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.

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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.