The introduction of new antiretroviral-based HIV prevention methods into health systems: key issues

Effective eradication of sexually transmitted diseases crucially requires the provision of drugs and biomedical products for the prevention and treatment of infection. Traditionally, private sector pharmaceutical companies have lacked sufficient profit incentives to develop new drugs and medical products to prevent sexually transmitted diseases, which disproportionately affect developing countries. This is because, “development of new drugs is expensive, lengthy, complex and risky, with most new compounds only reaching patients after a 10–12 year development process”.¹

In response to this market failure a new type of organisation was created to develop life-saving products considered commercially unviable for countries with high disease burdens. These organisations are categorised as Product Development Partnerships, which are “non-profit organizations with mandates to research, develop and support accessibility of new health technologies that target diseases disproportionately affecting developing countries”.² Their research portfolios have been supported by public sector donors, including development ministries from Organisation for Economic Co-operation and Development, member countries and private foundations.

In the field of research on biomedical prevention of HIV infection, the Product Development Partnership model has been beneficial, e.g. in the development of vaginal microbicides. Clinical research on the use of certain antiretrovirals for HIV prevention, which have been highly effective in managing HIV progression, has also been supported through partnerships between academic and public research funders. Donors for biomedical research in HIV prevention have become increasingly concerned about cost-effectiveness, however. In the current economic climate, these methods, which are still in development, including pre-exposure prophylaxis (PrEP), are facing constraints to complete the requisite safety and efficacy trials and regulatory processes. And this is before even greater challenges down the line are taken into account – in how health service delivery of these methods will be financed, through which services, and to whom in the population.

With intense pressure to develop these products, the onus cannot be on Product Development Partnerships or other research partnerships alone to ensure community level access and uptake. There is an urgent need for health systems financing to prime the appropriate services needed for their effective introduction. Health policy makers in countries will need to assess health system readiness to provide antiretroviral-based microbicides, pre-exposure prophylaxis (PrEP) and the use of antiretrovirals for prevention of HIV transmission as well as for treatment, alongside condoms and male circumcision. They will also need to decide whether these prevention modalities should be delivered in the same programmes as treatment, care and support for people living with HIV and/or elsewhere within the health system, such as sexual health clinics, or maternal health, family planning and abortion clinics.

Health policy makers will also need to determine how to manage user access. Importantly, this will include ensuring greater uptake of HIV testing and counselling, in order to determine eligibility for using these prevention methods, since there are still millions of people who do not know their HIV status. People who are HIV negative are the ones for whom microbicides and PrEP will be valuable; they have no preventative effect for people already living with HIV. Early uptake of antiretroviral treatment is now considered an effective prevention option for people living with HIV who seek a protective benefit for uninfected partners. And while vaginal microbicides have been developed primarily for women of reproductive age who are at high risk of HIV infection, to get round their inability to negotiate condom use, it is not clear whether successful strategies to overcome their limited access to and uptake of HIV testing and counselling will be forthcoming in access planning.

Recent research results

Proof of concept has been established that a microbicide containing 1% of the antiretroviral tenofovir in a topical vaginal gel could decrease the risk of HIV infection by 39% in women who used the gel consistently. These results, of the CAPRISA 004 trial, were released in July 2010.³ The euphoria around these results was somewhat dampened when reports emerged that the funding required to run a confirmatory trial had not been forthcoming.⁴ Sufficient funds were later leveraged, however, and that trial is now underway. Subject to results, it is estimated that this microbicide gel could receive regulatory approval in South Africa and be introduced there within two years.

US and European regulatory approval for the use of tenofovir gel are also being pursued. National regulatory approval for use in other countries in Africa and elsewhere may be required before the gel can be introduced in each country. WHO will develop guidance on use of tenofovir gel and will begin to disseminate it as soon as the first regulatory approval is granted. Development of other microbicide formulations is ongoing, including an advanced study of the efficacy of a monthly vaginal ring containing the antiretroviral dapivirine, which could at a later stage be combined with contraceptive hormones as a dual contraception/HIV prevention method.⁵ Other gel-based microbicides with a daily dose regimen are in development as well, along with forms of delivery such as vaginal film and pessaries.

Positive results of the efficacy of antiretrovirals to prevent HIV infection have also emerged in the last year. In December 2010, the iPrEx study showed that the antiretroviral combination emtricitabine and tenofovir reduced the risk of HIV infection in men who have sex with men by 44%.⁶ The July 2011 results of the Partners PrEP study demonstrated that pre-exposure prophylaxis with emtricitabine and tenofovir or with tenofovir alone reduced the risk of HIV infection by between 62% and 73%.⁷ The TDF2 study also showed that pre-exposure prophylaxis with emtricitabine and tenofovir reduced the risk of infection by between 62% and 78%.⁸ Then, in May 2011, the HPTN 052 study showed that early uptake of antiretrovirals for treatment reduced the risk of HIV transmission to an uninfected regular partner by at least 96%, a research outcome with the most relevance as a prevention option for people living with HIV.⁹

World Health Organization publication. In press, 2011

Provision and uptake of these new methods

The priority of health policy makers should be on determining which communities will benefit from the introduction of these different prevention methods and analysis of the most effective delivery mechanisms to have epidemiological impact. These considerations cannot be divorced from the reality of existing health system inefficiencies. Plans for how to prepare health systems for delivery of these methods need to be in place well before the products are ready. Any further development of “siloed” services, as was seen when HIV treatment services were initially introduced, is undesirable. Instead, it will be crucial to integrate these methods as essential commodities within existing sexual and reproductive health and HIV services.

The CAPRISA 008 study is testing the introduction of tenofovir gel through family planning clinics providing injectable contraceptives in KwaZulu-Natal, South Africa. This study will compare the monthly HIV testing and follow-up approach, used in the original CAPRISA 004 study, with a three-monthly HIV testing and follow-up schedule, to begin to provide information about implementation, demonstrating how tenofovir gel can be provided and monitored and determine the feasibility and acceptability of providing a microbicide through existing health services used by sexually active women.

There are concerns that outside the conduct of a clinical trial, real world scenarios often do not provide sufficient coverage to have an impact. Many of the methods in development could best be channelled through youth-friendly sexual health and family planning services to reach adolescents and young adults. Reliance on antenatal care, which has to date been the main clinical setting for HIV testing and counselling of reproductive age women, is less than ideal for provision of HIV prevention methods, as young people require information and methods before they have established unprotected sexual behaviours.

Family planning services are an ideal setting to conduct HIV counselling and testing for women, review risk factors to make sure that they understand how they could benefit from using a microbicide gel or vaginal ring, promote positive attitudes towards vaginal insertion of methods, and instruct on usage and dosing. The regimen with the tenofovir gel used in CAPRISA 004 is to apply the gel before sex, apply it again after sex and not use more than two applications in 24 hours. Initial counselling and follow-up will be important, to ensure correct use and adherence. The longer-lasting vaginal ring, which releases the antiretroviral drug steadily over a month, will be able to be self-inserted, with clinical follow-up to obtain new rings and discuss adherence.

Innovative ideas about where else microbicides and other antiretroviral prevention products could be introduced include immunisation centres, e.g. those working to deliver HPV vaccination, and school-based health services, particularly to capture adolescents. Establishing and expanding comprehensive sexuality education in schools to provide information on HIV prevention commodities would require careful negotiation, as this has not been much witnessed in national responses to HIV due to sensitivities about adolescent sexual relationships.

Obviously there are already established routes to access antiretrovirals as treatment – through formal health systems as well as informal means. There are perceptions that oral PrEP will become a popular – if not the dominant – form of HIV prevention as women (and men) may consider taking antiretroviral pills for prevention of transmission, as more user-friendly than a vaginal product (or condoms).

Thus, the introduction of oral PrEP would benefit from existing formal access channels. Evidence of under-the-counter and off-prescription purchasing, as well as sharing of drugs within households and among social networks, already exists in many countries with antiretroviral treatment programmes. This potentially erratic form of access raises the spectre of resistance to antiretroviral compounds, which could occur unless HIV testing and counselling are secured as a prerequisite to drug availability.

Greater understanding of the need for good adherence and the consequences of potential resistance of all these products needs to be disseminated at community level. There is also a need for further evidence on whether or not the use of vaginal microbicides could lead to resistance. The CAPRISA 009 study, for which funding is still being sought, would provide care, treatment and monitoring for former CAPRISA 004 trial participants who became infected with HIV while in that trial. It will also seek to compare treatment outcomes for those who receive combined antiretroviral treatment that includes tenofovir with those who receive combined antiretroviral treatment without tenofovir and apply findings to both prevention and treatment programming with tenofovir.¹⁰

A monthly vaginal ring containing dapivirine may be attractive, not only in terms of ease of use, but also because the antiretroviral it contains is not widely used for treatment, reducing the risk of resistance.

Key questions

Previous experiences of reproductive health commodities management demonstrate that donor and provider preferences for certain methods have obscured the uptake of other equally effective tools, and that these decisions have been based on resource considerations and what donors are willing to fund. There are several questions which will face decision makers at national level, as well as donors and product developers, in the context of the economic downturn and static or falling levels of global health financing for existing services and essential medicines:

•	Given that oral PrEP could be introduced through existing delivery systems for antiretroviral treatment, will there be sufficient motivation to complete the current research on vaginal microbicides and ensure their introduction and uptake into underfunded parts of the health system?
•	Are countries going to be in a position to provide all methods equally, factoring in the total cost of launch and promotion, training of health workers, provision and supply, measuring uptake, overcoming access issues, and ensuring effective use?
•	Will a dual-pronged approach for achieving national HIV reduction targets be used, which combines promotion of both antiretroviral prevention and treatment methods? Or will trade-offs be made due to the increasing resources needed to expand access to antiretrovirals for treatment, as against those needed for the introduction of the new prevention methods?
•	Would cost-effectiveness analysis demonstrating the long-term benefits of uptake of effective new prevention technologies help to make the case for accommodating them in national budgets for health commodities?
•	Finally, after research and development is complete, what will it take in a squeezed funding environment to channel resources into the most rational services for end users – especially young women?

Future perspectives and action

Determining the possible trajectory of different antiretroviral-based prevention methods should centre on analysis of national epidemic profiles, risk behaviours and community acceptance. Essential investments to address health system barriers which could prevent the maximum impact of new technologies are needed now. Existing inefficiencies should be analysed within the proposal development process of the Global Fund to Fight AIDS, TB and Malaria, the US President's Emergency Plan for AIDS Relief and other funders of HIV and AIDS services. Consistent leadership from UNAIDS, WHO and other multilateral partners is required to maintain a country-level focus on a “prevention revolution” to scale up access to existing and new HIV prevention methods and services, especially for young women.

Countries that decide to introduce antiretroviral-based microbicides, PrEP and early uptake of antiretrovirals as prevention into their HIV prevention programmes can take stock of their coverage of HIV testing and counselling and develop a scale-up plan, e.g. in applications for funding. Efforts to de-stigmatise HIV testing and achieve greater uptake could be helped by community-level understanding of effective prevention methods and the promise of new prevention technologies.

The promise of vaginal microbicides for HIV prevention has been that they will fill a gap in existing prevention methods and introduce a safe and effective woman-initiated method. The next few years will determine whether the introduction of microbicides will stimulate greater investment to enhance the ability of youth-friendly reproductive health and family planning services to deliver these new technologies.

Health policy makers should take stock of recent commitments, particularly those made by the UK and US governments, to increase financing of family planning and suggest where their health systems might benefit from greater investment. Countries cannot afford to wait until these products are market ready before user-centred plans and robust systems are put in place to deliver the promise of microbicides and other forms of antiretroviral prevention into the hands of those who need them the most.