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Farmacia Hospitalaria

versión On-line ISSN 2171-8695versión impresa ISSN 1130-6343

Farm Hosp. vol.41 no.5 Toledo sep./oct. 2017 


Pre-exposure prophylaxis (PrEP) against HIV: efficacy, safety and uncertainties

Matilde Sánchez-Conde1  2  , María-Jesús Vivancos1  2  , Santiago Moreno-Guillén1  2  3 

1Infectious Disease Unit, Hospital Ramón y Cajal, Madrid. Spain.

2Instituto Ramón y Cajal de Investigación Sanitaria (Ramón y Cajal Health Research Institute) (IRYCIS), Madrid. Spain.

3Department of Medicine, University of Alcalá de Henares, Madrid. Spain.


Despite the global stabilization of the number of new HIV infections in recent years, there has been an increase in new infections among men who have sex with men. This fact indicates the lack of effectiveness of the measures and prevention campaigns established so far for this group. It is therefore necessary to implement alternative preventive measures for them. Pre-exposure pharmacological prophylaxis (PrEP) is one of the best evaluated options and has had high protection rates in both clinical and real-life trials. The strategy has also shown an adequate profile in terms of safety, tolerance, adverse effects and cost-effectiveness in the studies carried out to assess this important topic

KEYWORDS: Pre-exposure prophylaxis; HIV infection; Efficacy


En los últimos años se ha objetivado un incremento de las nuevas infecciones por el VIH en el grupo de hombres que tienen sexo con hombres, lo que indica la ausencia de eficacia de las campañas y medidas preventivas instauradas en dicho grupo.

Es necesario, por tanto, implementar medidas preventivas alternativas, siendo la profilaxis farmacológica pre-exposición (PrEP) una de las opciones mejor evaluadas tanto en ensayos clínicos como en la vida real, habiéndose demostrado tasas de protección superiores al 80% cuando se administra en los casos indicados y con buen cumplimiento terapeútico. La estrategia ha demostrado, además, un perfil adecuado en seguridad, tolerancia y efectos adversos, siendo además coste-efectiva según los estudios realizados para valorar este importante aspecto.

PALABRAS CLAVE: Profilaxis preexposición; Infección por el VIH; Eficacia


According to the latest data presented regarding the number of new HIV infections in >13 -year-old patients, there has been a reduction in its overall incidence in the United States in the period from 2008 to 2014. However, when analyzing the different populations at risk of infection, it has been observed that there is an increase in new infections in the group of men who have sex with men (MSM) with ages between 25 and 34 years, as well as in those >55-year-old1.

In Spain, according to data by the Ministry of Health, 3,366 new cases of HIV infection were reported during 2014. After an estimation taking into account the current delay in the report of cases, it is calculated that in 2014 there were 9.34 new infections per 100,000 inhabitants, and 54% of them were in MSM. This represents an increase from previous years in the group of MSM population between 20 and 30 years of age2.

This increase in new infections in the MSM group within a context of overall stability, and even reduction in new cases during recent years, represents an indication of the lack of efficacy of prevention measures and campaigns implemented so far in said group. Therefore, it is necessary to implement alternative preventive measures; one of the better valued options is Pre-Exposure Pharmacological Prophylaxis (PrEP). It must be highlighted that clinical trial outcomes have been replicated consistently in some of the places where it has been widely used in cases within the indication.

Drug administration in order to prevent an infection or its clinical consequences is an already well-known strategy, and it has been applied in different medical scenarios, such as prevention of malaria by the administration of antimalarial treatment, or antibiotic administration as surgical prophylaxis. Similarly, the theoretical basis of PrEP consists in the administration of anti-retrovirals before the sexual contact that could transmit the HIV infection.

In this article, we will briefly review the main aspects of this strategy, with particular focus on its efficacy and safety.

Studies on prep efficacy as a prevention strategy for HIV infection

The first study which demonstrated the efficacy of oral PrEP as prevention strategy against HIV was the iPrex study, published in 20103. This study included 2,499 MSM subjects who were HIV-negative, or transgender women (TGW) who had sexual relationships with men. All of them were randomized to receive a combination of emtricitabine and tenofovir disoproxil fumarate (FTC/TDF) or placebo once a day. After one year of follow-up, 36 persons in the FTC-TDF group had become infected by HIV, vs. 64 in the placebo group, with a 44% reduction rate of new infections (CI95% 15-63) in the PrEP arm compared with placebo.

Further studies have been conducted after the first one, which have contributed with more and better data on the efficacy of this prevention strategy. We will discuss their most relevant aspects; there is also a summary of these data in Table 1.

Table 1 Main clinical trials published on PrEP 

Another significant study was the TDF2, sponsored by the Centres for Disease Control and Prevention (CDC) in Atlanta. This study analyzed the use of FTC/TDF or placebo in HIV-negative men and women in Botswana with high-risk sexual behavior4. During follow-up, there were 9 infections in the treatment arm (1.2 infections/100 person -years of follow -up (pyf) vs. 24 in the placebo arm (3.1 infections/100 pyf; which shows a 62-2% efficacy of the PrEP in this study (CI95%: 21.5-83.4).

The Partners study, conducted in Kenya and Uganda, included 4,757 serodiscordant heterosexual couples, who were randomized to receive TDF only, FTC/TDF in combination, or placebo5. During the 23 months of follow-up, there were 82 HIV infections: 17 in the TDF arm (0.65 instances/100 person-years of follow-up), 13 in the FTC/TDF arm (0.50/100 person -years of follow -up) and 52 in the placebo group (1.99/100 person-years of follow-up). Therefore, the use of TDF offered a 67% protection compared with the placebo arm (CI95% 44-81), and there was a 75% protection for the FTC/TDF arm (CI95% 55-87).

Since 2015, data from the studies conducted in Europe have also been reported. Of the two most important, the first was the PROUD study6, which included 544 MSM randomized to receive 1 daily FTC/TDF immediately, or to delay treatment initiation by 12 months. All participants received training on how to reduce risk during sexual relationships, and condoms were provided throughout the study. During follow-up, both arms presented a high incidence of STIs, without statistical differences between them. The study was interrupted by the Safety Committee, when it was confirmed that those persons with a delayed treatment initiation had a higher risk of HIV infection than those receiving immediate treatment. There were 3 infections in the immediate treatment arm, vs. 20 in the delayed group (9.0/100 persons-year), and with an 86% reduction (CI90% 64-96). According to these data, it would be necessary to initiate prophylaxis in 13 persons in order to prevent one new HIV infection. Of the three persons who were infected in the immediate treatment arm, one had entered the study with an existing infection (HIV-negative but positive HIV-PCR at baseline): while the other two had stopped taking prophylaxis some time before the infection.

The second study is the Ipergay, conducted in France and Canada, which included 400 MSM or transgender women (TGW) not infected by HIV and at high risk of infection7. After inclusion, they were randomized to receive prophylaxis with FTC/TDF or placebo. In this case, prophylaxis was on demand with the administration of 2 FTC/TDF tablets between 2 and 24 hours before having a sexual relationship, followed by 1 tablet at 24 hours, and another tablet at 48 hours after said relationship. In case that they continued having sexual relationships, they continued receiving 1 daily tablet until 48 hours after the last intercourse. If there were any subsequent sexual relationships, prophylaxis was initiated again, with 2 FTC/TDF tablets followed by 1 daily tablet until 48 hours after the last intercourse. The control arm received the same regimen, but with placebo. Just as in the PROUD study, all participants received training in order to minimize risk during intercourse, and condoms were provided throughout follow-up. Again, there was a high incidence of STIs during follow-up, which confirms high-risk relationships in both arms of the study. The same as in the PROUD study, the Safety Committee interrupted this study 9 months after its initiation, because there were 2 HIV infections during follow-up in the study arm (0.91 infections/100 person-years) vs. 14 in the placebo arm (6.6/100 person-years). Prophylaxis had an 86% efficacy (CI95% 40-98, p=0.002), and it was necessary to treat 18 persons in order to prevent 1 new infection. Again, none of the two persons infected in the FTC/TDF group had detectable TAF levels in blood.

The HPTN 067 / ADAPT study (Alternative Dosing to Augment PrEP Pill-Taking) is a Phase II clinical trial designed to confirm if non - daily PrEP dosing regimes could make compliance easier8. The study was conducted on 3 different populations: MSM in Bangkok, MSM in Harlem, and heterosexual women in Cape Town. In the three arms, participants were randomized to receive 1 daily TDF/FTC tablet, or a non-daily tablet based on time (1 tablet twice a week plus 1 extra tablet after each sexual contact), or based on sexual activity (1 tablet before and 1 tablet after each sexual contact). In the three sub-groups, daily prophylaxis achieved better rates in the reduction of new infections, also demonstrating better treatment adherence. Overall, the Harlem cohort achieved the worst response (65% for the Harlem cohort, 85% for the Bangkok cohort, 75% for the Cape Town cohort).

Against these studies which have demonstrated the efficacy of PrEP, other studies have been reported where this efficacy has been questioned. The FEM-Prep study included 2,120 HIV-negative women in Kenya, South Africa and Tanzania, who were randomized to FTC/TDF or placebo9. In total, 33 women were infected in the FTC/TAF group (incidence of 4.7 infections/100 person-years of follow-up (pyf)) vs. 35 in the placebo arm (5 infections/100 pyf), with a 0.94 HR of protection (CI95% 0.59-1.52). The Voice study, conducted in South Africa, Zimbabwe and Uganda, included 5,029 HIV-negative women who were randomized to TDF only, FTC/TDF, 1% vaginal TDF gel, and two placebo arms, one on oral treatment and the other one on vaginal gel10. In total, there were 312 infections with a 5.7/100 pyf incidence. In this instance, none of the 3 study arms offered protection vs. placebo. The efficacy of TDF administered as monotherapy was of -49%, FTC/TDF reached a -4.4% efficacy, and finally, the vaginal gel showed a 14.5% efficacy, in this last case without any statistical significance.

Outside sexual transmission, a study conducted in Bangkok showed a 48.9% level of protection (CI95% 9.6 -72.2), among 2,413 parenteral-drug addicts (PDAs) who were not infected with HIV, and who were randomized to receive TDF or to the control arm11.

In the majority of cases, the differences in PrEP efficacy between the different studies lie in their different treatment compliance. For example, in the VOICE study, were the efficacy of PrEP was not demonstrated, TDF levels were only detected in 30%, 29% and 25% of the patients randomized to receive TDF, FTC/TDF or TDF gel10. Likewise, only 28% of women assigned to the FTC/TDF arm had detectable FTC levels in the FEM-PrEP study9. In a sub-analysis of the iPrex study, when analyzing those persons randomized to receive FTC/TDF who were infected by HIV vs. those without the infection, the former presented lower TDF levels, both in the seroconversion visit (8% vs. 44%, p<0.001), and in the visit 90 days before (11% vs. 51%, p<0.001)9. In fact, a 90% reduction was demonstrated in the risk of HIV infection in those who presented detectable TDF concentrations in peripheral blood cells.

Similar data were found in the PARTNERS study; in this case, only 21% of the infected persons had levels considered as protective (>40 ng/mL) vs. 71% in non-infected persons5. Even in those persons who exceeded said concentration, there was an 88% efficacy of prophylaxis (CI95% 60-96) for those who received TDF and 91% (CI95% 47-98) for those who received FTC/TDF.

Finally, in the study conducted in Bangkok among PDAs, the efficacy reached 73.5% (CI95% 16.6-94) when the analysis was restricted to persons with good treatment compliance, and with detectable TDG levels11.

Besides low treatment adherence as a clear cause for PrEP failure, some studies might indicate that some pharmacological differences coulf also explain these discrepancies. For example, after PrEP administration, it has been confirmed that TDF levels in male rectal tissue are between 10 and 100 times higher than those reached in female cervico-vaginal tissue; this could point towards a worse efficacy of PrEP among women12.

Real-life data on PrEP

After the first published clinical trials, in 2012 the FDA approved the use of PrEP, and in 2014 the CDC issued some recommendations for its use13. Currently, many studies have been reported about its use in real life, and under these circumstances it does not seem that results will deviate too far from clinical trial reports. In data reported within the San Francisco area by the Kaiser Permanente Insurance Company, between July, 2012 and February, 2015, after PrEP was prescribed to 657 persons with a follow-up of 388 persons/year, and even though there was a high rate of TSI diagnosis (28% of these persons presented at least one TSI during follow-up), there were no cases of HIV infection14.

In the DEMO Project study, conducted in San Francisco and Miami clinics, PrEP was administered to 557 MSM and TGW between October, 2012 and January, 201415. In total, there were 5 HIV infections; three of them were considered primary infections existing at the time of inclusion, and only 1 appeared during follow-up (0.43/100 pyf incidence). Once more, none of these two last participants had protective levels of TDF in their blood at the time of infection.

It is worth highlighting the ATN 110 study, which analyzed the use of PrEP in a population of 200 18-to -22-year old MSM16. In total, there were 4 cases of HIV infection (3.29/100 pyf). In one of them, it was demonstrated that the patient was already infected with HIV at the time of inclusion; in the other 3 cases, TDF compliance was null at the time of infection (as demonstrated by TDF levels in blood).

Finally, in terms of efficacy data in real life, recently we have become aware of the confirmation of a significant reduction in new HIV infections among MSM, demonstrated since 2015 in 5 London clinics. This reduction would be justified by the use of PrEP, and at the same time by the effort made towards early diagnosis and treatment of new infections17,18.

All these data come to confirm those previously provided by clinical trials. After PrEP prescription, the incidence of HIV infection is low among a population where, given the high incidence of STI, it would be expected to find also a high incidence of new HIV infections. Likewise, these confirm the importance of treatment compliance, because PrEP is only effective when there is high adherence to treatment.


Both TDF alone and in combination with FTC are well-tolerated drugs, seldom associated with the development of adverse effects at short and medium term. This rule seems to apply also in the case of PrEP, and its tolerability and safety can be considered satisfactory. In the majority of the studies reviewed, there were no clinically significant differences between the TDF or FTC/TDF arms and the placebo arms regarding the development of any adverse effects, grade 3 / 4 adverse effects, gastrointestinal disorders, diarrhoea, or discontinuation of the study due to adverse effects.5,9.

Particular attention must be paid to the potential development of renal toxicity associated with the use of TDF. A sub-analysis of the PARTNERS study analyzed specifically this potential toxicity19. After 18 months of follow-up, there was a change in the estimated glomerular filtration rate from - 0.22, +0.14 or +1.37 mL/min/1.73 m2 in the FTC/TDF, TDF or placebo arms, respectively, and there was a >25% reduction in the estimated glomerular filtration rate over 18 months vs. the basal level in 0.41%, 0.25% or 0.83% of the FTC/TDF, TDF or placebo arms, respectively.

The use of TDF has also been associated with a loss in bone mineral density in those persons with HIV infection. A TDF2 sub-study assessed this potential loss in 109 persons who received FTC/TDF and 112 in the placebo arm. All of them underwent a basal densitometry, and then subsequent tests every 6 months20. Those persons who received FTC/TDF presented statistically significant worsening in T-scores or Z-scores throughout the study, both in lumbar spine as in hips. However, there were no differences in the incidence of bone fractures between both groups.

Regardless of this good profile of safety and tolerability, we must underline that those persons included in PrEP studies are young individuals, with few comorbidities, mostly male, and who received treatment during relatively short periods of time. However, according to data about the use of TDF during antiretroviral treatment, we know that TDF toxicity occurs at long term, typically after 3 to 5 years of treatment, and in persons with additional comorbidities such as hypertension or diabetes for renal toxicity, and women during menopause for the loss of bone mineral density. For these reasons, safety data for this strategy should be measured at long term, and with a longer follow-up.

Controversies: Prep failure, potential development of resistance mutations, and increase in STI diagnosis

Since the start of antiretroviral therapy, we know that treatment with sub-optimal therapies (monotherapy or dual) is associated with a high rate of development of resistance mutations. Their potential development during PrEP has been considered one of the major drawbacks that could appear. However, those studies conducted so far have not demonstrated an increase in resistance development with the use of PrEP. In a review that analyzed 10,045 persons included in different studies, 305 persons were infected during prophylaxis, and 18 of them (0.18% of the total number of persons included) presented resistance mutations21. However, half of those who developed some resistance mutation had been included in the study during their primary infection. Taking into account these facts, and excluding this group, there was a 0.9% resistance development among the total subjects included.

A case has been recently reported about a person infected with HIV while he was on PrEP, with good treatment compliance demonstrated through drug levels22. In this case, a resistance analysis demonstrated the presence of mutations to integrase inhibitor drugs (not included in the PrEP), while no mutations causing resistance to TDF were found: TDF is a drug included in the PrEP, and with high levels demonstrated in blood. Therefore, the conclusion of this case has been that this is not a failure in PrEP: this subject was exposed to a virus that already had resistance mutations, and this could not be prevented despite an adequate compliance with PrEP.

We know that viral replication is very high during the primary infection, and in these circumstances, monotherapy or dual therapy must be considered sub-optimal, and associated with a high development of resistance mutations. It has been calculated that there is a >25% development of resistance mutations in persons who were included in PrEP programs when they were already infected; this rate appears in contrast with the 0.09% previously stated23. As expected, the most frequently induced mutations were M184V/I and K65R, both in the reverse transcriptase gene. For this reason, follow-up must be conducted for those persons initiating PrEP, given the potential risk of developing resistance mutations in the early stage of an eventual seroconversion24,25.

Finally, given that no clinical trial or real-life study has demonstrated a 100% efficacy in PrEP, we must briefly discuss the likelihood of HIV transmission even if prophylaxis has been adequately prescribed and administered. This fact is so unusual that the confirmation of one HIV infection in the context of an adequate PrEP in one single person has deserved a recent communication to the scientific community26. This case has been observed in Amsterdam: a MSM male with a mean of 16 sexual contacts per month, consisting in anal sex without using condoms; there was a mean of 3.7 sexual partners in each contact. This repeated exposure to high-risk relation-ships without protection is the most likely cause for HIV infection regardless of an adequate PrEP.

Another potential controversy in the context of PrEP implementation is the fact that it might entail an increase in the transmission of other STIs. In a recent meta-analysis conducted in the University of California (UCLA), based on 18 cohort studies comparing a MSM population receiving PrEP vs. MSM who were not receiving PrEP, it was shown how the MSM arm on PrEP presented a risk 45 times higher of being diagnosed with 3 common STIs (syphilis, chlamydia and gonorrhoea) vs. the MSM arm not receiving PrEP27.

The potential risks, such as an increase in STI diagnosis in parallel with PrEP implementation, the potential infection by strains which already have resistance mutations, or potential infections by repeated exposure regardless of PrEP with adequate compliance, reinforce the need to continue conducting periodical screenings for STI, HIV and hepatitis, following the CDC recommendations.


PrEP is an effective and safe strategy for the prevention of HIV infection in persons at risk of said infection. Treatment compliance is particularly important in order to ensure its efficacy. However, there are still different issues that must be solved, such as improving its efficacy in women, long-term safety, or how to avoid its use during primary infection, in order to prevent an accumulation of resistance mutations.


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Received: May 30, 2017; Accepted: July 10, 2017

Autor para correspondencia. Correo electrónico: (Matilde Sánchez Conde)

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