Oral and parenteral preexposure prophylaxis (PrEP) to prevent HIV in people at risk: a systematic review of clinical effectiveness and safety with assessment of organisational, economic, patients/social, ethical and legal elements

Research area: Prevention and screening

Project authors: Mirjana Huic (Center for HTA/EBM, Croatia), Inanna Reinsperger 
Duration: November 2022 – March 2023
Language: English with German summary

Publication: HTA Projektbericht No. 152: https://eprints.aihta.at/1436/

 

Background: According to the European Centre for Disease Prevention and Control (ECDC), the 90-90-90 target (90% of people living with HIV [PLHIV] diagnosed, 90% of those diagnosed on anti-retroviral therapy [ART], 90% of those on treatment virally suppressed) set by the Joint United Nations Programme on HIV/AIDS (UNAIDS) has not been met consistently across EU/EEA countries [1].

The Report of the Austrian HIV Cohort study stated that 6516 HIV infections were newly diagnosed in Austria between 2001 and 2021. The infections occurred in 35.0% through heterosexual transmission, in 44.5% through MSM (Men who have sex with men) and in 14.3% through IDU (Injecting Drug Use) [2]. Among patients newly diagnosed in 2022, 24.3% have been infected through heterosexual contacts [3].  

A further and substantial reduction in HIV incidence is needed if Europe is to meet the Sustainable Development Goals by 2030. Reaching these goals requires a sustained focus on HIV prevention, including new interventions and approaches. New approaches include the implementation of Pre-exposure prophylaxis (PrEP) and clear minimum standards for standardised delivery and monitoring of PrEP across the EU/EEA. PrEP is an antiretroviral therapy-based HIV prevention strategy to prevent HIV infection in people who have not been infected with the virus but are at high risk of infection [4]. In the beginning of 2022, 941 men and 16 women used antiretroviral drugs to prevent HIV infections according to the Austrian HIV Cohort Study [3].

In 2015, ECDC recommended that the EU/EEA countries should consider integrating PrEP into their existing HIV-prevention packages for those most at risk of HIV infection, starting with men who have sex with men, based on several high-quality clinical trials results [5]. At the end of 2021, 22 countries in the WHO European Region have made PrEP available and fully reimburse it. In Austria, PrEP is available, but the costs are not reimbursed by the public sector [6].  ECDC has undertaken several actions to guide EU/EEA countries in their PrEP implementation efforts such as the development of an operational guidance “HIV PreExposure Prophylaxis in the EU/EEA and the UK: implementation, standards and monitoring” [4] as well as ECDC Technical report “Monitoring HIV pre-exposure prophylaxis programmes in the EU/EEA” [6].

Today, not only oral PrEP (daily or event-driven PrEP) is available. Dapivirine vaginal ring is intended for use outside the EU, for cisgender women at substantial risk of HIV. Long-acting injectable cabotegravir, as additional new option, has the potential to increase uptake and effective use of PrEP, and HIV prevention overall, as it allows people to choose a method that they prefer [7, 8].

In the US, the US Food and Drug Administration (FDA) has approved three medications for use as PrEP: two consist of a combination of drugs in a single oral tablet taken daily. The third medication is a medicine given by injection every 2 months.

1. Emtricitabine (F) 200 mg in combination with tenofovir disoproxil fumarate (TDF) 300 mg (F/TDF – brand name Truvada® or generic equivalent). 
2. Emtricitabine (F) 200 mg in combination with tenofovir alafenamide (TAF) 25 mg (F/TAF – brand name Descovy®). 
3. Cabotegravir (CAB) 600 mg injection (brand name Apretude®).

In the EU, only emtricitabine (F) 200 mg in combination with tenofovir disoproxil fumarate (TDF) 245 mg (equivalent to 300 mg of tenofovir disoproxil fumarate or 136 mg of tenofovir) - Truvada® is approved. Truvada is indicated in combination with safer sex practices for pre-exposure prophylaxis to reduce the risk of sexually acquired HIV-1 infection in adults and adolescents at high risk, as one tablet, once daily [9].

In addition to once daily oral PrEP schedule, literature data shows that other dosing regimen-schedules (as off-label use) are also used in real word setting, like event-driven PrEP [10]. This consists of the use of a double dose of oral PrEP 2–24 hours before sexual intercourse, followed by a third dose 24 hours after the first two doses and a fourth dose 48 hours after the first two doses. This has been described as 2+1+1. If more sex acts take place in the following days, a single dose can be continued daily as long as sexual risk continues, with a single daily dose taken for each of two days after the last sexual intercourse [10, 11].

Implementation of PrEP globally has been inadequate; this is especially the case for inequalities in uptake, which can be observed even in countries with comprehensive PrEP access. If countries want to pursue PrEP as a prevention strategy, various barriers need to be overcome, bothat country level (establishment of a 'PrEP-friendly' health system) and at individual level (such as low awareness, low willingness to use PrEP, and the gap between self-perceived and actual HIV risk) [12].

Aim of this review: The review aims to provide an update evidence synthesis based on a systematic literature search regarding the effectiveness and safety of FDA and/or European Medicine Agency (EMA) approved oral and parenteral antiretroviral pre-exposure prophylaxis (PrEP) to prevent HIV infection in populations at risk. The review will also address potential organisational, economic, patient/social, ethical and legal aspects to support evidence-based decision-making process on PrEP in Austria.

Research questions: The following research questions (RQ) will be addressed in this review:

Effectiveness and safety
What are the effectiveness and safety of FDA and/or EMA approved oral and parenteral antiretroviral PrEP medicines to prevent HIV infection in populations at risk?

Organisational, economic, patient/social, ethical and legal aspects
What are the potential organisational, economic, patient/social, ethical and legal aspects on antiretroviral PrEP therapy to prevent HIV infection in populations at risk?

Scope according to the PICO framework

Table 1. PICO framework

Population	HIV-negative people at risk for HIV Including: Men who have sex with men (MSM), Trans and gender diverse people, Heterosexuals (men and women), HIV-negative partners of serodifferent couples, People who inject drugs (PWID), Pregnant and breastfeeding women, Prisoners and other closed settings, Sex workers, Adolescents
Intervention	PrEP as any oral or parenteral-injectable pharmaceutical (approved by FDA and/or EMA): Oral* Emtricitabine (F) 200 mg in combination with tenofovir disoproxil fumarate (TDF) 300 mg (F/TDF – brand name Truvada® or generic equivalent) – Approved by FDA and EMA Emtricitabine (F) 200 mg in combination with tenofovir alafenamide (TAF) 25 mg (F/TAF – brand name Descovy®) - Approved by FDA Parenteral-injectable Cabotegravir (CAB) 600 mg injection (brand name Apretude®) - Approved by FDA (currently in submission to EMA, Nov 2022)
Comparison	Any active oral (daily and event-driven (on-demand) or intermittent dosing) or parenteral-injectable PrEP pharmaceutical, placebo or no PrEP
Outcomes	Effectiveness Domain: Main outcome: HIV infection incidence Additional outcomes: QoL Adherence to PrEP Sexual and reproductive health outcomes (i.e., Changes in sexual behaviour after PrEP initiation; Incidence of sexually transmitted infections) Drug resistance (Resistance to PrEP pharmaceuticals among seroconverters) Safety Domain: short-term and long-term AEs and SAEs Number of patients with one or more Adverse events (AE); Number of patients with one or more Serious adverse events (SAE); Number of deaths attributable to SAE; Number of withdrawals due to AEs; Description of most frequent AEs; Description of most frequent SAEs. Other Domains: Organisational, Economic, Patient/social, Ethical, Legal (according to the EUnetHTA Core HTA Model® 3.0), i.e., on Organisational: Implementation considerations (Accessibility, Training, Quality assurance and monitoring system); Economic: Economic implications of providing PrEP; Patient/social: Values and preferences regarding PrEP; Ethical: Equity and acceptability and factors that could prevent it; Legal: Regulation for the acquisition and use of the PrEP
Study design	Effectiveness and Safety Domains: Systematic Reviews (SR) (stand alone or related to clinical guidelines and Health Technology Assessments (HTA) and randomised controlled trials (RCT) Other Domains: Qualitative and quantitative studies, reports or opinions (according to the EUnetHTA Core HTA Model® 3.0), i.e., SRs, Clinical guidelines, RCTs, Real-world studies like prospective cohort, longitudinal studies and registries studies, qualitative studies
Restrictions	English and German language; SRs and RCTs; Time period: July 2020 – Nov 2022 (updated search) for the systematic literature search

*Different dosing regimen (schedule) of oral PrEP will be considered also, as off-label use

Methods
Effectiveness and Safety Domains: To avoid redundancies and duplication, this systematic review (SR) on effectiveness and safety will reuse data from the recently published SR [13], or SR from recently published HTAs [14] or clinical guidelines [7, 8, 15] to collect information and data on HIV PrEP, if they are applicable to our PICO framework. The data will be included according to the methodology suggested by Whitlock 2008 [16]  and Robinson 2014 [17] on how to integrate existing SRs into new SRs. New data will be added, according to the updated literature search below.

Other Domains: Organisational, economic, patient/social, ethical and legal aspects: The selection of assessment elements for potential organisational, economic, patient/social, ethical and legal aspects will be based on the EUnetHTA Core Model® Version 3.0 [18].

Literature search
Effectiveness and Safety Domains: The literature search from the sources mentioned above will be updated in November 2022, for the period from July 2020 to November 2022, in the following databases: MEDLINE via PubMed, EMBASE and The Cochrane Central Register of Controlled Trials, to find new SRs and RCTs on effectiveness and safety, related to HIV PrEP, in different groups of people at risk for HIV [13, 15].

Two reviewers will independently screen the titles and abstracts of the systematic literature search to identify potentially eligible studies. Full text articles will be obtained for all citations identified as potentially eligible. Both reviewers will independently read these to establish the relevance of the articles according to the pre-specified criteria. References will be included or excluded according to the Population-Intervention-Control-Outcome (PICO)-scheme and will be presented according to the PRISMA Statement [19].

Other Domains: Organisational, economic, patient/social, ethical and legal aspects: Literature search for other domains - qualitative and quantitative studies, reports or opinions (according to the EUnetHTA Core HTA Model® 3.0) will be undertaken by one reviewer through non-systematic literature search in the TRIP database and PubMed, from January 2020 – November 2022. In addition, relevant sources from the systematic literature search are consulted.

A separate Guideline (GL) search (TRIP-Database and hand search) will be performed as well, in November 2022, from January 2020 – November 2022, for all Domains.

Manual searches (from reference lists of relevant studies and website from ECDC, FDA, EMA…) will also be carried out by one reviewer, for all Domains.

Ongoing studies
The following clinical trial registries will be searched for ongoing RCTs (with restriction to phase 3 and 4 interventional trials), in January 2023: ClinicalTrials.gov (https://clinicaltrials.gov/), ISRCTN (https://www.isrctn.com/) and European Clinical Trials Registry (https://www.clinicaltrialsregister.eu/).

Data extraction and management
Effectiveness and Safety Domains: Data extraction will be performed by one reviewer on pre-defined extraction tables and double-checked regarding completeness and accuracy by a second reviewer. Any differences in extraction results will be discussed to achieve consensus; any disagreements will be resolved by a third reviewer. Qualitative or quantitative synthesis from existing SRs/meta-analyses (MA) will be used and presented in the Result section if available and appropriate for specific outcomes. If additional RCTs are found, new data will be added as well.

Other Domains: (see Effectiveness and Safety Domains)

Risk of bias and certainty of evidence
Effectiveness and Safety Domains: Risk of bias is assessed using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions [20] or will be reused from already published SR/MA source. Each study will be assessed with the Cochrane Risk of bias 2 (RoB 2) tool for randomized controlled trials [21] by one reviewer and double-checked by a second reviewer. For rating the certainty of the evidence, the Grading of Recommendations Assessment, Development and Evaluation (GRADE)-method will be applied [22].

Other domains: For other domains, no quality assessment tool will be used, but multiple sources will be used in order to validate individual, possibly biased, sources. Descriptive analyses of information will be performed from the various sources explored.

Patient involvement
As patient involvement is recognised as important at different levels of the HTA process, a call for patient input will be sent to relevant patient organisation(s) in January 2023. This call with a  questionnaire asks patient organisations to provide answers to the questions from people at risk of HIV and HIV patient and/or caregiver perspective and experiences. The call used by AIHTA asks general questions related to the impact of HIV; experience with currently available interventions for HIV prevention; expectations of/requirements for a new medicine for PrEP, and additional information which the people at risk of HIV and HIV patient and/or caregiver believed would be helpful to the HTA researchers. The questions are based on the modified Health Technology Assessment International questionnaire template, https://htai.org/. The results will be used to contextualise and better understand the issue from the patient's perspective.

Timetable:

November 2022	scoping, study protocol systematic literature search for effectiveness & safety
December 2022	abstract screening and study selection non-systematic literature search for other domains
January 2023	data extraction quality assessment patient questionnaire
February 2023	drafting of the report
March 2023	internal and external review finalisation of the report layout and publication of the report

References:

[1]         European Centre for Disease Prevention and Control (ECDC). Continuum of HIV care. Monitoring implementation of the Dublin Declaration on partnership to fight HIV/AIDS in Europe and Central Asia: 2021 progress report. Stockholm: ECDC, 2022. Available from: https://www.ecdc.europa.eu/sites/default/files/documents/Dublin-Continuum-of-HIV-care-2021-progress-report-final-with-covers-updated.pdf.

[2]         Leierer G., Rappold. M., Strickner S. and Zangerle R. HIV/AIDS in Austria. 41st Report of the Austrian HIV Cohort Study. 2021 [cited 21/12/2022]. Available from: https://aids.at/wp-content/uploads/2022/02/41st-Report-of-the-Austrian-HIV-Cohort-Study.pdf.

[3]         Leierer G., M. R., Strickner S. and Zangerle R. HIV / AIDS in Austria. 42nd Report of the Austrian HIV Cohort Study. 2022 Report No. 26/01/2023. Available from: https://aids.at/wp-content/uploads/2022/06/42_Kohortenbericht_Maerz_2022_oeffentlich.pdf.

[4]         European Centre for Disease Prevention and Control (ECDC). HIV Pre-Exposure Prophylaxis in the EU/EEA and the UK: implementation, standards and monitoring. Operational guidance. . Stockholm: European Centre for Disease Prevention and Control, 2021 Report No. 21/12/2022. Available from: https://www.ecdc.europa.eu/sites/default/files/documents/HIV-Pre-Exposure-Prophylaxis-in-the-EU-EEA-UK.pdf.

[5]         European Centre for Disease Prevention and Control (ECDC). Pre-exposure prophylaxis to prevent HIV among MSM in Europe 2015 [cited 21/12/2022]. Available from: https://www.ecdc.europa.eu/en/news-events/pre-exposure-prophylaxis-prevent-hiv-among-msm-europe.

[6]         European Centre for Disease Prevention and Control (ECDC). Monitoring HIV pre-exposure prophylaxis programmes in the EU/EEA. Technical Report. Stockholm: 2022 [cited 21/12/2022]. Available from: https://www.ecdc.europa.eu/sites/default/files/documents/Monitoring-HIV-pre-exposure-prophylaxis-programmes.pdf.

[7]         World Health Organization (WHO). Consolidated guidelines on HIV, viral hepatitis and STI prevention, diagnosis, treatment and care for key populations. Geneva: 2022 [cited 21/12/2022]. Available from: https://www.who.int/publications/i/item/9789240052390.

[8]         World Health Organization (WHO). Guidelines on long-acting injectable cabotegravir for HIV prevention. Geneva: WHO, 2022 Report No. 21/12/2022. Available from: https://www.who.int/publications/i/item/9789240054097.

[9]         European Medicines Agency (EMA). Truvada. EPAR - Product information. [cited 21/12/2022]. Available from: https://www.ema.europa.eu/en/documents/product-information/truvada-epar-product-information_en.pdf.

[10]       World Health Organization (WHO). Consolidated guidelines on HIV prevention, testing, treatment, service delivery and monitoring: recommendations for a public health approach. Geneva: WHO, 2021 Report No. 21/12/2022. Available from: https://www.who.int/publications/i/item/9789240031593.

[11]       World Health Organization (WHO). What’s the 2+1+1? Event driven PrEP to prevent HIV in gay men and other men who have sex with men: update to WHO’s recommendation on oral PrEP. Geneva: 2019 [cited 21/12/2022]. Available from: https://apps.who.int/iris/handle/10665/325955.

[12]       Bavinton B. R. and Grulich A. E. HIV pre-exposure prophylaxis: scaling up for impact now and in the future. Lancet Public Health. 2021;6(7):e528-e533. Epub 2021/06/05. DOI: 10.1016/S2468-2667(21)00112-2.

[13]       O. Murchu E., 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(5):e048478. Epub 2022/05/12. DOI: 10.1136/bmjopen-2020-048478.

[14]       Health Information and Quality Authority. Health technology assessment of a PrEP programme for populations at substantial risk of sexual acquisition of HIV. 2019 [cited 21/12/2022]. Available from: https://www.hiqa.ie/sites/default/files/2019-06/PrEP-HTA.pdf.

[15]       Fonner V., Ridgeway K., van der Straten A., Lorenzetti L., Dinh N., Rodolph M., et al. Web Annex B. Systematic review, meta-analysis and GRADE evidence profile on safety, efficacy, and effectiveness of long-acting injectable cabotegravir (CAB-LA) as pre-exposure prophylaxis (PrEP) to reduce the risk of HIV acquisition. In: Guidelines on long-acting injectable cabotegravir for HIV prevention. Geneva: 2022 [cited 21/12/2022]. Available from: https://apps.who.int/iris/bitstream/handle/10665/360826/9789240054127-eng.pdf.

[16]       Whitlock E. P., Lin J. S., Chou R., Shekelle P. and Robinson K. A. Using existing systematic reviews in complex systematic reviews. Annals of Internal Medicine. 2008;148(10):776-782. Epub 2008/05/21. DOI: 10.7326/0003-4819-148-10-200805200-00010.

[17]       Robinson K. A., Whitlock E. P., Oneil M. E., Anderson J. K., Hartling L., Dryden D. M., et al. Integration of existing systematic reviews into new reviews: identification of guidance needs. Syst Rev. 2014;3:60. Epub 2014/06/25. DOI: 10.1186/2046-4053-3-60.

[18]       European network for Health Technology Assessment (EUnetHTA). HTA Core Model Version 3.0 for the full assessment of Diagnostic Technologies, Medical and Surgical Interventions, Pharmaceuticals and Screening Technologies. 2016 [cited 21/12/2022]. Available from: https://www.eunethta.eu/wp-content/uploads/2018/03/HTACoreModel3.0-1.pdf.

[19]       Liberati A., Altman D. G., Tetzlaff J., Mulrow C., Gotzsche P. C., Ioannidis J. P., et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ. 2009;339:b2700. Epub 2009/07/23. DOI: 10.1136/bmj.b2700.

[20]       Higgins JPT, Thomas J, Chandler J, Cumpston M L. T., Page MJ and Welch VA (editors). Cochrane Handbook for Systematic Reviews of Interventions version 6.3 updated February 2022 [cited 21/12/2022]. Available from: www.training.cochrane.org/handbook.

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