Publications by authors named "Brandon L Guthrie"

41 Publications

Clustering of subpatent infections in households with asymptomatic rapid diagnostic test-positive cases in Bioko Island, Equatorial Guinea independent of travel to regions of higher malaria endemicity: a cross-sectional study.

Malar J 2021 Jul 12;20(1):313. Epub 2021 Jul 12.

Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA.

Background: Prevalence of falciparum malaria on Bioko Island remains high despite sustained, intensive control. Progress may be hindered by high proportions of subpatent infections that are not detected by rapid diagnostic tests (RDT) but contribute to onward transmission, and by imported infections. Better understanding of the relationship between subpatent infections and RDT-detected infections, and whether this relationship is different from imported versus locally acquired infections, is imperative to better understand the sources of infection and mechanisms of transmission to tailor more effective interventions.

Methods: Quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) was performed on a sub-set of samples from the 2015 Malaria Indicator Survey to identify subpatent infections. Households with RDT(+) individuals were matched 1:4 with households with no RDT(+) individuals. The association between living in a household with an RDT(+) individual and having a subpatent infection was evaluated using multivariate hierarchical logistic regression models with inverse probability weights for selection. To evaluate possible modification of the association by potential importation of the RDT(+) case, the analysis was repeated among strata of matched sets based on the reported eight-week travel history of the RDT(+) individual(s).

Results: There were 142 subpatent infections detected in 1,400 individuals (10.0%). The prevalence of subpatent infections was higher in households with versus without an RDT(+) individual (15.0 vs 9.1%). The adjusted prevalence odds of subpatent infection were 2.59-fold greater (95% CI: 1.31, 5.09) for those in a household with an RDT(+) individual compared to individuals in a household without RDT(+) individuals. When stratifying by travel history of the RDT(+) individual, the association between subpatent infections and RDT(+) infections was stronger in the strata in which the RDT(+) individual(s) had not recently travelled (adjusted prevalence odds ratio (aPOR) 2.95; 95% CI:1.17, 7.41), and attenuated in the strata in which recent travel was reported (aPOR 1.76; 95% CI: 0.54, 5.67).

Conclusions: There is clustering of subpatent infections around RDT(+) individual(s) when both imported and local infection are suspected. Future control strategies that aim to treat whole households in which an RDT(+) individual is found may target a substantial portion of infections that would otherwise not be detected.
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http://dx.doi.org/10.1186/s12936-021-03844-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8274032PMC
July 2021

Understanding how social norms affect modern contraceptive use.

BMC Public Health 2021 06 4;21(1):1061. Epub 2021 Jun 4.

The University of Washington, Seattle, USA.

Background: An aim of this study is to introduce a practitioner-friendly behavior model. Few theories of health behavior explicitly take the effect of social norms on behavior into account. Generally, theories that do take social norms into account assume that the effect of social norms on behavior operates through motivation. We use the Fogg Behavior Model (FBM), a behavior model that is new to public health, to explore whether social norms are associated with modern contraceptive use among Nigerian women, and whether they affect behavior through motivation or through ability. In other words, do social norms that discourage contraception lower women's motivation to use contraception or do they lower women's ability to use contraception.

Methods: This study uses data from a cross-sectional household survey of Nigerian women, ages 14-24. The survey collected data on socio-economic and demographic characteristics of women, whether they were sexually experienced, and whether they used contraception. Modern contraceptive use was the outcome of interest for the study. The survey also collected data on social norms around premarital sex and contraceptive use. Multivariate logistic regression was used for the analysis.

Results: After adjusting for a range of socio-economic and demographic variables, we found that social norms that discourage contraception had a statistically significant negative association with contraceptive use (aOR = 0.90, p < 0.001). The analysis found that the negative association between social norms and contraceptive use remained statistically significant after controlling for motivation but did not remain statistically significant after controlling for ability.

Conclusion: These findings suggest that social norms may affect contraceptive use in Nigeria through ability rather than motivation. In terms of programmatic implications, these finding suggest that public health interventions may be able to counter the negative effects of social norms that discourage contraceptive use by increasing women's ability to practice contraception.
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http://dx.doi.org/10.1186/s12889-021-11110-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8178889PMC
June 2021

Influence of Intramuscular Depot Medroxyprogesterone Acetate Initiation on Vaginal Microbiota in the Postpartum Period.

Clin Infect Dis 2021 06;72(12):e1093-e1102

Department of Medicine and Global Health, University of Washington, Seattle, Washington, USA.

Background: The vaginal microbiome plays a key role in women's reproductive health. Use of exogenous hormones, such as intramuscular depot medroxyprogesterone acetate (DMPA-IM), may alter the composition of vaginal bacterial community.

Methods: Vaginal swab samples were collected from postpartum Kenyan women initiating DMPA-IM or nonhormonal contraception (non-HC). Bacterial vaginosis was assessed by Nugent score (Nugent-BV) and bacterial community composition was evaluated using broad-range 16S ribosomal RNA gene polymerase chain reaction with high-throughput sequencing. Changes in Nugent score, alpha diversity (Shannon diversity index), and total bacterial load between contraceptive groups from enrollment to 3 months after initiation were estimated using multivariable linear mixed effects regression.

Results: Among 54 human immunodeficiency virus-negative women, 33 choosing DMPA-IM and 21 choosing non-HC, Nugent-BV was more common among DMPA-IM users at enrollment. At follow-up, Nugent score had decreased significantly among DMPA-IM users (change, -1.89; 95% confidence interval [CI], -3.53 to -.25; P = .02) while alpha diversity remained stable (0.03; -.24 to .30; P = .83). Conversely, Nugent score remained relatively stable among non-HC users (change, -0.73; 95% CI, -2.18 to .73; P = .33) while alpha diversity decreased (-0.34; -.67 to -.001; P = .05). The total bacterial load decreased slightly in DMPA-IM users and increased slightly among non-HC users, resulting in a significant difference in change between the contraceptive groups (difference, -0.64 log10 gene copies per swab sample; 95% CI, -1.19 to -.08; P = .02). While significant changes in Nugent score and alpha diversity were observed within contraceptive groups, changes between groups were not significantly different.

Conclusions: Postpartum vaginal bacterial diversity did not change in DMPA-IM users despite a reduction in Nugent-BV, but it decreased significantly among women using non-HC. Choice of contraception may influence Lactobacillus recovery in postpartum women.
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http://dx.doi.org/10.1093/cid/ciaa1876DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8204794PMC
June 2021

A risk scoring tool for predicting Kenyan women at high risk of contraceptive discontinuation.

Contracept X 2020 29;2:100045. Epub 2020 Oct 29.

Department of Global Health, University of Washington, Seattle, USA.

Objective: We developed and validated a pragmatic risk assessment tool for identifying contraceptive discontinuation among Kenyan women who do not desire pregnancy.

Study Design: Within a prospective cohort of contraceptive users, participants were randomly allocated to derivation ( = 558) and validation ( = 186) cohorts. Risk scores were developed by selecting the Cox proportional hazards model with the minimum Akaike information criterion. Predictive performance was evaluated using time-dependent receiver operating characteristic curves and area under the curve (AUC).

Results: The overall contraceptive discontinuation rate was 36.9 per 100 woman-years (95% confidence interval [CI] 30.3-44.9). The predictors of discontinuation selected for the risk score included use of a short-term method or copper intrauterine device (vs. injectable or implant), method continuation or switch (vs. initiation), < 9 years of completed education, not having a child aged < 6 months, and having no spouse or a spouse supportive of family planning (vs. having a spouse who has unsupportive or uncertain attitudes towards family planning). AUC at 24 weeks was 0.76 (95% CI 0.64-0.87) with 70.0% sensitivity and 78.6% specificity at the optimal cut point in the derivation cohort. Discontinuation was 3.8-fold higher among high- vs. low-risk women (95% CI 2.33-6.30). AUC was 0.68 (95% CI 0.47-0.90) in the validation cohort. A simplified score comprising routinely collected variables demonstrated similar performance (derivation-AUC: 0.73 [95% CI 0.60-0.85]; validation-AUC: 0.73 [95% CI 0.51-0.94]). Positive predictive value in the derivation cohort was 31.4% for the full and 28.1% for the simplified score.

Conclusions: The risk scores demonstrated moderate predictive ability but identified large proportions of women as high risk. Future research is needed to improve sensitivity and specificity of a clinical tool to identify women at high risk for experiencing method-related challenges.

Implications: Contraceptive discontinuation is a major driver of unmet contraceptive need globally. Few tools exist for identifying women who may benefit most from additional support in order to meet their contraceptive needs and preferences. This study developed and assessed the validity of a provider-focused risk prediction tool for contraceptive discontinuation among Kenyan women using modern contraception. High rates of early discontinuation observed in this study emphasize the necessity of investing in efforts to develop new contraceptive technologies and stronger delivery systems to better align with women's needs and preferences for voluntary family planning.
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http://dx.doi.org/10.1016/j.conx.2020.100045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7683324PMC
October 2020

Tuberculosis-related stigma among adults presenting for HIV testing in KwaZulu-Natal, South Africa.

BMC Public Health 2020 Sep 3;20(1):1338. Epub 2020 Sep 3.

Department of Medicine, University of Washington, Seattle, USA.

Background: Tuberculosis (TB)-related stigma presents a major barrier to care of persons with TB through its impact on treatment initiation and retention in care. This is particularly challenging in settings with high prevalence of both TB and HIV where fear of HIV/AIDS can amplify stigma surrounding TB. The purpose of this study was to validate a TB stigma scale for use among persons presenting for outpatient HIV screening in the Umlazi township of South Africa and evaluate factors associated with TB-related stigma in this high HIV burden setting.

Methods: In this cross-sectional study, we measured TB-related stigma in adults prior to HIV testing using a 12-item scale designed to assess experienced and felt TB-related stigma.

Results: Among 848 adults, mean age was 32 years, 54% were male, and the median TB stigma score was 19 of 36 (interquartile range 15-23). We identified two factors in the stigma scale which had excellent reliability (Cronbach's alpha 0.85, 0.89). Persons with high TB stigma were more likely to be male (adjusted relative risk ratio [aRRR] 1.56, 95% confidence interval [CI] 1.11-2.28) and have accurate knowledge of TB transmission (aRRR 1.90, 95% CI 1.16-3.10) as compared to those with low stigma. Variables not significantly associated with stigma in the multivariate model included education, income, prior TB or HIV diagnoses, and depression.

Conclusions: Male sex and TB knowledge were associated with higher TB stigma in an outpatient HIV clinic in a South African township. Identifying risk factors associated with stigma will be important to guide stigma reduction interventions.
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http://dx.doi.org/10.1186/s12889-020-09383-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7469347PMC
September 2020

Postpartum metabolic syndrome and high-sensitivity C-reactive protein after gestational hypertension and pre-eclampsia.

Int J Gynaecol Obstet 2020 Dec 16;151(3):443-449. Epub 2020 Sep 16.

Department of Epidemiology, University of Washington, Seattle, WA, USA.

Objective: To evaluate the association between metabolic syndrome (MetS) and high-sensitivity C-reactive protein (hsCRP), a biomarker of chronic inflammation and an independent predictor for cardiovascular disease overall and in subgroups of women with/without pre-eclampsia and gestational hypertension (GHT).

Methods: A prospective cohort study was conducted in Nairobi, Kenya. Women with pre-eclampsia or GHT and normotensive women within 12 weeks postpartum underwent physical, anthropometric, fasting lipid profile, plasma glucose, and hsCRP measurements at 6 months postpartum. A generalized linear regression model with Poisson distribution adjusted for body mass index and age was used to estimate the association between elevated hsCRP and MetS overall and stratified by pre-eclampsia or GHT.

Results: In the 171 women included in the study, risk of elevated hsCRP (>3 mg/L) was greater among women with compared to those without MetS (adjusted relative risk [ARR] 1.70, 95% confidence interval [CI] 1.05-2.73, P=0.03) and was statistically significantly higher in the hypertensive (ARR 2.16 95% CI 1.01-4.62, P=0.04) but not in the normotensive (ARR 1.46, 95% CI 0.93-2.28) group.

Conclusion: Increased risk of elevated hsCRP postpartum can guide longitudinal mechanistic and intervention studies to reduce postpartum cardiovascular morbidity in women with MetS, especially after pre-eclampsia or GHT.
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http://dx.doi.org/10.1002/ijgo.13352DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7722223PMC
December 2020

Peer Group Focused eHealth Strategies to Promote HIV Prevention, Testing, and Care Engagement.

Curr HIV/AIDS Rep 2020 10;17(5):557-576

University of Washington, Seattle, WA, USA.

Purpose Of Review: Electronic communication platforms are increasingly used to support all steps of the HIV care cascade (an approach defined as eHealth). Most studies have employed individual-level approaches in which participants are connected with information, reminders, or a healthcare worker. Recent growth in use of social media platforms, which create digital communities, has created an opportunity to leverage virtual peer-to-peer connection to improve HIV prevention and care. In this article, we describe the current landscape of peer group eHealth interventions in the HIV field, based on a review of published literature, an online survey of unpublished ongoing work, and discussions with practitioners in the field in an in-person workshop.

Recent Findings: We identified 45 published articles and 12 ongoing projects meeting our inclusion criteria. Most reports were formative or observational; only three randomized evaluations of two interventions were reported. Studies indicated that use of peer group eHealth interventions is acceptable and has unique potential to influence health behaviors, but participants reported privacy concerns. Evaluations of health outcomes of peer group eHealth interventions show promising data, but more rigorous evaluations are needed. Development of group eHealth interventions presents unique technological, practical, and ethical challenges. Intervention design must consider privacy and data sovereignty concerns, and respond to rapid changes in platform use. Innovative development of open-source tools with high privacy standards is needed.
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http://dx.doi.org/10.1007/s11904-020-00527-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7492479PMC
October 2020

Examining the relationship between diarrhea and linear growth in Kenyan HIV-exposed, uninfected infants.

PLoS One 2020 27;15(7):e0235704. Epub 2020 Jul 27.

Department of Global Health, University of Washington, Seattle, Washington, United States of America.

Background: Diarrhea in infancy can compromise linear growth and this relationship is likely influenced by diarrhea severity, number of episodes, and the timing of those episodes. HIV exposed, uninfected infants (HEU) have higher risk of growth faltering, infectious morbidity and mortality than HIV-unexposed infants and may be representative of children particularly vulnerable to diarrhea-associated linear growth faltering.

Methodology/principal Findings: We utilized data from a cohort of Kenyan HEU infants followed from birth to 12 months of age. Infant length and morbidity were ascertained at monthly study visits and sick visits. Longitudinal models estimated the association between diarrhea severity and length-for-age Z-score (LAZ) in the following month, at 12 months of age, and in 6-month intervals. The 372 enrolled infants experienced an average of 2.15 episodes (range: 0-8) of diarrhea and 0.54 episodes (0-4) of moderate-to-severe diarrhea (MSD) between birth and 12 months. Surviving infants had a mean LAZ of -0.97 (standard deviation: 1.2) at 12 months. MSD was significantly associated with an average loss of 0.14 (95% Confidence Interval [CI]: -0.24, -0.05, p = 0.003) in LAZ one month after the episode. Linear growth outcomes were not predicted by cumulative episodes of diarrhea, or timing of diarrhea during infancy.

Conclusions/significance: Diarrhea severity influenced the relationship between diarrhea and subsequent linear growth. HEU infants with MSD may benefit from nutritional interventions following severe diarrhea to protect against linear growth faltering.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0235704PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7384652PMC
September 2020

Training Exposure and Self-Rated Competence among HIV Care Providers Working with Adolescents in Kenya.

J Int Assoc Provid AIDS Care 2020 Jan-Dec;19:2325958220935264

Department of Global Health, University of Washington, Seattle, WA, USA.

Lack of health care worker (HCW) training is a barrier to implementing youth-friendly services. We examined training coverage and self-reported competence, defined as knowledge, abilities, and attitudes, of HCWs caring for adolescents living with HIV (ALWH) in Kenya. Surveys were conducted with 24 managers and 142 HCWs. Competence measures were guided by expert input and Kalamazoo II Consensus items. Health care workers had a median of 3 (interquartile range [IQR]: 1-6) years of experience working with ALWH, and 40.1% reported exposure to any ALWH training. Median overall competence was 78.1% (IQR: 68.8-84.4). In multivariable linear regression analyses, more years caring for ALWH and any prior training in adolescent HIV care were associated with significantly higher self-rated competence. Training coverage for adolescent HIV care remains suboptimal. Targeting HCWs with less work experience and training exposure may be a useful and efficient approach to improve quality of youth-friendly HIV services.
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http://dx.doi.org/10.1177/2325958220935264DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7322818PMC
May 2021

Evaluation of an Emergency Department and Hospital-Based Data Exchange to Improve HIV Care Engagement and Viral Suppression.

Sex Transm Dis 2020 Aug;47(8):535-540

From the Department of Epidemiology, School of Public Health, University of Washington.

Background: Emergency department (ED) visits and inpatient (IP) admissions may provide an opportunity to reengage poorly engaged people living with HIV and facilitate viral suppression. In 2015, Public Health Seattle and King County partnered with the University of Washington Medicine to implement a real-time data exchange to identify virally unsuppressed people living with HIV seen at the ED/IP hospital and reengage them in HIV care. We evaluated the impact of the data exchange on care engagement and viral suppression.

Methods: Public Health Seattle and King County received a text alert on weekdays 8 AM to 6 PM for ED/IP patients previously diagnosed with HIV with a most recent viral load ≥200 copies/mL. We compared viral load testing <3 months and viral suppression <6 months after an alert-eligible visit in the 2 years after intervention and the 7 to 30 months before intervention. To account for secular trends, we used difference-in-differences models to compare patients with alert-window visits to patients with visits outside the alert window before and after intervention.

Results: Patients with visits within the alert window in the postintervention period were 1.08 (95% confidence interval [CI], 0.97-1.20) times more likely to have a viral load test within 3 months after an ED visit/IP admission and 1.50 (95% CI, 1.27-1.76) times more likely to achieve viral suppression within 6 months than patients in the preintervention period. However, care engagement (difference-in-differences relative risk, 1.00; 95% CI, 0.84-1.18) and viral suppression (difference-in-differences relative risk, 1.01; 95% CI, 0.84-1.20) trends were similar among patients with visits outside the alert window.

Conclusions: Real-time data exchange with ED/IP hospitals was associated with improved viral suppression, but not increased care engagement. However, our results may reflect secular trends resulting from diverse interventions, of which ours was only one. More efforts are needed to improve the effectiveness of relinkage interventions guided by real-time data exchange.
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http://dx.doi.org/10.1097/OLQ.0000000000001195DOI Listing
August 2020

Comparing Methods for Record Linkage for Public Health Action: Matching Algorithm Validation Study.

JMIR Public Health Surveill 2020 04 30;6(2):e15917. Epub 2020 Apr 30.

Department of Biostatistics, School of Public Health, University of Washington, Seattle, WA, United States.

Background: Many public health departments use record linkage between surveillance data and external data sources to inform public health interventions. However, little guidance is available to inform these activities, and many health departments rely on deterministic algorithms that may miss many true matches. In the context of public health action, these missed matches lead to missed opportunities to deliver interventions and may exacerbate existing health inequities.

Objective: This study aimed to compare the performance of record linkage algorithms commonly used in public health practice.

Methods: We compared five deterministic (exact, Stenger, Ocampo 1, Ocampo 2, and Bosh) and two probabilistic record linkage algorithms (fastLink and beta record linkage [BRL]) using simulations and a real-world scenario. We simulated pairs of datasets with varying numbers of errors per record and the number of matching records between the two datasets (ie, overlap). We matched the datasets using each algorithm and calculated their recall (ie, sensitivity, the proportion of true matches identified by the algorithm) and precision (ie, positive predictive value, the proportion of matches identified by the algorithm that were true matches). We estimated the average computation time by performing a match with each algorithm 20 times while varying the size of the datasets being matched. In a real-world scenario, HIV and sexually transmitted disease surveillance data from King County, Washington, were matched to identify people living with HIV who had a syphilis diagnosis in 2017. We calculated the recall and precision of each algorithm compared with a composite standard based on the agreement in matching decisions across all the algorithms and manual review.

Results: In simulations, BRL and fastLink maintained a high recall at nearly all data quality levels, while being comparable with deterministic algorithms in terms of precision. Deterministic algorithms typically failed to identify matches in scenarios with low data quality. All the deterministic algorithms had a shorter average computation time than the probabilistic algorithms. BRL had the slowest overall computation time (14 min when both datasets contained 2000 records). In the real-world scenario, BRL had the lowest trade-off between recall (309/309, 100.0%) and precision (309/312, 99.0%).

Conclusions: Probabilistic record linkage algorithms maximize the number of true matches identified, reducing gaps in the coverage of interventions and maximizing the reach of public health action.
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http://dx.doi.org/10.2196/15917DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226047PMC
April 2020

Changes in key vaginal bacteria among postpartum African women initiating intramuscular depot-medroxyprogesterone acetate.

PLoS One 2020 5;15(3):e0229586. Epub 2020 Mar 5.

Department of Global Health, University of Washington, Seattle, WA, United States of America.

Background: The ECHO trial has relieved apprehension about intramuscular depot medroxyprogesterone acetate (DMPA-IM), however it is still important to understand how DMPA-IM affects the vaginal environment. We sought to describe how DMPA-IM initiation influences vaginal bacteria associated with HIV acquisition in postpartum women.

Methods: Vaginal swabs were collected for Nugent score determination and taxon-specific quantitative PCR of eight bacteria. Enrollment occurred at contraceptive initiation (DMPA-IM or non-hormonal contraception (non-HC)) and repeat vaginal swabs were collected after three months. Generalized estimating equations were used to estimate changes in Nugent score, total bacterial load, and taxa concentrations among contraceptive groups.

Results: Women who chose DMPA-IM (n = 33) were more likely to be married (97%vs.67%) and have resumed intercourse since delivery (52%vs.29%) compared to women who chose non-HC (n = 21). After three months, significant decreases in the concentrations of Sneathia species, Mycoplasma hominis, and Parvimonas species Type 1 were seen among non-HC users, however concentrations remained stable among DMPA-IM users; contraceptive method was associated with significantly different changes in M. hominis concentration between groups (p = 0.010).

Conclusions: Our findings suggest that postpartum use of DMPA-IM and non-HC may have differential impacts on the vaginal concentrations of some bacteria that have previously been associated with HIV acquisition.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0229586PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7058341PMC
June 2020

Mortality from HIV-associated meningitis in sub-Saharan Africa: a systematic review and meta-analysis.

J Int AIDS Soc 2020 01;23(1):e25416

Botswana Harvard AIDS Institute Partnership, Gaborone, Botswana.

Introduction: HIV-associated cryptococcal, TB and pneumococcal meningitis are the leading causes of adult meningitis in sub-Saharan Africa (SSA). We performed a systematic review and meta-analysis with the primary aim of estimating mortality from major causes of adult meningitis in routine care settings, and to contrast this with outcomes from clinical trial settings.

Methods: We searched PubMed, EMBASE and the Cochrane Library for published clinical trials (defined as randomized-controlled trials (RCTs) or investigator-managed prospective cohorts) and observational studies that evaluated outcomes of adult meningitis in SSA from 1 January 1990 through 15 September 2019. We performed random effects modelling to estimate pooled mortality, both in clinical trial and routine care settings. Outcomes were stratified as short-term (in-hospital or two weeks), medium-term (up to 10 weeks) and long-term (up to six months).

Results And Discussion: Seventy-nine studies met inclusion criteria. In routine care settings, pooled short-term mortality from cryptococcal meningitis was 44% (95% confidence interval (95% CI):39% to 49%, 40 studies), which did not differ between amphotericin (either alone or with fluconazole) and fluconazole-based induction regimens, and was twofold higher than pooled mortality in clinical trials using amphotericin based treatment (21% (95% CI:17% to 25%), 17 studies). Pooled short-term mortality of TB meningitis was 46% (95% CI: 33% to 59%, 11 studies, all routine care). For pneumococcal meningitis, pooled short-term mortality was 54% in routine care settings (95% CI:44% to 64%, nine studies), with similar mortality reported in two included randomized-controlled trials. Few studies evaluated long-term outcomes.

Conclusions: Mortality rates from HIV-associated meningitis in SSA are very high under routine care conditions. Better strategies are needed to reduce mortality from HIV-associated meningitis in the region.
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http://dx.doi.org/10.1002/jia2.25416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6970088PMC
January 2020

Human papillomavirus and abnormal cervical lesions among HIV-infected women in HIV-discordant couples from Kenya.

Sex Transm Infect 2020 09 9;96(6):457-463. Epub 2020 Jan 9.

Department of Epidemiology, Lineberger Comprehensive Cancer Center, University of North Carolina Gillings School of Global Public Health, Chapel Hill, North Carolina, USA

Objective: HIV infection increases the risk of high-grade cervical neoplasia and invasive cervical carcinoma. The study addresses the limited data describing human papillomavirus (HPV) infection and cervical neoplasia among HIV-infected women in HIV-discordant relationships in sub-Saharan Africa, which is needed to inform screening strategies.

Methods: A cross-sectional study of HIV-infected women with HIV-uninfected partners was conducted to determine the distribution of type-specific HPV infection and cervical cytology. This study was nested in a prospective cohort recruited between September 2007 and December 2009 in Nairobi, Kenya. Cervical cells for HPV DNA testing and conventional cervical cytology were collected. HPV types were detected and genotyped by Roche Linear Array PCR assay.

Results: Among 283 women, the overall HPV prevalence was 62%, and 132 (47%) had ≥1 high-risk (HR)-HPV genotype. Of 268 women with cervical cytology results, 18 (7%) had high-grade cervical lesions or more severe by cytology, of whom 16 (89%) were HR-HPV-positive compared with 82 (41%) of 199 women with normal cytology (p<0.001). The most common HR-HPV types in women with a high-grade lesion or more severe by cytology were HPV-52 (44%), HPV-31 (22%), HPV-35 (22%), HPV-51 (22%) and HPV-58 (22%). HR-HPV genotypes HPV-16 or HPV-18 were found in 17% of women with high-grade lesions or more severe. HR-HPV screening applied in this population would detect 89% of those with a high-grade lesion or more severe, while 44% of women with normal or low-grade cytology would screen positive.

Conclusion: HR-HPV prevalence was high in this population of HIV-infected women with an uninfected partner. Choice of screening for all HR genotypes versus a subset of HR genotypes in these HIV-infected women will strongly affect the performance of an HPV screening strategy relative to cytological screening. Regional and subpopulation differences in HR-HPV genotype distributions could affect screening test performance.
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http://dx.doi.org/10.1136/sextrans-2019-054052DOI Listing
September 2020

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

J Acquir Immune Defic Syndr 2019 12;82 Suppl 3:S322-S331

Network of AIDS Researchers of East and Southern Africa, Nairobi, Kenya.

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.
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http://dx.doi.org/10.1097/QAI.0000000000002220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6880809PMC
December 2019

Postpartum metabolic syndrome after gestational hypertension and preeclampsia, a prospective cohort study.

Pregnancy Hypertens 2019 Oct 19;18:35-41. Epub 2019 Aug 19.

Department of Epidemiology, University of Washington, Seattle, USA; Department of Global Health, University of Washington, Seattle, USA; Department of Medicine (Allergy and Infectious Diseases), University of Washington, Seattle, USA.

Objective: We evaluated the 6-month postpartum risk of metabolic syndrome (MetS), a marker of future cardiovascular disease (CVD) risk, comparing women whose most recent pregnancies were complicated with gestational hypertension (GH) or preeclampsia (PE) versus those who had normotensive pregnancies.

Study Design: This was a prospective cohort study in which women with GH or PE and normotensive women were actively enrolled during the first 12 weeks after delivery in Nairobi, Kenya. Participants were interviewed, blood pressures and anthropometric measurements including waist circumference obtained at enrollment and 6 months postpartum. Fasting lipid profile and plasma glucose were measured at 6 months postpartum. A generalized linear regression model with Poisson distribution was used to estimate crude relative risk (RR) of 6-month postpartum MetS and adjusted RR (ARR) after adjusting for apriori potential confounders.

Results: Among 194 postpartum women, 63 (32%) had experienced GH or PE. Prevalence of MetS at 6 months postpartum was higher among women whose pregnancies were complicated with GH or PE (34.9%) compared to those who were normotensive (11.5%). GH and PE were associated with a 3-fold or greater risk of MetS (ARR) 3.01; 95% Confidence interval [CI] 1.58, 5.71; p < 0.001) overall and three of the five components, namely hypertension (ARR 3.35 [2.04, 5.51], p < 0.001), hypertriglyceridemia (ARR 3.25 [1.16-9.10], p = 0.01), and fasting hyperglycemia (ARR 6.20 [1.07-35.76], p = 0.03), compared to having normal blood pressures during pregnancy.

Conclusion: At 6  months postpartum, GH and PE were associated with three-fold or higher risk of MetS and especially hypertension, fasting hypertriglyceridemia, and fasting hyperglycemia.
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http://dx.doi.org/10.1016/j.preghy.2019.08.088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6884686PMC
October 2019

Epidemiology of adult meningitis during antiretroviral therapy scale-up in southern Africa: Results from the Botswana national meningitis survey.

J Infect 2019 09 28;79(3):212-219. Epub 2019 Jun 28.

Botswana-UPenn Partnership, Gaborone, Botswana; University of Botswana, Gaborone, Botswana; Division of Infectious Diseases, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Botswana Harvard AIDS Institute Partnership, Gaborone, Botswana; Department of Clinical Research, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK.

Objectives: Data on meningitis epidemiology in high HIV-prevalence African settings following antiretroviral therapy scale-up are lacking. We described epidemiology of adult meningitis in Botswana over a 16-year period.

Methods: Laboratory records for adults undergoing lumbar puncture (LP) 2000-2015 were collected, with complete national data 2013-2014. Cerebrospinal fluid (CSF) findings and linked HIV-data were described, and national incidence figures estimated for 2013-2014. Temporal trends in meningitis were evaluated.

Results: Of 21,560 adults evaluated, 41% (8759/21,560) had abnormal CSF findings with positive microbiological testing and/or pleocytosis; 43% (3755/8759) of these had no confirmed microbiological diagnosis. Of the 5004 microbiologically-confirmed meningitis cases, 89% (4432/5004) were cryptococcal (CM) and 8% (382/5004) pneumococcal (PM). Seventy-three percent (9525/13,033) of individuals undergoing LP with identifiers for HIV registry linkage had documented HIV-infection. Incidence of LP for meningitis evaluation in Botswana 2013-2014 was 142.6/100,000 person-years (95%CI:138.3-147.1); incidence of CM was 25.0/100,000 (95%CI:23.2-26.9), and incidence of PM was 2.7/100,000 (95%CI:2.4-3.1). In contrast to previously reported declines in CM incidence with ART roll-out, no significant temporal decline in pneumococcal or culture-negative meningitis was observed.

Conclusions: CM remained the predominant identified aetiology of meningitis despite ART scale-up. A high proportion of cases had abnormal CSF with negative microbiological evaluation.
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http://dx.doi.org/10.1016/j.jinf.2019.06.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6679721PMC
September 2019

Mortality in adult patients with culture-positive and culture-negative meningitis in the Botswana national meningitis survey: a prevalent cohort study.

Lancet Infect Dis 2019 07;19(7):740-749

Botswana-UPenn Partnership, Gaborone, Botswana; Division of Infectious Diseases, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Botswana Harvard AIDS Institute Partnership, Gaborone, Botswana; Department of Clinical Research, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK.

Background: CNS infections are a leading cause of HIV-related deaths in sub-Saharan Africa, but causes and outcomes are poorly defined. We aimed to determine mortality and predictors of mortality in adults evaluated for meningitis in Botswana, which has an estimated 23% HIV prevalence among adults.

Methods: In this prevalent cohort study, patient records from 2004-15 were sampled from the Botswana national meningitis survey, a nationwide audit of all cerebrospinal fluid (CSF) laboratory records from patients receiving a lumbar puncture for evaluation of meningitis. Data from all patients with culture-confirmed pneumococcal and tuberculous meningitis, and all patients with culture-negative meningitis with CSF white cell count (WCC) above 20 cells per μL were included in our analyses, in addition to a random selection of patients with culture-negative CSF and CSF WCC of up to 20 cells per μL. We used patient national identification numbers to link CSF laboratory records from the national meningitis survey to patient vital registry and HIV databases. Univariable and multivariable Cox proportional hazards models were used to evaluate clinical and laboratory predictors of mortality.

Findings: We included data from 238 patients with culture-confirmed pneumococcal meningitis, 48 with culture-confirmed tuberculous meningitis, and 2900 with culture-negative CSF (including 1691 with CSF WCC of up to 20 cells per μL and 1209 with CSF WCC above 20 cells per μL). Median age was 37 years (IQR 31-46), 1605 (50%) of 3184 patients were male, 2188 (72%) of 3023 patients with registry linkage had documentation of HIV infection, and median CD4 count was 139 cells per μL (IQR 63-271). 10-week and 1-year mortality was 47% (112 of 238) and 49% (117 of 238) for pneumococcal meningitis, 46% (22 of 48) and 56% (27 of 48) for tuberculous meningitis, and 41% (1181 of 2900) and 49% (1408 of 2900) for culture-negative patients. When the analysis of patients with culture-negative CSF was restricted to those with known HIV infection, WCC (0-20 cells per μL vs >20 cells per μL) was not predictive of mortality (average hazard ratio 0·93, 95% CI 0·80-1·09).

Interpretation: Mortality from pneumococcal, tuberculous, and culture-negative meningitis was high in this setting of high HIV prevalence. There is an urgent need for improved access to diagnostics, to better define aetiologies and develop novel diagnostic tools and treatment algorithms.

Funding: National Institutes of Health, President's Emergency Plan for AIDS Relief, National Institute for Health Research.
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http://dx.doi.org/10.1016/S1473-3099(19)30066-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7645732PMC
July 2019

Health provider training is associated with improved engagement in HIV care among adolescents and young adults in Kenya.

AIDS 2019 07;33(9):1501-1510

Department of Global Health, University of Washington, Seattle, Washington, USA.

Objectives: Adolescents and young adults (AYA) have poorer retention, viral suppression, and survival than other age groups. We evaluated correlates of initial AYA engagement in HIV care at facilities participating in a randomized trial in Kenya.

Design: Retrospective cohort study.

Methods: Electronic medical records from AYA ages 10-24 attending 24 HIV care facilities in Kenya were abstracted. Facility surveys assessed provider trainings and services. HIV provider surveys assessed AYA training and work experience. Engagement in care was defined as return for first follow-up visit within 3 months among newly enrolled or recently re-engaged (returning after >3 months out of care) AYA. Multilevel regression estimated risk ratios and 95% confidence intervals (CIs), accounting for clustering by facility. Final models adjusted for AYA individual age and median AYA age and number enrolled per facility.

Results: Among 3662 AYA records at first eligible visit, most were female (75.1%), older (20-24 years: 54.5%), and on antiretroviral therapy (79.5%). Overall, 2639 AYA returned for care (72.1%) after enrollment or re-engagement visit. Engagement in care among AYA was significantly higher at facilities offering provider training in adolescent-friendly care (85.5 vs. 67.7%; adjusted risk ratio (aRR) 1.11, 95% CI: 1.01-1.22) and that used the Kenyan government's AYA care checklist (88.9 vs. 69.2%; aRR 1.14, 95% CI: 1.06-1.23). Engagement was also significantly higher at facilities where providers reported being trained in AYA HIV care (aRR 1.56, 95% CI: 1.13-2.16).

Conclusion: Adolescent-specific health provider training and tools may improve quality of care and subsequent AYA engagement. Health provider interventions are needed to achieve the '95-95-95' targets for AYA.
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http://dx.doi.org/10.1097/QAD.0000000000002217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6746576PMC
July 2019

A High-throughput Bead-based Affinity Assay Enables Analysis of Genital Protein Signatures in Women At Risk of HIV Infection.

Mol Cell Proteomics 2019 Mar 22;18(3):461-476. Epub 2020 Sep 22.

Department of Medicine Solna, Unit of Infectious Diseases, Center for Molecular Medicine, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.

Women at high risk of HIV infection, including sex workers and those with active genital inflammation, have molecular signatures of immune activation and epithelial barrier remodeling in samples of their genital mucosa. These alterations in the local immunological milieu are likely to impact HIV susceptibility. We here analyze host genital protein signatures in HIV uninfected women, with high frequency of condom use, living in HIV-serodiscordant relationships. Cervicovaginal secretions from women living in HIV-serodiscordant relationships (n = 62) were collected at three time points over 12 months. Women living in HIV-negative seroconcordant relationships (controls, n = 25) were sampled at one time point. All study subjects were examined for demographic parameters associated with susceptibility to HIV infection. The cervicovaginal samples were analyzed using a high-throughput bead-based affinity assay. Proteins involved in epithelial barrier function and inflammation were increased in HIV-serodiscordant women. By combining several methods of analysis, a total of five proteins (CAPG, KLK10, SPRR3, elafin/PI3, CSTB) were consistently associated with this study group. Proteins analyzed using the affinity set-up were further validated by label-free tandem mass spectrometry in a partially overlapping cohort with concordant results. Women living in HIV-serodiscordant relationships thus had elevated levels of proteins involved in epithelial barrier function and inflammation despite low prevalence of sexually transmitted infections and a high frequency of safe sex practices. The identified proteins are important markers to follow during assessment of mucosal HIV susceptibility factors and a high-throughput bead-based affinity set-up could be a suitable method for such evaluation.
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http://dx.doi.org/10.1074/mcp.RA118.000757DOI Listing
March 2019

A High-throughput Bead-based Affinity Assay Enables Analysis of Genital Protein Signatures in Women At Risk of HIV Infection.

Mol Cell Proteomics 2019 03 30;18(3):461-476. Epub 2018 Nov 30.

§Department of Medicine Solna, Unit of Infectious Diseases, Center for Molecular Medicine, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.

Women at high risk of HIV infection, including sex workers and those with active genital inflammation, have molecular signatures of immune activation and epithelial barrier remodeling in samples of their genital mucosa. These alterations in the local immunological milieu are likely to impact HIV susceptibility. We here analyze host genital protein signatures in HIV uninfected women, with high frequency of condom use, living in HIV-serodiscordant relationships. Cervicovaginal secretions from women living in HIV-serodiscordant relationships ( = 62) were collected at three time points over 12 months. Women living in HIV-negative seroconcordant relationships (controls, = 25) were sampled at one time point. All study subjects were examined for demographic parameters associated with susceptibility to HIV infection. The cervicovaginal samples were analyzed using a high-throughput bead-based affinity assay. Proteins involved in epithelial barrier function and inflammation were increased in HIV-serodiscordant women. By combining several methods of analysis, a total of five proteins (CAPG, KLK10, SPRR3, elafin/PI3, CSTB) were consistently associated with this study group. Proteins analyzed using the affinity set-up were further validated by label-free tandem mass spectrometry in a partially overlapping cohort with concordant results. Women living in HIV-serodiscordant relationships thus had elevated levels of proteins involved in epithelial barrier function and inflammation despite low prevalence of sexually transmitted infections and a high frequency of safe sex practices. The identified proteins are important markers to follow during assessment of mucosal HIV susceptibility factors and a high-throughput bead-based affinity set-up could be a suitable method for such evaluation.
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http://dx.doi.org/10.1074/mcp.RA118.000757DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6398207PMC
March 2019

Higher prevalence of viral control in HIV-1-infected women in serodiscordant relationships.

PLoS One 2018 5;13(12):e0208401. Epub 2018 Dec 5.

Department of Epidemiology, University of Washington, Seattle, Washington, United States of America.

Background: HIV-1-discordant couples that remain discordant despite repeated exposure may differ from the general population in their distribution of transmission risk factors, including low plasma viral load (PVL) in the infected partner even in the absence of antiretroviral therapy (ART).

Methods: We followed two cohorts of HIV-1-infected Kenyan women: females in discordant couples (FDC) and female sex workers (FSW). We compared the distribution of undetectable (<150 copies/mL) and low PVL (<1,000 copies/mL) between the cohorts using bootstrap methods and exact Poisson regression.

Results: We evaluated 296 FDC and 220 FSW. At baseline, FDC were more likely to have undetectable (RR = 6.94, bootstrap 95% CI: 3.47, 20.81) and low PVL (RR = 3.53, bootstrap 95% CI: 2.57, 5.65) than FSW. Similarly, both repeat undetectable PVL (RR = 9.36, bootstrap 95% CI: 6.04, 10.97) and repeat low (RR = 4.99, bootstrap 95% CI: 2.33, 14.04) PVL were more likely among FDC than FSW during follow-up.

Discussion: We observed higher prevalence of viral control in FDC compared to FSW in the absence of ART, suggesting potentially higher prevalence of biological HIV resistance factors among discordant couples.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0208401PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6281234PMC
May 2019

High background in ELISpot assays is associated with elevated levels of immune activation in HIV-1-seronegative individuals in Nairobi.

Immun Inflamm Dis 2018 09 4;6(3):392-401. Epub 2018 Jul 4.

Department of Medicine, University of Washington, Seattle, Washington, USA.

Introduction: Spontaneous interferon-γ (IFNγ) released detected by enzyme-linked immunospot (ELISpot) assays may be a biological phenomenon. Markers of immune activation levels were assessed as correlates of high background among individuals in Kenya.

Methods: Couples concordantly seronegative for HIV-1 were enrolled. IFN-γ ELISpot assays were conducted and negative control wells were categorized as having either high or low background (≥50 and <50 SFU/10 peripheral blood mononuclear cells [PBMC], respectively). PBMC were stained for CD4, CD8, and immune activation markers (CD38 and HLA-DR) and analyzed using flow cytometry. Proportions of activated T-cells were compared between those with low and high background by Mann-Whitney U test. Correlates of background SFU and immune activation were assessed using regression models.

Results: Among 58 individuals, 14 (24%) had high background. Frequencies of CD4 CD38 HLA-DR and CD8 CD38 HLA-DR cells were higher in individuals with high background compared to those with low background (P = 0.02). Higher background SFU was associated with history of sexually transmitted infections (P = 0.03), and illness in the past 3 months (P = 0.005), in addition to increased levels of activated CD4 and CD8 cells (P range = 0.008-0.03). Female gender and male circumcision decreased levels of CD4 and CD8 immune activation (P range = 0.002-0.03). Additionally, higher background SFU and activated CD4 and CD8 cells were individually associated with positive ELISpot responses to HIV-1 peptide pools (P range = 0.01-0.03).

Conclusions: These findings suggest that increased basal immune responses may be a biological mechanism contributing to higher background ELISpot SFU. Systematic exclusion of data from individuals with increased background in IFN-γ release assays may bias results in population-based studies.
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http://dx.doi.org/10.1002/iid3.231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6113767PMC
September 2018

Genital Injury Signatures and Microbiome Alterations Associated With Depot Medroxyprogesterone Acetate Usage and Intravaginal Drying Practices.

J Infect Dis 2017 02;215(4):590-598

National HIV and Retrovirology Labs, JC Wilt Infectious Disease Research Centre, Public Health Agency of Canada, Winnipeg, Manitoba, Canada

Background: Increasing evidence suggests depot medroxyprogesterone acetate (DMPA) and intravaginal practices may be associated with human immunodeficiency virus (HIV-1) infection risk; however, the mechanisms are not fully understood. This study evaluated the effect of DMPA and intravaginal practices on the genital proteome and microbiome to gain mechanistic insights.

Methods: Cervicovaginal secretions from 86 Kenyan women, including self-reported DMPA users (n = 23), nonhormonal contraceptive users (n = 63), and women who practice vaginal drying (n = 46), were analyzed using tandem-mass spectrometry.

Results: We identified 473 human and 486 bacterial proteins from 18 different genera. Depot medroxyprogesterone acetate use associated with increased hemoglobin and immune activation (HBD, HBB, IL36G), and decreased epithelial repair proteins (TFF3, F11R). Vaginal drying associated with increased hemoglobin and decreased phagocytosis factors (AZU1, MYH9, PLAUR). Injury signatures were exacerbated in DMPA users who also practiced vaginal drying. More diverse (H index: 0.71 vs 0.45; P = .009) bacterial communities containing Gardnerella vaginalis associated with vaginal drying, whereas DMPA showed no significant association with community composition or diversity.

Conclusions: These findings provide new insights into the impact of DMPA and vaginal drying on mucosal barriers. Future investigations are needed to confirm their relationship with HIV risk in women.
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http://dx.doi.org/10.1093/infdis/jiw590DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5388302PMC
February 2017

Depot Medroxyprogesterone Acetate Use Is Associated With Elevated Innate Immune Effector Molecules in Cervicovaginal Secretions of HIV-1-Uninfected Women.

J Acquir Immune Defic Syndr 2015 May;69(1):1-10

Departments of *Global Health; †Epidemiology, University of Washington, Seattle, WA; ‡Department of Medicine, Solna, Unit of Infectious Diseases, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden; §Department of Medicine, University of Washington, Seattle, WA; and ‖Center for Public Health Research, Kenya Medical Research Institute, Nairobi, Kenya.

Objective: The effects of sex hormones on the immune defenses of the female genital mucosa and its susceptibility to infections are poorly understood. The injectable hormonal contraceptive depot medroxyprogesterone acetate (DMPA) may increase the risk for HIV-1 acquisition. We assessed the local concentration in the female genital mucosa of cationic polypeptides with reported antiviral activity in relation to DMPA use.

Methods: HIV-1-uninfected women were recruited from among couples testing for HIV in Nairobi, Kenya. Cervicovaginal secretion samples were collected, and the concentrations of HNP1-3, LL-37, lactoferrin, HBD-2, and SLPI were measured by enzyme-linked immunosorbent assays. Levels of cationic polypeptides in cervicovaginal secretions were compared between women who were not using hormonal contraception and those using DMPA, oral, or implantable contraception.

Results: Among 228 women, 165 (72%) reported not using hormonal contraception at enrollment, 41 (18%) used DMPA, 16 (7%) used an oral contraceptive, and 6 (3%) used a contraceptive implant. Compared with nonusers of hormonal contraception, DMPA users had significantly higher mean levels of HNP1-3 (2.38 vs. 2.04 log₁₀ ng/mL; P = 0.024), LL-37 (0.81 vs. 0.40 log10 ng/mL; P = 0.027), and lactoferrin (3.03 vs. 2.60 log₁₀ ng/mL; P = 0.002), whereas SLPI and HBD-2 were similar.

Conclusions: Although all analyzed cationic polypeptides have intrinsic antiviral capacity, their interaction and cumulative effect on female genital mucosa susceptibility to infections in vivo has yet to be unraveled. This study suggests a potential mechanism underlying the effect of DMPA on the innate immune defenses, providing a rationale to investigate its effect on HIV-1 acquisition risk.
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http://dx.doi.org/10.1097/QAI.0000000000000533DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4424097PMC
May 2015

Individual and partner risk factors associated with abnormal cervical cytology among women in HIV-discordant relationships.

Int J STD AIDS 2014 Apr 18;25(5):315-24. Epub 2013 Sep 18.

School of Medicine, Virginia Commonwealth University, Richmond, VA, USA.

Individual and sexual partner characteristics may increase the risk of abnormal cervical cytology among women in human immunodeficiency virus (HIV)-discordant relationships. Papanicolaou smears were obtained in a prospective cohort of Kenyan HIV-discordant couples. Of 441 women, 283 (64%) were HIV-infected and 158 (36%) were HIV-uninfected with HIV-infected partners. Overall, 79 (18%) had low-grade and 25 (6%) high-grade cervical abnormalities. Male herpes simplex virus type 2 (HSV-2) seropositivity and lower couple socioeconomic status were associated with cervical abnormalities (p < 0.05). HIV-uninfected women with HIV-infected male sex partners (CD4 > 350 cells/µL) had the lowest prevalence of high-grade cervical lesions. HIV-infected women (CD4 > 350 cells/µL) and HIV-uninfected women with HIV-infected partners (CD4 ≤ 350 cells/µL) were at similar intermediate risk (p > 0.05), and HIV-infected women (CD4 ≤ 350 cells/µL) had significantly higher risk of high-grade cervical abnormalities (p = 0.05). Women in HIV-discordant relationships have high rates of cervical lesions and this may be influenced by couple-level factors, including HIV status and CD4 count of the infected partner.
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http://dx.doi.org/10.1177/0956462413504554DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3968186PMC
April 2014

Incident HSV-2 infections are common among HIV-1-discordant couples.

J Infect Dis 2013 Oct 9;208(7):1093-101. Epub 2013 Jul 9.

Harvard Medical School, Boston, Massachusetts, USA.

Background: The synergy between herpes simplex virus type 2 (HSV-2) and human immunodeficiency virus type 1 (HIV-1) is well known, but lack of knowledge about the epidemiology of HSV-2 acquisition in HIV-1-discordant couples hampers development of HSV-2 prevention interventions that could reduce HIV-1 transmission.

Methods: HIV-1-discordant couples were enrolled in Nairobi, Kenya, and followed for up to 2 years. HSV-2 status was determined using HerpeSelect HSV-2 ELISA. Correlates of prevalence and incidence were assessed. RESULTS.: Of 469 HIV-1-discordant couples, at baseline, 353 (75.3%) were affected by HSV-2, of which 189 (53.5%) were concordantly HSV-2 seropositive and 164 (46.5%) were HSV-2-discordant. Prevalence was lowest among HIV-1-uninfected men (39.9%) compared to HIV-1-infected women (64.8%), HIV-1-infected men (66.7%), and HIV-1-uninfected women (68.5%). During follow-up, HSV-2 seroincidence was 14.9 per 100 person-years. Incidence was 1.6-fold higher among females compared to males (95% confidence interval [CI], 1.00-2.48) and 2.5-fold higher in HIV-1-infected compared to uninfected women (95% CI, 1.12-5.74). At least 30% of incident HSV-2 infections originated from an outside partner.

Conclusions: The high HSV-2 prevalence and incidence in HIV-1-discordant couples in sub-Saharan Africa suggest HSV-2 treatment and prevention could be an effective targeted strategy to reduce HSV-2 and HIV-1 transmission in this high-risk population.
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http://dx.doi.org/10.1093/infdis/jit303DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3762386PMC
October 2013

High rates of relationship dissolution among heterosexual HIV-serodiscordant couples in Kenya.

AIDS Behav 2014 Jan;18(1):189-93

Department of Epidemiology, University of Washington, 325 Ninth Avenue, Seattle, WA, 98104, USA,

HIV-1 serodiscordant couples may experience increased risks of relationship dissolution; however, longitudinal stability of these relationships is poorly understood. We determined rates and correlates of separation among 469 serodiscordant couples in Nairobi and found that 113 (24 %) separated during 2 years of follow-up. Couples with a female HIV-1 infected partner (F+M-) and no income were more likely to separate than M+F- couples without income (HR = 5.0; 95 % CI 1.1-25.0), and F+M- and M+F- couples with income (HR = 2.4; 95 % CI 1.3-4.5 and HR = 2.3; 95 % CI 1.2-4.8, respectively). High separation rates may be important for couple support services and for conducting discordant couple studies.
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http://dx.doi.org/10.1007/s10461-013-0529-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3981202PMC
January 2014

HIV-1-specific enzyme-linked immunosorbent spot assay responses in HIV-1-exposed uninfected partners in discordant relationships compared to those in low-risk controls.

Clin Vaccine Immunol 2012 Nov 12;19(11):1798-805. Epub 2012 Sep 12.

Department of Epidemiology, University of Washington, Seattle, Washington, USA.

A number of studies of highly exposed HIV-1-seronegative individuals (HESN) have found HIV-1-specific cellular responses. However, there is limited evidence that responses prevent infection or are linked to HIV-1 exposure. Peripheral blood mononuclear cells (PBMC) were isolated from HESN in HIV-1-discordant relationships and low-risk controls in Nairobi, Kenya. HIV-1-specific responses were detected using gamma interferon (IFN-γ) enzyme-linked immunosorbent spot (ELISpot) assays stimulated by peptide pools spanning the subtype A HIV-1 genome. The HIV-1 incidence in this HESN cohort was 1.5 per 100 person years. Positive ELISpot responses were found in 34 (10%) of 331 HESN and 14 (13%) of 107 low-risk controls (odds ratio [OR] = 0.76; P = 0.476). The median immunodominant response was 18.9 spot-forming units (SFU)/10(6) peripheral blood mononuclear cells (PBMC). Among HESN, increasing age (OR = 1.24 per 5 years; P = 0.026) and longer cohabitation with the HIV-1-infected partner (OR = 5.88 per 5 years; P = 0.003) were associated with responses. These factors were not associated with responses in controls. Other exposure indicators, including the partner's HIV-1 load (OR = 0.99 per log(10) copy/ml; P = 0.974) and CD4 count (OR = 1.09 per 100 cells/μl; P = 0.238), were not associated with responses in HESN. HIV-1-specific cellular responses may be less relevant to resistance to infection among HESN who are using risk reduction strategies that decrease their direct viral exposure.
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http://dx.doi.org/10.1128/CVI.00179-12DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3491560PMC
November 2012

Cervicovaginal HIV-1-neutralizing immunoglobulin A detected among HIV-1-exposed seronegative female partners in HIV-1-discordant couples.

AIDS 2012 Nov;26(17):2155-63

Department of Medicine, University of Washington, Seattle, WA 98104, USA.

Objective: Cervicovaginal HIV-1-neutralizing immunoglobulin A (IgA) was associated with reduced HIV-1 acquisition in a cohort of commercial sex workers. We aimed to define the prevalence and correlates of HIV-1-neutralizing IgA from HIV-1-exposed seronegative (HESN) women in HIV-1-serodiscordant relationships.

Methods: HIV-1-serodiscordant couples in Nairobi were enrolled and followed quarterly up to 2 years, and women in concordant HIV-1-negative relationships were enrolled as controls. Cervicovaginal, seminal, and blood samples were collected at enrollment and follow-up. Cervicovaginal IgA was assessed for HIV-1-neutralizing activity by a peripheral blood mononuclear cell-based assay using an HIV-1 clade A primary isolate.

Results: HESN women in discordant relationships had significantly more HIV-1-neutralizing IgA detected in genital secretions compared with control women [36 of 155 (23%) vs. four of 70 (6%), respectively; odds ratio (OR) 5.0; 95% confidence interval (CI) 1.70-14.64; P = 0.003]. These responses persisted over time in all available follow-up cervicovaginal samples from women with detectable HIV-1-neutralizing IgA at baseline. Partner median HIV-1 plasma viral load was lower among women who had HIV-1-neutralizing IgA compared with women without detectable activity (4.3 vs. 4.8 log(10) copies/ml, respectively; OR 0.70; 95% CI 0.51-0.94; P = 0.02). A similar trend was found with partner seminal viral load (OR 0.57; 95% CI 0.32-1.02; P = 0.06).

Conclusion: HESN women were five times more likely to have neutralizing IgA in cervicovaginal secretions than low-risk control women, and these responses were inversely associated with partner viral load. These observations support the existence of antiviral activity in the mucosal IgA fraction following sexual HIV-1 exposure.
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http://dx.doi.org/10.1097/QAD.0b013e328359b99bDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3799883PMC
November 2012
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