at a tertiary teaching hospital in Zimbabwe. Participants were aged > or = 18 years, were ART naive, had received a first CM diagnosis, and were randomized to receive early ART (within 72 h after CM diagnosis) or delayed ART (after 10 weeks of treatment with fluconazole alone). Participants received 800 mg of fluconazole per day. The ART regimen used was stavudine, lamivudine, and nevirapine given twice daily. The duration of follow-up was up to 3 years. The primary end point was all-cause mortality. RESULTS. Fifty-four participants were enrolled in the study (28 in the early ART arm and 26 in the delayed ART arm). The median CD4 cell count at enrollment was 37 cells/mm(3) (interquartile range, 17-69 cells/mm(3)). The 3-year mortality rate differed significantly between the early and delayed ART groups (88% vs 54%; P < .006); the overall 3-year mortality rate was 73%. The median durations of survival were 28 days and 637 days in the early and delayed ART groups, respectively (P = .031, by log-rank test). The risk of mortality was almost 3 times as great in the early ART group versus the delayed ART group (adjusted hazard ratio, 2.85; 95% confidence interval, 1.1-7.23). The study was terminated early by the data safety monitoring committee. CONCLUSIONS. In resource-limited settings where CM management may be suboptimal, when compared with a delay of 10 weeks after a CM diagnosis, early initiation of ART results in increased mortality. Trial registration. ClinicalTrials.gov identifier: NCT00830856.

Simplified dolutegravir dosing for children with HIV weighing 20 kg or more: pharmacokinetic and safety substudies of the multicentre, randomised ODYSSEY trial.

BACKGROUND: Paediatric dolutegravir doses approved by stringent regulatory authorities (SRAs) for children weighing 20 kg to less than 40 kg until recently required 25 mg and 10 mg film-coated tablets. These tablets are not readily available in low-resource settings where the burden of HIV is highest. We did nested pharmacokinetic substudies in patients enrolled in the ODYSSEY-trial to evaluate simplified dosing in children with HIV. METHODS: We did pharmacokinetic and safety substudies within the open-label, multicentre, randomised ODYSSEY trial (NCT02259127) of children with HIV starting treatment in four research centres in Uganda and Zimbabwe. Eligible children were randomised to dolutegravir in ODYSSEY and weighed 20 kg to less than 40 kg. In children weighing 20 kg to less than 25 kg, we assessed dolutegravir's pharmacokinetics in children given once daily 25 mg film-coated tablets (approved by the SRAs at the time of the study) in part one of the study, and 50 mg film-coated tablets (adult dose) or 30 mg dispersible tablets in part two of the study. In children weighing 25 kg to less than 40 kg, we also assessed dolutegravir pharmacokinetics within-subject on film-coated tablet doses of 25 mg or 35 mg once daily, which were approved by the SRAs for the children's weight band; then switched to 50 mg film-coated tablets once daily. Steady-state 24 h dolutegravir plasma concentration-time pharmacokinetic profiling was done in all enrolled children at baseline and 1, 2, 3, 4, 6, and 24 h after observed dolutegravir intake. Target dolutegravir trough concentrations (Ctrough) were based on reference adult pharmacokinetic data and safety was evaluated in all children in the corresponding weight bands who consented to pharmacokinetic studies and received the studied doses. FINDINGS: Between Sept 22, 2016, and May 31, 2018, we enrolled 62 black-African children aged from 6 years to younger than 18 years (84 pharmacokinetic-profiles). In children weighing 20 kg to less than 25 kg taking 25 mg film-coated tablets, the geometric mean (GM) Ctrough (coefficient of variation) was 0·32 mg/L (94%), which was 61% lower than the GM Ctrough of 0·83 mg/L (26%) in fasted adults on dolutegravir 50 mg once-daily; in children weighing 25 kg to less than 30 kg taking 25 mg film-coated tablets, the GM Ctrough was 0·39 mg/L (48%), which was 54% lower than the GM Ctrough in fasted adults; and in those 30 kg to less than 40 kg taking 35 mg film-coated tablets the GM Ctrough was 0·46 mg/L (63%), which was 45% lower than the GM Ctrough in fasted adults. On 50 mg film-coated tablets or 30 mg dispersible tablets, Ctrough was close to the adult reference (with similar estimates on the two formulations in children in the 20 to <25 kg weight band), with total exposure (area under the concentration-time curve from 0 h to 24 h) in between reference values in adults dosed once and twice daily, where safety data are reassuring, although maximum concentrations were higher in children weighing 20 kg to less than 25 kg than in the twice-daily adult reference. Over a 24-week follow-up period in 47 children on 30 mg dispersible tablets or 50 mg film-coated tablets, none of the three reported adverse events (cryptococcal meningitis, asymptomatic anaemia, and asymptomatic neutropenia) were considered related to dolutegravir. INTERPRETATION: Adult dolutegravir 50 mg film-coated tablets given once daily provide appropriate pharmacokinetic profiles in children weighing 20 kg or more, with no safety signal, allowing simplified practical dosing and rapid access to dolutegravir. These results informed the WHO 2019 dolutegravir paediatric dosing guidelines and have led to US Food and Drug Administration approval of adult dosing down to 20 kg. FUNDING: Paediatric European Network for Treatment of AIDS Foundation, ViiV Healthcare, UK Medical Research Council.

Role of Faculty Development Programs in Medical Education at the University of Zimbabwe College of Health Sciences, Zimbabwe.

BACKGROUND: Major challenges are being experienced in medical education in sub-Saharan African Universities. These include emigration of faculty, infrequent curriculum review, inadequate training in medical education, poor investments in infrastructure and lack of faculty development programs. The USA government committed funding to improve the quality of medical education and research capacity in sub-Saharan Africa through the Medical Education Partnership Initiative (MEPI). OBJECTIVES: This article describes the implementation of faculty development at the University of Zimbabwe College of Health Sciences (UZCHS), a recipient of a MEPI award. METHODS: Data sources included annual surveys and reports of UZCHS MEPI activities, exit evaluation reports of faculty development workshops; results of a survey conducted in 2015 at the end of the MEPI grant. Questionnaires were developed based on the MEPI Zimbabwe evaluation plan and logic model. Surveys were administered to faculty members, postgraduate and undergraduate students. Qualitative data was collected through in-depth key informer interviews of stakeholder. FINDINGS: Different faculty development activities were implemented such as workshops, exchange visits, visiting professors program, advanced leadership training and curriculum development. The implementation of the activities brought positive developments to the college as confirmed by faculty and students. The majority of faculty interviewed (96%) confirmed that faculty development programs were very helpful in enhancing their expertise and skills. A similar number, i.e. 96%, also reported satisfaction with the training. CONCLUSIONS: We have described how the implementation of faculty development programs at the UZCHS contributed to the improvement of medical education at the College. The short term and long-term benefits of faculty development have been analyzed. Various forms of faculty development programs were described. Limitations of this analysis were the inability to collect data on students' performance and the demonstration of changes in teaching performance.

Lopinavir plus nucleoside reverse-transcriptase inhibitors, lopinavir plus raltegravir, or lopinavir monotherapy for second-line treatment of HIV (EARNEST): 144-week follow-up results from a randomised controlled trial.

BACKGROUND: Millions of HIV-infected people worldwide receive antiretroviral therapy (ART) in programmes using WHO-recommended standardised regimens. Recent WHO guidelines recommend a boosted protease inhibitor plus raltegravir as an alternative second-line combination. We assessed whether this treatment option offers any advantage over the standard protease inhibitor plus two nucleoside reverse-transcriptase inhibitors (NRTIs) second-line combination after 144 weeks of follow-up in typical programme settings. METHODS: We analysed the 144-week outcomes at the completion of the EARNEST trial, a randomised controlled trial done in HIV-infected adults or adolescents in 14 sites in five sub-Saharan African countries (Uganda, Zimbabwe, Malawi, Kenya, Zambia). Participants were those who were no longer responding to non-NRTI-based first-line ART, as assessed with WHO criteria, confirmed by viral-load testing. Participants were randomly assigned to receive a ritonavir-boosted protease inhibitor (lopinavir 400 mg with ritonavir 100 mg, twice per day) plus two or three clinician-selected NRTIs (protease inhibitor plus NRTI group), protease inhibitor plus raltegravir (400 mg twice per day; protease inhibitor plus raltegravir group), or protease inhibitor monotherapy (plus raltegravir induction for first 12 weeks, re-intensified to combination therapy after week 96; protease inhibitor monotherapy group). Randomisation was by computer-generated randomisation sequence, with variable block size. The primary outcome was viral load of less than 400 copies per mL at week 144, for which we assessed non-inferiority with a one-sided α of 0·025, and superiority with a two-sided α of 0·025. The EARNEST trial is registered with ISRCTN, number 37737787. FINDINGS: Between April 12, 2010, and April 29, 2011, 1837 patients were screened for eligibility, of whom 1277 patients were randomly assigned to an intervention group. In the primary (complete-case) analysis at 144 weeks, 317 (86%) of 367 in the protease inhibitor plus NRTI group had viral loads of less than 400 copies per mL compared with 312 (81%) of 383 in the protease inhibitor plus raltegravir group (p=0·07; lower 95% confidence limit for difference 10·2% vs specified non-inferiority margin 10%). In the protease inhibitor monotherapy group, 292 (78%) of 375 had viral loads of less than 400 copies per mL; p=0·003 versus the protease inhibitor plus NRTI group at 144 weeks. There was no difference between groups in serious adverse events, grade 3 or 4 adverse events (total or ART-related), or events that resulted in treatment modification. INTERPRETATION: Protease inhibitor plus raltegravir offered no advantage over protease inhibitor plus NRTI in virological efficacy or safety. In the primary analysis, protease inhibitor plus raltegravir did not meet non-inferiority criteria. A regimen of protease inhibitor with NRTIs remains the best standardised second-line regimen for use in programmes in resource-limited settings. FUNDING: European and Developing Countries Clinical Trials Partnership (EDCTP), UK Medical Research Council, Instituto de Salud Carlos III, Irish Aid, Swedish International Development Cooperation Agency, Instituto Superiore di Sanita, Merck, ViiV Healthcare, WHO.

Medical Education Partnership Initiative (MEPI) in Zimbabwe: Outcomes and Challenges.

BACKGROUND: Sub-Saharan Africa has an inadequate number of health professionals, leading to a reduced capacity to respond to health challenges, including HIV/AIDS. From 2010 to 2015, the Medical Education Partnership Initiative (MEPI)-sponsored by the U.S. Presidents Emergency Plan for AIDS Relief (PEPFAR) and the National Institutes of Health (NIH)-was enthusiastically taken up by the University of Zimbabwe College of Health Sciences (UZCHS) and 12 other sub-Saharan African universities to develop models of training to improve medical education and research capacity. In this article, we describe the outcomes and challenges of MEPI in Zimbabwe. METHODS: UZCHS in partnership with the University of Colorado, Denver; Stanford University; University of Cape Town; University College London; and King's College London designed the Novel Education Clinical Trainees and Researchers (NECTAR) program and 2 linked awards addressing cardiovascular disease and mental health to pursue MEPI objectives. A range of medical education and research capacity-focused programs were implemented, including faculty development, research support, mentored scholars, visiting professors, community-based education, information and technology support, cross-cutting curricula, and collaboration with partner universities and the ministries of health and education. We analyzed quantitative and qualitative data from several data sources, including annual surveys of faculty, students, and other stakeholders; workshop exit surveys; and key informant interviews with NECTAR administrators and leaders and the UZCHS dean. FINDINGS: Improved Internet connectivity and electronic resource availability were early successes of NECTAR. Over the 5-year period, 69% (115 of 166) of faculty members attended at least 1 of 15 faculty development workshops. Forty-one faculty members underwent 1-year advanced faculty development training in medical education and leadership. Thirty-three mentored research scholars were trained under NECTAR, and 52 and 12 in cardiovascular and mental health programs, respectively. Twelve MEPI scholars had joined faculty by 2015. Full-time faculty grew by 36% (122 to 166), annual postgraduate and medical student enrollment increased by 61% (75 to 121) and 71% (123 to 210), respectively. To institutionalize and sustain MEPI innovations, the Research Support Center and the Department of Health Professions Education were established at UZCHS. CONCLUSION: MEPI has synergistically revitalized medical education, research capacity, and leadership at UZCHS. Investments in creating a new research center, health professions education department, and, programs have laid the foundation to help sustain faculty development and research capacity in the country.