Long-Acting Injectable Antiretroviral Drugs for Pregnant and Breastfeeding Women: Current Advances, Challenges, and Future Directions

Abstract

Purpose of Review

This review explores the promise and challenges of integrating long-acting antiretroviral agents—cabotegravir, lenacapavir, and cabotegravir-rilpivirine—into HIV prevention and treatment programs for pregnant and breastfeeding populations. It aims to examine current evidence, implementation experiences, and barriers to equitable access.

Recent Findings

Emerging data support the efficacy and safety of long-acting agents during pregnancy and breastfeeding. Recent clinical trials have begun to include pregnant women by design, and national demonstration projects have successfully introduced injectable PrEP in maternal health settings. These developments signal growing recognition of the need for inclusive research and service delivery models.

Summary

Long-acting antiretrovirals have the potential to transform maternal HIV prevention and treatment. However, challenges such as delayed inclusion in trials, policy constraints, limited product choice, high costs, and funding limitations persist. Addressing these gaps is critical to ensuring equitable access and informing future research and implementation strategies.

Introduction

Antiretroviral drugs can effectively prevent and treat HIV; however, they must be administered properly and on time. Until recently, advancements in drug delivery have focused primarily on improving oral formulations of antiretroviral agents. With each new generation, agents have become more potent, tolerable, and easier to administer [1]. Drug half-lives are now longer and, for most first-line regimens, oral dosing have been reduced to once daily. Fixed-dose combination formulations—which bring together several different antiretroviral agents in a single pill—further reduce the pill burden. Such moves toward regimen simplification have led to better adherence; [2–5] however, for many, challenges persist due to a host of individual and structural barriers [2].

Long-acting injectables (LAIs) offer a promising alternative to the challenges of daily oral adherence. These formulations have demonstrated efficacy for both HIV treatment and prevention. Supporting adherence—whether for ART in treatment or PrEP in prevention—is especially critical during pregnancy and breastfeeding to reduce the risk of vertical transmission. Already, several formulations (e.g., cabotegravir, rilpivirine, and lenacapavir) have been shown to be efficacious [3–6] and, as such, have been incorporated into policy recommendations. However, questions persist about their safety [7], acceptability, and suitability for different populations, and the healthcare infrastructure to deliver timely and regular injection schedules. This is particularly true in settings where HIV burden is high and resources are limited.

In this review, we focus on LAI formulations of antiretroviral drugs for one such population: pregnant and breastfeeding women. These groups share important biological considerations, including inherent physiologic changes, possible effects on pregnancy outcomes, and fetal/newborn exposure to new antiretroviral drugs. In the highest HIV prevalence countries, reproductive age women represent the majority of new HIV infections, highlighting the critical need for effective and safe prevention and treatment products throughout their reproductive years including pregnancy and breastfeeding. Across social and cultural factors, they may share vulnerabilities for HIV, both in the contexts of prevention and treatment. We discuss the opportunities and challenges of these LAI formulations, from the evidence to date to new areas for future investigation.

Review of Current LAI Formulations

Several LAI antiretroviral drugs have been approved or are in advanced development. The most established formulations are cabotegravir (CAB-LA) and rilpivirine (RPV-LA), forming the first complete injectable regimen for HIV treatment; CAB-LA alone is also approved for HIV pre-exposure prophylaxis (PrEP) and lenacapavir (LEN) is a biannual injectable formulation that has been recently approved by the World Health Organization (WHO). Other agents are also in development, creating a pipeline of potential agents that have the potential to transform clinical care and public health delivery of HIV services.

Cabotegravir

Cabotegravir is a potent integrase strand transfer inhibitor (INSTI) [8]. It blocks HIV’s integrase enzyme, preventing viral DNA from integrating into the host genome. CAB-LA has been formulated as a long-acting intramuscular injection and is approved for two indications: (1) as part of a treatment regimen, with rilpivirine, for maintaining virologic suppression in adults [4] and (2) as a single-agent PrEP injection (branded Apretude) for HIV prevention [9]. For treatment, CAB-LA can be administered monthly or every two months as part of a two-drug regimen, offering an alternative to daily oral therapy for individuals who have already achieved viral suppression [4]. Clinical trials have also demonstrated the high efficacy of CAB-LA for HIV prevention when used alone. Two-monthly injectable cabotegravir significantly reduced HIV risk compared to daily oral PrEP. Among men, HIV incidence was 0.41 vs. 1.22 per 100 person-years (66% lower risk), and among women, 0.2 vs. 1.85 per 100 person-years (88% lower risk) [6, 10]. CAB-LA was approved for PrEP in 2021 by the U.S. Food and Drug Administration and has since been recommended by the WHO as an additional prevention option [11].

Rilpivirine

Rilpivirine is a second-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) that inhibits HIV’s reverse transcriptase enzyme, thus stopping viral RNA from being converted into DNA [12]. An extended-release injectable form of rilpivirine is approved as part of the first long-acting injectable ART regimen ( branded Cabenuva) [13]. RPV-LA is not used alone; it is given together with CAB-LA to maintain suppression in people already virally suppressed on oral ART. The two drugs are administered as intramuscular gluteal injections either monthly (CAB 400 mg + RPV-LA 600 mg) or every two months (CAB 600 mg + RPV-LA 900 mg)​ [4, 5].

Lenacapavir

Lenacapavir (LEN) is a first-in-class capsid inhibitor that disrupts multiple stages of the HIV lifecycle [14]. LEN attaches at the junction of two capsid protein monomers, disrupting multiple stages of capsid core formation and the breakdown, thereby blocking HIV replication [15].With a long half-life, it requires only twice-yearly subcutaneous injections. Initially approved (as Sunlenca) for multidrug-resistant HIV, LEN is administered after an oral loading phase, followed by subcutaneous injection every 6 months [14]. A once-yearly dosing option may become available in the near future [16]. For treatment of HIV, LEN is not used alone. It’s used as part of a combination antiretroviral therapy, especially in people with multi-drug resistant HIV-1 [17]. The long-acting formulation (every 6 months) is typically combined with optimized background therapy, which includes other active antiretrovirals based on resistance profiles [18]. LEN has also shown tremendous potential for HIV prevention when used as PrEP. The PURPOSE 1 trial, which compared LEN to daily oral PrEP, showed that this twice-yearly formulation had extremely high efficacy. In a randomized trial of 5338 adolescent girls and young women in South Africa and Uganda, no new HIV infections were observed among 2134 participants LEN arm, compared to 39 infections among 2136 participants in the comparator group receiving daily oral emtricitabine/tenofovir alafenamide [3]. In the PURPOSE 2 trial, significant reductions in HIV incidence were also observed among men, transgender men, transgender women, and non-binary persons allocated to the LEN study arm, although two breakthrough HIV infections observed were associated with the N74D capsid inhibitor resistance mutation [19]. LEN also demonstrated high efficacy, good safety and comparable pharmacokinetics between youth (aged 16-25) and adults in the PURPOSE 1 and 2 trials, supporting its potential to overcome adherence challenges with daily oral PrEP and reduce HIV incidence among young people [20]. LEN (branded Yeztugo) was recently approved in June 2025 for HIV prevention by the U.S. Food and Drug Administration [21]. Shortly after, in July 2025, the WHO issued new guidelines recommending LEN as an HIV prevention option,[22] in a landmark policy action that could help reshape the global HIV response. Table 1 below summarizes the mechanisms and dosing schedules of key LAIs.

Table 1.

Key long-acting injectable antiretroviral agents, their mechanisms and typical dosing intervals

Drug	Mechanism of Action (Drug Class)	Dosing Schedule	Regulatory approval for HIV prevention	Regulatory approval for HIV treatment
Cabotegravir (CAB-LA)	Integrase strand transfer inhibitor (INSTI)– blocks HIV integrase and prevents viral DNA integration into host genome​.	Intramuscular (gluteal) injection every 8 weeks for PrEP (after two initial doses 4 weeks apart)​. For treatment (with RPV-LA), given IM monthly or every 2 months (depending on regimen)​	U.S. Food and Drug Administration (FDA): Dec 2021 European Medicines Agency (EMA); Sept 2023	With Rilpivirine: FDA (Jan 2021), EMA (Dec 2020)
Rilpivirine (RPV-LA)	Non-nucleoside reverse transcriptase inhibitor (NNRTI)– binds reverse transcriptase, halting viral RNA→DNA conversion​	Intramuscular injection co-administered with CAB-LA, either monthly (e.g. 600 mg) or every 2 months (e.g. 900 mg), as part of a two-drug maintenance regimen​. RPV-LA is not used alone and is indicated only with concurrent CAB-LA.	—	With Cabotegravir: FDA (Jan 2021), EMA (Dec 2020)
Lenacapavir (LEN)	Capsid inhibitor– binds HIV capsid protein, disrupting viral assembly and uncoating processes​.	PrEP with LEN is initiated 927mg subcutaneously and 600mg orally on Day 1 and Day 2 and is continued with a 927mg subcutaneous injection every six months thereafter. LEN is being studied for both HIV prevention and treatment (with other ARVs).	FDA (June 2025, Yeztugo) WHO (July 2025)	FDA/EMA/Health Canada (CA) for Multi-drug resistant HIV (Sunlenca)

Other LAI Agents (Pipeline or Limited Use)

Several LAI antiretroviral formulations, currently in the pipeline, are noteworthy. Albuvirtide, a weekly IV HIV-1 fusion inhibitor for multidrug-resistant HIV, has shown non-inferiority in trials and was successfully used in one pregnant woman, achieving viral suppression with no safety concerns [23, 24]. Currently approved in China, it is now being reviewed by regulatory agents elsewhere. Islatravir (MK-8591), a nucleoside reverse transcriptase translocation inhibitor was explored as both a long-acting implant and oral tablet for PrEP and treatment, with PrEP and some treatment doses discontinued for toxicity reasons [25, 26]. A related drug, MK-8527; a one-monthly oral option, is currently undergoing further evaluation [27]. Ultra-long-acting formulations (ULA), like subcutaneous cabotegravir, are in early studies and may allow quarterly or less frequent dosing [28]. Broadly neutralizing antibodies (bNAbs), though not classical antiretroviral drugs are also being explored for prevention and treatment [29].

LAI Formulations for Pregnant and Breastfeeding Women

Pregnant and breastfeeding women have historically often been excluded from initial clinical trials of new HIV prevention and treatment agents, including LAIs [30]. As a result, empiric data about safety—including fetal and infant exposure, maternal drug toxicities, and antiretroviral resistance [31]—as well as maternal acceptability and adherence often lag. As a result, new PrEP modalities are often not recommended in pregnancy or lactation due to lack of data, leaving clinicians to weigh potential risks and benefits [32]. This evidence gap, however, is closing as recent trials and studies have started to include or specifically focus on pregnant and breastfeeding women to evaluate LAI pharmacokinetics, safety, and efficacy [3, 33–35]. Table 2 below summarizes some of the key studies involving LAI for ART or PrEP.

Table 2.

Key studies on long-acting injectable antiretroviral agents for ART or PrEP including pregnant and breastfeeding women

Drug/Regimen	Efficacy Trials	Bridging Studies (including pregnancy/breastfeeding women)	Implementation Studies/Demonstration Projects
Cabotegravir (CAB-LA) HIV prevention regimen	HPTN 083 and 084 [6, 10] Studies showed that CAB-LA was superior to oral PrEP; 66–89% HIV risk reduction in MSM, TGW, and cis women.	HPTN 084 OLE Pregnancy Sub-study [33]: Ongoing study tracking pregnancy outcomes of women enrolled in HPTN 084. PALISADE [36]: This study provides long-term follow-up of participants from HPTN 083/084, evaluating CAB-LA for PrEP, including pregnancy outcomes in those who become pregnant. Tshireletso [37]: Ongoing trial on Safety, efficacy and feasibility of Cabotegravir-LA PrEP in a high-risk breastfeeding population. 500 postpartum women and infants will be followed for 24 months to assess PrEP adherence, safety, and outcomes, including a PK sub study with 30 pairs. PrIMO [34]: Ongoing study on PrEP Pregnancy Registry and observational cohort evaluating the pregnancy, infant and maternal health outcomes among PrEP-eligible pregnant women and their infants up to one year postpartum. (A total of 621 mother-infant pairs on either CAB LA or oral PrEP).	SEARCH (Uganda/Kenya) [38, 39]: The trial found that CAB-LA was highly acceptable and expanded HIV prevention options, though users noted concerns around injection pain, side effects, and access. Path To Scale(Malawi), [40, 41]: Ongoing study that is tracking pregnancy outcomes on women on PrEP using a Pregnancy Registry. (N = ~ 900) PrEPared to Choose [42] (South Africa): The study evaluates CAB-LA delivery within a real-world HIV prevention program offering multiple PrEP options, focusing on uptake, preferences, and feasibility. *CATALYST [43] (South Africa, Zimbabwe, Lesotho, Uganda, Kenya): Study explores how to deliver and scale up client-centered HIV prevention, including CAB-LA and oral PrEP, across multiple African countries.
Lenacapavir (LEN) HIV prevention regimen	PURPOSE 1 and 2 [3, 19]:.PURPOSE 1: trial enrolled a total of 5,338 cisgender women, randomized as follows: 2,134 received LEN, 2,136 were assigned daily oral F/TAF, and 1,068 received daily oral F/TDF as the active comparator. 100% efficacy in the LEN group. PURPOSE 2 trial enrolled 3,265 MSM/TGW participants, HIV incidence was significantly lower in the LEN group (0.10 per 100 person-years) compared to both the F/TDF group (0.93 per 100 person-years) and the background population (2.37 per 100 person-years).	PURPOSE 1 Pregnancy Sub-study [3]: Study tracking the outcomes of pregnancies among women on LEN in PURPOSE 1. Breastmilk/infant PK is ongoing and initial data reassuring [35].	PURPOSE 3–5 [44]: Implementation trials in high-risk groups.
CAB + Rilpivirine (RPV-LA ) Long acting dual HIV Treatment regimen	ATLAS/FLAIR [4, 45]: Monthly injections of CAB+RPV-LA non-inferior to oral ART. ATLAS-2M [46]: 8weekly dosing (Q8W) non-inferior to 4 weekly dosing (Q4W) dosing. CARES [47]: CAB + RPV-LA had non-inferior efficacy compared with oral therapy with a good safety profile.IMPALA [48]: CAB/RPV-LA was non-inferior to oral ART in maintaining viral suppression at 48 weeks among individuals with previous adherence challenges, with 91% vs 89% achieving VL <50 copies/mL, respectively. While all cases of confirmed virologic failure occurred in the injectable group (1.9%), there were significantly fewer episodes of VL >1000 copies/mL, demonstrating some virologic superiority of injectable ART.	IMPAACT 2040 [49]: PK/safety of CAB/RPV-LA Q4W and Q8W in pregnancy. Up to 45 pregnant women (and their infants)—including 25 in the Q4W switch group and 10 in the Q8W continuation group	CUSTOMIZE (USA) [50]: Evaluated the implementation of CAB + RPV-LA across diverse healthcare settings in the United States. CARISEL (EU) [51]: Feasible clinic integration with high viral suppression and staff acceptability. Limited use in pregnancy pending safety data.

*Studies closed prematurely

Cabotegravir for PrEP

The HPTN 084 trial demonstrated CAB-LA’s high efficacy in preventing HIV among 3,224 young women in sub-Saharan Africa [6]. Originally, in the main trial, participants newly diagnosed with pregnancy during study follow-up were required to stop CAB-LA and switch to daily oral emtricitabine / tenofovir disoproxil fumarate. The introduction of the open-label extension (OLE) in 2022 allowed these women to continue CAB-LA through pregnancy and breastfeeding under close monitoring. Early data from HPTN 084 OLE confirmed CAB-LA’s safety and efficacy in pregnancy [33]. Among 3,845 person-years, 57 pregnancies occurred (30 CAB-LA, 27 TDF/FTC; 1.5 per 100 py) [33]. Median CAB-LA exposure before pregnancy was 342 days. Maternal adverse event rates and pregnancy outcomes were similar between groups, with no congenital anomalies reported. CAB’s half-life in pregnant women was comparable to non-pregnant women, with no link to pregnancy or BMI [52]. Importantly, no new HIV infections were reported during pregnancy and breastfeeding.

While the 2024 U.S. Antiretroviral Pregnancy Guidelines still classify CAB-LA in pregnancy and breastfeeding as investigational, anticipated data from the HPTN 084 OLE, PrIMO, and Tshireletso studies are expected to inform future updates [33, 34, 37]. In high HIV prevalence settings—and the context of individual HIV exposure risk—there exists ethical grounds to continue CAB-LA for women newly diagnosed with pregnancy, so long such decisions are informed and clinical monitoring is continued [22, 30, 37, 53].

Lenacapavir for PrEP

Early evidence on the safety of LEN during pregnancy and breastfeeding is promising, with no significant concerns identified to date [35]. The PURPOSE 1 trial, was uniquely designed to gather data during these periods by not requiring contraception and allowing participants who became pregnant to continue in the study with informed consent [3]. Among 2,140 participants receiving LEN, 193 pregnancies occurred in 184 individuals. Of the 105 pregnancies with known outcomes, there were 52 live births and 53 losses, including elective terminations, spontaneous abortions, and stillbirths [35]. Maternal adverse events were uncommon, with gestational hypertension and hyperemesis gravidarum being the most frequently reported with none deemed related to LEN administration. A single minor congenital anomaly—polydactyly—was reported in an infant whose mother received LEN; the condition was consistent with a family history. No HIV infections occurred among pregnant or breastfeeding participants. Pharmacokinetic data showed no significant differences in LEN exposure by pregnancy status, and while the drug was present in breast milk, infant exposure was minimal [35]. These initial findings support LEN as a safe, effective and well-tolerated HIV prevention option for pregnant and breastfeeding women. Nonetheless, further research and safety monitoring during pregnancy are necessary to detect uncommon maternal and infant outcomes, especially rare adverse events, through expanded PrEP surveillance efforts or antiretroviral pregnancy registries.

Cabotegravir + Rilpivirine for Treatment

The original efficacy trials for CAB/RPV-LA treatment maintenance (i.e., the FLAIR and ATLAS studies) excluded pregnant women at time of enrolment. Those who conceived during study follow-up were switched to oral ART [4, 5, 46]. As such, the clinical data to date about CAB/RPV-LA in pregnancy has been limited to short reports and case series. An analysis of pregnancy outcomes following CAB and RPV-LA exposure at conception, for example, reported 10 live births, including one with a congenital anomaly. Plasma CAB and RPV-LA washout levels during pregnancy remaining within the range observed in non-pregnant women [54]. A multicentre retrospective chart review of 23 pregnant women prescribed CAB/RPV-LA in the U.S. (2021–2024) demonstrated high rates of viral suppression and normal birth outcomes, particularly among those exposed prior to conception, though the sample size was small [52]. CAB and RPV-LA persist for months, with levels similar to non-pregnant adults [5]. A 2024 case report showed stable CAB levels but a 70–75% drop in RPV-LA, though virologic suppression was maintained and the infant was born uninfected with no abnormalities [56]. Placental transfer was noted, but no safety concerns emerged. Given the potential impact of pregnancy on RPV-LA levels, IMPAACT 2040/CREATE is studying CAB/RPV-LA in pregnancy and breastfeeding periods [49].

Until more data are available, guidelines advise against starting CAB/RPV-LA in pregnancy, with some experts recommending a switch to oral ART if pregnancy occurs. However, for women struggling with adherence, continued injections with monitoring may be an option. No teratogenic signals have been observed and animal studies show no reproductive toxicity.

Adoption of LAI Formulations in Pregnancy and Breastfeeding in a New Era

Since the approval of LAI-based ART in 2021, there has been a steady increase in the usage of these regimens in the U.S. In contrast, in low- and middle-income country settings, the availability of LAI formulations remains largely in research settings, especially for pregnant and breastfeeding women. Fortunately, policies are evolving.According to the latest WHO guidelines, current evidence supports the continued use of any approved PrEP options—including CAB-LA and LEN—during pregnancy and breastfeeding for HIV-negative women at substantial risk of HIV exposure [22] [57]. The decision to initiate, maintain or stop PrEP during pregnancy should be made by the individual in consultation with a healthcare provider, based on a shared understanding of potential risks and benefits.For treatment, CAB/RPV-LA lacks regulatory approval in pregnancy from agencies such as the U.S. Food and Drug Administration and European Medicines Agency. Most guidelines currently recommend a switch to oral ART with a new pregnancy, though some women have continued LAI these formulations after counseling [54]. Breastfeeding data are minimal and guidelines remain cautious. However, several upcoming trials could reshape recommendations, ensuring that pregnant and breastfeeding women are included in this new era of HIV prevention and treatment. Given their longer half-life and mode of administration, LAI antiretroviral drugs offer many advantages during pregnancy and breastfeeding [32].

In HIV treatment, injectable antiretroviral drug regimens can improve HIV outcomes by removing the need for daily adherence [58]. This addresses a known barrier to HIV treatment in the breastfeeding period, where as many as 30% of new mothers experience viral rebound while on oral regimens [59]. Integrating long-acting regimens into antenatal and postnatal care (i.e., use of oral antiretroviral therapy regimens during pregnancy, but switching to CAB/RPV-LA following delivery) could sustain maternal viral suppression and further reduce vertical transmission​ [60, 61]. Modeling studies suggest that switching to CAB/RPV-LA for HIV treatment in high-prevalence settings could offer significant benefits. However, for it to be cost-effective, its use may need to be strategically targeted to individuals with HIV who are at risk of poor adherence to oral antiretroviral therapy [62, 63]. One study evaluated CAB/RPV-LA in 35 people living with HIV who had challenges with adherence to oral therapy, with most achieving or maintaining virologic suppression [64]. One participant became pregnant twice while continuing CAB/RPV-LA therapy, contributing to limited but important data on use during pregnancy.

In the realm of HIV prevention, LAI antiretroviral formulations provide lengthier PrEP coverage during periods (i.e., pregnancy and breastfeeding) known to have increased HIV exposure risk [65]. Given the inherent difficulties in identifying at-risk exposures—as well as sociocultural norms that may limit a women’s ability to initiate daily oral PrEP in a timely fashion [9, 32, 66], —such formulations can have important individual and population effects. A modeling study in South Africa, for example, found that provision of CAB-LA to at-risk pregnant and breastfeeding women could reduce new maternal HIV infections by 41%. This, in turn, could reduce vertical HIV transmission by 30%​ [32].

Despite their promise, several challenges hinder the broader use of LAI formulations in pregnancy and breastfeeding. First, the evidence base has lagged. Pregnant and breastfeeding women are often excluded from pivotal trials of new agents, a practice that can lead to significant delays in safety and dosing data. Regulatory and guideline barriers further slow access, as pregnant and breastfeeding women are often excluded from product labeling and national guidelines pending formal data, even when accumulating evidence is favorable, as observed with CAB-LA PrEP [22, 57]. New paradigms are emerging that engage pregnant and breastfeeding women at earlier stages in product development and testing, based on ethical principles [31, 67]. The design of PURPOSE 1, for example, did not require women to be on contraception at time of study entry, an otherwise common requirement for such clinical trials. Instead, women were counseled about the potential risks and benefits of use and, if they became pregnant over the course of study follow-up, they were reconsented and permitted to continue the study agent [3]. In this manner, PURPOSE 1 generated valuable data about LEN in pregnancy and breastfeeding while setting a strong precedent for future studies [35]. From a practical standpoint, such study designs are particularly relevant for long-acting agents since, depending on the drug half-life and timing of last administered dose, ongoing exposures can last through much of fetal development and growth [68].

Second, the acceptability of LAI antiretroviral drugs should be carefully considered. While long-acting regimens present greater convenience and privacy, there may be lingering concerns about the duration of exposure per dose and resulting side effects and fetal exposure [69]. These views are consistent in long-acting contraceptives, such as Depo- Provera, where side effects, stigma, and lack of autonomy can limit uptake [70]. In such settings, comprehensive counseling about benefits and risks of LAI antiretroviral drugs is essential. An important component of such messaging is patient choice [71, 72]. The ability to identify and select the best-suited regimen—whether for HIV treatment or prevention—is a consistent theme across acceptability studies [73]. New approaches are needed to support medical decision-making. Shared decision-making models for PrEP, for example, hold tremendous promise and can lead to better self-efficacy, satisfaction, and adherence [74, 75]. The delivery of such counseling is also important. Researchers in the U.S. found that a universal patient education approach led to greater interest in LAI ART regimens, when compared to a selective education model [76]. How feasible such models are in high HIV prevalence settings require further consideration, particularly in the context of resource constraint.

Finally, for all their advantages, cost may represent a major barrier to the widespread use of LAI antiretroviral drugs globally. CAB-LA, for example, has been shown to be cost-effective for HIV prevention across numerous studies [77]. However, its budgetary impact is high, particularly for the low-resource settings where HIV burden is highest. Analysis of the HPTN 083/084 data found that, for South Africa, cost for CAB-LA would need to be $63–101 per person per year (pppy) to meet or exceed the cost-effectiveness of daily oral PrEP with emtricitabine/tenofovir disoproxil fumarate (a formulation with generic formulation that is produced at high volumes for HIV treatment) [78]. The current estimated cost for CAB-LA is as much as $22,200 pppy, over 200 times this threshold [77]. Similar studies are not yet available for LEN, but its annual cost is estimated at $25,395 to $44,819 pppy [79]. Analysis about its production suggests that these yearly costs could be as low as $41–94 pppy (depending on volume of production) were voluntary licensing secured by multiple suppliers [79].LEN may be cost-effective if priced below key thresholds, particularly under US$ 500 per DALY averted [80, [81]. In South Africa, studies estimated cost-effective prices ranging from US$ 106–225 pppy, depending on population targeting and coverage [80–82]. In lower-prevalence areas like western Kenya and Zimbabwe, feasible prices were much lower—US$ 10–42 pppy [80, 81]. One model in Zimbabwe found long-acting PrEP for female sex workers most cost-efficient at US$ 1081 per infection averted [83]. Key cost-effectiveness drivers across models included LEN price, delivery costs, adherence and targeting by HIV risk [80–82]. In addition,sustainability of these regimens are further threatened by the changes in donor support to HIV programs globally, especially in Africa.The dramatic down-scaling of U.S. foreign assistance has fostered new urgency around the funding of comprehensive HIV prevention and treatment services worldwide [84]. This includes the accessibility and availability of these innovative and effective LAI agents.

Conclusions

LAI antiretroviral drugs represent a frontier in HIV care for pregnant and breastfeeding women, with potential to transform prevention and treatment paradigms [26]. However, new approaches are needed to address long-standing challenges. Regulatory reforms are required to expedite trials and approvals in pregnancy, avoiding delays like those seen with initial dolutegravir roll-outs​ [85]. New implementation strategies are needed, including integration into maternal and child health platforms and differentiated service delivery models. Sustained funding is critical amid global uncertainties [86, 87]. There is a moral imperative to equitably include pregnant and breastfeeding populations in the long-acting antiretroviral drug revolution​—both in research and access—with an emphasis on equity and justice. Such advances will ensure that long-acting agents like CAB-LA, LEN and CAB/RPV-LA can deliver on their promise to safeguard mothers and infants in the decades ahead.

Key References

• Bekker LG, Das M, Karim QA, et al. Twice-Yearly Lenacapavir or Daily F/TAF for HIV Prevention in Cisgender Women. N Engl J Med. 2024;391(13):1179–1192. 10.1056/NEJMoa2407001.

• • Randomised trial that demonstrated efficacy of Lenapavir among cisgender women.

• Orkin C, Arasteh K, Górgolas Hernández-Mora M, et al. Long-Acting Cabotegravir and Rilpivirine after Oral Induction for HIV-1 Infection. N Engl J Med. 2020;382(12):1124–1135. 10.1056/NEJMoa1909512.

• • Trial on long-Acting Cabotegravir and Rilpivirine after Oral Induction for HIV-1 Infection.

• Patel P, Ford SL, Baker M, et al. Pregnancy outcomes and pharmacokinetics in pregnant women living with HIV exposed to long-acting cabotegravir and rilpivirine in clinical trials. HIV Med. 2023;24(5):568–579. 10.1111/hiv.13439.

• • A study highlighting some initial data on pregnancy outcomes and pharmacokinetics among pregnant women living with HIV exposed to long-acting cabotegravir and rilpivirine.

• Delany-Moretlwe S, Hughes JP, Bock P, et al. Cabotegravir for the prevention of HIV-1 in women: results from HPTN 084, a phase 3, randomised clinical trial. Lancet Lond Engl. 2022;399(10337):1779–1789. 10.1016/S0140-6736(22)00538-4.

• • Randomised trial that demonstrated efficacy of Cabotegravir among cisgender women.

Author Contributions

FS, MCH and BHC wrote the manuscript. All the authors have reviewed and approved the final manuscript.

Funding

FS and MH’s time was supported the Eunice Kennedy Shriver National Institute of Child Health and Human Development (P01 HD112215). BHC’s time was supported by National Institute of Allergy and Infectious Diseases (K24 AI120796, P30 AI050410). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Data Availability

No datasets were generated or analysed during the current study.

Declarations

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Competing Interests

The authors declare no competing interests.