Proximate and distant determinants of maternal and neonatal mortality in the postnatal period: A scoping review of data from low- and middle-income countries.

Global maternal and neonatal mortality rates remain unacceptably high. The postnatal period, encompassing the first hour of life until 42 days, is critical for mother-baby dyads, yet postnatal care (PNC) coverage is low. Identifying mother-baby dyads at increased risk for adverse outcomes is critical. Yet few efforts have synthesized research on proximate and distant factors associated with maternal and neonatal mortality during the postnatal period. This scoping review identified proximate and distant factors associated with maternal and neonatal mortality during the postnatal period within low- and middle-income countries (LMICs). A rigorous, systematic search of four electronic databases was undertaken to identify studies published within the last 11 years containing data on risk factors among nationally representative samples. Results were synthesized narratively. Seventy-nine studies were included. Five papers examined maternal mortality, one focused on maternal and neonatal mortality, and the rest focused on neonatal mortality. Regarding proximate factors, maternal age, parity, birth interval, birth order/rank, neonate sex, birth weight, multiple-gestation, previous history of child death, and lack of or inadequate antenatal care visits were associated with increased neonatal mortality risk. Distant factors for neonatal mortality included low levels of parental education, parental employment, rural residence, low household income, solid fuel use, and lack of clean water. This review identified risk factors that could be applied to identify mother-baby dyads with increased mortality risk for targeted PNC. Given risks inherent in pregnancy and childbirth, adverse outcomes can occur among dyads without obvious risk factors; providing timely PNC to all is critical. Efforts to reduce the prevalence of risk factors could improve maternal and newborn outcomes. Few studies exploring maternal mortality risk factors were available; investments in population-based studies to identify factors associated with maternal mortality are needed. Harmonizing categorization of factors (e.g., age, education) is a gap for future research.

On the road to universal coverage of postnatal care: considerations for a targeted postnatal care approach for at-risk mother-baby dyads in low-income and middle-income countries informed by a consultation with global experts.

INTRODUCTION: The potential of timely, quality postnatal care (PNC) to reduce maternal and newborn mortality and to advance progress toward universal health coverage (UHC) is well-documented. Yet, in many low-income and middle-income countries, coverage of PNC remains low. Risk-stratified approaches can maximise limited resources by targeting mother-baby dyads meeting the evidence-based risk criteria which predict poor postnatal outcomes. OBJECTIVES: To review evidence-based risk criteria for identification of at-risk mother-baby dyads, drawn from a literature review, and to identify key considerations for their use in a risk-stratified PNC approach. DESIGN/SETTING/PARTICIPANTS: A virtual, semi-structured group discussion was conducted with maternal and newborn health experts on Zoom. Participants were identified through purposive sampling based on content and context expertise. RESULTS: Seventeen experts, (5 men and 12 women), drawn from policymakers, implementing agencies and academia participated and surfaced several key themes. The identified risk factors are well-known, necessitating accelerated efforts to address underlying drivers of risk. Risk-stratified PNC approaches complement broader UHC efforts by providing an equity lens to identify the most vulnerable mother-baby dyads. However, these should be layered on efforts to strengthen PNC service provision for all mothers and newborns. Risk factors should comprise context-relevant, operationalisable, clinical and non-clinical factors. Even with rising coverage of facility delivery, targeted postnatal home visits still complement facility-based PNC. CONCLUSION: Risk-stratified PNC efforts must be considered within broader health systems strengthening efforts. Implementation research at the country level is needed to understand feasibility and practicality of clinical and non-clinical risk factors and identify unintended consequences.

Does Capacity Development Increase Demand for Health Services and Rights Among Key Populations Affected by HIV? A Systematic Review of Evidence from Low and Middle-Income Countries.

Capacity development is a process by which individuals, organizations and societies develop abilities to perform functions, solve problems and achieve objectives. This systematic review sought to document capacity development interventions, the associated outcomes and its effectiveness in increasing demand for rights and health services among key populations (KP) in low and middle-income countries. Twenty papers met our review's selection criteria. Significant improvements in health service utilization were achieved in most community mobilization and peer-led interventions. Whilst we found ample evidence linking capacity development to uptake of services, there was a striking dearth of research examining the impact of capacity development on demand for rights among KP. There was inadequate contextual data to explain variations in intervention effectiveness across different projects. More evidence is needed on the impact of capacity development on demand for health services and rights among KP. Consensus on parameters of capacity development and priority outcomes is required.

Repeat Use of Post-exposure Prophylaxis for HIV Among Nairobi-Based Female Sex Workers Following Sexual Exposure.

As ART-based prevention becomes available, effectively targeting these interventions to key populations such as female sex workers (FSW) will be critical. In this study we analyze patterns of repeated post-exposure prophylaxis (PEP) access in the context of a large FSW program in Nairobi. During close to 6000 person-years of follow-up, 20 % of participants (n = 1119) requested PEP at least once and 3.7 % requested PEP more than once. Repeat PEP users were younger, had a higher casual partner volume, and were more likely to use condoms with casual and regular partners, have a regular partner, and test for HIV prior to enrolment. Barriers to PEP included stigma, side effects, and lack of knowledge, suggesting repeated promotion may be required for higher rates of uptake. A small subset of FSW, potentially those with heightened risk perception, showed a higher frequency of PEP use; these individuals may be most amenable to rollout of pre-exposure prophylaxis.

Risk Factors for HIV Acquisition in a Prospective Nairobi-Based Female Sex Worker Cohort.

With two million new HIV infections annually, ongoing investigations of risk factors for HIV acquisition is critical to guide ongoing HIV prevention efforts. We conducted a prospective cohort analysis of HIV uninfected female sex workers enrolled at an HIV prevention clinic in Nairobi (n = 1640). In the initially HIV uninfected cohort (70 %), we observed 34 HIV infections during 1514 person-years of follow-up, i.e. an annual incidence of 2.2 % (95 % CI 1.6-3.1 %). In multivariable Cox Proportional Hazard analysis, HIV acquisition was associated with a shorter baseline duration of sex work (aHR 0.76, 95 % CI 0.63-0.91), minimum charge/sex act (aHR 2.74, 0.82-9.15, for low vs. intermediate; aHR 5.70, 1.96-16.59, for high vs. intermediate), N. gonorrhoeae infection (aAHR 5.89, 95 % CI 2.03-17.08), sex with casual clients during menses (aHR 6.19, 95 % CI 2.58-14.84), Depo Provera use (aHR 5.12, 95 % CI 1.98-13.22), and estimated number of annual unprotected regular partner contacts (aHR 1.004, 95 % CI 1.001-1.006). Risk profiling based on baseline predictors suggested that substantial heterogeneity in HIV risk is evident, even within a key population. These data highlight several risk factors for HIV acquisition that could help to re-focus HIV prevention messages.

Early HIV-1 infection is associated with reduced frequencies of cervical Th17 cells.

BACKGROUND: The hallmark of HIV infection is progressive but variable rates of systemic and mucosal CD4 depletion, leading to immunodeficiency. The impact of early HIV infection on cervical CD4 T-cell populations in humans remains poorly described. METHODS: We analyzed cytobrush-derived immune cells by flow cytometry and cytokines in cervicovaginal lavage from participants in early HIV (<6 months postinfection), chronic HIV, and HIV-uninfected controls. RESULTS: CD4:CD8 ratios declined rapidly in both the cervix and the blood following HIV infection. In contrast, absolute cervical CD4 T-cell counts in early HIV were comparable to HIV-uninfected participants, declining only in chronic infection. Early HIV infection was associated with increases in RANTES and MIP3a in cervicovaginal fluids. Concurrently, slight increases in activated cells (CD38HLA-DR) and higher levels of CTLA4 expression on Tregs in the cervix were observed. Although study groups did not differ with respect to levels of CCR5, integrin B7, or CD69, the frequencies of Th17 cells (defined as CCR6CCR10) was reduced by >10-fold in early HIV infection and Th1 cells (defined as CCR6CXCR3) were reduced by >2-fold. Although CCR6CCR10 cells did not differ in HIV receptor expression, these cells produced higher levels of interferon gamma and interleukin 17. CONCLUSIONS: These data support the model of initial CD4 T-cell depletion followed by overall T-cell influx in response to infection and concomitant increases in immune activation, inflammation, and regulatory markers. These data are among the earliest characterization of the cellular milieu in the female genital tract following male-to-female HIV transmission.

Optimizing viable leukocyte sampling from the female genital tract for clinical trials: an international multi-site study.

BACKGROUND: Functional analysis of mononuclear leukocytes in the female genital mucosa is essential for understanding the immunologic effects of HIV vaccines and microbicides at the site of HIV exposure. However, the best female genital tract sampling technique is unclear. METHODS AND FINDINGS: We enrolled women from four sites in Africa and the US to compare three genital leukocyte sampling methods: cervicovaginal lavages (CVL), endocervical cytobrushes, and ectocervical biopsies. Absolute yields of mononuclear leukocyte subpopulations were determined by flow cytometric bead-based cell counting. Of the non-invasive sampling types, two combined sequential cytobrushes yielded significantly more viable mononuclear leukocytes than a CVL (p<0.0001). In a subsequent comparison, two cytobrushes yielded as many leukocytes (∼ 10,000) as one biopsy, with macrophages/monocytes being more prominent in cytobrushes and T lymphocytes in biopsies. Sample yields were consistent between sites. In a subgroup analysis, we observed significant reproducibility between replicate same-day biopsies (r = 0.89, p = 0.0123). Visible red blood cells in cytobrushes increased leukocyte yields more than three-fold (p = 0.0078), but did not change their subpopulation profile, indicating that these leukocytes were still largely derived from the mucosa and not peripheral blood. We also confirmed that many CD4(+) T cells in the female genital tract express the α4ß7 integrin, an HIV envelope-binding mucosal homing receptor. CONCLUSIONS: CVL sampling recovered the lowest number of viable mononuclear leukocytes. Two cervical cytobrushes yielded comparable total numbers of viable leukocytes to one biopsy, but cytobrushes and biopsies were biased toward macrophages and T lymphocytes, respectively. Our study also established the feasibility of obtaining consistent flow cytometric analyses of isolated genital cells from four study sites in the US and Africa. These data represent an important step towards implementing mucosal cell sampling in international clinical trials of HIV prevention.

High HIV risk in a cohort of male sex workers from Nairobi, Kenya.

OBJECTIVES: Men who have sex with men (MSM) are at high risk of HIV-1 acquisition and transmission, yet there remains limited data in the African context, and for men who sell sex to men (MSM SW) in particular. METHODS: We enrolled 507 male sex workers in a Nairobi-based prospective cohort study during 2009-2012. All participants were offered HIV/STI screening, counselling and completed a baseline questionnaire. RESULTS: Baseline HIV prevalence was 40.0% (95% CI 35.8% to 44.3%). Prevalent HIV infection was associated with age, less postsecondary education, marijuana use, fewer female partners and lower rates of prior HIV testing. Most participants (73%) reported at least two of insertive anal, receptive anal and insertive vaginal sex in the past 3 months. Vaginal sex was reported by 37% of participants, and exclusive MSM status was associated with higher HIV rates. Condom use was infrequent, with approximately one-third reporting 100% condom use during anal sex. HIV incidence was 10.9 per 100 person-years (95% CI 7.4 to 15.6). Predictors of HIV risk included history of urethral discharge (aHR 0.29, 95% CI 0.08 to 0.98, p=0.046), condom use during receptive anal sex (aHR 0.05, 95% CI 0.01 to 0.41, p=0.006) and frequency of sex with male partners (aHR 1.33/sex act, 95% CI 1.01 to 1.75, p=0.04). CONCLUSIONS: HIV prevalence and incidence were extremely high in Nairobi MSM SW; a combination of interventions including increasing condom use, pre-exposure prophylaxis and access to effective treatment is urgently needed to decrease HIV transmission in this key population.

HIV postexposure prophylaxis in an urban population of female sex workers in Nairobi, Kenya.

OBJECTIVES: To assess biological and behavioral factors in HIV-uninfected female sex workers (FSWs) accessing postexposure prophylaxis (PEP) and to characterize the circumstances preceding PEP, time to access, and adherence. METHODS: Participants were HIV-uninfected FSWs enrolled in an HIV care and prevention program in Nairobi, Kenya. Those accessing PEP between 2009 and 2010 were enrolled and compared with controls. Multiple logistic regression models were used to compare PEP-related biological and behavioral parameters. RESULTS: PEP users (n = 326) had been involved in sex work for a shorter duration than nonusers [n = 2570; 3.3 vs. 5.1 yrs, AOR: 0.92, 95% confidence interval (CI): 0.89 to 0.95] and were less likely to report a regular partner (54.9% vs. 72.5%, AOR: 0.52, 0.39 to 0.68). PEP use was associated with gonorrhea infection (6.9% vs. 2.6%, AOR: 2.37, 95% CI: 1.34 to 4.21) and alcohol use (84.3% vs. 76.1%, AOR: 1.58, 95% CI: 1.09 to 2.31), but with increased condom use (85.1% vs. 68.2%, AOR 1.80, 95% CI: 1.38-2.35) and a history of prior HIV testing (89.2 vs. 76.2%, AOR: 2.22, 95% CI: 1.45 to 3.40). Reasons for PEP access centered on issues of client mistrust. The median time from exposure to PEP was 18 hours, with an estimated adherence of 49%. Precise PEP efficacy could not be calculated, but HIV incidence was 0.6% in users (2/326) compared with 2.1% (30/1417) in nonusers (Cox regression P = 0.35). CONCLUSIONS: "PEP services were accessed by 10% of FSWs during the study period and were not implicated in any incident HIV cases." Users had indicators of increased sexual risk and higher health care literacy. Increasing PEP access and compliance in FSWs may be an important HIV prevention strategy.

Characterization of a human cervical CD4+ T cell subset coexpressing multiple markers of HIV susceptibility.

The HIV pandemic disproportionately affects women, with most infections acquired through receptive vaginal sex. Although the target cells by which HIV establishes infection in the female genital tract remain poorly defined, it is known that immune activation results in CD4(+) T cells with enhanced susceptibility, as does expression of the mucosal integrin α4ß7 and the HIV coreceptor CCR5. Blood and cervical cytobrush specimens were collected from female sex workers (FSWs) in Nairobi, Kenya. Genital infection diagnostics were performed, T cell populations were defined by multiparameter flow cytometry based on their expression of surface receptors relevant to mucosal homing and/or HIV acquisition, and cytokine production was assayed by intracellular cytokine staining. The integrin α4ß7 was expressed on 26.0% of cervical CD4(+) T cells, and these cells were more likely to express both the HIV coreceptor CCR5 (p < 0.0001) and the early activation marker CD69 (p < 0.0001) but not CXCR4 (p = 0.34). Cervical Th17 frequencies were enhanced compared with blood (7.02 versus 1.24%; p < 0.0001), and cervical IL-17A(+) CD4(+) T cells preferentially coexpressed α4ß7 and CCR5. Expression of IFN-γ and IL-22 was greater in cervical Th17 cells than in blood Th17 cells. In keeping with the hypothesis that these cells are preferential HIV targets, gp120 preferentially bound CCR5(+) cervical T cells, and cervical Th17 cells were almost completely depleted in HIV(+) FSWs compared with HIV(-) FSWs. In summary, a subset of Th17 CD4(+) T cells in the cervical mucosa coexpresses multiple HIV susceptibility markers; their dramatic depletion after HIV infection suggests that these may serve as key target cells during HIV transmission.