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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.

Nearly one-quarter of HIV-infected patients in our setting present with advanced immune suppression at initial encounter. Being male, older age, and living further away from clinic are associated with late engagement to care.

Background: Since 2001, anti-retroviral therapy (ART) has been provided to over 75,000 HIV-infected patients at the USAID-Academic Model Providing Access to Healthcare (AMPATH) Partnership in western Kenya. Over 1000 of these patients have switched to second-line ART. We therefore set out to determine factors associated with first-line ART failure amongst these patients. Methods: This case controlled study matched patients (in the ratio 1:2) from the electronic AMPATH Medical Record System on the basis of age, gender, and ART initiation date. Cases were adults (≥18 years) who initiated second-line ART between January 1, 2007 and July 31, 2011 after at least one viral load measurement >5000 copies/ml or satisfying the WHO immunological or clinical failure criteria. Controls were those on non-failing first-line ART with a CD4 count > 400 /ml within the last 12 months, at the time of case incidence. Conditional logistic regression for paired data was used to assess association. We evaluated the strength of association of risk factors using stratified Cox model. Results: Of the 1084 cases and 2149 controls included in the analysis, 62% were female. Median age was 36.5 years (IQR = 30.7 - 43.1); median baseline CD4 cell count was 161 /ml (IQR = 72 - 277); Median time to ART failure was 37 months (IQR = 24 - 47). Low baseline CD4 count < 50 /ml (H.R = 7.07, (95% CI = 4.92 - 10.15); Zidovudine based ART (H.R 1.76, 95% CI = 1.25 - 2.48) and imperfect ART adherence (H.R = 2.77, 95% CI = 2.20 - 3.49) were independently associated with treatment failure. Conclusion: In this setting, low baseline CD4 count, zidovudine-based ART and imperfect adherence are associated with first-line ART treatment failure

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 Antimicrobial resistance has been named as one of the top ten threats to public health in the world. Hospital-based antimicrobial stewardship programs (ASPs) can help reduce antimicrobial resistance. The purpose of this study was to determine perceived barriers to the development and implementation of ASPs in tertiary care centers in three low- and middle-income countries (LMICs). Methods Interviews were conducted with 45 physicians at tertiary care hospitals in Sri Lanka (n = 22), Kenya (12), and Tanzania (11). Interviews assessed knowledge of antimicrobial resistance and ASPs, current antimicrobial prescribing practices, access to diagnostics that inform antimicrobial use, receptiveness to ASPs, and perceived barriers to implementing ASPs. Two independent reviewers coded the interviews using principles of applied thematic analysis, and comparisons of themes were made across the three sites. Results Barriers to improving antimicrobial prescribing included prohibitively expensive antimicrobials, limited antimicrobial availability, resistance to changing current practices regarding antimicrobial prescribing, and limited diagnostic capabilities. The most frequent of these barriers in all three locations was limited drug availability. Many physicians in all three sites had not heard of ASPs before the interviews. Improved education was a suggested component of ASPs at all three sites. The creation of guidelines was also recommended, without prompting, by interviewees at all three sites. Although most participants felt microbiological results were helpful in tailoring antibiotic courses, some expressed distrust of laboratory culture results. Biomarkers like erythrocyte sedimentation rate and c-reactive protein were not felt to be specific enough to guide antimicrobial therapy. Despite limited or no prior knowledge of ASPs, most interviewees were receptive to implementing protocols that would include documentation and consultation with ASPs regarding antimicrobial prescribing. Conclusions Our study highlighted several important barriers to implementing ASPs that were shared between three tertiary care centers in LMICs. Improving drug availability, enhancing availability of and trust in microbiologic data, creating local guidelines, and providing education to physicians regarding antimicrobial prescribing are important steps that could be taken by ASPs in these facilities.

Background: Antibiotics are the most prescribed medicines worldwide, accounting for 20%–30% of total drug expenditures in most settings. Antimicrobial stewardship activities can provide guidance for the most appropriate antibiotic use. Objective: In an effort to generate baseline data to guide antimicrobial stewardship recommendations, we conducted point-prevalence surveys at 3 hospitals in Kenya. Methods: Sites included referral hospitals located in Nairobi (2,000 beds), Eldoret (900 beds) and Mombasa (700 beds). [Results are presented in this order.] Hospital administrators, heads of infection prevention and control units, and laboratory department heads were interviewed about ongoing antimicrobial stewardship activities, existing infection prevention and control programs, and microbiology diagnostic capacities. Patient-level data were collected by a clinical or medical officer and a pharmacist. A subset of randomly selected, consenting hospital patients was enrolled, and data were abstracted from their medical records, treatment sheets, and nursing notes using a modified WHO point-prevalence survey form. Results: Overall, 1,071 consenting patients were surveyed from the 3 hospitals (n = 579, n = 263, and n = 229, respectively) of whom >60% were aged >18 years and 53% were female. Overall, 489 of 1,071 of patients (46%) received ≥1 antibiotic, of whom 254 of 489 (52%) received 1 antibiotic, 201 of 489 (41%) received 2 antibiotics, 31 of 489 (6%) received 3 antibiotics, and 3 of 489 (1%) received 4 antibiotics. Antibiotic use was higher among those aged <5 years: 150 of 244 (62%) compared with older individuals (337 of 822, 41%). Amoxicillin/clavulanate was the most commonly used antibiotic (66 of 387, 17%) at the largest hospital (in Nairobi) whereas ceftriaxone was the most common at the other 2 facilities: 57 of 184 (31%) in Eldoret and 55 of 190 (29%) in Mombasa. Metronidazole was the next most commonly prescribed antibiotic (15%–19%). Meropenem was the only carbapenem reported: 22 of 387 patients (6%) in Nairobi, 2 of 190 patients (1%) in Eldoret, and 8 of 184 patients (4%) in Mombasa. Stop dates or review dates were not indicated for 106 of 390 patients (27%) in Nairobi, 75 of 190 patients (40%) in Eldoret, and 113 of 184 patients (72%) in Mombasa receiving antibiotics. Of 761 antibiotic prescriptions, 45% had a least 1 missed dose. Culture and antibiotic susceptibility tests were limited to 50 of 246 patients (20%) in Nairobi, 17 of 124 patients (14%) in Eldoret, and 23 of 119 patients (19%) in Mombasa who received antibiotics. The largest hospital had an administratively recognized antimicrobial stewardship committee. Conclusions: The prevalence of antibiotic use found by our study was 46%, generally lower than the rates reported in 3 similar studies from other African countries, which ranged from 56% to 65%. However, these survey findings indicate that ample opportunities exist for improving antimicrobial stewardship efforts in Kenya considering the high usage of empiric therapy and low microbiologic diagnostic utilization.Funding: NoneDisclosures: None

Sickle cell disease (SCD) is a genetic disorder resulting from a mutation in the hemoglobin (Hb) gene. Sickle cell disease results in chronic anemia and a variety of acute and chronic complications that can lead to early mortality. A child with both SCD and HIV presents a management challenge, particularly in a resource-limited setting. In this case report, we describe the case of an 18-month-old Kenyan girl with SCD and HIV who developed a severe hypersensitivity reaction to first-line antiretroviral therapy (ART). Selecting an appropriate drug substitute for a child with SCD and HIV presents a management dilemma when the available options have problematic side effect profiles or are inaccessible or inappropriate according to national guidelines. The challenges in choosing an appropriate ART regimen for a child with SCD and HIV highlight the lack of data and scarcity of treatment options for pediatric patients.