Article Text
PDF
Abstract
Introduction/objectives The use of non-occupational post-exposure prophylaxis (nPEP) emerges as a strategic intervention to reduce HIV infection risk following sexual encounters in our setting. Notwithstanding, there is a scarcity of contemporary data regarding adherence to this treatment, its effectiveness and tolerance. Our study aims to delve into these factors among individuals who have resorted to nPEP after high-risk sexual encounters.
Methods We conducted a retrospective observational study of cases administered nPEP for HIV from 1 January 2018 to 31 December 2021 at a tertiary hospital in Madrid. The study included all adults over 18 years who sought care at the emergency department of the Fundación Jiménez Díaz Hospital following a risky sexual encounter and were subsequently recommended HIV nPEP treatment.
Results 878 individuals received nPEP for HIV and underwent initial serological tests. Of these, 621 had comprehensive follow-ups. The prescribed regimen for all was raltegravir (RAL) 1200 mg combined with tenofovir/emtricitabine (TDF/FTC) 245/200 mg daily for 28 days. The study revealed a 1.1% rate (n=10) of previously undetected infection and a 0.16% (n=1) failure rate of nPEP. Regarding regimen tolerability, 5.6% (n=35) experienced symptoms linked to the treatment, yet none necessitated discontinuation of the regimen. On the contrary, six per cent (n=53) reported symptoms consistent with an STI during one of the medical visits; specifically, 4.4% had urethritis, and 1.6% had proctitis.
Conclusion nPEP with RAL/TDF/FTC demonstrates high efficacy and safety, contingent on proper adherence. There is an observed increase in STI prevalence in this cohort, with nearly half of the participants not engaging in appropriate follow-up after initiating nPEP.
- HIV
- Post-Exposure Prophylaxis
- AIDS
- Pre-Exposure Prophylaxis
Data availability statement
No data are available.
Statistics from Altmetric.com
WHAT IS ALREADY KNOWN ON THIS TOPIC
Non-occupational post-exposure prophylaxis (nPEP) involves taking HIV medications within 72 hours of a potential HIV exposure to prevent infection and should only be used in emergency situations.
WHAT THIS STUDY ADDS
It provides information about the effectiveness and safety of the nPEP regimen in a cohort of individuals who, after a risky encounter, have had access to this treatment as secondary prevention.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
Future studies could explore interventions to enhance adherence and assess long-term efficacy outcomes with shorter treatment regimens. Additionally, the study’s findings may inform public health initiatives aimed at promoting awareness of nPEP as an effective HIV prevention strategy.
Introduction
In 2022, it was estimated that 39 million individuals were living with HIV infection, with approximately 1.3 million new cases annually.1 Over the past two decades, significant strides have been made in curbing the epidemic; however, in our context, the reduction in new cases has been modest and only recently observed.2 Various strategies, including early diagnosis, the rapid and universal initiation of antiretroviral therapy (ART) and the implementation of pre-exposure prophylaxis (PrEP), have played a role in this progress. Although, current data on another effective tool, non-occupational post-exposure prophylaxis (nPEP) remain limited.
Presently, it is understood that viral loads below 1500 copies/mL in patients with HIV make sexual transmission unlikely.3 This is supported by studies such as the PARTNER trial, which demonstrated that the risk of HIV transmission in unprotected sexual intercourse by a person with HIV receiving ART with a viral load <200 copies/mL is close to zero.4
The nPEP serves as a secondary preventative measure, aiming to avert HIV when primary prevention has failed.5 It is indicated within the first 72 hours after accidental sexual or percutaneous contact with blood and/or other potentially HIV-infected biological fluids outside of occupational or perinatal settings.6 Sexual transmission is the most common route of HIV acquisition, with receptive anal intercourse being the highest risk exposure (0.8–3%).7 In the current context, where STIs are on the rise,8 which in turn can facilitate HIV acquisition, governmental bodies recommend the use and promotion of nPEP as a tool for reducing new cases.9 Evidence supporting the use of nPEP is drawn from HIV infection prevention studies in animal models using tenofovir prophylaxis,10 administration of zidovudine to neonates of untreated HIV-infected mothers11 and observational studies conducted to date.12–15
The current recommended nPEP regimen spans 28 days, combining two nucleoside reverse transcriptase inhibitors (NRTIs) with a third antiretroviral drug (ARV) from another class.16 Tenofovir/emtricitabine (TDF/FTC) is preferred for its tolerability as NRTIs, with zidovudine/lamivudine (ZDV/3TC) as an alternative. Due to its low likelihood of resistance, minimal drug interactions and established efficacy, the recommended third ARV is an integrase inhibitor, specifically raltegravir (RAL),17 with others as alternatives.9 Its effectiveness depends on various factors, including the time elapsed since exposure, adherence to treatment and the HIV-1 viral load of the potential source. The prescribed regimen for our patients was RAL 600 mg, two tablets, plus TDF/FTC 245/200 mg once daily for 28 days.
Therefore, nPEP is a potentially vital tool in reducing the risk of acquiring HIV infection following predominantly sexual exposure in our environment. There is a dearth of recent data on its adherence, efficacy and tolerability, and our objective is to analyse these aspects in a cohort of individuals who, after a risk encounter, have had access to nPEP.
Materials and methods
This is an observational and retrospective study of cases that received nPEP against HIV from 01January 2018 to 31 December 2021 at a tertiary-level hospital in Madrid, Spain.
The study included all adults over the age of 18 years who voluntarily presented at the emergency service of the Fundación Jiménez Díaz Hospital within the first 72 hours following a risk contact and were advised to receive post-exposure prophylactic treatment against HIV during the study period. Patients who did not follow-up and those from whom information on adherence, tolerability or effectiveness of the regimen could not be obtained were excluded (flow chart: figure 1). Indication for the initiation of prophylactic treatment was considered having contact with potentially infectious fluid through the mucosa (rectum, vagina, eyes, mouth or other membranes, non-intact skin or percutaneous contact) with a person of unknown serological status in an epidemiological context compatible with potential risk.
Flowchart of pre-exposure prophylaxis against HIV (nPEP) users.
Epidemiological, clinical, diagnostic and therapeutic data, those related to the treatment and its side effects, and the evolution of nPEP users were collected. The centre’s care protocol recommends specific follow-up by specialists for 3 months, with baseline, 1 month and 3month post-treatment initiation serological evaluation and control.
Anogenital samples were analysed from those patients who reported symptoms compatible with an STI at any of the medical visits.
An occult HIV infection was defined as one detected in baseline analytics and an infection due to nPEP treatment failure as one occurring within the first 3 months from the start of treatment. A new infection not related to the efficacy of nPEP was considered to be one diagnosed after 3 months from the start of the nPEP regimen and confirmed to have occurred due to new exposures.
The nPEP care pathway in our centre: users go to the emergency service where, if PEP is indicated, they are provided with medication for 3 days and an appointment in the infectious diseases section with a serological analytical test. On the next working day, subjects go to the hospital pharmacy to receive the rest of the medication to complete the 28 days of treatment. Two analyses were performed: on one hand, the baseline cohort analysis including those subjects from whom baseline serological study data were available (rate of occult HIV infection, baseline epidemiological and clinical characteristics, prevalence of baseline STIs); on the other hand, an analysis of the efficacy and tolerability of the regimen in those who completed follow-up.
In the statistical analysis, qualitative variables were described with frequencies and percentages and quantitative variables with mean and SD, or median and IQR depending on the normality test (Kolmogorov-Smirnov test). Comparisons of qualitative variables were made using the χ2 test or, if necessary, Fisher’s exact test. Comparisons of quantitative variables were made using Student’s t-test, and the statistical analysis was carried out with the SPSS V.20 programme.
The study was conducted in accordance with the recommendations of the Declaration of Helsinki, revised at successive world assemblies (last in Fortaleza, Brazil, October 2013), compliance with the Organic Law on Data Protection, and Good Clinical Practice Standards.
Results
A total of 1202 individuals received nPEP against HIV. Among them, 878 underwent the initial baseline serological study (included in the baseline analysis) and 621 completed the comprehensive follow-up assessment (follow-up analysis: assessing the efficacy and tolerability of the regimen) (figure 1). Of the participants, 97.5% were male, and the key characteristics are detailed in table 1.
Baseline characteristics of nPEP users (N=878)
The median age of nPEP users was 34±8 years, with 8% being under 25 years old and 4% over 50 years old. Of the users, 67.6% were Spanish, 19.7% were Latin American, 9.1% were European (excluding Spanish) and 3.5% were from other countries.
The average time from emergency care to infectious diseases consultation was 14.97 days, while the mean time from a patient’s visit to the emergency department (ED) to the administration of a serological test was 18.79 days. 27% required nPEP initiation before (table 1). These serological tests were carried out at the hospital before receiving the medication or during the initial days, and they were requested by both emergency physicians and specialists in infectious diseases who saw the patients in consultation.
The prescribed regimen in all cases was RAL 1200 mg plus TDF/FTC 245/200 mg once daily for 28 days.
Regarding the tolerability of the regimen, 5.6% (n=35) experienced some symptoms associated with the treatment received, with gastrointestinal symptoms being the most common in 3.7% of cases (n=23), followed by cutaneous symptoms in 0.5% (n=3), renal function alterations in the same proportion 0.5% (n=3) and finally, other symptoms such as dizziness, headache and fatigue in 0.8% (n=5), with none of them leading to the discontinuation of the regimen.
A confirmed diagnosis of HIV was observed in 10 individuals during the baseline analysis, resulting in an occult infection rate among nPEP users of 1.1% (10/878). In three individuals, HIV diagnosis occurred after 6 months of follow-up, with previous negative controls and documentation of persistent risky behaviours, leading to the consideration of new infections unrelated to nPEP use. A case of nPEP failure (0.16%—1/621) was identified in a subject who tested positive for serology 2 months after initiating treatment. This individual completed the course, having a baseline analysis with negative HIV antibodies and p24 Ag.
In the study of other STIs, 4.9% had active syphilis and required specific treatment, while an additional 8.5% had a history of past syphilis. Two subjects (2.2%) had hepatitis B (positive surface antigen for hepatitis B virus) and two had hepatitis C (positive hepatitis C virus HCV IgG and detectable HCV RNA), all cases were previously unknown and required treatment. Hepatitis A serology (IgG) was performed on 667 subjects, with 42.6% testing positive. Two subjects (0.3%) showed suggestive data of acute hepatitis A (positive IgM with elevated transaminases), with none meeting severity criteria.
Six per cent (n=53) reported symptoms consistent with an STI during one of the medical visits; specifically, 4.4% had urethritis and 1.6% had proctitis. In 24 of them, a positive microbiological result was obtained for Neisseria gonorrhoeae, 12 for Chlamydia trachomatis (including one case of lymphogranuloma venereum), 2 for Mycoplasma genitalium and 3 for Herpes simplex virus (HSV-1 and HSV-2).
Discussion
The likelihood of acquiring HIV varies depending on the type of sexual relationship (higher in receptive anal sex), factors specific to the source (high viral load (HIV-1 RNA)) or other factors such as the presence of STIs, lack of circumcision or certain genetic factors of the infected individual.3 18 Therefore, it is important to assess individuals who have potential exposure to HIV to determine whether offering pre-exposure prophylaxis with ART is warranted, thereby reducing the risk of virus transmission.
While there are significant differences between occupational and non-occupational exposure, many experts still recommend nPEP after a high-risk exposure,19 despite the disparity of opinions on this matter.
An important aspect of our study is the rate of occult infection in this group, reaching 1.1%, and it could be even higher as data is unavailable for 27% of the subjects who were prescribed nPEP from the ED. Our rate of occult infection exceeds that of the general population (0.3%)20 21 or those who visit the ED (0.6–0.9%),22 highlighting the importance of implementing tools to prevent underdiagnosis of this infection in individuals accessing healthcare services.23 The fact that 27% of subjects receiving nPEP do not have a serological study underscores the need to change the process of attention in our centre to facilitate obtaining such serological tests. This prompts us to consider other options, such as conducting rapid HIV tests during the initial assessment. In this regard, one of the measures implemented after this study was to systematise immediate follow-up in the specialised consultation of infectious diseases for the continuity of nPEP.
Our infection rate due to a potential failure of nPEP was 0.16%: a single patient out of 621 who underwent follow-up became infected with HIV. This confirms the high effectiveness of this tool, which should be considered among those available to reduce the incidence of new diagnoses in our country, along with PrEP and universal access to treatment for all individuals with HIV. In our case, the factors involved in this failure could not be confirmed, and they may include some of those described in the literature, such as poor adherence to the regimen, delayed initiation of treatment or ongoing exposures to HIV.24
On the contrary, we have observed a high rate of patients receiving nPEP on multiple occasions, specifically 27.2% requiring nPEP in the past. It is noteworthy that the nPEP user population is among those with the highest prevalence of HIV infection due to repeated exposure, not always accompanied by nPEP. Therefore, it is important to offer the possibility of transitioning from a post-exposure regimen to pre-exposure prophylaxis, if deemed appropriate by the user and the specialist, to complete the prevention circuit.25
Although the optimal duration of nPEP is unknown, guidelines recommend a 28-day course of ART for individuals with significant exposure to HIV.19 25 26 In our study, it is observed that the adherence rate in subjects undergoing follow-up is high, at 98.4%. On the contrary, it should be noted that if the serological status of the source had been available during follow-up, the discontinuation of prophylaxis could have been considered earlier, an aspect not analysed in this study due to its retrospective nature.
In our hospital centre, a three-drug regimen is employed following the guidelines established by the clinical guidelines published by the European AIDS Clinical Society in 2023.27 The regimen prescribed for our patients was RAL 600 mg two tablets plus TDF/FTC 245/200 mg once daily, based on available data regarding its high efficacy, tolerability and long-term safety.28 Although other validated options with demonstrated efficacy are also available.
Regarding the side effects reported by users, only 5.6% experienced any symptoms associated with the treatment received, significantly lower than that observed by Mayer et al,28 whose most common adverse events align with those observed in our study (nausea or vomiting, diarrhoea, headache and fatigue). In our case, all these were mild and did not lead to the discontinuation of the medication in any instance. It is essential to consider that, due to the retrospective nature of our study, many mild side effects may not have been reported by patients since there was no systematic follow-up for them.
Serological follow-up for screening HIV infection is recommended at least 4 and 12 weeks after exposure.25 In our cohort, 29% (257/878) did not complete the follow-up in our centre, and it could have been conducted in primary care, specific STI centres or community organisations. The specific characteristics of our healthcare system provide the possibility of care and follow-up in different settings but complicate the monitoring of some indicators due to the absence of a universal clinical record for each person. This may have consequences on the decision-making and adherence to nPEP by our patients.
In the current context of the constant increase in STIs, it is important to emphasise the high incidence of STIs diagnosed in patients receiving nPEP.29 Specifically, in our sample, 4.9% had syphilis and 6% had symptoms compatible with an STI at some of the medical visits. This supports the possibility of administering antimicrobial treatment along with the classic nPEP to those users who have had a recent bacterial STI, as demonstrated in the recent study by Luetkemeyer et al.30 57.4% and 47.6% of our sample did not have adequate immunity to hepatitis A and B, respectively, highlighting the need to promote vaccination programmes in this at-risk group. This once again underscores the importance of using other preventive measures to prevent the increase in these infections, as well as the recommendation and referral to a prevention programme such as PrEP or at least systematic STI screening.
In our study, several limitations were observed. First, those inherent to its retrospective nature limit the possibility of having a systematic follow-up of subjects to determine, for example, the reasons for the lack of follow-up or to confirm complete adherence to the regimen. The fact that our hospital is located in the centre of a large city condition that a percentage of users in this programme may have undergone subsequent follow-up at their referral hospital, which could limit access to complete information from the initial cohort. Despite these limitations, and given the large number of subjects included in the cohort, as well as the consistency of the collected data, we believe that the results are robust, presenting one of the largest cohorts recently published.
Conclusions
Users of nPEP show high rates of occult HIV infection and a high prevalence of STIs, making systematic screening and referral to PrEP programmes highly advisable. The nPEP regimen with RAL+TDF/FTC is a prophylaxis tool with a high rate of efficacy and safety in this setting.
Abstract translation
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.Data availability statement
No data are available.
Ethics statements
Patient consent for publication
Ethics approval
This study involves human participants and was approved by the Ethics Committee of the Jiménez Díaz Foundation (EO 019-21).
References
Supplementary materials
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Footnotes
Handling editor Mark Charles Atkins
IC, MG and AC conceived the study, participated in its design, data analysis and drafted the manuscript. MLdlH, SCM, LP-P, BAA, AWA-H, JIS-I, SLF, PQL, MEAD, MBP, PAM, BSB, RBR and MH-S were responsible for managing the database and have participated in its design and drafted the manuscript. All the authors contributed to the final version of the manuscript.
The responsible authors for the overall content as guarantors are ICA, ACU, and MG.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.