Population pharmacokinetics of primaquine and its metabolites in African males.

BACKGROUND: Primaquine (PQ) is the prototype 8-aminoquinoline drug, a class which targets gametocytes and hypnozoites. The World Health Organization (WHO) recommends adding a single low dose of primaquine to the standard artemisinin-based combination therapy (ACT) in order to block malaria transmission in regions with low malaria transmission. However, the haemolytic toxicity is a major adverse outcome of primaquine in glucose-6-phosphate dehydrogenase (G6PD)-deficient subjects. This study aimed to characterize the pharmacokinetic properties of primaquine and its major metabolites in G6PD-deficient subjects. METHODS: A single low-dose of primaquine (0.4-0.5 mg/kg) was administered in twenty-eight African males. Venous and capillary plasma were sampled up to 24 h after the drug administration. Haemoglobin levels were observed up to 28 days after drug administration. Only PQ, carboxy-primaquine (CPQ), and primaquine carbamoyl-glucuronide (PQCG) were present in plasma samples and measured using liquid chromatography mass spectrometry. Drug and metabolites' pharmacokinetic properties were investigated using nonlinear mixed-effects modelling. RESULTS: Population pharmacokinetic properties of PQ, CPQ, and PQCG can be described by one-compartment disposition kinetics with a transit-absorption model. Body weight was implemented as an allometric function on the clearance and volume parameters for all compounds. None of the covariates significantly affected the pharmacokinetic parameters. No significant correlations were detected between the exposures of the measured compounds and the change in haemoglobin or methaemoglobin levels. There was no significant haemoglobin drop in the G6PD-deficient patients after administration of a single low dose of PQ. CONCLUSIONS: A single low-dose of PQ was haematologically safe in this population of G6PD-normal and G6PD-deficient African males without malaria. Trial registration NCT02535767.

Advancing the use of Long-Acting Extended Delivery formulations for HIV prevention in sub-Saharan Africa: challenges, opportunities, and recommendations.

INTRODUCTION: The burden of HIV in sub-Saharan Africa (SSA) remains unacceptably high, and disproportionately affects girls and women. While the introduction of oral HIV pre-exposure prophylaxis (PrEP) in 2012 revolutionized HIV prevention, its effectiveness is dependent on user adherence and its implementation in SSA has faced numerous challenges. Patient-level, interpersonal and structural barriers, including, for example, daily pill burden, side effects, lack of partner support, testing and disclosure, and costs have been found to reduce adherence to oral PrEP. DISCUSSION: Long-acting extended delivery (LAED) formulations for PrEP, such as injectable long-acting cabotegravir (CAB-LA) and dapivirine vaginal ring (DPV-VR) are critical additions to the HIV prevention toolkit and are especially important for populations such as adolescent girls and young women (AGYW) and other key populations who remain at significant risk of HIV acquisition while facing substantial barriers to preventive services. These LAED formulations have been shown to result in better adherence and fewer side effects, with CAB-LA being superior to oral PrEP in reducing the risk of HIV acquisition. They can be used to overcome user burden and adherence challenges. However, the successful rollout of the DPV-VR and CAB-LA may be hampered by issues such as a shortage of healthcare providers (HCPs), inadequate parenteral medication infrastructure, increased workload for HCPs, patient concerns, the price of the medications and the possibility of drug resistance. CONCLUSIONS: SSA must develop laboratory capabilities for monitoring patients on LAED formulations and enhance research on developing more non-injectable LAED formulations. There is a need to train and retain more HCPs, implement task shifting, invest in healthcare infrastructure and integrate healthcare services. To reduce costs and improve availability, the region must advocate for patent license waivers for LAED formulations and procure drugs collectively as a region.

Preventing HIV and achieving pregnancy among HIV sero-different couples: Pilot study of a safer conception intervention in Zimbabwe.

Safer conception services are needed to minimize HIV transmission among HIV sero-different couples desiring pregnancy. Few studies have evaluated the choices couples make when offered multiple safer conception methods or real-world method acceptability and effectiveness. We piloted a comprehensive safer conception program (Clintrials.gov identifier: NCT03049176) for HIV sero-different couples planning pregnancy in Zimbabwe to measure feasibility, method uptake, acceptability, pregnancy outcome, and HIV transmission. This study was not designed to compare rates of HIV transmission by safer conception method choice but rather to understand choices couples make when seeking to minimize risk of HIV transmission and maximize likelihood of pregnancy. Couples in this prospective, non-randomized study were given a choice of one or more currently available safer conception methods: antiretroviral therapy (ART) with monthly viral load (VL) monitoring for the HIV-positive partner (ART/VL), pre-exposure prophylaxis (PrEP) for the HIV-negative partner, vaginal insemination (VI) for couples with an HIV-positive woman, and semen washing (SW) for couples with an HIV-positive man. Couples were followed monthly for up to 12 months of pregnancy attempts, quarterly during pregnancy, and 12 weeks post-partum. At each visit, data on method use, urine for pregnancy testing, and blood for HIV antibody testing, or viral load if HIV-positive, were obtained. Infants born to HIV-positive women were tested for HIV at 6 and 12 weeks. Between March 2017 and June 2019, 46 individuals from 23 HIV sero-different partnerships were enrolled and followed. At enrollment, all couples chose ART/VL, and all couples chose at least one additional method; 74% chose PrEP, 36% chose SW, and 25% chose VI. During pre-pregnancy follow-up visits, three couples discontinued SW, and one couple discontinued VI; all four of these couples opted for ART/VL plus PrEP. Satisfaction with safer conception methods was high among those who chose ART/VL and PrEP. Twelve couples achieved pregnancy. There were no cases of HIV transmission to partners, and no infants tested positive for HIV. This safer conception program is feasible and acceptable, allowing sero-different couples to safely achieve pregnancy. Sero-different couples in Zimbabwe seek a combination of HIV prevention methods, particularly ART/VL plus PrEP. Trial Registration: Clintrials.gov, NCT03049176.

Safety of single-dose primaquine as a Plasmodium falciparum gametocytocide: a systematic review and meta-analysis of individual patient data.

BACKGROUND: In 2012, the World Health Organization (WHO) recommended single low-dose (SLD, 0.25 mg/kg) primaquine to be added as a Plasmodium (P.) falciparum gametocytocide to artemisinin-based combination therapy (ACT) without glucose-6-phosphate dehydrogenase (G6PD) testing, to accelerate malaria elimination efforts and avoid the spread of artemisinin resistance. Uptake of this recommendation has been relatively slow primarily due to safety concerns. METHODS: A systematic review and individual patient data (IPD) meta-analysis of single-dose (SD) primaquine studies for P. falciparum malaria were performed. Absolute and fractional changes in haemoglobin concentration within a week and adverse effects within 28 days of treatment initiation were characterised and compared between primaquine and no primaquine arms using random intercept models. RESULTS: Data comprised 20 studies that enrolled 6406 participants, of whom 5129 (80.1%) had received a single target dose of primaquine ranging between 0.0625 and 0.75 mg/kg. There was no effect of primaquine in G6PD-normal participants on haemoglobin concentrations. However, among 194 G6PD-deficient African participants, a 0.25 mg/kg primaquine target dose resulted in an additional 0.53 g/dL (95% CI 0.17-0.89) reduction in haemoglobin concentration by day 7, with a 0.27 (95% CI 0.19-0.34) g/dL haemoglobin drop estimated for every 0.1 mg/kg increase in primaquine dose. Baseline haemoglobin, young age, and hyperparasitaemia were the main determinants of becoming anaemic (Hb < 10 g/dL), with the nadir observed on ACT day 2 or 3, regardless of G6PD status and exposure to primaquine. Time to recovery from anaemia took longer in young children and those with baseline anaemia or hyperparasitaemia. Serious adverse haematological events after primaquine were few (9/3, 113, 0.3%) and transitory. One blood transfusion was reported in the primaquine arms, and there were no primaquine-related deaths. In controlled studies, the proportions with either haematological or any serious adverse event were similar between primaquine and no primaquine arms. CONCLUSIONS: Our results support the WHO recommendation to use 0.25 mg/kg of primaquine as a P. falciparum gametocytocide, including in G6PD-deficient individuals. Although primaquine is associated with a transient reduction in haemoglobin levels in G6PD-deficient individuals, haemoglobin levels at clinical presentation are the major determinants of anaemia in these patients. TRIAL REGISTRATION: PROSPERO, CRD42019128185.

Efficacy of Single-Dose Primaquine With Artemisinin Combination Therapy on Plasmodium falciparum Gametocytes and Transmission: An Individual Patient Meta-Analysis.

BACKGROUND: Since the World Health Organization recommended single low-dose (0.25 mg/kg) primaquine (PQ) in combination with artemisinin-based combination therapies (ACTs) in areas of low transmission or artemisinin-resistant Plasmodium falciparum, several single-site studies have been conducted to assess efficacy. METHODS: An individual patient meta-analysis to assess gametocytocidal and transmission-blocking efficacy of PQ in combination with different ACTs was conducted. Random effects logistic regression was used to quantify PQ effect on (1) gametocyte carriage in the first 2 weeks post treatment; and (2) the probability of infecting at least 1 mosquito or of a mosquito becoming infected. RESULTS: In 2574 participants from 14 studies, PQ reduced PCR-determined gametocyte carriage on days 7 and 14, most apparently in patients presenting with gametocytemia on day 0 (odds ratio [OR], 0.22; 95% confidence interval [CI], .17-.28 and OR, 0.12; 95% CI, .08-.16, respectively). Rate of decline in gametocyte carriage was faster when PQ was combined with artemether-lumefantrine (AL) compared to dihydroartemisinin-piperaquine (DP) (P = .010 for day 7). Addition of 0.25 mg/kg PQ was associated with near complete prevention of transmission to mosquitoes. CONCLUSIONS: Transmission blocking is achieved with 0.25 mg/kg PQ. Gametocyte persistence and infectivity are lower when PQ is combined with AL compared to DP.

Mechanistic Modeling of Primaquine Pharmacokinetics, Gametocytocidal Activity, and Mosquito Infectivity.

Clinical studies have shown that adding a single 0.25 mg base/kg dose of primaquine to standard antimalarial regimens rapidly sterilizes Plasmodium falciparum gametocytes. However, the mechanism of action and overall impact on malaria transmission is still unknown. Using data from 81 adult Malians with P. falciparum gametocytemia who received the standard dihydroartemisinin-piperaquine treatment course and were randomized to receive either a single dose of primaquine between 0.0625 and 0.5 mg base/kg or placebo, we characterized the pharmacokinetic-pharmacodynamic relationships for transmission blocking activity. Both gametocyte clearance and mosquito infectivity were assessed. A mechanistically linked pharmacokinetic-pharmacodynamic model adequately described primaquine and carboxy-primaquine pharmacokinetics, gametocyte dynamics, and mosquito infectivity at different clinical doses of primaquine. Primaquine showed a dose-dependent gametocytocidal effect that precedes clearance. A single low dose of primaquine (0.25 mg/kg) rapidly prevented P. falciparum transmissibility.

Efficacy and safety of primaquine and methylene blue for prevention of Plasmodium falciparum transmission in Mali: a phase 2, single-blind, randomised controlled trial.

BACKGROUND: Primaquine and methylene blue are gametocytocidal compounds that could prevent Plasmodium falciparum transmission to mosquitoes. We aimed to assess the efficacy and safety of primaquine and methylene blue in preventing human to mosquito transmission of P falciparum among glucose-6-phosphate dehydrogenase (G6PD)-normal, gametocytaemic male participants. METHODS: This was a phase 2, single-blind, randomised controlled trial done at the Clinical Research Centre of the Malaria Research and Training Centre (MRTC) of the University of Bamako (Bamako, Mali). We enrolled male participants aged 5-50 years with asymptomatic P falciparum malaria. G6PD-normal participants with gametocytes detected by blood smear were randomised 1:1:1:1 in block sizes of eight, using a sealed-envelope design, to receive either sulfadoxine-pyrimethamine and amodiaquine, sulfadoxine-pyrimethamine and amodiaquine plus a single dose of 0·25 mg/kg primaquine, dihydroartemisinin-piperaquine, or dihydroartemisinin-piperaquine plus 15 mg/kg per day methylene blue for 3 days. Laboratory staff, investigators, and insectary technicians were masked to the treatment group and gametocyte density of study participants. The study pharmacist and treating physician were not masked. Participants could request unmasking. The primary efficacy endpoint, analysed in all infected patients with at least one infectivity measure before and after treatment, was median within-person percentage change in mosquito infectivity 2 and 7 days after treatment, assessed by membrane feeding. This study is registered with ClinicalTrials.gov, number NCT02831023. FINDINGS: Between June 27, 2016, and Nov 1, 2016, 80 participants were enrolled and assigned to the sulfadoxine-pyrimethamine and amodiaquine (n=20), sulfadoxine-pyrimethamine and amodiaquine plus primaquine (n=20), dihydroartemisinin-piperaquine (n=20), or dihydroartemisinin-piperaquine plus methylene blue (n=20) groups. Among participants infectious at baseline (54 [68%] of 80), those in the sulfadoxine-pyrimethamine and amodiaquine plus primaquine group (n=19) had a median 100% (IQR 100 to 100) within-person reduction in mosquito infectivity on day 2, a larger reduction than was noted with sulfadoxine-pyrimethamine and amodiaquine alone (n=12; -10·2%, IQR -143·9 to 56·6; p<0·0001). The dihydroartemisinin-piperaquine plus methylene blue (n=11) group had a median 100% (IQR 100 to 100) within-person reduction in mosquito infectivity on day 2, a larger reduction than was noted with dihydroartemisinin-piperaquine alone (n=12; -6·0%, IQR -126·1 to 86·9; p<0·0001). Haemoglobin changes were similar between gametocytocidal arms and their respective controls. After exclusion of blue urine, adverse events were similar across all groups (59 [74%] of 80 participants had 162 adverse events overall, 145 [90%] of which were mild). INTERPRETATION: Adding a single dose of 0·25 mg/kg primaquine to sulfadoxine-pyrimethamine and amodiaquine or 3 days of 15 mg/kg per day methylene blue to dihydroartemisinin-piperaquine was highly efficacious for preventing P falciparum transmission. Both primaquine and methylene blue were well tolerated. FUNDING: Bill & Melinda Gates Foundation, European Research Council.

What motivates serodiscordant couples to prevent HIV transmission within their relationships: findings from a PrEP implementation study in Kenya.

With the planned scale-up of pre-exposure prophylaxis (PrEP) for HIV prevention among serodiscordant couples in resource-limited settings, gaining an understanding of what motivates serodiscordant couples to prevent HIV is critical. We conducted 44 semi-structured, in-depth individual or couple interviews with 63 participants (33 HIV-infected and 30 HIV-uninfected participants) enrolled in a prospective implementation study of oral antiretroviral-based prevention in Kisumu, Kenya. Transcripts were iteratively analysed using inductive content analysis. Findings point to the importance of maintaining the emotional and economic stability of the partnership and family as motivators in preventing HIV transmission. Female participants identified fear of blame or potential violence for transmitting HIV as a motivator. Furthermore, couples primarily held the HIV-infected individual responsible for HIV prevention, but also held women more accountable for the use of prevention methods such as condoms. These themes substantiate traditional gender norms but also reveal how dyadic interdependence challenges these norms. As programmes in resource-limited settings scale up PrEP access, they should simultaneously capitalise on HIV serodiscordant couples' motivations for HIV prevention and address gender norms so women do not find themselves unduly responsible for the prevention of HIV transmission.

"Since both of us are using antiretrovirals, we have been supportive to each other": facilitators and barriers of pre-exposure prophylaxis use in heterosexual HIV serodiscordant couples in Kisumu, Kenya.

INTRODUCTION: Since 2015, the World Health Organization recommends pre-exposure prophylaxis (PrEP) for all persons at substantial risk for HIV, including HIV-uninfected partners in serodiscordant relationships in resource-limited settings. As PrEP moves from clinical trials to real-world use, understanding facilitators of and barriers to PrEP initiation and adherence is critical to successful PrEP implementation and rollout. METHODS: We conducted 44 in-depth individual or couple interviews with 63 participants (30 without HIV and 33 with HIV) enrolled in the Partners Demonstration Project in Kisumu, Kenya, between August and September 2014. The semi-structured interviews discussed the following: 1) perceived advantages and disadvantages of antiretroviral therapy (ART)/PrEP; 2) reasons for accepting or declining ART/PrEP and 3) influence of prevention of transmission to partner or infant on ART/PrEP use. Transcripts from the interviews were iteratively analyzed using inductive content analysis. RESULTS: Our study identified three key factors that may facilitate initiation of PrEP in this population. First, participants using PrEP felt reduced stress and increased trust in their HIV serodiscordant relationships. Second, greater community-wide knowledge of PrEP was thought to likely increase PrEP acceptance. Third, greater education and counselling by providers on PrEP use was also considered to likely increase the adoption of PrEP. We also identified three key barriers to initiation of and adherence to PrEP. First, most participants who declined PrEP expressed doubts about the relative additional effectiveness of PrEP in combination with other prevention tools. Second, perceived stigma related to PrEP use was an important barrier to PrEP initiation. Third, many struggled with overcoming perceived side effects or logistical challenges of taking daily PrEP, particularly when they themselves were not ill. CONCLUSIONS: Leveraging the facilitators and overcoming barriers to PrEP uptake may enhance the successful rollout of PrEP among HIV serodiscordant couples in Kenya and other areas in sub-Saharan Africa, thereby reducing sexual transmission of HIV. Further research focused on how best to provide counselling on combination HIV prevention tools in the context of PrEP use is a crucial next step to delivering PrEP.

Facilitators and Barriers of Antiretroviral Therapy Initiation among HIV Discordant Couples in Kenya: Qualitative Insights from a Pre-Exposure Prophylaxis Implementation Study.

INTRODUCTION: The World Health Organization now recommends antiretroviral therapy (ART) initiation for all HIV-infected individuals regardless of CD4 cell count or disease status. Understanding the facilitators and barriers to initiation of and adherence to ART is essential to successful scale-up of "universal" ART. METHODS: To investigate facilitators and barriers to ART initiation, we conducted 44 in-depth individual or couple interviews with 63 participants (33 participants with HIV and 30 without HIV) already enrolled in a prospective implementation study of oral antiretroviral-based prevention in Kisumu, Kenya between August and September 2014. A semi-structured interview guided discussions on: 1) perceived advantages and disadvantages of ART; 2) reasons for accepting or declining ART initiation; and 3) influence of prevention of transmission to partner or infant influencing ART use. Transcripts from the interviews were iteratively analyzed using inductive content analysis. RESULTS: HIV-infected participants indicated that living a healthier life, preventing HIV transmission to others, and appearing "normal" or "healthy" again facilitated their initiation of ART. While appearing "normal" allowed these individuals to interact with their communities without stigmatization, they also perceived community opposition to their initiating ART, because appearing "normal" again prevented community members from easily identifying infected individuals in their community. Denial of diagnosis, disclosure stigma, perceived side-effects, and challenges in obtaining refills were additional barriers to ART initiation. CONCLUSIONS: Community perceptions play an important role in both facilitating and inhibiting ART initiation. Perceived stigma, including perceived community opposition to widespread ART use, is an important barrier to ART initiation. Addressing such barriers, while capitalizing on facilitators, to ART initiation should be central to universal ART scale-up efforts.

Motivations for Intravaginal Product Use among a Cohort of Women in Los Angeles.

OBJECTIVE: Intravaginal practices-including behaviors such as intravaginal cleansing and insertion of products-have been linked to a number of adverse reproductive health outcomes, including increased risk for bacterial vaginosis, sexually transmitted infections, and HIV. Currently, little is known about the motivations for intravaginal practices among women in the United States. The objective of this study was to identify and describe motivations for intravaginal washing and intravaginal insertion of products among women of differing ages and racial/ethnic groups. METHODS: Between 2008 and 2010, we enrolled a convenience sample of sexually active women aged 18-65 years living in Los Angeles recruited through community education and outreach activities in HIV/AIDS service organizations, women's health clinics, community-based organizations, and HIV testing sites. At the enrollment visit, women completed a self-administered, computer-assisted questionnaire covering demographics, sexual behaviors, intravaginal practices, and motivations for intravaginal practices over the past month and past year. RESULTS: We enrolled 141 women; 34% of participants were Caucasian, 40% African American, and 26% Latina. Peri-sexual intravaginal washing was common in all groups, whether to clean up after sex (70%) or to prepare for sex (54%). African American women were more likely to report learning to wash intravaginally from their mothers compared to Latina or Caucasian women (70% vs. 49%, P = 0.04). Sixty-one percent of African American women reported using a douching device over the past year compared to 41% of Latina and 40% of Caucasian women (p = 0.02). Younger women were more likely to report that their male partners wanted them to wash intravaginally than older women (77% vs. 24%, P<0.01), and more likely to report the removal of odors as a motive than older women (65% vs. 40%, P = 0.04). The most commonly used intravaginal products included sexual lubricants, petroleum jelly, body lotions, oils, and wet wipes. Use of these products varied by race, and motives given included increasing lubrication, preparing for sex, smelling good, and preventing sexually transmitted infections. CONCLUSION: Women's intravaginal practices and motivations for these practices differ across race and age. Motivations for use also vary by type of intravaginal product used. Given that some intravaginal practices have been shown to be harmful, interventions, programs and counseling messages to encourage less harmful practices are needed, and should consider underlying motivations that influence women's vaginal practices. Practitioners may use these results to better support women in achieving vaginal health.

Primaquine to reduce transmission of Plasmodium falciparum malaria in Mali: a single-blind, dose-ranging, adaptive randomised phase 2 trial.

BACKGROUND: Single low doses of primaquine, when added to artemisinin-based combination therapy, might prevent transmission of Plasmodium falciparum malaria to mosquitoes. We aimed to establish the activity and safety of four low doses of primaquine combined with dihydroartemisinin-piperaquine in male patients in Mali. METHODS: In this phase 2, single-blind, dose-ranging, adaptive randomised trial, we enrolled boys and men with uncomplicated P falciparum malaria at the Malaria Research and Training Centre (MRTC) field site in Ouelessebougou, Mali. All participants were confirmed positive carriers of gametocytes through microscopy and had normal function of glucose-6-phosphate dehydrogenase (G6PD) on colorimetric quantification. In the first phase, participants were randomly assigned (1:1:1) to one of three primaquine doses: 0 mg/kg (control), 0·125 mg/kg, and 0·5 mg/kg. Randomisation was done with a computer-generated randomisation list (in block sizes of six) and concealed with sealed, opaque envelopes. In the second phase, different participants were sequentially assigned (1:1) to 0·25 mg/kg primaquine or 0·0625 mg/kg primaquine. Primaquine tablets were dissolved into a solution and administered orally in a single dose. Participants were also given a 3 day course of dihydroartemisinin-piperaquine, administered by weight (320 mg dihydroartemisinin and 40 mg piperaquine per tablet). Outcome assessors were masked to treatment allocation, but participants were permitted to find out group assignment. Infectivity was assessed through membrane-feeding assays, which were optimised through the beginning part of phase one. The primary efficacy endpoint was the mean within-person percentage change in mosquito infectivity 2 days after primaquine treatment in participants who completed the study after optimisation of the infectivity assay, had both a pre-treatment infectivity measurement and at least one follow-up infectivity measurement, and who were given the correct primaquine dose. The safety endpoint was the mean within-person change in haemoglobin concentration during 28 days of study follow-up in participants with at least one follow-up visit. This study is registered with ClinicalTrials.gov, number NCT01743820. FINDINGS: Between Jan 2, 2013, and Nov 27, 2014, we enrolled 81 participants. In the primary analysis sample (n=71), participants in the 0·25 mg/kg primaquine dose group (n=15) and 0·5 mg/kg primaquine dose group (n=14) had significantly lower mean within-person reductions in infectivity at day 2-92·6% (95% CI 78·3-100; p=0·0014) for the 0·25 mg/kg group; and 75·0% (45·7-100; p=0·014) for the 0·5 mg/kg primaquine group-compared with those in the control group (n=14; 11·3% [-27·4 to 50·0]). Reductions were not significantly different from control for participants assigned to the 0·0625 mg/kg dose group (n=16; 41·9% [1·4-82·5]; p=0·16) and the 0·125 mg/kg dose group (n=12; 54·9% [13·4-96·3]; p=0·096). No clinically meaningful or statistically significant drops in haemoglobin were recorded in any individual in the haemoglobin analysis (n=70) during follow-up. No serious adverse events were reported and adverse events did not differ between treatment groups. INTERPRETATION: A single dose of 0·25 mg/kg primaquine, given alongside dihydroartemisinin-piperaquine, was safe and efficacious for the prevention of P falciparum malaria transmission in boys and men who are not deficient in G6PD. Future studies should assess the safety of single-dose primaquine in G6PD-deficient individuals to define the therapeutic range of primaquine to enable the safe roll-out of community interventions with primaquine. FUNDING: Bill & Melinda Gates Foundation.

The independent effect of living in malaria hotspots on future malaria infection: an observational study from Misungwi, Tanzania.

BACKGROUND: As malaria transmission declines, continued improvements of prevention and control interventions will increasingly rely on accurate knowledge of risk factors and an ability to define high-risk areas and populations at risk for focal targeting of interventions. This paper explores the independent association between living in a hotspot and prospective risk of malaria infection. METHODS: Malaria infection status defined by nPCR and AMA-1 status in year 1 were used to define geographic hotspots using two geospatial statistical methods (SaTScan and Kernel density smoothing). Other malaria risk factors for malaria infection were explored by fitting a multivariable model. RESULTS: This study demonstrated that residing in infection hotspot of malaria transmission is an independent predictor of malaria infection in the future. CONCLUSION: It is likely that targeting such hotspots with better coverage and improved malaria control strategies will result in more cost-efficient uses of resources to move towards malaria elimination.

Predischarge postpartum methicillin resistant Staphylococcus aureus infection and group B streptococcus carriage at the individual and hospital levels.

BACKGROUND: We sought to characterize the relationship between individual group B streptococcus (GBS) colonization and pre-discharge postpartum methicillin resistant Staphylococcus aureus (MRSA) infection in United States women delivering at term. We also sought to examine the association between hospital GBS colonization prevalence and MRSA infection. MATERIALS AND METHODS: Data was from the Nationwide Inpatient Sample, a representative sample of United States community hospitals. Hierarchical regression models were used to estimate odds ratios adjusted for patient age, race, expected payer, and prepregnancy diabetes and hospital teaching status, urbanicity, ownership, size, and geographic region. We used multiple imputation for missing covariate data. RESULTS: There were 3,136,595 deliveries and 462 cases of MRSA infection included in this study. The odds ratio for individual GBS colonization was 1.2 (95% confidence interval: 0.9 to 1.5). For a five-percent increase in the hospital prevalence of GBS colonization, the odds ratio was 0.9 (95% CI: 0.1 to 5.6). CONCLUSIONS: The odds ratio estimate for the association of hospital GBS prevalence with MRSA infection is too imprecise to make conclusions about its magnitude and direction. Barring major bias in our estimates, individual GBS carriage does not appear to be strongly associated with predischarge postpartum MRSA infection.

Hot spot or not: a comparison of spatial statistical methods to predict prospective malaria infections.

BACKGROUND: Within affected communities, Plasmodium falciparum infections may be skewed in distribution such that single or small clusters of households consistently harbour a disproportionate number of infected individuals throughout the year. Identifying these hotspots of malaria transmission would permit targeting of interventions and a more rapid reduction in malaria burden across the whole community. This study set out to compare different statistical methods of hotspot detection (SaTScan, kernel smoothing, weighted local prevalence) using different indicators (PCR positivity, AMA-1 and MSP-1 antibodies) for prediction of infection the following year. METHODS: Two full surveys of four villages in Mwanza, Tanzania were completed over consecutive years, 2010-2011. In both surveys, infection was assessed using nested polymerase chain reaction (nPCR). In addition in 2010, serologic markers (AMA-1 and MSP-119 antibodies) of exposure were assessed. Baseline clustering of infection and serological markers were assessed using three geospatial methods: spatial scan statistics, kernel analysis and weighted local prevalence analysis. Methods were compared in their ability to predict infection in the second year of the study using random effects logistic regression models, and comparisons of the area under the receiver operating curve (AUC) for each model. Sensitivity analysis was conducted to explore the effect of varying radius size for the kernel and weighted local prevalence methods and maximum population size for the spatial scan statistic. RESULTS: Guided by AUC values, the kernel method and spatial scan statistics appeared to be more predictive of infection in the following year. Hotspots of PCR-detected infection and seropositivity to AMA-1 were predictive of subsequent infection. For the kernel method, a 1 km window was optimal. Similarly, allowing hotspots to contain up to 50% of the population was a better predictor of infection in the second year using spatial scan statistics than smaller maximum population sizes. CONCLUSIONS: Clusters of AMA-1 seroprevalence or parasite prevalence that are predictive of infection a year later can be identified using geospatial models. Kernel smoothing using a 1 km window and spatial scan statistics both provided accurate prediction of future infection.

Hospital and provider patient volumes, cesarean section rates, and early postpartum invasive methicillin-resistant Staphylococcus aureus infection.

OBJECTIVE: We sought to examine whether hospital and provider volumes and cesarean section rates influenced early postpartum invasive methicillin-resistant Staphylococcus aureus (MRSA) infection. METHODS: We used data from the Nationwide Inpatient Sample, a representative sample of US community hospitals. Multivariate hierarchical regression models were used to estimate odds ratios adjusted for hospital total discharges, nurse:patient ratio, urbanicity, teaching status, bed size, ownership, and geographic region and patient age, race, expected payer, and comorbidities. RESULTS: The total sample size for the hospital analysis was 3,487,350 deliveries, which included 555 cases of MRSA infection. The total sample size for the provider analysis was 1,186,703 deliveries, with 221 cases of MRSA infection. Hospital and provider patient (deliveries) volumes and cesarean section rates were not associated with early postpartum invasive MRSA infection. CONCLUSIONS: Barring major bias in our estimates, our results suggest that transmission from providers may not be a predominant route of postpartum MRSA infection in US hospitals.

Intravaginal practices and risk of bacterial vaginosis and candidiasis infection among a cohort of women in the United States.

OBJECTIVE: To measure intravaginal practices among women of differing ages, ethnicities, and human immunodeficiency virus status and the association between intravaginal practices and bacterial vaginosis and candidiasis infection. METHODS: Between 2008 and 2010, we recruited and followed sexually active women aged 18-65 years living in Los Angeles. At the enrollment and month 12 visit, participants completed a self-administered, computer-assisted questionnaire covering demographics, sexual behaviors, vaginal symptoms, and intravaginal practices over the past month. At each visit, bacterial vaginosis and candidiasis infection were diagnosed by Nugent criteria and DNA probe, respectively. RESULTS: We enrolled 141 women. Two thirds (66%) reported an intravaginal practice over the past month; 49% reported insertion of an intravaginal product (other than tampons) and 45% reported intravaginal washing. The most commonly reported practices included insertion of commercial sexual lubricants (70%), petroleum jelly (17%), and oils (13%). In univariable analysis, intravaginal use of oils was associated with Candida species colonization (44.4% compared with 5%, P<.01). In multivariable analysis, women reporting intravaginal use of petroleum jelly over the past month were 2.2 times more likely to test positive for bacterial vaginosis (adjusted relative risk 2.2, 95% confidence interval 1.3-3.9). CONCLUSION: Intravaginal insertion of over-the-counter products is common among women in the United States and is associated with increased risk of bacterial vaginosis. The context, motivations for, and effects of intravaginal products and practices on vaginal health are of concern and warrant further study. LEVEL OF EVIDENCE: III.

Intimate partner violence and anal intercourse in young adult heterosexual relationships.

CONTEXT: Although intimate partner violence and anal intercourse are common in young adult relationships, few studies have examined whether these behaviors are associated with each other. METHODS: Data from 6,280 women aged 18-28 who took part in Wave 3 of the National Longitudinal Study of Adolescent Health were used to examine the association between physical and sexual intimate partner violence and anal intercourse in 10,462 relationships. Multivariate hierarchical random effects models were used to adjust for the clustered survey design and for the multiple relationships reported per participant. RESULTS: Physical violence occurred in 29% of relationships, sexual violence in 11% and anal intercourse in 14%. The odds that a couple had had anal intercourse were greater among relationships that included physical violence perpetrated by both partners or only by the woman than among nonviolent relationships (odds ratios, 1.7 and 1.9, respectively). The odds of anal intercourse were also elevated among sexually abusive relationships, although only if the woman was the sole victim or the sole perpetrator (1.3 and 2.0, respectively). In relationships that included anal intercourse, the odds of condom use were lower if the woman was a victim of physical violence than if no violence occurred (0.2). Sexual violence was not associated with condom use. CONCLUSION: Women in physically violent relationships may be at increased risk for STDs because of their elevated exposure to unprotected anal intercourse. More information on the context surrounding anal intercourse and intimate partner violence is needed to understand the nuances of this association.

HPV Type Distribution and Cervical Cytology among HIV-Positive Tanzanian and South African Women.

Background. There are limited data on high-risk human papillomavirus (hr-HPV) genotypes among HIV-positive women in Africa, and little is known about their relationship with cervical cytology in these populations. Methods. We conducted a cross-sectional study among 194 HIV-positive women (143 from Tanzania, and 51 from South Africa) to evaluate HPV genotypes among HIV-positive women with normal and abnormal cytology. Cervical samples were genotyped for HPV types, and slides were evaluated for atypical squamous cell changes according to the Bethesda classification system. Results. Prevalence of high grade squamous intraepithelial dysplasia (HSIL) was 9%. Overall, more than half (56%) of women were infected with an hr-HPV type; 94% of women with HSIL (n = 16), 90% of women with LSIL (n = 35), and 42% of women within normal limits (WNL) (n = 58) tested positive for hr-HPV. Overall, the most prevalent hr-HPV subtypes were HPV16 (26%) and HPV52 (30%). Regional differences in the prevalence of HPV18 and HPV35 were found. Conclusion. Regional differences in HPV genotypes among African women warrant the need to consider different monitoring programmes for cervical preneoplasia. HPV-based screening tests for cervical preneoplasia would be highly inefficient unless coupled with cytology screening of the HPV-positive sample, especially in HIV-positive women.

Intimate partner violence and sexually transmitted infections among young adult women.

BACKGROUND: Intimate partner violence (IPV) is common among young adult relationships, and is associated with significant morbidity, including sexually transmitted infections (STI). This study measured the association between IPV victimization and perpetration and prevalent STIs and STI-risk behaviors among a sample of young women. METHODS: This analysis uses wave 3 of the National Longitudinal Study of Adolescent Health and was restricted to the 3548 women who reported on a sexual relationship that occurred in the previous 3 months and agreed to STI testing. A multivariate random effects model was used to determine associations between STI and STI-risk behaviors and IPV. RESULTS: The IPV prevalence over the past year was 32%-3% victim-only, 12% perpetrator-only, and 17% reciprocal. The STI prevalence was 7.1%. Overall, 17% of participants reported partner concurrency and 32% reported condom use at last vaginal intercourse. In multivariate analysis, victim-only and reciprocal IPV were associated with not reporting condom use at last vaginal intercourse. Perpetrator-only, victim-only, and reciprocal IPV were associated with partner concurrency. Victim-only IPV was associated with a higher likelihood of having a prevalent STI (odds ratio: 2.1; 95% confidence interval: 1.0-4.2). CONCLUSIONS: This analysis adds to the growing body of literature that suggests that female IPV victims have a higher STI prevalence, as well as a higher prevalence of STI-risk behaviors, compared with women in nonviolent relationships. Women in violent relationships should be considered for STI screening in clinics, and IPV issues should be addressed in STI prevention messages, given its impact on risk for STI acquisition.