SummaryBackgroundCross-resistance after first-line antiretroviral therapy (ART) failure is expected to impair activity of nucleoside reverse-transcriptase inhibitors (NRTIs) in second-line therapy for patients with HIV, but evidence for the effect of cross-resistance on virological outcomes is limited. We aimed to assess the association between the activity, predicted by resistance testing, of the NRTIs used in second-line therapy and treatment outcomes for patients infected with HIV.MethodsWe did an observational analysis of additional data from a published open-label, randomised trial of second-line ART (EARNEST) in sub-Saharan Africa. 1277 adults or adolescents infected with HIV in whom first-line ART had failed (assessed by WHO criteria with virological confirmation) were randomly assigned to a boosted protease inhibitor (standardised to ritonavir-boosted lopinavir) with two to three NRTIs (clinician-selected, without resistance testing); or with raltegravir; or alone as protease inhibitor monotherapy (discontinued after week 96). We tested genotypic resistance on stored baseline samples in patients in the protease inhibitor and NRTI group and calculated the predicted activity of prescribed second-line NRTIs. We measured viral load in stored samples for all patients obtained every 12–16 weeks. This trial is registered with Controlled-Trials.com (number ISRCTN 37737787) and ClinicalTrials.gov (number NCT00988039).FindingsBaseline genotypes were available in 391 (92%) of 426 patients in the protease inhibitor and NRTI group. 176 (89%) of 198 patients prescribed a protease inhibitor with no predicted-active NRTIs had viral suppression (viral load <400 copies per mL) at week 144, compared with 312 (81%) of 383 patients in the protease inhibitor and raltegravir group at week 144 (p=0·02) and 233 (61%) of 280 patients in the protease inhibitor monotherapy group at week 96 (p<0·0001). Compared with results with no active NRTIs, 95 (85%) of 112 patients with one predicted-active NRTI had viral suppression (p=0·3) and 20 (77%) of 26 patients with two or three active NRTIs had viral suppression (p=0·08). Over all follow-up, greater predicted NRTI activity was associated with worse viral load suppression (global p=0·0004).InterpretationGenotypic resistance testing might not accurately predict NRTI activity in protease inhibitor-based second-line ART. Our results do not support the introduction of routine resistance testing in ART programmes in low-income settings for the purpose of selecting second-line NRTIs.FundingEuropean and Developing Countries Clinical Trials Partnership, UK Medical Research Council, Institito de Salud Carlos III, Irish Aid, Swedish International Development Cooperation Agency, Instituto Superiore di Sanita, WHO, Merck.
SummaryBackgroundMillions of HIV-infected people worldwide receive antiretroviral therapy (ART) in programmes using WHO-recommended standardised regimens. Recent WHO guidelines recommend a boosted protease inhibitor plus raltegravir as an alternative second-line combination. We assessed whether this treatment option offers any advantage over the standard protease inhibitor plus two nucleoside reverse-transcriptase inhibitors (NRTIs) second-line combination after 144 weeks of follow-up in typical programme settings.MethodsWe analysed the 144-week outcomes at the completion of the EARNEST trial, a randomised controlled trial done in HIV-infected adults or adolescents in 14 sites in five sub-Saharan African countries (Uganda, Zimbabwe, Malawi, Kenya, Zambia). Participants were those who were no longer responding to non-NRTI-based first-line ART, as assessed with WHO criteria, confirmed by viral-load testing. Participants were randomly assigned to receive a ritonavir-boosted protease inhibitor (lopinavir 400 mg with ritonavir 100 mg, twice per day) plus two or three clinician-selected NRTIs (protease inhibitor plus NRTI group), protease inhibitor plus raltegravir (400 mg twice per day; protease inhibitor plus raltegravir group), or protease inhibitor monotherapy (plus raltegravir induction for first 12 weeks, re-intensified to combination therapy after week 96; protease inhibitor monotherapy group). Randomisation was by computer-generated randomisation sequence, with variable block size. The primary outcome was viral load of less than 400 copies per mL at week 144, for which we assessed non-inferiority with a one-sided α of 0·025, and superiority with a two-sided α of 0·025. The EARNEST trial is registered with ISRCTN, number 37737787.FindingsBetween April 12, 2010, and April 29, 2011, 1837 patients were screened for eligibility, of whom 1277 patients were randomly assigned to an intervention group. In the primary (complete-case) analysis at 144 weeks, 317 (86%) of 367 in the protease inhibitor plus NRTI group had viral loads of less than 400 copies per mL compared with 312 (81%) of 383 in the protease inhibitor plus raltegravir group (p=0·07; lower 95% confidence limit for difference 10·2% vs specified non-inferiority margin 10%). In the protease inhibitor monotherapy group, 292 (78%) of 375 had viral loads of less than 400 copies per mL; p=0·003 versus the protease inhibitor plus NRTI group at 144 weeks. There was no difference between groups in serious adverse events, grade 3 or 4 adverse events (total or ART-related), or events that resulted in treatment modification.InterpretationProtease inhibitor plus raltegravir offered no advantage over protease inhibitor plus NRTI in virological efficacy or safety. In the primary analysis, protease inhibitor plus raltegravir did not meet non-inferiority criteria. A regimen of protease inhibitor with NRTIs remains the best standardised second-line regimen for use in programmes in resource-limited settings.FundingEuropean and Developing Countries Clinical Trials Partnership (...
Background Clinical practice guidelines (CPG) are developed based on a synthesis of evidence regarding the best options for the assessment, diagnosis and treatment of diseases and are recognized as essential quality improvement tools. However, despite growing availability of CPG, research evaluating their use for mental disorders in Uganda is lacking. For a successful implementation of CPG to be achieved, a number of considerations need to be put in place. Objective This study aimed to assess the feasibility and acceptability of the educational intervention that we developed towards improvement of the primary health care providers (PHCPs) uptake of the Uganda Clinical Guidelines (UCG) in integrating mental health services into PHC in Mbarara district, southwestern Uganda. Methods This was a descriptive cross-sectional qualitative study with a semi-structured in-depth interview guide. The educational intervention we were assessing had four components: (i) summarized UCG on common mental disorders; (ii) modified Health Management Information System (HMIS) registers to include mental health; (iii) clinician’s checklist outlining the steps to be followed; and iv) support supervision/training. Results Six themes emerged from the study while the components of the intervention formed the apriori subthemes. Key results based on the subthemes show: (i) summarized UCG: the participants liked the packaging stating that it eased their work, was time saving and user friendly; (ii) modified register: participants appreciated the modifications made to the register updating the existing record in the Health Management Information System (HMIS) registers to include mental health disorders; (iii) TRAINING and support supervision: the PHCPs attributed the success in using the summarized UCG to the training they received, and they further expressed the need to regularize the training in assessment for mental health and support by the mental health specialists. Conclusion Our study demonstrates that the use of summarized UCG, modified HMIS registers to include mental health, training and support supervision by mental health specialists in implementing the UCG in integrating mental health at PHC settings is feasible and acceptable by the PHCPs in Mbarara district, southwestern Uganda. Given the need for improved mental health care in Uganda, this intervention could be rigorously evaluated for effectiveness, scalability and generalizability. Electronic supplementary material The online version of this article (10.1186/s13033-019-0304-9) contains supplementary material, which is available to authorized users.
Introduction: Multi-disease community health campaigns can be effective for population-wide HIV testing in a research setting (SEARCH: NCT01864603). We sought to evaluate feasibility and uptake of a community-led health campaign (CLHC) planned and implemented by village leaders and local clinic workers in Uganda.Methods: Over five months in 2014, locally elected village leaders and Ministry of Health (MoH) clinic staff in a rural parish in Uganda planned a census followed by a CLHC, after training by two SEARCH trial consultants and by leaders from a neighbouring parish that had previously participated in a SEARCH health campaign. We defined feasibility as: (1) elected leaders’ participation in training and implementation of pre-campaign census and mobilization activities; (2) implementation of all campaign activities by MoH-funded, local clinic staff; and (3) community participation in the campaign, including point-of-care screening for HIV, malaria, hypertension and diabetes, and same-day referral for male circumcision and family planning (FP). Costing of all salaries and supplies was conducted.Results: Elected leaders from all eight villages in the parish participated in CLHC training. They and local clinic staff met monthly to select and plan CLHC services. Village leaders then leveraged existing volunteer health teams to perform a door-to-door census, enumerating 5,202 parish residents over 2 weeks. 2,753 (53%) residents participated in the 6-day CLHC. Of 1,584 adult participants, 1,474 (93%) tested for HIV: 105/1,474 (7.1%) tested HIV positive. 27% (751/2,753) of participants reported fever and underwent malaria rapid diagnostic testing: 5.3% (40/751) tested positive. Among adults screened, 19% (271/1,452) were hypertensive, and 3% (18/637) had a random blood sugar >11.1 mmol/L. Of 805 men and boys (>10 years), 91 (11%) accepted same-day clinic referral and underwent medical circumcision. Of 900 women offered same-day long-term FP referrals, 25 accepted. The CLHC cost, including census, mobilization and testing services, was $23,597 ($8.57/participant).Conclusions: Elected village leaders successfully planned and conducted a 6-day multi-disease health campaign with service provision by local clinic staff that reached over half of a rural Ugandan community. These data suggest it is feasible for local leaders and clinics to adopt a multi-disease health campaign approach to scale-up HIV testing in rural Africa.
BackgroundThe prevalence of HIV infection among older persons is increasing yet older age at initiation of antiretroviral therapy (ART) may be associated with poorer treatment outcomes including mortality. However, majority of these studies have been done in the western world and there is limited data in resource limited settings. Our study used routinely collected health facility data to assess trends in age at initiation of ART, the effect of age at ART initiation on mortality and immunological response at a large urban hospital in south western Uganda.MethodsWe conducted a retrospective records review of patients attending the HIV clinic at Mbarara Regional Referral Hospital in western Uganda. We retrieved records for 8,533 patients who started ART between January 2006 and December 2012. Their data had been collected and stored as part of the larger International Epidemiological Database for the Evaluation of AIDS (IeDEA). Age was stratified into three categories namely; 18–34 (young adults), 35–49 (mid-age) and 50 years or older (older adults). Survival analysis procedures with Kaplan-Meier’s plots were used to calculate the survival probability with mortality as the endpoint and Poisson regression analysis used to determine the adjusted relative risks (RR) of mortality.ResultsThe proportion of young adults and patients at WHO stage I initiating ART increased steadily over the 7-year period. Older age at ART initiation (> = 50 years) was associated with a higher risk of mortality with adjusted relative risk (RR) at 1.63, (95% CI 1.26–2.11) compared to younger age. Male gender, WHO stages III and IV, lower CD4 count and lower body mass index were also all independently and significantly associated with higher risk for mortality. Older adults also had a poorer immunological response RR = 1.79 (95% CI 0.89–3.58) but was not statistically significant.ConclusionsFollowing ART initiation, older adults compared to the young, have a higher risk of mortality. This age group should be targeted first for ‘screen and treat’ approach. Optimization of ART treatment regimens for this age group is also required to reduce mortality and improve immunological response.
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