Identifying research questions for HIV, tuberculosis, tuberculosis-HIV, malaria, and neglected tropical diseases through the World Health Organization guideline development process: a retrospective analysis, 2008-2018.

OBJECTIVES: World Health Organization (WHO) guidelines for health programmes and healthcare delivery are the foundation of its technical leadership in public health and essential to decision-making globally. A key function of guideline development is to identify areas in which further evidence is needed because filling these gaps will lead to future improvements in population health. The objective of this study was to examine the knowledge gaps and research questions for addressing those gaps generated through the WHO guideline development process, with the goal of informing future strategies for improving and strengthening the guideline development process. STUDY DESIGN: We did a systematic, retrospective analysis of research questions identified in the published guidelines. METHODS: We analyzed guidelines published between January 1, 2008, and December 31, 2018, by the Communicable Diseases Cluster in five disease areas: tuberculosis (TB), HIV, malaria, TB-HIV, and neglected tropical diseases (NTDs). Research questions were extracted independently by two researchers. We analyzed the distribution of research questions by disease and by topic category and did a qualitative assessment of optimum practice for research question generation during the guideline development process. RESULTS: A total of 48 guidelines were included: 26 on HIV, 1 on malaria, 11 on TB, 5 on TB/HIV, and 5 on NTDs. Overall, 36 (75%) guidelines encompassed a total of 360 explicit research questions; the remainder did not contain specific research questions. The number of research questions that focused on TB was 49, TB/HIV was 38, HIV was 250, and NTDs was 23. The number of research questions that focused on diagnosis was 43 (11.9%) of 360, prevention was 62 (17.2%), treatment was 103 (28.6%), good practice was 12 (3.3%), service delivery was 86 (23.8%), and other areas was 54 (15%). Research questions were often not formulated in a specific or actionable way and were hard to identify in the guideline. Examples of good practice identified by the review team involved the generation of specific and narrowly defined research questions, with accompanying recommendations for appropriate study design. CONCLUSIONS: The WHO must strengthen its approach to identifying and presenting research questions during the guideline development process. Ensuring access to research questions is a key next step in adding value to the guideline development process.

Renal dysfunction by baseline CD4 cell count in a cohort of adults starting antiretroviral treatment regardless of CD4 count in the HIV Prevention Trials Network 071 [HPTN 071; Population Effect of Antiretroviral Therapy to Reduce HIV Transmission (PopART)] study in South Africa.

OBJECTIVES: Renal dysfunction is a significant cause of morbidity and mortality among HIV-positive individuals. This study evaluated renal dysfunction in a cohort of adults who started antiretroviral treatment (ART) regardless of CD4 count at three Department of Health (DOH) clinics included in the HIV Prevention Trials Network 071 (HPTN 071) Population Effect of Antiretroviral Therapy to Reduce HIV Transmission (PopART) trial. METHODS: A retrospective cohort analysis of routine data for HIV-positive individuals starting ART between January 2014 and November 2015 was completed. Incident renal dysfunction was defined as an estimated glomerular filtration rate (eEGFR) < 60 mL/min after ART initiation among individuals with a baseline (pre-ART) eGFR ≥ 60 mL/min. RESULTS: Overall, 2423 individuals, with a median baseline CD4 count of 328 cells/µL [interquartile range (IQR) 195-468 cells/µL], were included in the analysis. Forty-seven individuals had a baseline eGFR < 60 mL/min. Among 1634 nonpregnant individuals started on a tenofovir-containing ART regimen and with a baseline eGFR ≥ 60 mL/min, 27 developed an eGFR < 60 mL/min on ART. Regression analysis showed lower odds of baseline eGFR < 60 mL/min at baseline CD4 counts of > 500 cells/µL [adjusted odds ratio (aOR) 0.29; 95% confidence interval (CI) 0.11-0.80], 351-500 cells/µL (aOR 0.22; 95% CI 0.08-0.59) and 201-350 (aOR 0.48; 95% CI: 0.24-0.97) compared with baseline CD4 counts < 200 cells/µL. CONCLUSIONS: This study showed low rates of renal dysfunction at baseline and on ART, with lower rates of baseline renal dysfunction among individuals with baseline CD4 counts > 200 cells/µL. Strategies that use baseline characteristics, such as age, to identify individuals at high risk of renal dysfunction on ART for enhanced eGFR monitoring may be effective and should be the subject of future research.

Forecasting the global demand for HIV monitoring and diagnostic tests: A 2016-2021 analysis.

INTRODUCTION: Despite considerable progress, just over half of the 37 million people eligible to start antiretroviral therapy (ART) have accessed treatment and millions of HIV-positive people still do not know their status. With demand for ART continuing to grow, meeting the ambitious 90-90-90 HIV treatment targets will depend on improved access to high-quality diagnostics to both diagnose infection and monitor treatment adherence in low and middle-income countries (LMICs). Robust projections of future demand for CD4, viral load (VL), HIV early-infant-diagnosis (EID) tests and HIV rapid diagnostic tests (RDTs) are needed as scale-up continues. METHODS: We estimate the current coverage for HIV diagnostics and project future demand to 2021 using a consolidated forecast using data on past coverage and current demand from a number of sources, from 130 predominantly LMIC countries. RESULTS: We forecast that the overall number of CD4 tests is expected to decline between now and 2021 as more countries adopt test-and-treat and shift to VL testing for patient monitoring. Our consolidated forecast projects a gradual decline in demand for CD4 tests to 16.6 million by 2021. We anticipate that demand for VL tests will increase to 28.5 million by 2021, reflecting the increasing number of people who will receive ART and the adoption of VL testing for patient monitoring. We expect that the demand for EID tests will grow more rapidly than in past years, driven by the implementation of testing at birth in programmes globally, in line with WHO guideline recommendations, doubling to 2.1 million tests by 2021. Demand for rapid diagnostic tests is also likely to increase, reaching 509 million tests by 2021. DISCUSSION: In order to achieve the ambitious 90-90-90 targets, it will be essential to maintain and improve access to CD4, VL, EID tests and RDTs. These projections provide insight into the global demand we can expect to see for these HIV monitoring and diagnostic tests, both in relation to historical trends, and the 90-90-90 targets. Our projections will better enable producers to ensure adequate supply, and to support procurement organisations in planning future funding and purchase plans to meet the anticipated demand. The findings highlight the ongoing need for governments and international funding bodies to prioritise improving capacity and access to HIV diagnostic and monitoring technologies in line with demand.

Three-month weekly rifapentine plus isoniazid for tuberculosis preventive treatment: a systematic review.

BACKGROUND: Uptake of preventive treatment for tuberculosis (TB) remains poor. A 3-month regimen of rifapentine (RPT) plus isoniazid (INH) (3HP) could facilitate its scale-up. We conducted a systematic review to assess the effects of 3HP compared with daily 6- or 9-month INH monotherapy. METHODS: We searched the following databases to identify randomised controlled trials: PubMed, Embase, the Web of Science, Cochrane Central Register of Controlled Trials, three ongoing trial registers and conference abstracts up to 24 January 2017. Where possible, we pooled data using a random-effects model. RESULTS: Four studies were included. Of those, we included two studies that compared 3HP with daily 6- or 9-month INH (6/9H) among adults with human immunodeficiency virus (HIV) co-infection, one among HIV-negative adults and one among predominantly HIV-negative children and adolescents. Risk of active TB was not significantly different between 3HP and 6/9H (risk ratio [RR] 0.73, 95%CI 0.23-2.29, in adults with HIV; RR 0.44, 95%CI 0.18-1.07, in adults without HIV; RR 0.13, 95%CI 0.01-2.54, in children and adolescents). Risk of hepatotoxicity was significantly lower in the 3HP group among adults with HIV (RR 0.26, 95%CI 0.12-0.55) and those without HIV (RR 0.16, 95%CI 0.10-0.27). 3HP was also associated with a higher completion rate in all subgroups. CONCLUSIONS: HP was shown to have a preventive effect similar to that of INH monotherapy, with fewer adverse events and higher completion rates. 3HP can contribute significantly to the scale-up of preventive treatment.

Time to treatment for rifampicin-resistant tuberculosis: systematic review and meta-analysis.

BACKGROUND: To reduce transmission and improve patient outcomes, rapid diagnosis and treatment of rifampicin-resistant tuberculosis (RR-TB) is required. OBJECTIVE: To conduct a systematic review and meta-analysis assessing time to treatment for RR-TB and variability using diagnostic testing methods and treatment delivery approach. DESIGN: Studies from 2000 to 2015 reporting time to second-line treatment initiation were selected from PubMed and published conference abstracts. RESULTS: From 53 studies, 83 cohorts (13 034 patients) were included. Overall weighted mean time to treatment from specimen collection was 81 days (95%CI 70-91), and was shorter with ambulatory (57 days, 95%CI 40-74) than hospital-based treatment (86 days, 95%CI 71-102). Time to treatment was shorter with genotypic susceptibility testing (38 days, 95%CI 27-49) than phenotypic testing (108 days, 95%CI 98-117). The mean percentage of diagnosed patients initiating treatment was 76% (95%CI 70-83, range 25-100). CONCLUSION: Time to second-line anti-tuberculosis treatment initiation is extremely variable across studies, and often unnecessarily long. Reduced delays are associated with genotypic testing and ambulatory treatment settings. Routine monitoring of the proportion of diagnosed patients initiating treatment and time to treatment are necessary to identify areas for intervention.

Respiratory-gated KES imaging of a rat model of acute lung injury at the Canadian Light Source.

In this study, contrast-enhanced X-ray tomographic imaging for monitoring and quantifying respiratory disease in preclinical rodent models is proposed. A K-edge imaging method has been developed at the Canadian Light Source to very accurately obtain measurements of the concentration of iodinated contrast agent in the pulmonary vasculature and inhaled xenon in the airspaces of rats. To compare the iodine and xenon concentration maps, a scout projection image was acquired to define the region of interest within the thorax for imaging and to ensure the same locations were imaged in each K-edge subtraction (KES) acquisition. A method for triggering image acquisition based on the real-time measurements of respiration was also developed to obtain images during end expiration when the lungs are stationary, in contrast to other previously published studies that alter the respiration to accommodate the image acquisition. In this study, images were obtained in mechanically ventilated animals using physiological parameters at the iodine K-edge in vivo and at the xenon K-edge post mortem (but still under mechanical ventilation). The imaging techniques were performed in healthy Brown Norway rats and in age-matched littermates that had an induced lung injury to demonstrate feasibility of the imaging procedures and the ability to correlate the lung injury and the quantitative measurements of contrast agent concentrations between the two KES images. The respiratory-gated KES imaging protocol can be easily adapted to image during any respiratory phase and is feasible for imaging disease models with compromised lung function.

Micro-computed tomography analysis of post space preparation in root canals filled with carrier-based thermoplasticized gutta-percha.

AIM: To determine whether post space preparation deviated from the root canal preparation in canals filled with Thermafil, GuttaCore or warm vertically compacted gutta-percha. METHODOLOGY: Forty-two extracted human permanent maxillary lateral incisors were decoronated, and their root canals instrumented using a standardized protocol. Samples were divided into three groups and filled with Thermafil (Dentsply Tulsa Dental Specialties, Johnson City, TN, USA), GuttaCore (Dentsply Tulsa Dental Specialties) or warm vertically compacted gutta-percha, before post space preparation was performed with a GT Post drill (Dentsply Tulsa Dental Specialties). Teeth were scanned using micro-computed tomography after root filling and again after post space preparation. Scans were examined for number of samples with post space deviation, linear deviation of post space preparation and minimum root thickness before and after post space preparation. Parametric data were analysed with one-way analysis of variance (anova) or one-tailed paired Student's t-tests, whilst nonparametric data were analysed with Fisher's exact test. RESULTS: Deviation occurred in eight of forty-two teeth (19%), seven of fourteen from the Thermafil group (50%), one of fourteen from the GuttaCore group (7%), and none from the gutta-percha group. Deviation occurred significantly more often in the Thermafil group than in each of the other two groups (P < 0.05). Linear deviation of post space preparation was greater in the Thermafil group than in both of the other groups and was significantly greater than that of the gutta-percha group (P < 0.05). Minimum root thickness before post space preparation was significantly greater than it was after post space preparation for all groups (P < 0.01). CONCLUSIONS: The differences between the Thermafil, GuttaCore and gutta-percha groups in the number of samples with post space deviation and in linear deviation of post space preparation were associated with the presence or absence of a carrier as well as the different carrier materials.

Factors associated with HIV status awareness and Linkage to Care following home based testing in rural Malawi.

OBJECTIVE: HIV diagnosis and linkage to care are the main barriers in Africa to achieving the UNAIDS 90-90-90 targets. We assessed HIV-positive status awareness and linkage to care among survey participants in Chiradzulu District, Malawi. METHOD: Nested cohort study within a population-based survey of persons aged 15-59 years between February and May 2013. Participants were interviewed and tested for HIV (and CD4 if found HIV-positive) in their homes. Multivariable regression was used to determine factors associated with HIV-positive status awareness prior to the survey and subsequent linkage to care. RESULTS: Of 8277 individuals eligible for the survey, 7270 (87.8%) participated and were tested for HIV. The overall HIV prevalence was 17.0%. Among HIV-positive participants, 77.0% knew their status and 72.8% were in care. Women (adjusted odds ratio [aOR] 6.5, 95% CI 3.2-13.1) and older participants (40-59 vs. 15-29 years, aOR 10.1, 95% CI 4.0-25.9) were more likely to be aware of their positive status. Of those newly diagnosed, 47.5% were linked to care within 3 months. Linkage to care was higher among older participants (40-59 vs. 15-29, adjusted hazard ratio [aHR] 3.39, 95% CI 1.83-6.26), women (aHR 1.73, 95% CI 1.12-2.67) and those eligible for ART (aHR 1.61, 95% CI 1.03-2.52). CONCLUSIONS: In settings with high levels of HIV awareness, home-based testing remains an efficient strategy to diagnose and link to care. Men were less likely to be diagnosed, and when diagnosed to link to care, underscoring the need for a gender focus in order to achieve the 90-90-90 targets.

Vitamin D and incident urinary incontinence in older adults.

BACKGROUND/OBJECTIVES: The aim of this study is to determine whether vitamin D status is associated with incident urinary incontinence (UI) among community-dwelling older adults. SUBJECTS/METHODS: The University of Alabama at Birmingham Study of Aging is a prospective cohort study of community-dwelling Medicare enrollees. Standardized assessment of UI was conducted using the validated Incontinence Severity Index. The analysis of 25-hydroxyvitamin D [25(OH)D] levels was performed on stored baseline sera. UI was assessed every 6-12 months for up to 42 months. The analyses included multivariable logistic regression and Cox proportional hazard models. RESULTS: Of 350 participants (175 male, 147 black, mean age 73.6±5.8), 54% (189/350) were vitamin D deficient (25(OH)D <20 ng/ml) and 25% (87/350) were vitamin D insufficient (25(OH)D: 20 ng/ml to <30 ng/ml). Among the 187 subjects with no UI at baseline, 57% (107/187) were vitamin D deficient and 24% (45/187) were vitamin D insufficient. A total of 175 of the 187 subjects had follow-up evaluation for incident UI over 42 months, and incident UI occurred in 37% (65/175). After adjustment, cumulative incident UI at 42 months was associated with baseline vitamin D insufficiency (P=0.03) and demonstrated a trend association with deficiency (P=0.07). There was no association between baseline vitamin D status and the time to incident UI. CONCLUSIONS: These preliminary results support an association between vitamin D and incident UI in community-dwelling older adults. Future studies may target specific at-risk groups, such as men with BPH or women with pelvic floor disorders for evaluation of the impact of vitamin D supplementation on urinary symptoms.

Risk factors affecting child cognitive development: a summary of nutrition, environment, and maternal-child interaction indicators for sub-Saharan Africa.

An estimated 200 million children worldwide fail to meet their development potential due to poverty, poor health and unstimulating environments. Missing developmental milestones has lasting effects on adult human capital. Africa has a large burden of risk factors for poor child development. The objective of this paper is to identify scope for improvement at the country level in three domains--nutrition, environment, and mother-child interactions. We used nationally representative data from large-scale surveys, data repositories and country reports from 2000 to 2014. Overall, there was heterogeneity in performance across domains, suggesting that each country faces distinct challenges in addressing risk factors for poor child development. Data were lacking for many indicators, especially in the mother-child interaction domain. There is a clear need to improve routine collection of high-quality, country-level indicators relevant to child development to assess risk and track progress.

Treatment outcomes for HIV and MDR-TB co-infected adults and children: systematic review and meta-analysis.

BACKGROUND: The incidence of multidrug-resistant tuberculosis (MDR-TB) is increasing in high human immunodeficiency virus (HIV) prevalence settings, with high associated mortality. Treatment outcomes in HIV-co-infected adults and children are poorly documented. OBJECTIVE: To systematically assess treatment outcomes among HIV-MDR-TB co-infected patients. METHODS: We searched two databases and the proceedings of an annual international conference up to November 2014 for studies reporting on major clinical outcomes among HIV-MDR-TB-co-infected adults and children, and pooled the results using random-effects meta-analysis. RESULTS: Of 4812 abstracts and articles screened, 30 studies providing data on 2578 adults and 147 children were included. Overall pooled treatment success was 56.9% (95% confidence interval [CI] 46.2-67.6), 49.9% (95%CI 38.5-61.2) among adults and 83.4% (95%CI 74.7-92) among children. Mortality was 38% in adults (95%CI 28-48.1) and 11.4% (95%CI 5.8-17.1) in children. Loss to follow-up was higher among adults (16.1%, 95%CI 9-23.2) than among children (3.9%, 95%CI 0.9-6.9). Adverse events were experienced by the majority of patients; however, this was inconsistently documented. The use of fluoroquinolones, aminoglycosides and Group IV drugs appeared to be associated with treatment success. CONCLUSION: The proportion of HIV-MDR-TB-co-infected patients achieving treatment success was similar to success rates reported among MDR-TB patients in general, regardless of HIV status; however, mortality was higher, particularly among adults, highlighting the need for early diagnosis and more effective treatment regimens.

Measuring absorbed dose for i-CAT CBCT examinations in child, adolescent and adult phantoms.

OBJECTIVES: Design and construct child and adolescent head phantoms to measure the absorbed doses imparted during dental CBCT and compare with the absorbed dose measured in an adult phantom. METHODS: A child phantom was developed to represent the smallest patients receiving CBCT, usually for craniofacial developmental concerns, and an adolescent phantom was developed to represent healthy orthodontic patients. Absorbed doses were measured using a thimble ionization chamber for the custom-built child and adolescent phantoms and compared with measurements using a commercially available adult phantom. Imaging was performed with an i-CAT Next Generation (Imaging Sciences International, Hatfield, PA) CBCT using two different fields of view covering the craniofacial complex (130 mm high) or maxilla/mandible (60 mm high). RESULTS: Measured absorbed doses varied depending on the location of the ionization chamber within the phantoms. For CBCT images obtained using the same protocol for all phantoms, the highest absorbed dose was measured in all locations of the small child phantom. The lowest absorbed dose was measured in the adult phantom. CONCLUSIONS: Images were obtained with the same protocol for the adult, adolescent and child phantoms. A consistent trend was observed with the highest absorbed dose being measured in the smallest phantom (child), while the lowest absorbed dose was measured in the largest phantom (adult). This study demonstrates the importance of child-sizing the dose by using dedicated paediatric protocols optimized for the imaging task, which is critical as children are more sensitive to harmful effects of radiation and have a longer life-span post-irradiation for radiation-induced symptoms to develop than do adults.

Realizing the potential for HIV self-testing.

HIV self-testing (HIVST), a process in which an individual performs a HIV rapid diagnostic test and interprets the result in private, is an emerging approach that is well accepted, potentially cost-effective and empowering for those who may not otherwise test. To further explore the potential of HIVST, the Liverpool School of Tropical Medicine and World Health Organization held the first global symposium on the legal, ethical, gender, human rights and public health implications of HIVST. The meeting highlighted the potential of HIVST to increase access to and uptake of HIV testing, and emphasized the need to further develop evidence around the quality of HIVST and linkage to post-test services, and to assess the risks and the benefits associated with scale-up. This special issue of AIDS and Behavior links directly to the symposium and presents some of the latest research and thinking on the scale-up of HIV self-testing.

Management of BU-HIV co-infection.

BACKGROUND: Buruli Ulcer (BU)-HIV co-infection is an important emerging management challenge for BU disease. Limited by paucity of scientific studies, guidance for management of this co-infection has been lacking. METHODS: Initiated by WHO, a panel of experts in BU and HIV management developed guidance principles for the management of BU-HIV co-infection based on review of available scientific evidence, current treatment experience, and global recommendations established for management of HIV infection and tuberculosis. RESULTS: The expert panel agreed that all BU patients should be offered quality provider-initiated HIV testing and counselling. In areas with high prevalence of malaria and/or bacterial infections, all patients with HIV co-infection should be started on cotrimoxazole preventative therapy. Combination antibiotic treatment for BU should be commenced before starting antiretroviral therapy (ART) and provided for 8 weeks duration. The suggested combination is rifampicin (10 mg/kg daily up to a maximum of 600 mg/day) plus streptomycin (15 mg/kg daily). An alternative regimen is rifampicin plus clarithromycin (7.5 mg/kg twice daily up to a maximum of 1000 mg daily) although due to drug interactions with antiretroviral drugs this regimen should be used with caution. ART should be initiated in all BU-HIV co-infected patients with symptomatic HIV disease (WHO clinical stage 3 or 4) regardless of CD4 cell count and in asymptomatic individuals with CD4 count ≤500 cells/mm(3) . If CD4 count is not available, BU-HIV co-infected individuals with category 2 or 3 BU disease should be offered ART. For eligible individuals, ART should be commenced as soon as possible within 8 weeks after commencing BU treatment, and as a priority in those with advanced HIV disease (CD4 ≤ 350 cells/mm(3) or WHO stage 3 or 4 disease). All co-infected patients should be actively screened for tuberculosis before commencing BU treatment and before starting ART. Programmes should implement a monitoring and reporting system to document the outcomes of BU-HIV interventions. CONCLUSIONS: Knowledge of the clinical and epidemiological interactions between BU and HIV disease is limited. While awaiting more urgently needed evidence, current management practice of both diseases has been useful to build simple 'common sense' preliminary guidance on how to manage BU-HIV co-infection.

Dose measurements for dental cone-beam CT: a comparison with MSCT and panoramic imaging.

To date there is a lack of published information on appropriate methods to determine patient doses from dental cone-beam computed tomography (CBCT) equipment. The goal of this study is to apply and extend the methods recommended in the American Association of Physicists in Medicine (AAPM) Report 111 for CBCT equipment to characterize dose and effective dose for a range of dental imaging equipment. A protocol derived from the one proposed by Dixon et al (2010 Technical Report 111, American Association of Physicist in Medicine, MD, USA), was applied to dose measurements of multi-slice CT, dental CBCT (small and large fields of view (FOV)) and a dental panoramic system. The computed tomography dose index protocol was also performed on the MSCT to compare both methods. The dose distributions in a cylindrical polymethyl methacrylate phantom were characterized using a thimble ionization chamber and Gafchromic™ film (beam profiles). Gafchromic™ films were used to measure the dose distribution in an anthropomorphic phantom. A method was proposed to extend dose estimates to planes superior and inferior to the central plane. The dose normalized to 100 mAs measured in the center of the phantom for the large FOV dental CBCT (11.4 mGy/100 mAs) is two times lower than that of MSCT (20.7 mGy/100 mAs) for the same FOV, but approximately 15 times higher than for a panoramic system (0.6 mGy/100 mAs). The effective dose per scan (in clinical conditions) found for the dental CBCT are 167.60 ± 3.62, 61.30 ± 3.88 and 92.86 ± 7.76 mSv for the Kodak 9000 (fixed scan length of 3.7 cm), and the iCAT Next Generation for 6 cm and 13 cm scan lengths respectively. The method to extend the dose estimates from the central slice to superior and inferior slices indicates a good agreement between theory and measurement. The Gafchromic™ films provided useful beam profile data and 2D distributions of dose in phantom.

Strategies for reducing treatment default in drug-resistant tuberculosis: systematic review and meta-analysis.

BACKGROUND: Scaling up treatment for multidrug-resistant tuberculosis is a global health priority. However, current treatment regimens are long and associated with side effects, and default rates are consequently high. This systematic review aimed to identify strategies for reducing treatment default. METHODS: We conducted a systematic search up to May 2012 to identify studies describing interventions to support patients receiving treatment for multidrug-resistant tuberculosis (MDR-TB). The potential influence of study interventions were explored through subgroup analyses. RESULTS: A total of 75 studies provided outcomes for 18,294 patients across 31 countries. Default rates ranged from 0.5% to 56%, with a pooled proportion of 14.8% (95%CI 12.4-17.4). Strategies identified to be associated with lower default rates included the engagement of community health workers as directly observed treatment (DOT) providers, the provision of DOT throughout treatment, smaller cohort sizes and the provision of patient education. CONCLUSION: Current interventions to support adherence and retention are poorly described and based on weak evidence. This review was able to identify a number of promising, inexpensive interventions feasible for implementation and scale-up in MDR-TB programmes. The high default rates reported from many programmes underscore the pressing need to further refine and evaluate simple intervention packages to support patients.

Nevirapine- and efavirenz-associated hepatotoxicity under programmatic conditions in Kenya and Mozambique.

To describe the frequency, risk factors, and clinical signs and symptoms associated with hepatotoxicity (HT) in patients on nevirapine- or efavirenz-based antiretroviral therapy (ART), we conducted a retrospective cohort analysis of patients attending the ART clinic in Kibera, Kenya, from April 2003 to December 2006 and in Mavalane, Mozambique, from December 2002 to March 2007. Data were collected on 5832 HIV-positive individuals who had initiated nevirapine- or efavirenz-based ART. Median baseline CD4+ count was 125 cells/µL (interquartile range [IQR] 55-196). Over a median follow-up time of 426 (IQR 147-693) days, 124 (2.4%) patients developed HT. Forty-one (54.7%) of 75 patients with grade 3 HT compared with 21 (80.8%) of 26 with grade 4 had associated clinical signs or symptoms (P = 0.018). Four (5.7%) of 124 patients with HT died in the first six months compared with 271 (5.3%) of 5159 patients who did not develop HT (P = 0.315). The proportion of patients developing HT was low and HT was not associated with increased mortality. Clinical signs and symptoms identified 50% of grade 3 HT and most cases of grade 4 HT. This suggests that in settings where alanine aminotransferase measurement is not feasible, nevirapine- and efavirenz-based ART may be given safely without laboratory monitoring.