Targeted malaria elimination interventions reduce Plasmodium falciparum infections up to 3 kilometers away.

Malaria elimination interventions in low-transmission settings aim to extinguish hot spots and prevent transmission to nearby areas. In malaria elimination settings, the World Health Organization recommends reactive, focal interventions targeted to the area near malaria cases shortly after they are detected. A key question is whether these interventions reduce transmission to nearby uninfected or asymptomatic individuals who did not receive interventions. Here, we measured direct effects (among intervention recipients) and spillover effects (among non-recipients) of reactive, focal interventions delivered within 500m of confirmed malaria index cases in a cluster-randomized trial in Namibia. The trial delivered malaria chemoprevention (artemether lumefantrine) and vector control (indoor residual spraying with Actellic) separately and in combination using a factorial design. We compared incidence, infection prevalence, and seroprevalence between study arms among intervention recipients (direct effects) and non-recipients (spillover effects) up to 3 km away from index cases. We calculated incremental cost-effectiveness ratios accounting for spillover effects. The combined chemoprevention and vector control intervention produced direct effects and spillover effects. In the primary analysis among non-recipients within 1 km from index cases, the combined intervention reduced malaria incidence by 43% (95% CI 20%, 59%). In secondary analyses among non-recipients 500m-3 km from interventions, the combined intervention reduced infection by 79% (6%, 95%) and seroprevalence 34% (20%, 45%). Accounting for spillover effects increased the cost-effectiveness of the combined intervention by 37%. Our findings provide the first evidence that targeting hot spots with combined chemoprevention and vector control interventions can indirectly benefit non-recipients up to 3 km away.

Cost and cost effectiveness of reactive case detection (RACD), reactive focal mass drug administration (rfMDA) and reactive focal vector control (RAVC) to reduce malaria in the low endemic setting of Namibia: an analysis alongside a 2×2 factorial design cluster randomised controlled trial.

OBJECTIVES: To estimate the cost and cost effectiveness of reactive case detection (RACD), reactive focal mass drug administration (rfMDA) and reactive focal vector control (RAVC) to reduce malaria in a low endemic setting. SETTING: The study was part of a 2×2 factorial design cluster randomised controlled trial within the catchment area of 11 primary health facilities in Zambezi, Namibia. PARTICIPANTS: Cost and outcome data were collected from the trial, which included 8948 community members that received interventions due to their residence within 500 m of malaria index cases. OUTCOME MEASURES: The primary outcome was incremental cost effectiveness ratio (ICER) per in incident case averted. ICER per prevalent case and per disability-adjusted life years (DALY) averted were secondary outcomes, as were per unit interventions costs and personnel time. Outcomes were compared as: (1) rfMDA versus RACD, (2) RAVC versus no RAVC and (3) rfMDA+RAVC versus RACD only. RESULTS: rfMDA cost 1.1× more than RACD, and RAVC cost 1.7× more than no RAVC. Relative to RACD only, the cost of rfMDA+RAVC was double ($3082 vs $1553 per event). The ICERs for rfMDA versus RACD, RAVC versus no RAVC and rfMDA+RAVC versus RACD only were $114, $1472 and $842, per incident case averted, respectively. Using prevalent infections and DALYs as outcomes, trends were similar. The median personnel time to implement rfMDA was 20% lower than for RACD (30 vs 38 min per person). The median personnel time for RAVC was 34 min per structure sprayed. CONCLUSION: Implemented alone or in combination, rfMDA and RAVC were cost effective in reducing malaria incidence and prevalence despite higher implementation costs in the intervention compared with control arms. Compared with RACD, rfMDA was time saving. Cost and time requirements for the combined intervention could be decreased by implementing rfMDA and RAVC simultaneously by a single team. TRIAL REGISTRATION NUMBER: NCT02610400; Post-results.

Serological evaluation of the effectiveness of reactive focal mass drug administration and reactive vector control to reduce malaria transmission in Zambezi Region, Namibia: Results from a secondary analysis of a cluster randomised trial.

BACKGROUND: Due to challenges in measuring changes in malaria at low transmission, serology is increasingly being used to complement clinical and parasitological surveillance. Longitudinal studies have shown that serological markers, such as Etramp5.Ag1, can reflect spatio-temporal differences in malaria transmission. However, these markers have yet to be used as endpoints in intervention trials. METHODS: Based on data from a 2017 cluster randomised trial conducted in Zambezi Region, Namibia, evaluating the effectiveness of reactive focal mass drug administration (rfMDA) and reactive vector control (RAVC), this study conducted a secondary analysis comparing antibody responses between intervention arms as trial endpoints. Antibody responses were measured on a multiplex immunoassay, using a panel of eight serological markers of Plasmodium falciparum infection - Etramp5.Ag1, GEXP18, HSP40.Ag1, Rh2.2030, EBA175, PfMSP119, PfAMA1, and PfGLURP.R2. FINDINGS: Reductions in sero-prevalence to antigens Etramp.Ag1, PfMSP119, Rh2.2030, and PfAMA1 were observed in study arms combining rfMDA and RAVC, but only effects for Etramp5.Ag1 were statistically significant. Etramp5.Ag1 sero-prevalence was significantly lower in all intervention arms. Compared to the reference arms, adjusted prevalence ratio (aPR) for Etramp5.Ag1 was 0.78 (95%CI 0.65 - 0.91, p = 0.0007) in the rfMDA arms and 0.79 (95%CI 0.67 - 0.92, p = 0.001) in the RAVC arms. For the combined rfMDA plus RAVC intervention, aPR was 0.59 (95%CI 0.46 - 0.76, p < 0.0001). Significant reductions were also observed based on continuous antibody responses. Sero-prevalence as an endpoint was found to achieve higher study power (99.9% power to detect a 50% reduction in prevalence) compared to quantitative polymerase chain reaction (qPCR) prevalence (72.9% power to detect a 50% reduction in prevalence). INTERPRETATION: While the observed relative reduction in qPCR prevalence in the study was greater than serology, the use of serological endpoints to evaluate trial outcomes measured effect size with improved precision and study power. Serology has clear application in cluster randomised trials, particularly in settings where measuring clinical incidence or infection is less reliable due to seasonal fluctuations, limitations in health care seeking, or incomplete testing and reporting. FUNDING: This study was supported by Novartis Foundation (A122666), the Bill & Melinda Gates Foundation (OPP1160129), and the Horchow Family Fund (5,300,375,400).

Effectiveness and safety of reactive focal mass drug administration (rfMDA) using dihydroartemisinin-piperaquine to reduce malaria transmission in the very low-endemic setting of Eswatini: a pragmatic cluster randomised controlled trial.

INTRODUCTION: To reduce malaria transmission in very low-endemic settings, screening and treatment near index cases (reactive case detection (RACD)), is widely practised, but the rapid diagnostic tests (RDTs) used miss low-density infections. Reactive focal mass drug administration (rfMDA) may be safe and more effective. METHODS: We conducted a pragmatic cluster randomised controlled trial in Eswatini, a very low-endemic setting. 77 clusters were randomised to rfMDA using dihydroartemisin-piperaquine (DP) or RACD involving RDTs and artemether-lumefantrine. Interventions were delivered by the local programme. An intention-to-treat analysis was used to compare cluster-level cumulative confirmed malaria incidence among clusters with cases. Secondary outcomes included safety and adherence. RESULTS: From September 2015 to August 2017, 222 index cases from 47 clusters triggered 46 RACD events and 64 rfMDA events. RACD and rfMDA were delivered to 1455 and 1776 individuals, respectively. Index case coverage was 69.5% and 62.4% for RACD and rfMDA, respectively. Adherence to DP was 98.7%. No serious adverse events occurred. For rfMDA versus RACD, cumulative incidences (per 1000 person-years) of all malaria were 2.11 (95% CI 1.73 to 2.59) and 1.97 (95% CI 1.57 to 2.47), respectively; and of locally acquired malaria, they were 1.29 (95% CI 1.00 to 1.67) and 0.97 (95% CI 0.71 to 1.34), respectively. Adjusting for imbalance in baseline incidence, incidence rate ratio for rfMDA versus RACD was 0.95 (95% CI 0.55 to 1.65) for all malaria and 0.82 (95% CI 0.40 to 1.71) for locally acquired malaria. Similar results were obtained in a per-protocol analysis that excluded clusters with <80% index case coverage. CONCLUSION: In a very low-endemic, real-world setting, rfMDA using DP was safe, but did not lower incidence compared with RACD, potentially due to insufficient coverage and/or power. To assess impact of interventions in very low-endemic settings, improved coverage, complementary interventions and adaptive ring trial designs may be needed. TRIAL REGISTRATION NUMBER: NCT02315690.

Crystal Structure and Mechanistic Molecular Modeling Studies of Mycobacterium tuberculosis Diterpene Cyclase Rv3377c.

Terpenes make up the largest class of natural products, with extensive chemical and structural diversity. Diterpenes, mostly isolated from plants and rarely prokaryotes, exhibit a variety of important biological activities and valuable applications, including providing antitumor and antibiotic pharmaceuticals. These natural products are constructed by terpene synthases, a class of enzymes that catalyze one of the most complex chemical reactions in biology: converting simple acyclic oligo-isoprenyl diphosphate substrates to complex polycyclic products via carbocation intermediates. Here we obtained the second ever crystal structure of a class II diterpene synthase from bacteria, tuberculosinol pyrophosphate synthase (i.e., Halimadienyl diphosphate synthase, MtHPS, or Rv3377c) from Mycobacterium tuberculosis (Mtb). This enzyme transforms (E,E,E)-geranylgeranyl diphosphate into tuberculosinol pyrophosphate (Halimadienyl diphosphate). Rv3377c is part of the Mtb diterpene pathway along with Rv3378c, which converts tuberculosinol pyrophosphate to 1-tuberculosinyl adenosine (1-TbAd). This pathway was shown to exist only in virulent Mycobacterium species, but not in closely related avirulent species, and was proposed to be involved in phagolysosome maturation arrest. To gain further insight into the reaction pathway and the mechanistically relevant enzyme substrate binding orientation, electronic structure calculation and docking studies of reaction intermediates were carried out. Results reveal a plausible binding mode of the substrate that can provide the information to guide future drug design and anti-infective therapies of this biosynthetic pathway.

Effectiveness of reactive focal mass drug administration and reactive focal vector control to reduce malaria transmission in the low malaria-endemic setting of Namibia: a cluster-randomised controlled, open-label, two-by-two factorial design trial.

BACKGROUND: In low malaria-endemic settings, screening and treatment of individuals in close proximity to index cases, also known as reactive case detection (RACD), is practised for surveillance and response. However, other approaches could be more effective for reducing transmission. We aimed to evaluate the effectiveness of reactive focal mass drug administration (rfMDA) and reactive focal vector control (RAVC) in the low malaria-endemic setting of Zambezi (Namibia). METHODS: We did a cluster-randomised controlled, open-label trial using a two-by-two factorial design of 56 enumeration area clusters in the low malaria-endemic setting of Zambezi (Namibia). We randomly assigned these clusters using restricted randomisation to four groups: RACD only, rfMDA only, RAVC plus RACD, or rfMDA plus RAVC. RACD involved rapid diagnostic testing and treatment with artemether-lumefantrine and single-dose primaquine, rfMDA involved presumptive treatment with artemether-lumefantrine, and RAVC involved indoor residual spraying with pirimiphos-methyl. Interventions were administered within 500 m of index cases. To evaluate the effectiveness of interventions targeting the parasite reservoir in humans (rfMDA vs RACD), in mosquitoes (RAVC vs no RAVC), and in both humans and mosquitoes (rfMDA plus RAVC vs RACD only), an intention-to-treat analysis was done. For each of the three comparisons, the primary outcome was the cumulative incidence of locally acquired malaria cases. This trial is registered with ClinicalTrials.gov, number NCT02610400. FINDINGS: Between Jan 1, 2017, and Dec 31, 2017, 55 enumeration area clusters had 1118 eligible index cases that led to 342 interventions covering 8948 individuals. The cumulative incidence of locally acquired malaria was 30·8 per 1000 person-years (95% CI 12·8-48·7) in the clusters that received rfMDA versus 38·3 per 1000 person-years (23·0-53·6) in the clusters that received RACD; 30·2 per 1000 person-years (15·0-45·5) in the clusters that received RAVC versus 38·9 per 1000 person-years (20·7-57·1) in the clusters that did not receive RAVC; and 25·0 per 1000 person-years (5·2-44·7) in the clusters that received rfMDA plus RAVC versus 41·4 per 1000 person-years (21·5-61·2) in the clusters that received RACD only. After adjusting for imbalances in baseline and implementation factors, the incidence of malaria was lower in clusters receiving rfMDA than in those receiving RACD (adjusted incidence rate ratio 0·52 [95% CI 0·16-0·88], p=0·009), lower in clusters receiving RAVC than in those that did not (0·48 [0·16-0·80], p=0·002), and lower in clusters that received rfMDA plus RAVC than in those receiving RACD only (0·26 [0·10-0·68], p=0·006). No serious adverse events were reported. INTERPRETATION: In a low malaria-endemic setting, rfMDA and RAVC, implemented alone and in combination, reduced malaria transmission and should be considered as alternatives to RACD for elimination of malaria. FUNDING: Novartis Foundation, Bill & Melinda Gates Foundation, and Horchow Family Fund.

The role of drug resistance in poor viral suppression in rural South Africa: findings from a population-based study.

BACKGROUND: Understanding factors driving virological failure, including the contribution of HIV drug resistance mutations (DRM), is critical to ensuring HIV treatment remains effective. We examine the contribution of drug resistance mutations for low viral suppression in HIV-positive participants in a population-based sero-prevalence survey in rural South Africa. METHODS: We conducted HIV drug resistance genotyping and ART analyte testing on dried blood spots (DBS) from HIV-positive adults participating in a 2014 survey in North West Province. Among those with virologic failure (> 5000 copies/mL), we describe frequency of DRM to protease inhibitors (PI), nucleoside reverse transcriptase inhibitors (NRTI), and non-nucleoside reverse transcriptase inhibitors (NNRTI), report association of resistance with antiretroviral therapy (ART) status, and assess resistance to first and second line therapy. Analyses are weighted to account for sampling design. RESULTS: Overall 170 DBS samples were assayed for viral load and ART analytes; 78.4% of men and 50.0% of women had evidence of virologic failure and were assessed for drug resistance, with successful sequencing of 76/107 samples. We found ≥1 DRM in 22% of participants; 47% were from samples with detectable analyte (efavirenz, nevirapine or lopinavir). Of those with DRM and detectable analyte, 60% showed high-level resistance and reduced predicted virologic response to ≥1 NRTI/NNRTI typically used in first and second-line regimens. CONCLUSIONS: DRM and predicted reduced susceptibility to first and second-line regimens were common among adults with ART exposure in a rural South African population-based sample. Results underscore the importance of ongoing virologic monitoring, regimen optimization and adherence counseling to optimize durable virologic suppression.

"We were afraid of the lion that has roared next to us"; community response to reactive focal mass drug administration for malaria in Eswatini (formerly Swaziland).

BACKGROUND: Reactive focal mass drug administration (rfMDA), or presumptive treatment without malaria testing of household members and neighbours of a passively identified malaria case, is currently being explored as a possible malaria elimination strategy in low transmission settings. One of the primary factors determining the effectiveness of rfMDA on reducing or interrupting transmission is achieving high coverage of the target population with drug administration. This study aims to explore the acceptability of rfMDA and identify facilitators and barriers to its potential implementation, as well as the community's general knowledge, attitudes and beliefs with regard to malaria elimination. METHODS: A qualitative study was performed using focus group discussions (FGDs) among villagers that received rfMDA through the National Malaria Control Programme in the low transmission setting of Eswatini as part of a 2-year clinical trial. FGDs were audio-recorded, transcribed and translated into English. All transcripts were managed in Dedoose and underwent qualitative content analysis. RESULTS: The majority of participants perceived their community to be at high risk of malaria. Witnessing others in their community suffer from malaria, proximity to Mozambique, various ecological factors, and the presence of mosquitoes contributed to this perception. The greatest motivator of participation in rfMDA was witnessing someone else suffer from malaria, since most participants had not personally experienced malaria themselves. Participants valued the education on rfMDA and on malaria in general, particularly when communicated by nurses and other health workers from the Ministry of Health. Participants were overwhelmingly motivated to participate in rfMDA in order to obtain protection from malaria. Most participants did not understand the concept of sub-clinical infection and, therefore, did not perceive the anti-malarial medication given in rfMDA to be a treatment medication. CONCLUSIONS: Perceived risk for malaria was a major driver of acceptability; therefore, future intervention campaigns could aim to better quantify risk to inform interventions and encourage uptake. There were misunderstandings about the asymptomatic reservoir of parasites in humans. Given that this phenomenon is the rationale for rfMDA, this misunderstanding could threaten the uptake of the intervention if it persists in the community. Using local authorities to deliver messaging, additional education on this concept with re-inforcement that risk of malaria is ongoing, even in the absence of frequent cases, may help to maximize and maintain acceptability.

Study protocol for a cluster randomised controlled factorial design trial to assess the effectiveness and feasibility of reactive focal mass drug administration and vector control to reduce malaria transmission in the low endemic setting of Namibia.

INTRODUCTION: To interrupt malaria transmission, strategies must target the parasite reservoir in both humans and mosquitos. Testing of community members linked to an index case, termed reactive case detection (RACD), is commonly implemented in low transmission areas, though its impact may be limited by the sensitivity of current diagnostics. Indoor residual spraying (IRS) before malaria season is a cornerstone of vector control efforts. Despite their implementation in Namibia, a country approaching elimination, these methods have been met with recent plateaus in transmission reduction. This study evaluates the effectiveness and feasibility of two new targeted strategies, reactive focal mass drug administration (rfMDA) and reactive focal vector control (RAVC) in Namibia. METHODS AND ANALYSIS: This is an open-label cluster randomised controlled trial with 2×2 factorial design. The interventions include: rfMDA (presumptive treatment with artemether-lumefantrine (AL)) versus RACD (rapid diagnostic testing and treatment using AL) and RAVC (IRS with Acellic 300CS) versus no RAVC. Factorial design also enables comparison of the combined rfMDA+RAVC intervention to RACD. Participants living in 56 enumeration areas will be randomised to one of four arms: rfMDA, rfMDA+RAVC, RACD or RACD+RAVC. These interventions, triggered by index cases detected at health facilities, will be targeted to individuals residing within 500 m of an index. The primary outcome is cumulative incidence of locally acquired malaria detected at health facilities over 1 year. Secondary outcomes include seroprevalence, infection prevalence, intervention coverage, safety, acceptability, adherence, cost and cost-effectiveness. ETHICS AND DISSEMINATION: Findings will be reported on clinicaltrials.gov, in peer-reviewed publications and through stakeholder meetings with MoHSS and community leaders in Namibia. TRIAL REGISTRATION NUMBER: NCT02610400; Pre-results.

Attrition and Opportunities Along the HIV Care Continuum: Findings From a Population-Based Sample, North West Province, South Africa.

BACKGROUND: Attrition along the HIV care continuum slows gains in mitigating the South African HIV epidemic. Understanding population-level gaps in HIV identification, linkage, retention in care, and viral suppression is critical to target programming. METHODS: We conducted a population-based household survey, HIV rapid testing, point-of-care CD4 testing, and viral load measurement from dried blood spots using multistage cluster sampling in 2 subdistricts of North West Province from January to March, 2014. We used weighting and multiple imputation of missing data to estimate HIV prevalence, undiagnosed infection, linkage and retention in care, medication adherence, and viral suppression. RESULTS: We sampled 1044 respondents aged 18-49. HIV prevalence was 20.0% (95% confidence interval: 13.7 to 26.2) for men and 26.7% (95% confidence interval: 22.1 to 31.4) for women. Among those HIV positive, 48.4% of men and 75.7% of women were aware of their serostatus; 44.0% of men and 74.8% of women reported ever linking to HIV care; 33.1% of men and 58.4% of women were retained in care; and 21.6% of men and 50.0% of women had dried blood spots viral loads <5000 copies per milliliter. Among those already linked to care, 81.7% on antiretroviral treatment (ART) and 56.0% of those not on ART were retained in care, and 51.8% currently retained in care on ART had viral loads <5000 copies per milliliter. CONCLUSIONS: Despite expanded treatment in South Africa, attrition along the continuum of HIV care is slowing prevention progress. Improved detection is critically needed, particularly among men. Reported linkage and retention is reasonable for those on ART; however, failure to achieve viral suppression is worrisome.

The role of drug vendors in improving basic health-care services in Nigeria.

OBJECTIVE: To characterize patent and proprietary medicine vendors and shops in Nigeria and to assess their ability to help improve access to high-quality, primary health-care services. METHODS: In 2013 and 2014, a census of patent and proprietary medicine shops in 16 states of Nigeria was carried out to determine: (i) the size and coverage of the sector; (ii) the basic characteristics of shops and their staff; and (iii) the range of products stocked for priority health services, particularly for malaria, diarrhoea and family planning. The influence of the medical training of people in charge of the shops on the health-care products stocked and registration with official bodies was assessed by regression analysis. FINDINGS: The number of shops per 100,000 population was higher in southern than in northern states, but the average percentage of people in charge with medical training across local government areas was higher in northern states: 52.6% versus 29.7% in southern states. Shops headed by a person with medical training were significantly more likely to stock artemisinin-based combination therapy, oral rehydration salts, zinc, injectable contraceptives and intrauterine contraceptive devices. However, these shops were less likely to be registered with the National Association of Patent and Proprietary Medicine Dealers and more likely to be registered with the regulatory body, the Pharmacist Council of Nigeria. CONCLUSION: Many patent and proprietary medicine vendors in Nigeria were medically trained. With additional training and oversight, they could help improve access to basic health-care services. Specifically, vendors with medical training could participate in task-shifting interventions.

Care-seeking at patent and proprietary medicine vendors in Nigeria.

BACKGROUND: To achieve health development goals, policymakers are increasingly focused on improving primary care in low- and middle-income countries, and private sector drug retailers offer one channel through which basic services may be delivered. In Nigeria, patent and proprietary medicine vendors (PPMVs) serve as a main source of medications, but little is known about their clientele or how care is sought at PPMVs for common illnesses. We explore differences in care-seeking at PPMV shops based on the most commonly reported symptoms. METHODS: In Kogi and Kwara states, Nigeria, 250 PPMV shop workers and 2,359 customers purchasing drugs were surveyed, and each worker-customer interaction was observed. Multivariate regression analysis was used to assess the association of commonly reported symptoms with care-seeking behavior prior to attending the shop and while interacting with the provider at the shop. RESULTS: Most customers sought care for headache (30.5 %), fever (22.9 %), cough/cold (18.1 %), or diarrhea (8.4 %). Customers with fever were more likely to report being diagnosed by a formally trained person, to have discussed the illness with and be examined by the shop worker, and have more difficulty paying. In contrast, customers with headache symptoms were less likely to experience these outcomes and spent less money purchasing drugs. Those reporting cough or cold symptoms were less likely to have been diagnosed by a formally trained person, waited longer before visiting the PPMV shop, and were more likely to discuss the illness with the shop worker, but were less likely to be examined or to recommend the purchased drug themselves. If a sick child was brought to the shop, a discussion of the illness and an exam were more likely and more money was spent on drugs. CONCLUSIONS: Because care-seeking behaviors vary by symptoms and the sick person's age, PPMVs should be trained to treat common illnesses for which customers are unlikely to seek a formal medical consultation. Interventions aimed at improving primary care need to target the places where most people access care, and equip PPMV workers with knowledge and tools to provide basic services.

Management of paediatric illnesses by patent and proprietary medicine vendors in Nigeria.

BACKGROUND: In Nigeria and elsewhere, informal drug sellers, or patent and proprietary medicine vendors (PPMVs), are a common source of care for children with malaria, diarrhoea, and pneumonia. However, their knowledge and stocking of recommended treatments for these common childhood illnesses are not well understood. METHODS: A census of PPMV shops was conducted in Kogi and Kwara states. A shop survey was conducted on a subset of 250 shops. Multivariate regression analysis was used to assess associations between shop worker characteristics and (1) knowledge of optimal treatments for malaria, diarrhoea, and pneumonia, and (2) stocking of essential medicines to treat these illnesses. RESULTS: From the census, 89.9% of shops stocked oral rehydration solution (ORS), while 61.1% of shops stocked artemisinin-based combination therapies and 72.2% of shops stocked amoxicillin. Stocking patterns varied by state, urban/rural location, and according to whether or not the shop was headed by someone with formal health training (e.g. having a professional health education degree). In multivariate analyses, selling drugs wholesale and participating in any training in the past year was associated with a higher likelihood of naming the correct treatment for malaria, and having formal health training was associated with stocking ORS. However, few other PPMV characteristics were predictive of correct knowledge of optimal treatments and stocking behaviour. CONCLUSION: Many PPMVs lack the knowledge and tools to properly treat common childhood illnesses. PPMV knowledge and selling of essential medicines for these illnesses should be strengthened to improve child health in Nigeria.

Design and implementation of an external quality assessment program for HIV viral load measurements using dried blood spots.

An external quality assurance program was developed for HIV-1 RNA viral load measurements taken from dried blood spots using a reference panel and field-collected specimens. The program demonstrated that accurate and reproducible quantitation can be obtained from field-collected specimens. Residual proviral DNA may confound interpretation in virologically suppressed subjects.

Rifampin monoresistant tuberculosis and HIV comorbidity in California, 1993-2008: a retrospective cohort study.

OBJECTIVE: Rifampin monoresistant tuberculosis (RMR-TB) is increasingly identified because of scale-up of rapid molecular tests. The longitudinal association of RMR-TB, multidrug-resistant TB (MDR-TB), and HIV/AIDS is incompletely described. METHODS: We examined clinical characteristics and treatment outcomes of patients with RMR-TB, isoniazid monoresistant TB (IMR-TB), MDR-TB, and drug-susceptible TB during a 16-year period (1993-2008) in California. TB cases were cross-matched with the state HIV/AIDS registry, and HIV prevalence denominators modeled using nonparametric backcalculation. RESULTS: Of 42,582 TB cases, 178 (0.4%), 3469 (8.1%), and 635 (1.5%) were RMR-TB, IMR-TB, and MDR-TB, respectively. From the pre-HAART (1993-1996) to HAART (2005-2008) era, RMR-TB rates declined rapidly (12.0 vs. 0.5 per 100,000) among patients with HIV infection. The proportion of patients for whom rifampin resistance indicated RMR-TB (rather than MDR-TB) decreased from 31% [95% confidence interval (CI) 26-38%] to 11% (95% CI 5-19%). In multivariate analysis controlling for HIV coinfection and other covariates, patients with RMR-TB were twice as likely to die as patients with drug-sensitive TB (relative risk 1.94, 95% CI 1.40-2.69). CONCLUSION: RMR-TB/HIV rates declined substantially over time in association with improved TB control and HIV control in California. Mortality among patients with RMR-TB was high, even after adjusting for HIV status.