Risk of Adverse Birth Outcomes in Two Cohorts of Pregnant Women With HIV in Zambia.

BACKGROUND: A trial of progesterone to prevent preterm birth among HIV-infected Zambian women [Improving Pregnancy Outcomes with Progesterone (IPOP)] found no treatment effect, but the risk of the primary outcome was among the lowest ever documented in women with HIV. In this secondary analysis, we compare the risks of preterm birth (<37 weeks), stillbirth, and a composite primary outcome comprising the two in IPOP versus an observational pregnancy cohort [Zambian Preterm Birth Prevention Study (ZAPPS)] in Zambia, to evaluate reasons for the low risk in IPOP. METHODS: Both studies enrolled women before 24 gestational weeks, during August 2015-September 2017 (ZAPPS) and February 2018-January 2020 (IPOP). We used linear probability and log-binomial regression to estimate risk differences and risk ratios (RR), before and after restriction and standardization with inverse probability weights. RESULTS: The unadjusted risk of composite outcome was 18% in ZAPPS (N = 1450) and 9% in IPOP (N = 791) (RR = 2.0; 95% CI = 1.6, 2.6). After restricting and standardizing the ZAPPS cohort to the distribution of IPOP baseline characteristics, the risk remained higher in ZAPPS (RR = 1.6; 95% CI = 1.0, 2.4). The lower risk of preterm/stillbirth in IPOP was only partially explained by measured risk factors. CONCLUSIONS: Possible benefits in IPOP of additional monetary reimbursement, more frequent visits, and group-based care warrant further investigation.

Screening for tuberculosis and testing for human immunodeficiency virus in Zambian prisons.

OBJECTIVE: To improve the Zambia Prisons Service's implementation of tuberculosis screening and human immunodeficiency virus (HIV) testing. METHODS: For both tuberculosis and HIV, we implemented mass screening of inmates and community-based screening of those residing in encampments adjacent to prisons. We also established routine systems ­ with inmates as peer educators ­ for the screening of newly entered or symptomatic inmates. We improved infection control measures, increased diagnostic capacity and promoted awareness of tuberculosis in Zambia's prisons. FINDINGS: In a period of 9 months, we screened 7638 individuals and diagnosed 409 new patients with tuberculosis. We tested 4879 individuals for HIV and diagnosed 564 cases of infection. An additional 625 individuals had previously been found to be HIV-positive. Including those already on tuberculosis treatment at the time of screening, the prevalence of tuberculosis recorded in the prisons and adjacent encampments ­ 6.4% (6428/100,000) ­ is 18 times the national prevalence estimate of 0.35%. Overall, 22.9% of the inmates and 13.8% of the encampment residents were HIV-positive. CONCLUSION: Both tuberculosis and HIV infection are common within Zambian prisons. We enhanced tuberculosis screening and improved the detection of tuberculosis and HIV in this setting. Our observations should be useful in the development of prison-based programmes for tuberculosis and HIV elsewhere.

Weekly 17 alpha-hydroxyprogesterone caproate to prevent preterm birth among women living with HIV: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Women with HIV face an increased risk of preterm birth. 17 alpha-hydroxyprogesterone caproate (17P) has been shown in some trials to reduce early delivery among women with a history of spontaneous preterm birth. We investigated whether 17P would reduce this risk among women with HIV. METHODS: We did a randomised, double-blind, placebo-controlled trial in pregnant women with HIV at the University Teaching Hospital and Kamwala District Health Centre in Lusaka, Zambia. Eligible patients were women aged 18 years or older with confirmed HIV-1 infection, viable intrauterine singleton pregnancy at less than 24 weeks of gestation, and were receiving or intending to commence antiretroviral therapy during pregnancy. Exclusion criteria were major uterine or fetal anomaly; planned or in situ cervical cerclage; evidence of threatened miscarriage, preterm labour, or ruptured membranes at screening; medical contraindication to 17P; previous participation in the trial; or history of spontaneous preterm birth. Eligible participants provided written informed consent and were randomly assigned (1:1) to receive 250 mg intramuscular 17P or placebo once per week, starting between 16 and 24 weeks of gestation until delivery, stillbirth, or reaching term (37 weeks). Participants and study staff were masked to assignment, except for pharmacy staff who did random assignment and prepared injections but did not interact with participants. The primary outcome was a composite of delivery before 37 weeks or stillbirth at any gestational age. Patients attended weekly visits for study drug injections and antenatal care. We estimated the absolute and relative difference in risk of the primary outcome and safety events between treatment groups by intention to treat. This trial is registered with ClinicalTrials.gov, NCT03297216, and is complete. FINDINGS: Between Feb 7, 2018 and Jan 13, 2020, we assessed 1042 women for inclusion into the study. 242 women were excluded after additional assessments, and 800 eligible patients were enrolled and randomly assigned to receive intramuscular 17P (n=399) or placebo (n=401). Baseline characteristics were similar between groups. Adherence to study drug injections was 98% in both groups, no patients were lost to follow-up, and the final post-partum visit was on Aug 6, 2020. 36 (9%) of 399 participants assigned to 17P had preterm birth or stillbirth, compared with 36 (9%) of 401 patients assigned to placebo (risk difference 0·1, 95% CI -3·9 to 4·0; relative risk 1·0, 95% CI 0·6 to 1·6; p=0·98). Intervention-related adverse events were reported by 140 (18%) of 800 participants and occurred in similar proportions in both randomisation groups. No serious adverse events were reported. INTERPRETATION: Although 17P seems to be safe and acceptable to participants, available data do not support the use of the drug to prevent preterm birth among women whose risk derives solely from HIV infection. The low risk of preterm birth in both randomisation groups warrants further investigation. FUNDING: US National Institutes of Health and the Bill and Melinda Gates Foundation.

Acceptability of a trial of vaginal progesterone for the prevention of preterm birth among HIV-infected women in Lusaka, Zambia: A mixed methods study.

Antenatal progesterone prevents preterm birth (PTB) in women with a short cervix or prior PTB in daily vaginal or weekly injectable formulations, respectively. Neither has been tested for the indication of maternal HIV, which is associated with an elevated risk of PTB. The Vaginal Progesterone (VP) Trial was a pilot feasibility study of VP to prevent HIV-related PTB in Lusaka, Zambia. Using mixed methods, we concurrently evaluated the acceptability of the trial and the study product among participants. Over a 1-year period, we enrolled 140 pregnant women living with HIV into a double-masked, placebo-controlled, randomized trial of daily self-administered VP or placebo. We administered an endline questionnaire to all participants and conducted in-depth interviews with 30 participants to assess barriers and facilitators to uptake and retention in the trial and to study product adherence. All interviews were audiotaped, transcribed, translated into English as needed, and independently coded by two analysts to capture emerging themes. Of 131 participants who completed the questionnaire, 128 (98%) reported that nothing was difficult when asked the hardest part about using the study product. When given a hypothetical choice between vaginal and injectable progesterone, 97 (74%) chose vaginal, 31 (24%) injectable, and 3 (2%) stated no preference. Most interviewees reported no difficulties with using the study product; others cited minor side effects and surmountable challenges. Strategies that supported adherence included setting alarms, aligning dosing with antiretrovirals, receiving encouragement from friends and family, sensing a benefit to their unborn baby, and positive feedback from study staff. Participants who reported preference of a vaginal medication over injectable described familiarity with the vaginal product, a fear of needles and resulting pain, and inconvenience of a weekly clinic visit. Those who would prefer weekly injections cited fewer doses to remember. Perceived barriers to study participation included mistrust about the motivations behind research, suspicion of Satanism, and futility or possible harm from a placebo. We report key influences on acceptability of a randomized trial of VP to prevent PTB among HIV-infected women in Zambia, which should inform methods to promote uptake, adherence, and retention in a full-scale trial.

Vaginal progesterone to prevent preterm delivery among HIV-infected pregnant women in Zambia: A feasibility study.

Antenatal vaginal progesterone (VP) reduces the risk of preterm birth (PTB) in women with shortened cervical length, and we hypothesize that it may also prevent PTB in women with HIV as their primary risk factor. We conducted a pilot feasibility study in Lusaka, Zambia to investigate uptake, adherence, and retention in preparation for a future efficacy trial. This was a double-masked, placebo-controlled, randomized trial of 200mg daily self-administered VP suppository or placebo. Pregnant women with HIV who were initiating or continuing antiretroviral therapy were eligible for participation. Potential participants underwent ultrasound to assess eligibility; we excluded those ≥24 gestational weeks, with non-viable, multiple gestation, or extrauterine pregnancies, with short cervix (<2.0cm), or with prior spontaneous PTB. Participants initiated study product between 20-24 weeks of gestation and continued to 37 weeks (or delivery, if sooner). The primary outcome was adherence (proportion achieving ≥80% study product use), assessed by dye stain assay of returned single-use vaginal applicators. Secondary outcomes with pre-defined feasibility targets were: uptake (≥50% eligible participants enrolled) and retention (≥90% ascertainment of delivery outcomes). We also evaluated preliminary efficacy by comparing the risk of spontaneous PTB <37 weeks between groups. From July 2017 to June 2018, 208 HIV-infected pregnant women were eligible for screening and 140 (uptake = 67%) were randomly allocated to VP (n = 70) or placebo (n = 70). Mean adherence was 94% (SD±9.4); 91% (n = 125/137) achieved overall adherence ≥80%. Delivery outcomes were ascertained from 134 (96%) participants. Spontaneous PTB occurred in 10 participants (15%) receiving placebo and 8 (12%) receiving progesterone (RR 0.82; 95%CI:0.34-1.97). Spontaneous PTB < 34 weeks occurred in 6 (9%) receiving placebo and 4 (6%) receiving progesterone (RR 0.67; 95%CI:0.20-2.67). In contrast to findings from vaginal microbicide studies in HIV-uninfected, non-pregnant women, our trial participants were highly adherent to daily self-administered vaginal progesterone. The study's a priori criteria for uptake, adherence, and retention were met, indicating that a phase III efficacy trial would be feasible.

Associations between health systems capacity and mother-to-child HIV prevention program outcomes in Zambia.

INTRODUCTION: Zambia has made substantial investments in health systems capacity, yet it remains unclear whether improved service quality improves outcomes. We investigated the association between health system capacity and use of prevention of mother-to-child HIV transmission (PMTCT) services in Zambia. MATERIALS AND METHODS: We analyzed data from two studies conducted in rural and semi-urban Lusaka Province in 2014-2015. Health system capacity, our primary exposure, was measured with a validated balanced scorecard approach. Based on WHO building blocks for health systems strengthening, we derived overall and domain-specific facility scores (range: 0-100), with higher scores indicating greater capacity. Our outcome, community-level maternal antiretroviral drug use at 12 months postpartum, was measured via self-report in a large cohort study evaluating PMTCT program impact. Associations between health systems capacity and our outcome were analyzed via linear regression. RESULTS: Among 29 facilities, median overall facility score was 72 (IQR:67-74). Median domain scores were: patient satisfaction 75 (IQR 71-78); human resources 85 (IQR:63-87); finance 50 (IQR:50-67); governance 82 (IQR:74-91); service capacity 77 (IQR:68-79); service provision 60 (IQR:52-76). Our programmatic outcome was measured from 804 HIV-infected mothers. Median community-level antiretroviral use at 12 months was 81% (IQR:69-89%). Patient satisfaction was the only domain score significantly associated with 12-month maternal antiretroviral use (ß:0.22; p = 0.02). When we excluded the human resources and finance domains, we found a positive association between composite 4-domain facility score and 12-month maternal antiretroviral use in peri-urban but not rural facilities. CONCLUSIONS: In these Zambian health facilities, patient satisfaction was positively associated with maternal antiretroviral 12 months postpartum. The association between overall health system capacity and maternal antiretroviral drug use was stronger in peri-urban versus rural facilities. Additional work is needed to guide strategic investments for improved outcomes in HIV and broader maternal-child health region-wide.

Infant Human Immunodeficiency Virus-free Survival in the Era of Universal Antiretroviral Therapy for Pregnant and Breastfeeding Women: A Community-based Cohort Study From Rural Zambia.

BACKGROUND: Lifelong antiretroviral therapy (ART) is now recommended for all human immunodeficiency virus (HIV)-infected pregnant and breastfeeding women; however, few have described overall infant outcomes in this new era for the prevention of mother-to-child HIV transmission (PMTCT). METHODS: As part of an assessment of PMTCT program impact, we enrolled a prospective cohort study in 4 predominantly rural districts in Zambia. HIV-infected mothers and their newborns (≤30 days old) were recruited and followed at 6 weeks, 6 months and 12 months postpartum; infant specimens were tested via HIV DNA polymerase chain reaction. In Kaplan-Meier analyses, we estimated overall infant HIV-free survival and then stratified by district, community and maternal ART use. We investigated the relationship between community-level 12-month, self-reported maternal ART use and infant HIV-free survival via linear regression. RESULTS: From June 2014 to November 2015, we enrolled 827 mother-infant pairs in 33 communities. At 12 months, small proportions of infants had died (2.8%), were HIV-infected (3.0%) or were lost to follow-up (4.3%). Overall, infant HIV-free survival was 99.0% [95% confidence interval (CI): 98.0%-99.5%] at 6 weeks, 97.5% (95% CI: 96.1%-98.4%) at 6 months and 96.3% (95% CI: 94.8%-97.4%) at 12 months. Women reporting ART use at enrollment had higher infant HIV-free survival than those who did not (97.4% vs. 89.0%, P = 0.01). Differences were noted at the district and site levels (P = 0.01). In community-level analysis, no relationship was observed between 12-month infant HIV-free survival and self-reported maternal ART use (P = 0.65). CONCLUSION: Although encouraging, these findings highlight the need for rigorous monitoring and evaluation of PMTCT services at the population level.

The high burden of tuberculosis (TB) and human immunodeficiency virus (HIV) in a large Zambian prison: a public health alert.

BACKGROUND: Tuberculosis (TB) and human immunodeficiency virus (HIV) represent two of the greatest health threats in African prisons. In 2010, collaboration between the Centre for Infectious Disease Research in Zambia, the Zambia Prisons Service, and the National TB Program established a TB and HIV screening program in six Zambian prisons. We report data on the prevalence of TB and HIV in one of the largest facilities: Lusaka Central Prison. METHODS: Between November 2010 and April 2011, we assessed the prevalence of TB and HIV amongst inmates entering, residing, and exiting the prison, as well as in the surrounding community. The screening protocol included complete history and physical exam, digital radiography, opt-out HIV counseling and testing, sputum smear and culture. A TB case was defined as either bacteriologically confirmed or clinically diagnosed. RESULTS: A total of 2323 participants completed screening. A majority (88%) were male, median age 31 years and body mass index 21.9. TB symptoms were found in 1430 (62%). TB was diagnosed in 176 (7.6%) individuals and 52 people were already on TB treatment at time of screening. TB was bacteriologically confirmed in 88 cases (3.8%) and clinically diagnosed in 88 cases (3.8%). Confirmed TB at entry and exit interventions were 4.6% and 5.3% respectively. Smear was positive in only 25% (n = 22) of bacteriologically confirmed cases. HIV prevalence among inmates currently residing in prison was 27.4%. CONCLUSION: Ineffective TB and HIV screening programs deter successful disease control strategies in prison facilities and their surrounding communities. We found rates of TB and HIV in Lusaka Central Prison that are substantially higher than the Zambian average, with a trend towards concentration and potential transmission of both diseases within the facility and to the general population. Investment in institutional and criminal justice reform as well as prison-specific health systems is urgently required.