Background:Integrase mutations associated with dolutegravir resistance have been well characterized, but based on limited data from non-B subtypes. Objectives:We aim to identify integrase mutations not currently classified as integrase strand transfer inhibitor (INSTI) resistance mutations (DRMs) in individuals with viremia on dolutegravir-based regimens. Methods:Mutations in integrase sequences in the DTG RESIST study from African countries were detected using Stanford HIVdb v9.8. We used a viral genome-wide association study (GWAS) approach to identify mutations not classified as major or accessory INSTI DRMs but associated with dolutegravir resistance. We performed the same GWAS on drug-naïve sequences from the Los Alamos HIV-1 database to identify mutations associated with viraemia under DTG exposure. Results:Among 387 sequences, 107 (27.6%) showed at least intermediate dolutegravir resistance. Fourteen integrase mutations not classified as major or accessory DRMs (S39R, L45I, I72L, L74I, V79I, F100Y, I113V, S119R, V126A, K156N, Q177L, I208M, A265V, and R284G) were significantly associated with resistance. V79I (adjusted odds ratio [aOR] 169.2, 95% credible interval [CrI] 18.2-2871.4) and I72L (aOR 67.7, 95% CrI 7.1-1326.2) were strongly associated with resistance. S39R, L45I, I72L, L74I, V79I, F100Y, S119R, and K156N were linked to established INSTI resistance pathways, and I72L, L74I, V79I, V126A, and K156N were associated with viraemia under DTG exposure. Conclusions:We identified several integrase mutations outside established DRM categories that are strongly associated with dolutegravir resistance. Dolutegravir resistance evolution is complex; likely involves mutations not currently classified as DRMs.
BACKGROUND:The COVID-19 pandemic challenged healthcare systems, particularly in settings with high infectious disease burden. We examined the postpandemic long-term impacts of COVID-19 on tuberculosis (TB) services at anti-retroviral therapy (ART) clinics in lower-income countries. METHODS:Using standardised online questionnaires, we conducted a cross-sectional site survey among ART clinics providing TB services in Africa and Asia from July to September 2023 (site-level information and number of TB diagnoses and tests). RESULTS:Of 45 participating ART clinics, 32 (71%) were in Africa and 13 (29%) in Asia. During the COVID-19 pandemic (2020-2022), 43 (96%) clinics reported implementing social distancing or separation measures, 39 (87%) personal protections for staff members and 32 (71%) protections for patients. Infection control measures were in place in 45% of the clinics before the pandemic (until 2019), 23% introduced measures during the pandemic and 15% maintained them after the pandemic (after 2022). Service provision was affected during the pandemic in 33 (73%) clinics, including TB services in 22 (49%) clinics. TB service restrictions were addressed by introducing changes in directly observed therapy provision in 8 (18%) clinics, multimonth TB drug dispensing in 23 (51%), telehealth services in 25 (56%) and differentiated service delivery in 19 (42%). These changes were sustained after the pandemic at 4 (9%), 11 (24%), 17 (38%) and 12 (27%) clinics, respectively. Compared with 2018-2019, the number of TB diagnoses decreased sharply in 2020-2021 and improved after the pandemic. CONCLUSIONS:COVID-19 affected TB care services in ART clinics in Africa and Asia. This was paralleled by a reduction in TB diagnoses, which partly resumed after the pandemic. Infection control measures and alternative modes of service delivery were adopted during the pandemic and only partially maintained. Efforts should be made to sustain the lessons learnt during the COVID-19 pandemic, particularly approaches that reduce the risk of transmission of infectious diseases, including TB, in ART clinics.
BACKGROUND:The Integrated Management of Childhood Illness (IMCI) guidelines are implemented within primary health centres (PHCs) in resource-limited settings. These symptom-based algorithms under-diagnose severe hypoxemia, which contributes to the under-five'mortality in sub-Saharan Africa. To improve the diagnosis and management of severe hypoxaemia, the Améliorer l'Identification des détresses Respiratoires chez l'Enfant (AIRE) project implemented the routine use of pulse oximetry (PO) within IMCI consultations in Burkina Faso, Guinea, Mali and Niger. We described the intervention sites and measured their capacity to offer IMCI care prior to project implementation. METHODS:A cross-sectional quantitative survey was conducted in all the AIRE PHCs and their district hospitals (DHs) from March to July 2020. RESULTS:Overall, 215 PHCs and 8 DHs were surveyed. Almost all the PHCs were public structures, mainly managed by nurses. At least one healthcare worker was IMCI trained in >99% of PHCs. At baseline, PO was available in only 2/215 (1%) PHCs and 4/8 (50%) DH. Median referral rate was estimated to 1.5% per PHC; 35/215 (16%) PHCs had functional ambulances for managing referrals to DHs, including two with mobile oxygen. IMCI consultations were free of fees in Burkina Faso and Niger, but charged for in Guinea and Mali (from US$0.5 to US$1). All the DHs had capacities to provide specialised paediatric care, although the use of PO was not systematic. Oxygen was available at all DHs except one. Parents of children requiring hospitalisation had to pay out of pocket costs ranging from US$1.7 to US$8.4 per day. CONCLUSIONS:This survey highlights the weak adoption of IMCI guidelines in these settings, the absence of PO's at PHC level and their low use at hospital level, as well as difficulties in managing severe cases, referral to hospital and accessing oxygen. It has guided the choice of the AIRE research PHCs and the upgrading of PHCs including IMCI training.
IntroductionIn 2023, almost 200,000 children under 15 years died from tuberculosis, most without appropriate treatment. Treatment decision algorithms (TDAs), developed to facilitate rapid anti-tuberculosis treatment initiation in children, were recommended by the World Health Organization (WHO) in 2022, conditional on validation in different cohorts and settings. We performed a retrospective external evaluation of WHO TDAs using an individual participant dataset (IPD).Methods and findingsThe IPD comprised four paediatric cohorts, restricted to children with presumptive pulmonary TB < 10 years, and including children in high-risk groups (children living with HIV "CLHIV", children with severe acute malnutrition "SAM", and children <2 years). All children in the IPD were retrospectively evaluated using both TDA A (an algorithm including chest X-ray) and TDA B (without chest X-ray), excluding the triage step. The diagnostic accuracy against a composite reference standard (confirmed and unconfirmed tuberculosis versus unlikely tuberculosis) was determined and reported as sensitivities and specificities. Of 1,886 children included (RaPaed-TB: n = 740, Umoya: n = 474, TB-Speed HIV: n = 204, TB-Speed Decentralisation: n = 468), the median age was 2.9 years (interquartile range [IQR]:1.3,5.5), 741 (39.3%) were <2 years, 382 (20.3%) were CLHIV, and 284 (15.1%) had SAM. 281 (14.9%) had confirmed tuberculosis, 672 (35.6%) were classified as unconfirmed tuberculosis (clinically diagnosed, microbiological investigations negative), and 933 (49.5%) as unlikely tuberculosis. For TDAs A and B, algorithm sensitivity was 84.3% (95% CI: 74.8, 90.6) and 90.6% (95% CI: 83.8, 94.7), respectively, with a specificity of 50.6% (95% CI: 30.4, 70.7) and 30.8% (95% CI: 21.5, 42.0), respectively. For TDA A, estimated sensitivity in children in high-risk groups was lower than those with low-risk (83.0%, 95% CI: 79.4%, 86.1%; versus 88.0%, 95% CI: 84.8%, 90.6%), while having a gain in specificity (50.0%, 95% CI: 44.9%, 55.1%; versus 36.6%, 95% CI: 32.7%, 40.7%). Trends were similar for TDA B. As for limitations, most diagnostic tuberculosis studies in children, including two of those included in the IPD, are performed at secondary or tertiary hospitals with higher levels of healthcare and thus the target population might differ somewhat from the IPD, potentially limiting the generalisability of our results.ConclusionsThis retrospective external evaluation of WHO TDAs in a large IPD shows high sensitivity but sub-optimal specificity for both TDAs, in line with the meta-analyses that generated the algorithms. Prospective studies that evaluate the entire TDA, including triage step are needed. Additionally, the integration of novel diagnostic tools within the TDAs should aim to enhance the accuracy, especially the specificity.
BACKGROUND:Due to the low number of individuals with HIV-2, no randomised trials of HIV-2 treatment have ever been done. We hypothesised that a non-comparative study describing the outcomes of several antiretroviral therapy (ART) regimens in parallel groups would improve understanding of how differences between HIV-1 and HIV-2 might lead to different therapeutic approaches. METHODS:This pilot, phase 2, non-comparative, open-label, randomised controlled trial was done in Burkina Faso, Côte d'Ivoire, Senegal, and Togo. Adults with HIV-2 who were ART naive with CD4 counts of 200 cells per μL or greater were randomly assigned 1:1:1 to one of three treatment groups. A computer-generated sequentially numbered block randomisation list stratified by country was used for online allocation to the next available treatment group. In all groups, tenofovir disoproxil fumarate (henceforth tenofovir) was dosed at 245 mg once daily with either emtricitabine at 200 mg once daily or lamivudine at 300 mg once daily. The triple nucleoside reverse transcriptase inhibitor (NRTI) group received zidovudine at 250 mg twice daily. The ritonavir-boosted lopinavir group received lopinavir at 400 mg twice daily boosted with ritonavir at 100 mg twice daily. The raltegravir group received raltegravir at 400 mg twice daily. The primary outcome was the rate of treatment success at week 96, defined as an absence of serious morbidity event during follow-up, plasma HIV-2 RNA less than 50 copies per mL at week 96, and a substantial increase in CD4 cells between baseline and week 96. This trial is registered at ClinicalTrials.gov, NCT02150993, and is closed to new participants. FINDINGS:Between Jan 26, 2016, and June 29, 2017, 210 participants were randomly assigned to treatment groups. Five participants died during the 96 weeks of follow-up (triple NRTI group, n=2; ritonavir-boosted lopinavir group, n=2; and raltegravir group, n=1), eight had a serious morbidity event (triple NRTI group, n=4; ritonavir-boosted lopinavir group, n=3; and raltegravir group, n=1), 17 had plasma HIV-2 RNA of 50 copies per mL or greater at least once (triple NRTI group, n=11; ritonavir-boosted lopinavir group, n=4; and raltegravir group, n=2), 32 (all in the triple NRTI group) switched to another ART regimen, and 18 permanently discontinued ART (triple NRTI group, n=5; ritonavir-boosted lopinavir group, n=7; and raltegravir group, n=6). The Data Safety Monitoring Board recommended premature termination of the triple NRTI regimen for safety reasons. The overall treatment success rate was 57% (95% CI 47-66) in the ritonavir-boosted lopinavir group and 59% (49-68) in the raltegravir group. INTERPRETATION:The raltegravir and ritonavir-boosted lopinavir regimens were efficient and safe in adults with HIV-2. Both regimens could be compared in future phase 3 trials. The results of this pilot study suggest a trend towards better virological and immunological efficacy in the raltegravir-based regimen. FUNDING:ANRS MIE.
