A Review and Economic Analysis of the Dapivirine Vaginal Ring as HIV Pre-Exposure Prophylaxis for Women, to Inform South African Public-Sector Guidelines

Supplemental Digital Content is Available in the Text.

Abstract

Background:

South Africa has a high HIV incidence and oral pre-exposure prophylaxis (PrEP) is available as public-sector standard of care. Access to alternative prevention methods for women may further reduce HIV acquisition.

Setting:

South African public sector.

Methods:

We performed a systematic search for high-quality up-to-date guidelines recommending dapivirine rings as PrEP using the Grading of Recommendations Assessment, Development, and Evaluation-Adolopment process. We appraised the systematic review and randomized controlled trial (RCT) evidence underpinning the selected guideline's recommendations and conducted a cost-effectiveness analysis. The Grading of Recommendations Assessment, Development, and Evaluation evidence-to-decision framework guided the adaptation of source guideline recommendations, according to our local context.

Results:

We identified the 2021 World Health Organization PrEP Guidelines, informed by 2 placebo-controlled RCTs, which were included in a contemporaneous systematic review. There were 23 fewer HIV acquisitions per 1000 clients with dapivirine ring vs placebo (95% confidence interval: 10 to 34), with no increase in adverse events (moderate certainty evidence). We found no RCTs comparing dapivirine to oral PrEP or among adolescent/pregnant/breastfeeding clients. Dapivirine is less cost-effective than oral PrEP at $14.59/ring, at the current price.

Conclusions:

The source guideline recommendation was adapted for the local context. Dapivirine ring seems to be less efficacious than oral PrEP, although comparative studies are lacking. Data on adolescents and pregnancy are also lacking, currently limiting the use of dapivirine as an alternative for women unable to take oral PrEP. At the current price, dapivirine is not cost-effective and unaffordable for inclusion in the South African Essential Medicines List.

INTRODUCTION

Pre-exposure prophylaxis (PrEP) is a prevention strategy for HIV-negative individuals at high risk of acquiring HIV infection.¹ Oral PrEP (fixed-dose tenofovir/emtricitabine) used consistently (>70% adherence) achieves a 70% reduction in HIV infection [95% confidence intervals (CI): 55% to 79%].¹ Thus, effectiveness is markedly reduced in poorly adherent clients.² The microbicide dapivirine, a drug-eluting vaginal ring, inhibits HIV replication acting locally in reproductive tract mucosa and has a 3-month duration of action.³ Dapivirine may be a PrEP alternative for women at risk of HIV acquisition, particularly those who struggle with adherence and cannot tolerate oral PrEP.⁴

South Africa has a high prevalence and incidence of HIV, with an estimated prevalence of 27.3% among women (15–49 years), as reported in 2022.⁵ Oral PrEP is recommended in the South African Primary Healthcare (PHC), South African Essential Medicines List (EML), and Standard Treatment Guidelines (STGs), 2020 edition, as the current standard of care in the public sector.⁶ Dapivirine ring has been reported to be cost-effective compared with oral PrEP⁷ or no PrEP.⁸ Interestingly, in South African trials among female sex workers in KwaZulu-Natal, dapivirine was cost-saving compared with no PrEP.⁸ Modeling suggested that dapivirine could avert 2.2%–6.4% of new infections in South Africa depending on the coverage achieved.⁷ Among participants, a systematic review found that dapivirine had good acceptability and was easily inserted and removed.⁹ However, to access dapivirine as a PrEP option in the public sector, it has to be listed in the EML and STGs. These are maintained by the National Essential Medicines List Committee (NEMLC), a nonstatutory, ministerially appointed advisory body provided for by the National Drug Policy (1996),¹⁰ to ensure consistent availability of affordable, good-quality essential medicines to all South Africans.¹¹ NEMLC uses the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) evidence-to-decision (EtD) framework^12,13 to systematically and transparently formulate evidence-informed recommendations, considering public health relevance, effectiveness, safety, equity, resource use, feasibility, and stakeholder acceptability.¹⁴

We undertook a rapid evidence review to inform NEMLC's decision whether to include dapivirine vaginal ring in the South African national EML guidelines.

METHODS

We performed a rapid review of the evidence and conducted guideline adaptation using the GRADE-Adolopment approach.^15,16 Figure 1 describes the GRADE-Adolopment process, and we reported the review according to PRISMA guidelines.¹⁷

FIGURE 1.

GRADE-adolopment process.

Evidence of Benefit and Harms

Inclusion Criteria

During the topic prioritization phase, where medicine reviews are prioritized, a preliminary scoping of the literature identified 1 guideline and showed a paucity of randomized controlled trial (RCT) data for dapivirine directly compared with oral PrEP. The PHC technical subcommittee of NEMLC proposed that the PICO (Population, Intervention, Comparator, Outcomes) eligibility criteria be adapted to include placebo-controlled trials aligned with the retrieved guideline (see Table 1).

TABLE 1.

PICO Inclusion Eligibility Criteria

Population	Women at substantial risk of HIV infection (defined as HIV incidence of >3 per 100 person-years in the absence of PrEP)
Intervention	Dapivirine vaginal ring
Comparator	No intervention
Outcome	HIV infection; any adverse event; any grade 3 or 4 adverse event; drug resistance; contraception effectiveness; pregnancy-related adverse events; therapeutic/elective abortion; number of sexual partners, measured pre- to postintervention; condom use at last sex act, measured pre- to postintervention
Studies	Guidelines, systematic reviews of randomized controlled trials

Search Strategy, Selection Criteria, and Data Extraction

We searched the Guideline International Network (GIN) library and World Health Organization (WHO) database on May 4, 2022, using search terms “dapivirine” and “HIV prevention” to identify the most up-to-date guideline/s that addressed our prioritized question/s and which used the GRADE EtD framework.

We used the eligibility criteria from the selected guideline/s to identify additional relevant systematic reviews of RCTs. We searched PubMed and Epistemonikos databases electronically through September 8, 2023, using medical subject heading terms, keywords, and word variants for dapivirine and prevention of HIV, restricted to systematic reviews of RCTs published in English (see Appendices 1 and 2, Supplemental Digital Content, http://links.lww.com/QAI/C333). We did not apply any date restrictions, nor did we search the gray literature.

Quality Assessment

Two assessors (J.N. and T.D.L.) independently appraised guidelines and systematic reviews using the AGREE II¹⁸ instrument and AMSTAR 2 tool,¹⁹ respectively.

Certainty of Evidence

We assessed the certainty of evidence for each outcome using the GRADE approach.¹² We rated the certainty of the evidence as “high,” “moderate,” “low,” or “very low” by considering the risk of bias, inconsistency, imprecision, and indirectness following GRADE guidance.

Evidence Synthesis

If the up-to-date guideline/s were of sufficient quality, we planned to use the GRADE-Adolopment methodology to adapt the guidelines.¹⁶

Economic Evidence

Modeling Assumptions and Scenarios

We estimated the impact of PrEP (oral PrEP or dapivirine ring) on the HIV epidemic using the Thembisa model (version 4.4), a deterministic compartmental HIV transmission model of the South African HIV epidemic.²⁰ We assumed oral PrEP effectiveness of 65% for women,²⁰ taking both efficacy and adherence into account,²¹ and dapivirine ring effectiveness as 29% based on pooled results from 2 phase III placebo-controlled RCTs, the ASPIRE and RING studies.^3,22 A second scenario was included to model an effectiveness estimate of 62%, the upper limit effectiveness estimate from 2 open-label extension projects, HOPE²³ and DREAM.²⁴

We modeled PrEP provision to women aged 15–49 years, including sex workers. We scaled up coverage to 5% for oral PrEP and dapivirine ring, separately, and measured the impact over 20 years (2023–2042). The oral PrEP scenario assumed no dapivirine ring usage, and conversely the dapivirine ring scenario assumed no oral PrEP usage. Based on data from the South African PrEP implementation program, the average duration of oral PrEP use was estimated to be 6 months.²⁰ We assumed the same duration of use for dapivirine because no implementation data outside of a trial setting are available. We assumed that those at the lowest risk of HIV acquisition were 0.33 times as likely to initiate PrEP as those in the high-risk group, based on a Kenyan study²⁵ of PrEP uptake in pregnant women. Our baseline scenario assumed no PrEP coverage but included the current trajectory of existing HIV prevention interventions, such as condom provision, HIV testing services, and medical male circumcision. Thembisa, a dynamic HIV transmission model, allowed us to analyze how each PrEP technology can reduce HIV incidence and subsequently affect the need for HIV treatment.

Costs and Cost-Effectiveness

Costs were estimated from the South African government's perspectives and were presented in 2021 US Dollars (USD) with no discounting. We presented the number of women on dapivirine ring and the total cost for the next 5 years to inform the health budget. We used an ingredients-based approach to estimate the average cost of providing oral PrEP and dapivirine, using data from PrEP demonstration sites and implementation programs, and aligned with PrEP guidelines. Methodology for estimating oral PrEP cost has been described elsewhere.²⁶ The cost of dapivirine ring provision was structured using a similar methodology; however, we adjusted the ingredients to include the dapivirine ring, additional professional nurse time for insertion and removal of the ring, and removed laboratory monitoring tests, which were not required (eg, ALT and creatinine testing, which are included in the oral PrEP costs). In line with standard of care, visits were scheduled every 3 months for both oral PrEP and dapivirine provision. The cost of oral PrEP was set at $4.70/month (drugs only), with tender price sourced from Master Procurement Circular January 2021, whereas the cost of 1 dapivirine ring (for a month) was set at $14.59/ring, provided by the International Partnership for Microbicides (see Appendix 3, Supplemental Digital Content, http://links.lww.com/QAI/C333). The estimated cost of the HIV program followed the same methodology as the South African HIV Investment Case.^27,28

We estimated cost-effectiveness as the incremental cost per HIV infection averted and per life-year saved over 20 years. We conducted a threshold analysis to estimate the price level at which the dapivirine ring is similarly cost-effective compared with oral PrEP. We performed 1-way sensitivity analyses varying oral PrEP effectiveness between 10% and 90%.

GRADE-Adolopment Process

The GRADE-Adolopment process¹⁶ was followed including the identification of good-quality, timely, and relevant Clinical Practice Guidelines with supporting evidence that matched our PICO question; adaptation of selected guideline's EtD framework with consideration of source guideline's GRADE tables and local contextual evidence; and the deliberation on whether to adopt or adapt the selected guideline's recommendations. The technical report, economic analysis, and proposed recommendation were then presented to NEMLC to make a final recommendation.

RESULTS

Guideline and Study Selection

We identified the 2021 WHO Consolidated Guidelines on HIV Prevention, Testing, Treatment, Service Delivery and Monitoring: Recommendations for a public health approach, with recommendations that matched our question.⁴ The guideline recommends the dapivirine ring as an additional prevention choice for women at substantial risk of HIV infection (conditional recommendation, moderate certainty evidence).⁴ “Substantial risk of HIV infection” was defined as HIV incidence >3 per 100 person-years in the absence of PrEP.

We searched for additional systematic review evidence conducted after the 2021 WHO Guidelines and identified 1²⁹ that met our inclusion criteria; see the PRISMA flowchart in Figure 2.

FIGURE 2.

PRISMA flowchart for the selection of systematic review/s.

Table 2 describes the characteristics of the included systematic review of microbicides for the prevention of sexually transmitted infections, conducted in sub-Saharan Africa. Two of the 12 RCTs investigated the safety and efficacy of the dapivirine ring compared with placebo among heterosexual women—the “Ring” (IPM-027)²² and “ASPIRE” (MTN-020)³ studies conducted in clinics and community-based locations in Malawi, South Africa, Uganda, and Zimbabwe, which informed the 2021 WHO Guidelines’ recommendations.⁴

TABLE 2.

Characteristics of Included Systematic Review

Citation	Study Design	Population	Intervention vs Comparator	Outcomes	Effect Sizes	Comments
Systematic review
Obiero J et al, 2021.29 Topical microbicides for preventing sexually transmitted infections (review). Cochrane Database Syst Rev. 2021; 3(3):CD007961	Systematic review and meta-analysis	12 RCTs; 32 464 participants. (12 trials conducted in sub-Saharan Africa, with 1 having a study site in the United States, and another a site in India). Note: The population specific to the dapivirine vaginal ring was 4588 women from 2 RCTs. Eligible participants were sexually active nonpregnant heterosexual women	Intervention: Dapivirine (2 RCTs, n = 4588); Comparator: Placebo	Primary outcomes	Risk of acquiring HIV infection (dapivirine vs placebo): 55 per 1000 vs 78 per 1000; RR 0.71 (95% CI: 0.57 to 0.89); I2 = 0%; (moderate certainty evidence)	There is a concern that only 2 RCTs3,21 have to date assessed the dapivirine vaginal ring. Thus, the certainty of evidence for the risk of acquiring HIV infection was downgraded 1 level, from high to moderate certainty for imprecision, because of lack of optimal information size
				Risk of acquiring HIV infection—incidence of laboratory-confirmed HIV	Serious adverse events: There was no clear evidence of a difference between dapivirine vaginal ring vs placebo: 288/2620 vs 216/1968; RR 1.12 (95% CI: 0.94 to 1.32); I2 = 87% (low certainty evidence)	Risk of bias: Overall assessment described in the Cochrane review—low risk
				Serious adverse events	No trials assessed the acceptability of the intervention	Random sequence generation (selection bias)—low risk
						Allocation concealment (selection bias)—low risk
						Blinding of participants and personnel (performance bias)—low risk
						Blinding of outcome assessment (detection bias)—low risk
						Incomplete outcome data (attrition bias)—low risk
						Selective reporting (reporting bias)—low risk
						Other bias—low risk

The excluded systematic reviews with rationale for exclusion are listed in Appendix 2, Supplemental Digital Content, http://links.lww.com/QAI/C333.

Quality Assessment

We assessed the source guideline as good quality, using the AGREE II Tool (see Appendix 4, Supplemental Digital Content, http://links.lww.com/QAI/C333) and the systematic review of the 2 RCTs, underpinning the guideline recommendations, as high quality, using the AMSTAR 2 instrument (see Appendix 5, Supplemental Digital Content, http://links.lww.com/QAI/C333).

Evidence of Benefit and Harms

Effectiveness of the Use of Dapivirine Ring vs Nonuse

Risk of Acquiring HIV Infection

The systematic review²⁹ showed that dapivirine reduces the risk of HIV infection to 55 HIV acquisitions per 1000 women compared with placebo (78 per 1000). The risk ratio (RR) was 0.71 with a 95% CI: 0.57 to 0.89, based on 2 RCTs involving 4588 women (moderate-certainty evidence). In the systematic review, Cochrane reviewers assessed the 2 RCTs as low risk of bias and downgraded the certainty of evidence by 1 level for imprecision because of the lack of optimal information size.

South Africa has a high prevalence and incidence of HIV among younger women, making them a priority group for prevention.⁵ Unfortunately, age-stratified results were not presented in the systematic review. Hence, we reviewed the published reports of the 2 RCTs to extract data specific to younger women. The age-stratified analysis of the ASPIRE study³ showed that dapivirine did not reduce HIV incidence among women <25 years. The risk difference (RD) was 10%, with a 95% CI: −41 to 43. However, dapivirine reduced HIV incidence by 61% (95% CI: 32 to 77) among women aged ≥25 years. Similarly, the Ring Study²² found little difference in the seroconversion rate per 100 person-years of dapivirine ring compared with placebo, among women ≤21 years, (RD −15.15%, 95% CI: −54.91 to 59.70) but was efficacious in women >21 years (RD −37.47%, 95% CI: −59.49 to −3.49). The age-stratified analyses suggested that the dapivirine ring was not efficacious in younger women.

Adverse Events

Adverse events were mild and similar in the dapivirine and placebo groups. For serious adverse events, there was little to no difference between the dapivirine and placebo groups (RR 1.12, 95% CI: 0.94 to 1.32). The quality of the evidence was assessed as low because of imprecision, inconsistency, and lack of optimal information size.

Social Harm

The ASPIRE RCT³ reported on study-related social harm, defined as “non-medical adverse consequences of dapivirine vaginal ring use or trial participation.”³⁰ Ninety-four instances of social harm were reported (3% of women) with 4680 person-years of follow-up, of which 93% (n = 87) were partner-related³; 61% (n = 85) had disclosed study participation to their primary partners, and 40% of the cases were categorized as having a more than minimal impact on the quality of life. Younger women (18–26 years) were more than twice as likely to experience social harm than older women, resulting in decreased product adherence. Social harm was triggered by partners discovering the ring, notifying partners of a sexually transmitted infection, or partners suspecting that dapivirine was associated with ill health, “promiscuity,” or “witchcraft.” Experiences of social harm included destruction of the ring, physical violence, or ending the relationship.

Certainty of Evidence

The evidence was rated as moderate certainty, overall. We found no studies comparing dapivirine ring with oral PrEP. However, a larger relative reduction in HIV acquisition was seen for oral PrEP compared with placebo (RR 0.49; 95% CI: 0.33 to 0.73) than with dapivirine (RR 0.71; 95% CI: 0.57 to 0.89), with differences in efficacy in subgroups of high-risk individuals. Among women, oral PrEP was less efficacious (RR 0.57; 95% CI: 0.34 to 0.94; n = 8,714) compared with men (RR 0.38; 95% CI: 0.25 to 0.60; n = 8,704). See Appendix 6 (the 2021 WHO Guidelines’ GRADE evidence profiles) and Appendix 7 of the Supplemental Digital Content (the adapted EtD framework), http://links.lww.com/QAI/C333.⁴

Cost-Effectiveness Analysis

Over a 20-year time horizon, scaling up dapivirine ring coverage to 5% averts approximately 27,000 and 60,000 new HIV infections under 29% and 62% effectiveness assumptions, respectively, compared with baseline. Oral PrEP at 5% coverage averts 63,000 new HIV infections over the same period (Table 3). Similarly, the total life years saved would be 83,000, 171,000, and 179,000 for dapivirine ring with 29% effectiveness, 62% effectiveness, and oral PrEP, respectively. Oral PrEP was more cost-effective, at $13,445/HIV infection averted, compared with the dapivirine ring under both 29% effectiveness ($60,707/HIV infection averted) and 62% effectiveness ($26,549/HIV infection averted) (Table 3). The estimated price at which the dapivirine becomes similarly cost-effective compared with oral PrEP would be $4.25/ring (assuming 29% effectiveness) and $8.82/ring (assuming 62% effectiveness). In the 1-way sensitivity analysis, if the dapivirine ring is 62% effective, oral PrEP is more cost-effective than the dapivirine ring at effectiveness levels exceeding 37% (comparing incremental cost per HIV infection averted) or 35% (comparing incremental cost per life year saved). If the dapivirine ring is 29% effective, oral PrEP is more cost-effective than the dapivirine ring at effectiveness levels exceeding 17% (comparing incremental cost per HIV-infection averted) and 16% (comparing incremental cost per life year saved) (Fig. 3 and Appendix 8, Supplemental Digital Content, http://links.lww.com/QAI/C333).

TABLE 3.

Economic Analyses. Cost Estimates for Budget Impact Analysis, Years 2022/23 to 2026/27

	Baseline	Dapivirine Ring		Oral PrEP (65% Effectiveness)
		29% Effectiveness	62% Effectiveness
Total cost of the HIV program* (2021 USD, millions)	41.40	43.05	43.00	42.25
Incremental cost (2021 USD, billions)	—	1,650 (4%)	1,598 (4%)	850 (2%)
Total new HIV infections (millions)	2.94	2.91	2.88	2.88
HIV infections averted (thousands)	—	27 (1%)	60 (2%)	63 (2%)
Total life years lost to AIDS (millions)	36.02	35.94	35.85	35.84
Life years saved (thousands)	—	83 (0.2%)	171 (0.5%)	179 (0.5%)
Incremental cost per HIV infection averted (2021 USD)	—	60,707	26,549	13,445
Incremental cost per life year saved (2021 USD)	—	19,985	9,337	4,741
Threshold price of dapivirine ring	—	$4.25	$8.82	—

^*Total cost of the HIV program includes the cost of antiretroviral treatment, inpatient care of those with HIV, palliative care, HIV testing (different modalities considered), condom distribution, medical male circumcision, postexposure prophylaxis (PEP), supply chain management, and pharmacovigilance costs.

FIGURE 3.

Incremental cost per new HIV infection averted (A) and incremental cost per life year saved (B) comparing dapivirine ring and oral PrEP, one-way sensitivity analysis varying oral PrEP effectiveness. ICER, incremental cost-effectiveness ratio.

Assuming a coverage rate of 5% for women aged 15–49 years, 528,000 to 575,000 women would use dapivirine ring for $68-$75 million per year (fully loaded cost; cost breakdown in Appendix 3, Supplemental Digital Content, http://links.lww.com/QAI/C333). These results assume that the cost of the ring, which makes up 68% of the total cost, remains at $14.59/ring and women remain on dapivirine for an average of 6 months (Table 4).

TABLE 4.

Economic Analyses. Cost Estimates for Budget Impact Analysis, Years 2022/23 to 2026/27

	2022/23	2023/24	2024/25	2025/26	2026/27
Number of clients starting dapivirine ring use	528,259	535,369	547,638	561,056	575,189
Total cost of dapivirine ring* (USD, millions)	68	69	71	73	75

^*Fully loaded cost includes the cost of the ring (68%), staff time (21%), overheads (6%), laboratory testing (5%), and consumables (<0.1%).

GRADE-Adolopment Process

The PHC technical subcommittee reviewed the 2021 WHO Guidelines' EtD framework with additional contextual evidence, to inform local consensus judgments for the 12 EtD domains—summarized in Table 5. The source guideline judgment for each EtD domain was either adopted or adapted (see Appendix 7, Supplemental Digital Content, http://links.lww.com/QAI/C333 for the comprehensive ETD framework), and the final evidence synthesis report with the adapted ETD framework was presented to NEMLC to inform a recommendation.

TABLE 5.

Summary of Judgments

Question: Is Dapivirine Vaginal Ring Safe and Effective in Preventing HIV Acquisition in Women at Substantial Risk of HIV Infection?
Criteria	WHO guideline panel's judgment	Primary healthcare technical subcommittee of NEMLC's judgment	Additional contextual evidence and additional considerations reviewed by the primary healthcare technical subcommittee of NEMLC
Is the problem a priority?	Not provided	Yes	The WHO EtD framework provided data in the global image of HIV, specifically among women and girls living with HIV and described the challenges of oral PrEP uptake.
			Additional considerations: In South Africa, the prevalence and incidence of HIV is high, with 230,000 new adult HIV infections in 2020, of which 140,000 were women and were ≥ 15 years of age. The prevalence rate of adults aged 15–59 years reported as ± 7.79; of women aged 15–49 years ±24.7, and of women aged 15–24 years is ±10.4 per 1000 population
			Pregnant and postpartum women have higher rates of HIV acquisition compared with nonpregnant women.30
How substantial are the desirable anticipated effects?	Not provided	Moderate	The WHO EtD framework provided evidence that among women, dapivirine use compared with placebo demonstrated a significant reduction in HIV incidence. Pooled risk-stratified data from ASPIRE3 and ring21 RCTs showed that HIV-1 risk reduction was significantly higher in participants > 21 years, and no risk reduction was observed in participants ≤21 years. An ASPIRE subanalysis showed a significant relationship between adherence and efficacy, though open-label extension projects (HOPE22 and DREAM23) reported 39%–62% reduction in HIV incidence among women study participants with increased adherence to dapivirine compared with adherence measured in RCTs.
			Additional considerations: Other systematic reviews27,31 also pooled data from placebo-controlled ASPIRE and the ring RCTs showed that the dapivirine ring reduced HIV incidence: RR 0.71 (95% CI: 0.57 to 0.89, I2 = 0%, n = 4588 women; moderate-certainty evidence). Notably, there are no head-to-head comparative trials of dapivirine vs oral PrEP, and placebo-controlled oral PrEP studies (RR 0.49; 95% CI: 0.33 to 0.73) suggest that oral PrEP may be more efficacious than the dapivirine ring.
How substantial are the undesirable anticipated effects?	Not provided	Small	The WHO EtD framework provided evidence that showed no increased risk of adverse events, comparing women randomized to the dapivirine ring vs placebo ring. However, study-related social harm was reported in the ASPIRE RCT by 3% of women, of which 93% were partner-related; 40% of cases had an impact on quality of life; and younger women (18–26 years) were more than twice as likely to experience social harm than older women, resulting in decreased product adherence. RCT data showed no difference in the number of NNRTI mutations found among seroconverters comparing women using dapivirine ring vs placebo. One analysis from ASPIRE found no difference in pregnancy incidence comparing dapivirine with placebo, across all hormonal contraceptive methods, and limited data from 1 study site found no significant differences in adverse pregnancy-related events between dapivirine and placebo. Behavioral outcomes between dapivirine and placebo showed little to no difference for change in reports of noncondom use of 2 or more sexual partners at baseline vs at trial completion and of rates of curable STI incidence.
			Additional considerations: There were no additional considerations.
What is the overall certainty of the evidence of effects?	Not provided	Moderate	The WHO EtD framework: Mostly moderate certainty of evidence for HIV infection, adverse event outcomes, contraceptive effectiveness, and sexual behavior outcomes. Mostly low certainty of evidence for outcomes related to drug resistance and adverse pregnancy-related outcomes. Data from 3 RCTs and 2 observational studies (n = 5000) only for women ≥ 18 years, with limited data for reproductive health outcomes.
			Additional considerations: Studies, follow-up studies, and the open-label extension studies reviewed by the WHO panel included South African sites. There is a paucity of real-world feasibility studies, and no head-to-head comparative trials of dapivirine ring compared with oral PrEP.
Is there important uncertainty about or variability in how much people value the main outcomes?	Not provided	Possibly important uncertainty or variability	The WHO EtD framework: Dapivirine ring highly valued across all stakeholders and women value this discrete PrEP modality. We are uncertain if there is behavioral risk compensation for use of dapivirine ring among adolescent girls and young women.
			Additional considerations: Systematic review32 found favorable acceptability pooled prevalence of 85.6% (95% CI: 81.3 to 89.0), more so among European and Asian clients and multiregion sites and lower acceptability rates in African studies.
Does the balance between desirable and undesirable effects favor the intervention or the comparison?	Not provided	Probably favors the intervention (compared with placebo)	The WHO EtD framework: Results from the systematic review showed that the dapivirine ring has promising benefits regarding HIV prevention among women and a few undesirable clinical effects. No safety concerns, no evidence of increased drug resistance among seroconverters, and no evidence of behavioral risk compensation associated with the dapivirine ring (though low levels of partner-specific social harms (3%) associated with dapivirine in ASPIRE RCT). More research is needed to understand the use of and adherence to dapivirine ring among adolescent women and girls and among pregnant and lactating women.
			Additional considerations: As mentioned above, compared with placebo, oral PrEP (RR 0.49; 95% CI: 0.33 to 0.73)1 seems more efficacious than the dapivirine ring27 (RR 0.71; 95% CI: 0.57 to 0.89), in preventing HIV acquisition. Limited study-related social harm was reported with use of dapivirine ring, but no data were identified for association with use of oral PrEP. Overall, there were little to no safety concerns; however, no benefit was found in women younger than 21 years, requiring further research.
How large are the resource requirements (costs)?	Not provided	Large costs	The WHO EtD framework: International partnership for microbicides current cost of goods is $8 per ring and various modeling studies estimated that the total annual cost of dapivirine (medicine, laboratory, and service delivery costs) is between $107 and $115, with variation by target group and country. Dapivirine expected to have lower health system costs than oral PrEP because no creatinine monitoring or Hepatitis B testing is required. Various service-delivery models to access dapivirine.
			Additional considerations: Most recent estimated unit cost of dapivirine ring provided by the NDoH program was $15.31 (previously was estimated at $14.59). Assuming a 5-year retention of a client using dapivirine ring on the NDoH program, estimated cost of providing dapivirine ring is S130/client (inclusive of drug, laboratory costs, and service delivery).
What is the certainty of the evidence of resource requirements (costs)?	Not provided	Low	The WHO EtD framework: Cost of resource requirements would vary by setting.
			Additional considerations: Resource requirements are dependent on the unit cost of dapivirine ring and uptake of intervention, once program has been rolled out (assumed coverage was modeled on oral PrEP program uptake of 5%, but uptake of dapivirine ring remains uncertain).
Does the cost-effectiveness of the intervention favor the intervention or the comparison?	Not provided	Favors the comparison (compared with SOC: oral PrEP—TE)	The WHO EtD framework: 3 cost-effectiveness studies showed that dapivirine would be a cost-effective intervention among those at high risk of HIV infection, dapivirine would be a cost-saving intervention for KwaZulu Natal if the intervention was prioritized for female sex workers, and a GOALS modelling study (based on scenarios in Kenya, South Africa, Uganda, Zimbabwe) found that the impact of dapivirine would vary, dependant on treatment coverage and the potential intervention cost—in the South African context: the cost per HIV infection averted varied between $13,000 and $121,000. Studies highlighted uncertainty regarding adherence and demand for/uptake as critical aspects of determining cost-effectiveness and impact.
			Additional considerations: Over a 20-year time horizon, daily oral PrEP is estimated to be more cost-effective compared with dapivirine, over a baseline with no PrEP: at $13,445/HIV infection averted (oral PrEP), vs both dapivirine ring effectiveness assumptions (29%: $60,707/HIV infection averted and 62%: $26,549/HIV infection averted). For price parity with oral PrEP, the dapivirine ring will need to be lower at approximately $4/ring (assuming 29% effectiveness of dapivirine ring) and up to $8.80/ring (assuming 62% effectiveness of dapivirine ring).
What would be the impact on health equity?	Not provided	Varies	The WHO EtD framework: Additional, discrete, woman-controlled biomedical HIV prevention option. Dapivirine in addition to oral PrEP could meet the diverse needs and preferences of women—increased options may lead to increased use. Providing access to dapivirine ring avails additional opportunities for sexual and reproductive health services.
			Additional considerations: For those women who cannot use oral PrEP (which is current standard of care), accessing dapivirine ring would promote equity for PrEP.
Is the intervention acceptable to key stakeholders?	Not provided	Possibility/probably yes	The WHO EtD framework: The overall acceptability (proportion of women reporting a favorable experience) across 46 studies and 19,080 was 87.4% (95% CI: 83.5% to 90.5%). The majority reported the ring was easy to insert and remove. Women expressed preferences for devices that were easily accessible, long-acting, and partner-approved that could prevent both HIV infection and pregnancy and that could also be used without the partner's awareness, with minimal impact on sex, and with a few side effects. The review also noted that partner influence can affect ring use and that perceived community awareness and acceptance of the ring was important.
			Additional considerations: There were no additional considerations.
Is the intervention feasible to implement?	Not provided	Probably yes	The WHO EtD framework: multiple studies of the dapivirine vaginal ring have been conducted, thus proving its feasibility across a variety of trial settings and it is relatively easy to transport and store.
			Additional considerations: Dapivirine ring is SAHPRA registered and can be implemented using the existing NDoH Programmatic infrastructure.

EtD framework: Evidence to decision framework; GRADE approach: Grading of Recommendations Assessment, Development, and Evaluation approach; NDoH, National Department of Health (South Africa); NNRTI, non-nucleoside reverse transcriptase inhibitors; SAHPRA, South African Health Products Regulatory Authority; STI, sexually transmitted infection. See Appendix 5, Supplemental Digital Content, http://links.lww.com/QAI/C333 for the comprehensive ETD framework.

The NEMLC decided not to recommend the dapivirine ring as an additional option for the prevention of HIV acquisition in women in South Africa (conditional recommendation, moderate certainty of evidence). However, this decision would be revisited if the price of dapivirine ring is reduced, if there is new evidence of social harms associated with the use of PrEP (including dapivirine), and if new implementation research shows differential uptake rates of dapivirine ring compared with other PrEP modalities.

DISCUSSION

We followed a systematic “adolopment” process to guide whether to recommend inclusion of the dapivirine ring as an additional PrEP option to standard-of-care oral PrEP in the South African EML and STGs. The 2021 WHO Consolidated Guidelines,⁴ which includes a conditional recommendation for dapivirine as a prevention choice for women at high risk of HIV acquisition, was assessed as good quality and was selected for GRADE-Adolopment. Following the review of the WHO guideline panel's EtD framework and local contextual evidence, dapivirine was not recommended for the national EML. Key reasons for this decision were that dapivirine is likely less efficacious than oral PrEP compared with placebo, efficacy may be lower in young women, with a paucity of effectiveness data among adolescent girls and pregnant women, who are at higher risk of HIV acquisition in South Africa, and implementing dapivirine (at the current proposed price) would be unaffordable.

Based on indirect comparisons of the placebo-controlled trials for both interventions, a greater reduction in HIV acquisition was seen for oral PrEP compared with placebo¹ than with the dapivirine ring.²⁹ Adverse events associated with dapivirine were limited and mild in severity, but further research is needed to understand social harms associated with PrEP (including both oral PrEP and the dapivirine ring). Of concern, the ASPIRE trial³ found that women younger than 25 years had poorer adherence to the dapivirine ring, with lower efficacy and heightened experiences of social harm and stigma.

Our economic model suggests that the dapivirine ring would need to be priced as low as $4.25 to be as cost-effective as oral PrEP, based on its lower published efficacy of 29% efficacy in preventing HIV infection compared with oral PrEP, assuming similar real-world effectiveness. Even with dapivirine efficacy as high as 62%, a substantial reduction to the current $14.95 price would still be required to match the cost-effectiveness of oral PrEP. In our sensitivity analysis, if dapivirine were 62% effective, it would be less cost-effective than oral PrEP per HIV infection averted, provided that oral PrEP effectiveness is 37% or higher, at current prices. The dapivirine ring could be a useful alternative for women who cannot take oral PrEP or prefer dapivirine to oral PrEP. However, it is currently not affordable or cost-effective for broad rollout in South Africa.

Pregnant and postpartum women have higher rates of HIV acquisition than nonpregnant women.³¹ Preliminary results from the randomized, open-label DELIVER study (MTN-042)³² showed that in pregnant women in their third trimester, pregnancy complications in the dapivirine ring (n = 207) and oral PrEP (n = 100) groups were rare and similar to background rates.³³ Preliminary results for the open-label, randomized B-PROTECTED (MTN-043) study³⁴ suggest low transfer of dapivirine (n = 148) and oral PrEP (n = 101), from breastfeeding mother to infant. There were a few serious adverse events in mothers and infants and no infant adverse events were related to the study products. Full results of these studies are needed to inform decisions on the use of dapivirine in pregnant women.

In the more recent findings from the REACH trial³⁵ among African adolescent girls and young women, aged 16–21 years, 57% were compliant on the dapivirine ring and oral PrEP, with a higher preference for the dapivirine ring. The study noted limitations in generalizability due to selection bias. However, several South African implementation studies, funded by external organizations, are ongoing to assess the feasibility of offering the dapivirine ring at public PHC facilities. These studies will assess user preferences, uptake, compliance, and ease of use of the dapivirine ring, oral PrEP, and long-acting injectable cabotegravir, with the data from these studies potentially influencing decisions on including the dapivirine ring as an additional PrEP option in the EML and STGs.

The source 2021 WHO Guidelines recommends dapivirine as part of a comprehensive combination prevention approach, allowing women to choose between PrEP options. However, the 2023 WHO Model EML³⁶ does not list dapivirine, demonstrating poor linkage between the WHO Guidelines and EML processes. In September 2023, the Joint United Nations Programme on HIV/AIDS (UNAIDS) launched the HIV prevention choice manifesto for women and girls in Africa emphasizing choice in methods, similar to family planning.³⁷ The DREAMS PrEP Choice Study will analyze South African women's perceptions of the different HIV PrEP options.³⁸

Using the GRADE-Adolopment approach, we efficiently adapted the 2021 WHO Guidelines for the South African context. This approach may help other resource-constrained countries and institutions develop credible guidelines,³⁹ maintaining methodological rigor, within a shorter timeframe and at a reduced cost compared with local guideline development.⁴⁰ Adolopment approaches have been used effectively in high- and low-to-middle-income countries such as Australia,⁴¹ Italy,⁴² the Kingdom of Saudi Arabia,⁴³ and Pakistan.⁴⁴

There are some limitations to this work. The technical subcommittee initiated the first attempt to implement the GRADE-Adolopment process to inform a South African NEMLC recommendation. The lack of comprehensive methodology guidance, prior training, and specific templates posed challenges. However, the work was supported by a methodologist (MM). Using the GRADE-Adolopment process, we developed guideline recommendations within 4 months. Additional training and experience could have potentially shortened the time required for completion.

The GRADE-Adolopment methodology can only be applied to existing guideline recommendations and depends on source guideline's ETD completeness. We could not access the WHO panel's judgments because they were not included in the guideline document. However, we could evaluate the quality and generalizability of the underlying evidence in the EtD framework. We used the same PICO elements as the WHO Guidelines for efficiency, but the WHO PICO did not address the key question for our context, comparing dapivirine efficacy to standard of care (oral PrEP). Amending the PICO would have required a de novo systematic review, with more resources.

Our costing analysis uses efficacy data from RCTs for oral PrEP and the dapivirine ring. Real-world effectiveness may differ from trial findings, which would influence the cost-effectiveness estimates. Studies assessing effectiveness of oral PrEP and dapivirine ring would be useful to inform future decisions about including dapivirine ring in the South African national EML.

We compared dapivirine ring with oral PrEP as if the choice for the other was not available, partly due to insufficient data at the time on demographic and behavioral characteristics associated with the choice of PrEP modality. Studies are underway exploring PrEP preferences that may provide data for future evaluations.⁴⁵ Ideally women should have access to a PrEP modality that they find acceptable, in line with the UNAIDS HIV prevention choice manifesto.⁴⁶ However, severely limited healthcare budgets constrain the availability of more costly, less cost-effective options.

CONCLUSIONS

Developing evidence-based public health policies and guidelines is complex, time-consuming, and requires dedicated resources. Adolopment methodology allowed us to rapidly adapt existing guidance documents to our local context, considering local evidence, costs, culture, feasibility, acceptability, and equity. Based on this evidence synthesis informed by data available at the time of the decision, the South African NEMLC did not endorse the use of the dapivirine ring as an additional HIV-PrEP option in women. This recommendation may be revised if the price is reduced (comparable to the proposed price threshold), new evidence of differential uptake of the dapivirine ring compared with other PrEP modalities becomes available, or if there is updated evidence of social harms associated with all PrEP modalities. GRADE-Adolopment supported reproducible, credible, and transparent evidence to recommendation process, balancing efficiency with methodological rigor.

Supplementary Material

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