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.