The rate of HIV infection remains greater than the number of people initiating treatment. This imbalance will stop the eradication of HIV/AIDS. It begs for increased investment into primary prevention.
Primary prevention caters to people who are HIV negative. It aims to reduce their chance of becoming infected. There are certain populations, now referred to as key populations, in whom the burden of infection is disproportionately high. These include men who have sex with men, sex workers, people who inject drugs, transgender people, and, in sub-Saharan Africa, adolescent girls and young women. Primary prevention should be tailored, and scaled up, for these groups.
Primary prevention can be provided in a number of ways. But the most exciting new innovation is pre-exposure prophylaxis (PrEP). PrEP is the use of anti-retrovirals by HIV-uninfected people to prevent HIV transmission. It is commonly given as a daily pill (sold as Truvada) to be taken orally in the same way that contraceptives are used to prevent pregnancy or antimalarial pills are taken before travelling to a high malaria risk area.
Numerous clinical trials and demonstration projects in diverse settings and populations have been conducted with PrEP all showing that it works. PrEP is easy to take. It is also largely side effect free and safe. There is one hitch: it has to be taken consistently at the time of HIV exposure. Adherence has been oral PrEP’s biggest stumbling block.
That’s why a huge effort is being made to find alternative ways to take PrEP. New formulations in the pipeline include long-acting injections, monthly vaginal rings, implants and topical gels, films and dissolving topical pills. The hope is that new formulations will make PrEP more accessible and convenient, particularly for adolescents and young people who may find a daily intervention cumbersome.
Adherence is PrEP’s Achilles’ heel
Adherence is key. To block HIV transmission PrEP must be “in the system” at the time of HIV exposure. Its effectiveness decreases rapidly when this “effective coverage” is inconsistent. Good adherence gives almost 100% HIV transmission prevention. Poor adherence results in little to no protection.
This is why, where possible, a daily dose during times of risk is recommended. But this may be difficult to achieve for some.
In PrEP trials the following reasons were given for poor adherence:
fear/experience of side effects,
fear of interactions with alcohol and other drugs,
dislike of pill-taking, and
fear of the discrimination associated with taking an anti-HIV pill.
Alternative dosing strategies using longer acting formulations and PrEP delivery methods may well be another way to increase PrEP effectiveness.
New PrEP frontiers
Topical gels, which can be applied pre and post sex to rectal and vaginal tissue, were the first alternative formulations to be tested. But the results in women have been inconsistent. This formulation still holds promise in men who have sex with men although efficacy trials haven’t yet been conducted.
An alternative strategy is a monthly vaginal ring, which in its current form contains slow-release dapivirine (another antiretroviral). Two large phase III clinical trials have demonstrated that the ring is effective and can reduce the chance of HIV infection by 27%-31%. In a sub analysis of different ages, older women once again fared better than young women.
The benefit of the vaginal ring is that there are less side effects because the drug is released locally and only a small amount enters the blood stream. The other huge plus is that women are encouraged to insert and forget, only changing the ring on a monthly basis. The obvious catch is that this is only suitable for women and vaginal intercourse.
The vaginal ring is undergoing further investigation.
Another tool that is being investigated and could overcome the need for a daily pill is a long-acting monthly injection. An injection of the antiretroviral cabotegravir (cabotegravir LA) has been shown to be very effective at lowering viral loads in people being treated for HIV when administered every two months.
Also being investigated are dissolving vaginal films – a bit like the breath fresheners that can be bought over the counter – as well as quick dissolving pills.
Perhaps most exciting of all is the prospect of an implant, a small rod which can be surgically placed just under the skin and will be able to slowly release antiviral protection over months.
Finally, new formulations are currently being investigated that will combine treatment for both contraception and preventing sexually transmitted infections. It is hoped that these multifunctional preventions may further encourage people to consistently use these products.
A new challenge to the field is how these new clinical trials can be efficiently designed. To qualify for first-line use of PrEP, new pills and products will need to have improved or equivalent efficacy compared to the current oral PrEP. And they would need to have reduced or equivalent side effects. All these formulations and delivery methods are still in the early stages of testing, but look to be out on the market within the next two to five years depending on their success.
PrEP for Africa
In sub-Saharan Africa, teenage girls and young women are most at risk of HIV infection. There are 2000 new infections in this group every week. These women are vulnerable because of the high prevalence of both gender-based violence and the commonality of age-disparate relationships and transactional sex. These conditions can make it difficult for women to negotiate safer sex practices. PrEP would enable these women to protect themselves in advance, without their partner’s knowledge or consent.
Kenya and South Africa are the only two African countries that have granted regulatory approval for PrEP. Neither have started to roll it out.
New interventions can only be useful if deployed and scaled up to the populations most in need. This raises questions of cost versus impact. It is hoped that new formulations and delivery systems will enhance choice, encourage use, and provide a platform from which PrEP roll out can be advocated.