Yield and Efficiency of Novel Intensified Tuberculosis Case-Finding Algorithms for People Living with HIV.

RATIONALE: The recommended tuberculosis (TB) intensified case finding (ICF) algorithm for people living with HIV (symptom-based screening followed by Xpert MTB/RIF [Xpert] testing) is insufficiently sensitive and results in unnecessary Xpert testing. OBJECTIVES: To evaluate whether novel ICF algorithms combining C-reactive protein (CRP)-based screening with urine Determine TB-LAM (TB-LAM), sputum Xpert, and/or sputum culture could improve ICF yield and efficiency. METHODS: We compared the yield and efficiency of novel ICF algorithms inclusive of point-of-care CRP-based TB screening and confirmatory testing with urine TB-LAM (if CD4 count ≤100 cells/µl), sputum Xpert, and/or a single sputum culture among consecutive people living with HIV with CD4 counts less than or equal to 350 cells/µl initiating antiretroviral therapy in Uganda. MEASUREMENTS AND MAIN RESULTS: Of 1,245 people living with HIV, 203 (16%) had culture-confirmed TB including 101 (49%) patients with CD4 counts less than or equal to 100 cells/µl. Compared with the current ICF algorithm, point-of-care CRP-based TB screening followed by Xpert testing had similar yield (56% [95% confidence interval, 49-63] vs. 59% [95% confidence interval, 51-65]) but consumed less than half as many Xpert assays per TB case detected (9 vs. 4). Addition of TB-LAM did not significantly increase diagnostic yield relative to the current ICF algorithm but provided same-day diagnosis for 26% of TB patients with advanced HIV. Addition of a single culture to TB-LAM and Xpert substantially improved ICF yield, identifying 78% of all TB cases. CONCLUSIONS: Point-of-care CRP-based screening can improve ICF efficiency among people living with HIV. Addition of TB-LAM and a single culture to Xpert confirmatory testing could enable HIV programs to increase the speed of TB diagnosis and ICF yield.

Provision of family planning vouchers and early initiation of postpartum contraceptive use among women living with HIV in southwestern Uganda: A randomized controlled trial.

BACKGROUND: Unwanted pregnancies remain a burden for women living with HIV (WLWH). Family planning prevents unplanned pregnancies while promoting longer birth intervals, key strategies to eliminate perinatal transmission of HIV and promote maternal and child health. We evaluated the effect of a family planning voucher, inclusive of immediate postpartum counseling, on uptake, early initiation, and continuation of modern contraceptive methods among recently postpartum WLWH delivering at a publicly funded regional referral hospital in rural, southwestern Uganda. METHODS AND FINDINGS: We performed a randomized controlled trial between October, 2016 and June, 2018 at a referral hospital in southwestern Uganda. This interim analysis includes adult WLWH randomized and enrolled equally to receive a family planning voucher or standard of care (control). Enrolled postpartum WLWH completed an interviewer-administered questionnaire at enrollment and 6 months postpartum. Our primary outcome of interest for this analysis is initiation of a modern family planning method within 8 weeks postpartum. Secondary outcomes included family planning initiation at 12, 14, 16, and 20 weeks postpartum, family planning discontinuation and/or change, pregnancy incidence, and mean time without contraception. The trial was registered with clinicaltrials.gov (NCT02964169). At enrollment, half of the women in both the voucher (N = 87, 55%) and control (N = 86, 54%) groups wanted to have a child in 2 years postpartum. Over 80% of referent pregnancies in the voucher (N = 136, 86%) and control (N = 128, 81%) groups were planned. All women were accessing ART. The mean CD4 count was 396 cells/mm3 (SD = 61) for those enrolled in the control group versus 393 cells/mm3 (SD = 64) in the family planning voucher group. By 8 weeks postpartum, family planning was initiated in 144 (91%) participants in the voucher group and 83 (52%) participants in the control group (odds ratio [OR] 9.42; CI 4.67-13.97, P < 0.001). We also found high family planning uptake rates for both groups, with higher rates among the intervention group at 12 weeks (OR 5.66; CI 2.65-12.12, P < 0.001), 14 weeks (OR 2.51; CI 1.31-4.79, P < 0.001), 16 weeks (OR 4.02; CI 1.66-9.77, P = 0.001), and 20 weeks (OR 3.65; CI 1.40-9.47, P = 0.004) postpartum. The average time to family planning initiation was reduced to 5.9 weeks (SD = 2.4) for those in the voucher group compared to 9.3 weeks (SD = 5) in the control (P < 0.001). One pregnancy was recorded in the group receiving standard of care; none were reported in the voucher group. Method mix did not differ by group: injectables were selected by most women (N = 150, 50%), and 52% of this proportion were in the experimental arm, with <10% in each arm selecting condoms, oral contraception, or intrauterine devices (IUDs). Similar proportions of women changed contraceptive methods over the 6-month follow-up in the voucher and control groups (N = 8, 5% versus N = 5, 4%; P = 0.467). More women in the control group discontinued contraception for 1 to 2 weeks (N = 19, 13% versus N = 7, 5%; P = 0.008) or more than 4 weeks (N = 15, 10% versus N = 3, 2%; P = 0.002) compared to those given a family planning voucher. The main limitation of this study is that its findings may not be generalized to settings without improved availability of contraceptives in publicly funded facilities. CONCLUSION: These findings indicate that a well-structured, time-bound family planning voucher program appeared to increase early postpartum contraceptive uptake and continuation in a setting in which users are faced with financial, knowledge, and structural barriers to contraceptive services. Further work should clarify the role of vouchers in empowering WLWH to avoid unintended pregnancies over time. TRIAL REGISTRATION: ClinicalTrials.gov NCT02964169.

Factors Associated with Pregnancy Intentions Amongst Postpartum Women Living with HIV in Rural Southwestern Uganda.

Comprehensive HIV treatment and care makes it safer for women living with HIV (WLWH) to have the children they desire, partly through provision and appropriate use of effective contraception. However, nearly one third of WLWH in-care in a large Ugandan cohort became pregnant within 3 years of initiating ART and half of these incident pregnancies (45%) were unplanned. We therefore describe future pregnancy plans and associated factors among postpartum WLWH in rural southwestern Uganda in order to inform interventions promoting postpartum contraceptive uptake. This analysis includes baseline data collected from adult WLWH enrolled into a randomized controlled trial to evaluate the effect of family planning support versus standard of care at 12 months postpartum in southwestern Uganda. Enrolled postpartum WLWH completed an interviewer-administered questionnaire at enrolment. Among 320 enrolled women, mean age, CD4 count, and duration on ART was 28.9 (standard deviation [SD] 5.8) years, 395 cells/mm3 (SD = 62) and 4.6 years (SD = 3.9), respectively. One-hundred and eighty nine (59%) of women reported either personal (175, 55%) or partner (186, 58%) desire for more children in the next 2 years. Intentions to have more children was strongly associated with partner's desire for more children (AOR = 31.36; P < 0.000), referent pregnancy planned (AOR = 2.69; P = 0.050) and higher household income > 150,000 Shs per month (AOR = 1.37; P = 0.010). Previous use of modern contraception (AOR = 0.07; P = 0.001), increasing age (AOR = 0.34; P = 0.012), having > 2 own children living in a household (AOR = 0.42; P = 0.021) and parity > 2 (AOR = 0.59; P = 0.015) were associated with reduced odds of pregnancy intention. Our findings highlight the role male partners play in influencing pregnancy intentions postpartum and the importance of engaging men in sexual and reproductive health counselling about child spacing for the health of women, children, and families. This should be addressed alongside key individual-level social, demographic, economic and structural factors within which couples can understand risks of unplanned pregnancies and access effective contraceptive methods when they need or want them.

Transaminitis prevalence among HIV-infected adults eligible for tuberculosis preventive therapy.

OBJECTIVE: To assess the prevalence of severe transaminitis precluding tuberculosis (TB) preventive therapy (TPT) initiation for people with HIV (PWH) in a high TB/HIV burden setting. DESIGN/METHODS: We conducted a secondary analysis of data from a prospective cohort study of PWH with pre-antiretroviral therapy (ART) CD4 + counts 350 cells/µl or less undergoing systematic TB screening from two HIV clinics in Uganda. For this analysis, we excluded patients with culture-confirmed TB and patients without aspartate transaminase (AST) or alanine transaminase (ALT) levels measured within three months of enrollment. We compared the proportion of patients with any transaminitis (AST or ALT greater than one times the upper limit of normal ULN) and severe transaminitis (AST or ALT >3 times ULN) for patients screening negative for TB by symptoms and for those screening negative by C-reactive protein (CRP). We also assessed the proportion of patients with transaminitis by self-reported alcohol consumption. RESULTS: Among 313 participants [158 (50%) women, median age 34 years (IQR 27-40)], 75 (24%) had any transaminitis and six (2%) had severe transaminitis. Of 32 of 313 (10%) who screened negative for TB by symptoms, none had severe transaminitis. In contrast, six-times more PWH screened negative for TB by CRP (194 of 313; 62%), of whom only four (2.1%) had severe transaminitis. Differences in the proportion with any and severe transaminitis according to alcohol consumption were not statistically significant. CONCLUSION: Prevalence of severe transaminitis was low among PWH without culture-confirmed TB in this setting, and is therefore, unlikely to be a major barrier to scaling-up TPT.

Structured and sustained family planning support facilitates effective use of postpartum contraception amongst women living with HIV in South Western Uganda: A randomized controlled trial.

BACKGROUND: Despite low pregnancy intentions, many women accessing contraception discontinue use, increasing the risk of unwanted pregnancies among women living with HIV (WLWH). We evaluate whether a family planning support intervention, inclusive of structured immediate one-on-one postpartum counseling, and a follow-up mechanism through additional health information and SMS reminders affects continuous contraceptive use and pregnancy incidence among recently postpartum WLWH. METHODS: We performed a randomized controlled trial between October 2016 and June 2018 at a referral hospital in southwestern Uganda. We included adult WLWH randomized and enrolled in a 1:1 ratio to receive family planning support or standard of care (control) and completed an interviewer-administered questionnaire at enrolment, 6 and 12 months postpartum. Our two primary outcomes of interest were; continuous use of contraception, and incidence of pregnancy. Secondary outcomes included contraception uptake, method change, discontinuation and pregnancy intentions. The trial was registered with clinicaltrials.gov (NCT02964169). RESULTS: A total of 317(99%) completed all study procedures. Mean age was 29.6 (SD = 6.0) vs 30.0 (SD = 5.9) years for the intervention vs control groups respectively. All women were enrolled on ART. Total women using contraception continuously were 126 (79.8%) in the intervention compared to 110 (69.2%) in control group (odds ratio (OR) = 1.75; confidence interval (CI) = 1.24-2.75, P = 0.003). Pregnancy rates were 2% (N = 3) in the intervention vs 9% (N = 14) in the control group (OR = 0.20, 95% CI = 0.05-0.62, P = 0.006). Pregnancy intention was lower in the intervention vs control group (OR = 0.23, 95% CI = 0.08-0.64, P = 0.002). Women actively enrolled on contraception reduced more in the control compared to the intervention group (OR = 3.92, 95% CI = 1.66-9.77, P = 0.001). Women enrolled on each contraceptive method did not differ by group except for implants. More women initiating contraception use within three months postpartum had better continued use for either intervention (N = 123, 97.6% vs N = 3,2.4%) or control group (N = 86,78.2% vs N = 24,21.8%). Method-related side effects were less reported in the intervention group (OR = 0.25, 95% CI = 0.10-0.60, P = 0.001). CONCLUSION: We found that sustained and structured family planning support facilitates continuous use of contraception and lowers rates of pregnancy amongst postpartum WLWH in rural southwestern Uganda. Women who initiated contraception within three months postpartum were more likely to maintain continuous use of contraception than those initiating later. Further evaluation of actual and perceived facilitators to the continuous contraception use by this support intervention will help replication in similar settings. TRIAL REGISTRATION: NCT02964169.

Patient choice improves self-efficacy and intention to complete tuberculosis preventive therapy in a routine HIV program setting in Uganda.

A 12-dose weekly regimen of rifapentine plus isoniazid (3HP) is recommended for the prevention of active tuberculosis (TB); however, it is unclear whether 3HP should be provided by directly observed therapy (DOT) or self-administered therapy (SAT). In addition, the introduction of patient informed choice between delivery modalities may have a positive impact on factors leading to treatment completion. The authors randomized 252 participants with HIV to a hypothetical scenario of providing preventive therapy by either DOT or an informed choice between DOT and SAT. Out of 104 participants who were randomized to a choice between DOT and SAT, 103 chose therapy by SAT. Participants rated their level of confidence and intention to complete therapy. Compared to those assigned to the DOT scenario, patients assigned to the choice scenario expressed greater confidence and intention to complete preventive therapy. Convenience and travel required to complete 3HP therapy were important factors in deciding between delivery modalities. Those assigned to DOT identified more barriers to completing therapy than those given a choice. Empowering patients to make informed decisions about how they receive TB preventive therapy may improve completion rates.

Operational evaluation of a service for prevention of mother-to-child transmission of HIV in rural Uganda: barriers to uptake of single-dose nevirapine and the role of birth reporting.

SUMMARY OBJECTIVES: To determine factors associated with pregnant women being HIV positive, barriers to the uptake of single-dose nevirapine (sdNVP) for prevention of mother-to-child transmission (PMTCT) and feasibility and effectiveness of reporting HIV-exposed infants born in facilities with no PMTCT services so as to receive NVP. METHODS: From 2002 to 2007, a sdNVP PMTCT service was implemented in 53 rural villages of south-west Uganda. Twenty-five of them were HIV-surveillance study villages. The proportions of mothers testing positive and mother and newborns receiving and ingesting sdNVP and associated factors were determined. RESULTS: Women with incomplete primary or no education, aged 25-34 years or not living with their partners were at increased risk of being HIV infected. Seventy-seven percentage of pregnant women with HIV (PWH) received therapy. Of the 63 PWH who received therapy and had surviving live births, only 39 (62%) reported births and received newborn prophylaxis within 72 h. Women were more likely to collect and ingest NVP if they were from study villages, preferred home administration of newborn NVP or presented at a more advanced stage of pregnancy. Newborns were more likely to be reported and receive NVP if mothers were aged 25-34 years, on antiretroviral therapy (ART) or came from study villages. CONCLUSIONS: The uptake of PMTCT services was unacceptably low. Asking PWH with less advanced pregnancies to return to collect NVP leads to missed opportunities especially if PWH are less educated. Birth reporting enabled the programme to provide NVP to some infants who otherwise would have missed. Antenatal, delivery and PMTCT services should be integrated.

Point-of-care C-reactive protein and risk of early mortality among adults initiating antiretroviral therapy.

OBJECTIVES: In resource-limited settings, mortality in the initial months following antiretroviral therapy (ART) initiation remains unacceptably high. Novel tools to identify patients at highest risk of poor outcomes are needed. We evaluated whether elevated C-reactive protein (CRP) concentrations predict poor outcomes among people living with HIV (PLWH) initiating ART. METHODS: We enrolled and followed for 3-months consecutive PLWH with pre-ART CD4 T-cell counts 350 cells/µl or less initiating ART from two HIV clinics in Uganda. Pre-ART CRP concentrations were measured from capillary blood using a point-of-care (POC) assay. After excluding patients with prevalent tuberculosis - the leading cause of HIV death - we measured 3-month mortality rates using Kaplan-Meier curves, used Cox regression to compare differences in survival, and used logistic regression to compare differences in the odds of opportunistic infections, between patients with and without elevated POC CRP (≥8 mg/l). RESULTS: Of 1293 patients included [median CD4 T-cell count 181 (interquartile range 82-278)], 23 (1.8%) died within 3 months, including 19 of 355 (5.4%) with elevated POC CRP and four of 938 (0.4%) with nonelevated POC CRP. Eighty-six (6.7%) patients were diagnosed with opportunistic infections, including 39 of 355 (11.0%) with elevated POC CRP and 47 of 938 (5.0%) with nonelevated POC CRP. Elevated POC CRP was associated with mortality (adjusted hazard ratio 10.87, 95% confidence interval 3.64-32.47) and opportunistic infection (adjusted odds ratio 1.95, 95% confidence interval 1.23-3.07). CONCLUSION: Among PLWH with advanced HIV, elevated pre-ART POC CRP concentrations are associated with early mortality and opportunistic infections. Pre-ART POC CRP testing may reduce mortality by identifying patients at high risk for poor outcomes.

Brief Report: Yield and Efficiency of Intensified Tuberculosis Case-Finding Algorithms in 2 High-Risk HIV Subgroups in Uganda.

BACKGROUND: Tuberculosis (TB) risk varies among different HIV subgroups, potentially impacting intensified case finding (ICF) performance. We evaluated the performance of the current ICF algorithm [symptom screening, followed by Xpert MTB/RIF (Xpert) testing] in 2 HIV subgroups and evaluated whether ICF performance could be improved if TB screening was based on C-reactive protein (CRP) concentrations. METHODS: We enrolled consecutive adults with CD4 counts ≤350 cells/µL initiating antiretroviral therapy and performed symptom screening, CRP testing using a low-cost point-of-care (POC) assay, and collected sputum for Xpert testing. We compared the yield and efficiency of the current ICF algorithm to POC CRP-based ICF among patients new to HIV care and patients engaged in care. RESULTS: Of 1794 patients, 126/1315 (10%) new patients and 21/479 (4%) engaged patients had Xpert-positive TB. The current ICF algorithm detected ≥98% of all TB cases in both subgroups but required ≥85% of all patients to undergo Xpert testing. POC CRP-based ICF halved the proportion of patients in both subgroups requiring Xpert testing relative to the current ICF algorithm and had lower yield among patients engaged in care [81% vs. 100%, difference -19% (95% confidence interval: -41 to 3)]. Among patients new to care, POC CRP-based ICF had similar yield as the current ICF algorithm [93% vs. 98%, difference -6% (95% confidence interval: -11 to 0)]. CONCLUSIONS: Among patients new to care, POC CRP-based screening can improve ICF efficiency without compromising ICF yield, whereas symptom-based screening may be necessary to maximize ICF yield among patients engaged in care.

Point-of-care C-reactive protein-based tuberculosis screening for people living with HIV: a diagnostic accuracy study.

BACKGROUND: Symptom-based screening for tuberculosis is recommended for all people living with HIV. This recommendation results in unnecessary Xpert MTB/RIF testing in many individuals living in tuberculosis-endemic areas and thus poor implementation of intensified case finding and tuberculosis preventive therapy. Novel approaches to tuberculosis screening are needed to help achieve global targets for tuberculosis elimination. We assessed the performance of C-reactive protein (CRP) measured with a point-of-care assay as a screening tool for active pulmonary tuberculosis. METHODS: For this prospective study, we enrolled adults (aged ≥18 years) living with HIV with CD4 cell count less than or equal to 350 cells per µL who were initiating antiretroviral therapy (ART) from two HIV/AIDS clinics in Uganda. CRP concentrations were measured at study entry with a point-of-care assay using whole blood obtained by fingerprick (concentration ≥10 mg/L defined as screen positive for tuberculosis). Sputum samples were collected for Xpert MTB/RIF testing and culture. We calculated the sensitivity and specificity of point-of-care CRP and WHO symptom-based screening in reference to culture results. We repeated the sensitivity analysis with Xpert MTB/RIF as the reference standard. FINDINGS: Between July 8, 2013, and Dec 15, 2015, 1237 HIV-infected adults were enrolled and underwent point-of-care CRP testing. 60 (5%) patients with incomplete or contaminated cultures were excluded from the analysis. Of the remaining 1177 patients (median CD4 count 165 cells per µL [IQR 75-271]), 163 (14%) had culture-confirmed tuberculosis. Point-of-care CRP testing had 89% sensitivity (145 of 163, 95% CI 83-93) and 72% specificity (731 of 1014, 95% CI 69-75) for culture-confirmed tuberculosis. Compared with WHO symptom-based screening, point-of-care CRP testing had lower sensitivity (difference -7%, 95% CI -12 to -2; p=0·002) but substantially higher specificity (difference 58%, 95% CI 55 to 61; p<0·0001). When Xpert MTB/RIF results were used as the reference standard, sensitivity of point-of-care CRP and WHO symptom-based screening were similar (94% [79 of 84] vs 99% [83 of 84], respectively; difference -5%, 95% CI -12 to 2; p=0·10). INTERPRETATION: The performance characteristics of CRP support its use as a tuberculosis screening test for people living with HIV with CD4 count less than or equal to 350 cells per µL who are initiating ART. HIV/AIDS programmes should consider point-of-care CRP-based tuberculosis screening to improve the efficiency of intensified case finding and increase uptake of tuberculosis preventive therapy. FUNDING: National Institutes of Health; President's Emergency Plan for AIDS Relief; University of California, San Francisco, Nina Ireland Program for Lung Health.

A livelihood intervention to improve economic and psychosocial well-being in rural Uganda: Longitudinal pilot study.

HIV and poverty are inextricably intertwined in sub-Saharan Africa. Economic and livelihood intervention strategies have been suggested to help mitigate the adverse economic effects of HIV, but few intervention studies have focused specifically on HIV-positive persons. We conducted three pilot studies to assess a livelihood intervention consisting of an initial orientation and loan package of chickens and associated implements to create poultry microenterprises. We enrolled 15 HIV-positive and 22 HIV-negative participants and followed them for up to 18 months. Over the course of follow-up, participants achieved high chicken survival and loan repayment rates. Median monthly income increased, and severe food insecurity declined, although these changes were not statistically significant (P-values ranged from 0.11 to 0.68). In-depth interviews with a purposive sample of three HIV-positive participants identified a constellation of economic and psychosocial benefits, including improved social integration and reduced stigma.

Measuring Post-Partum Haemorrhage in Low-Resource Settings: The Diagnostic Validity of Weighed Blood Loss versus Quantitative Changes in Hemoglobin.

BACKGROUND: Accurate estimation of blood loss is central to prompt diagnosis and management of post-partum hemorrhage (PPH), which remains a leading cause of maternal mortality in low-resource countries. In such settings, blood loss is often estimated visually and subjectively by attending health workers, due to inconsistent availability of laboratory infrastructure. We evaluated the diagnostic accuracy of weighed blood loss (WBL) versus changes in peri-partum hemoglobin to detect PPH. METHODS: Data from this analysis were collected as part of a randomized controlled trial comparing oxytocin with misoprostol for PPH (NCT01866241). Blood samples for complete blood count were drawn on admission and again prior to hospital discharge or before blood transfusion. During delivery, women were placed on drapes and had pre-weighed sanitary towels placed around their perineum. Blood was then drained into a calibrated container and the sanitary towels were added to estimate WBL, where each gram of blood was estimated as a milliliter. Sensitivity, specificity, negative and positive predictive values (PPVs) were calculated at various blood volume loss and time combinations, and we fit receiver-operator curves using blood loss at 1, 2, and 24 hours compared to a reference standard of haemoglobin decrease of >10%. RESULTS: A total of 1,140 women were enrolled in the study, of whom 258 (22.6%) developed PPH, defined as a haemoglobin drop >10%, and 262 (23.0%) had WBL ≥500mL. WBL generally had a poor sensitivity for detection of PPH (<75% for most volume-time combinations). In contrast, the specificity of WBL was high with blood loss ≥ 500mL at 1h and ≥750mL at any time points excluding PPH in over 97% of women. As such, WBL has a high PPV (>85%) in high prevalence settings when WBL exceeds 750mL. CONCLUSION: WBL has poor sensitivity but high specificity compared to laboratory-based methods of PPH diagnosis. These characteristics correspond to a high PPV in areas with high PPH prevalence. Although WBL is not useful for excluding PPH, this low-cost, simple and reproducible method is promising as a reasonable method to identify significant PPH in such settings where quantifiable red cell indices are unavailable.