PrEP: preventing HIV infection without a vaccine

Forty years after the iden­ti­fic­a­tion of the Human Immun­ode­fi­ciency Vir­us (HIV), respons­ible for Acquired Immun­ode­fi­ciency Syn­drome (AIDS), the HIV pan­dem­ic has still not been stopped. More than a mil­lion people are infec­ted each year world­wide¹ and, in France, around 5,000 people a year are dia­gnosed as HIV-pos­it­ive². We still don’t have an effect­ive vac­cine against HIV. But did you know that, in addi­tion to con­doms, there is a pre­ven­tion meth­od that is over 90% effect­ive? It has been avail­able free of charge in France since 2016?

Known as pre-expos­ure pro­phy­lax­is, or PrEP, the prin­ciple is simple: take anti­vir­al treat­ment before poten­tial expos­ure to HIV, to pre­vent infec­tion by the vir­us. The first data con­firm­ing the effect­ive­ness of this approach date back to 2010, via two stud­ies. In the CAPRISA 004 tri­al, con­duc­ted in South Africa, a vagin­al gel con­tain­ing teno­fo­vir (a com­pound that inhib­its the HIV reverse tran­scriptase enzyme, essen­tial to the vir­us func­tions) was tested in 889 young women³. In the iPrEx tri­al, con­duc­ted in six coun­tries, tab­lets con­tain­ing a com­bin­a­tion of teno­fo­vir and anoth­er reverse tran­scriptase inhib­it­or, emtri­cit­abine, were used by almost 2,500 trans women or men who have sex with men⁴.

The idea is simple: take anti­vir­al treat­ment before poten­tial expos­ure to HIV, to pre­vent infec­tion by the virus.

These stud­ies pro­duced sim­il­ar res­ults and, from the out­set, high­lighted three import­ant points. Firstly, PrEP works. Pre­vent­ive anti­vir­al treat­ment reduced the risk of HIV infec­tion by 39% in the CAPRISA 004 tri­al and by 44% in the iPrEx tri­al. Secondly, and this explains the rel­at­ively low effic­acy rates, com­pli­ance is highly vari­able. Wheth­er it was a vagin­al gel used occa­sion­ally or a daily tab­let, the pro­tocol was far from being fol­lowed to the let­ter by all par­ti­cipants. Among the most assidu­ous par­ti­cipants, the pro­tec­tion afforded by the gel was 54% and that afforded by the tab­lets 92%. Finally, neither of the two tri­als showed any sig­ni­fic­ant side-effects from PrEP.

Numer­ous clin­ic­al tri­als and real-life stud­ies have since been car­ried out in vari­ous parts of the world, not just in developed coun­tries. These tri­als involved dif­fer­ent pop­u­la­tions: men who have sex with oth­er men, inject­ing drug users, serodis­cord­ant couples, trans and cis­gender women, het­ero­sexu­al men, etc. The res­ults obtained led the World Health Organ­isa­tion (WHO) to recom­mend the use of oral teno­fo­vir-based PrEP for all people at sub­stan­tial risk of expos­ure to HIV in 2015⁵. Sub­stan­tial risk is defined as an incid­ence rate of more than 3 new cases of HIV per 100 people per year in the pop­u­la­tion con­cerned, in the absence of PrEP.

The pro­files and situ­ations of people likely to bene­fit from PrEP are extremely var­ied, par­tic­u­larly in terms of access to med­ic­al facil­it­ies, even in developed coun­tries. How­ever, the effect­ive­ness of PrEP depends mainly on how reg­u­larly it is taken. A real-life study in France involving men at high risk of HIV infec­tion showed, for example, that con­tinu­ous oral PrEP pro­tects against HIV infec­tion to an aver­age of 60%, and 93% when taken reg­u­larly⁶. To max­im­ise the effect­ive­ness of PrEP, it is there­fore neces­sary to devel­op a range of products and meth­ods of admin­is­tra­tion that meet the real needs and con­straints of the people likely to use them.

In France, PrEP has been access­ible and fully reim­bursed since 2016, with the pos­sib­il­ity of dis­pens­ing it without advance pay­ment in CeGIDDs (free inform­a­tion, screen­ing and dia­gnos­is centres). It takes the form of oral tab­lets com­bin­ing teno­fo­vir and emtri­cit­abine (Truvada, or its gen­er­ics). They can be taken con­tinu­ously, at the rate of one tab­let a day at a fixed time, or occa­sion­ally. In the lat­ter case, two tab­lets should be taken sim­ul­tan­eously 2 to 24 hours before the risk situ­ation, then one tab­let a day for the fol­low­ing two days. More than 80,000 people have used this pre­ven­tion meth­od since it was first made avail­able, and the num­ber con­tin­ues to rise. Of these, 97% are men, with an aver­age age of 36, liv­ing mainly in urb­an areas. How­ever, the pro­por­tions of women, people liv­ing in rur­al areas and people bene­fit­ing from solid­ar­ity-based health cov­er are gradu­ally increas­ing⁷.

PrEP does not neces­sar­ily mean oral tab­lets. In recent years, two oth­er approaches have been added to the WHO recom­mend­a­tions. The first involves sil­ic­one vagin­al rings, which must be worn for 28 days and gradu­ally release dap­ivir­ine, anoth­er HIV reverse tran­scriptase inhib­it­or. Recom­men­ded by the WHO since 2021⁸, this form of PrEP is used in sev­er­al coun­tries in sub-Saha­ran Africa, where women are the pop­u­la­tion most at risk from HIV. These vagin­al rings are more dis­creet than daily tab­lets and offer great­er autonomy, mak­ing them more access­ible to some users. Based on the same prin­ciple, oth­er deliv­ery meth­ods are being stud­ied, such as vagin­al films or sol­uble inserts under the MATRIX pro­gramme⁹.

Redu­cing the fre­quency with which drugs are taken not only makes them more dis­creet, but also facil­it­ates patient com­pli­ance, which is a major factor in the effect­ive­ness of PrEP. In this area, the WHO has been recom­mend­ing since 2022 that caboteg­ravir be added to the arsen­al of drugs avail­able for PrEP¹⁰. Caboteg­ravir is an inhib­it­or of the HIV integ­rase enzyme, delivered in the form of injec­tions every two months. Tested in men and women in dif­fer­ent parts of the world, this form of PrEP is prov­ing to be even more effect­ive than stand­ard oral PrEP. Fig­ures vary from tri­al to tri­al, but on aver­age, it appears to reduce the risk of infec­tion by around 80% com­pared with oral PrEP, mainly because com­pli­ance is bet­ter with injections.

In Septem­ber 2023, Apre­t­ude, an inject­able form of caboteg­ravir, was val­id­ated by the European Medi­cines Agency¹¹. The CABOPrEP clin­ic­al tri­al, designed to assess the effic­acy of inject­able PrEP in France, is due to start in early 2024. This approach, which requires only one injec­tion every two months, is a wel­come addi­tion to the range of PrEP treat­ments avail­able to people liv­ing with HIV, but it has its own draw­backs. The injec­tions can­not be self-admin­istered and are there­fore aimed more at pop­u­la­tions in con­tact with med­ic­al facil­it­ies. And, unlike oth­er forms of PrEP, the use of caboteg­ravir seems to be asso­ci­ated with the appear­ance of some res­ist­ant strains of HIV, which calls for a high­er degree of vigilance.

The remark­able effect­ive­ness of pre-expos­ure pro­phy­lax­is is a revolu­tion in the fight against HIV. To max­im­ise its bene­fits, it is recom­men­ded that it be used in con­junc­tion with oth­er risk-reduc­tion meas­ures, rather than repla­cing them. But since PrEP is a recent devel­op­ment, and can take sev­er­al forms and be based on dif­fer­ent anti­vir­als, it con­tin­ues to evolve in line with research find­ings. Sev­er­al com­pounds are cur­rently being stud­ied to assess their poten­tial for use in PrEP, such as the reverse tran­scriptase inhib­it­or MK-8527¹² or len­acapavir, the first HIV capsid inhib­it­or, which has long-term effic­acy and could allow injec­tions every six months¹³.

The accu­mu­la­tion of stud­ies has also high­lighted a num­ber of points to watch out for. In addi­tion to vir­al res­ist­ance linked to caboteg­ravir, side effects asso­ci­ated with the tenofovir/emtricitabine com­bin­a­tion used in Truvada and its equi­val­ents have been iden­ti­fied. This affects few­er than one in ten people, but naus­ea, diarrhoea and abdom­in­al pain may appear when this form of PrEP is star­ted, and sub­sequently go away¹⁵. Very rare sub-clin­ic­al effects on the kid­neys¹⁶¹⁷ and bone dens­ity¹⁸ have also been observed. A return to nor­mal was observed after PrEP was stopped, but the recom­mend­a­tions have been adap­ted and this form of pre­ven­tion is now not recom­men­ded by the WHO in cases of ren­al insuf­fi­ciency (cre­at­in­ine clear­ance of less than 60 mL/min).

Anoth­er form of oral PrEP, com­bin­ing emtri­cit­abine with a dif­fer­ent form of teno­fo­vir and caus­ing few­er side effects, was then put for­ward: Descovy. How­ever, Descovy is not avail­able in Europe, due to a fail­ure to reach agree­ment on its price and a lack of cer­tainty about the bene­fits com­pared with Truvada¹⁹. The price of drugs remains a key issue, par­tic­u­larly in coun­tries with lim­ited resources, where most people affected by HIV live. Gen­er­ally speak­ing, mak­ing PrEP and anti­vir­al treat­ments avail­able to all pop­u­la­tions affected by the vir­us, in all coun­tries, remains a major challenge.

The find­ings of the imple­ment­a­tion sci­ences thus play an import­ant role in the WHO’s recom­mend­a­tions on HIV²⁰. To ensure that every­one finds a solu­tion tailored to their needs, it is neces­sary to offer dif­fer­ent med­ic­al devices (tab­lets, injec­tions, vagin­al rings, etc.), to use dif­fer­ent com­pounds, and also to devel­op dif­fer­ent dis­tri­bu­tion meth­ods. Mobile devices, tele­con­sulta­tions, dis­pens­ing in com­munity set­tings, dir­ect access in phar­ma­cies: research is also needed to identi­fy the solu­tions best suited to each con­text. Devel­op­ing the best thera­peut­ic approaches is point­less if they are not access­ible to the people who need them.