Abstract:

The adverse effects of oral pre-exposure prophylaxis (PrEP) using tenofovir disoproxil fumarate are barriers to PrEP initiation and continuation. Although serious effects are rare and predictable, evidence for this assessment among men who have sex with men (MSM) and transgender women (TGW) is still limited. This study assesses the adverse effects of daily oral PrEP in MSM and TGW. This is a systematic review and meta-analysis of clinical trials and cohort studies on the use of daily oral PrEP selected from the PubMed/MEDLINE, Embase, LILACS, and Cochrane CENTRAL databases. Data extraction included adverse effects and changes in renal and hepatic markers. Random effects models were used to summarize the risk of adverse effects throughout the study. Heterogeneity was assessed using the Cochran’s Q test and the inconsistency test (I²). The risk of bias and the certainty of the evidence were assessed using the Cochrane Collaboration recommendations. The search identified 653 references. Of these, 10 were selected. All studies assessed the eligibility of renal and hepatic markers. The use of daily oral PrEP was not associated with grade 3 or 4 adverse events (RR = 0.99; 95%CI: 0.83-1.18; I² = 26.1%), any serious adverse event (RR = 1.04; 95%CI: 0.58-1.87; I² = 88.4%), grade 3+4 creatinine level (RR = 0.66; 95%CI: 0.24-1.84; I² = 79.9%), and grade 3 or 4 hypophosphatemia (RR = 0.56; 95%CI: 0.15-2.10). The certainty of the evidence ranged from high to moderate for the outcomes analyzed. Daily oral PrEP is safe and well tolerated by MSM and TGW. Adverse effects were minimal and evenly distributed between intervention and control.

Keywords:
Pre-Exposure Prophylaxis; Drug-Related Side Effects and Adverse Reactions; HIV; Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination

Resumo:

Os efeitos adversos da profilaxia pré-exposição (PrEP) oral com fumarato de tenofovir desoproxila são barreiras para o início e a continuidade da PrEP. Embora os efeitos graves sejam raros e previsíveis, as evidências dessa avaliação entre homens que fazem sexo com homens (HSH) e mulheres transgênero (MTG) ainda são limitadas. Este estudo avalia os efeitos adversos da PrEP oral diária em HSH e MTG. Trata-se de uma revisão sistemática e metanálise de ensaios clínicos e coortes que demonstram o uso de PrEP oral diária selecionados nas bases de dados PubMed/MEDLINE, Embase, LILACS e Cochrane CENTRAL. A extração de dados incluiu os efeitos adversos e alterações nos marcadores renais e hepáticos. Modelos de efeitos aleatórios foram usados para resumir o risco de efeitos adversos ao longo do estudo. A heterogeneidade foi avaliada pelo teste Q de Cochran e inconsistência (I²). O risco de viés e a certeza da evidência foram avaliados por meio das recomendações da Colaboração Cochrane. Foram identificadas 653 referências. Destes, dez foram selecionadas. Todos os estudos avaliaram marcadores renais de elegibilidade e marcadores hepáticos. O uso diário de PrEP oral não foi associado a eventos de grau 3 ou 4 (RR = 0,99; IC95%: 0,83-1,18; I² = 26,1%), a qualquer evento adverso grave (RR = 1,04; IC95%: 0,58-1,87; I² =88,4%), à creatinina grau 3 ou 4 (RR = 0,66; IC95%: 0,24-1,84; I² = 79,9%) e à hipofosfatemia grau 3 ou 4 (RR = 0,56; IC95%: 0,15-2,10). A certeza das evidências variou de alta a moderada para os desfechos analisados. A PrEP oral diária é segura e bem tolerada por HSH e MTG. Os efeitos adversos foram mínimos e distribuídos uniformemente entre a intervenção e o controle.

Palavras-chave:
Profilaxia Pré-Exposição; Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos; HIV; Combinação Emtricitabina e Fumarato de Tenofovir Desoproxila

Resumen:

Los efectos adversos de la profilaxis preexposición (PrEP) oral con fumarato de disoproxilo de tenofovir son barreras para el inicio y la continuación de la PrEP. Aunque los efectos graves son raros y predecibles, la evidencia de esta evaluación entre hombres que tienen sexo con hombres (HSH) y mujeres transgénero (MTG) sigue siendo limitada. Este estudio evalúa los efectos adversos de la PrEP oral diaria en HSH y MTG. Se trata de una revisión sistemática y un metaanálisis de ensayos clínicos y cohortes que demuestran el uso de la PrEP oral diaria seleccionada de las bases de datos PubMed/MEDLINE, Embase, LILACS y Cochrane CENTRAL. La recolección de datos incluyó efectos adversos y cambios en los marcadores renales y hepáticos. Se utilizaron modelos de efectos aleatorios para resumir el riesgo de efectos adversos a lo largo del estudio. La heterogeneidad se evaluó mediante la prueba Q de Cochran y la inconsistencia (I²). El riesgo de sesgo y la certeza de la evidencia se evaluaron utilizando las recomendaciones de la Colaboración Cochrane. Se identificaron 653 referencias. De estas, se seleccionaron diez. Todos los estudios evaluaron los marcadores renales de elegibilidad y los marcadores hepáticos. El uso diario de la PrEP oral no se asoció con eventos de grado 3 o 4 (RR = 0,99; IC95%: 0,83-1,18; I² = 26,1%), con ningún evento adverso grave (RR = 1,04; IC95%: 0,58-1,87; I² = 88,4%), con creatinina de grado 3 o 4 (RR = 0,66; IC95%: 0,24-1,84; I² = 79,9%) y con hipofosfatemia de grado 3 o 4 (RR = 0,56, IC95%: 0,15-2,10). La certeza de la evidencia varió de alta a moderada para los resultados analizados. La PrEP oral diaria es segura y bien tolerada por HSH y MTG. Los efectos adversos fueron mínimos y se distribuyeron uniformemente entre la intervención y el control.

Palabras-clave:
Profilaxis Pre-Exposición; Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos; VIH; Combinación Emtricitabina y Fumarato de Tenofovir Disoproxil

Introduction

Pre-exposure prophylaxis (PrEP) is one of the key combination prevention strategies to control the HIV epidemic, especially for populations at substantial risk of HIV infection ¹1. Koechlin FM, Fonner VA, Dalglish SL, O'Reilly KR, Baggaley R, Grant RM, et al. Values and preferences on the use of oral pre-exposure prophylaxis (PrEP) for HIV prevention among multiple populations: a systematic review of the literature. AIDS Behav 2017; 21:1325-35., as recommended by the World Health Organization (WHO) in September 2015. Oral PrEP with tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) is highly effective in preventing HIV infection when used as recommended by WHO guidelines ²2. World Health Organization. Pre-exposure prophylaxis (PrEP). https://www.who.int/teams/global-hiv-hepatitis-and-stis-programmes/hiv/prevention/pre-exposure-prophylaxis (accessed on 05/May/2022).
https://www.who.int/teams/global-hiv-hep... . The use of PrEP requires an initial clinical assessment by anamnesis, an evaluation of contraindications, and monitoring of adverse events.

Although oral PrEP is well tolerated, it can lead to mild or moderate adverse events and rarely to severe conditions ³3. Pilkington V, Hill A, Hughes S, Nwokolo N, Pozniak A. How safe is TDF/FTC as PrEP? A systematic review and meta-analysis of the risk of adverse events in 13 randomised trials of PrEP. J Virus Erad 2018; 4:215-24.. Therefore, due to the risk of nephrotoxicity, the WHO recommends that participants undergo medical examinations before starting PrEP, to identify any history of kidney injury and thus exclude the association with the medication after initiation ⁴4. World Health Organization. WHO implementation tool for pre-exposure prophylaxis (?PrEP)? of HIV infection: module 1: clinical. https://apps.who.int/iris/handle/10665/255889 (accessed on 05/May/2022).
https://apps.who.int/iris/handle/10665/2... . Moreover, creatinine levels should be measured during PrEP initiation and every six months, with more frequent monitoring in individuals with kidney-related comorbidities and less frequent monitoring in individuals aged < 45 years ⁴4. World Health Organization. WHO implementation tool for pre-exposure prophylaxis (?PrEP)? of HIV infection: module 1: clinical. https://apps.who.int/iris/handle/10665/255889 (accessed on 05/May/2022).
https://apps.who.int/iris/handle/10665/2... .

Evidence from clinical trials and cohort studies on the use of PrEP shows rare adverse effects and changes in renal ³3. Pilkington V, Hill A, Hughes S, Nwokolo N, Pozniak A. How safe is TDF/FTC as PrEP? A systematic review and meta-analysis of the risk of adverse events in 13 randomised trials of PrEP. J Virus Erad 2018; 4:215-24.^,55. Schaefer R, Amparo da Costa Leite PH, Silva R, Abdool Karim Q, Akolo C, Cáceres CF, et al. Kidney function in tenofovir disoproxil fumarate-based oral pre-exposure prophylaxis users: a systematic review and meta-analysis of published literature and a multi-country meta-analysis of individual participant data. Lancet HIV 2022; 9:e242-53.^,66. Yacoub R, Nadkarni GN, Weikum D, Konstantinidis I, Boueilh A, Grant RM, et al. Elevations in serum creatinine with tenofovir-based HIV pre-exposure prophylaxis: a meta-analysis of randomized placebo-controlled trials. J Acquir Immune Defic Syndr 2016; 71:e115-8. and bone markers ⁷7. Baranek B, Wang S, Cheung AM, Mishra S, Tan DH. The effect of tenofovir disoproxil fumarate on bone mineral density: a systematic review and meta-analysis. Antivir Ther 2020; 25:21-32.. These changes are generally mild and do not lead to significant effects ⁸8. Chou R, Evans C, Hoverman A, Sun C, Dana T, Bougatsos C, et al. Preexposure prophylaxis for the prevention of HIV infection: evidence report and systematic review for the US Preventive Services Task Force. JAMA 2019; 321:2214-30.. However, these studies analyzed multiple groups, but not specifically men who have sex with men (MSM) or transgender women (TGW). A study with a representative sample of transgender individuals in the United States recorded higher rates of certain adverse effects associated with PrEP, such as nausea, diarrhea, kidney failure, and changes in bone density, compared with studies that included only MSM in the same country, despite the limitations and differences in the assessment of these outcomes between the studies ⁹9. Poteat T, Wirtz A, Malik M, Cooney E, Cannon C, Hardy WD, et al. A gap between willingness and uptake: findings from mixed methods research on HIV prevention among black and Latina transgender women. J Acquir Immune Defic Syndr 2019; 82:131-40.^,1010. Grant RM, Lama JR, Anderson PL, McMahan V, Liu AY, Vargas L, et al. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med 2010; 363:2587-99..

A systematic review found that the risk of a decline in estimated creatinine clearance may differ slightly according to gender ⁵5. Schaefer R, Amparo da Costa Leite PH, Silva R, Abdool Karim Q, Akolo C, Cáceres CF, et al. Kidney function in tenofovir disoproxil fumarate-based oral pre-exposure prophylaxis users: a systematic review and meta-analysis of published literature and a multi-country meta-analysis of individual participant data. Lancet HIV 2022; 9:e242-53., but cisgender and transgender or non-binary individuals showed no difference regarding risk, although data were scarce. Therefore, it is essential to understand that these findings are not universally applicable to all individuals in each group. Therefore, investigating the adverse effects of PrEP may increase the knowledge about these effects in PrEP users. Moreover, as adverse events can affect the effectiveness of medications ¹¹11. Strom BL, Melmon KL. The use of pharmacoepidemiology to study beneficial drug effects. In: Strom BL, Kimmel SE, Hennessy S, editors. Pharmacoepidemiology. 6th Ed. Hoboken: John Wiley & Sons, Ltd; 2019. p. 813-36., estimating the adverse effects associated with PrEP in MSM and TGW is important, since they are at a high risk of HIV infection.

Low adherence to PrEP among individuals for whom it is indicated is a substantial problem affecting many groups. The short- and long-term safety of PrEP among individuals at risk of HIV infection raises doubts. Qualitative studies with MSM and TGW reported that concerns about side effects were associated with a lower willingness to take PrEP ⁹9. Poteat T, Wirtz A, Malik M, Cooney E, Cannon C, Hardy WD, et al. A gap between willingness and uptake: findings from mixed methods research on HIV prevention among black and Latina transgender women. J Acquir Immune Defic Syndr 2019; 82:131-40.^,1212. Rael CT, Martinez M, Giguere R, Bockting W, MacCrate C, Mellman W, et al. Barriers and facilitators to oral PrEP use among transgender women in New York City. AIDS Behav 2018; 22:3627-36.^,1313. Cahill S, Taylor SW, Elsesser SA, Mena L, Hickson D, Mayer KH. Stigma, medical mistrust, and perceived racism may affect PrEP awareness and uptake in black compared to white gay and bisexual men in Jackson, Mississippi and Boston, Massachusetts. AIDS Care 2017; 29:1351-8.^,1414. Holloway IW, Tan D, Gildner JL, Beougher SC, Pulsipher C, Montoya JA, et al. Facilitators and barriers to pre-exposure prophylaxis willingness among young men who have sex with men who use geosocial networking applications in California. AIDS Patient Care STDS 2017; 31:517-27., as well as a lack of research with TGW ¹²12. Rael CT, Martinez M, Giguere R, Bockting W, MacCrate C, Mellman W, et al. Barriers and facilitators to oral PrEP use among transgender women in New York City. AIDS Behav 2018; 22:3627-36.. Moreover, individuals from different social groups, such as MSM and TGW, may have different risks of adverse reactions to medications, which may be related to failures in treatment follow-up due to factors that alter the risk of problem occurrence or monitoring ⁹9. Poteat T, Wirtz A, Malik M, Cooney E, Cannon C, Hardy WD, et al. A gap between willingness and uptake: findings from mixed methods research on HIV prevention among black and Latina transgender women. J Acquir Immune Defic Syndr 2019; 82:131-40.^,1212. Rael CT, Martinez M, Giguere R, Bockting W, MacCrate C, Mellman W, et al. Barriers and facilitators to oral PrEP use among transgender women in New York City. AIDS Behav 2018; 22:3627-36.^,1414. Holloway IW, Tan D, Gildner JL, Beougher SC, Pulsipher C, Montoya JA, et al. Facilitators and barriers to pre-exposure prophylaxis willingness among young men who have sex with men who use geosocial networking applications in California. AIDS Patient Care STDS 2017; 31:517-27.^,1515. Cottrell ML, Prince HMA, Schauer AP, Sykes C, Maffuid K, Poliseno A, et al. Decreased tenofovir diphosphate concentrations in a transgender female cohort: implications for human immunodeficiency virus preexposure prophylaxis. Clin Infect Dis 2019; 69:2201-4.. Notably, these groups are a priority for HIV prevention, especially transgender individuals considering using PrEP to prevent HIV, who are concerned about the adverse effects and the interactions of the medication with gender-affirming hormone therapy ⁹9. Poteat T, Wirtz A, Malik M, Cooney E, Cannon C, Hardy WD, et al. A gap between willingness and uptake: findings from mixed methods research on HIV prevention among black and Latina transgender women. J Acquir Immune Defic Syndr 2019; 82:131-40.^,1515. Cottrell ML, Prince HMA, Schauer AP, Sykes C, Maffuid K, Poliseno A, et al. Decreased tenofovir diphosphate concentrations in a transgender female cohort: implications for human immunodeficiency virus preexposure prophylaxis. Clin Infect Dis 2019; 69:2201-4..

Therefore, assessing the adverse effects of using oral PrEP in different key populations, such as MSM and TGW, can provide a better understanding of adverse effects in these populations, since systematic reviews have not yet stratified the adverse effects of subgroups ³3. Pilkington V, Hill A, Hughes S, Nwokolo N, Pozniak A. How safe is TDF/FTC as PrEP? A systematic review and meta-analysis of the risk of adverse events in 13 randomised trials of PrEP. J Virus Erad 2018; 4:215-24.^,66. Yacoub R, Nadkarni GN, Weikum D, Konstantinidis I, Boueilh A, Grant RM, et al. Elevations in serum creatinine with tenofovir-based HIV pre-exposure prophylaxis: a meta-analysis of randomized placebo-controlled trials. J Acquir Immune Defic Syndr 2016; 71:e115-8., focusing, when available, on renal parameters ⁵5. Schaefer R, Amparo da Costa Leite PH, Silva R, Abdool Karim Q, Akolo C, Cáceres CF, et al. Kidney function in tenofovir disoproxil fumarate-based oral pre-exposure prophylaxis users: a systematic review and meta-analysis of published literature and a multi-country meta-analysis of individual participant data. Lancet HIV 2022; 9:e242-53.. On the other hand, fear of the adverse effects of PrEP is considered a barrier for individuals start using PrEP ¹⁶16. Wood S, Gross R, Shea JA, Bauermeister JA, Franklin J, Petsis D, et al. Barriers and facilitators of PrEP adherence for young men and transgender women of color. AIDS Behav 2019; 23:2719-29.^,1717. Muhumuza R, Ssemata AS, Kakande A, Ahmed N, Atujuna M, Nomvuyo M, et al. Exploring perceived barriers and facilitators of PrEP uptake among young people in Uganda, Zimbabwe, and South Africa. Arch Sex Behav 2021; 50:1729-42..

Understanding the barriers to PrEP use and producing new evidence on the topic, such as the side effects of PrEP, is essential to ensure its effective implementation ¹⁸18. Mayer KH, Agwu A, Malebranche D. Barriers to the wider use of pre-exposure prophylaxis in the United States: a narrative review. Adv Ther 2020; 37:1778-811., particularly among populations with disproportionate and/or increasing rates of HIV infection. Moreover, the use of oral PrEP has increased, along with the evaluation of recommendations for monitoring its adverse effects. Therefore, this study aimed to assess the adverse effects of daily oral PrEP in MSM and TGW.

Methods

Protocol and registration

This systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines ¹⁹19. Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 2021; 372:n71. and was based on the methodological recommendations of the Cochrane Collaboration ²⁰20. Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, et al., editors. Cochrane Handbook for Systematic Reviews of Interventions. 2nd Ed. Chichester: John Wiley & Sons; 2019.. The study protocol was registered in the PROSPERO database (protocol n. CRD42020203079).

The study answers the research question: “What are the adverse effects of oral PrEP in MSM and TGW compared with individuals who do not use this prophylaxis?”.

Eligibility criteria

The PICOT structure was used to define the following eligibility criteria:

The populations of interest (P) were MSM and TGW at any age, regardless of sexual orientation;

The intervention (I) considered was the daily use of oral PrEP: (i) emtricitabine 200mg + tenofovir disoproxil fumarate 300mg (FTC/TDF); (ii) emtricitabine 200mg + tenofovir alafenamide (TAF) 25mg (FTC/TAF); or (iii) tenofovir disoproxil fumarate (TDF);

The comparison group (C) consisted of individuals who did not use PrEP (control group). A comparison group was included to avoid or control for possible nocebo effects in adverse events between the groups;

The outcomes of interest (O) were any serious adverse event, any grade 3 or 4 event, total grade creatinine, and grade 3 or 4 hypophosphatemia (Supplementary Material 1: https://cadernos.ensp.fiocruz.br/static//arquivo/suppl-1-e00089522_4764.pdf).

The study design (T) included cohort studies and clinical trials on PrEP.

This study did not apply restrictions on age, origin, or language of publication. Studies on women, mixed groups (e.g., female sex workers and MSM), serodiscordant heterosexual couples, and sex workers were excluded.

Search strategy

Searches were performed in the bibliographic databases PubMed/MEDLINE, Embase, Cochrane Central Register of Controlled Trials, LILACS, and OpenGray in May 2020 and updated in April 2022. Medical Subject Headings (MeSH), Emtree, and Health Sciences (DeCS) keywords were used to identify studies published in these databases: “Pre-Exposure Prophylaxis”, “chemoprevention”, “HIV”, “human immunodeficiency virus infection”, “Drug-Related Side Effects and Adverse Reactions”, and “Adverse Drug Reaction”. These keywords were combined with the Boolean operators “OR” and “AND” and their entry terms in all databases. This study also searched grey literature in ProQuest and references to systematic reviews on PrEP to identify studies not included in the electronic search. Supplementary Material 2 (https://cadernos.ensp.fiocruz.br/static//arquivo/suppl-2-e00089522_8074.pdf) shows the details of the search process.

Study selection

The publications found in the databases were inserted into the Rayyan application (https://www.rayyan.ai/), a free software that helps select studies. Two evaluators (M.P. and T.A.O.) independently screened titles and abstracts to identify potentially eligible studies. The eligibility of the publications that met the inclusion criteria in the initial phase was confirmed by reading them in full. Studies that met all eligibility criteria were included in the qualitative synthesis. Disagreements regarding the inclusion of studies were resolved by a third evaluator (L.M.).

Data extraction

Using a standardized form, the reviewers (M.P., C.T.C., T.A.O., F.S.G., P.R.S.N., and F.M.F.N.) independently extracted data from the included studies. Extracted data included year of publication, study design, study site, sample size, mean age of participants, medications used, adverse reactions identified, and the criteria and frequency of measurement of adverse effects. At the end of this study, the lead author (M.P.) reviewed all the information. Moreover, authors whose studies were not available in the databases were contacted by the corresponding author to request the full text.

Methodological quality assessment

The methodological quality of all the studies that met the eligibility criteria was assessed using the risk of bias scale for estimates of effectiveness and safety in non-randomized intervention studies recommended by the Cochrane Collaboration, the Risk of Bias in Non-randomized Studies of Interventions (ROBINS-I) ²¹21. Sterne JA, Hernán MA, Reeves BC, Savovic J, Berkman ND, Viswanathan M, et al. ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions. BMJ 2016; 355:i4919.. This tool assesses seven domains of bias classified by moment of occurrence: pre-intervention (bias due to confounding and bias in selection of participants into the study), at intervention (bias in classification of interventions), and post-intervention (bias due to deviations from intended interventions, bias due to missing data, bias in measurement of outcomes, and bias in selection of the reported result).

The items were classified as low, moderate, severe, or critical risk of bias or no information, according to the descriptions in the Cochrane Handbook for Systematic Reviews of Interventions²⁰20. Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, et al., editors. Cochrane Handbook for Systematic Reviews of Interventions. 2nd Ed. Chichester: John Wiley & Sons; 2019..

Statistical analysis

A random effects meta-analysis was conducted using the rate of adverse events for the following outcomes: any serious adverse event, any grade 3 or 4 event, total grade creatinine (subgroups 1+2 and 3+4), and grade 3 or 4 hypophosphatemia (Supplementary Material 1: https://cadernos.ensp.fiocruz.br/static//arquivo/suppl-1-e00089522_4764.pdf). These are described as follows:

Any serious adverse event: any unforeseen medical event that, at any dose, leads to death, is life-threatening, requires hospitalization or prolongation of an existing hospitalization, or causes persistent or significant disability or incapacity ²²22. Division of AIDS. DAIDS adverse event grading tables. https://rsc.niaid.nih.gov/clinical-research-sites/daids-adverse-event-grading-tables (accessed on 07/May/2022).
https://rsc.niaid.nih.gov/clinical-resea... ;

Any grade 3 or 4 event: severe or potentially life-threatening event;

Total grade creatinine (subgroups 1+2 and 3+4): all serum creatinine elevations from 1.1 to 1.3 times the upper limit of typical levels. Grade 2 and higher events include serum creatinine elevations of 1.3 to 1.8 times the upper limit of typical levels or 1.3 to 1.5 times the participants’ baseline value ²²22. Division of AIDS. DAIDS adverse event grading tables. https://rsc.niaid.nih.gov/clinical-research-sites/daids-adverse-event-grading-tables (accessed on 07/May/2022).
https://rsc.niaid.nih.gov/clinical-resea... ;

Hypophosphatemia: grade 3 includes serum phosphate < 2.0-1.0mg/dL or < 0.6-0.3mmol/L. Grade 4 includes serum phosphate < 1.0mg/dL or < 0.3mmol/L and life-threatening consequences ²²22. Division of AIDS. DAIDS adverse event grading tables. https://rsc.niaid.nih.gov/clinical-research-sites/daids-adverse-event-grading-tables (accessed on 07/May/2022).
https://rsc.niaid.nih.gov/clinical-resea... .

These biochemical outcomes were selected because when they are altered in individuals under PrEP, discontinuation is recommended. In studies with no events in the intervention or control groups, a value of one was entered to estimate the summary mean.

The measures adopted to summarize the results were the relative risk (RR) and their respective 95% confidence intervals (95%CI). Cochran’s Q statistical test and the inconsistency test (I²) were used to assess the heterogeneity and consistency of the studies ²³23. Harris RJ, Bradburn MJ, Deeks JJ, Altman DG, Harbord RM, Sterne JAC. Metan: fixed- and random-effects meta-analysis. Stata J 2008; 8:3-28.. In the presence of heterogeneity (p < 0.05; I² > 25%), a random model with inverse variance was used, weighted by the results of the individual studies ²⁴24. Higgins JPT, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med 2002; 21:1539-58.. A minimum of eight studies were considered to assess publication bias by preparing the funnel plot and performing Egger’s test ²⁰20. Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, et al., editors. Cochrane Handbook for Systematic Reviews of Interventions. 2nd Ed. Chichester: John Wiley & Sons; 2019.^,2525. Sterne JAC, Harbord RM. Funnel plots in meta-analysis. Stata J 2004; 4:127-41..

Assessment of the certainty of the evidence

The certainty of the evidence was assessed using GRADEpro software (https://www.gradepro.org/). The GRADE (Grading of Recommendations Assessment, Development, and Evaluation) system classifies the quality of the evidence into four levels: high, moderate, low, and very low, according to study design limitations, indirect evidence, inconsistency of results, imprecision of results, and a significant probability of publication bias ²⁶26. Schünemann H, Brozek J, Guyatt G, Oxman A, editors. GRADE handbook. https://gdt.gradepro.org/app/handbook/handbook.html (accessed on 07/Jan/2022).
https://gdt.gradepro.org/app/handbook/ha... .

Results

Study selection

We identified 653 references using the search strategies adopted, of which 99 were selected to assess their eligibility and 10 studies, that is, 16 articles ¹⁰10. Grant RM, Lama JR, Anderson PL, McMahan V, Liu AY, Vargas L, et al. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med 2010; 363:2587-99.^,2727. Deutsch MB, Glidden DV, Sevelius J, Keatley J, McMahan V, Guanira J, et al. HIV pre-exposure prophylaxis in transgender women: a subgroup analysis of the iPrEx trial. Lancet HIV 2015; 2:e512-9.^,2828. McCormack S, Dunn DT, Desai M, Dolling DI, Gafos M, Gilson R, et al. Pre-exposure prophylaxis to prevent the acquisition of HIV-1 infection (PROUD): effectiveness results from the pilot phase of a pragmatic open-label randomised trial. Lancet 2016; 387:53-60.^,2929. Grant RM, Mannheimer S, Hughes JP, Hirsch-Moverman Y, Loquere A, Chitwarakorn A, et al. Daily and nondaily oral preexposure prophylaxis in men and transgender women who have sex with men: the human immunodeficiency virus prevention trials network 067/ADAPT Study. Clin Infect Dis 2018; 66:1712-21.^,3030. Solomon MM, Lama JR, Glidden DV, Mulligan K, McMahan V, Liu AY, et al. Changes in renal function associated with oral emtricitabine/tenofovir disoproxil fumarate use for HIV pre-exposure prophylaxis. AIDS 2014; 28:851-9.^,3131. Liu AY, Vittinghoff E, Sellmeyer DE, Irvin R, Mulligan K, Mayer K, et al. Bone mineral density in HIV-negative men participating in a tenofovir pre-exposure prophylaxis randomized clinical trial in San Francisco. PLoS One 2011; 6:e23688.^,3232. Mayer KH, Molina J-M, Thompson MA, Anderson PL, Mounzer KC, De Wet JJ, et al. Emtricitabine and tenofovir alafenamide vs emtricitabine and tenofovir disoproxil fumarate for HIV pre-exposure prophylaxis (DISCOVER): primary results from a randomised, double-blind, multicentre, active-controlled, phase 3, non-inferiority trial. Lancet 2020; 396:239-54.^,3333. Wheeler DP, Fields SD, Beauchamp G, Chen YQ, Emel LM, Hightow-Weidman L, et al. Pre-exposure prophylaxis initiation and adherence among black men who have sex with men (MSM) in three US cities: results from the HPTN 073 study. J Int AIDS Soc 2019; 22:e25223.^,3434. Grohskopf LA, Chillag KL, Gvetadze R, Liu AY, Thompson M, Mayer KH, et al. Randomized trial of clinical safety of daily oral tenofovir disoproxil fumarate among HIV-uninfected men who have sex with men in the United States. J Acquir Immune Defic Syndr 2013; 64:79-86.^,3535. Havens PL, Stephensen CB, Van Loan MD, Schuster GU, Woodhouse LR, Flynn PM, et al. Decline in bone mass with tenofovir disoproxil fumarate/emtricitabine is associated with hormonal changes in the absence of renal impairment when used by HIV-uninfected adolescent boys and young men for HIV preexposure prophylaxis. Clin Infect Dis 2017; 64:317-25.^,3636. Hosek SG, Landovitz RJ, Kapogiannis B, Siberry GK, Rudy B, Rutledge B, et al. Safety and feasibility of antiretroviral preexposure prophylaxis for adolescent men who have sex with men aged 15 to 17 years in the United States. JAMA Pediatr 2017; 171:1063-71.^,3737. Hosek SG, Rudy B, Landovitz R, Kapogiannis B, Siberry G, Rutledge B, et al. An HIV preexposure prophylaxis demonstration project and safety study for young MSM. J Acquir Immune Defic Syndr 2017; 74:21-9.^,3838. Hosek SG, Siberry G, Bell M, Lally M, Kapogiannis B, Green K, et al. The acceptability and feasibility of an HIV preexposure prophylaxis (PrEP) trial with young men who have sex with men. JAIDS J Acquir Immune Defic Syndr 2013; 62:447-56.^,3939. Liu AY, Cohen SE, Vittinghoff E, Anderson PL, Doblecki-Lewis S, Bacon O, et al. Preexposure prophylaxis for HIV infection integrated with municipal- and community-based sexual health services. JAMA Intern Med 2016; 176:75-84.^,4040. Tang EC, Vittinghoff E, Anderson PL, Cohen SE, Doblecki-Lewis S, Bacon O, et al. Changes in kidney function associated with daily tenofovir disoproxil fumarate/emtricitabine for HIV preexposure prophylaxis use in the United States Demonstration Project. J Acquir Immune Defic Syndr 2018; 77:193-8.^,4141. Ogbuagu O, Ruane PJ, Podzamczer D, Salazar LC, Henry K, Asmuth DM, et al. Long-term safety and efficacy of emtricitabine and tenofovir alafenamide vs emtricitabine and tenofovir disoproxil fumarate for HIV-1 pre-exposure prophylaxis: week 96 results from a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet HIV 2021; 8:e397-407. were included in the systematic review (Figure 1). The exclusion criteria involved the study population (n = 20), the outcomes analyzed (n = 23), the PrEP regimen (n = 17), the clinical trial protocol (n = 15), and the cross-sectional study design (n = 1) (Figure 1).

Assessment of risk of bias

Figure 2 shows the results of the quality assessment of the included studies. Among them, risk of bias was predominantly low ¹⁰10. Grant RM, Lama JR, Anderson PL, McMahan V, Liu AY, Vargas L, et al. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med 2010; 363:2587-99.^,2929. Grant RM, Mannheimer S, Hughes JP, Hirsch-Moverman Y, Loquere A, Chitwarakorn A, et al. Daily and nondaily oral preexposure prophylaxis in men and transgender women who have sex with men: the human immunodeficiency virus prevention trials network 067/ADAPT Study. Clin Infect Dis 2018; 66:1712-21.^,3030. Solomon MM, Lama JR, Glidden DV, Mulligan K, McMahan V, Liu AY, et al. Changes in renal function associated with oral emtricitabine/tenofovir disoproxil fumarate use for HIV pre-exposure prophylaxis. AIDS 2014; 28:851-9.^,3636. Hosek SG, Landovitz RJ, Kapogiannis B, Siberry GK, Rudy B, Rutledge B, et al. Safety and feasibility of antiretroviral preexposure prophylaxis for adolescent men who have sex with men aged 15 to 17 years in the United States. JAMA Pediatr 2017; 171:1063-71.^,3939. Liu AY, Cohen SE, Vittinghoff E, Anderson PL, Doblecki-Lewis S, Bacon O, et al. Preexposure prophylaxis for HIV infection integrated with municipal- and community-based sexual health services. JAMA Intern Med 2016; 176:75-84.^,4040. Tang EC, Vittinghoff E, Anderson PL, Cohen SE, Doblecki-Lewis S, Bacon O, et al. Changes in kidney function associated with daily tenofovir disoproxil fumarate/emtricitabine for HIV preexposure prophylaxis use in the United States Demonstration Project. J Acquir Immune Defic Syndr 2018; 77:193-8. and moderate ³²32. Mayer KH, Molina J-M, Thompson MA, Anderson PL, Mounzer KC, De Wet JJ, et al. Emtricitabine and tenofovir alafenamide vs emtricitabine and tenofovir disoproxil fumarate for HIV pre-exposure prophylaxis (DISCOVER): primary results from a randomised, double-blind, multicentre, active-controlled, phase 3, non-inferiority trial. Lancet 2020; 396:239-54.^,3333. Wheeler DP, Fields SD, Beauchamp G, Chen YQ, Emel LM, Hightow-Weidman L, et al. Pre-exposure prophylaxis initiation and adherence among black men who have sex with men (MSM) in three US cities: results from the HPTN 073 study. J Int AIDS Soc 2019; 22:e25223.^,3434. Grohskopf LA, Chillag KL, Gvetadze R, Liu AY, Thompson M, Mayer KH, et al. Randomized trial of clinical safety of daily oral tenofovir disoproxil fumarate among HIV-uninfected men who have sex with men in the United States. J Acquir Immune Defic Syndr 2013; 64:79-86.^,3838. Hosek SG, Siberry G, Bell M, Lally M, Kapogiannis B, Green K, et al. The acceptability and feasibility of an HIV preexposure prophylaxis (PrEP) trial with young men who have sex with men. JAIDS J Acquir Immune Defic Syndr 2013; 62:447-56.^,4141. Ogbuagu O, Ruane PJ, Podzamczer D, Salazar LC, Henry K, Asmuth DM, et al. Long-term safety and efficacy of emtricitabine and tenofovir alafenamide vs emtricitabine and tenofovir disoproxil fumarate for HIV-1 pre-exposure prophylaxis: week 96 results from a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet HIV 2021; 8:e397-407., and two were critical ²⁸28. McCormack S, Dunn DT, Desai M, Dolling DI, Gafos M, Gilson R, et al. Pre-exposure prophylaxis to prevent the acquisition of HIV-1 infection (PROUD): effectiveness results from the pilot phase of a pragmatic open-label randomised trial. Lancet 2016; 387:53-60.^,3737. Hosek SG, Rudy B, Landovitz R, Kapogiannis B, Siberry G, Rutledge B, et al. An HIV preexposure prophylaxis demonstration project and safety study for young MSM. J Acquir Immune Defic Syndr 2017; 74:21-9.. The main criteria contributing to moderate or critical risk of bias were bias due to confounding, bias due to missing data, and bias in in measurement of outcomes.

Characterization and qualitative synthesis of the selected studies

Table 1 presents the main characteristics of the included studies. We analyzed information on adverse effects (US CDC PrEP ³¹31. Liu AY, Vittinghoff E, Sellmeyer DE, Irvin R, Mulligan K, Mayer K, et al. Bone mineral density in HIV-negative men participating in a tenofovir pre-exposure prophylaxis randomized clinical trial in San Francisco. PLoS One 2011; 6:e23688.^,3434. Grohskopf LA, Chillag KL, Gvetadze R, Liu AY, Thompson M, Mayer KH, et al. Randomized trial of clinical safety of daily oral tenofovir disoproxil fumarate among HIV-uninfected men who have sex with men in the United States. J Acquir Immune Defic Syndr 2013; 64:79-86., iPrEx ¹⁰10. Grant RM, Lama JR, Anderson PL, McMahan V, Liu AY, Vargas L, et al. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med 2010; 363:2587-99.^,2727. Deutsch MB, Glidden DV, Sevelius J, Keatley J, McMahan V, Guanira J, et al. HIV pre-exposure prophylaxis in transgender women: a subgroup analysis of the iPrEx trial. Lancet HIV 2015; 2:e512-9.^,3030. Solomon MM, Lama JR, Glidden DV, Mulligan K, McMahan V, Liu AY, et al. Changes in renal function associated with oral emtricitabine/tenofovir disoproxil fumarate use for HIV pre-exposure prophylaxis. AIDS 2014; 28:851-9., US PrEP Demonstration Project ³⁹39. Liu AY, Cohen SE, Vittinghoff E, Anderson PL, Doblecki-Lewis S, Bacon O, et al. Preexposure prophylaxis for HIV infection integrated with municipal- and community-based sexual health services. JAMA Intern Med 2016; 176:75-84.^,4040. Tang EC, Vittinghoff E, Anderson PL, Cohen SE, Doblecki-Lewis S, Bacon O, et al. Changes in kidney function associated with daily tenofovir disoproxil fumarate/emtricitabine for HIV preexposure prophylaxis use in the United States Demonstration Project. J Acquir Immune Defic Syndr 2018; 77:193-8., and PrEPare ³⁶36. Hosek SG, Landovitz RJ, Kapogiannis B, Siberry GK, Rudy B, Rutledge B, et al. Safety and feasibility of antiretroviral preexposure prophylaxis for adolescent men who have sex with men aged 15 to 17 years in the United States. JAMA Pediatr 2017; 171:1063-71.^,3737. Hosek SG, Rudy B, Landovitz R, Kapogiannis B, Siberry G, Rutledge B, et al. An HIV preexposure prophylaxis demonstration project and safety study for young MSM. J Acquir Immune Defic Syndr 2017; 74:21-9.) and study extension (PrePare ATN 08 3MV ³⁸38. Hosek SG, Siberry G, Bell M, Lally M, Kapogiannis B, Green K, et al. The acceptability and feasibility of an HIV preexposure prophylaxis (PrEP) trial with young men who have sex with men. JAIDS J Acquir Immune Defic Syndr 2013; 62:447-56., ATN 117 ³⁵35. Havens PL, Stephensen CB, Van Loan MD, Schuster GU, Woodhouse LR, Flynn PM, et al. Decline in bone mass with tenofovir disoproxil fumarate/emtricitabine is associated with hormonal changes in the absence of renal impairment when used by HIV-uninfected adolescent boys and young men for HIV preexposure prophylaxis. Clin Infect Dis 2017; 64:317-25., ADAPT Study ²⁹29. Grant RM, Mannheimer S, Hughes JP, Hirsch-Moverman Y, Loquere A, Chitwarakorn A, et al. Daily and nondaily oral preexposure prophylaxis in men and transgender women who have sex with men: the human immunodeficiency virus prevention trials network 067/ADAPT Study. Clin Infect Dis 2018; 66:1712-21., HPTN 073 ³³33. Wheeler DP, Fields SD, Beauchamp G, Chen YQ, Emel LM, Hightow-Weidman L, et al. Pre-exposure prophylaxis initiation and adherence among black men who have sex with men (MSM) in three US cities: results from the HPTN 073 study. J Int AIDS Soc 2019; 22:e25223., DISCOVER ³²32. Mayer KH, Molina J-M, Thompson MA, Anderson PL, Mounzer KC, De Wet JJ, et al. Emtricitabine and tenofovir alafenamide vs emtricitabine and tenofovir disoproxil fumarate for HIV pre-exposure prophylaxis (DISCOVER): primary results from a randomised, double-blind, multicentre, active-controlled, phase 3, non-inferiority trial. Lancet 2020; 396:239-54.^,4141. Ogbuagu O, Ruane PJ, Podzamczer D, Salazar LC, Henry K, Asmuth DM, et al. Long-term safety and efficacy of emtricitabine and tenofovir alafenamide vs emtricitabine and tenofovir disoproxil fumarate for HIV-1 pre-exposure prophylaxis: week 96 results from a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet HIV 2021; 8:e397-407., and PROUD ²⁸28. McCormack S, Dunn DT, Desai M, Dolling DI, Gafos M, Gilson R, et al. Pre-exposure prophylaxis to prevent the acquisition of HIV-1 infection (PROUD): effectiveness results from the pilot phase of a pragmatic open-label randomised trial. Lancet 2016; 387:53-60..

The studies consisted of clinical trials (n = 7) and cohort studies (n = 3) and mostly involved MSM (n = 4), young MSM (n = 4), and MSM/TGW (n = 2). Moreover, the years of publication ranged from 2011 to 2021, the samples from 78 to 5,387 participants, and the ages from 15 to 67 years. Four studies had a follow-up duration of ≤ 1 year ²⁸28. McCormack S, Dunn DT, Desai M, Dolling DI, Gafos M, Gilson R, et al. Pre-exposure prophylaxis to prevent the acquisition of HIV-1 infection (PROUD): effectiveness results from the pilot phase of a pragmatic open-label randomised trial. Lancet 2016; 387:53-60.^,2929. Grant RM, Mannheimer S, Hughes JP, Hirsch-Moverman Y, Loquere A, Chitwarakorn A, et al. Daily and nondaily oral preexposure prophylaxis in men and transgender women who have sex with men: the human immunodeficiency virus prevention trials network 067/ADAPT Study. Clin Infect Dis 2018; 66:1712-21.^,3838. Hosek SG, Siberry G, Bell M, Lally M, Kapogiannis B, Green K, et al. The acceptability and feasibility of an HIV preexposure prophylaxis (PrEP) trial with young men who have sex with men. JAIDS J Acquir Immune Defic Syndr 2013; 62:447-56.^,4040. Tang EC, Vittinghoff E, Anderson PL, Cohen SE, Doblecki-Lewis S, Bacon O, et al. Changes in kidney function associated with daily tenofovir disoproxil fumarate/emtricitabine for HIV preexposure prophylaxis use in the United States Demonstration Project. J Acquir Immune Defic Syndr 2018; 77:193-8.and the others < 1 year.

Table 2 presents the adverse event monitoring data evaluated at baseline and in the study segment. All studies addressed renal function markers at eligibility or baseline. Hepatic markers were reported in only five studies (US CDC PrEP, iPrEx, PrEPare, and ADAPT Study). Markers of adverse effects were assessed at different times in the participants’ segment and, in most cases, classified according to the U.S. Division of AIDS criteria ²²22. Division of AIDS. DAIDS adverse event grading tables. https://rsc.niaid.nih.gov/clinical-research-sites/daids-adverse-event-grading-tables (accessed on 07/May/2022).
https://rsc.niaid.nih.gov/clinical-resea... .

Meta-analysis results

Figure 3 shows the results of the meta-analysis. Publication bias could not be assessed due to the small number of studies analyzed. We obtained the following results:

Any grade 3 or 4 event: no statistically significant effect (RR = 0.99; 95%CI: 0.83-1.18; I² = 26.1%) on the total number of grade 3 or 4 adverse events in PrEP users compared with the control group (Figure 3a);

Any serious adverse event: six studies reported serious adverse effects. The use of oral PrEP was not associated with serious adverse effects (RR = 0.99; 95%CI: 0.54-1.80; I² = 90.1%) (Figure 3b);

Creatinine changes: four studies reported data on serious adverse events related to creatinine, but only two were included in the meta-analysis due to the number of observations (> 0). The use of daily oral PrEP was not associated with the occurrence of grade 1 or 2 (RR = 1.12; 95%CI: 0.34-3.65; I² = 0%) or grade 3 or 4 creatinine levels (RR = 0.66; 95%CI: 0.24-1.84; I² = 79.9%) (Figure 3c);

Grade 3 or 4 hypophosphatemia: the meta-analyses of grade 3 or 4 hypophosphatemia found no significant difference (p = 0.53) between the number of events in PrEP users compared with the control group (RR = 0.56; 95%CI: 0.15-2.10). Heterogeneity between trials was moderate (I² = 48.3%) (Figure 3d).

Certainty of evidence

The certainty of the evidence for any grade 3 or 4 event and creatinine changes was high. However, it was moderate for the outcomes of any serious adverse event and grade 3 or 4 hypophosphatemia due to the high unexplained heterogeneity, the few included studies in the meta-analysis, and the number of outcome observations (Table 3).

Discussion

Main findings of the review

In this study, we reviewed clinical trials and cohort studies on the adverse effects of oral PrEP in MSM and TGW. This is the first systematic review to assess the adverse effects of daily oral PrEP in MSM and TGW.

The results of this systematic review showed that most studies on PrEP use did not present a risk of serious adverse events. The meta-analysis confirmed these observations, with the lack of statistically significant association with serious adverse outcomes in the control group. Daily oral PrEP in MSM, young MSM, and TGW showed no statistically significant association with the occurrence of serious adverse events, grade 3 or 4 adverse events, serious changes in creatinine levels (grade 3+4), and grade 3 or 4 hypophosphatemia. Thus, this study showed that the daily use of PrEP was safe and well tolerated in the study population.

These findings are important, since adverse events can reduce adherence to PrEP. Adherence is a major challenge for effective PrEP implementation, particularly among young MSM and TGW ¹⁶16. Wood S, Gross R, Shea JA, Bauermeister JA, Franklin J, Petsis D, et al. Barriers and facilitators of PrEP adherence for young men and transgender women of color. AIDS Behav 2019; 23:2719-29.^,4242. Grinsztejn B, Hoagland B, Moreira RI, Kallas EG, Madruga JV, Goulart S, et al. Retention, engagement, and adherence to pre-exposure prophylaxis for men who have sex with men and transgender women in PrEP Brasil: 48 week results of a demonstration study. Lancet HIV 2018; 5:e136-45.. Although our meta-analysis focused on clinical trials and cohort studies, the adverse events found in the studies may determine the effectiveness of this therapy in preventing HIV in MSM and TGW. Moreover, our findings may help prescribers assess the risk-benefit of the use of PrEP by MSM and TGW in clinical practice.

Most studies assessed baseline renal parameters and the eligibility of participants. However, these studies did not address renal markers ²⁸28. McCormack S, Dunn DT, Desai M, Dolling DI, Gafos M, Gilson R, et al. Pre-exposure prophylaxis to prevent the acquisition of HIV-1 infection (PROUD): effectiveness results from the pilot phase of a pragmatic open-label randomised trial. Lancet 2016; 387:53-60.. Renal function was assessed predominantly by measuring serum creatinine levels and estimating creatinine clearance using the Cockcroft-Gault equation ⁴³43. Levey AS, Stevens LA. Estimating GFR using the CKD Epidemiology Collaboration (CKD-EPI) creatinine equation: more accurate GFR estimates, lower CKD prevalence estimates, and better risk predictions. Am J Kidney Dis 2010; 55:622-7.. Another correlation of renal function assessment analyzed in this study was the serum phosphate level measured in PrEP users in three studies. Only four studies assessed hepatic function, considering liver transaminases (aspartate aminotransferase and alanine aminotransferase) as the main factors.

In the segment of PrEP users, studies have no consensus on the evaluation period of the analyzed renal and hepatic markers. However, many of these studies reported consistent associations, showing that daily oral PrEP does not pose a substantial risk of serious adverse events.

These results are greatly relevant, especially for TGW, since their hormone therapy is often based on a combination of estradiol and an antiandrogen ⁴⁴44. Janini JP, Oliveira LCS, Souza VM. Hormone therapy in an elderly transsexual woman: a case study. Res Soc Dev 2022; 11:e550111033113.. The use of these substances along with PrEP could potentiate or lead to serious adverse reactions, which were not observed in this meta-analysis.

Comparisons with other studies in the literature

The results of this study, particularly the association between the use of TDF/FTC and the risk of adverse events, are in line with other studies. A systematic review and meta-analysis of 13 studies that compared 15,678 randomized participants who used PrEP (TDF/FTC or TDF) with individuals who used a placebo or received no treatment found no significant difference in the risk of grade 3 or 4 clinical adverse events or serious adverse effects between the groups. Moreover, the authors found no significant difference in the risk of specific adverse renal or bone outcomes ³3. Pilkington V, Hill A, Hughes S, Nwokolo N, Pozniak A. How safe is TDF/FTC as PrEP? A systematic review and meta-analysis of the risk of adverse events in 13 randomised trials of PrEP. J Virus Erad 2018; 4:215-24..

A meta-analysis evaluating the effect of PrEP on serum creatinine level using 10 clinical trials that included 17,220 participants randomized to daily oral PrEP (n = 9,913) and placebo (n = 7,307) groups found the opposite result ⁶6. Yacoub R, Nadkarni GN, Weikum D, Konstantinidis I, Boueilh A, Grant RM, et al. Elevations in serum creatinine with tenofovir-based HIV pre-exposure prophylaxis: a meta-analysis of randomized placebo-controlled trials. J Acquir Immune Defic Syndr 2016; 71:e115-8.. Participants assigned to the daily PrEP group had a modestly increased risk of grade 1 or higher creatinine events (odds ratio - OR = 1.36; 95%CI: 1.09-1.71). The absolute risk increase was lower (pooled risk increase 0.6%; 95%CI: 0.1-1.2) ⁶6. Yacoub R, Nadkarni GN, Weikum D, Konstantinidis I, Boueilh A, Grant RM, et al. Elevations in serum creatinine with tenofovir-based HIV pre-exposure prophylaxis: a meta-analysis of randomized placebo-controlled trials. J Acquir Immune Defic Syndr 2016; 71:e115-8.. However, these studies were not methodologically adequate to provide robust evidence of this relationship, due to the lack of a subgroup analysis similar to that performed in this study, as well as the risk of bias and the certainty of the meta-analysis evidence.

A systematic review and meta-analysis of individual data from PrEP users also showed results similar to ours regarding serious adverse effects. A meta-analysis of 11 clinical trials with 13,523 participants showed that the use of PrEP increases the risk of grade 1 or higher renal adverse events and grade 2 or higher renal events. However, the association between grade 2 and higher events was not statistically significant. Events are rare, non-progressive, and disappear when PrEP is discontinued ⁵5. Schaefer R, Amparo da Costa Leite PH, Silva R, Abdool Karim Q, Akolo C, Cáceres CF, et al. Kidney function in tenofovir disoproxil fumarate-based oral pre-exposure prophylaxis users: a systematic review and meta-analysis of published literature and a multi-country meta-analysis of individual participant data. Lancet HIV 2022; 9:e242-53.. A subgroup analysis showed that the highest risks were associated with increasing age and baseline creatinine clearance of 60.00-89.99mL/minute. The study highlighted the importance of screening and monitoring renal function in older individuals, individuals with baseline creatinine clearance < 90mL/minute, and individuals with kidney-related comorbidities ⁵5. Schaefer R, Amparo da Costa Leite PH, Silva R, Abdool Karim Q, Akolo C, Cáceres CF, et al. Kidney function in tenofovir disoproxil fumarate-based oral pre-exposure prophylaxis users: a systematic review and meta-analysis of published literature and a multi-country meta-analysis of individual participant data. Lancet HIV 2022; 9:e242-53.. A similar result was identified by the U.S. Preventive Services Task Force review for renal adverse events, but most of them were mild and reversible ⁴⁵45. Farahi N, McEachern M. Sexual assault of women. Am Fam Physician 2021; 103:168-76..

A recent meta-analysis found that PrEP was safe for MSM, serodiscordant couples, heterosexual individuals, and injecting drug users. However, unrecognized HIV at the time of notification increases the risk of drug-resistant viral mutations ⁴⁶46. Murchu EO, Marshall L, Teljeur C, Harrington P, Hayes C, Moran P, et al. Oral pre-exposure prophylaxis (PrEP) to prevent HIV: a systematic review and meta-analysis of clinical effectiveness, safety, adherence and risk compensation in all populations. BMJ Open 2022; 12:e048478.. The meta-analysis of placebo-controlled trial showed no significant difference between the groups for any reported adverse events (RR = 1.01; 95%CI: 0.99-1.03; I² = 42%) and the risk of serious adverse events (RR = 0.91; 95%CI: 0.74-1.13; I² = 67), but the meta-analysis for renal function was not presented ⁴⁶46. Murchu EO, Marshall L, Teljeur C, Harrington P, Hayes C, Moran P, et al. Oral pre-exposure prophylaxis (PrEP) to prevent HIV: a systematic review and meta-analysis of clinical effectiveness, safety, adherence and risk compensation in all populations. BMJ Open 2022; 12:e048478..

These findings reinforce the safety of PrEP, especially in this study with MSM and TGW, who suffered from interpersonal violence, discrimination, and health disparities ⁴⁷47. Gomes R, Murta D, Facchini R, Meneghel SN. Gender and sexual rights: their implications on health and healthcare. Ciênc Saúde Colet 2018; 23:1997-2006., which can alter the risk of occurrence and monitoring of adverse events.

Limitations and strengths

This study has some limitations. The studies reviewed showed a high degree of heterogeneity between them. Besides statistical heterogeneity, the studies had different designs and involved different dosages, duration of exposure, follow-up time, time to event, and frequency of assessment of adverse effects, which may influence our results.

Some studies did not report the criteria for assessing adverse effects according to the U.S. Division of AIDS ²²22. Division of AIDS. DAIDS adverse event grading tables. https://rsc.niaid.nih.gov/clinical-research-sites/daids-adverse-event-grading-tables (accessed on 07/May/2022).
https://rsc.niaid.nih.gov/clinical-resea... , which limited the inclusion of this information in the meta-analysis. These criteria are important, as they consider the evolution of events in the study population. Moreover, most studies were conducted in countries such as the United States, allowing the comparison of results between countries.

This review focused on the assessment of biochemical parameters and did not analyze the adverse effects on bone health markers. We did not assess long-term safety because the maximum follow-up period was two years, focusing only on the use of daily oral PrEP to avoid comparing adverse effects with other types of PrEP. Moreover, the searches were performed by a specialist in systematic reviews and underwent slight variations according to the databases in order to retrieve studies on the topic with more sensitivity. Finally, we did not perform a meta-analysis by type of PrEP, given the small number of studies included in this review and the population, since some studies did not stratify the results for the populations analyzed (MSM and TGW). We also did not perform a subgroup analysis, probably due to the low frequency of adverse events associated with daily oral PrEP.

Despite the limitations imposed by the analyzed studies, they were conducted following rigorous methods, qualifying the findings presented in this review. It is possible to highlight the strengths of this study as a comprehensive review and an extensive search of the scientific literature on the topic, in accordance with the PRISMA and Cochrane Collaboration guidelines. The strengths of this study include the assessment of the risk of bias and the certainty of the evidence. Moreover, the study was methodologically rigorous and was performed by independent reviewers, including a gray literature database.

Another strength of this systematic review and meta-analysis was the focus, except for renal events, on studies with grade 3 or higher events, which are the most dangerous adverse events and may require medical intervention. Finally, this is the first meta-analysis to assess the potential adverse effects of the use of PrEP among MSM and TGW.

Implications and recommendations

The high and moderate evidence from this review suggests that the use of daily oral PrEP has few adverse effects in MSM and TGW. The total number of adverse events, any grade 3 and 4 adverse effect, and changes in creatinine and phosphate level were similarly distributed between participants using PrEP and the control group. We recommend recording and reporting adverse events in studies that follow the monitoring recommendations ²²22. Division of AIDS. DAIDS adverse event grading tables. https://rsc.niaid.nih.gov/clinical-research-sites/daids-adverse-event-grading-tables (accessed on 07/May/2022).
https://rsc.niaid.nih.gov/clinical-resea... and increasing the number of studies on the use of PrEP in low- and middle-income countries, since most studies have focused on high and middle-income countries. Health services and policies on PrEP should expand information on the minimal risk and safety of its use by individuals with clinically healthy renal and hepatic function to reduce barriers to PrEP in individuals at increased risk of HIV infection.

References

Publication Dates

History