Comparative Effectiveness of Interventions to Improve the HIV Continuum of Care and HIV Preexposure Prophylaxis in Kenya: A Model-Based Analysis.

BACKGROUND: In Western Kenya up to one-quarter of the adult population was human immunodeficiency virus (HIV)-infected in 2012. The Ministry of Health, Médecins Sans Frontières, and partners implemented an HIV program that surpassed the 90-90-90 UNAIDS targets. In this generalized epidemic, we compared the effectiveness of preexposure prophylaxis (PrEP) with improving continuum of care. METHODS: We developed a dynamic microsimulation model to project HIV incidence and infections averted to 2030. We modeled 3 strategies compared to a 90-90-90 continuum of care base case: (1) scaling up the continuum of care to 95-95-95, (2) PrEP targeting young adults with 10% coverage, and (3) scaling up to 95-95-95 and PrEP combined. RESULTS: In the base case, by 2030 HIV incidence was 0.37/100 person-years. Improving continuum levels to 95-95-95 averted 21.5% of infections, PrEP averted 8.0%, and combining 95-95-95 and PrEP averted 31.8%. Sensitivity analysis showed that PrEP coverage had to exceed 20% to avert as many infections as reaching 95-95-95. CONCLUSIONS: In a generalized HIV epidemic with continuum of care levels at 90-90-90, improving the continuum to 95-95-95 is more effective than providing PrEP. Continued improvement in the continuum of care will have the greatest impact on decreasing new HIV infections.

Two-fold increase in the HIV viral load suppression rate along with decreased incidence over six years in Ndhiwa sub-county, Kenya.

BACKGROUND: HIV-positive individuals who maintain an undetectable viral load cannot transmit the virus to others. In 2012, an HIV population-based survey was conducted in Ndhiwa sub-county (Kenya) to provide information on the HIV local epidemic. We carried out a second survey 6 years after the first one, to assess progress in HIV diagnosis and care and differences in the HIV prevalence and incidence between the two surveys. METHODS: A cross-sectional, population-based survey using cluster sampling and geospatial random selection was implemented in 2018, using the same design as 2012. Consenting participants aged 15-59 years were interviewed and tested for HIV at home. HIV-positive individuals received viral load testing (viral suppression defined as <1000 copies/ml) and Lag-Avidity EIA assay (to measure recent infection). The 90-90-90 UNAIDS indicators were also assessed. RESULTS: Overall, 6029 individuals were included in 2018. HIV prevalence was 16.9%. Viral suppression among all HIV-positive was 88.3% in 2018 (vs. 39.9% in 2012, p < 0.001). HIV incidence was 0.75% in 2018 vs. 1.90% in 2012 (p = 0.07). In 2018, the 90-90-90 indicators were 93%-97%-95% (vs. 60%-68%-83% in 2012). CONCLUSION: A two-fold increase in the HIV viral load suppression rate along with a decreasing trend in incidence was observed over 6 years in Ndhiwa sub-county. Achieving high rates of viral suppression in HIV populations that can lead to reducing HIV transmission in sub-Saharan contexts is feasible. Nevertheless, we will need further efforts to sustain this progress.

Implementation and operational feasibility of SAMBA I HIV-1 semi-quantitative viral load testing at the point-of-care in rural settings in Malawi and Uganda.

OBJECTIVE: We monitored a large-scale implementation of the Simple Amplification-Based Assay semi-quantitative viral load test for HIV-1 version I (SAMBA I Viral Load = SAMBA I VL) within Médecins Sans Frontières' HIV programmes in Malawi and Uganda, to assess its performance and operational feasibility. METHODS: Descriptive analysis of routine programme data between August 2013 and December 2016. The dataset included samples collected for VL monitoring and tested using SAMBA I VL in five HIV clinics in Malawi (four peripheral health centres and one district hospital), and one HIV clinic in a regional referral hospital in Uganda. SAMBA I VL was used for VL testing in patients who had been receiving ART for between 6 months and ten years, to determine whether plasma VL was above or below 1000 copies/mL of HIV-1, reflecting ART failure or efficacy. Randomly selected samples were quantified with commercial VL assays. SAMBA I instruments and test performance, site throughput, and delays in communicating results to clinicians and patients were monitored. RESULTS: Between August 2013 and December 2016 a total of 60 889 patient samples were analysed with SAMBA I VL. Overall, 0.23% of initial SAMBA I VL results were invalid; this was reduced to 0.04% after repeating the test once. Global test failure, including instrument failure, was 1.34%. Concordance with reference quantitative testing of VL was 2620/2727, 96.0% (1338/1382, 96.8% in Malawi; 1282/1345, 95.3% in Uganda). For Chiradzulu peripheral health centres and Arua Hospital HIV clinic, where testing was performed on-site, same-day results were communicated to clinicians for between 91% and 97% of samples. Same-day clinical review was obtained for 84.7% across the whole set of samples tested. CONCLUSIONS: SAMBA I VL testing is feasible for monitoring cohorts of 1000 to 5000 ART-experienced patients. Same-day results can be used to inform rapid clinical decision-making at rural and remote health facilities, potentially reducing time available for development of resistance and conceivably helping to reduce morbidity and mortality.

OBJECTIF: Nous avons suivi une mise en œuvre à grande échelle du test de la charge virale semi-quantitative du VIH -1 basé sur de Test de Simple Amplification version I (SAMBA I Viral Load = SAMBA I VL) au sein des programmes VIH de Médecins Sans Frontières au Malawi et en Ouganda, afin d'évaluer sa performance et sa faisabilité opérationnelle. MÉTHODES: Analyse descriptive des données du programme de routine entre août 2013 et décembre 2016. L'ensemble des données comprenait des échantillons collectés pour le suivi de la CV et testés à l'aide de SAMBA I VL dans cinq cliniques VIH au Malawi (quatre centres de santé périphériques et un hôpital de district), et une clinique VIH dans un hôpital régional de référence en Ouganda. SAMBA I VL a été utilisé pour le test de la CV chez les patients qui recevaient l'ART depuis 6 mois à dix ans, afin de déterminer si la CV plasmatique était supérieure ou inférieure à 1000 copies/ml de VIH-1, reflétant l'échec ou l'efficacité de l'ART. Des échantillons sélectionnés aléatoirement ont été quantifiés avec des tests de CV commerciaux. Les instruments de SAMBA I et les performances des tests, le débit du site et les délais dans la communication des résultats aux cliniciens et aux patients ont été suivis. RÉSULTATS: Entre août 2013 et décembre 2016, un total de 60.889 échantillons de patients ont été analysés avec SAMBA I VL. Dans l'ensemble, 0,23% des résultats initiaux de SAMBA I VL étaient invalides; ceux-ci ont été été réduits à 0,04% après avoir répété le test une fois. L'échec global du test, y compris l'échec de l'instrument, était de 1,34%. La concordance avec les tests quantitatifs de référence de la CV était de 2620/2727; 96,0% (1338/1382; 96,8% au Malawi; 1282/1345; 95,3% en Ouganda). Pour les centres de santé périphériques de Chiradzulu et la clinique VIH de l'hôpital d'Arua, où les tests ont été effectués sur place, les résultats ont été communiqués le jour même aux cliniciens pour entre 91% et 97% des échantillons. Un examen clinique le jour même a été obtenu pour 84,7% de l'ensemble des échantillons testés. CONCLUSIONS: Le test SAMBA I VL est réalisable pour le suivi de cohortes de 1.000 à 5.000 patients déjà sous ART. Les résultats le jour même peuvent être utilisés pour éclairer la prise de décision clinique rapide dans les établissements de santé ruraux et éloignés, réduisant potentiellement le temps disponible pour le développement de la résistance et contribuant éventuellement à réduire la morbidité et la mortalité.

Diagnostic value of the urine lipoarabinomannan assay in HIV-positive, ambulatory patients with CD4 below 200 cells/µl in 2 low-resource settings: A prospective observational study.

BACKGROUND: Current guidelines recommend the use of the lateral flow urine lipoarabinomannan assay (LAM) in HIV-positive, ambulatory patients with signs and symptoms of tuberculosis (TB) only if they are seriously ill or have CD4 count ≤ 100 cells/µl. We assessed the diagnostic yield of including LAM in TB diagnostic algorithms in HIV-positive, ambulatory patients with CD4 < 200 cells/µl, as well as the risk of mortality in LAM-positive patients who were not diagnosed using other diagnostic tools and not treated for TB. METHODS AND FINDINGS: We conducted a prospective observational study including HIV-positive adult patients with signs and symptoms of TB and CD4 < 200 cells/µl attending 6 health facilities in Malawi and Mozambique. Patients were included consecutively from 18 September 2015 to 27 October 2016 in Malawi and from 3 December 2014 to 22 August 2016 in Mozambique. All patients had a clinical exam and LAM, chest X-ray, sputum microscopy, and Xpert MTB/RIF assay (Xpert) requested. Culture in sputum was done for a subset of patients. The diagnostic yield was defined as the proportion of patients with a positive assay result among those with laboratory-confirmed TB. For the 456 patients included in the study, the median age was 36 years (IQR 31-43) and the median CD4 count was 50 cells/µl (IQR 21-108). Forty-five percent (205/456) of the patients had laboratory-confirmed TB. The diagnostic yields of LAM, microscopy, and Xpert were 82.4% (169/205), 33.7% (69/205), and 40.0% (84/205), respectively. In total, 50.2% (103/205) of the patients with laboratory-confirmed TB were diagnosed only through LAM. Overall, the use of LAM in diagnostic algorithms increased the yield of algorithms with microscopy and with Xpert by 38.0% (78/205) and 34.6% (71/205), respectively, and, specifically among patients with CD4 100-199 cells/µl, by 27.5% (14/51) and 29.4% (15/51), respectively. LAM-positive patients not diagnosed through other tools and not treated for TB had a significantly higher risk of mortality than LAM-positive patients who received treatment (adjusted risk ratio 2.57, 95% CI 1.27-5.19, p = 0.009). Although the TB diagnostic conditions in the study sites were similar to those in other resource-limited settings, the added value of LAM may depend on the availability of microscopy or Xpert results. CONCLUSIONS: LAM has diagnostic value for identifying TB in HIV-positive patients with signs and symptoms of TB and advanced immunodeficiency, including those with a CD4 count of 100-199 cells/µl. In this study, the use of LAM enabled the diagnosis of TB in half of the patients with confirmed TB disease; without LAM, these patients would have been missed. The rapid identification and treatment of TB enabled by LAM may decrease overall mortality risk for these patients.

High Proportions of Patients With Advanced HIV Are Antiretroviral Therapy Experienced: Hospitalization Outcomes From 2 Sub-Saharan African Sites.

Background: Human immunodeficiency virus (HIV) remains an important cause of hospitalization and death in low- and middle- income countries. Yet morbidity and in-hospital mortality patterns remain poorly characterized, with prior antiretroviral therapy (ART) exposure and treatment failure status largely unknown. Methods: We studied HIV-infected inpatients aged ≥13 years from cohorts in Kenya and the Democratic Republic of Congo (DRC), assessing clinical and demographic characteristics and hospitalization outcomes. Kenyan inpatients were prospectively enrolled during hospitalization; identical retrospective data were extracted for Congolese patients meeting the study criteria using routine medical information. Results: Among 338 HIV-infected patients in Kenya and 411 in DRC, 83.7% (95% confidence interval [CI], 79.4%-87.3%) and 97.3% (95% CI, 95.2%-98.5%), were admitted with advanced disease (defined as CD4 <200 cells/µL or World Health Organization stage 3/4 illness). Among inpatients with advanced HIV, 35.4% and 21.7% were ART-naive at admission. Patients under care had a median time of 44.1 (interquartile range [IQR], 18.4-90.5) months and 55.9 (IQR, 28.1-99.6) months on treatment; 17.2% (95% CI, 13.5%-21.6%) and 29.6% (95% CI, 25.4%-34.3%) died, 25.9% (95% CI, 16.0%-39.0%) and 22.5% (95% CI, 15.8%-31.0%) of these within 48 hours. Conclusions: Across 2 diverse clinical contexts in sub-Saharan Africa, advanced HIV inpatients were frequently admitted with low CD4 counts, often failing first-line ART. Earlier identification of treatment failure and rapid switching to second-line ART are needed.

Mortality and clinical outcomes in children treated with antiretroviral therapy in four African vertical programmes during the first decade of paediatric HIV care, 2001-2010.

OBJECTIVE: To assess mortality and clinical outcomes in children treated with antiretroviral therapy (ART) in four African vertical programmes between 2001 and 2010. METHODS: Cohort analysis of data from HIV-infected children (<15 years old) initiating ART in four sub-Saharan HIV programmes in Kenya, Uganda and Malawi, between December 2001 and December 2010. Rates of mortality, programme attrition and first-line clinico-immunological failure were calculated by age group (<2, 2-4 and 5-14 years), 1 or 2 years after ART initiation, and risk factors were examined. RESULTS: A total of 3949 children, 22.7% aged <2 years, 32.2% 2-4 years and 45.1% 5-14 years, were included. At ART initiation, 60.8% had clinical stage 3 or 4, and 46.5% severe immunosuppression. Overall mortality, attrition and 1-year failure rates were 5.1, 10.8 and 9.0 per 100 person-years, respectively. Immunosuppression, stage 3 or 4, and underweight were associated with increased rates of mortality, attrition and treatment failure. Adjusted estimates showed lower mortality hazard ratios (HR) among children aged 2-4 years (HR = 0.57, 95% CI 0.42-0.77 than children aged 5-14 years). One-year treatment failure incidence rate ratios (IRR) were similar regardless of age (IRR = 0.91, 95% CI 0.67-1.25 for <2 years; 1.01, 95% CI 0.83-1.23 for 2-4 years, vs. 5-14 years). CONCLUSIONS: Good treatment outcomes were achieved during the first decade of HIV paediatric care despite the late start of therapy. Encouraging early HIV infant diagnosis in and outside prevention of mother-to-child transmission programmes, and linkage to care services for early ART initiation, is needed to reduce mortality and delay treatment failure.

SAMBA HIV semiquantitative test, a new point-of-care viral-load-monitoring assay for resource-limited settings.

Routine viral-load (VL) testing of HIV-infected individuals on antiretroviral therapy (ART) is used to monitor treatment efficacy. However, due to logistical challenges, implementation of VL has been difficult in resource-limited settings. The aim of this study was to evaluate the performance of the SAMBA semi-Q (simple amplification-based assay semiquantitative test for HIV-1) in London, Malawi, and Uganda. The SAMBA semi-Q can distinguish between patients with VLs above and below 1,000 copies/ml. The SAMBA semi-Q was validated with diluted clinical samples and blinded plasma samples collected from HIV-1-positive individuals. SAMBA semi-Q results were compared with results from the Roche COBAS AmpliPrep/COBAS TaqMan HIV-1 test, v2.0. Testing of 96 2- to 10-fold dilutions of four samples containing HIV-1 subtype C as well as 488 samples from patients in the United Kingdom, Malawi, and Uganda yielded an overall accuracy for the SAMBA semi-Q of 99% (95% confidence interval [CI], 93.8 to 99.9%) and 96.9% (95% CI 94.9 to 98.3%), respectively, compared to to the Roche test. Analysis of VL data from patients in Malawi and Uganda showed that the SAMBA cutoff of 1,000 copies/ml appropriately distinguished treated from untreated individuals. Furthermore, analysis of the viral loads of 232 patients on ART in Malawi and Uganda revealed similar patterns for virological control, defined as either <1,000 copies/ml (SAMBA cutoff) or <5,000 copies/ml (WHO 2010 criterion; WHO, Antiretroviral Therapy for HIV Infection in Adults and Adolescents: Recommendations for a Public Health Approach, 2010). This study suggests that the SAMBA semi-Q has adequate concurrency with the gold standard measurements for viral load. This test can allow VL monitoring of patients on ART at the point of care in resource-limited settings.

Community-supported models of care for people on HIV treatment in sub-Saharan Africa.

OBJECTIVES: Further scale-up of antiretroviral therapy (ART) to those in need while supporting the growing patient cohort on ART requires continuous adaptation of healthcare delivery models. We describe several approaches to manage stable patients on ART developed by Médecins Sans Frontières together with Ministries of Health in four countries in sub-Saharan Africa. METHODS: Using routine programme data, four approaches to simplify ART delivery for stable patients on ART were assessed from a patient and health system perspective: appointment spacing for clinical and drug refill visits in Malawi, peer educator-led ART refill groups in South Africa, community ART distribution points in DRC and patient-led community ART groups in Mozambique. RESULTS: All four approaches lightened the burden for both patients (reduced travel and lost income) and health system (reduced clinic attendance). Retention in care is high: 94% at 36 months in Malawi, 89% at 12 months in DRC, 97% at 40 months in South Africa and 92% at 48 months in Mozambique. Where evaluable, service provider costs are reported to be lower. CONCLUSION: Separating ART delivery from clinical assessments was found to benefit patients and programmes in a range of settings. The success of community ART models depends on sufficient and reliable support and resources, including a flexible and reliable drug supply, access to quality clinical management, a reliable monitoring system and a supported lay workers cadre. Such models require ongoing evaluation and further adaptation to be able to reach out to more patients, including specific groups who may be challenged to meet the demands of frequent clinic visits and the integrated delivery of other essential chronic disease interventions.

Changes Over Time in the Proportion of Advanced HIV Disease in Two High HIV Prevalence Settings in Ndhiwa (Kenya) and Eshowe (South Africa).

BACKGROUND: The burden of advanced HIV disease remains a significant concern in sub-Saharan Africa. In 2015, the World Health Organization released recommendations to treat all people living with HIV (PLHIV) regardless of CD4 ("treat all") and in 2017 guidelines for managing advanced HIV disease. We assessed changes over time in the proportion of PLHIV with advanced HIV and their care cascade in two community settings in sub-Saharan Africa. METHODS: Cross-sectional population-based surveys were conducted in Ndhiwa (Kenya) in 2012 and 2018 and in Eshowe (South Africa) in 2013 and 2018. We recruited individuals aged 15-59 years. Consenting participants were interviewed and tested for HIV at home. All participants with HIV had CD4 count measured. Advanced HIV was defined as CD4 < 200 cells/µL. RESULTS: Overall, 6076 and 6001 individuals were included in 2012 and 2018 (Ndhiwa) and 5646 and 3270 individuals in 2013 and 2018 (Eshowe), respectively. In Ndhiwa, the proportion of PLHIV with advanced HIV decreased from 2012 (159/1376 (11.8%; 95% CI: 9.8-14.2)) to 2018 (53/1000 (5.0%; 3.8-6.6)). The proportion of individuals with advanced HIV on antiretroviral therapy (ART) was 9.1% (6.9-11.8) in 2012 and 4.2% (3.0-5.8) in 2018. In Eshowe, the proportion with advanced HIV was 130/1400 (9.8%; 8.0-11.9) in 2013 and 38/834 (4.5%; 3.3-6.1) in 2018. The proportion with advanced HIV among those on ART was 6.9% (5.5-8.8) in 2013 and 2.8% (1.8-4.3) in 2018. There was a significant increase in coverage for all steps of the care cascade among people with advanced HIV between the two Ndhiwa surveys, with all the changes occurring among men and not women. No significant changes were observed in Eshowe between the surveys overall and by sex. CONCLUSION: The proportion with advanced HIV disease decreased between the first and second surveys where all guidelines have been implemented between the two HIV surveys.

Distribution of advanced HIV disease between two time periods in Ndhiwa (Kenya) and Eshowe (South Africa)We examined changes over time in the proportion of people living with HIV (PLHIV) with advanced HIV and their care cascade in two community settings in sub-Saharan Africa: Ndhiwa (Kenya) and Eshowe (South Africa). In 2012 and 2018, a total of 6,076 and 6,001 individuals were included in Ndhiwa, and 5,646 and 3,270 individuals were included in Eshowe in 2013 and 2018, respectively. In Ndhiwa, the proportion of PLHIV with advanced HIV decreased from 11.8% in 2012 to 5.0% in 2018. The proportion of individuals with advanced HIV on antiretroviral therapy (ART) decreased from 9.1% in 2012 to 4.2% in 2018. In Eshowe, the proportion PLHIV with advanced HIV decreased from 9.8% in 2013 to 4.5% in 2018. Among those on ART, the proportion of PLHIV with advanced HIV decreased from 6.9% in 2013 to 2.8% in 2018. The results also showed a significant increase in coverage for all steps of the care cascade among people with advanced HIV in Ndhiwa in 2018 compared to 2012, with these changes observed only among men and not women. No significant changes were observed in Eshowe between the surveys, both overall and when comparing by sex.

Paediatric HIV care in sub-Saharan Africa: clinical presentation and 2-year outcomes stratified by age group.

OBJECTIVES: To examine age differences in mortality and programme attrition amongst paediatric patients treated in four African HIV programmes. METHODS: Longitudinal analysis of data from patients enrolled in HIV care. Two-year mortality and programme attrition rates per 1000 person-years stratified by age group (<2, 2-4 and 5-15 years) were calculated. Associations between outcomes and age and other individual-level factors were studied using multiple Cox proportional hazards (mortality) and Poisson (attrition) regression models. RESULTS: Six thousand two hundred and sixty-one patients contributed 9500 person-years; 27.1% were aged <2 years, 30.1% were 2-4, and 42.8% were 5-14 years old. At programme entry, 45.3% were underweight and 12.6% were in clinical stage 4. The highest mortality and attrition rates (98.85 and 244.00 per 1000 person-years), and relative ratios (adjusted hazard ratio [aHR] = 1.92, 95% CI 1.56-2.37; incidence ratio [aIR] = 2.10, 95% CI 1.86-2.37, respectively, compared with the 5- to 14-year group) were observed amongst the youngest children. Increased mortality and attrition were also associated with advanced clinical stage, underweight and diagnosis of tuberculosis at programme entry. CONCLUSIONS: These results highlight the need to increase access, diagnose and provide early HIV care and to accelerate antiretroviral treatment initiation for those eligible. Adapted education and support for children and their families would also be important.

Incidence, risk factors and causes of death in an HIV care programme with a large proportion of injecting drug users.

OBJECTIVES: To identify factors influencing mortality in an HIV programme providing care to large numbers of injecting drug users (IDUs) and patients co-infected with hepatitis C (HCV). METHODS: A longitudinal analysis of monitoring data from HIV-infected adults who started antiretroviral therapy (ART) between 2003 and 2009 was performed. Mortality and programme attrition rates within 2 years of ART initiation were estimated. Associations with individual-level factors were assessed with multivariable Cox and piece-wise Cox regression. RESULTS: A total of 1671 person-years of follow-up from 1014 individuals was analysed. Thirty-four percent of patients were women and 33% were current or ex-IDUs. 36.2% of patients (90.8% of IDUs) were co-infected with HCV. Two-year all-cause mortality rate was 5.4 per 100 person-years (95% CI, 4.4-6.7). Most HIV-related deaths occurred within 6 months of ART start (36, 67.9%), but only 5 (25.0%) non-HIV-related deaths were recorded during this period. Mortality was higher in older patients (HR = 2.50; 95% CI, 1.42-4.40 for ≥40 compared to 15-29 years), and in those with initial BMI < 18.5 kg/m(2) (HR = 3.38; 95% CI, 1.82-5.32), poor adherence to treatment (HR = 5.13; 95% CI, 2.47-10.65 during the second year of therapy), or low initial CD4 cell count (HR = 4.55; 95% CI, 1.54-13.41 for <100 compared to ≥100 cells/µl). Risk of death was not associated with IDU status (P = 0.38). CONCLUSION: Increased mortality was associated with late presentation of patients. In this programme, death rates were similar regardless of injection drug exposure, supporting the notion that satisfactory treatment outcomes can be achieved when comprehensive care is provided to these patients.

Viral suppression and HIV-1 drug resistance 1 year after pragmatic transitioning to dolutegravir first-line therapy in Malawi: a prospective cohort study.

BACKGROUND: Many countries are now replacing non-nucleoside reverse transcriptase inhibitor (NNRTI)-based first-line antiretroviral therapy (ART) with a regimen containing tenofovir disoproxil fumarate, lamivudine, and dolutegravir (TLD). Recognising laboratory limitations, Malawi opted to transition those on NNRTI-based first-line ART to TLD without viral load testing. We aimed to assess viral load and HIV drug resistance during 1 year following transition to TLD without previous viral load testing. METHODS: In this prospective cohort study, we monitored 1892 adults transitioning from NNRTI-based first-line ART to the TLD regimen in the Médecins Sans Frontières-supported decentralised HIV programme in Chiradzulu District, Malawi. Eligible adults were enrolled between Jan 17 and May 11, 2019, at Ndunde and Milepa health centres, and between March 8 and May 11, 2019, at the Boma clinic. Viral load at the start of the TLD regimen was assessed retrospectively and measured at month 3, 6, and 12, and additionally at month 18 for those ever viraemic (viral load ≥50 copies per mL). Dolutegravir minimal plasma concentrations (Cmin) were determined for individuals with viraemia. Drug-resistance testing was done at the start of TLD regimen and at viral failure (viral load ≥50 copies per mL, followed by viral load ≥500 copies per mL; resistance defined as Stanford score ≥15). FINDINGS: Of 1892 participants who transitioned to the TLD regimen, 101 (5·3%) were viraemic at TLD start. 89 of 101 had drug-resistance testing with 31 participants (34·8%) with Lys65Arg mutation, 48 (53·9%) with Met184Val/Ile, and 42 (40·4%) with lamivudine and tenofovir disoproxil fumerate dual resistance. At month 12 (in the per-protocol population), 1725 (97·9% [95% CI 97·1-98·5]) of 1762 had viral loads of less than 50 copies per mL, including 83 (88·3% [80·0-94·0]) of 94 of those who were viraemic at baseline. At month 18, 35 (97·2% [85·5-99·9]) of 36 who were viraemic at TLD start with lamivudine and tenofovir disoproxil fumarate resistance and 27 (81·8% [64·5-93·0]) of 33 of those viraemic at baseline without resistance had viral load suppression. 14 of 1838 with at least two viral load tests upon transitioning had viral failure (all with at least one dolutegravir Cmin value <640 ng/mL; active threshold), suggesting suboptimal adherence. High baseline viral load was associated with viral failure (adjusted odds ratio [aOR] 14·1 [2·3-87·4] for 1000 to <10 000 copies per mL; aOR 64·4 [19·3-215·4] for ≥10 000 copies per mL). Two people with viral failure had dolutegravir resistance at 6 months (Arg263Lys or Gly118Arg mutation), both were viraemic with lamivudine and tenofovir disoproxil fumarate resistance at baseline. INTERPRETATION: High viral load suppression 1 year after introduction of the TLD regimen supports the unconditional transition strategy in Malawi. However, high pre-transition viral load, ongoing adherence challenges, and possibly existing nucleoside reverse transcriptase inhibitor resistance can lead to rapid development of dolutegravir resistance in a few individuals. This finding highlights the importance of viral load monitoring and dolutegravir-resistance surveillance after mass transitioning to the TLD regimen. FUNDING: Médecins Sans Frontières. TRANSLATIONS: For the French and Portuguese translations of the abstract see Supplementary Materials section.

Benefit of viral load testing for confirmation of immunological failure in HIV patients treated in rural Malawi.

OBJECTIVE: Viral load testing is used in the HIV programme of Chiradzulu, Malawi, to confirm the diagnosis of immunological failure to prevent unnecessary switching to second-line therapy. Our objective was to quantify the benefit of this strategy for management of treatment failure in a large decentralized HIV programme in Africa. METHODS: Retrospective analysis of monitoring data from adults treated with first-line antiretroviral regimens for >1 year and meeting the WHO immunological failure criteria in an HIV programme in rural Malawi. The positive predictive value of using immunological failure criteria to diagnose virological failure (viral load >5000 copies/ml) was estimated. RESULTS: Of the 227 patients with immunological failure (185 confirmed with a repeat CD4 measurement), 155 (68.2%) had confirmatory viral load testing. Forty-four (28.4%) had viral load >5000 copies/ml and 57 (36.8%) >1000 copies/ml. Positive predictive value was 28.4% (95% CI 21.4-36.2%). Repeat CD4 count testing showed that 41% of patients initially diagnosed with immunological failure did no longer meet failure criteria. CONCLUSIONS: Our results support the need for confirming all cases of immunological failure with viral load testing before switching to second-line ART to optimize the use of resources in developing countries.

Urine Lipoarabinomannan Testing for All HIV Patients Hospitalized in Medical Wards Identifies a Large Proportion of Patients With Tuberculosis at Risk of Death.

BACKGROUND: Diagnosing tuberculosis (TB), the leading cause of death in people with HIV, remains a challenge in resource-limited countries. We assessed TB diagnosis using a strategy that included systematic urine lipoarabinomannan (LAM) testing for all HIV patients hospitalized in medical wards and 6-month mortality according to LAM results. METHODS: This prospective, observational study included adult HIV patients hospitalized in the medical wards of a public district hospital in Malawi regardless of their TB symptoms or CD4 count. Each patient had a clinical examination, and Alere Determine TB-LAM, sputum microscopy, sputum GeneXpert MTB/RIF (Xpert), chest x-ray, and CD4 count were systematically requested. RESULTS: Among 387 inpatients, 54% had a CD4 <200 cells/µL, 64% had presumptive TB, and 90% had ≥1 TB symptom recorded in their medical file. LAM results were available for 99.0% of patients, microscopy for 62.8%, and Xpert for 60.7%. In total, 26.1% (100/383) had LAM-positive results, 48% (48/100) of which were grades 2-4. Any TB laboratory test result was positive in 30.8% (119/387). Among patients with no Xpert result, 28.5% (43/151) were LAM-positive. Cumulative 6-month mortality was 40.1% (151/377): 50.5% (49/97) in LAM-positives and 36.2% (100/276) in LAM-negatives (P = .013). In multivariable regression analyses, LAM-positive patients had a higher risk of mortality than LAM-negatives (adjusted odds ratio, 2.5; 95% CI, 1.1-5.8; P = .037). CONCLUSIONS: In resource-limited hospital medical wards with high TB prevalence, a diagnostic strategy including systematic urine LAM testing for all HIV patients is an easily implementable strategy that identifies a large proportion of patients with TB at risk of death.

High Prevalence of NRTI and NNRTI Drug Resistance Among ART-Experienced, Hospitalized Inpatients.

BACKGROUND: Patients hospitalized with advanced HIV have a high mortality risk. We assessed viremia and drug resistance among differentiated care services and explored whether expediting the switching of failing treatments may be justified. SETTING: Hospitals in the Democratic Republic of (DRC) Congo (HIV hospital) and Kenya (general hospital including HIV care). METHODS: Viral load (VL) testing and drug resistance (DR) genotyping were conducted for HIV inpatients ≥15 years, on first-line antiretroviral therapy (ART) for ≥6 months, and CD4 ≤350 cells/µL. Dual-class DR was defined as low-, intermediate-, or high-level DR to at least 1 nucleoside reverse transcriptase inhibitor and 1 non-nucleoside reverse transcriptase inhibitor. ART regimens were considered ineffective if dual-class DR was detected at viral failure (VL ≥1000 copies/mL). RESULTS: Among 305 inpatients, 36.7% (Kenya) and 71.2% (DRC) had VL ≥1000 copies/mL, of which 72.9% and 73.7% had dual-class DR. Among viral failures on tenofovir disoproxil fumarate (TDF)-based regimens, 56.1% had TDF-DR and 29.8% zidovudine (AZT)-DR; on AZT regimens, 71.4% had AZT-DR and 61.9% TDF-DR, respectively. Treatment interruptions (≥48 hours during past 6 months) were reported by 41.7% (Kenya) and 56.7% (DRC). Approximately 56.2% (Kenya) and 47.4% (DRC) on TDF regimens had tenofovir diphosphate concentrations <1250 fmol/punch (suboptimal adherence). Among viral failures with CD4 <100 cells/µL, 76.0% (Kenya) and 84.6% (DRC) were on ineffective regimens. CONCLUSIONS: Many hospitalized, ART-experienced patients with advanced HIV were on an ineffective first-line regimen. Addressing ART failure promptly should be integrated into advanced disease care packages for this group. Switching to effective second-line medications should be considered after a single high VL on non-nucleoside reverse transcriptase inhibitor-based first-line if CD4 ≤350 cells/µL or, when VL is unavailable, among patients with CD4 ≤100 cells/µL.

Vital status of pre-ART and ART patients defaulting from care in rural Malawi.

OBJECTIVES: To ascertain the outcome of pre-Antiretroviral therapy (ART) and ART patients defaulting from care and investigate reasons for defaulting. METHODS: Patients defaulting from HIV care in Chiradzulu between July 2004 and September 2007 were traced at last known home address. Deaths and moves were recorded, and patients found alive were interviewed. Defaulting was defined as missed last appointment by more than 1 month among patients of unknown vital status. RESULTS: A total of 1637 individuals were traced (54%-88% of eligible), 981 pre-ART and 656 ART patients. Of 694 pre-ART patients found, 49% had died (51% of adults and 38% of children), a median of 47 days after defaulting, and 14% had moved away. Of 451 ART patients found, 54% had died (54% of adults and 50% of children), a median of 52 days after defaulting, and 20% had moved away. Overall, 221 patients were interviewed (90% of those found alive), 42% had worked outside the district in the previous year; 49% of pre-ART and 19% of ART patients had not disclosed their HIV status to other household members. Main reasons for defaulting were stigma (43%), care dissatisfaction (34%), improved health (28%) and for ART discontinuation, poor understanding of disease or treatment (56%) and drug side effects (42%). CONCLUSION: This study in a rural African HIV programme reveals the dynamics related to health service access and use, and it provides information to correct programme mortality estimates for adults and children.

"We give them threatening advice ": expectations of adherence to antiretroviral therapy and their consequences among adolescents living with HIV in rural Malawi.

INTRODUCTION: Many adolescents living with HIV in sub-Saharan Africa struggle to achieve optimal adherence to antiretroviral therapy (ART), but few studies have investigated how their treatment-taking decisions are influenced by their social interactions with providers, caregivers and community leaders. This study aims to explore the narratives that define expectations of adherence to ART among adolescents living with HIV in a rural Malawian setting. METHODS: Overall, 45 in-depth interviews were conducted in 2016 with adolescents living with HIV, caregivers, health workers and community leaders, and four group sessions using participatory tools were undertaken with adolescents. Interviews and group sessions were audio-recorded, transcribed and translated into English. Data were coded inductively and analysed thematically. RESULTS: Adolescents were given strict behavioural codes around optimal treatment adherence, which were often enforced through encouragement, persuasian and threats. In HIV clinics, some staff supported adolescents with broader concerns relating to living with HIV, but other measures to address sub-optimal adherence in HIV clinics were perceived by patients as punitive, including pill-counts and increased frequency of clinic visits. Community leaders felt responsible for young peoples' health, sometimes attempting to influence their treatment-taking by threatening to withdraw services, or to publically "out" those deemed to be non-adherent. At home, discussions with adolescents about HIV were often limited to dose reminders, and some caretakers resorted to physical punishment to ensure adherence. While some adolescents complied with strictly-enforced adherence rules, others demonstrated resistance by hiding missed doses, secretly throwing away drugs, or openly refusing to take them. CONCLUSIONS: The potential of young people to adhere to their ART may be undermined by restrictive messages and punitive approaches to enforce and control their engagement with treatment at home, in the clinic and in the wider community. Interventions should focus on creating safe spaces for adolescents to speak frankly about the adherence challenges that they face and support for caregivers including home-based interventions.

Should Urine-LAM Tests Be Used in TB Symptomatic HIV-Positive Patients When No CD4 Count Is Available? A Prospective Observational Cohort Study From Malawi.

BACKGROUND: Current eligibility criteria for urine lateral-flow lipoarabinomannan assay (LF-LAM) in ambulatory, HIV-positive patients rely on the CD4 count. We investigated the diagnostic yield of LF-LAM and the 6-month mortality in ambulatory, TB symptomatic, HIV-positive patients regardless of their CD4 count. METHODS: We conducted a prospective, observational study that included all ambulatory, ≥15-year-old, TB symptomatic (cough, weight loss, fever, or night sweats) HIV-positive patients presenting at 4 health facilities in Malawi. Patients received a clinical examination and were requested urine LF-LAM, sputum microscopy, and Xpert MTB/RIF. TB was defined as bacteriologically confirmed if Xpert was positive. RESULTS: Of 485 patients included, 171 (35.3%) had a CD4 <200 and 32 (7.2%) were seriously ill. Median CD4 count was 341 cells/µL (interquartile range: 129-546). LAM was positive in 24.9% patients with CD4 < 200 (50% LAM grades 2-4) and 12.5% with CD4 ≥ 200 (12.8% LAM grades 2-4). Xpert was positive in 14.1% (44/312). Among Xpert-positive patients, LAM positivity was 56.7% (CD4 < 200) and 42.9% (CD4 ≥ 200), P = 0.393. Of the patients without an Xpert result, 13.4% (23/172) were LAM positive (ie, potentially missed patients). Overall, mortality was 9.2% (44/478). More pronounced LAM-positive patients had higher mortality than LAM-negative (grades 2-4: 36.0%; grade 1: 9.1%; negative: 7.4%; P < 0.001). LAM-positive patients with CD4 <200 cells/µL had higher risk of mortality than LAM negatives (adjusted hazard ratio: 3.2, 95% confidence interval: 1.4 to 7.2, P = 0.006), particularly those with LAM grades 2-4 (adjusted hazard ratio: 4.9, 95% confidence interval: 1.8 to 13.3, P = 0.002). CONCLUSIONS: Urine-LAM testing can be useful for TB diagnosis in HIV-positive TB-symptomatic patients with no CD4 cell count. LAM grade can identify patients at higher risk of death in this situation.

Framework for the implementation of advanced HIV disease diagnostics in sub-Saharan Africa: programmatic perspectives.

Patients with advanced HIV disease have a high risk of mortality, mainly from tuberculosis and cryptococcal meningitis. The advanced HIV disease management package recommended by WHO, which includes diagnostics, therapeutics, and patient psychosocial support, is barely implemented in many different countries. Here, we present a framework for the implementation of advanced HIV disease diagnostics. Laboratory and point-of-care-based reflex testing, coupled with provider-initiated requested testing, for cryptococcal antigen and urinary Mycobacterium tuberculosis lipoarabinomannan antigen, should be done for all patients with CD4+ cell counts of 200 cells per µL or less. Implementation of the advanced HIV disease package should be encouraged within primary health-care facilities and task shifting of testing to lay cadres could facilitate access to rapid results. Implementation of differentiated antiretroviral therapy delivery models can allow clinicians enough time to focus on the management of patients with advanced HIV disease. Efficient up-referral and post-discharge systems, including the development of patient-centric advanced HIV disease literacy, are also crucial. Implementation of the advanced HIV disease package is feasible at all health-care levels, and it should be part of the core of the global response towards ending AIDS as a public health threat.

Point-of-care viral load monitoring: outcomes from a decentralized HIV programme in Malawi.

INTRODUCTION: Routinely monitoring the HIV viral load (VL) of people living with HIV (PLHIV) on anti-retroviral therapy (ART) facilitates intensive adherence counselling and faster ART regimen switch when treatment failure is indicated. Yet standard VL-testing in centralized laboratories can be time-intensive and logistically difficult in low-resource settings. This paper evaluates the outcomes of the first four years of routine VL-monitoring using Point-of-Care technology, implemented by Médecins Sans Frontières (MSF) in rural clinics in Malawi. METHODS: We conducted a retrospective cohort analysis of patients eligible for routine VL- testing between 2013 and 2017 in four decentralized ART-clinics and the district hospital in Chiradzulu, Malawi. We assessed VL-testing coverage and the treatment failure cascade (from suspected failure (first VL>1000 copies/mL) to VL suppression post regimen switch). We used descriptive statistics and multivariate logistic regression to assess factors associated with suspected failure. RESULTS AND DISCUSSION: Among 21,400 eligible patients, VL-testing coverage was 85% and VL suppression was found in 89% of those tested. In the decentralized clinics, 88% of test results were reviewed on the same day as blood collection, whereas in the district hospital the median turnaround-time for results was 85 days. Among first-line ART patients with suspected failure (N = 1544), 30% suppressed (VL<1000 copies/mL), 35% were treatment failures (confirmed by subsequent VL-testing) and 35% had incomplete VL follow-up. Among treatment failures, 80% (N = 540) were switched to a second-line regimen, with a higher switching rate in the decentralized clinics than in the district hospital (86% vs. 67%, p < 0.01) and a shorter median time-to-switch (6.8 months vs. 9.7 months, p < 0.01). Similarly, the post-switch VL-testing rate was markedly higher in the decentralized clinics (61% vs. 26%, p < 0.01). Overall, 79% of patients with a post-switch VL-test were suppressed. CONCLUSIONS: Viral load testing at the point-of-care in Chiradzulu, Malawi achieved high coverage and good drug regimen switch rates among those identified as treatment failures. In decentralized clinics, same-day test results and shorter time-to-switch illustrated the game-changing potential of POC-based VL-testing. Nevertheless, gaps were identified along all steps of the failure cascade. Regular staff training, continuous monitoring and creating demand are essential to the success of routine VL-testing.