Background HIV and schistosomiasis are the most widespread infections worldwide. The two diseases share the same epidemiological space, especially in poor regions where endemicity is high. Co-infections are therefore common. We conducted a clinical study to determine the effect of efavirenz and ritonavir on the pharmacokinetics of R- and S-praziquantel (PZQ) in healthy male participants. The aim was to increase knowledge towards the safe and efficacious use of PZQ especially in cases of coinfection and mass drug treatment programs where HIV status and concomitant drug intake is not considered prior to administration. Methods We conducted a non-randomized, open-label, single-dose, one sequence crossover study with 2 arms. A single oral dose of 40 mg/kg PZQ followed by a daily oral dose of either 400 mg efavirenz or 100 mg ritonavir was given to participants for 14 consecutive days. On day 14, they ingested a single 40 mg/kg dose of PZQ. We measured plasma levels up to 12 h on day 1 and day 14. Samples were analyzed by LC-MS. Pharmacokinetic analysis was conducted in WinNonlin to determine the primary endpoints (plasma T1/2, Cmin, and AUC). Results Efavirenz had a significant effect on the pharmacokinetics of PZQ (p < .05), reducing the AUC by 4-fold (1213.15 vs. 281.35 h·ng/ml for R-PZQ and 5669 vs. 871.84 h·ng/ml for S-PZQ). Ritonavir had no significant effect on R-PZQ but increased the AUC 2-fold for S-PZQ (p < .05) (4154.79 vs. 7291.05 h·ng/ml). Conclusion Our study showed clinically significant drug-drug interactions involving PZQ and efavirenz that should be considered in the treatment of schistosomiasis in regions where efavirenz-based ART is common. Using PZQ in HIV patients needs investigation, as there is a risk of both treatment failure and adverse effects because of induction and inhibition. Strategies to avoid these detrimental DDI should therefore be explored.

Objective: HIV viral load (VL) monitoring is generally conducted 6–12 monthly in low- and middle-income countries, risking relatively prolonged periods of poor viral control. We explored the effects of different levels of loss of viral control on immune reconstitution and activation. Design: Two hundred and eight participants starting protease inhibitor (PI)-based second-line therapy in the EARNEST trial (ISRCTN37737787) in Uganda and Zimbabwe were enrolled and CD38+/HLA-DR+ immunophenotyping performed (CD8-FITC/CD38-PE/CD3-PerCP/HLA-DR-APC; centrally gated) in real-time at 0, 12, 48, 96 and 144 weeks from randomization. Methods: VL was assayed retrospectively on samples collected every 12–16 weeks and classified as continuous suppression (<40 copies/ml throughout); suppression with transient blips; low-level rebound (two or more consecutive VL >40, <5000 copies/ml); high-level rebound/nonresponse (two or more consecutive VL >5000 copies/ml). Results: Immunophenotype reconstitution varied between that defined by numbers of cells and that defined by cell percentages. Furthermore, VL dynamics were associated with substantial differences in expression of CD4+ and CD8+ cell activation markers, with only individuals with high-level rebound/nonresponse (>5000 copies/ml) experiencing significantly greater activation and impaired reconstitution. There was little difference between participants who suppressed consistently and who exhibited transient blips or even low-level rebound by 144 weeks (P > 0.2 vs. suppressed consistently). Conclusion: Detectable viral load below the threshold at which WHO guidelines recommend that treatment can be maintained without switching (1000 copies/ml) appear to have at most, small effects on reconstitution and activation, for patients taking a PI-based second-line regimen.

Introduction Non-adherence to antiretroviral therapy (ART) is the main cause of viral non-suppression and its risk is increased by depression. In countries with high burden of HIV, there is a lack of trained professionals to deliver depression treatments. This paper describes the protocol for a 2-arm parallel group superiority 1:1 randomised controlled trial, to test the effectiveness and cost effectiveness of the TENDAI stepped care task-shifted intervention for depression, ART non-adherence and HIV viral suppression delivered by lay interventionists. Methods and analysis Two hundred and ninety people living with HIV aged ≥18 years with probable depression (Patient Health Questionnaire=>10) and viral non-suppression (≥ 1000 HIV copies/mL) are being recruited from HIV clinics in towns in Zimbabwe. The intervention group will receive a culturally adapted 6-session psychological treatment, Problem-Solving Therapy for Adherence and Depression (PST-AD), including problem-solving therapy, positive activity scheduling, skills to cope with stress and poor sleep and content to target barriers to non-adherence to ART. Participants whose score on the Patient Health Questionnaire-9 remains ≥10, and/or falls by less than 5 points, step up to a nurse evaluation for possible antidepressant medication. The control group receives usual care for viral non-suppression, consisting of three sessions of adherence counselling from existing clinic staff, and enhanced usual care for depression in line with the WHO Mental Health Gap intervention guide. The primary outcome is viral suppression (<1000 HIV copies/mL) at 12 months post-randomisation. Ethics and dissemination The study and its tools were approved by MRCZ/A/2390 in Zimbabwe and RESCM-18/19–5580 in the UK. Study findings will be shared through the community advisory group, conferences and open access publications. Trial registration number NCT04018391 .

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/mm(3); 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.

BACKGROUND The use of rifamycin antibiotics for TB prevention carries a risk of detrimental drug-drug interactions with concomitantly used ART. OBJECTIVES To evaluate the interaction of the antiretroviral drug nevirapine in combination with 4 weeks of daily rifapentine and isoniazid for TB prevention in people living with HIV. METHODS Participants were individuals enrolled in the BRIEF-TB study receiving nevirapine and randomized to the rifapentine/isoniazid arm of the study. Participants provided sparse pharmacokinetic (PK) sampling at baseline and weeks 2 and 4 for trough nevirapine determination. Nevirapine apparent oral clearance (CL/F) was estimated and the geometric mean ratio (GMR) of CL/F prior to and during rifapentine/isoniazid was calculated. RESULTS Seventy-eight participants had evaluable PK data: 61 (78%) female, 51 (65%) black non-Hispanic and median (range) age of 40 (13-66) years. Median (IQR) nevirapine trough concentrations were: week 0, 7322 (5266-9302) ng/mL; week 2, 5537 (3552-8462) ng/mL; and week 4, 5388 (3516-8243) ng/mL. Sixty out of 78 participants (77%) had nevirapine concentrations ≥3000 ng/mL at both week 2 and 4. Median (IQR) nevirapine CL/F values were: week 0 pre-rifapentine/isoniazid, 2.03 (1.58-2.58) L/h; and during rifapentine/isoniazid, 2.62 (1.81-3.42) L/h. The GMR (90% CI) for nevirapine CL/F was 1.30 (1.26-1.33). CONCLUSIONS The CL/F of nevirapine significantly increased with concomitant rifapentine/isoniazid. The decrease in nevirapine trough concentrations during rifapentine/isoniazid therapy suggests induction of nevirapine metabolism, consistent with known rifapentine effects. The magnitude of this drug-drug interaction suggests daily rifapentine/isoniazid for TB prevention should not be co-administered with nevirapine-containing ART.

BACKGROUND Rifapentine-based regimens have potent antimycobacterial activity that may allow for a shorter course in patients with drug-susceptible pulmonary tuberculosis. METHODS In an open-label, phase 3, randomized, controlled trial involving persons with newly diagnosed pulmonary tuberculosis from 13 countries, we compared two 4-month rifapentine-based regimens with a standard 6-month regimen consisting of rifampin, isoniazid, pyrazinamide, and ethambutol (control) using a noninferiority margin of 6.6 percentage points. In one 4-month regimen, rifampin was replaced with rifapentine; in the other, rifampin was replaced with rifapentine and ethambutol with moxifloxacin. The primary efficacy outcome was survival free of tuberculosis at 12 months. RESULTS Among 2516 participants who had undergone randomization, 2343 had a culture positive for Mycobacterium tuberculosis that was not resistant to isoniazid, rifampin, or fluoroquinolones (microbiologically eligible population; 768 in the control group, 791 in the rifapentine-moxifloxacin group, and 784 in the rifapentine group), of whom 194 were coinfected with human immunodeficiency virus and 1703 had cavitation on chest radiography. A total of 2234 participants could be assessed for the primary outcome (assessable population; 726 in the control group, 756 in the rifapentine-moxifloxacin group, and 752 in the rifapentine group). Rifapentine with moxifloxacin was noninferior to the control in the microbiologically eligible population (15.5% vs. 14.6% had an unfavorable outcome; difference, 1.0 percentage point; 95% confidence interval [CI], -2.6 to 4.5) and in the assessable population (11.6% vs. 9.6%; difference, 2.0 percentage points; 95% CI, -1.1 to 5.1). Noninferiority was shown in the secondary and sensitivity analyses. Rifapentine without moxifloxacin was not shown to be noninferior to the control in either population (17.7% vs. 14.6% with an unfavorable outcome in the microbiologically eligible population; difference, 3.0 percentage points [95% CI, -0.6 to 6.6]; and 14.2% vs. 9.6% in the assessable population; difference, 4.4 percentage points [95% CI, 1.2 to 7.7]). Adverse events of grade 3 or higher occurred during the on-treatment period in 19.3% of participants in the control group, 18.8% in the rifapentine-moxifloxacin group, and 14.3% in the rifapentine group. CONCLUSIONS The efficacy of a 4-month rifapentine-based regimen containing moxifloxacin was noninferior to the standard 6-month regimen in the treatment of tuberculosis. (Funded by the Centers for Disease Control and Prevention and others; Study 31/A5349 ClinicalTrials.gov number, NCT02410772.).

Background: Most Zimbabweans access medical care through tiered health systems, with decentralized HIV care and centralized oncology care. Local health centre staff are trained in ART administration but not in AIDS-associated Kaposi sarcoma (AIDS-KS) diagnosis or management. To improve AIDS-KS prognoses, interventions on screening, diagnosis, and treatment must be integrated into primary HIV care settings. We conducted a community-based randomized step-wedge cluster trial for a package of KS care training interventions.Methods: Interventions intended to improve KS detection and management included a standardized KS clinical evaluation tool, palliative care integration, standardized treatment, and improved consultative services. Interventions were evaluated at eight Zimbabwe primary HIV care sites by monitoring KS diagnoses and outcomes, including early diagnosis (T0 vs T1 tumor stage), patient retention, and mortality. Analyses controlled for within clinic correlations.Findings: 1102 suspected KS patients (96% HIV+) were enrolled: 47% newly diagnosed, 20% previously diagnosed, and 33% determined as not KS (incorrectly diagnosed). Diagnosis at T0 stage increased post-intervention, though not significant statistically (adjusted odds ratio (aOR)=1·48 (95% confidence interval (95%CI):0·66-3·79);p=0·37). New KS diagnosis rates increased 103% (95%CI:11%-273%);p=0·02) post-intervention, with parallel increased odds of incorrect diagnosis (aOR=2·08 (95%CI:0·33-3·24);p=0·001). Post-intervention, non-significant changes in 90-day return rates (adjusted hazard ratio (aHR)=0·69 (95%CI:0·38-1·45);p=0·21) and survival (aHR=1·36 (95%CI:0·85-2·20);p=0·20) were estimated.Interpretation: KS training interventions increased overall and incorrect KS diagnosis, but not early KS diagnosis, 90-day return rates, or survival at HIV primary care sites. Approaches to increase KS diagnosis accuracy in low-resource settings are needed.Trial Registration: Study design details are available at ClinicalTrials.gov NCT01764360.Funding: Funding was provided by the National Cancer Institute, National Institutes of Health:grant 1R01CA172050. Declaration of Interest: None to declare. Ethical Approval: The study was approved by the institutional review boards of Zimbabwe (Medical Research Council of Zimbabwe, MRCZ), University of Colorado Anschutz Medical Campus (COMIRB), and the Joint Parirenyatwa Hospital and University of Zimbabwe College of Health Sciences Research Ethics Committee (JREC).

Background Dolutegravir (DTG)-based antiretroviral therapy (ART) is highly effective and well-tolerated in adults and is rapidly being adopted globally. We describe the design of the ODYSSEY trial which evaluates the efficacy and safety of DTG-based ART compared with standard-of-care in children and adolescents. The ODYSSEY trial includes nested pharmacokinetic (PK) sub-studies which evaluated pragmatic World Health Organization (WHO) weight-band-based DTG dosing and opened recruitment to children < 14 kg while dosing was in development. Methods ODYSSEY (Once-daily DTG based ART in Young people vS. Standard thErapY) is an open-label, randomised, non-inferiority, basket trial comparing the efficacy and safety of DTG + 2 nucleos(t) ides (NRTIs) versus standard-of-care (SOC) in HIV-infected children < 18 years starting first-line ART (ODYSSEY A) or switching to second-line ART (ODYSSEY B). The primary endpoint is clinical or virological failure by 96 weeks. Results Between September 2016 and June 2018, 707 children weighing ≥14 kg were enrolled; including 311 ART-naïve children and 396 children starting second-line. 47% of children were enrolled in Uganda, 21% Zimbabwe, 20% South Africa, 9% Thailand, 4% Europe. 362 (51%) participants were male; median age [range] at enrolment was 12.2 years [2.9–18.0]. 82 (12%) children weighed 14 to < 20 kg, 135 (19%) 20 to < 25 kg, 206 (29%) 25 to < 35 kg, 284 (40%) ≥35 kg. 128 (18%) had WHO stage 3 and 60 (8%) WHO stage 4 disease. Challenges encountered include: (i) running the trial across high- to low-income countries with differing frequencies of standard-of-care viral load monitoring; (ii) evaluating pragmatic DTG dosing in PK sub-studies alongside FDA- and EMA-approved dosing and subsequently transitioning participants to new recommended doses; (iii) delays in dosing information for children weighing 3 to < 14 kg and rapid recruitment of ART-naïve older/heavier children, which led to capping recruitment of participants weighing ≥35 kg in ODYSSEY A and extending recruitment (above 700) to allow for ≥60 additional children weighing between 3 to < 14 kg with associated PK; (iv) a safety alert associated with DTG use during pregnancy, which required a review of the safety plan for adolescent girls. Conclusions By employing a basket design, to include ART-naïve and -experienced children, and nested PK sub-studies, the ODYSSEY trial efficiently evaluates multiple scientific questions regarding dosing and effectiveness of DTG-based ART in children. Trial registration NCT, NCT02259127 , registered 7th October 2014; EUDRACT, 2014–002632-14, registered 18th June 2014 ( https://www.clinicaltrialsregister.eu/ctr-search/trial/2014-002632-14/ES ); ISRCTN, ISRCTN91737921 , registered 4th October 2014.

AbstractWe conducted a clinical study to determine the effect of efavirenz and ritonavir on the pharmacokinetics of R‐ and S‐PZQ in healthy male participants. This was toward evaluating the risk of drug‐drug interactions, which may occur after PZQ administration to HIV patients on efavirenz or ritonavir containing regimens. A non‐randomized, open‐label, single‐dose, one sequence crossover study with 2 arms was conducted. We gave 26 healthy volunteers a single oral dose of 40 mg/kg PZQ followed by a daily oral dose of either 400 mg efavirenz or 100 mg ritonavir for 14 consecutive days. On day 14, they ingested a single 40 mg/kg dose of PZQ. We measured plasma levels up to 12 h on day 1 and day 14. Samples were analyzed by LC‐MS. Pharmacokinetic analysis was conducted in WinNonlin to determine the primary endpoints (plasma T1/2, Cmin, and AUC). Efavirenz had a significant effect on the pharmacokinetics of PZQ (p < .05), reducing the AUC by 4‐fold (1213.15 vs. 281.35 h·ng/ml for R‐PZQ and 5669 vs. 871.84 h·ng/ml for S‐PZQ). Ritonavir had no significant effect on R‐PZQ but increased the AUC 2‐fold for S‐PZQ (p < .05) (4154.79 vs. 7291.05 h·ng/ml). Using PZQ in HIV patients needs investigation, as there is a risk of both treatment failure and adverse effects because of induction and inhibition, respectively.

Background: WHO treatment guidelines recommend tenofovir plus lamivudine or emtricitabine as the nucleoside reverse transcriptase inhibitor backbone in first-line regimens for HIV-infected adults. Lamivudine alone is not recommended, because of the risk of hepatitis B virus (HBV) resistance. We studied HBV responses in a large cohort of co-infected patients in a resource-limited setting. Setting: Clinical centers in Uganda and Zimbabwe. Methods: DART was a randomized trial of monitoring practices in HIV-infected adults starting antiretroviral therapy. Baseline samples were tested retrospectively for HBV serological markers and HBV DNA. Longitudinal HBV DNA testing at 48 weeks and the last available sample before HBV-relevant modification of antiretroviral therapy was performed on patients with detectable HBV DNA at baseline. Results: Two hundred twenty-four hepatitis B surface antigen-positive patients were followed for up to 4.8 years. Of the drugs with anti-HBV activity, 166 were prescribed lamivudine-tenofovir and 58 lamivudine alone. Ninety-eight percent (96/98) patients with baseline HBV DNA <6 log(10) IU/mL achieved viral suppression at 48 weeks (HBV DNA <48 IU/mL), regardless of regimen, compared with 50%(26/52) for HBV DNA >6 log(10) IU/mL. Of the 83 patients suppressed at 48 weeks and with follow-up data, only 7(8%) experienced viral rebound (range 200-3460 IU/mL). Of the 20 patients not suppressed at 48 weeks and with follow-up data, HBV DNA levels generally declined with lamivudine-tenofovir, but increased with lamivudine alone. Alanine transaminase flares were not observed in any patient who experienced viral rebound. Conclusions: The suppressive effect of lamivudine alone was highly durable (up to 5 years) in HIV-HBV co-infected patients with baseline HBV DNA <6 log(10) IU/mL. It may be feasible to develop stratified approaches using lamivudine as the only drug with anti-HBV activity.

BACKGROUND:The World Health Organization recommends dolutegravir with two nucleoside reverse-transcriptase inhibitors (NRTIs) for second-line treatment of human immunodeficiency virus type 1 (HIV-1) infection. Evidence is limited for the efficacy of this regimen when NRTIs are predicted to lack activity because of drug resistance, as well as for the recommended switch of an NRTI from tenofovir to zidovudine. METHODS:In a two-by-two factorial, open-label, noninferiority trial, we randomly assigned patients for whom first-line therapy was failing (HIV-1 viral load, ≥1000 copies per milliliter) to receive dolutegravir or ritonavir-boosted darunavir and to receive tenofovir or zidovudine; all patients received lamivudine. The primary outcome was a week 48 viral load of less than 400 copies per milliliter, assessed with the Food and Drug Administration snapshot algorithm (noninferiority margin for the between-group difference in the percentage of patients with the primary outcome, 12 percentage points). RESULTS:We enrolled 464 patients at seven sub-Saharan African sites. A week 48 viral load of less than 400 copies per milliliter was observed in 90.2% of the patients in the dolutegravir group (212 of 235) and in 91.7% of those in the darunavir group (210 of 229) (difference, -1.5 percentage points; 95% confidence interval [CI], -6.7 to 3.7; P = 0.58; indicating noninferiority of dolutegravir, without superiority) and in 92.3% of the patients in the tenofovir group (215 of 233) and in 89.6% of those in the zidovudine group (207 of 231) (difference, 2.7 percentage points; 95% CI, -2.6 to 7.9; P = 0.32; indicating noninferiority of tenofovir, without superiority). In the subgroup of patients with no NRTIs that were predicted to have activity, a viral load of less than 400 copies per milliliter was observed in more than 90% of the patients in the dolutegravir group and the darunavir group. The incidence of adverse events did not differ substantially between the groups in either factorial comparison. CONCLUSIONS:Dolutegravir in combination with NRTIs was effective in treating patients with HIV-1 infection, including those with extensive NRTI resistance in whom no NRTIs were predicted to have activity. Tenofovir was noninferior to zidovudine as second-line therapy. (Funded by Janssen; NADIA ClinicalTrials.gov number, NCT03988452.).

OBJECTIVES To assess baseline prevalence of cryptococcal antigen (CrAg) positivity; and its contribution to reductions in all-cause mortality, deaths from cryptococcus and unknown causes, and new cryptococcal disease in the REALITY trial. DESIGN Retrospective CrAg testing of baseline and week-4 plasma samples in all 1805 African adults/children with CD4<100 cells/μL starting antiretroviral therapy who were randomised to receive 12-week enhanced-prophylaxis (fluconazole 100 mg/day, azithromycin, isoniazid, cotrimoxazole) vs. standard-prophylaxis (cotrimoxazole). METHODS Proportional hazards models were used to estimate the relative impact of enhanced-prophylaxis vs. standard-cotrimoxazole on all, cryptococcal and unknown deaths, and new cryptococcal disease, through 24-weeks, by baseline CrAg positivity. RESULTS Excluding 24(1.4%) participants with active/prior cryptococcal disease at enrolment (all treated for cryptococcal disease), 133/1781(7.5%) participants were CrAg-positive. By 24-weeks, 105 standard-cotrimoxazole vs. 78 enhanced-prophylaxis participants died. Of 9 standard-cotrimoxazole and 3 enhanced-prophylaxis cryptococcal deaths, 7 and 2 respectively were CrAg-positive at baseline. Among deaths of unknown cause, only 1/46 standard-cotrimoxazole and 1/28 enhanced-prophylaxis were CrAg-positive at baseline. There was no evidence that relative reductions in new cryptococcal disease associated with enhanced-prophylaxis varied between baseline CrAg-positives (hazard-ratio, HR = 0.36 (95% CI 0.13-0.98), incidence 19.5 vs. 56.5/100 person-years) and CrAg-negatives (HR = 0.33 (0.03-3.14), incidence 0.3 vs. 0.9/100 person-years; pheterogeneity = 0.95); nor for all deaths, cryptococcal deaths or unknown deaths (pheterogeneity > 0.3). CONCLUSIONS Relative reductions in cryptococcal disease/death did not depend on CrAg status. Deaths of unknown cause were unlikely to be cryptococcus-related; plausibly azithromycin contributed to their reduction. Findings support including 100 mg fluconazole in an enhanced-prophylaxis package at ART initiation where CrAg screening is unavailable/impractical.

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.

BackgroundPaediatric 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.MethodsWe 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.FindingsBetween 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.InterpretationAdult 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.FundingPaediatric European Network for Treatment of AIDS Foundation, ViiV Healthcare, UK Medical Research Council.

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).

Price, Huw; Dunn, David; Zachary, Tamale; Vudriko, Tobias; Chirara, Michael; Kityo, Cissy; Munderi, Paula; Spyer, Moira; Hakim, James; Gilks, Charles; +4 more... Kaleebu, Pontiano; Pillay, Deenan; Gilson, Richard; DART Virology Group; (2017) Hepatitis B serological markers and plasma DNA concentrations. AIDS (London, England), 31 (8). pp. 1109-1117. ISSN 0269-9370 DOI: https://doi.org/10.1097/QAD.0000000000001454 Downloaded from: http://researchonline.lshtm.ac.uk/id/eprint/4649869/ DOI: https://doi.org/10.1097/QAD.0000000000001454

Objective We conducted a descriptive cross-sectional study using survey and programme data to assess district-level performance along the HIV care cascade (HIV testing target achievement, linkage to ART and ART coverage) in order to formulate district-specific recommendations, taking into consideration prevalence and yield of testing. Results Data from 60 districts were analysed. Forty-eight districts (80.0%) surpassed 90% of their 2018 HIV testing targets. Linkage to ART was less than 90% in 40 districts (83.3%). Thirty districts (50.0%) had ART coverage above 90%. Of the 30 districts with suboptimal (< 90%) ART coverage, 18 districts had achieved high HIV testing target but with suboptimal linkage to ART, 6 had achieved high HIV testing targets and high linkage to ART, 4 had both suboptimal HIV testing target achievement and linkage to ART and 2 had suboptimal HIV testing target achievement and high linkage to ART. Priority should be given to districts with suboptimal ART coverage. Remediation strategies should be tailored to address the poorly performing stage of the cascade in each of the districts.

Background. Distal sensory peripheral neuropathy (DSPN) is a complication of human immunodeficiency virus (HIV). We estimate DSPN prevalence in 7 resource-limited settings (RLSs) for combination antiretroviral therapy (cART)-naive people living with HIV (PLWH) compared with matched participants not living with HIV and in PLWH virally suppressed on 1 of 3 cART regimens. Methods. PLWH with a CD4+ count <300 cells/mm(3) underwent standardized neurological examination and functional status assessments before and every 24 weeks after starting cART. Matched individuals not living with HIV underwent the same examinations once. Associations between covariates with DSPN at entry were assessed using the chi(2) test, and virally suppressed PLWH were assessed using generalized estimating equations. Results. Before initiating cART, 21.3% of PLWH had DSPN compared with 8.5% of people not living with HIV (n = 2400; chi(2)(df = 1) = 96.5; P < .00001). PLWH with DSPN were more likely to report inability to work [chi(2)(df = 1) = 10.6; P = .001] and depression [chi(2)(df = 1) = 8.9; P = .003] than PLWH without DSPN. Overall prevalence of DSPN among those virally suppressed on cART decreased: 20.3%, week 48; 15.3%, week 144; and 10.3%, week 192. Incident DSPN was seen in 127 PLWH. Longitudinally, DSPN was more likely in older individuals (P < .001) and PLWH with less education (P = .03). There was no significant association between cART regimen and DSPN. Conclusions. Although the prevalence of DSPN decreased following cART initiation in PLWH, further research could identify strategies to prevent or ameliorate residual DSPN after initiating cART in RLSs.

Stroke occurs suddenly and has major impact on both the survivor and their caregiver.A third of stroke victims usually die from its direct effects or complications.The survivors usually have functional deficits resulting in the need for caregiver support.The caregivers may have inadequate knowledge of how to care for their affected relatives.The result is high caregiver burden and complications among the survivors.Once a person has stroke, it becomes important that their caregivers and their needs are determined so that they get the necessary support from the health professionals.Education of both the stroke survivors and the caregivers, and follow-up to determine if their needs are being met may be the support required.This is important in low resource settings where the survivors and caregivers may not always afford to go to stroke clinics for support visits and follow-up.Furthermore, stroke will result in reduced quality of life, poor functional outcomes, and poor community reintegration, which are important areas in life.Caregivers who look after the survivor for long periods may suffer burnout and have poor quality of life.Educating both the stroke survivor and their caregiver may result in better quality of life and survival rate.

Abstract Background HIV affects the central nervous system resulting in HIV associated neurocognitive impairment (NCI) in approximately 50% of people living with HIV. It typically affects memory, learning, working memory, fine motor skills, speed of information processing, verbal fluency and executive functioning cognitive domains. NCI can affect adherence to antiretroviral therapy (ART), employability, driving ability and activities of daily living. NCI is not routinely screened for in Zimbabwe, and the burden is not known in this setting. The objectives of this study were: 1) To determine NCI prevalence using a comprehensive neuropsychological battery at two primary health care clinics in Harare; 2) To assess the pattern of cognitive impairment across cognitive domains using a gold standard neuropsychological (NP) battery in HIV-positive patients compared to HIV-negative controls. Methods Inclusion criteria: 18 years or older; minimum 7 years education; no neurological or psychiatric disorders. HIV-positive participants were on ART for ≥3 months; HIV-negative participants had a confirmed HIV negative status in the past month. A comprehensive NP battery, functional assessments, demographic and medical history questionnaires were administered. The NP battery consisted of tests assessing memory, learning, working memory, fine motor skills, speed of information processing, verbal fluency and executive functioning. Results Two-hundred-and-thirty-one participants were recruited. Of those, 155 were HIV-positive (Female = 70%, Age M = 37.8; SD 11.2) and 76 HIV-negative (Female = 63%, Age M = 31.2; SD 9.9). HIV-positive participants were on ART for an average of 6 years. NCI was present in 49.7% HIV positive participants. Compared to HIV-negative participants, the HIV-positive group had significantly poorer scores in 5 out of 7 cognitive domains. A good level of education is negatively correlated with NCI. Conclusions NCI prevalence in HIV-positive population Zimbabwe is consistent with global estimates. NCI persists in adults who are on ART. Routine assessment of NCI in adults attending primary care clinics using this adapted battery is therefore important so that they are identified early and are provided the necessary interventions.