Improving preparedness for introducing and scaling up long-acting HIV pre-exposure prophylaxis in Asia

Introduction

Oral HIV pre-exposure prophylaxis (PrEP) is highly effective,^1,2 and use has substantially grown over the past decade.^3,4 However, its impact on reducing new HIV infections, particularly among key populations, has been limited due to challenges, such as limited awareness, availability, accessibility, uptake, effective use, adherence and stigma.⁵ New PrEP products have been developed, including long-acting formulations.⁶ The long-acting injectable form of cabotegravir (CAB-LA), administered via intramuscular gluteal injection every 8 weeks, was proven highly efficacious in randomised controlled trials involving men who have sex with men, transgender women and cisgender women.^7,8 CAB-LA was recommended by the World Health Organization (WHO) as an additional HIV prevention option in 2022.⁹ CAB-LA has the potential to attract more people to HIV prevention services and support persistence on PrEP, including those experiencing burdens associated with regular pill-taking, or who prefer injections for convenience or discretion.¹⁰

A roundtable discussion, organised by Institute of HIV Research and Innovation with support from the WHO, United States Agency for International Development and FHI 360, on research and implementation considerations for CAB-LA and other long-acting PrEP options in Asia was held in June 2023 in Singapore. Attendees included 29 representatives from seven countries in Asia working in community-based organisations, universities, international non-government organisations, the pharmaceutical industry, Joint United Nations Programme on HIV/AIDS and WHO. We reviewed and discussed the following topics: overview of the long-acting PrEP pipeline, as well as global and regional CAB-LA implementation progress; real-world experience in demedicalising long-acting injectables; implementation science studies planned globally and in Asia; and potential learnings between Asia and Africa. The discussions were focused on building a set of recommendations towards accelerating preparedness for long-acting PrEP introduction in the areas of research and implementation science, product licensing and accessibility, and capacity to scale up following introduction.

Attendees strongly agreed that long-acting PrEP, and CAB-LA specifically, offers opportunities to increase PrEP scale up. Recent research demonstrates considerable interest in such options among key populations, with the PrEP APPEAL study across 15 Asian countries showing a large unmet need for PrEP,¹¹ and that 40% and 39% of men who have sex with men and transgender women, respectively, were interested in long-acting injectable PrEP.¹² Although approximately 30 implementation projects involving CAB-LA were being planned (including in Thailand, Vietnam and Australia, and more recently, Cambodia and the Philippines), none had yet commenced. Avoiding long delays between efficacy evidence and scale up is a critical priority for CAB-LA and all new long-acting products, especially in Asia, where oral PrEP uptake has been slow and lags behind other regions.¹³ We present here a call-to-action for better preparedness in long-acting PrEP in three main areas that will accelerate the introduction and scale up of long-acting PrEP: (1) research and implementation science, (2) product licensing and accessibility, and (3) capacity for scale up.

Research and implementation science preparedness

We are now in an era of increasing PrEP choices. Preventing unnecessary delays between efficacy trials and implementation is essential in maximising the use of new PrEP products and reducing HIV incidence. Despite being recommended by the WHO and receiving regulatory approval from an increasing number of countries, there are several outstanding evidence gaps for CAB-LA implementation that must be urgently addressed, including HIV testing algorithms, service delivery models and targeting populations for greatest impact.^14,15 Stakeholders should be engaged early (including communities, regulatory agencies, generic manufacturers, clinicians and policymakers) to ensure that relevant and comprehensive research questions and methodologies are developed in a timely manner. It was strongly suggested that regional coordination across Asia and Australasia could help to focus research on questions that may have broader applicability than to a single, specific upcoming product, such as CAB-LA, or to a specific location, and could reduce duplication, and increase research power, usefulness and efficiency.

To June 2023, only one country (Australia) in the Asia–Pacific region had CAB-LA PrEP regulatory approval. Without regulatory approval, implementation research must be conducted under clinical trial frameworks, typically involving higher costs and resource requirements. However, there are also a range of research questions that can be explored, even while waiting for regulatory approval and access to new products, such as further research on preferences about PrEP¹² and various implementation questions (Box 1).

Product licensing and accessibility preparedness

Oral PrEP implementation and scale up are continuing at a slow pace in Asia,¹³ and CAB-LA is likely to face similar delays. There are several critical barriers to the prompt introduction of new products. First, manufacturers may prioritise implementation projects (including research trials) in settings with regulatory approval for the new product. However, regulatory approval can be slow, and relies on manufacturers prioritising submissions in each country, which means ‘low priority’ countries can miss out. Second, manufacturing capacity for new products takes time to scale up, and is governed by complex regulation. CAB-LA can be used for both PrEP and treatment, which puts pressure on manufacturing capacity. Third, even with regulatory approval and access to drugs, it takes time to develop local legal and policy frameworks (e.g. procurement and importation).

As new long-acting products emerge, it is imperative that more efficient approaches to regulatory approval, manufacturing and legal frameworks are developed and supported, utilising multi-country or regional mechanisms where available. This should involve countries further behind in PrEP scale up rather than focusing only on countries that are already progressing well. CAB-LA is being considered under a formal joint assessment procedure, where the same application is simultaneously submitted to participating Association of Southeast Asian Nations national medicines regulatory authorities. Countries can opt into this procedure. It involves a handful of countries, but does not currently include critical countries, such as Indonesia, and cannot include non-Association of Southeast Asian Nations countries.

Even with regulatory approval, manufacturing scale up and production by generic manufacturers, price will remain an impediment to new long-acting PrEP products. The price of new products, such as CAB-LA, will need to be low to be considered cost-effective,¹⁶ and modelled prices may be too low to be acceptable to manufacturers. The Medicines Patent Pool mechanism, although beneficial to lower-to-middle income countries, does not apply to all nations.¹⁷ The current purchasers of PrEP in many lower-to-middle-income countries are the Global Fund and President’s Emergency Plan for AIDS Relief. Although this is welcome, it is only a short-term solution, and several countries in Asia with sizeable key populations are middle-income countries and are not eligible for reduced pricing. High-income countries/territories in Asia are far behind in oral PrEP scale up (e.g. Singapore, Japan, South Korea), and this is likely to continue for new products. In these countries, costs of oral PrEP have stayed high and there is no sign of them decreasing. These countries cannot gain access to generic medicines or large donor programs. Governments not supportive of key populations are unlikely to be motivated to provide new PrEP products at scale or negotiate reduced prices with manufacturers, leaving key populations not being able to afford the high local costs.

Capacity preparedness and scale up

There are a range of issues pertaining to the service-level capacity for new long-acting PrEP products and, in particular, CAB-LA. There are major concerns about clinical and organisational capacity to deliver injection-based services within existing resources and infrastructure.^10,14,18 Currently, CAB-LA requires injections every 8 weeks, compared with the recommended 12-weekly visits for oral PrEP users; injections must be delivered by a trained healthcare worker during the visit, which has the potential to add more time to visits and restrict the capacity of non-clinicians to provide the service; and follow-up visits must be monitored more closely than for oral PrEP, and may require active follow up, given the strict 2-week window for on-time injections. Some of these concerns may be alleviated over time. For example, in our roundtable discussion, it was noted that in the US experience of CAB-LA rollout, 30 min were initially allotted for injections, but the average time had reduced to approximately 5 min.

Options for task-shifting have been utilised in the US, such as involving nurses or pharmacists. It was agreed that implementation of CAB-LA at-scale will not be possible in Asia without task-shifting. However, local policies and regulations can present barriers. In Thailand, community pharmacists cannot give injections, and regulations prevent them from having private rooms. Many pharmacists may not feel comfortable taking a sexual history or facilitating HIV testing. Furthermore, in Thailand and Vietnam – the settings of Asia’s two most successful PrEP programs – lay providers have been a cornerstone of PrEP services. In 2021, 82% of PrEP users in Thailand received PrEP from lay providers at key population-led services.¹⁹ Key population-led services may not have clinical staff onsite to deliver injections, thereby limiting the accessibility of CAB-LA. Attendees felt that there is likely to be pushback from medical societies and Ministries of Health against lay providers giving CAB-LA injections. Consequently, injectable PrEP may represent a re-medicalisation of PrEP services after considerable efforts towards de-medicalisation.²⁰ Attendees were worried that the argument for the importance of key population-led services may need to be made with overcautious governments and donors all over again. Meanwhile, resources and time may be wasted attempting to implement injectable PrEP in government clinics that are less acceptable to already-stigmatised key populations, and unable to provide the high-volume services necessary to support scale up. Successful community-led models of PrEP service delivery must not be undermined by the introduction of promising new PrEP products. Implementation science projects will be needed to explore these concerns.

Conclusion

The emergence of long-acting PrEP options, including CAB-LA, presents opportunities to enhance HIV prevention efforts in Asia and beyond. However, to maximise the impact of these innovations, challenges related to research preparedness, product licensing and accessibility, and service-level readiness and capacity must be addressed. Collaborative efforts involving diverse stakeholders, including communities, regulatory agencies, healthcare providers, policymakers and industry, are essential. The urgent need for streamlined regulatory processes, cost-effective pricing and thoughtful implementation strategies must not overshadow the vital role of community-led PrEP services in providing accessible and stigma-free HIV prevention options. By navigating these complex issues collectively, these ground-breaking advancements in HIV prevention can reach those who need them most, in a timely manner, and ultimately bring us closer to ending the HIV epidemic in Asia.