Perinatal outcomes associated with pre-exposure prophylaxis for HIV prevention during pregnancy: a systematic review and meta-analysis

Background: The World Health Organization (WHO) recommends tenofovir disoproxil fumarate (TDF)-based oral pre-exposure prophylaxis (PrEP), the dapivirine vaginal ring, and long-acting intramuscular injectable cabotegravir (CAB-LA) for HIV prevention in populations at substantial risk of HIV infection. Pregnancy is a period of elevated risk of maternal HIV infection and transmission to the infant. This systematic review and meta-analysis assessed the risk of adverse perinatal outcomes among HIV-negative pregnant women with exposure to any PrEP modality. Methods: We conducted a systematic review by searching Medline, EMBASE, CINAHL, Global Health, the Cochrane Library, WHO ICTR, ISRCTN, PACTR, and ClinicalTrials.gov for studies published between 1 January 2000 and 29 August 2023. We included studies reporting on the association of antenatal exposure to any PrEP modality with 13 perinatal outcomes: preterm birth (PTB), very PTB, spontaneous PTB, spontaneous very PTB, low birthweight (LBW), very LBW, term LBW, preterm LBW, small for gestational age (SGA), very SGA, miscarriage, stillbirth, or neonatal death (NND). Quality assessments of included studies were performed. Fixed-effect meta-analyses were conducted to calculate odds ratios (ORs) and 95% confidence intervals (95% CIs). The protocol is registered with PROSPERO, CRD42022339825. Findings: Of 18,598 citations identified, 13 studies (eight randomised controlled trials (RCTs) and five cohort studies), assessing 8712 pregnant women in Africa, were included. Oral PrEP, compared to no PrEP, was not associated with PTB in meta-analyses of six RCTs (OR 0.73, 95% CI 0.43–1.26; I2 = 0.0%) or five unadjusted cohort studies (OR 0.84, 95% CI 0.69–1.03; I2 = 0.0%), but was associated with a reduced risk of PTB in three adjusted cohort studies (aOR 0.67; 95% CI 0.52–0.88, I2 = 0.0%). There was no association of oral PrEP with LBW, vLBW, SGA, or NND, compared to no PrEP. There was no association with PTB when oral TDF/emtricitabine (FTC) PrEP, oral TDF PrEP, and tenofovir vaginal gel were compared to each other. There was no association of the dapivirine vaginal ring with PTB or NND, compared to placebo or oral TDF/FTC PrEP. We found no data on CAB-LA. Interpretation: We found no evidence of adverse perinatal outcomes associated with PrEP exposure during pregnancy. Our findings support the WHO recommendation to provide oral PrEP to women of reproductive age and pregnant women. More data is needed to assess the safety of all PrEP modalities in pregnancy. Funding: None

A randomized trial to optimize HIV/TB care in South Africa: design of the Sizanani trial

Background: Despite increases in HIV testing, only a fraction of people newly diagnosed with HIV infection enter the care system and initiate antiretroviral therapy (ART) in South Africa. We report on the design and initial enrollment of a randomized trial of a health system navigator intervention to improve linkage to HIV care and TB treatment completion in Durban, South Africa. Methods/Design We employed a multi-site randomized controlled trial design. Patients at 4 outpatient sites were enrolled prior to HIV testing. For all HIV-infected participants, routine TB screening with sputum for mycobacterial smear and culture were collected. HIV-infected participants were randomized to receive the health system navigator intervention or usual care. Participants in the navigator arm underwent a baseline interview using a strengths-based case management approach to assist in identifying barriers to entering care and devising solutions to best cope with perceived barriers. Over 4 months, participants in the navigator arm received scheduled phone and text messages. The primary outcome of the study is linkage and retention in care, assessed 9 months after enrollment. For ART-eligible participants without TB, the primary outcome is 3 months on ART as documented in the medical record; participants co-infected with TB are also eligible to meet the primary outcome of completion of 6 months of TB treatment, as documented by the TB clinic. Secondary outcomes include mortality, receipt of CD4 count and TB test results, and repeat CD4 counts for those not ART-eligible at baseline. We hypothesize that a health system navigator can help identify and positively affect modifiable patient factors, including self-efficacy and social support, that in turn can improve linkage to and retention in HIV and TB care. Discussion We are currently evaluating the clinical impact of a novel health system navigator intervention to promote entry to and retention in HIV and TB care for people newly diagnosed with HIV. The details of this study protocol will inform clinicians, investigators, and policy makers of strategies to best support HIV-infected patients in resource-limited settings. Trial registration Clinicaltrials.gov. unique identifier: NCT01188941

The Linkage Outcomes of a Large-scale, Rapid Transfer of HIV-infected Patients From Hospital-based to Community-based Clinics in South Africa

Background: President's Emergency Plan for AIDS Relief (PEPFAR) funding changes have resulted in human immunodeficiency virus (HIV) clinic closures. We evaluated linkage to care following a large-scale patient transfer from a PEPFAR-funded, hospital-based HIV clinic to government-funded, community-based clinics in Durban. Methods: All adults were transferred between March and June 2012. Subjects were surveyed 5–10 months post-transfer to assess self-reported linkage to the target clinic. We validated self-reports by auditing records at 8 clinics. Overall success of transfer was estimated using linkage to care data for both reached and unreached subjects, adjusted for validation results. Results: Of the 3913 transferred patients, 756 (19%) were assigned to validation clinics; 659 (87%) of those patients were reached. Among those reached, 468 (71%) had a validated clinic record visit. Of the 46 who self-reported attending a different validation clinic than originally assigned, 39 (85%) had a validated visit. Of the 97 patients not reached, 59 (61%) had a validated visit at their assigned clinic. Based on the validation rates for reached and unreached patients, the estimated success of transfer for the cohort overall was 82%. Conclusions: Most patients reported successful transfer to a community-based clinic, though a quarter attended a different clinic than assigned. Validation of attendance highlights that nearly 20% of patients may not have linked to care and may have experienced a treatment interruption. Optimizing transfers of HIV care to community sites requires collaboration with receiving clinics to ensure successful linkage to care

Mobile HIV Screening in Cape Town, South Africa: Clinical Impact, Cost and Cost-Effectiveness

Background: Mobile HIV screening may facilitate early HIV diagnosis. Our objective was to examine the cost-effectiveness of adding a mobile screening unit to current medical facility-based HIV testing in Cape Town, South Africa. Methods and Findings: We used the Cost Effectiveness of Preventing AIDS Complications International (CEPAC-I) computer simulation model to evaluate two HIV screening strategies in Cape Town: 1) medical facility-based testing (the current standard of care) and 2) addition of a mobile HIV-testing unit intervention in the same community. Baseline input parameters were derived from a Cape Town-based mobile unit that tested 18,870 individuals over 2 years: prevalence of previously undiagnosed HIV (6.6%), mean CD4 count at diagnosis (males 423/µL, females 516/µL), CD4 count-dependent linkage to care rates (males 31%–58%, females 49%–58%), mobile unit intervention cost (includes acquisition, operation and HIV test costs, $29.30 per negative result and$31.30 per positive result). We conducted extensive sensitivity analyses to evaluate input uncertainty. Model outcomes included site of HIV diagnosis, life expectancy, medical costs, and the incremental cost-effectiveness ratio (ICER) of the intervention compared to medical facility-based testing. We considered the intervention to be “very cost-effective” when the ICER was less than South Africa's annual per capita Gross Domestic Product (GDP) ($8,200 in 2012). We projected that, with medical facility-based testing, the discounted (undiscounted) HIV-infected population life expectancy was 132.2 (197.7) months; this increased to 140.7 (211.7) months with the addition of the mobile unit. The ICER for the mobile unit was$2,400/year of life saved (YLS). Results were most sensitive to the previously undiagnosed HIV prevalence, linkage to care rates, and frequency of HIV testing at medical facilities. Conclusion: The addition of mobile HIV screening to current testing programs can improve survival and be very cost-effective in South Africa and other resource-limited settings, and should be a priority

Model-derived survival and engagement in care of HIV-infected individuals in Cape Town at 5 years from the start of observation.

<p>The bar graphs shows the proportion (out of the initial 1,240 HIV-infected population) at 5 years who are alive, diagnosed, linked to and retained in care, are on ART, and are HIV RNA suppressed on ART. HIV: human immunodeficiency virus, RNA: ribonucleic acid, ART: antiretroviral therapy.</p

Multi-way sensitivity analyses on prevalence of HIV, linkage to care and facility-based HIV testing frequency.

<p>Prevalence of undiagnosed HIV is varied on the horizontal axis and linkage to care on the vertical axis. Figure a) represents the base case medical facility-based program HIV testing frequency of once every 4 years. Figure b) represents annual medical facility-based program HIV testing. Light gray represents scenarios with an incremental cost-effectiveness ratio (ICER) <1× South African <i>per capita</i> gross domestic product ($8,200), dark gray represents scenarios with an ICER$8,200/YLS to $24,600/YLS and black represents scenarios with an ICER >$24,600/YLS. HIV: human immunodeficiency virus, ICER: incremental cost-effectiveness ratio.</p

Model outcomes and cost-effectiveness of mobile unit HIV testing in Cape Town, South Africa.

*<p>Incremental cost-effectiveness ratios <1× South African <i>per capita</i> gross domestic product (8,200) considered very cost-effective based on WHO suggestions [28]. Costs in 2012 US. Discounted at 3% per year (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0085197#s2" target="_blank">methods</a>). YLS: years of life saved.</p

Model-derived mechanisms of HIV linkage in Cape Town, South Africa.

<p>The charts display the proportion of HIV-infected individuals linked to care with the medical facility-based strategy, and the mobile unit intervention strategy. HIV: human immunodeficiency virus, OI: Opportunistic Infection.</p