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Before HIV treatment was available, prevention focused on ABC: ‘Abstinence, Be Faithful, or use Condoms‘. This paradigm had its limitations, and HIV prevention programmes have since refocused their strategies. There is greater recognition of the heterogeneity of the epidemic in sub-Saharan Africa and among various vulnerable ‘key populations’ around the world. New prevention strategies include voluntary medical male circumcision (VMMC) and ‘treatment-as-prevention’ (TAP). Unfortunately, an effective vaccine, the holy grail of HIV prevention, is not yet on the horizon.
Pre-exposure prophylaxis, or PrEP, is a new and highly effective prevention method. In this article, we will discuss what PrEP is, what its efficacy and effectiveness is, and how trials and demonstration studies impact PrEP provision. We also share some prospects of PrEP provision in sub-Saharan Africa (sSA).

What is prep?

Pre-exposure prophylaxis entails taking anti-microbial or antiviral drugs before the exposure to the microbe or virus has occurred. Prophylaxis against malaria with antimalarials is the best known example of this approach. For HIV, the concept dates back at least 15 years, when animal experiments with a new generation of antiretroviral medicines suggested that new antiretroviral medicines could prevent HIV acquisition.

PrEP can be topical or systemic. Vaginal microbicides, to be applied prior to sexual intercourse, are a topical form of PrEP. Various topical products have been examined in phase 2 and phase 3 studies. By and large, these products have been disappointing. Some did not work at all, while others did work but adherence was low. Topical products are presently not rolled out as public health interventions.

Systemic PrEP is the oral or intramuscular administration of antiretrovirals (ARV). So far, only one ARV combination has been registered for use as PrEP: Emtricitabine/Tenofovir Disoproxil (FTC/TDF).

Oral PrEP can be taken on a daily basis (daily one tablet FTC 200 mg/TDF 245 mg), or on an on-demand basis. This latter option was demonstrated to be highly efficacious in one RCT [1] and in subsequent demonstration projects in Belgium, France, and the Netherlands. [2-4] This so-called ‘event-driven PrEP’ consists of two tablets of FTC/TDF between 2 and 24 hours prior to sex, and one tablet daily after sex for two days. If a person has sex on subsequent days, taking a daily dose continues until he or she has taken PrEP for two days following the last sex act. A phase I trial of intermittent dosing in men who have sex with men (MSM) conducted in Kenya in 2009-2010 showed that adherence to coitally-dependent doses may be more difficult than adherence to daily dosing. In a qualitative assessment, social impacts such as stigma, rumours, and relationship difficulties due to being perceived as HIV positive were prevalent, and adherence was challenged by complexities of daily life. [5]

What is the efficacy/ effectiveness of prep?

In the various efficacy trials conducted over the past 10 years, HIV protection was directly proportional to adherence in the trial population. The first trial (iPREX), conducted among MSM and transgender women, showed a promising protective efficacy of 46%.[6]

Some have postulated that the tissue levels of the drugs after oral administration are lower in the lower female genital tract than in the anorectal area, and that this might partly explain some of the reduced efficacy in women. Nevertheless, currently recommended dosing regimens are the same for men and women.

In studies with good data, almost all cases of incident HIV infections could be attributed to one of three reasons: (1) acute HIV infection at time of PrEP initiation, which was not detected by HIV tests at baseline; (2) low adherence; (3) stopping taking PrEP. In fact, the occurrence of an HIV infection in an adherent PrEP user is a rare event, and documented cases attract considerable attention. [7] Accordingly, current thinking is that efficacy is nearly 100% if PrEP is adhered to; break-through infections are due to non-adherence or pre-existing drug resistance, and not to an inherent lack of efficacy of FTC/TDF.

From efficacy trials to demonstration studies to prep roll out

A total of 98 demonstration studies, including 41 in sSA, are being conducted or completed.[8] These studies provide a strong impetus to PrEP roll-out in HIV prevention programmes. The World Health Organization (WHO) has issued guidelines on the use of PrEP. [9] The WHO recommends the use of PrEP in populations ‘at substantial risk of HIV’. Substantial risk was initially defined as populations with an HIV incidence of ≥3% (i.e. 3 infections in 100 HIV-negative people followed for a year). However, how to assess if a person belongs to a population with a substantial risk of HIV infection is a challenge. The Kenya PrEP programme illustrates this. It is providing PrEP free of charge and targets individuals who report any of the following: a sexual partner who is HIV positive or has unknown HIV status, transactional sex, a recent sexually transmitted infection (STI), recurrent use of post-exposure prophylaxis, having sex while under the influence of alcohol, inconsistent condom use, and injection drug use with shared needles and syringes. [10] Many individuals in Kenya who meet one or more of these criteria may have some risk of acquiring HIV, but should they take daily PrEP for sustained periods of time? Notably, current PrEP guidelines in Kenya do not specifically target known risk factors for HIV acquisition among MSM, including anal intercourse without the use of condoms and group sex, although Kenya has large populations of MSM.[11]

Prospects for prep use in sub-saharan Africa

Currently, PrEP programmes in sSA focus mostly on adolescent girls and young women (AGYW) and individuals in sero-discordant couples. Regarding the latter group: the partner newly diagnosed with HIV should start ART immediately, but as it may take up to 6 months before he or she is virally suppressed, the negative partner should be offered PrEP as a ‘bridge’ (i.e. for 6 months) until the HIV-infected partner is no longer infectious. To facilitate uptake of PrEP among AGYW, three key issues need to be addressed: create demand for PrEP, ensure supply of PrEP, and support adherence to PrEP. [12]

Prep and drug-resistance

If a person who is taking PrEP is exposed to an HIV strain that is resistant to either FTC or TDF or both, PrEP may not be effective. As resistance is not an all-or-nothing phenomenon, PrEP effectiveness may simply be reduced in such instances.

Initially, many in the HIV field were concerned that PrEP might lead to drug-resistance and therefore severely undercut therapeutic options in users and non-users alike. The roll-out of PrEP is still limited, and empirical data are not available to either prove or disprove this possibility. However, mathematical model studies have quite convincingly shown that it is highly unlikely that PrEP would lead to substantial additional drug-resistance in a population. [13,14]

Prep and condoms

The efficacy of oral PrEP against HIV is very high, and for those who have good adherence to PrEP the risk of acquiring HIV is very low. So if the aim is only to prevent HIV, condoms may not be needed to supplement PrEP. Unfortunately, other STIs like syphilis, gonorrhoea, herpes simplex disease, HPV and chlamydia are not prevented by PrEP.

PrEP use may lead to reduced condom use [15] – and thus indirectly lead to an increase in other STIs. This is clearly an undesirable side-effect of PrEP roll-out. In high-income countries with good testing facilities and enough funding for regular monitoring of PrEP users, testing for other STIs is part of such monitoring. In such programs, increased frequency of testing for STIs leads to increased detection and treatment of STIs, and may actually lead to a reduction in the incidence of STIs. [16] This may not be feasible in lower-income countries in view of the high costs of testing for gonorrhoea and chlamydia.

New developments

A large multicentre, multinational randomised controlled trial (DISCOVER trail) is underway to compare the efficacy of a new antiretroviral, Tenofovir Alafenamide (TAF), combined with Emtricitabine, against the use of FTC/ TDF. [17] TAF is already being used for the treatment of established HIV infection. It is as effective as TDF but at only 1/10 of the dose. As TDF has renal and bone side-effects, TAF may be preferable for HIV patients who suffer or may suffer from such side effects. As PrEP is given to healthy individuals, the safety of the drugs may be even more important, and fewer side effects make TAF/ FTC an attractive alternative to FTC/TDF. However, this has serious cost implications. The combination FTC/TDF is no longer on patent, and the current price for 30 tablets of FTC/TDF in the Netherlands is around €50; the current cost of 30 tablets of FTC/TAF is €533.

Another promising development is intramuscular administration of PrEP, or subcutaneous depots through a rod. This could be an attractive alternative for those who find daily tablet taking a challenge, or for those who do not want to be seen by household members or intimate partners taking tablets that are also used for HIV treatment.

Conclusions

PrEP is an important new prevention method that shows great promise for impacting the course of the HIV epidemic in both low- and high-income countries. Among the general population in sSA, there is a clear role for PrEP initiation in sero-discordant couples. However, as large numbers of new HIV infections will occur among vulnerable populations, including young girls and adolescent women as well as MSM and Transgender women, many of whom are often not engaged in current prevention programmes, the effects of PrEP may be limited in these groups in sSA. PrEP could potentially lead to a reduction in the use of condoms and an increase in the incidence and prevalence of other STIs.

References

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