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 Evidence based medicine (EBM) helps clinicians to integrate latest research evidence into their daily clinical practice. There is a need for all healthcare professions to adopt it in order to provide safe and most cost-effective care. Postgraduate doctors are at the frontline of healthcare delivery and all medical institutions should strive to produce practitioners of EBM. Studies have shown that physicians are still struggling to adapt to this paradigm shift in the practice of medicine but very few studies have been done in Sub Saharan Africa. This study explored the self-reported knowledge, attitudes, practices and barriers of evidence-based practice among resident physicians in a tertiary teaching hospital. Methods A mixed methods cross-sectional study that used convergent parallel design was conducted. The quantitative arm was conducted among all residents enrolled in the Master of Medicine programme at Aga Khan University Hospital Nairobi (AKUHN). It included an online survey exploring self-reported knowledge, attitudes, practices and barriers of EBM among all residents. Simultaneously, semi-structured In-Depth Interviews were carried out among 18 purposefully selected residents in order to explore the same themes in more depth. Results One hundred and one residents (99%) responded to the survey. The mean scores for self-reported knowledge, attitude and practice of EBM among residents were 73.88, 66.96 and 63.19% respectively, which were generally higher than in comparable studies. There was a significant association between year of residency and practice of EBM. The most common barriers faced by residents were lack of time, lack of EBM skills and patients’ unawareness about EBM. From the qualitative study, residents demonstrated good knowledge and support of EBM but practice remained relatively poor. Barriers to EBM were characterized by lack of motivation, time, skills and resources, patient overload and fear of challenging consultants. Conclusion There was good understanding and support of EBM among residents at AKUHN, though challenges were experienced in regards to practice of EBM because of lack of time and skills. Therefore resources should be allocated towards integrating EBM into undergraduate medical curricula to cultivate critical thinking skills at an early stage before transition into residency.

Preconception care (PCC) aims to improve maternal and fetal health outcomes, however, its utilization remains low in developing countries. This pilot study assesses the level and determinants of PCC in an urban and a rural health facility in Kenya. Unselected pregnant women were recruited consecutively at the Mother and Child Health (MCH) clinics in Aga Khan University Hospital, Nairobi (AKUH, N-urban) and Maragua Level Four Hospital (MLFH-rural). The utilization of PCC was defined as contact with any health care provider before current pregnancy and addressing pregnancy planning and preparation. A cross-sectional approach was employed and data were analyzed using SPSS version 22. 194 participants were recruited (97 in each setting) of whom, 25.8% received PCC. Age, marital status, education, parity and occupation were significant determinants of PCC uptake. There was also a significant difference in PCC uptake between the rural (16.5%) and urban (35.1%) participants (p < 0.01), OR of 0.3 (0.19–0.72, 95% CI). The low level of PCC in Kenya revealed in this study is consistent with the low levels globally. However, this study was not powered to allow firm conclusions and analyze the true effects of PCC determinants. Therefore, further research in the field is recommended in order to inform strategies for increasing PCC utilization and awareness in Kenya.