Safety surveillance for PrEP in pregnant and breastfeeding women.

The risk of HIV acquisition is higher during pregnancy and postpartum than other times. Newly acquired maternal HIV infection associated with high primary viraemia, substantially increases the risk of vertical HIV transmission. Pre-exposure prophylaxis (PrEP) reduces the risk of HIV acquisition. Currently available products include oral tenofovir/emtricitabine (TDF/FTC) and tenofovir alafenamide (TAF)/FTC), long-acting cabotegravir (CAB-LA) and the dapivirine ring (DVR). All except oral TDF/FTC have limited safety data available for use in pregnant and breastfeeding women. The safety of new PrEP agents for pregnant women and the fetus, infant and child, either exposed in utero or during breastfeeding is an ongoing concern for health care workers and pregnant and breastfeeding women, particularly as the safety risk appetite for antiretroviral (ARV) agents used as PrEP is lower in pregnant and breastfeeding women who are HIV-uninfected, compared to women living with HIV taking ARVs as treatment. With the widespread rollout of TDF/FTC among pregnant women in South Africa and other low-middle income countries (LMIC) and the potential introduction of new PrEP agents for pregnant women, there is a need for safety surveillance systems to identify potential signals of risk to either the mother or fetus, measure the burden of such a risk, and where appropriate, provide specific reassurance to PrEP users. Safety data needs to be collected across the continuum of the product life cycle from pre-licensure into the post-marketing period, building a safety profile through both passive and active surveillance systems, recognising the strengths and limitations of each, and the potential for bias and confounding. Pharmacovigilance systems that aim to assess the risk of adverse birth outcomes in pregnant women exposed to PrEP and other agents need to consider the special requirements of pregnancy epidemiology to ensure that the data derived from surveillance are sufficiently robust to inform treatment policies. Here we review the known safety profiles of currently available PrEP candidates in women of child-bearing potential, pregnancy and breastfeeding and discuss pragmatic approaches for such surveillance in HIV-endemic LMICs.

Impact and cost-effectiveness of the national scale-up of HIV pre-exposure prophylaxis among female sex workers in South Africa: a modelling analysis.

INTRODUCTION: In 2016, South Africa (SA) initiated a national programme to scale-up pre-exposure prophylaxis (PrEP) among female sex workers (FSWs), with ∼20,000 PrEP initiations among FSWs (∼14% of FSW) by 2020. We evaluated the impact and cost-effectiveness of this programme, including future scale-up scenarios and the potential detrimental impact of the COVID-19 pandemic. METHODS: A compartmental HIV transmission model for SA was adapted to include PrEP. Using estimates on self-reported PrEP adherence from a national study of FSW (67.7%) and the Treatment and Prevention for FSWs (TAPS) PrEP demonstration study in SA (80.8%), we down-adjusted TAPS estimates for the proportion of FSWs with detectable drug levels (adjusted range: 38.0-70.4%). The model stratified FSW by low (undetectable drug; 0% efficacy) and high adherence (detectable drug; 79.9%; 95% CI: 67.2-87.6% efficacy). FSWs can transition between adherence levels, with lower loss-to-follow-up among highly adherent FSWs (aHR: 0.58; 95% CI: 0.40-0.85; TAPS data). The model was calibrated to monthly data on the national scale-up of PrEP among FSWs over 2016-2020, including reductions in PrEP initiations during 2020. The model projected the impact of the current programme (2016-2020) and the future impact (2021-2040) at current coverage or if initiation and/or retention are doubled. Using published cost data, we assessed the cost-effectiveness (healthcare provider perspective; 3% discount rate; time horizon 2016-2040) of the current PrEP provision. RESULTS: Calibrated to national data, model projections suggest that 2.1% of HIV-negative FSWs were currently on PrEP in 2020, with PrEP preventing 0.45% (95% credibility interval, 0.35-0.57%) of HIV infections among FSWs over 2016-2020 or 605 (444-840) infections overall. Reductions in PrEP initiations in 2020 possibly reduced infections averted by 18.57% (13.99-23.29). PrEP is cost-saving, with $1.42 (1.03-1.99) of ART costs saved per dollar spent on PrEP. Going forward, existing coverage of PrEP will avert 5,635 (3,572-9,036) infections by 2040. However, if PrEP initiation and retention doubles, then PrEP coverage increases to 9.9% (8.7-11.6%) and impact increases 4.3 times with 24,114 (15,308-38,107) infections averted by 2040. CONCLUSIONS: Our findings advocate for the expansion of PrEP to FSWs throughout SA to maximize its impact. This should include strategies to optimize retention and should target women in contact with FSW services.

Process evaluation of peer-to-peer delivery of HIV self-testing and sexual health information to support HIV prevention among youth in rural KwaZulu-Natal, South Africa: qualitative analysis.

OBJECTIVE: Peer-to-peer (PTP) HIV self-testing (HIVST) distribution models can increase uptake of HIV testing and potentially create demand for HIV treatment and pre-exposure prophylaxis (PrEP). We describe the acceptability and experiences of young women and men participating in a cluster randomised trial of PTP HIVST distribution and antiretroviral/PrEP promotion in rural KwaZulu-Natal. METHODS: Between March and September 2019, 24 pairs of trained peer navigators were randomised to two approaches to distribute HIVST packs (kits+HIV prevention information): incentivised-peer-networks where peer-age friends distributed packs within their social network for a small incentive, or direct distribution where peer navigators distributed HIVST packs directly. Standard-of-care peer navigators distributed information without HIVST kits. For the process evaluation, we conducted semi-structured interviews with purposively sampled young women (n=30) and men (n=15) aged 18-29 years from all arms. Qualitative data were transcribed, translated, coded manually and thematically analysed using an interpretivist approach. RESULTS: Overall, PTP approaches were acceptable and valued by young people. Participants were comfortable sharing sexual health issues they would not share with adults. Coupled with HIVST, peer (friends) support facilitated HIV testing and solidarity for HIV status disclosure and treatment. However, some young people showed limited interest in other sexual health information provided. Some young people were wary of receiving health information from friends perceived as non-professionals while others avoided sharing personal issues with peer navigators from their community. Referral slips and youth-friendly clinics were facilitators to PrEP uptake. Family disapproval, limited information, daily pills and perceived risks were major barriers to PrEP uptake. CONCLUSION: Both professional (peer navigators) and social network (friends) approaches were acceptable methods to receive HIVST and sexual health information. Doubts about the professionalism of friends and overly exclusive focus on HIVST information materials may in part explain why HIVST kits, without peer navigators support, did not create demand for PrEP.

Effect of peer-distributed HIV self-test kits on demand for biomedical HIV prevention in rural KwaZulu-Natal, South Africa: a three-armed cluster-randomised trial comparing social networks versus direct delivery.

STUDY OBJECTIVE: We investigated two peer distribution models of HIV self-testing (HIVST) in HIV prevention demand creation compared with trained young community members (peer navigators). METHODS: We used restricted randomisation to allocate 24 peer navigator pairs (clusters) in KwaZulu-Natal 1:1:1: (1) standard of care (SOC): peer navigators distributed clinic referrals, pre-exposure prophylaxis (PrEP) and antiretroviral therapy (ART) information to 18-30 year olds. (2) peer navigator direct distribution (PND): Peer navigators distributed HIVST packs (SOC plus two OraQuick HIVST kits) (3) incentivised peer networks (IPN): peer navigators recruited young community members (seeds) to distribute up to five HIVST packs to 18-30 year olds within their social networks. Seeds received 20 Rand (US$1.5) for each recipient who distributed further packs. The primary outcome was PrEP/ART linkage, defined as screening for PrEP/ART eligibility within 90 days of pack distribution per peer navigator month (pnm) of outreach, in women aged 18-24 (a priority for HIV prevention). Investigators and statisticians were blinded to allocation. Analysis was intention to treat. Total and unit costs were collected prospectively. RESULTS: Between March and December 2019, 4163 packs (1098 SOC, 1480 PND, 1585 IPN) were distributed across 24 clusters. During 144 pnm, 272 18-30 year olds linked to PrEP/ART (1.9/pnm). Linkage rates for 18-24-year-old women were lower for IPN (n=26, 0.54/pnm) than PND (n=45, 0.80/pnm; SOC n=49, 0.85/pnm). Rate ratios were 0.68 (95% CI 0.28 to 1.66) for IPN versus PND, 0.64 (95% CI 0.26 to 1.62) for IPN versus SOC and 0.95 (95% CI 0.38 to 2.36) for PND versus SOC. In 18-30 year olds, PND had significantly more linkages than IPN (2.11 vs 0.88/pnm, RR 0.42, 95% CI 0.18 to 0.98). Cost per pack distributed was cheapest for IPN (US$36) c.f. SOC (US$64). Cost per person linked to PrEP/ART was cheaper in both peer navigator arms compared with IPN. DISCUSSION: HIVST did not increase demand for PrEP/ART. Incentivised social network distribution reached large numbers with HIVST but resulted in fewer linkages compared with PrEP/ART promotion by peer navigators. TRIAL REGISTRATION NUMBER: NCT03751826.

Factors influencing uptake, continuation, and discontinuation of oral PrEP among clients at sex worker and MSM facilities in South Africa.

BACKGROUND: South Africa became the first country in Africa to introduce oral PrEP in June 2016. The National Department of Health has used a phased approach to rollout, allowing for a dynamic learn-and-adapt process which will lead ultimately to scale-up. Phased rollout began with provision of oral PrEP at facilities providing services to sex workers in 2016 and was expanded in 2017, first to facilities providing services to MSM and then to students at selected university campus clinics, followed by provision at primary health care facilities. Programmatic data shows variability in initiation and continuation between these populations. This study examines factors related to PrEP initiation, continuation, and discontinuation at facilities providing services to sex workers and MSM during the national PrEP rollout. METHODS: A cross-sectional survey was administered September 2017-January 2018 among clients (ages 18-62 and providers at 9 facilities implementing oral PrEP in South Africa, followed by in-depth interviews. The client survey captured PrEP initiation, continuation and discontinuation. Analysis was performed in STATA 13 for survey data and thematic analysis was performed in NViVO 11 for in-depth interview data. RESULTS: 299 clients (203 from sex worker facilities, 96 from MSM facilities) participated in the survey and additionally, in-depth interviews were conducted with 29 clients. Participants self-identified as either current users (n = 94; 36.2%), past users (n = 80; 30.8%) and never users of PrEP (n = 86; 33.1%). Participants who had never used PrEP either cited not being offered PrEP by a provider (57%, n = 49) or declining PrEP (43%, n = 37) as reasons for lack of uptake. The primary reason for declining to use oral PrEP was fear of side effects (41.7%, n = 15). The primary reasons for initiating and continuing on oral PrEP were all related to perceived risk associated with sexual activity. The majority of participants (87.9%, n = 153) also noted that printed IEC materials influenced their decision to initiate PrEP. Qualitative data suggested that several clients initiated on PrEP because they wanted additional protection beyond using condoms due to challenges such as partners refusing to use condoms, having partners with unknown HIV status, having multiple partners, involvement in sex work, or having a partner living with HIV. The majority (73.8%, n = 59) of participants who discontinued oral PrEP cited side effects as the primary reason for discontinuation, followed by feeling stigmatized (18.8%, n = 15). CONCLUSION: This study provides valuable insights on early rollout of PrEP of how clients perceive oral PrEP and where to target efforts to improve the uptake of this highly effective HIV prevention product. By identifying strengths and areas for improvement, the ACCESS study has generated evidence that can be used to guide high quality scale-up in South Africa and may be instructive for other countries' efforts to expand quality access to oral PrEP.

The impact of self-selection based on HIV risk on the cost-effectiveness of preexposure prophylaxis in South Africa.

OBJECTIVES: We explored the impact and cost-effectiveness of preexposure prophylaxis (PrEP) provision to different populations in South Africa, with and without effective self-selection by individuals at highest risk of contracting HIV (through concurrent partnerships and/or commercial sex). DESIGN AND METHODS: We used a previously developed HIV transmission model to analyse the epidemiological impact of PrEP provision to adolescents, young adults, pregnant women, female sex workers (FSWs) and (MSM), and data from South African PrEP programmes to estimate the cost and cost-effectiveness of PrEP (cost in 2019 USD per HIV infection averted over 20 years, 2019, 38). PrEP uptake followed data from early implementation sites, scaled-up linearly over 3 years, with target coverage set to 18% for adolescents, young adults and pregnant women, 30% for FSW and 54% for MSM. RESULTS: The annual cost of PrEP provision ranges between $75 and $134 per person. PrEP provision adolescents and young adults, regardless of risk behaviour, will each avert 3.2--4.8% of HIV infections over 20 years; provision to high-risk individuals only has similar impact at lower total cost. The incremental cost per HIV infection averted is lower in high-risk vs. all-risk sub-populations within female adolescents ($507 vs. $4537), male adolescents ($2108 vs. $5637), young women ($1592 vs. $10 323) and young men ($2605 vs. $7715), becoming cost saving within 20 years for high-risk adolescents, young women, MSM and FSWs. CONCLUSION: PrEP is an expensive prevention intervention but uptake by those at the highest risk of HIV infection will make it more cost-effective, and cost-saving after 14-18 years.

Novel metric for evaluating pre-exposure prophylaxis programme effectiveness in real-world settings.

Although large-scale provision of HIV pre-exposure prophylaxis (PrEP) is gaining momentum, no systematic method to evaluate or compare the effectiveness of different scale-up strategies in real-world settings exists. To date, estimating the effectiveness of PrEP has relied on clinical trials or mathematical models. We propose a novel and pragmatic metric to evaluate and compare programme effectiveness using routine implementation data. Using South African and Zambian PrEP guidelines, we provide two examples of how to consistently measure PrEP-programme effectiveness with routinely collected data. PrEP effectiveness should account for HIV seroconversion, the variable risk of HIV infection (seasons of risk) estimated with routine risk assessment at each clinic visit (when available), and the persistence of PrEP use. Three criteria should be met in order to be considered a successful outcome: first, a person who initiates PrEP must not seroconvert; second, there should be no more than one period at high risk of HIV infection during the follow-up period when not taking PrEP; and finally, an individual must continue to attend health-care visits or discontinue prophylaxis in consultation with a health-care provider within a specified follow-up period. The number of PrEP successes could then be compared with the total number of people initiating PrEP to establish a success ratio. This outcome is a useful and easily interpretable metric to monitor effectiveness of PrEP programmes with routinely collected clinical data and can be used in cost-effectiveness analyses. These measurements allow for comparisons of scale-up strategies for PrEP programmes and, if widely adopted, will allow comparative studies of different approaches for PrEP service delivery.

Understanding and measuring uptake and coverage of oral pre-exposure prophylaxis delivery among adolescent girls and young women in sub-Saharan Africa.

In response to World Health Organization (WHO) guidance recommending oral pre-exposure prophylaxis (PrEP) for all individuals at substantial risk for HIV infection, significant investments are being made to expand access to oral PrEP globally, particularly in sub-Saharan Africa. Some have interpreted early monitoring reports from new programs delivering oral PrEP to adolescent girls and young women (AGYW) as suggestive of low uptake. However, a lack of common definitions complicates interpretation of oral PrEP uptake and coverage measures, because various indicators with different meanings and uses are used interchangeably. Furthermore, operationalising these measures in real-world settings is challenged by the difficulties in defining the denominator for measuring uptake and coverage among AGYW, due to the lack of data and experience required to identify the subset of AGYW at substantial risk of HIV infection. This paper proposes an intervention-centric cascade as a framework for developing a common lexicon of metrics for uptake and coverage of oral PrEP among AGYW. In codifying these indicators, approaches to clearly define metrics for uptake and coverage are outlined, and the discussion on 'low' uptake is reframed to focus on achieving the highest possible proportion of AGYW using oral PrEP when they need and want it Recommendations are also provided for making increased investments in implementation research to better quantify the sub-group of AGYW in potential need of oral PrEP.and for improving monitoring systems to more efficiently address bottlenecks in the service delivery of oral PrEP to AGYW so that implementation can be taken to scale.

Human Papillomavirus Vaccine Introduction in South Africa: Implementation Lessons From an Evaluation of the National School-Based Vaccination Campaign.

BACKGROUND: In April 2014, a national school-based human papillomavirus (HPV) vaccination program was rolled out in South Africa, targeting Grade 4 girls aged ≥9 years. A bivalent HPV vaccine with a 2-dose (6 months apart) schedule was used. At the request of the National Department of Health (NDoH), we conducted an external assessment of the first-dose phase of the vaccination program to evaluate program coverage and vaccine safety and identify factors that influenced implementation. METHODS: We based our cross-sectional and mixed-methods approach on a process evaluation framework, which included a review of key planning and implementation documents and monitoring data; observation at vaccination sites; key informant interviews (N=34); and an assessment of media coverage and content related to the campaign.Findings: There was overall success in key measures of coverage and safety. Over 350,000 Grade 4 girls were vaccinated in more than 16,000 public schools across South Africa, which translated to 94.6% of schools reached and 86.6% of age-eligible learners vaccinated. No major adverse events following immunization were detected. We attributed the campaign's successes to careful planning and coordination and strong leadership from the NDoH. The primary challenges we identified were related to obtaining informed consent, vulnerabilities in cold chain capacity, and onsite management of minor adverse events. While campaign planners anticipated and prepared for some negative media coverage, they did not expect the use of social media for spreading misinformation about HPV vaccination. CONCLUSIONS: The first phase of the national school-based HPV vaccination campaign was successfully implemented at scale in this setting. Future implementation will require improvement in the storage and monitoring of vaccine doses, better communication of role expectations to all stakeholders, and streamlined consent processes to ensure program sustainability.