Scaling-up and scaling-out the Systems Analysis and Improvement Approach to optimize the hypertension diagnosis and care cascade for HIV infected individuals (SCALE SAIA-HTN): a stepped-wedge cluster randomized trial.

BACKGROUND: Undiagnosed and untreated hypertension is a main driver of cardiovascular disease and disproportionately affects persons living with HIV (PLHIV) in low- and middle-income countries. Across sub-Saharan Africa, guideline application to screen and manage hypertension among PLHIV is inconsistent due to poor service readiness, low health worker motivation, and limited integration of hypertension screening and management within HIV care services. In Mozambique, where the adult HIV prevalence is over 13%, an estimated 39% of adults have hypertension. As the only scaled chronic care service in the county, the HIV treatment platform presents an opportunity to standardize and scale hypertension care services. Low-cost, multi-component systems-level strategies such as the Systems Analysis and Improvement Approach (SAIA) have been found effective at integrating hypertension and HIV services to improve the effectiveness of hypertension care delivery for PLHIV, reduce drop-offs in care, and improve service quality. To build off lessons learned from a recently completed cluster randomized trial (SAIA-HTN) and establish a robust evidence base on the effectiveness of SAIA at scale, we evaluated a scaled-delivery model of SAIA (SCALE SAIA-HTN) using existing district health management structures to facilitate SAIA across six districts of Maputo Province, Mozambique. METHODS: This study employs a stepped-wedge design with randomization at the district level. The SAIA strategy will be "scaled up" with delivery by district health supervisors (rather than research staff) and will be "scaled out" via expansion to Southern Mozambique, to 18 facilities across six districts in Maputo Province. SCALE SAIA-HTN will be introduced over three, 9-month waves of intensive intervention, where technical support will be provided to facilities and district managers by study team members from the Mozambican National Institute of Health. Our evaluation of SCALE SAIA-HTN will be guided by the RE-AIM framework and will seek to estimate the budget impact from the payer's perspective. DISCUSSION: SAIA packages user-friendly systems engineering tools to support decision-making by frontline health workers and to identify low-cost, contextually relevant improvement strategies. By integrating SAIA delivery into routine management structures, this pragmatic trial will determine an effective strategy for national scale-up and inform program planning. TRIAL REGISTRATION: ClinicalTrials.gov NCT05002322 (registered 02/15/2023).

Plasma proteomic signatures of enteric permeability among hospitalized and community children in Kenya and Pakistan.

We aimed to establish if enteric permeability was associated with similar biological processes in children recovering from hospitalization and relatively healthy children in the community. Extreme gradient boosted models predicting the lactulose-rhamnose ratio (LRR), a biomarker of enteric permeability, using 7,500 plasma proteins and 34 fecal biomarkers of enteric infection among 89 hospitalized and 60 community children aged 2-23 months were built. The R2 values were calculated in test sets. The models performed better among community children (R2: 0.27 [min-max: 0.19, 0.53]) than hospitalized children (R2: 0.07 [min-max: 0.03, 0.11]). In the community, LRR was associated with biomarkers of humoral antimicrobial and cellular lipopolysaccharide responses and inversely associated with anti-inflammatory and innate immunological responses. Among hospitalized children, the selected biomarkers had few shared functions. This suggests enteric permeability among community children was associated with a host response to pathogens, but this association was not observed among hospitalized children.

Association between service readiness and PMTCT cascade effectiveness: a 2018 cross-sectional analysis from Manica province, Mozambique.

BACKGROUND: Despite high coverage of maternal and child  health services in Mozambique, prevention of mother-to-child transmission of HIV (PMTCT) cascade outcomes remain sub-optimal. Delivery effectiveness is modified by health system preparedness. Identifying modifiable factors that impact quality of care and service uptake can inform strategies to improve the effectiveness of PMTCT programs. We estimated associations between facility-level modifiable health system readiness measures and three PMTCT outcomes: Early infant diagnosis (polymerase chain reaction (PCR) before 8 weeks of life), PCR ever (before or after 8 weeks), and positive PCR test result. METHODS: A 2018 cross-sectional, facility-level survey was conducted in a sample of 36 health facilities covering all 12 districts in Manica province, central Mozambique, as part of a baseline assessment for the SAIA-SCALE trial (NCT03425136). Data on HIV testing outcomes among 3,427 exposed infants were abstracted from at-risk child service registries. Nine health system readiness measures were included in the analysis. Logistic regressions were used to estimate associations between readiness measures and pediatric HIV testing outcomes. Odds ratios (OR) and 95% confidence intervals (95%CI) are reported. RESULTS: Forty-eight percent of HIV-exposed infants had a PCR test within 8 weeks of life, 69% had a PCR test ever, and 6% tested positive. Staffing levels, glove stockouts, and distance to the reference laboratory were positively associated with early PCR (OR = 1.02 [95%CI: 1.01-1.02], OR = 1.73 [95%CI: 1.24-2.40] and OR = 1.01 [95%CI: 1.00-1.01], respectively) and ever PCR (OR = 1.02 [95%CI: 1.01-1.02], OR = 1.80 [95%CI: 1.26-2.58] and OR = 1.01 [95%CI: 1.00-1.01], respectively). Catchment area size and multiple NGOs supporting PMTCT services were associated with early PCR testing OR = 1.02 [95%CI: 1.01-1.03] and OR = 0.54 [95%CI: 0.30-0.97], respectively). Facility type, stockout of prophylactic antiretrovirals, the presence of quality improvement programs and mothers' support groups in the health facility were not associated with PCR testing. No significant associations with positive HIV diagnosis were found. CONCLUSION: Salient modifiable factors associated with HIV testing for exposed infants include staffing levels, NGO support, stockout of essential commodities and accessibility of reference laboratories. Our study provides insights into modifiable factors that could be targeted to improve PMTCT performance, particularly at small and rural facilities.

Enteric Permeability, Systemic Inflammation, and Post-Discharge Growth Among a Cohort of Hospitalized Children in Kenya and Pakistan.

OBJECTIVES: To determine whether gut permeability is associated with post-discharge growth and systemic inflammation among hospitalized children in low- and middle-income countries. METHODS: Children aged 2-23 months being discharged from Civil Hospital Karachi (Pakistan) and Migori County Referral Hospital (Kenya) underwent lactulose-rhamnose ratio (LRR) permeability testing and were compared to age-matched children from their home communities. Linear mixed effect models estimated the associations between LRR among discharged children with change in length-for-age (LAZ) and weight-for-age z score (WAZ) at 45, 90, and 180 days after discharge. Linear regression tested if relationships between LRR, systemic inflammation [C-reative protein (CRP), Cluster of Differentiation 14 (CD14), Tumour Necrosis Factor Alpha (TNFα), Interleukin-6 (IL-6)], and enterocyte damage [Intestinal Fatty-Acid Binding protein (I-FABP)] differed between the hospitalized and community groups. RESULTS: One hundred thirty-seven hospitalized and 84 community participants were included. The hospitalized group had higher log-LRR [0.43, 95% confidence interval (CI): 0.15-0.71, P = 0.003] than the community children. Adjustment for weight-for-length z score at discharge attenuated this association (0.31, 95% CI: 0.00-0.62, P = 0.049). LRR was not associated with changes in WAZ or LAZ in the post-discharge period. Associations between LRR and CRP (interaction P = 0.036), TNFα ( P = 0.017), CD14 ( P = 0.078), and IL-6 ( P = 0.243) differed between community and hospitalized groups. LRR was associated with TNFα ( P = 0.004) and approached significance with CD14 ( P = 0.078) and IL-6 ( P = 0.062) in community children, but there was no evidence of these associations among hospitalized children. CONCLUSIONS: Although increased enteric permeability is more prevalent among children being discharged from hospital compared to children in the community, it does not appear to be an important determinant of systemic inflammation or post-discharge growth among hospitalized children.

Cost of community-based human papillomavirus self-sampling in Peru: A micro-costing study.

Background: Cost data of human papillomavirus (HPV) self-sampling programs from low-and-middle-income countries is limited. We estimated the total and unit costs associated with the Hope Project, a community-based HPV self-sampling social entrepreneurship in Peru. Methods: We conducted a micro-costing analysis from the program perspective to determine the unit costs of (1) recruitment/training of community women (Hope Ladies); (2) Hope Ladies distributing HPV self-sampling kits in their communities and the laboratory testing; and (3) Hope Ladies linking screened women with follow-up care. A procedural manual was used to identify the program's activities. A structured questionnaire and in-depth interviews were conducted with administrators to estimate the resource/time associated with activities. We obtained unit costs for each input previously identified from budgets and expenditure reports. Findings: From November 2018 to March 2020, the program recruited and trained 62 Hope Ladies who distributed 4,882 HPV self-sampling kits in their communities. Of the screened women, 586 (12%) tested HPV positive. The annual cost per Hope Lady recruited/trained was $147·51 (2018 USD). The cost per HPV self-sampling kit distributed/tested was $45·39, the cost per woman followed up with results was $55·64, and the cost per HPV-positive woman identified was $378·14. Personnel and laboratory costs represented 56·1% and 24·7% of the total programmatic cost, respectively. Interpretation: Our findings indicate that implementation of a community-based HPV self-sampling has competitive prices, which increases its likelihood to be feasible in Peru. Further economic evaluation is needed to quantify the incremental benefits of HPV self-sampling compared to more established options such as Pap tests. Funding: Thomas Francis Jr. Fellowship provided funding for data collection. The Hope Project was funded by grants from Grand Challenges Canada (TTS-1812-21131), Uniting for Health Innovation, Global Initiative Against HPV and Cervical Cancer, University of Manitoba, and the John E. Fogarty International Center (5D43TW009375-05).

Forecasting the effectiveness of the DeWorm3 trial in interrupting the transmission of soil-transmitted helminths in three study sites in Benin, India and Malawi.

BACKGROUND: The DeWorm3 project is an ongoing cluster-randomised trial assessing the feasibility of interrupting the transmission of soil-transmitted helminths (STH) through mass drug administration (MDA) using study sites in India, Malawi and Benin. In this article, we describe an approach which uses a combination of statistical and mathematical methods to forecast the outcome of the trial with respect to its stated goal of reducing the prevalence of infection to below 2%. METHODS: Our approach is first to define the local patterns of transmission within each study site, which is achieved by statistical inference of key epidemiological parameters using the baseline epidemiological measures of age-related prevalence and intensity of STH infection which have been collected by the DeWorm3 trials team. We use these inferred parameters to calibrate an individual-based stochastic simulation of the trial at the cluster and study site level, which is subsequently run to forecast the future prevalence of STH infections. The simulator takes into account both the uncertainties in parameter estimation and the variability inherent in epidemiological and demographic processes in the simulator. We interpret the forecast results from our simulation with reference to the stated goal of the DeWorm3 trial, to achieve a target of [Formula: see text] prevalence at a point 24 months post-cessation of MDA. RESULTS: Simulated output predicts that the two arms will be distinguishable from each other in all three country sites at the study end point. In India and Malawi, measured prevalence in the intervention arm is below the threshold with a high probability (90% and 95%, respectively), but in Benin the heterogeneity between clusters prevents the arm prevalence from being reduced below the threshold value. At the level of individual study arms within each site, heterogeneity among clusters leads to a very low probability of achieving complete elimination in an intervention arm, yielding a post-study scenario with widespread elimination but a few 'hot spot' areas of persisting STH transmission. CONCLUSIONS: Our results suggest that geographical heterogeneities in transmission intensity and worm aggregation have a large impact on the effect of MDA. It is important to accurately assess cluster-level, or even smaller scale, heterogeneities in factors which influence transmission and aggregation for a clearer perspective on projecting the outcomes of MDA control of STH and other neglected tropical diseases.

Development and application of an electronic treatment register: a system for enumerating populations and monitoring treatment during mass drug administration.

We developed an electronic treatment register for the DeWorm3 Project, a cluster-randomised, controlled trial in Benin, India, and Malawi testing the feasibility of interrupting transmission of soil-transmitted helminths through community-wide mass drug administration. The electronic treatment register was designed in xlsform, deployed via the SurveyCTO mobile data collection platform, and implemented on smartphones running the Android operating system. The versatile system enables collection of census and treatment status information, facilitates data aggregation and visualisation, and permits real-time feedback loops during implementation of mass drug administration. Here we describe the system's design and use within the DeWorm3 Project and key features, and by sharing the register here, we hope our readers will further explore its use within their research and disease-control activities.

What does soil-transmitted helminth elimination look like? Results from a targeted molecular detection survey in Japan.

BACKGROUND: Japan is one of the few countries believed to have eliminated soil-transmitted helminths (STHs). In 1949, the national prevalence of Ascaris lumbricoides was 62.9%, which decreased to 0.6% in 1973 due to improvements in infrastructure, socioeconomic status, and the implementation of national STH control measures. The Parasitosis Prevention Law ended in 1994 and population-level screening ceased in Japan; therefore, current transmission status of STH in Japan is not well characterized. Sporadic cases of STH infections continue to be reported, raising the possibility of a larger-scale recrudescence of STH infections. Given that traditional microscopic detection methods are not sensitive to low-intensity STH infections, we conducted targeted prevalence surveys using sensitive PCR-based assays to evaluate the current STH-transmission status and to describe epidemiological characteristics of areas of Japan believed to have achieved historical elimination of STHs. METHODS: Stool samples were collected from 682 preschool- and school-aged children from six localities of Japan with previously high prevalence of STH. Caregivers of participants completed a questionnaire to ascertain access to water, sanitation and hygiene (WASH), and potential exposures to environmental contamination. For fecal testing, multi-parallel real-time PCR assays were used to detect infections of Ascaris lumbricoides, Necator americanus, Ancylostoma duodenale and Trichuris trichiura. RESULTS: Among the 682 children, no positive samples were identified, and participants reported high standards of WASH. CONCLUSIONS: To our knowledge, this is the first STH-surveillance study in Japan to use sensitive molecular techniques for STH detection. The results suggest that recrudescence of STH infections has not occurred, and that declines in prevalence have been sustained in the sampled areas. These findings suggest that reductions in prevalence below the elimination thresholds, suggestive of transmission interruption, are possible. Additionally, this study provides circumstantial evidence that multi-parallel real-time PCR methods are applicable for evaluating elimination status in areas where STH prevalence is extremely low.

Usability and Feasibility of an Innovative mLearning Approach for Nurses Providing Option B+ Services in Manica and Sofala Provinces, Mozambique.

The scaling of Option B+ services, whereby all pregnant women who test HIV positive are started on lifelong antiretroviral therapy upon diagnosis regardless of CD4 T-cell count, is ongoing in many high HIV burden, low-resource countries. We developed and evaluated a tablet-based mobile learning (mLearning) training approach to build Option B+ competencies in frontline nurses in central Mozambique. Its acceptability and impact on clinical skills were assessed in maternal child health nurses and managers at 20 intervention and 10 control clinics. Results show that skill and knowledge of nurses at intervention clinics improved threefold compared with control clinics (p = .04), nurse managers at intervention clinics demonstrated a 9- to 10-fold improvement, and nurses reported strong acceptance of this approach. "mLearning" is one viable modality to enhance nurses' clinical competencies in areas with limited health workforce and training budgets. This study's findings may guide future scaling and investments in commercially viable mLearning solutions.

Cascade Analysis: An Adaptable Implementation Strategy Across HIV and Non-HIV Delivery Platforms.

BACKGROUND: Cascades have been used to characterize sequential steps within a complex health system and are used in diverse disease areas and across prevention, testing, and treatment. Routine data have great potential to inform prioritization within a system, but are often inaccessible to frontline health care workers (HCWs) who may have the greatest opportunity to innovate health system improvement. METHODS: The cascade analysis tool (CAT) is an Excel-based, simple simulation model with an optimization function. It identifies the step within a cascade that could most improve the system. The original CAT was developed for HIV treatment and the prevention of mother-to-child transmission of HIV. RESULTS: CAT has been adapted 7 times: to a mobile application for prevention of mother-to-child transmission; for hypertension screening and management and for mental health outpatient services in Mozambique; for pediatric and adolescent HIV testing and treatment, HIV testing in family planning, and cervical cancer screening and treatment in Kenya; and for naloxone distribution and opioid overdose reversal in the United States. The main domains of adaptation have been technical-estimating denominators and structuring steps to be binary sequential steps-as well as logistical-identifying acceptable approaches for data abstraction and aggregation, and not overburdening HCW. DISCUSSION: CAT allows for prompt feedback to HCWs, increases HCW autonomy, and allows managers to allocate resources and time in an equitable manner. CAT is an effective, feasible, and acceptable implementation strategy to prioritize areas most requiring improvement within complex health systems, although adaptations are being currently evaluated.

Depressive symptoms, suicidal ideation, and mental health care-seeking in central Mozambique.

PURPOSE: There is scant research on depressive symptoms (DS), suicidal ideation (SI), and mental health care-seeking in Mozambique. METHODS: Generalized estimating equations were used to assess factors associated with DS, SI, and mental health care-seeking among 3080 individuals interviewed in a representative household survey in Sofala and Manica provinces, Mozambique. RESULTS: 19% (CI 17-21%) of respondents reported DS in the past year and 17% (CI 15-18%) lifetime SI. Overall, only 10% (CI 8-11%) of respondents ever sought any care for mental illness, though 26% (CI 23-29%) of those reporting DS and/or SI sought care. 90% of those who sought care for DS received treatment; however, only 46% of those who sought care for SI received treatment. Factors associated with DS and SI include: female gender, divorced/separated, widowed, and > 55 years old. Respondents in the bottom wealth quintile reported lower DS, while those in upper wealth quintiles reported higher prevalence of SI. Individuals with DS or SI had significantly elevated measures of disability-especially in doing household chores, work/school activities, standing for long periods, and walking long distances. Factors associated with care-seeking include: female gender, rural residence, divorced/separated, and > 45 years old. Individuals in lower wealth quintiles and with no religious affiliation had lower odds of seeking care. CONCLUSIONS: DS and SI are prevalent in central Mozambique and treatment gaps are high (68% and 89%, respectively). An urgent need exists for demand- and supply-side interventions to optimize the delivery of comprehensive community-based mental healthcare in Mozambique.

Defining stopping criteria for ending randomized clinical trials that investigate the interruption of transmission of soil-transmitted helminths employing mass drug administration.

The current World Health Organization strategy to address soil-transmitted helminth (STH) infections in children is based on morbidity control through routine deworming of school and pre-school aged children. However, given that transmission continues to occur as a result of persistent reservoirs of infection in untreated individuals (including adults) and in the environment, in many settings such a strategy will need to be continued for very extended periods of time, or until social, economic and environmental conditions result in interruption of transmission. As a result, there is currently much discussion surrounding the possibility of accelerating the interruption of transmission using alternative strategies of mass drug administration (MDA). However, the feasibility of achieving transmission interruption using MDA remains uncertain due to challenges in sustaining high MDA coverage levels across entire communities. The DeWorm3 trial, designed to test the feasibility of interrupting STH transmission, is currently ongoing. In DeWorm3, three years of high treatment coverage-indicated by mathematical models as necessary for breaking transmission-will be followed by two years of surveillance. Given the fast reinfection (bounce-back) rates of STH, a two year no treatment period is regarded as adequate to assess whether bounce-back or transmission interruption have occurred in a given location. In this study, we investigate if criteria to determine whether transmission interruption is unlikely can be defined at earlier timepoints. A stochastic, individual-based simulation model is employed to simulate core aspects of the DeWorm3 community-based cluster-randomized trial. This trial compares a control arm (annual treatment of children alone with MDA) with an intervention arm (community-wide biannual treatment with MDA). Simulations were run for each scenario for both Ascaris lumbricoides and hookworm (Necator americanus). A range of threshold prevalences measured at six months after the last round of MDA and the impact of MDA coverage levels were evaluated to see if the likelihood of bounce-back or elimination could reliably be assessed at that point, rather than after two years of subsequent surveillance. The analyses suggest that all clusters should be assessed for transmission interruption after two years of surveillance, unless transmission interruption can be effectively ruled out through evidence of low treatment coverage. Models suggest a tight range of homogenous prevalence estimates following high coverage MDA across clusters which do not allow for discrimination between bounce back or transmission interruption within 24 months following cessation of MDA.

Strategies to improve treatment coverage in community-based public health programs: A systematic review of the literature.

BACKGROUND: Community-based public health campaigns, such as those used in mass deworming, vitamin A supplementation and child immunization programs, provide key healthcare interventions to targeted populations at scale. However, these programs often fall short of established coverage targets. The purpose of this systematic review was to evaluate the impact of strategies used to increase treatment coverage in community-based public health campaigns. METHODOLOGY/ PRINCIPAL FINDINGS: We systematically searched CAB Direct, Embase, and PubMed archives for studies utilizing specific interventions to increase coverage of community-based distribution of drugs, vaccines, or other public health services. We identified 5,637 articles, from which 79 full texts were evaluated according to pre-defined inclusion and exclusion criteria. Twenty-eight articles met inclusion criteria and data were abstracted regarding strategy-specific changes in coverage from these sources. Strategies used to increase coverage included community-directed treatment (n = 6, pooled percent change in coverage: +26.2%), distributor incentives (n = 2, +25.3%), distribution along kinship networks (n = 1, +24.5%), intensified information, education, and communication activities (n = 8, +21.6%), fixed-point delivery (n = 1, +21.4%), door-to-door delivery (n = 1, +14.0%), integrated service distribution (n = 9, +12.7%), conversion from school- to community-based delivery (n = 3, +11.9%), and management by a non-governmental organization (n = 1, +5.8%). CONCLUSIONS/SIGNIFICANCE: Strategies that target improving community member ownership of distribution appear to have a large impact on increasing treatment coverage. However, all strategies used to increase coverage successfully did so. These results may be useful to National Ministries, programs, and implementing partners in optimizing treatment coverage in community-based public health programs.

Testing for soil-transmitted helminth transmission elimination: Analysing the impact of the sensitivity of different diagnostic tools.

In recent years, an increased focus has been placed upon the possibility of the elimination of soil-transmitted helminth (STH) transmission using various interventions including mass drug administration. The primary diagnostic tool recommended by the WHO is the detection of STH eggs in stool using the Kato-Katz (KK) method. However, detecting infected individuals using this method becomes increasingly difficult as the intensity of infection decreases. Newer techniques, such as qPCR, have been shown to have greater sensitivity than KK, especially at low prevalence. However, the impact of using qPCR on elimination thresholds is yet to be investigated. In this paper, we aim to quantify how the sensitivity of these two diagnostic tools affects the optimal prevalence threshold at which to declare the interruption of transmission with a defined level of confidence. A stochastic, individual-based STH transmission model was used in this study to simulate the transmission dynamics of Ascaris and hookworm. Data from a Kenyan deworming study were used to parameterize the diagnostic model which was based on egg detection probabilities. The positive and negative predictive values (PPV and NPV) were calculated to assess the quality of any given threshold, with the optimal threshold value taken to be that at which both were maximised. The threshold prevalence of infection values for declaring elimination of Ascaris transmission were 6% and 12% for KK and qPCR respectively. For hookworm, these threshold values are lower at 0.5% and 2% respectively. Diagnostic tests with greater sensitivity are becoming increasingly important as we approach the elimination of STH transmission in some regions of the world. For declaring the elimination of transmission, using qPCR to diagnose STH infection results in the definition of a higher prevalence, than when KK is used.

Prospects for elimination of soil-transmitted helminths.

PURPOSE OF REVIEW: Soil-transmitted helminths (STH) are endemic in 120 countries and are associated with substantial morbidity and loss of economic productivity. Although current WHO guidelines focus on morbidity control through mass drug administration (MDA), there is global interest in whether a strategy targeting disease elimination might be feasible in some settings. This review summarizes the prospects for switching from control to an elimination strategy. RECENT FINDINGS: STH control efforts have reduced the intensity of infections in targeted populations with associated reductions in morbidity. However, adults are not frequently targeted and remain important reservoirs for reinfection of treated children. Recent modeling suggests that transmission interruption may be possible through expanded community-wide delivery of MDA, the feasibility of which has been demonstrated by other programs. However, these models suggest that high levels of coverage and compliance must be achieved. Potential challenges include the risk of prematurely dismantling STH programs and the potential increased risk of antihelminthic resistance. SUMMARY: Elimination of STH may offer an opportunity to eliminate substantial STH-related morbidity while reducing resource needs of neglected tropical disease programs. Evidence from large community trials is needed to determine the feasibility of interrupting the transmission of STH in some geographic settings.

Assisted partner services for HIV in Kenya: a cluster randomised controlled trial.

BACKGROUND: Assisted partner services for index patients with HIV infections involves elicitation of information about sex partners and contacting them to ensure that they test for HIV and link to care. Assisted partner services are not widely available in Africa. We aimed to establish whether or not assisted partner services increase HIV testing, diagnoses, and linkage to care among sex partners of people with HIV infections in Kenya. METHODS: In this cluster randomised controlled trial, we recruited non-pregnant adults aged at least 18 years with newly or recently diagnosed HIV without a recent history of intimate partner violence who had not yet or had only recently linked to HIV care from 18 HIV testing services clinics in Kenya. Consenting sites in Kenya were randomly assigned (1:1) by the study statistician (restricted randomisation; balanced distribution in terms of county and proximity to a city) to immediate versus delayed assisted partner services. Primary outcomes were the number of partners tested for HIV, the number who tested HIV positive, and the number enrolled in HIV care, in those who were interviewed at 6 week follow-up. Participants within each cluster were masked to treatment allocation because participants within each cluster received the same intervention. This trial is registered with ClinicalTrials.gov, number NCT01616420. FINDINGS: Between Aug 12, 2013, and Aug 31, 2015, we randomly allocated 18 clusters to immediate and delayed HIV assisted partner services (nine in each group), enrolling 1305 participants: 625 (48%) in the immediate group and 680 (52%) in the delayed group. 6 weeks after enrolment of index patients, 392 (67%) of 586 partners had tested for HIV in the immediate group and 85 (13%) of 680 had tested in the delayed group (incidence rate ratio 4·8, 95% CI 3·7-6·4). 136 (23%) partners had new HIV diagnoses in the immediate group compared with 28 (4%) in the delayed group (5·0, 3·2-7·9) and 88 (15%) versus 19 (3%) were newly enrolled in care (4·4, 2·6-7·4). Assisted partner services did not increase intimate partner violence (one intimate partner violence event related to partner notification or study procedures occurred in each group). INTERPRETATION: Assisted partner services are safe and increase HIV testing and case-finding; implementation at the population level could enhance linkage to care and antiretroviral therapy initiation and substantially decrease HIV transmission. FUNDING: National Institutes of Health.

Maternal Highly Active Antiretroviral Therapy Reduces Vertical Cytomegalovirus Transmission But Does Not Reduce Breast Milk Cytomegalovirus Levels.

To evaluate the impact of highly active antiretroviral therapy (HAART) on CMV transmission and breast milk level in the context of maternal HIV. Specimens from a randomized trial conducted in Nairobi, Kenya between 2003-2005 were used to compare CMV transmission and breast milk levels between mother-infant pairs randomized to HAART versus short-course antenatal zidovudine plus single-dose nevirapine (ZDV/sdNVP) for prevention of mother-to-child HIV transmission (PMTCT). Fifty-one antiretroviral-naïve women ≤32 weeks gestation, and CD4 between 200-500 cells/mm3 were randomized at 34 weeks to begin either antenatal ZDV/sdNVP, or HAART through 6 months postpartum. Mean breast milk CMV levels and transmission were compared between arms. Age, sociodemographics, CD4%, and HIV plasma RNA viral load were similar between arms at baseline. CMV viral loads were measured from 243 infant plasma and 185 breast milk specimens during the first year postpartum. The probability of infant CMV infection at 12 months was 19% lower in the HAART arm compared to ZDV/sdNVP (75% vs. 94%, p = .04). All women had CMV detected in breast milk, with 72%, 98%, and 97% testing positive during the first, second, and third weeks postpartum, respectively. There was a trend for early higher mean breast milk CMV level in the HAART arm at 1 week (p = .08), and there was significantly slower decline in breast milk CMV levels (area under the curve, p = .01). HAART started during the third trimester may decrease infant CMV infections, by mechanisms independent of breast milk CMV levels. CLINICAL TRIALS REGISTRATION: NCT00167674.

Differences in virologic and immunologic response to antiretroviral therapy among HIV-1-infected infants and children.

BACKGROUND: Virologic and immunologic responses to antiretroviral treatment (ART) in infants may differ from older children due to immunologic, clinical, or epidemiologic characteristics. METHODS: Longitudinal ART responses were modeled and compared in HIV-infected infants and children enrolled in cohorts in Nairobi, Kenya. Participants were enrolled soon after HIV diagnosis, started on ART, and followed for 2 years. Viral load decline was compared between infant and child cohorts using a nonlinear mixed effects model and CD4% reconstitution using a linear mixed effects model. RESULTS: Among 121 infants, median age at ART was 3.9 months; among 124 children, median age was 4.8 years. At baseline, viral load was higher among infants than children (6.47 vs. 5.91 log10 copies/ml, P < 0.001). Infants were less likely than children to suppress viral load to less than 250 copies/ml following 6 months of ART (32% infants vs. 73% children, P < 0.0001). CD4% was higher at baseline in infants than children (19 vs. 7.3%, P < 0.001). Older children had more rapid CD4% reconstitution than infants, but failed to catch up to infant CD4%. CONCLUSION: Despite substantially higher CD4% at ART initiation, viral suppression was significantly slower among infants than older children. New strategies are needed to optimize infant outcomes on ART.

Breastfeeding Is Associated with Decreased Risk of Hospitalization among HIV-Exposed, Uninfected Kenyan Infants.

BACKGROUND: Human immunodeficiency virus (HIV)-exposed uninfected (HEU) infants are a growing population in sub-Saharan Africa, with higher morbidity and mortality than HIV-unexposed infants. HEU infants may experience increased morbidity due to breastfeeding avoidance. OBJECTIVES: We sought to describe the burden and identify predictors of hospitalization among HEU infants in the first year of life. METHODS: Using a retrospective cohort of HIV-infected mothers and their HEU infants in Nairobi, Kenya, we identified infants who were HIV-uninfected at birth and were followed monthly until their last negative HIV test, death, loss to follow-up, or study exit at 1 year of age. Incidence, timing, and reason for hospitalization was assessed overall as well as stratified by feeding method. Predictors of first infectious disease hospitalization were identified using competing risk regression, with HIV acquisition and death as competing risks. RESULTS: Among 388 infants, 113 hospitalizations were reported (35/100 infant-years [the combined years of observation contributed by all infants in the study]; 95% confidence interval [CI], 29-42). Ninety hospitalizations were due to 1 or more infectious diseases (26/100 infant-years; 95% CI, 21-32)-primarily pneumonia (n = 40), gastroenteritis (n = 17), and sepsis (n = 14). Breastfeeding was associated with decreased risk of infectious disease hospitalization (subhazard ratio = 0.39; 95% CI, 0.24-0.64), as was time-updated nutrition status (subhazard ratio = 0.73; 95% CI, 0.61-0.89). Incidence of infectious disease hospitalization among formula-fed infants was 51/100 infant-years (95% CI, 37-70) compared to 19/100 infant-years (95% CI, 14-25) among breastfed infants. CONCLUSION: Among HEU infants, breastfeeding and nutrition status were associated with reduced hospitalization during the first year of life.