Preexposure Prophylaxis (PrEP) Using Antiretroviral Therapy to Prevent Human Immunodeficiency Virus (HIV) Infection

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The Centers for Medicare & Medicaid Services (CMS) has determined that Pre-Exposure Prophylaxis (PrEP) using antiretroviral drugs to prevent Human Immunodeficiency Virus (HIV) is covered as an additional preventive service under §1861(ddd)(1) of the Social Security Act (the Act). Specifically, CMS has determined that PrEP using antiretroviral drugs to prevent HIV is reasonable and necessary for the prevention of an illness or disability; is recommended with a grade of A by the United States Preventive Services Task Force (USPSTF); and is appropriate for individuals entitled to Medicare benefits under Part A or enrolled under Part B. After considering the public comments, CMS is expanding coverage from our proposed decision and will cover PrEP using antiretroviral drugs approved by the U.S. Food and Drug Administration (FDA) to prevent HIV in individuals at increased risk of HIV acquisition. The determination of whether an individual is at increased risk for HIV is made by the physician or health care practitioner who assesses the individual’s history. CMS also covers furnishing HIV PrEP using antiretroviral drugs, including the supplying or dispensing of these drugs and the administration of injectable PrEP. For individuals being assessed for or using PrEP to prevent HIV, CMS covers all the following as an additional preventive service: a) Up to eight individual counseling visits every 12 months, that include HIV risk assessment (initial or continued assessment of risk), HIV risk reduction, and medication adherence. Counseling must be furnished by a physician or other health care practitioner. Individuals must be competent and alert at the time that counseling is provided. b) Up to eight HIV screening tests every 12 months. c) A single screening for hepatitis B virus (HBV). These screening tests are covered when the appropriate FDA-approved laboratory tests and point of care tests are used consistent with FDA-approved labeling and in compliance with the Clinical Laboratory Improvement Amendments of 1988 (CLIA) regulations. See Appendix B for the draft National Coverage Determinations manual language.

Decision Memo: TO: Administrative File: CAG-00464N FROM: Coverage and Analysis Group SUBJECT: Final National Coverage Determination for Pre-Exposure Prophylaxis (PrEP) for Human Immunodeficiency Virus (HIV) Prevention DATE: September 30, 2024 I. Decision The Centers for Medicare & Medicaid Services (CMS) has determined that Pre-Exposure Prophylaxis (PrEP) using antiretroviral drugs to prevent Human Immunodeficiency Virus (HIV) is covered as an additional preventive service under §1861(ddd)(1) of the Social Security Act (the Act). Specifically, CMS has determined that PrEP using antiretroviral drugs to prevent HIV is reasonable and necessary for the prevention of an illness or disability; is recommended with a grade of A by the United States Preventive Services Task Force (USPSTF); and is appropriate for individuals entitled to Medicare benefits under Part A or enrolled under Part B. After considering the public comments, CMS is expanding coverage from our proposed decision and will cover PrEP using antiretroviral drugs approved by the U.S. Food and Drug Administration (FDA) to prevent HIV in individuals at increased risk of HIV acquisition. The determination of whether an individual is at increased risk for HIV is made by the physician or health care practitioner who assesses the individual’s history. CMS also covers furnishing HIV PrEP using antiretroviral drugs, including the supplying or dispensing of these drugs and the administration of injectable PrEP. For individuals being assessed for or using PrEP to prevent HIV, CMS covers all the following as an additional preventive service: a) Up to eight individual counseling visits every 12 months, that include HIV risk assessment (initial or continued assessment of risk), HIV risk reduction, and medication adherence. Counseling must be furnished by a physician or other health care practitioner. Individuals must be competent and alert at the time that counseling is provided. b) Up to eight HIV screening tests every 12 months. c) A single screening for hepatitis B virus (HBV). These screening tests are covered when the appropriate FDA-approved laboratory tests and point of care tests are used consistent with FDA-approved labeling and in compliance with the Clinical Laboratory Improvement Amendments of 1988 (CLIA) regulations. See Appendix B for the draft National Coverage Determinations manual language. II. Background Throughout this document we use numerous acronyms, some of which are not defined as they are presented in direct quotations. Please find below a list of these acronyms and corresponding full terminology: AIDS – Acquired immunodeficiency syndrome AAHIVS - American Academy of HIV Medicine Specialists APHL – Association of Public Health Laboratories ART – Antiretroviral therapy CAB – Cabotegravir CDC – Centers for Disease Control and Prevention CMS – Centers for Medicare & Medicaid Services CD4+ – cluster of differentiation 4+ T helper cells or CD4 count FDA – US Food and Drug Administration HBV – Hepatitis B Virus HHS – Department of Health and Human Services HIBC – High-intensity behavioral counseling HIV – Human Immunodeficiency Virus Infection IDU – Intravenous drug use kg – kilogram MSM – Men who have sex with men mg – milligram mL – milliliter NASTAD - National Alliance of State and Territorial AIDS Directors NCA – National Coverage Analysis NCD – National Coverage Determination NDRN – National Disability Rights Network NIA – National Institute on Aging NIAID – National Institute of Allergy & Infectious Disease NIH – National Institutes of Health NLM – National Library of Medicine OI – Opportunistic infection PEP – Post-exposure prophylaxis PWID – people who inject drugs PrEP – Pre-Exposure Prophylaxis RCT – Randomized controlled trial RNA – Ribonucleic acid STD – sexually transmitted disease STI – sexually transmitted infection TAF-FTC – emtricitabine in combination with tenofovir alafenamide TDF-FTC – emtricitabine in combination with tenofovir disoproxil fumarate TGW – transgender women US – United States USPSTF – United States Preventive Services Task Force U=U – Undetectable=Untransmittable WHO – World Health Organization Epidemiology There were approximately 39 million people across the globe with HIV in 2022 (United States (US) Department of Health and Human Services (HHS), 2023a). In the US, the condition continues to be a serious public health issue. In 2022, an estimated 1.2 million people aged 13 and older had HIV in the US, and for every 100 people with HIV, 87 people knew their HIV status (Centers for Disease Control & Prevention (CDC), 2023a). An estimated 1.3 million individuals worldwide acquired HIV in 2022, marking a 38% decline in new HIV infections since 2010 (HHS, 2023a). New HIV infections, or HIV incidence, refers to the estimated number of people who newly acquired HIV during a given period such as a year, which is different from the total number of people who already have been diagnosed (new and pre-existing cases) with HIV during a year, or HIV prevalence. Due to continuing medical advances, earlier initiation, and expanded access to medications, HIV is now considered a chronic condition rather than a terminal illness (World Health Organization (WHO), 2023). Antiretroviral therapy (ART) is known to reduce HIV-related morbidity and mortality. The WHO recognizes that people living with HIV are now surviving, aging, and requiring lifelong care and treatment (WHO, 2023). People living with HIV are at risk of developing chronic complications and comorbidities, such as noncommunicable diseases and mental health disorders, which may be pre-existing, HIV-associated, or due to aging. Over 53% of the people in the US diagnosed with HIV are aged 50 and older (HHS, 2023b). Additionally, HIV is newly diagnosed in thousands of people aged 50 and older every year. From 2015 through 2019 in the US and 6 dependent areas, the largest percentage increase (48%) in the rate of persons living with diagnosed HIV was among persons aged ≥65 years (from 145.5 in 2015 to 216.0 in 2019; rates are per 100,000 population) (CDC, 2021b). At year-end 2019, persons aged 55–59 years made up the largest percentage of persons living with diagnosed HIV (15% of 1,061,482 total). The highest rate (741.1 per 100,000 of the US population) was among persons aged 50–54 years, followed by those aged 55–59 years (737.7 per 100,000 US population) and those aged 45–49 years (577.2 per 100,000 US population). HIV disproportionately impacts identifiable racial and ethnic groups. African Americans, more than any other racial/ethnic group, bear the most severe burden of HIV in the US followed by those who are Hispanic (CDC, 2021b). In 2021, of the estimated number of persons living with diagnosed or undiagnosed HIV, 40% were Black/African American, 68% of whom were male. The prevalence rate for Black/African American persons was 7 times the rate for White persons (CDC, 2021a; HHS, 2023c). Of the estimated number of persons living with diagnosed or undiagnosed HIV, 25% were Hispanic/Latino, of whom 83% were male. The prevalence rate for Hispanic/Latino persons (625.8) was 3 times the rate for White persons. This disproportionate impact is related to these racial/ethnic groups having higher rates of HIV in their communities (HHS, 2023c). In addition, a range of social, economic, and demographic factors, such as stigma, discrimination, income, education, and geographic region can affect people’s risk for HIV as well as their HIV-related outcomes. Risk HIV is spread through contact with the blood, semen, pre-seminal fluid, rectal fluids, vaginal fluids, or breast milk of a person with HIV. Anyone can get HIV, but certain groups have a higher risk of acquiring HIV, including people who have another sexually transmitted infection (STI), people who inject drugs with shared needles, gay and bisexual men, especially those who are Black/African American or Hispanic/Latino American, and people who engage in risky sexual behaviors, such as not using condoms (National Library of Medicine (NLM), 2021). In the US, HIV is spread mainly by having anal or vaginal sex or sharing injection drug equipment, such as syringes or needles, with a person who has HIV. In the US in 2022, men who had sex with men (MSM) accounted for 67% of all new HIV infections (CDC, 2023b). Heterosexual sex accounted for 22% and persons with injection drug use constituted about 7% of new HIV diagnoses. HIV/Acquired immunodeficiency syndrome (AIDS) HIV is a virus that attacks the body’s immune system by destroying cluster of differentiation 4+ or CD4+ T helper cells (referred to as CD4 count), a type of white blood cell that is vital to fighting off infection (National Institute of Allergy & Infectious Disease (NIAID), 2020; CDC, 2024). The first signs of HIV infection may be flu-like symptoms, including fever, chills, rash, night sweats, muscle aches, sore throat, fatigue, swollen lymph nodes, and mouth ulcers (NLM, 2021). These symptoms may come and go within two to four weeks. This stage is called acute HIV infection. If the infection is not treated, it becomes chronic HIV infection. Without taking HIV medicine, this period may last a decade or longer, but some may progress faster. Often, there are no symptoms during this stage. If it is not treated, eventually the virus will weaken the body's immune system. As the disease progresses, the amount of HIV in the blood (called viral load) goes up and the number of CD4 cells goes down. The person may have symptoms as the virus levels increase in the body. Then the infection will progress to AIDS. This is the late stage of HIV infection. With AIDS, the immune system is badly damaged causing increasingly severe infections, known as opportunistic infections (OIs), such as pneumonia, salmonella infection, candidiasis, toxoplasmosis, and tuberculosis. AIDS is defined by a CD4 count of 200 cells/mm 3 or one or more AIDS-defining neoplastic conditions or opportunistic infections. Thus, a person may be living with HIV for years before the condition is suspected. So, the only way to know for sure whether a person has HIV is to get HIV screening. [1] Treatment The treatment for HIV is called antiretroviral therapy (ART) and involves taking a combination of HIV medicines (called an HIV treatment regimen) every day (NIH, 2021). ART is recommended as a life-long treatment for everyone who has HIV and also reduces the risk of HIV transmission. These medications prevent HIV from multiplying or making copies of itself, which reduces the amount of HIV in the body (called the viral load). Having less HIV in the body gives the immune system a chance to recover and produce more CD4 cells. Even though there is still some HIV in the body, the immune system is strong enough to fight off infections and certain HIV-related cancers. By reducing the amount of HIV in the body, HIV medicines also reduce the risk of HIV transmission. A main goal of HIV treatment is to reduce a person’s viral load to an undetectable level. An undetectable viral load means that the level of HIV in the blood is too low to be detected by a viral load test. People with HIV who maintain an undetectable viral load have effectively no risk of transmitting HIV to their HIV-negative partners through sex, a concept known as Undetectable=Untransmittable, or U=U. Preventive Options Pre-exposure prophylaxis (PrEP) involves the use of ART on an ongoing basis (e.g., daily or every two months) or before and after HIV exposure events (“on-demand” or “event-driven” PrEP) to decrease the risk of acquiring HIV from sex or injection drug use (CDC, 2022). When taken as prescribed, PrEP is effective for preventing HIV. PrEP can be an oral medication or an injection. As of the date of this publication, the FDA has approved three medications for use as PrEP: emtricitabine (FTC) 200 mg in combination with tenofovir disoproxil fumarate (TDF) 300 mg (TDF-FTC – brand name Truvada® or generic equivalent); emtricitabine (FTC) 200 mg in combination with tenofovir alafenamide (TAF) 25 mg (TAF-FTC – brand name Descovy®); and cabotegravir (CAB) 600 mg injection (brand name Apretude®). Truvada® is indicated in at-risk adults and adolescents weighing at least 35 kg for pre-exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1 infection. The FDA approval for TAF-FTC or Descovy® excluded persons at risk from receptive vaginal sex because the efficacy of Descovy® to reduce the risk of HIV-1 infection from vaginal exposures was not evaluated. Apretude® is prescribed for people at risk of acquiring HIV through sex who weigh at least 77 pounds (lbs) (35 kilograms (kg)). Tenofovir, a nucleotide/nucleoside reverse transcriptase inhibitor of HIV, inhibits viral replication in cells (HHS, 2023d). Although tenofovir alafenamide and tenofovir disoproxil fumarate are both prodrugs of tenofovir, tenofovir alafenamide transports the active metabolite, tenofovir diphosphate, more rapidly into peripheral blood mononuclear cells (PBMCs) than tenofovir disoproxil fumarate with at least four times higher concentrations resulting in increased antiviral activity. [2] Cabotegravir (Apretude®) is an extended-release injectable integrase strand transferase inhibitor. Cabotegravir inhibits HIV integrase by binding to the integrase active site and blocking the strand transfer step of retroviral deoxyribonucleic acid (DNA) integration that is essential for the HIV replication cycle. Scientific evidence demonstrates that PrEP is a safe and effective tool that can help reduce new cases of HIV, when taken as prescribed, yet PrEP usage remains limited (CDC, 2021c). In 2019, the CDC estimated that approximately 285,000 of 1.2 million (or 23%) eligible individuals for PrEP received it, an increase from about 20% in 2015. Chou et al. (2023) notes that a number of clinician and patient barriers to wider use of PrEP have been identified, including lack of knowledge or awareness of PrEP (particularly among primary care providers), perception of HIV risk, stigma, distrust of healthcare providers and systems, access to PrEP and costs, and concerns about harms. Factors that may affect the balance of benefits and harms in persons prescribed PrEP include adverse effects, such as possible injection site reactions and reduced kidney function, the potential for antiretroviral resistance in persons who unknowingly acquire HIV while taking PrEP, and the potential for behavioral risk compensation (Chou et al., 2023). Behavioral risk compensation refers to an increase in behaviors associated with HIV transmission (e.g., sex without a condom or multiple sexual partners). Because PrEP does not protect against other sexually transmitted infections (STIs), such as syphilis, chlamydia, and gonorrhea, behavioral risk compensation could increase the rate of STIs, in addition to reducing HIV prevention benefits. (See analysis section of this decision memo for more details regarding benefits and harms of PrEP using ART to prevent HIV.) United States Preventive Services Task Force (USPSTF) The USPSTF recommends that clinicians prescribe PrEP using effective ART to persons who are at increased risk of HIV acquisition to decrease the risk of acquiring HIV (USPSTF Grade A Recommendation, 2023). The recommendation was based on convincing evidence that PrEP is of substantial benefit in decreasing the risk of HIV infection in persons at increased risk of HIV acquisition and adequate evidence of small harms, including kidney and gastrointestinal adverse effects, resulting in high certainty of substantial net benefit (Barry et al., 2023; Owens et al., 2019). The USPSTF also found convincing evidence that the effectiveness of PrEP is highly correlated with adherence. (See Analysis section for discussion on benefits and harms.) The USPSTF assigns one of five letter grades to each of its recommendations (A, B, C, D, I). The following tables from the USPSTF website provides the current grade definitions and descriptions of levels of certainty ( https://www.uspreventiveservicestaskforce.org/uspstf/about-uspstf/methods-and-processes/grade-definitions ). Grade Definitions Grade Definition Suggestions for Practice A The USPSTF recommends the service. There is high certainty that the net benefit is substantial. Offer or provide this service. B The USPSTF recommends the service. There is high certainty that the net benefit is moderate or there is moderate certainty that the net benefit is moderate to substantial. Offer or provide this service. C The USPSTF recommends selectively offering or providing this service to individual patients based on professional judgment and patient preferences. There is at least moderate certainty that the net benefit is small. Offer or provide this service for selected patients depending on individual circumstances. D The USPSTF recommends against the service. There is moderate or high certainty that the service has no net benefit or that the harms outweigh the benefits. Discourage the use of this service. I Statement The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of the service. Evidence is lacking, of poor quality, or conflicting, and the balance of benefits and harms cannot be determined. Read the clinical considerations section of USPSTF Recommendation Statement. If the service is offered, patients should understand the uncertainty about the balance of benefits and harms. Levels of Certainty Regarding Net Benefit Level of Certainty Description High The available evidence usually includes consistent results from well-designed, well-conducted studies in representative primary care populations. These studies assess the effects of the preventive service on health outcomes. This conclusion is therefore unlikely to be strongly affected by the results of future studies. Moderate The available evidence is sufficient to determine the effects of the preventive service on health outcomes, but confidence in the estimate is constrained by such factors as: The number, size, or quality of individual studies. Inconsistency of findings across individual studies. Limited generalizability of findings to routine primary care practice. Lack of coherence in the chain of evidence. As more information becomes available, the magnitude or direction of the observed effect could change, and this change may be large enough to alter the conclusion. Low The available evidence is insufficient to assess effects on health outcomes. Evidence is insufficient because of: The limited number or size of studies. Important flaws in study design or methods. Inconsistency of findings across individual studies. Gaps in the chain of evidence. Findings not generalizable to routine primary care practice. Lack of information on important health outcomes. More information may allow estimation of effects on health outcomes. * The USPSTF defines certainty as "likelihood that the USPSTF assessment of the net benefit of a preventive service is correct." The net benefit is defined as benefit minus harm of the preventive service as implemented in a general, primary care population. The USPSTF assigns a certainty level based on the nature of the overall evidence available to assess the net benefit of a preventive service. III. History of Medicare Coverage CMS may add coverage of "additional preventive services" under Part B if the statutory requirements set forth at section 1861(ddd)(1)-(2) of the Act are met. Our regulations provide: 42 CFR §410.64 Additional preventive services (a) Medicare Part B pays for additional preventive services not described in paragraph (1) or (3) of the definition of “preventive services” under §410.2, that identify medical conditions or risk factors for individuals if the Secretary determines through the national coverage determination process (as defined in section 1869(f)(1)(B) of the Act) that these services are all of the following: 1. Reasonable and necessary for the prevention or early detection of illness or disability. 2. Recommended with a grade of A or B by the United States Preventive Services Task Force. 3. Appropriate for individuals entitled to benefits under Part A or enrolled under Part B. (b) In making determinations under paragraph (a) of this section regarding the coverage of a new preventive service, the Secretary may conduct an assessment of the relation between predicted outcomes and the expenditures for such services and may take into account the results of such an assessment in making such national coverage determinations. A. Current Request CMS received a complete, formal request to consider a National Coverage Determination (NCD) for provider-administered PrEP for HIV prevention from ViiV Healthcare, asking CMS to review new scientific evidence and to adopt the USPSTF’s evidence-based recommendation. The request letter is available at: https://www.cms.gov/Medicare/Coverage/DeterminationProcess/downloads/id310.pdf B. Benefit Category Medicare is a defined benefit program. For an item or service to be covered by the Medicare program, it must fall within one of the statutorily defined benefit categories outlined in the Act. PrEP using antiretroviral drugs for the prevention of HIV may be considered an “additional preventive service” that falls within the benefit category under §1861(s)(2)(BB). CMS is authorized to cover "additional preventive services" if certain statutory requirements are met as provided under §1861(ddd) of the Act. IV. Timeline of Recent Activities Date Actions Taken 01/12/2023 CMS initiates this national coverage analysis. A 30-day public comment period begins. 02/11/2023 First public comment period ends. CMS receives 37 comments. 07/12/2023 Proposed Decision Memorandum posted. 30-day public comment period begins. 08/11/2023 30-day public comment period ends. CMS receives 81 comments. 08/22/2023 USPTSF issued their Final Recommendation titled “Prevention of Acquisition of HIV: Preexposure Prophylaxis.” The recommendation is available at https://www.uspreventiveservicestaskforce.org/uspstf/recommendation/prevention-of-human-immunodeficiency-virus-hiv-infection-pre-exposure-prophylaxis 10/10/2023 CMS did not issue a final NCD but announced a decision would be forthcoming. 04/15/2024 Fact sheet posted https://www.cms.gov/files/document/fact-sheet-potential-medicare-part-b-coverage-preexposure-prophylaxis-prep-using-antiretroviral.pdf 06/25/2024 Technical frequently asked questions posted https://www.cms.gov/files/document/faq-prep-hiv-06242024.pdf 08/01/2024 Memo to Medicare Advantage Organizations and Part D Plan Sponsors https://www.cms.gov/files/document/proposed-national-coverage-determination-ncd-preexposure-prophylaxis-prep-human-immunodeficiency.pdf 8/13/2024 Informational website posted https://www.cms.gov/medicare/coverage/prep V. Food and Drug Administration (FDA) Status In July 2012, the FDA approved an indication for the use of daily oral TDF-FTC (Truvada®) “in combination with safer sex practices for pre-exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1 in adults at high risk” (FDA, 2013). In May 2018, the approval for TDF-FTC was extended to adolescents weighing at least 35 kg (77 lbs) based on safety trials in adolescents and young adults. As of April 2024, the FDA label states that “Truvada® is indicated in at-risk adults and adolescents weighing at least 35 kg for [PrEP] to reduce the risk of sexually acquired HIV-1 infection.” The label also states: Prior to or when initiating Truvada®, test for hepatitis B virus infection; prior to initiation and during use of Truvada®, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all individuals; in individuals with chronic kidney disease, also assess serum phosphorus; screen all individuals for HIV-1 immediately prior to initiating Truvada® for HIV-1 PrEP and at least once every 3 months while taking Truvada®, and upon diagnosis of any other sexually transmitted infections (STIs); use as part of a comprehensive prevention strategy including other prevention measures; strictly adhere to dosing schedule; counsel individuals on the use of other prevention measures (e.g., consistent and correct condom use, knowledge of partner(s)’ HIV-1 status, including viral suppression status, regular testing for STIs that can facilitate HIV-1 transmission); inform uninfected individuals about and support their efforts in reducing sexual risk behavior. In addition, the Truvada® label states: Published studies indicate an increased risk of HIV-1 infection during pregnancy and an increased risk of mother to child transmission during acute HIV-1 infection. In women at risk of acquiring HIV-1, consideration should be given to methods to prevent acquisition of HIV, including continuing or initiating Truvada® for HIV-1 PrEP, during pregnancy…. Truvada® is not recommended in HIV-uninfected individuals if creatinine clearance is below 60 mL/min. In October 2019, the FDA approved daily oral TAF-FTC (Descovy®) for PrEP in at-risk adults and adolescents weighing at least 35 kg to reduce the risk of HIV-1 infection from sexual acquisition, excluding persons at risk from receptive vaginal sex (FDA, 2022). The latter population was specifically excluded from the Descovy® approval because the efficacy of Descovy® to reduce the risk of HIV-1 infection from vaginal exposures was not evaluated. The FDA label for Descovy® reflects the same testing/screening and counseling guidance as Truvada®; Descovy® may be used in adults and adolescents weighing at least 35 kg and with a creatinine clearance greater than or equal to 30 mL per minute. In December 2021, the injectable integrase strand transferase inhibitor extended-release cabotegravir (Apretude®) was FDA-approved for PrEP, which can be administered every 8 weeks, after 2 loading doses given 4 weeks apart (FDA, 2023). The FDA label states: Apretude® is indicated in at-risk adults and adolescents weighing at least 35 kg for PrEP to reduce the risk of sexually acquired HIV-1 infection; screen for HIV-1 immediately prior to initiating and prior to each injection; clinical and laboratory monitoring should be considered for hepatotoxicity; counsel individuals on the use of other prevention measures (e.g., consistent and correct condom use, knowledge of partner(s)’ HIV-1 status, including viral suppression status, regular testing for STIs that can facilitate HIV-1 transmission); inform uninfected individuals about and support their efforts in reducing sexual risk behavior; discuss the benefit-risk of using Apretude® with individuals of childbearing potential or during pregnancy. The Truvada®, Descovy® and Apretude® labels state that risk for HIV-1 acquisition includes behavioral, biological, or epidemiologic factors including but not limited to condomless sex, past or current STIs, self-identified HIV risk, having sexual partners of unknown HIV-1 viremic status, or sexual activity in a high prevalence area or network (FDA, 2020; 2022; 2023). VI. General Methodological Principles When making NCDs concerning additional preventive services, CMS applies the statutory criteria in § 1861(ddd)(1) of the Act and regulations at 42 CFR § 410.64, and evaluates relevant clinical evidence to determine whether or not the service is reasonable and necessary for the prevention or early detection of illness or disability, is recommended with a grade of A or B by the USPSTF, and is appropriate for individuals entitled to benefits under Part A or enrolled under Part B of the Medicare program. VII. Evidence A. Introduction The evidence summarized in this section includes the peer-reviewed, published medical literature on pertinent clinical trials of PrEP using ART for persons at increased risk of HIV acquisition. Our assessment focuses on the key evidence questions below. B. Discussion of Evidence 1. Evidence Questions [3] Question 1: Is the evidence sufficient to determine that the USPSTF recommends that clinicians prescribe PrEP using effective ART to persons at high risk 3 of HIV acquisition with a grade of A or B recommendation? Question 2: Is the evidence sufficient to determine that prescribing PrEP with effective antiretroviral drugs for persons at high risk 3 of HIV acquisition is reasonable and necessary for the prevention or early detection of illness or disability under §1861(ddd)(1) of the Act? Question 3: Is the evidence sufficient to determine that prescribing PrEP with effective antiretroviral drugs for persons at high risk 3 of HIV acquisition is appropriate for Medicare beneficiaries under Part A or Part B? The USPSTF 2019 recommendation used the term “high risk,” but the USPSTF 2023 final recommendation uses “increased risk” and language in the Evidence Questions reflected the USPSTF 2019 decision. We adopt in this decision the modified language in the 2023 USPSTF recommendation. However, we did not change our evidence questions from the proposed decision memorandum to the final decision memorandum to maintain consistency of documentation. We note the USPSTF (2023) states that the 2023 USPSTF recommendation concerning the identification of persons to be considered for HIV PrEP is consistent with their 2019 recommendation. 2. External Technology Assessments CMS did not request an external technology assessment (TA) on this issue. 3. Internal Technology Assessment Literature Search Methods The reviewed evidence was gathered from articles submitted by the requester, resources suggested by public commenters, two systematic reviews performed by AHRQ for the USPSTF (Chou et al., 2019; Chou et al., 2023), and from a literature search of PubMed performed by CMS staff. Keywords for the search included, “preexposure prophylaxis or prep or tenofovir or truvada or descovy or cabotegravir and Anti-HIV Agents or hiv or human immunodeficiency virus.” Publications that presented original human clinical data on PrEP regimens approved by the FDA were considered. Abstracts, meeting presentations, reviews, animal studies, and non-English language publications were excluded. Studies examining on-demand dosing, oral TDF monotherapy, oral maraviroc, tenofovir vaginal gel, injectable rilpivirine, and dapivirine vaginal ring were excluded. One study focusing on the risk factor of people who inject drugs (PWID) and oral TDF monotherapy was included because it was the only clinical trial focusing on this population. 4. Medicare Evidence Development & Coverage Advisory Committee (MEDCAC) A MEDCAC meeting was not convened on this issue. 5. Evidence Tables Below are two evidence tables. Table 1 contains summary descriptive information about the key clinical trials of PrEP. Table 2 contains summary results from the key clinical trials of PrEP. The full citation for the publication can be found in the bibliography of this decision memorandum. Table 1. Study characteristics of key clinical trials of PrEP (adapted from Chou et al., 2019; Chou et al., 2023) Study name Author, year of publication Country Duration of follow-up (months or years) Study design Quality 4 Interventions in study trial arms (n = sample size) Trial arms: A. vs. B. (vs. C. vs. D) HIV risk group(s) based on risk-based inclusion criteria Patient characteristics Medication adherence (method for measuring adherence) FEM PrEP Van damme 2012 Kenya, South Africa, Tanzania 1 year Placebo-controlled RCT Good (and Agot, 2015; Mandala, 2014, report on adverse events) A. oral TDF-FTC 300/200mg once daily (n=1,062) B. Placebo (n=1,058) High-risk women: > 1 vaginal sex acts in previous 2 weeks or > 1 sex partner in the previous month A vs.B Age (mean): 24 vs. 24 years Female: 100% Race: NR 37% (plasma, tenofovir level ≥10 ng/mL [consistent with dose in last 48 hours]) IAVI Uganda Study Kibengo 2013 Uganda 4 months Placebo-controlled RCT Good A. daily TDF-FTC 300/200mg (n=24) B. Intermittent TDF-FTC (Monday,Friday and within 2 hours postcoital, not to exceed 1 dose/day) (n=24) C. Daily placebo (n=12) D. Intermittent placebo (n=12) High-risk heterosexual men and women: Unprotected vaginal sex with ART-naive HIV-infected partner in the previous 3 months A vs. B vs. C vs. D Age (mean): 33 vs. 33 vs. 33 vs. 33 years Female: 50% vs. 46% vs. 67% vs. 42% Race NR 98% (MEMS [daily dosing]) IAVI Kenya Study Mutua 2012 Kenya 4 months Placebo-controlled RCT Good A. daily TDF-FTC 300/200mg (n=24) B. Intermittent TDF-FTC (Monday, Friday and within 2 hours postcoital, not to exceed 1 dose/day) (n=24) C. Daily placebo (n=12) D. Intermittent placebo (n=12) MSM and high-risk women: Current or previous STI, multiple episodes of unprotected vaginal or anal sex, or engaging in transactional sex in the previous 3 months A vs. B vs. C vs. D Age (mean): 26 vs. 26 vs. 27 vs. 28 years Female: 12% vs. 0% vs. 8% vs. 8% Race: NR 82% (MEMS [daily dosing]) iPrEx Grant 2010 Brazil, Ecuador, Peru, Thailand, South Africa, United States 1.2 years (median) Placebo-controlled RCT Good A. TDF-FTC 300/200 mg (n=1,251) B. Placebo (n=1,248) Men who have sex with men: Anal sex with ≥4 male partners, a diagnosis of an STI, history of transactional sex activity, condomless anal sex with an HIV-infected partner or partner of unknown infection status in the previous 6 months Overall age range: 18 – 67 years old A vs. B Ages 18 to 24 years: 47% vs. 53% Ages 25 to 29 years: 22% vs. 19% Ages 30 to 39 years: 20% vs. 18% Age ≥40 years: 11% vs. 10% Born male: 100% vs. 100% Black: 9% vs. 8% White: 18% vs. 17% Mixed race or other: 68% vs. 70% Asian: 5% vs. 5% Hispanic: 72% vs. 73% US residency: A. 9% vs. B. 9.1% 48% (plasma, tenofovir or FTC detectable) Partners PrEP Baeten 2012 Kenya, Uganda 2 years (median) Placebo-controlled RCT Good A. Once-daily TDF 300 mg + placebo TDF-FTC (n=1,571) B. Once-daily TDF-FTC 300/200 mg + placebo TDF (n=1,565) C. Placebo TDF + placebo TDF-FTC (n=1,570) All participants received a comprehensive package of HIV-1 prevention services and were offered HBV vaccination High-risk heterosexual men and women: ART-naive HIV-infected partner Overall age range not reported; inclusion criteria for study: 18 – 65 years old A vs. B vs. C Ages 18 to 24 years: 12% vs. 11% vs. 11% Ages 25 to 34 years: 46% vs. 44% vs. 43% Ages 35 to 44 years: 30% vs. 32% vs. 32% Age ≥45 years: 13% vs. 14% vs. 13% Male: 62% vs. 64% vs. 61% Race: NR 82% (plasma, tenofovir detectable) PROUD McCormack 2016 England 1 year Placebo-controlled RCT Fair A. Immediate TDF-FTC 245/200 mg (n=275) B. TDF-FTC deferred for 1 year (n=269) Men who have sex with men: Anal intercourse without a condom in the previous 90 days and likely to have anal intercourse without a condom in the next 90 days A vs. B Age (mean): 35 vs. 35 years Male: 100% vs. 100% White: 81% vs. 83% Asian: 5% vs. 6% Black: 4% vs. 4% Other race: 10% vs. 8% 100% (plasma, tenofovir detectable) ‡ TDF2 Thigpen 2012 Botswana 1 year (median) Placebo-controlled RCT Good A. Oral TDF-FTC 300/200 mg, once daily (n=611) B. Placebo, once daily (n=608) High-risk heterosexual men and women: Sexually active in high-prevalence area A vs. B Ages 18 to 20 years: 2% vs. 3% Ages 21 to 29 years: 90% vs. 87% Ages 30 to 39 years: 8% vs. 10% Female: 46% vs. 46% Race: NR 80% (plasma, tenofovir detectable) VOICE Marrazzo 2015 South Africa, Uganda, Zimbabwe 3 years (maximum) Placebo-controlled RCT Good A. Oral TDF 300 mg and TDF-FTC placebo (n=1,007) B. Oral TDF-FTC 300/200 mg and TDF placebo (n=1,003) C. Oral TDF placebo and oral TDF-FTC placebo (n=1,009) High-risk women: Sexually active in a high-prevalence area A vs. B vs. C Age (mean): 26 vs. 25 vs. 25 years Female: 100% all groups Race: NR 30% (plasma, tenofovir detectable) ADAPT/ HPTN 067 Bekker 2018 South Africa 34 weeks Head-to-head trial Fair A. Daily TDF-FTC (n=59) B. Time-driven TDF-FTC (one tablet twice a week, plus a dose after sex; n=59) C. Event-driven TDF-FTC (one tablet both before and after sex; n=60) High-risk women or transgender men: History of an acute STI, transactional sex, intercourse without a condom with someone of unknown or HIV-infected status, or > 1 sex partner in 6 months A vs. B vs. C Age, mean: 25 vs. 26 vs. 25 years Female: 100% (no transgender men enrolled) Black: 98% vs. 100% vs. 100% A vs. B vs. C (plasma level ≥2.5 ng/mL at week 30 [consistent with ≥2 doses/week [daily and time-driven] or when reporting sex in prior week [event-driven]): 54% vs. 36% vs. 31% ADAPT/ HPTN 067 Grant, 2018 Thailand, U.S. 34 weeks Head-to-head trial Fair A. Daily TDF-FTC (n=119) B. Time-driven TDF-FTC (one tablet twice a week, plus a dose after sex; n=119) C. Event-driven TDF-FTC (one tablet both before and after sex; n=119) MSM: Reported anal or neovaginal sex with a man in the past 6 months, and have at least 1 of the following in the past 6 months: sex with > 1 man or transgender woman; history of an acute STI; sex in exchange for money, goods, or favors; or intercourse without a condom with an HIV-infected partner or partner of unknown HIV infection status A vs. B vs. C Bangkok site: Age 18 to 24 years: 13% vs. 20% vs. 14% Ages 25 to 29 years: 22% vs. 32% vs. 27% Age 30 to 39 years: 60% vs. 39% vs. 48% Age ≥40 years: 5% vs. 9% vs. 12% MSM: 98% vs. 98% vs. 100% Transgender: 2% vs. 2% vs. 0% Race NR Harlem site: Age 18 to 24 years: 32% vs. 28% vs. 28% Age 25 to 29 years: 22% vs. 18% vs. 13% Age 30 to 39 years:19% vs. 20% vs. 23% Age ≥40 years: 27% vs. 33% vs. 35% MSM: 97% vs. 98% vs. 97% Transgender: 3% vs. 0% vs. 2% Gender queer: 0% vs. 2% vs. 2% Overall race: Black 70%, White 13%, Asian 3%, Native American 3%, Hispanic 25%, Other 21% A vs. B vs. C Bangkok site: (peripheral blood mononuclear cell levels consistent with ≥2 tablets on visits when sex was reported in prior week) 97.6% vs. 98.7% vs. 95.7% Harlem site: (dried blood spot levels consistent with ≥2 tablets on visits when sex was reported in prior week) 48.5% vs. 30.9% vs. 16.7% Kwan, 2021 Hong Kong 32 weeks Head-to-head trial Fair A: Daily TDF-FTC (n=59) B: Event-driven TDF-FTC (n=60) MSM: Had condomless anal intercourse in the preceding 6 months A vs B Age, mean: 29 vs. 30 years Median 100% vs. 93% (self-report, proportion of days with PrEP-covered condomless anal intercourse) DISCOVER Mayer, 2020 Europe and North America 96 weeks Head-to-head trial Good A: TAF-FTC (n=2670) B: TDF-FTC (n=2665) Cisgender MSM or transgender women who have sex with men: Condomless anal sex with at least two partners in the previous 12 weeks or syphilis, rectal gonorrhea, or rectal chlamydia in the prior 24 weeks Overall age range: 18 – 76 (median 34 years); US participant enrollment: 60% (3220/5387); Canadian and European participant enrollment: 40% (2167 of 5387) A vs. B Age (mean): 34 vs. 34 years Cisgender MSM: 98% vs. 99% Transgender women who have sex with men: 2% vs. 1% White: 84% vs. 84% Black: 9% vs. 9% Asian: 4% vs. 4% Other race: 3% vs. 3% Hispanic or Latinx ethnicity: 24% vs. 25% A vs. B 88%-96% vs. 84%-93% (dried blood spot, random sample consistent with ≥4 doses/week) HPTN 083 Landovitz, 2021 International Median 1.4 years Head-to-head trial Good A: Cabotegravir long-acting injectable 600 mg at weeks 5, 9, 17, and every 8 weeks afterward and oral placebo (n=2,282) B: Oral tenofovir disoproxil fumarate 300 mg + emtricitabine 200 mg once daily and injectable placebo (n=2,284) Cisgender MSM and transgender women who have sex with men Number of participants ≥ 60 years old (no. (%)): 13 (0.3); 37.2% of participants in the US; 845/1698 (49.8%) participants from the United States identified as Black A vs. B Age category — no. (%) Age 18−29: 1572 (68.9%) vs. 1508 (66.0%) Age 30−39: 498 (21.8) vs. 550 (24.1) Age 40−49: 145 (6.4) vs. 170 (7.4) Age 50−59 60 (2.6) vs. 50 (2.2) Age ≥60: 7 (0.3) vs. 6 (0.3) Median age: 26 vs. 26 years MSM: 88% vs. 87% Transgender women who have sex with men: 12% vs. 13% A vs. B 91.5% (received injection with no delay ≥2 weeks) vs. 74% (plasma, tenofovir level > 40 ng/mL [consistent with ≥4 doses/week]) HPTN 084 Delany-Moretwle, 2022 Sub-Sahara Africa Median 1.24 years Head-to-head trial Good A: Cabotegravir 600 mg in 3 mL intramuscular injectable every 8 weeks (n=1,592) B: Daily TDF-FTC 300 mg + 200 mg (n=1,586) High risk women: Reporting at least 2 episodes of vaginal intercourse in the previous 30 days at risk of HIV infection based on an HIV risk score Age range NR Inclusion criteria: 18 – 45 years old A vs. B Median age: 25 vs. 25 years Race/ethnicity: 97.2% vs. 96.5% Black Gender identity: 99.9% vs. 99.8% female, 0% vs 0.2% male, and 0.1% vs. 0% transgender male A vs. B 93% (received injection with no delay ≥2 weeks) vs. 42% (plasma, tenofovir level ≥40 ng/mL) ‡Sample of patients who reported that they were taking Abbreviations: ART=antiretroviral therapy; FTC=emtricitabine; iPrEx=Pre-Exposure Prophylaxis Initiative; MEMS=medication event monitoring system; mg=milligram; mL=milliliter; ng/mL=nanograms per milliliter; NR=not reported; PrEP=pre-exposure prophylaxis; PROUD=Pre-Exposure Option for Reducing HIV in the UK: Immediate or Deferred; RCTs=randomized, controlled trials; STI=sexually transmitted infection; TDF=tenofovir disoproxil fumarate; TDF2=Tenofovir Disoproxil Fumarate 2 Study; VOICE=Vaginal and Oral Interventions to Control the Epidemic. Table 2. HIV Pre-Exposure Prophylaxis Key Clinical Trials: Results (adapted from USPSTF 2019 and 2023) Study name Author, year of publication Country Duration of follow-up (months or years) Quality 5 Interventions in trial arms (n = sample size) Trial arms: A vs. B (vs. C vs. D) Clinical health outcomes (such as frequency count, percent, hazard ratio [HR], risk ratio [RR], or number needed to treat [NNT]) (sample size) Adverse events FEM PrEP Van damme 2012 Kenya, South Africa, Tanzania 1 year Good (and Agot, 2015) ( FEM-PrEP Mandala, 2014, report on adverse events) A. oral TDF-FTC 300/200mg once daily (n=1,062) B. Placebo (n=1,058) A vs. B HIV infection: 5% (31/1,024) vs. 5% (35/1,032); HR, 0.94 (95% CI, 0.59 to 1.52); NNT, 275 Risk behaviors: Narratively described reduction in number of partners, vaginal sex acts, and sex without a condom from baseline, no between-group data reported A vs. B Mortality: 0.1% (1/1,024) vs. 0.1% (1/1,032); RR, 1.01 (95% CI, 0.06 to 16) Any serious adverse event: 3.2% (33/1,025) vs. 2.2% (23/1,033); RR, 1.43 (95% CI, 0.84 to 2.42) Any adverse event: 74.1% (760/1,025) vs. 72.3% (747/1,033); RR, 1.01 (95% CI, 0.93 to 1.09) Withdrawals due to adverse event: 5.3% (55/1,025) vs. 3.2% (33/1,033) Withdrawals due to hepatic or renal lab abnormalities (temporary or permanent): 4.7% (48/1,024) vs. 3.0% (31/1,032) Elevated ALT ( > Grade 3): 0.6% (6/1,025) vs. 0.8% (8/1,033); RR, 0.75 (95% CI, 0.26 to 2.17) Elevated AST ( > Grade 3): 0.3% (3/1,025) vs. 0.1% (1/1,033); RR, 3.01 (95% CI, 0.31 to 28.9) Elevated creatinine ( > Grade 2): 0.4% (4/1,025) vs. 0.2% (2/1,033); RR, 2.01 (95% CI, 0.36 to 10.95) Withdrawals due to renal events: 0.1% (1/1,025) vs. 0% (0/1,033) Trichomoniasis: 3.5% (36/1,024) vs. 5.8% (60/1,032); RR, 0.60 (95% CI, 0.40 to 0.91) Candidiasis: 15.2% (156/1,024) vs. 15.2% (157/1,032); RR, 1.00 (95% CI, 0.82 to 1.23) Gonorrhea: 4.9% (50/1,024) vs. 3.2% (33/1,032); RR, 1.53 (95% CI, 0.99 to 2.35) Chlamydia: 13.3% (136/1,024) vs. 12.0% (124/1,032); RR, 1.11 (95% CI, 0.88 to 1.39) Nausea: 4.9% (50/1,024) vs. 3.1% (32/1,032); RR, 1.57 (95% CI, 1.02 to 2.43) Vomiting: 3.6% (37/1,024) vs. 1.2% (12/1,032); RR, 3.11 (95% CI, 1.63 to 5.92) Diarrhea: 1.7% (17/1,024) vs. 0.8% (8/1,032); RR, 2.14 (95% CI, 0.93 to 4.94) Serious GI events: 0.4% (4/1,025) vs. 0.1% (1/1,033) Withdrawals due to GI adverse events: 0.1% (1/1,025) vs. 0% (0/1,033) Any adverse pregnancy-related outcomes, among women who became pregnant: 32.4% (24/74) vs. 23.5% (12/51); RR, 1.38 (95% CI, 0.76 to 2.50) Spontaneous abortion, among women who became pregnant: 14.9% (11/74) vs. 13.7% (7/51); RR, 1.08 (95% CI, 0.45 to 2.61) IAVI Uganda Study Kibengo 2013 Uganda 4 months Good A. daily TDF-FTC 300/200mg (n=24) B. Intermittent TDF-FTC (Monday, Friday and within 2 hours postcoital, not to exceed 1 dose/day) (n=24) C. Daily placebo (n=12) D. Intermittent placebo (n=12) HIV infection: Narrative report of no infections in any group A + B vs. C + D Pregnancy outcomes: 1 spontaneous abortion and 1 molar pregnancy vs. 1 term pregnancy HIV immune response: Positive Env response, week 16: 1 vs. 0 vs. 1 vs. 0 (no other data reported) Positive IFN-y ELISPOT, week 16: 0 vs. 1 vs. 0 vs. 0 (no other data reported) Risk behavior, number of sexual partners: Reported to be 1 (IQR, 1 to 1) for all groups A vs. B vs. C vs. D Severe or very severe adverse event: 0% (0/24) vs. 0% (0/24) vs. 0% (0/12) vs. 8% (1/12) Severe neutropenia, A + B vs. C + D: 0% (0/48) vs. 4.1% (1/24) GI complaint, A + B vs. C + D: 33% (16/48) vs. 29% (7/24) Elevated serum creatinine, A + B vs. C + D: 4% (2/48) vs. 0% (0/24) Spontaneous abortion, among women who became pregnant, A + B vs. C + D: 100% (1/1) vs. 0% (0/1) IAVI Kenya Study Mutua 2012 Kenya 4 months Good A. daily TDF-FTC 300/200mg (n=24) B. Intermittent TDF-FTC (Monday, Friday and within 2 hours postcoital, not to exceed 1 dose/day) (n=24) C. Daily placebo (n=12) D. Intermittent placebo (n=12) A vs.B vs.C vs.D HIV infection: Narrative report of one HIV infection in a placebo group participant (daily or intermittent NR) HIV immune response: Positive IFN-y, week 16: 0 vs. 1 vs. 0 vs. 0 Positive Env peptide: 0 vs. 2 vs. 0 vs. 0 Positive RT peptide: 0 vs. 0 vs. 0 vs. 1 Risk behavior, number of sexual partners: No between-group data reported; narrative report of increase from median 3 to 4 partners at month 4 A vs. B vs. C vs. D Severe or very severe adverse event: 13% (3/24) vs. 4% (1/24) vs. 0% vs. 0% Any GI adverse event, A + B vs. C + D: 42% (20/48) vs. 21% (5/24) Elevated serum creatinine, A + B vs. C + D: 6% (3/48) vs. 0% (0/24) Abnormal creatinine clearance: 2% (1/48) vs. 4% (1/24) iPrEx Grant 2010 Brazil, Ecuador, Peru, Thailand, South Africa, United States 1.2 years (median) Good A. TDF-FTC 300/200 mg (n=1,251) B. Placebo (n=1,248) A vs. B HIV infection: 3.0% (38/1,251) vs 5.8% (72/1,248); HR, 0.53 (95% CI, 0.36 to 0.78); NNT, 37 A vs. B Death: 0.1% (1/1,251) vs. 0.3% (4/1,248); RR, 0.25 (95% CI, 0.03 to 2.23) Serious adverse events: 5% (60/1,251) vs. 5% (67/1,248); RR, 0.89 (95% CI, 0.64 to 1.25) Withdrawal due to adverse event: 6.3% (79/1,251) vs 5.8% (72/1,248) Acute HBV infection: 0.1% (2/1,244) vs. 0.0% (1/1,217); RR, 1.96 (95% CI, 0.18 to 21.6) Syphilis: 4.2% (527/1,244) vs. 4.0% (491/1,217); OR, 0.54 (95% CI, 0.35 to 0.81) Warts: 9.8% (122/1,244) vs. 9.0%(110/1,217); OR, 1.09 (95% CI, 0.83 to 1.43) Urethral gonorrhea: 1.1% (14/1,244) vs. 1.4% (17/1,217); OR, 0.80 (95% CI, 0.39 to 1.64) Urethral chlamydia: 0.8% (10/1,244) vs. 1.2% (14/1,217); OR, 0.70 (95% CI, 0.31 to 1.57) Bone fracture: 1% (15/1,251) vs. 1% (11/1,248); RR, 1.36 (95% CI, 0.63 to 2.95) Diarrhea: 3.7% (46/1,251) vs. 4.5% (56/1,248); RR, 0.82 (95% CI, 0.56 to 1.20) Grade 3 or 4 diarrhea: (3/1,251) vs. (2/1,248) Nausea: 1.6% (20/1,251) vs. 0.7% (9/1,248); RR, 2.21 (95% CI, 1.01 to 4.85) Grade 3 or 4 nausea: No cases in either group Permanent discontinuation of study drug: 2% (25/1,251) vs. 2% (27/1,248); RR, 0.92 (95% CI, 0.54 to 1.58) Permanent or temporary discontinuation of study drug: 6% (79/1,251) vs. 6% (72/1,248); RR, 1.09 (95% CI, 0.80 to 1.49) HSV-2: 9.7% (65/671) vs 8.9% (60/676); RR, 1.12 (95% CI, 0.80 to 1.56) Fracture data from Food and Drug Administration: 21 vs. 17 Partners PrEP Baeten 2012 Kenya, Uganda 2 years (median) Good A. Once-daily TDF 300 mg + placebo TDF-FTC (n=1,571) B. Once-daily TDF-FTC 300/200 mg + placebo TDF (n=1,565) C. Placebo TDF + placebo TDF-FTC (n=1,570) All participants received a comprehensive package of HIV-1 prevention services and were offered HBV vaccination A vs.B vs.C HIV infection: 1.1% (17/1,572) vs. 0.8% (13/1,568) vs. 3.3% (52/1,586); A vs. B: RR, 1.30 (95% CI, 0.64 to 2.68) NNT, 397; A vs. C: RR, 0.33 (95% CI, 0.19 to 0.56) NNT, 46; B vs. C: RR, 0.25 (95% CI, 0.14 to 0.46) NNT, 41 HIV infection among patients whose partner had not yet initiated ART: 14/17 vs. 13/13 vs. 50/52 A vs. B. vs. C Serious adverse events: 7.4% (118/1,584) vs. 7.3% (115/1,579) vs. 7.4% (118/1,584) Death: 0.5% (8/1,584) vs. 0.5% (8/1,579) vs. 0.6% (9/1,584) Withdrawal due to adverse events: 0.6% vs. 0.7% vs. 0.6% Grade 4 adverse events: 2.1% (34/1,584) vs. 2.8% (44/1,579) vs. 2.5% (39/1,584) Grade 3 adverse events: 18.2% (289/1,584) vs. 18.6% 293/1,579) vs. 16.9% (268/1,584) Bone fracture: < 1% (11/1,584) vs. 0.6% (9/1,579) vs. 0.8% (12/1,584) Elevated creatinine grade 1: 1.0% (16/1,584) vs. 1.1% (18/1,579) vs. 0.8%% (12/1,584) Elevated creatinine grade 2 or 3: 0.2% (3/1,584) vs. 0.1% (2/1,579) vs. 0.1% (1/1,584) Nausea: 0.2% (3/1,584) vs. 0.1% (1/1,579) vs. 0% (0/1,584); A vs. C: RR, 3.50 (95% CI, 0.18 to 68); B vs. C: RR, 1.51 (95% CI, 0.06 to 37) Diarrhea: 3.0% (48/1,584) vs. 2.4% (38/1,579) vs. 2.5% (39/1,584); A vs. C: RR, 1.23 (95% CI, 0.81 to 1.87); B vs. C: RR, 0.98 (95% CI, 0.63 to 1.52) STI ( N. gonorrhoeae, C. trachomatis, or T. vaginalis) : 5.8% (102/1,584) vs. 4.2% (76/1,579) vs. 4.8% (85/1,584) Syphilis: 2% (28/1,584) vs. 2% (27/1,579) vs. 1% (23/1,584) Fracture data from Food and Drug Administration: 19 (PrEP) vs. 13 (placebo) PROUD McCormack 2016 England 1 year Fair A. Immediate TDF-FTC 245/200 mg (n=275) B. TDF-FTC deferred for 1 year (n=269) A vs. B HIV infection: 1.1% (3/268) vs. 7.5% (20/255); RR, 0.14 (95% CI, 0.04 to 0.47); 1.2 cases/100 person-years (90% CI, 0.4 to 2.9) vs. 9.0/100 person-years (90% CI, 6.1 to 12.8); NNT, 13 A vs. B Mortality: 0.4% (1/275) vs. 0% (0/269) Serious adverse events: 8% (21/275) vs. 2% (6/269); RR, 3.42 (95% CI, 1.40 to 8.35) Fracture/broken bone: 1% (3/275) vs. 0.4% (1/269); RR, 2.93 (95% CI, 0.31 to 28) Diarrhea (se