TO: Administrative File: CAG-00464N
FROM: Coverage and Analysis Group
SUBJECT: Proposed National Coverage Determination for Pre-Exposure Prophylaxis (PrEP) for Human Immunodeficiency Virus (HIV) Infection Prevention
DATE: July 12, 2023
I. Proposed Decision
The Centers for Medicare and Medicaid Services (CMS) proposes that the evidence is adequate to conclude that the United States Preventive Services Task Force (USPSTF) recommends offering Pre-Exposure Prophylaxis (PrEP) with effective antiretroviral therapy (ART) to persons at high risk of Human Immunodeficiency Virus (HIV) acquisition with a grade of A recommendation, is reasonable and necessary for the prevention or early detection of illness or disability under §1861(ddd)(1) of the Social Security Act (the Act), and is appropriate for individuals entitled to benefits under Part A or enrolled under Part B.
CMS proposes to cover PrEP using antiretroviral drugs (whether oral or injectable) approved by the US Food and Drug Administration (FDA) to prevent HIV infection in individuals at high risk of HIV acquisition. The determination of whether an individual is at high risk for HIV infection is made by the physician or health care practitioner who assesses the individual’s history. In addition, CMS proposes to also cover the administration of injectable PrEP using antiretroviral drugs to prevent HIV infection.
CMS also proposes to cover up to seven 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 and individuals must be competent and alert at the time that counseling is provided.
Additionally, for individuals being assessed for or who are taking PrEP using ART to prevent HIV infection, CMS proposes to cover HIV screening up to seven times annually and a single screening for hepatitis B virus (HBV). These screening tests are proposed to be covered with the appropriate FDA approved laboratory tests and point of care tests, used consistent with FDA approved labeling and in compliance with the Clinical Laboratory Improvement Act (CLIA) regulations.
See Appendix B for the proposed manual language.
CMS is seeking comments on our proposed decision pursuant to § 1862(l)(3)(B) of the Act.
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
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 38.4 million people across the globe with HIV in 2021 (US Department of Health & Human Services (HHS), 2022). In the United States (US), the condition continues to be a serious public health issue. In 2021, 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), 2023). An estimated 1.5 million individuals worldwide acquired HIV in 2021, marking a 32% decline in new HIV infections since 2010 (HHS, 2022). 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, ageing 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 ageing. Nearly half of the people in the US diagnosed with HIV are aged 50 and older (National Institute on Aging (NIA), 2021). 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 infection 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 infection 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 United States followed by those who are Hispanic (CDC, 2021b). At year-end 2019, of the estimated number of persons living with diagnosed or undiagnosed HIV infection, 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). Of the estimated number of persons living with diagnosed or undiagnosed HIV infection, 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, 2023a). 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 getting it, 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 2019, men who had sex with men (MSM) accounted for 65% of all new HIV infections (CDC, 2022a). While heterosexual contact accounted for 23% and persons with injection drug use constituted about 7% of new HIV diagnoses.
HIV/Acquired immunodeficiency syndrome (AIDS)
HIV is a ribonucleic acid retrovirus 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, 2021c). 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 CD4 cell count 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/mm3 or one or more AIDS-defining neoplastic conditions or opportunistic infections. Thus, a person may be infected with HIV for years before the condition is suspected. So, the only way to know for sure whether a person has HIV infection 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 Treatment
Pre-exposure prophylaxis (PrEP) involves the use of ART on an ongoing basis (e.g., daily or bimonthly) or before and after HIV exposure events (“on-demand” or “event-driven” PrEP) to decrease the risk of acquiring HIV infection from sex or injection drug use (CDC, 2022b). When taken as prescribed, PrEP is highly effective for preventing HIV. PrEP can be an oral medication or an injection. 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®). 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 infection 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, 2023b). 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. In 2019, the CDC estimated that approximately 285,000 of 1.2 million eligible individuals for PrEP (or 23%) received it, an increase from about 20 percent in 2015 (CDC, 2021d). Chou et al. (2022) 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 being considered to be 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., 2022). 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 proposed decision memo for more details regarding benefits and harms of PrEP using ART to prevent HIV infection).
United States Preventive Services Task Force (USPSTF)
The USPSTF (2019) recommends that clinicians offer PrEP with effective ART to persons who are at high risk of HIV acquisition (grade A recommendation).
The recommendation was based on convincing evidence that PrEP is of substantial benefit in decreasing the risk of HIV infection in persons at high risk of HIV acquisition and adequate evidence of small harms, including kidney and gastrointestinal adverse effects, resulting in high certainty of substantial net benefit (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 provide 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
Pursuant to §1861(ddd) of the Act, CMS may add coverage of "additional preventive services" if certain statutory requirements 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 an 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. 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. |
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, 2020).” 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. 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 infection immediately prior to initiating Truvada® for HIV 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 status, including viral suppression status, regular testing for STIs that can facilitate HIV 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.
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 that Apretude® is indicated in at-risk adults and adolescents weighing at least 35 kg for PrEP to reduce the risk of sexually acquired HIV infection; screen for HIV 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 status, including viral suppression status, regular testing for STIs that can facilitate HIV transmission); inform uninfected individuals about and support their efforts in reducing sexual risk behavior; and healthcare providers should 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 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 status, or sexual activity in a high prevalence area or network (FDA, 2020; 2022; 2023).
VI. Public Comment
Public comments sometimes cite published clinical evidence and give CMS useful information. Public comments that give information on unpublished evidence such as the results of individual practitioners or patients are less rigorous and therefore less useful for making a coverage determination. Public comments that contain personal
health information will be redacted or not be made available to the public.
CMS uses the initial public comments to inform its proposed decision. CMS responds in detail to the public comments on a proposed decision when issuing the final decision memorandum. All comments that were submitted without personal health information may be viewed in their entirety by using the following link: PrEP to prevent HIV infection NCA initial public comments.
Initial Public Comment Period: 01/12/2023 – 02/11/2023
During the 30-day comment period following the release of the tracking sheet, CMS received 37 comments. The vast majority of commenters supported Medicare coverage of PrEP to prevent HIV infection and to align with the USPSTF grade A recommendation. Commenters noted the safety and efficacy of PrEP as an essential tool to ending the HIV epidemic. They emphasized the need to improve PrEP uptake, adherence, and access. Numerous comments focused on access to the newest PrEP drug, the injectable cabotegravir or Apretude®. Two commenters were not in support of Medicare coverage of PrEP using ART to prevent HIV infection. In part, one of these commenters did not agree with the FDA approval of these drugs, disagreed with the outcome measure in the trials, and believed that the PrEP antiretroviral drugs are not appropriate for the Medicare population due to adverse effects to the kidneys and the need for longer term studies. The other commenter does not support PrEP to prevent HIV infection due to their belief that Medicare coverage would negatively impact users of the 340B drug pricing program.
CMS received comments from community health centers, patient advocacy organizations, pharmaceutical companies, institutions of higher education, health systems and medical centers, physicians and other health care professionals, attorneys, and individuals.
Ten comments were provided by professional associations/organizations, including the American Academy of HIV Medicine Specialists (AAHIVS), Gerontological Society of America, Association of Nurses in AIDS Care, HIV Medicine Association, International Association of Providers of AIDS Care, HealthHIV, National Alliance of State and Territorial AIDS Directors (NASTAD), National Coalition of STD Directors, National Disability Rights Network (NDRN), and National Association of Social Workers.
Several commenters provided references for our deliberation of this NCD. We appreciate this information. All such references were assessed for inclusion in our evidence review.
VII. 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 high risk of HIV acquisition. Our assessment focuses on the key evidence questions below.
B. Discussion of Evidence
1. Evidence Questions
Question 1: Is the evidence sufficient to determine that the USPSTF recommends that clinicians offer PrEP with effective ART to persons at high risk of HIV acquisition with a grade of A or B recommendation?
Question 2: Is the evidence sufficient to determine that offering PrEP with effective ART for persons at high risk 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 offering PrEP with effective ART for persons at high risk of HIV acquisition is appropriate for Medicare beneficiaries under Part A or Part B?
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., 2022), 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. Although one study focusing on the risk factor of people who inject drugs (PWID) and oral TDF monotherapy was included since it was the only clinical trial focusing on this population.
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 proposed decision memorandum.
Table 1. Study characteristics of key clinical trials of PrEP (adapted from Chou et al., 2019; Chou et al., 2022)
Study name
Author, year of publication
Country
Duration of follow-up (months or years)
Study design
Quality3 |
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 PrEP.
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 2022)
| Study name
Author, year of publication
Country
Duration of follow-up (months or years)
Quality[4] |
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); R, 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 (serious): 1.5% (4/275) vs. 0% (0/269); RR, 8.80 (95% CI, 0.48 to 163) Vomiting (serious): 0.7% (2/275) vs. 0% (0/269); RR, 4.89 (95% CI, 0.24 to 101) Any STI: 57% (152/265) vs 50% (124/247); OR, 1.33 (95% CI, 0.94 to 1.89); aOR (adjusted for number of screenings for specific infection), 1.07 (95% CI, 0.78 to 1.46) Gonorrhea: 39% (103/261) vs. 37% (89/242); OR, 1.12 (95% CI, 0.78 to 1.61); aOR, 0.86 (95% CI, 0.62 to 1.20) Chlamydia: 30% (77/261) vs. 22% (54/242); OR, 1.46 (95% CI, 0.97 to 2.18); aOR, 1.27 (95% CI, 0.89 to 1.80) |
| TDF2 Thigpen 2012 Botswana 1 year (median) Good |
A. Oral TDF-FTC 300/200 mg, once daily (n=611) B. Placebo, once daily (n=608) |
A vs. B HIV infection: 1.6% (10/601) vs. 4.2% (26/606); RR, 0.39 (95% CI, 0.19 to 0.81); 1.2 cases/100 person-years (90% CI, 0.4 to 2.9) vs. 3.1 cases/100 person- years (90% CI, 0.03 to 3.2); NNT, 52 |
A vs. B Mortality: 0.3% (2/611) vs. 0.7% (4/608); RR, 0.50 (95% CI, 0.09 to 2.71) Serious adverse events: 10% (68/611) vs. 11% (79/608); RR, 0.85 (95% CI, 0.63 to 1.16) No Grade 3 or 4 creatinine elevation or GI events Fracture/broken bone: 1% (7/611) vs. 1% (6/608) Elevated creatinine: 0.2 (1/611) vs. 0% (0/608); RR, 2.98 (95% CI, 0.12 to 73.14) Diarrhea: 12.4% (76/611) vs. 10.7% (65/608) Nausea: 18.5% (113/611) vs. 7.1% (43/608) Neisseria gonorrheae infection: 4.6% (28/611) vs. 3.0% (18/608) Chlamydia trachomatis infection: 12.4% (76/611) vs. 12.3% (75/608) Trichomoniasis: 3.3% (20/611) vs. 3.0% (18/608) Genital herpes: 4.6% (28/611) vs. 5.8% (35/608) BMD changes, A (n=109) vs. B (n=112): There was a decline in T-scores and z-scores at the forearm, hip, and lumbar spine in participants who received TDF-FTC, compared with those who received placebo (p=0.004 for both T-scores and z-scores at the forearm and p<0.001 for both scores at the hip and lumbar spine) HSV-2: 4.6% (28/611) vs 5.8% (35/608); RR, 0.80 (95% CI, 0.49 to 1.29) |
| VOICE Marrazzo 2015 South Africa, Uganda, Zimbabwe 3 years (maximum) 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) |
A vs.B vs.C Number of HIV-1 infections: 5% (52/1,007) vs.6% (61/1,003) vs. 6% (60/1,009); A vs. C: RR, 0.87 (95% CI, 0.61 to 1.25); B vs. C: RR, 1.02 (95% CI, 0.72 to 1.44) |
A vs. B vs. C Mortality: 0% (0/1,007) vs. 0% (0/1,003) vs. 0.3% (3/1,009) Serious adverse events: 8.6% (87/1,007) vs. 12.2% (123/1,003) vs. 11.3% (114/1,009) Grade 4 events: 0.4% (4/1,007) vs. 1.4% (14/1,003) vs. 1.7% (17/1,009) Lower limb fracture: 0.2% (2/1,007) vs. 0.1% (1/1,003) vs. 0% (0/1,009) Creatinine event: 0.4% (4/1,007) vs. 1.3% (13/1,003) vs. 0.2% (2/1,009) Nausea grade 2 or higher: 1.3% (13/1,007) vs. 0.8% (8/1,003) vs. 1.5% (15/1,009) Vomiting grade 2 or higher: 0.1% (6/1,007) vs. 0.1% (6/1,003) vs. 0.1% (9/1,009) Diarrhea grade 2 or higher: 1.2% (12/1,007) vs. 1.8% (18/1,003) vs. 2.1% (21/1,009) Any Grade 3 or 4 GI event: 0% (0/1,007 vs. 0.3% (3/1,003) vs. 0.7% (7/1,009) Chlamydia infection: 10.4% (105/1,007) vs. 14.4% (144/1,003) vs. 15.2% (153/1,009) Gonococcal infection: 2.6% (26/1,007) vs. 4.6% (46/1,003) vs. 4.5% (45/1,009) Syphilis infection: 1.5% (15/1,007) vs. 1.0% (10/1,003) vs. 1.5% (15/1,009) |
| ADAPT/ HPTN 067 Bekker 2018 South Africa 34 weeks 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) |
A vs. B vs. C HIV infection: 0% (0/59) vs. 3% (2/59) vs. 3% (2/60); A vs. B: RR, 0.20 (95% CI, 0.01 to 4.08); A vs. C: RR, 0.20 (95% CI, 0.01 to 4.15) |
A vs. B vs. C Any headache, dizziness, or lightheadedness: 12% (43/348) vs. 6% (20/331) vs. 8% (26/332); A vs. B: OR, 2.19 (95% CI, 1.13 to 4.27); A vs. C: OR, 1.66 (95% CI, 0.88 to 3.13) Any GI symptom: 11% (37/348) vs. 9% (29/331) vs. 5% (18/332); A vs. B: OR, 1.24 (95% CI, 0.61 to 2.51); A vs. C: OR, 2.08 (95% CI, 0.98 to 4.40) |
| ADAPT/ HPTN 067 Grant, 2018 Thailand, US 34 weeks 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) |
A vs. B vs. C HIV infection: 0.8% (1/119) vs. 0% (0/119) vs. 0% (0/119); A vs. B; A vs. C: RR, 3.03 (95% CI, 0.12 to 75) South Africa (from Bekker 2017), Bangkok and Harlem sites combined: 0.6% (1/178) vs. 1.1% (2/178) vs. 1.1% (2/179); A vs. B: RR, 0.50 (95% CI, 0.04 to 5.53); A vs. C: RR, 1.01 (95% CI, 0.14 to 7.22) |
A vs. B vs. C Bangkok Proportion of visits when patients reported neurologic events: 14.2% vs. 14.3% vs. 13.3% Proportion of visits when patients reported GI events: 13.1% vs. 8.5% vs. 10.5% Harlem Proportion of visits when patients reported neurologic events: 6.1% vs. 3.3% vs. 4.5% Proportion of visits when patients reported GI events: 8.0% vs. 5.8% vs. 7.1% |
| Kwan, 2021 Hong Kong 32 weeks Fair |
A: Daily TDF-FTC (n=59) B: Event-driven TDF-FTC (n=60) |
NR |
A vs. B Creatinine clearance: no difference between arms |
| DISCOVER Mayer, 2020 Europe and North America 96 weeks Good |
A: TAF-FTC (n=2670) B: TDF-FTC (n=2665) |
HIV infection: 0.16 vs. 0.34 per 100 person-years, IRR 0.47 (95% CI 0.19 to 1.15); 0.3% (7/2670) vs. 0.6% (15/2665), RR 0.47 (0.19 to 1.14) ‡ HIV prevention: IRR 0.54 (0.23 to 1.26) |
Mortality: 0.04% (1/2694) vs. 0.04% (1/2693), RR 1.00 (95% CI 0.06 to 15.97)
Serious adverse event: 6% (169/2694) vs. 5% (138/2693), RR 1.22 (95% CI 0.98 to 1.52)
Discontinuation of study drug due to adverse event: 1% (36/2694) vs. 2% (49/2693), RR 0.75 (95% CI 0.49 to 1.15)
Any adverse event: 93% (2498/2694) vs. 93% (2494/2693), RR 1.00 (95% CI 0.99 to 1.02)
Rectal chlamydia: 29% (770/2694) vs. 29% (792/2693)
Oropharyngeal gonorrhea: 27% (740/2694) vs. 27% (722/2693)
Rectal gonorrhea: 26% (693/2694) vs. 25% (671/2693)
Syphilis: 13% (342/2694) vs. 12% (321/2693), RR 1.06 (95% CI 0.92 to 1.23)
Urethral chlamydia: 10% (280/2694) vs. 10% (259/2693)
Any grade 3 or 4 laboratory abnormality: 7% (196/2694) vs. 8% (206/2693), RR 0.95 (95% CI 0.79 to 1.15)
Increased alanine aminotransferase (>5 times upper limit of normal): 1% (39/2694) vs. 2% (40/2693), RR 0.97 (95% CI 0.63 to 1.51)
Any renal adverse event: 10% (263/2694) vs. 10% (266/2693), RR 0.99 (95% CI, 0.84 to 1.16) Grade ≥3 renal adverse event: 0.07% (2/2694) vs. 0.1% (3/2693), RR 0.67 (95% CI 0.11 to 3.99) Renal adverse event leading to discontinuation: 0.07% (2/2694) vs. 0.2% (6/2693), RR 0.33 (95% CI 0.07 to 1.65)
Proximal renal tubulopathy: 0% (0/2694) vs. 0.04% (1/2693) Creatinine clearance, median percentage change from baseline: -2.3% vs. +1.8%, p<0.0001
Quantitative proteinuria at 48 hours: 0.04% (1/2694) vs. 0.07% (2/2693), p=0.005 (rank ANCOVA, adjusting for baseline category) Fracture: 2% (53/2694) vs. 2%
(53/2693), RR 1.00 (95% CI 0.68 to 1.46) Nontraumatic fracture: 0.04% (1/2694) vs. 0.07% (2/2693), RR 0.50 (95% CI 0.05 to 5.51) Hip bone mineral density, percent change from baseline: +0.18% vs. -0.99%, p<0.0001 Spine bone mineral density, percent change from baseline: +0.50% vs. -1.12%, p<0.0001
Diarrhea: 16% (430/2694) vs. 16% (422/2693) Nausea: 4% (114/2694) vs. 5%
(123/2693) Acute myocardial infarction: 0.07% (2/2694) vs. 0.04% (1/2693)
Increased fasting LDL (>4.92 mmol/L): 2% (51/2694) vs. 1% (18/2693), RR 2.83 (95% CI 1.66 to 4.83) LDL concentration (median, change
from baseline): +0.03 vs. -0.18 mmol/L, p<0.0001 Body weight:, change from baseline: +1.1 vs. -0.1 kg, p<0.0001
|
| HPTN 083 Landovitz, 2021 International Median 1.4 years 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) |
A vs. B HIV infection: 0.57% (13/2,243) vs. 1.71% (39/2,247); RR 0.33 (95% CI, 0.18 to 0.62‡); incidence rate per 100 person-years, 0.41 vs. 1.22; HR 0.34 (95% CI 0.18 to 0.62) |
A vs. B Serious adverse events: 5.3% (120/2,280) vs. 5.3% (121/2,282), RR 0.99 (95% CI 0.78 to 1.27) Grade 3 or higher adverse events: 31.9% (727/2,280) vs. 33.6% (767/2,282) Hepatic-related discontinuations: 2.1% (47/2,280) vs. 2.1% (48/2,282) Seizures: 0.1% (2/2,280) vs. 0.2% (5/2,282)
Decreased creatinine cleareance: 7.0% (159/2,280) vs. 8.3% (190/2,282) Increased aspartate aminotransferase: 2.3% (53/2,280) vs. 3.0% (69/2,282) Increased alanine aminotransferase: 1.0% (23/2,280) vs. 1.4% (32/2,282) Deaths: 0.18% (4/2,280) vs. 0 |
| HPTN 084 Delany-Moretwle, 2022 Sub-Sahara Africa Median 1.24 years Good |
A: Cabotegravir 600 mg in 3 mL IM injectable every 8 weeks (n=1,592) B: Daily TDF-FTC 300 mg + 200 mg (n=1,586) |
A vs. B HIV infection: 0.3% (4/1,592) vs. 2.3% (36/1,586); RR 0.11 (95% CI 0.04 to 0.31‡); incidence rate per 100 person-years, 0.20 (95% CI 0.06 to 0.52) vs. 1.85 (95% CI 1.30 to 2.57); HR 0.12 (95% C, 0.05 to 0.31) |
A vs. B Serious adverse events: 2.0% (33/1,614) vs. 2.0% (33/1,610), RR 1.00 (95% CI 0.62 to 1.61) Grade 3 or higher adverse events: 17.1% (276/1,614) vs. 17.4% (280/1,610) Hepatic-related discontinuation: 0.9% (15/1,614) vs. 1.1% (18/1,610) Seizures: 0 vs. 0.1% (1/1,610) Deaths: 0.2% (3/1,614) vs. 0 Chlamydia: 16.2% (261/1,614) vs. 17.8% (287/1,610), RR 0.91 (95% CI 0.78 to 1.06) Gonorrhea: 7.8% (126/1,614) vs. 7.8% (125/1,610), RR 1.01 (95% CI 0.79 to 1.28) Trichomonas: 7.7% (124/,1614) vs. 6.8% (109/1,610), RR 1.13 (95% CI 0.89 to 1.45) Grade 3 decreased creatinine clearance: 6.8% (110/1,614) vs. 7.8% (125/1,610) |
‡Relative risk calculated from data provided in the trial.
Abbreviations: ADAPT=Alternative Dosing to Augment PrEP pill Taking; aHR=adjusted hazard ratio; aOR = adjusted odds ratio; ALT=alanine aminotransferase; ART=antiretroviral therapy; AST=aspartate aminotransferase; BMD=bone mineral density; CDC=Centers for Disease Control and Prevention; CI=confidence interval;DEXA=dual energy
X-ray absorptiometry; eGFR=estimated glomerular filtration rate; ELISPOT=Enzyme-Linked ImmunoSpot assay; Env=Env peptide pool; FEM-PrEP=Pre-Exposure Prophylaxis Trial for HIV Prevention Among African Women; FTC=emtricitabine; GI=gastrointestinal; GFR=glomerular filtration rate; HR=hazard ratio; HBsAg=surface antigen of hepatitis B; HBV=hepatitis B virus; HCV=hepatitis C virus; HPTN= HIV Prevention Trials Network; HSV=herpes simplex virus; IAVI=International AIDS Vaccine Initiative; IFN-y=interferon gamma; IM=intramuscular; iPrEx=Pre-Exposure Prophylaxis Initiative; IPERGAY=Intervention Préventive de l’Exposition aux Risques Avec et Pour les GAYs; IRR=incidence rate ratio; IQR=interquartile range; ISCD=International Society for Clinical Densiometry; L2=second lumbar vertebra; L4=fourth lumbar vertebra; LDL=low density lipoprotein; LS=lumbosacral spine; mg = milligram; mL = milliliter; MSM=men who have sex with men; NA=not applicable; NNRTI=nonnucleoside reverse transcriptase inhibitor; NNT=number needed to treat; NR=not reported; OR=odds ratio; PrEP=pre-exposure prophylaxis; PROUD=Pre-Exposure Option for Reducing HIV in the UK: Immediate or Deferred; PWID=persons who inject drugs; RAI=receptive anal intercourse; RNA=ribonucleic acid; RR=relative risk; RCT=randomized, controlled trial; RT=retention time; SD=standard deviation; STI=sexually transmitted infection; TAF=tenofovir alafenamide; TDF=tenofovir disoproxil fumarate; TDF2=Tenofovir Disoproxil Fumarate 2 Study; TDF-FTC=emtricitabine/tenofovir disoproxil fumarate; TFV= tenofovir; TH=thoracic vertebra; ULN=upper limit of normal; US=United States; VOICE=Vaginal and Oral Interventions to Control the Epidemic; WHO=World Health Organization.
Evidence-based Guidelines
The CDC/United States Public Health Service guideline, “PrEP for the Prevention of HIV Infection in the United States – 2021 Update: A Clinical Practice Guideline
(CDC, 2021e),” encourages healthcare providers to increase awareness of PrEP and offer PrEP as a core primary care service in order to reduce missed opportunities for providing PrEP. The CDC recommends taking a brief, targeted sexual history of all adult and adolescent patients as part of ongoing primary care and PrEP to be offered to
sexually active adults and adolescents at substantial risk of HIV acquisition. The guideline criteria for identifying patients at high risk of acquiring HIV infection
follow the inclusion criteria of the major randomized trials of PrEP. The criteria include: sexually-active adults who have had anal or vaginal sex in the past six months and any of the following: HIV-positive sexual partner (especially if partner has an unknown or detectable viral load); or a bacterial STI in the past six months; or a history of inconsistent or no condom use with sexual partner(s). The CDC states that most persons who inject drugs are sexually active and report sexual behaviors that
confer risk of HIV acquisition. The guideline states that PWID are likely to benefit from PrEP with any FDA-approved medication with or without an identified sexual behavior risk of HIV acquisition. PWID who have a HIV-positive injecting partner or sharing injection equipment are at high risk of acquiring HIV infection. The CDC guideline also includes various recommendations regarding baseline and follow-up visit timing of laboratory tests for patients receiving daily oral PrEP (see table 3 below) and cabotegravir (see table 4 below).
Table 3. CDC Guideline daily oral PrEP timing of laboratory tests (CDC, 2021e)
| Test | Oral PrEP Initiation Visit/Screening/Baseline visit |
Follow-up visits |
| HIV status |
HIV Ag/AB test (lab preferred) |
HIV-1 qualitative RNA + Ag/Ab (every 3 months) |
| Renal status |
eCrCL ≥60 ml/min (prescribe TDF-FTC or TAF-FTC) ≥30 ml/min (prescribe TAF-FTC) |
Assess every 6 months if baseline Age >50 years or eCrCL <90 ml/min Otherwise assess every 12 months |
| STI infection status |
Syphilis, gonorrhea, and chlamydia |
Repeat STI screen for MSM/TGW every 3 months; Repeat syphilis, gonorrhea screen for heterosexually active men and women every 6 months; chlamydia screen for heterosexually active men and women every 12 months |
| Lipid screen |
Only for persons prescribed TAF-FTC |
Repeat every 12 months for persons prescribed TAF-FTC |
Screen for active HBV |
Hep B serology |
If not done at initiation visit |
| Screen for HCV |
Hep C serology |
Periodically for those who continue to be at increased risk of HCV |
| Prescription for oral PrEP |
90-day supply |
90-day refill if HIV test is negative |
Abbreviations: Ag/AB= antigen / antibody; eCrCL=estimated creatinine clearance; FTC=emtricitabine; HBV=hepatitis B virus; HCV=hepatitis C virus; HIV HIV-1 qualitative RNA=Qualitative detection of presence or absence of human immunodeficiency virus type 1 (HIV-1) RNA in human blood; MSM=men who have sex with men; ml/min=milliliters per minute; PWID=people who inject drugs; PrEP=pre-exposure prophylaxis; STI=sexually transmitted infection; TAF=tenofovir alafenamide; TDF=tenofovir disoproxil fumarate; TGW=transgender women
Table 4. CDC Guideline Cabotegravir injection PrEP timing of laboratory tests (CDC, 2021e)
| Test |
Injectable PrEP Initiation Visit |
Follow-up visits |
| HIV status |
HIV Ag/AB test (lab preferred) |
HIV-1 qualitative RNA + Ag/Ab (1 month after initiation, then every 2 months) |
| STI infection status |
Syphilis, gonorrhea, and chlamydia |
Repeat STI screen for MSM/TGW every 4 months; Repeat syphilis and gonorrhea screen for heterosexually active men and women every 6 months; Repeat chlamydia screen MSM/TGW every 6 months; Chlamydia screen for heterosexually active men and women every 12 months |
Abbreviations: Ag/AB= antigen / antibody; HIV HIV-1 qualitative RNA=Qualitative detection of presence or absence of human immunodeficiency virus type 1 (HIV-1) RNA in human blood; MSM=men who have sex with men; PWID=people who inject drugs; PrEP=pre-exposure prophylaxis; STI=sexually transmitted infection; TGW=transgender women
The World Health Organization (WHO) recommends oral PrEP containing TDF, dapivirine vaginal ring (for individuals assigned female at birth), and cabotegravir as additional prevention choices for people at substantial risk of HIV as part of combination HIV prevention approaches (WHO, 2022). The WHO notes that risk of HIV acquisition varies greatly within populations and geographical locations.
“Population-level HIV incidence is an important determinant of individual-level risk of HIV acquisition. However, when considering who could benefit from PrEP, it is important to consider the characteristics and behaviors of individuals and their partners that could lead to HIV exposure. Even in locations with a low overall HIV incidence, there may be individuals at substantial risk who could benefit from PrEP services. Individuals requesting PrEP should be given priority to be offered PrEP since requesting PrEP indicates that there is likely to be a risk of acquiring HIV (WHO, 2022, p. 11).”
To note, the dapivirine vaginal ring has been withdrawn by its manufacturer from FDA review related to the manufacturer’s assessment that there is little chance of obtaining approval (Gollub & Vaughan, 2022).
Professional Society Recommendations
The International Antiviral Society – USA Panel updated their recommendations for ART for treatment and prevention of HIV infection in December 2022 (Gandhi et al.,
2023). The society recommends discussing PrEP with all sexually active adolescents and adults and anyone who injects nonprescription drugs or who has a substance use disorder, without specific criteria for risk behaviors or screening tools.
Populations with disproportionately high HIV incidence rates should be particularly encouraged to consider PrEP as part of their HIV prevention plans; these include cisgender men and transgender individuals who have sex with men; young adults and adolescents; people whose sexual partners are from regions of generalized HIV epidemic; persons who use nonprescription drugs and alcohol; individuals who exchange sex for money, goods, or services; partners of incarcerated individuals; and anyone with a recent bacterial STI (p. 72).
The society recommends oral daily PrEP containing TDF-FTC as an option for all risk groups, daily TAF-FTC for MSM at risk for kidney dysfunction, osteoporosis or
osteopenia and injectable cabotegravir for cisgender men/women, transgender women, and transgender men at increased risk for HIV acquisition.
4. Medicare Evidence Development & Coverage Advisory Committee (MEDCAC)
A MEDCAC meeting was not convened on this issue.
IX. CMS Analysis
Introduction
National coverage determinations (NCDs) are determinations by the Secretary with respect to whether or not a particular item or service is covered nationally under title XVIII of the Social Security Act (§ 1869(f)(1)(B)). In order to be covered by Medicare, an item or service must fall within one or more benefit categories contained
within Part A or Part B, and must not be otherwise excluded from coverage. CMS is authorized to cover "additional preventive services" if certain statutory requirements are met as provided under § 1861(ddd)(1) of the Act.
Regulations at 42 C.F.R. § 410.64 provides:
(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.
When making NCDs, it is important to consider whether the evidence is relevant to the Medicare beneficiary population. In considering the generalizability of the results of the body of evidence to the Medicare population, it is necessary to consider at least the age, race and gender of the study participants.
Evidence Review Summary
Question 1: Is the evidence sufficient to determine that the USPSTF recommends that clinicians offer PrEP with effective antiretroviral therapy to persons who are at high risk of HIV acquisition with a grade of A or B by the United States Preventive Services Task Force?
The USPSTF (2019) recommended (Owens et al., 2019):
| Population |
Recommendation summary |
Grade |
| Persons at high risk of HIV acquisition |
The USPSTF recommends that clinicians offer preexposure prophylaxis (PrEP) with effective antiretroviral therapy to persons who are at high risk of HIV acquisition. See the Clinical Considerations section for information about identification of persons at high risk and selection of effective antiretroviral therapy. |
A |
https://www.uspreventiveservicestaskforce.org/uspstf/recommendation/prevention-of-human-immunodeficiency-virus-hiv-infection-pre-exposure-prophylaxis#bootstrap-panel—6
The USPSTF also found:
Convincing evidence that PrEP is of substantial benefit in decreasing the risk of HIV infection in persons at high risk of HIV acquisition. The USPSTF also found convincing evidence that adherence to PrEP is highly associated with its efficacy in preventing the acquisition of HIV infection; thus, adherence to PrEP is central to realizing its benefit. The USPSTF found adequate evidence that PrEP is associated with small harms, including kidney and gastrointestinal adverse effects. The USPSTF concludes with high certainty that the magnitude of benefit of PrEP with oral tenofovir disoproxil fumarate–based therapy to reduce the risk of acquisition of HIV infection in persons at high risk is substantial (Owens et al., 2019).
In 2022, the USPSTF released a draft recommendation that is consistent with the 2019 recommendation and continues as a grade “A” recommendation (USPSTF, 2022). For the
draft recommendation, the USPSTF reviewed additional evidence on new formulations of PrEP, including the oral drug TAF-FTC and the injectable cabotegravir. The USPSTF has not yet issued a final recommendation after considering public input.
Consequently, based on the 2019 recommendation, CMS proposes that the evidence is sufficient to determine that the USPSTF recommends that clinicians offer PrEP with effective antiretroviral therapy to persons who are at high risk of HIV acquisition with a grade of A.
Question 2: Is the evidence sufficient to determine that PrEP using ART for persons at high risk of HIV acquisition is reasonable and necessary for the prevention or early detection of illness or disability under §1861(ddd)(1) of the Act?
Our reviewed evidence is limited to FDA approved PrEP using ART to prevent HIV infection and does not include studies examining the dapivirine vaginal ring, oral TDF monotherapy, alternative (non-daily) oral dosing schedules (e.g., event-driven [on-demand] or intermittent dosing), and other PrEP regimens (e.g., oral maraviroc, tenofovir vaginal gel, or injectable rilpivirine).
Quality and strength of evidence
The evidence base for this proposed decision is mainly derived from two recent systematic reviews, which were prepared for the USPSTF recommendation on PrEP with effective ART for persons who are at high risk of HIV acquisition to decrease the risk of acquiring HIV infection (Chou et al., 2019; Chou et al., 2022). CMS agrees with the USPSTF that the evidence demonstrates benefits and small harms for PrEP with ART, when used as prescribed, in reducing the risk of HIV infection in persons at increased risk of HIV acquisition. The evidence demonstrated efficacy and safety of PrEP; in addition to the beneficial effects of repeated condom provision, sexual risk-reduction counseling, and the diagnosis and treatment of sexually transmitted infections (STIs), all of which were provided to clinical trial participants. The evidence demonstrating small harms for PrEP with ART reveals the need for ongoing risk assessment, counseling, and monitoring for safety, such as HIV screening, during the administration of PrEP with ART.
Benefits
Chou et al. (2019; 2022) reviewed 11 randomized controlled trials (RCTs) that evaluated the effect of daily oral TDF-FTC PrEP (Truvada®) on the risk of HIV acquisition:
iPrEx (Grant et al., 2010)
Partners PrEP (Baeten et al., 2012)
IAVI Kenya Study (Mutua et al., 2012)
TDF2 (Thigpen et al., 2012)
FEM PrEP (Van Damme et al., 2012)
IAVI Uganda Study (Kibengo et al., 2013)
VOICE (Marrazzo et al., 2015)
PROUD (McCormack et al., 2016)
ADAPT/HPTN 067 (Bekker et al., 2018)
ADAPT/HPTN 067 (Grant et al., 2018)
Kwan et al., 2021
The pivotal trials that led to the FDA approval of Truvada® were iPrEx and Partners PrEP.
The reviewed randomized trials for oral TDF-FTC as PrEP main comparisons were PrEP versus placebo or no PrEP (Chou et al., 2019; Chou et al., 2022). The primary outcome was the rate of HIV infection; other outcomes were mortality, quality of life, and harms, including rates of non-HIV STIs (gonorrhea, syphilis, chlamydia, herpes simplex virus [HSV] infection, or any STI), hepatitis B and C virus infection, renal insufficiency, fractures, gastrointestinal adverse events, and pregnancy-related outcomes (see below for further discussion). They found that oral PrEP with TDF-FTC was associated with a statistically significant decreased risk of acquiring HIV infection in populations at high risk of acquiring HIV. Oral PrEP with TDF-FTC was consistently associated with decreased risk of HIV infection versus placebo when trials were stratified according to HIV risk category, study duration, setting (high- or low-income), and study quality, and in subgroup analyses based on age and gender.
The newer PrEP regimens, TAF-FTC (Descovy®) and cabotegravir (Apretude®) have only been compared against TDF-FTC. Tenofovir alafenamide, combined with
emtricitabine (TAF-FTC), was shown to be non-inferior to TDF-FTC as daily PrEP among MSM in the one pivotal DISCOVER multi-national, RCT, done at 94 community, public health, and hospital-associated clinics located in regions of Europe and North America (Mayer et al., 2020). Oral TAF-FTC was associated with a non-statistically significant decreased risk of incident HIV infection versus TDF-FTC among cisgender MSM and transgender women who have sex with men.
As shown in Table 2, long-acting injectable cabotegravir was associated with statistically significant decreased risk of HIV infection versus oral TDF-FTC in the HPTN 083 pivotal trial (Landovitz et al., 2021) of cisgender MSM and transgender women who have sex with men and in the HPTN 084 pivotal trial (Delany-Moretwle et al., 2022) of
African women at high risk of HIV infection.
In subsequent discussions, each clinical trial will be referred to by its acronym when appropriate.
Chou et al. (2022) noted that evidence on beneficial effects of oral PrEP on clinical outcomes other than HIV infection was sparse and trials were not designed to address mortality risk. Although a number of TDF-FTC trials reported mortality, the numbers of mortality events were small. Oral TDF-FTC PrEP was associated with a modestly decreased risk of mortality that was not statistically significant (Baeten et al., 2012; Choopanya et al., 2013; Chou et al., 2022; Grohskopf et al., 2013; Marrazzo et al., 2015; Peterson et al., 2007; Molina et al., 2015; Mutua et al., 2012; McCormack et al., 2016; Grant et al., 2010; Thigpen et al., 2012; Van Damme et al., 2012); however, Chou et al. (2022) stated that due to the small numbers of mortality events, risk estimates from individual trials and the pooled estimate were imprecise. In addition, the DISCOVER trial was not designed to evaluate mortality; at 96 weeks, there were a total of five deaths (2 in the TAF-FTC arm and 3 in the TDF-FTC arm (Mayer et al., 2020). In the HPTN 083 trial, four deaths were reported in the cabotegravir arm and none in the TDF-FTC control arm (Landovitz, 2021). In the HPTN 084 trial, three deaths were reported in the cabotegravir arm and none in the TDF-FTC control arm (Delany-Moretwle, 2022). Thus, we focused our analysis on the clinical health outcome of HIV infection and not mortality, given the sparse clinical trial mortality data.
Chou et al. (2022) stated that the reviewed study limitations included being restricted to the English language; some pooled analyses having statistical heterogeneity
or imprecise estimates; most trials evaluating risk of sexually transmitted infections were blinded to receipt of PrEP; most randomized trials were conducted in low-income settings, potentially limiting applicability to US primary care settings, and evidence lacking in adolescents and pregnant women.
The majority of the clinical trials were considered good quality by the USPSTF (Chou et al., 2022). The USPSTF used their own predefined criteria and studies were rated as “good,” “fair,” or “poor” based on the seriousness of methodological shortcomings. They evaluated the credibility of subgroup analyses based on whether the subgroups were predefined, whether subgroup characteristics were measured at baseline, whether the analyses were across or within studies, whether within-study comparisons were randomized, whether statistical tests for interaction were significant, the precision of estimates, the consistency of subgroup effects across studies, and whether results were biologically plausible. Thus in 2022, the USPSTF released a draft recommendation for PrEP with ART to prevent HIV infection that is consistent with the 2019 recommendation and continues as a grade “A” recommendation.
Defining ‘high risk’[5]
The risk-based inclusion criteria from the key clinical drug trials, along with epidemiologic data, served as a foundation for the USPSTF (2019) and CDC (2021e) recommendations for who should be considered for PrEP to prevent HIV infection (see table 5 below).
Table 5. Key RCTs of PrEP to prevent HIV infection risk-based inclusion criteria
| Study (n) |
Risk Based Inclusion criteria |
| iPrEx (n=2499) Grant et al., 2010 TDF-FTC Placebo-controlled RCT |
Men who have sex with men:
Anal sex with ≥4 male partners, a diagnosis of an STI, history of transactional sex activity, or condomless anal sex with an
HIV-infected partner or partner of unknown infection status in the previous 6 months |
| Partners PrEP (n=4747) Baeten et al., 2012 TDF-FTC Placebo-controlled RCT |
High-risk heterosexual men and women: ART-naive HIV-infected partner |
| Bangkok Tenofovir Study (n=2413) Choopanya et al., 2013 TDF alone Placebo-controlled RCT |
People who inject drugs (PWID) in previous 12 months |
| DISCOVER (n=5335) Mayer, 2020 TAF-FTC Head-to-head randomized trial |
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 |
| HPTN 083 (n=4456) Landovitz, 2021 Cabotegravir Head-to-head randomized trial |
Cisgender MSM and transgender women who have sex with men |
| HPTN 084 (n=3178) Delany-Moretwle, 2022 Cabotegravir Head-to-head randomized trial |
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 |
Chou et al. (2022) found that PrEP was effective across different population subgroups defined by a variety of HIV risk categories. They found no clear differences in estimates of effectiveness for PrEP versus placebo or no PrEP in risk of HIV infection when clinical trial analyses were stratified according to whether they enrolled
men and women at increased risk of HIV infection via heterosexual contact (Baeten et al., 2012; Marrazzo et al., 2015; Peterson et al., 2007; Kibengo et al., 2013; Thigpen et al., 2012; Van Damme et al., 2012), MSM or transgender women (Grohskopf et al., 2013; Molina et al., 2015; McCormack et al., 2016; Grant et al., 2010), or PWID (Choopanya et al., 2013), although evidence of effectiveness in PWID was limited to one trial conducted in Asia. The Truvada®, Descovy® and Apretude® FDA labels state that risk for HIV 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 status, or sexual activity in a high prevalence area or network (FDA, 2020; 2022; 2023).
PWID discussion
The Bangkok Tenofovir study (Choopanya et al., 2013) was a randomized, double-blind, placebo-controlled trial conducted from 2005 – 2012 and is the only clinical trial we are aware of that evaluated the effectiveness of PrEP for PWID. The trial was conducted in Thailand and compared daily tenofovir alone to placebo. During the 7-year study, 14.7% of participants were lost to follow-up (Martin et al., 2015). The results demonstrated a 48.9% reduction in HIV incidence among participants randomized to tenofovir. Medication adherence was higher among participants 40–59 years old than younger participants. The study found that as adherence improved, the effectiveness of PrEP increased; from 48.9% overall to 58.0% for participants with at least 75% adherence, and to 83.5% for those with at least 97.5% adherence. Findings from this study provide the evidence to show PrEP is effective in preventing HIV infection in PWID. However, the results of this study have not been confirmed nor replicated in a subsequent study so level of certainty of benefit for these patients may be impacted. Additional research would be helpful. In an evidence review, Chou (2022) noted: “Evidence on the effectiveness of PrEP in persons at risk due to injection drug use remains limited.” Since the study was conducted in Thailand, there may also be a question about generalizability to other populations.
As Karim (2013) points out, there is no biological marker to distinguish between HIV transmission that occurs through sex and that which occurs parenterally and therefore, it is less clear as to whether the findings from the Bangkok Tenofovir study show that PrEP prevents parenteral transmission of HIV. People who inject drugs can acquire HIV through either unprotected sexual intercourse or sharing of needles and syringes. These two routes of HIV transmission are often linked epidemiologically and so methods of HIV prevention should consider targeting those groups at risk of HIV transmission through either unprotected sexual intercourse or sharing of needles and syringes.
In terms of “high risk,” the USPSTF (2019) recommends that the following persons be considered for PrEP:
1. Men who have sex with men, are sexually active, and have 1 of the following characteristics:
A serodiscordant sex partner (ie, in a sexual relationship with a partner living with HIV)
Inconsistent use of condoms during receptive or insertive anal sex
A sexually transmitted infection (STI) with syphilis, gonorrhea, or chlamydia within the past 6 months
2. Heterosexually active women and men who have 1 of the following characteristics:
A serodiscordant sex partner (ie, in a sexual relationship with a partner living with HIV)
Inconsistent use of condoms during sex with a partner whose HIV status is unknown and who is at high risk (eg, a person who injects drugs or a man who has sex with men and women)
An STI with syphilis or gonorrhea within the past 6 months
3. Persons who inject drugs and have 1 of the following characteristics:
Shared use of drug injection equipment
Risk of sexual acquisition of HIV (see above)
Since there are multiple individual patient factors in the consideration of patient risk, CMS proposes that the decision of who is at high risk for HIV acquisition and who should be considered for PrEP using ART based on the evidence and drug labeling information of the FDA approved drugs is at the discretion of the physician or
health care practitioner.
Various screening tools are available for screening for high risk of HIV acquisition. CMS does not identify specific HIV risk screening tools. Rather, the decision to use a specific tool is at the discretion of the physician or health care practitioner in the health care setting. In addition, the USPSTF found inadequate evidence for specific risk assessment tools that can accurately identify persons at high risk of HIV acquisition.
In general, the reviews found that there was no significant difference between oral PrEP vs placebo in risk of serious adverse events or withdrawal because of adverse events (Chou et al., 2019; Chou et al., 2022). Serious renal and gastrointestinal events were rare and most events were mild and reversible. As an example, oral PrEP with TDF-FTC was associated with a small, non-statistically significant increased risk of fracture versus placebo. The DISCOVER trial found no difference between TAF-FTC versus TDF-FTC in risk of serious adverse events or discontinuation of study drug due to adverse events, which was uncommon. TAF-FTC was associated with positive short-term effects on bone mineral density versus TDF-FTC. In HPTN 083 and 084, there were no differences between long-acting injectable cabotegravir versus daily oral TDF-FTC in risk of serious adverse events or grade 3 or higher adverse events. Overall, beneficiaries who are being considered for PrEP using ART to prevent HIV infection will require various laboratory screenings, along with ongoing laboratory monitoring due to a number of potential harms, which we discuss below.
Screening for HIV before initiating PrEP and ongoing monitoring is needed because PrEP alone is not an effective treatment for HIV infection and its use in persons living with HIV can lead to drug-resistant HIV infection. Drug-resistant HIV variants have been identified with use of PrEP by individuals with undiagnosed HIV infection. Chou et al. (2022) found that seven RCT on TDF-FTC reported rates of antiretroviral drug resistance in persons randomized to oral PrEP with TDF-FTC (Baeten et al., 2012; Marrazzo et
al., 2015; Molina et al., 2015; McCormack et al., 2016; Grant et al., 2010; Thigpen et al., 2012; Van Damme et al., 2012). Resistance rates were low, with 0.3 percent of patients on TDF-FTC were identified as having incident HIV infection with a drug resistance mutation.
The DISCOVER Trial found four participants randomized to TDF-FTC, who were suspected of having an HIV infection at baseline, to have an antiretroviral resistance mutation (Mayer et al., 2020).
Chou et al. (2022) reported that the HTPN 083 and 084 trials provided data on resistance mutations and found that among all patients randomized to cabotegravir, the proportion with a resistance mutation was 0.1 percent (4/3874). Among individuals randomized to TDF-FTC across both trials, the proportion with antiretroviral resistance
mutations was 0.1 percent (5/3870).
The FDA drug labels, CDC (2021e) and USPSTF (2022) state that HIV screening should be conducted at least every three months for Truvada® and Descovy®; and for Apretude®, screening should be done at initiation, then one month later, and then every two months thereafter. The 2019 USPSTF recommendation states:
Before prescribing PrEP, clinicians should exclude persons with acute or chronic HIV infection through taking a medical history and HIV testing. The 2-drug antiretroviral regimen used in [oral] PrEP, when used alone, is not an effective treatment for HIV infection, and its use in persons living with HIV can lead to the emergence of, or selection for, drug-resistant HIV infection…Ongoing follow-up and monitoring, including HIV testing every 3 months, is also suggested.
Emtricitabine and tenofovir are primarily eliminated by the kidney. Chou et al. (2022) noted that the clinical trials for oral PrEP with TDF-FTC demonstrated an association with increased risk of renal adverse events (mostly ≥ grade 1 serum creatinine elevation) and renal abnormalities generally resolved following PrEP cessation (Baeten et al., 2012; Marrazzo et al., 2015; Mutua et al., 2012; Kibengo et al., 2013; McCormack et al., 2016; Grant et al., 2010; Thigpen et al., 2012; Van Damme et
al., 2012). Clinical trials and observational studies of TDF-FTC for PrEP have demonstrated safety when prescribed to healthy, HIV-uninfected adults with an estimated creatinine clearance (eCrCl) ≥60 ml/min (CDC, 2021e). Safety data for TDF-FTC prescribed for PrEP to patients with renal function <60 ml/min are not available. The FDA Truvada® label (FDA, 2020) and the CDC (2021e) guideline state that TDF-FTC is not recommended for people with an eCrCl below 60 mL/min and eCrCl should be monitored while using TDF-FTC for PrEP. The CDC guideline (2021e) states that in one observational study with TDF-FTC, the development of decreased renal function was more likely in patients >50 years of age or who had an eCrCl <90 ml/min when initiating PrEP with TDF-FTC (Marcus et al., 2016; Gandhi et al., 2016).
The DISCOVER trial demonstrated no difference in clinically important renal health measures (e.g., grade 3 or 4 serious adverse renal events) between men taking TDF-FTC or TAF-FTC (Mayer et al., 2020). However, the CDC (2021e) notes that changes were seen in some biochemical markers of proximal tubular function (e.g., ꞵ2-microlobulin:creatinine ratio, retinol binding protein:creatinine ratio) that favored TAF-FTC and this may indicate a longer-term safety benefit of prescribing TAF-FTC for men with pre-existing risk factors for renal dysfunction (e.g., hypertension, diabetes). TAF-FTC is FDA approved for PrEP use in patients with an eCrCl ≥30 ml/min (FDA, 2022).
The CDC (2021e) recommends that eCrCl be assessed every 6 months for patients over age 50 or those who have an eCrCl <90 ml/min at initiation and for all other daily oral PrEP patients, eCrCl should be assessed at least every 12 months. The FDA labels (2022; 2023) state that prior to initiation and during use of Truvada® and Descovy®, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all individuals; and in individuals with chronic kidney disease, also assess serum phosphorus. The USPSTF (2019; 2022) also refers to the CDC (2021e) recommendations for a complete discussion of baseline and follow-up testing and monitoring of kidney function (Owens et al., 2019). The USPSTF (2019) recommendation states that, “It is also generally recommended
that kidney function testing, serologic testing for hepatitis B and C virus, testing for other STIs, and pregnancy testing (when appropriate) be conducted at the time of or just before initiating PrEP.”
PrEP does not reduce the risk of other STIs. STIs can increase the potential for HIV acquisition in people at risk for HIV (Cohen, Council, & Chen, 2019). In addition, some STIs can increase blood HIV concentration and promote progression of disease. Many patients receiving PrEP continue to engage in increased-risk sexual behaviors. In clinical trials of MSM, approximately 30 to 50 percent of the men who received PrEP were diagnosed with a bacterial STI (Grant et al., 2010; McCormack et al., 2016). The DISCOVER trial noted that trial participants maintained a high risk of sexual HIV acquisition, with high rates of rectal gonorrhea (Descovy®, 24%; Truvada®, 25%), rectal chlamydia (Descovy®, 30%; Truvada, 31%), and syphilis (14% in both treatment groups) during the trial (Mayer et al., 2020). In the HPTN
084 trial, chlamydia, gonorrhea, and trichomonas were present in both the cabotegravir and the TDF-FTC control arms (Delany-Moretwle et al., 2022).
The CDC guidelines (2021e) state that all patients receiving oral PrEP should have repeat STI testing for sexually active persons with signs or symptoms of infection and screening for asymptomatic MSM at high risk for recurrent bacterial STIs (e.g., those with syphilis, gonorrhea, or chlamydia at prior visits or multiple sex partners) at least every three months. Every six months: conduct STI screening for other sexually active persons (i.e., syphilis, gonorrhea, for all PrEP patients, and chlamydia for MSM and TGW even if asymptomatic). Every 12 months: conduct chlamydia screening for heterosexual women and men even if asymptomatic. The FDA (2020; 2022; 2023) labels for Truvada®, Descovy® and Apretude® refer to regular testing for STIs that can facilitate HIV transmission, but do not specify frequencies or other details.
Medicare has an existing policy for screening for STIs and high-intensity behavioral counseling (HIBC) to prevent STIs (NCD 210.10). CMS covers screening for chlamydia and gonorrhea for women at increased risk for STIs annually; and screening for syphilis for men and women at increased risk for STIs annually. We recognize that the CMS
STI screening policy differs from the above CDC recommendations regarding the frequencies of STI screenings and chlamydia and gonorrhea screening in men receiving PrEP. Additional screening for these STIs is outside the scope of this proposed decision memorandum. Screening for syphilis, gonorrhea and chlamydia and treatment, when needed, does not change if and how a person is prescribed PrEP for HIV infection prevention. In addition, Medicare coverage of additional preventive services at 42 CFR § 410.64 is dependent, in part, upon USPSTF recommendations with a grade of A or B. The USPSTF (2021) STI screening recommendation concluded that the current evidence is insufficient to assess the balance of benefits and harms of screening for chlamydia and gonorrhea in men, grade I for “inconclusive.” In the future, we may consider screening for additional populations if recommended with a Grade A or B by the USPSTF. However, diagnostic STI testing may be performed for any sexually active beneficiary with signs or symptoms of infection.
In the DISCOVER clinical trial comparing TDF-FTC and TAF-FTC for PrEP in MSM and transgender women, higher rates of triglyceride and LDL cholesterol elevation and weight gain were seen among men taking TAF-FTC than among men taking TDF-FTC (Mayer et al, 2020). Decreases were seen in total cholesterol and HDL cholesterol (although decreases were smaller for people on Descovy® versus Truvada®). The CDC (2021e) recommends that monitoring of triglyceride, cholesterol levels, and weight should be done every 12 months for patients prescribed TAF-FTC for PrEP. The USPSTF recommendation does not mention lipid or body weight screening.
Hepatitis B virus screening
The FDA labels for Truvada® and Descovy® include boxed warnings that severe acute exacerbations of hepatitis B virus (HBV) have been reported in HBV-infected individuals who have discontinued products containing emtricitabine (FTC) and/or tenofovir disoproxil fumarate (TDF) and may occur with discontinuation of Descovy® or Truvada®. Such products have been used to treat HBV. The Chou et al. (2022) systematic review found that almost all randomized trials excluded patients with HBV infection at baseline and some trials provided HBV vaccination to eligible patients. The VOICE trial reported one case of incident HBV infection, (Marrazzo et al., 2015) though this outcome was not a specified outcome in any trial. In one older trial of 56 patients with active HBV infection at baseline, the risk of grade 1 asparate or alanine transaminase elevations following discontinuation of study drug was 4.3% (1/23) for those randomized to TDF and 9.1% (3/33) for those randomized to placebo (Chou et al., 2022; Peterson et al., 2007). In another trial (iPrEx), no cases of hepatitis flare occurred following discontinuation of TDF-FTC in five patients with chronic HBV infection (Chou et al., 2022; Solomon et al., 2016). In patients with chronic HBV infection, very limited evidence suggests that cessation of oral PrEP is not associated with hepatitis flare (Peterson et al., 2007; Solomon et al., 2016). The CDC (2021e) guideline reinforces this, stating:
Patients with HBV infection who discontinue taking PrEP medication should be monitored closely for hepatitis flares. Although documented to occur in some patients discontinuing tenofovir-containing medication as part of their treatment regimens, such flares have not yet been seen in HIV-uninfected patients with chronic active HBV infection who have stopped taking TDF-containing PrEP regimens. Nonetheless, when such patients discontinue PrEP, they should continue to receive care from a clinician experienced in the management of HBV infection so that if flares occur, they can be detected promptly and treated appropriately (p. 47).
The CDC (2021e) and the USPSTF (Owens et al., 2019) recommend that prior to prescribing oral PrEP, patients should be screened for HBV and in the event a person has HBV infection, they can be informed of the danger of stopping PrEP medication without appropriate monitoring for potential hepatitis flares.
Medicare will address coverage of HBV screening for beneficiaries being considered for PrEP.
Pregnancy
Chou et al. (2019; 2022) found that no trials of PrEP enrolled persons who were pregnant and trials where people became pregnant did not demonstrate an increased risk of spontaneous abortion. One trial (Partners PrEP) found no differences between TDF-FTC or TDF alone and placebo in pregnancy rate, risk of preterm birth, congenital anomalies, or postpartum infant mortality. In one trial of cabotegravir enrolling females (HPTN 084), pregnancy incidence was low with both cabotegravir and TDF-FTC, and no congenital abnormalities were observed. The CDC (2021e) recommends pregnancy testing, when appropriate, for people being considered for PrEP.
Therefore, based on the evidence, CMS proposes to cover PrEP using antiretroviral drugs (whether oral or injectable) approved by the US Food and Drug Administration (FDA) to prevent HIV infection in individuals at high risk of HIV acquisition. The determination of whether an individual is at high risk for HIV infection is made by the physician or health care practitioner who assesses the individual’s history. In addition, CMS proposes to also cover the administration of injectable PrEP using antiretroviral drugs to prevent HIV infection.
Additionally, for individuals being assessed for or who are taking PrEP using ART to prevent HIV infection, CMS proposes to cover HIV screening up to seven times annually and a single screening for hepatitis B virus (HBV). These screening tests are proposed to be covered with the appropriate FDA approved laboratory tests and point of care tests, used consistent with FDA approved labeling and in compliance with the Clinical Laboratory Improvement Act (CLIA) regulations.
The remaining recommended laboratory screenings and ongoing monitoring for beneficiaries prescribed PrEP to prevent HIV infection, including pregnancy, kidney function,
liver function, and lipid testing, may be ordered at the physician or health care practitioner’s discretion under existing Medicare coverage.
CMS notes that any effect of the use of these screening tests is their coordination with treatment. CMS concludes that FDA approval or clearance of screening tests used consistent with FDA approved labeling provides a greater likelihood that a potential harm of screening testing, that is, taking action based on inaccurate screening test results, can be avoided. We further conclude that compliance by testing laboratories with CLIA regulatory requirements provides an additional, on-going safeguard for screening test quality. CMS considers these conditions essential to maximize patient safety.
Setting
Chou et al. (2022) stated that most of the randomized trials for PrEP were conducted in low-income settings, potentially limiting applicability to US primary care settings. We recognize that Medicare beneficiaries receive health care services through a continuum of health care settings.
HIV risk reduction and medication adherence counseling
The clinical trials on oral and injectable PrEP demonstrated that reduced adherence is associated with marked declines in effectiveness and adherence is also needed to reduce the risk of selecting for a drug-resistant virus if HIV infection occurs (CDC, 2021e; Owens et al., 2019; Chou et al., 2019; Chou et al., 2022). The USPSTF (2019)
recommendation noted that all trials of PrEP also included behavioral and adherence counseling, and most specified providing condoms to all trial participants. Methods for evaluating adherence varied between studies and included patient diaries and self-report, pill counts, adherence monitoring devices, drug levels (e.g., plasma or dried blood spots), and prescription fill data (Chou et al., 2022). The USPSTF (2019) recommendation states that adherence support is a key component of providing PrEP, especially for populations shown to have lower adherence to PrEP, such as young persons and racial/ethnic minorities (Owens et al., 2019). They recognize components of adherence support to include establishing trust and open communication with patients, patient education, reminder systems for taking medication, and attention to medication adverse effects and having a plan to address them. The USPSTF stated that additional information on adherence support is available from the CDC guidelines. The CDC guideline (2021e) states:
Approaches that can effectively support medication adherence include educating patients about their medications; helping them anticipate and manage side effects; asking about adherence successes and issues at follow-up visits, helping them establish dosing routines that mesh with their work and social schedules; providing reminder systems and tools; addressing financial, substance use disorder, or mental health needs that may impede adherence; and facilitating social support (p. 41).
The CDC also recommends a team-based approach comprised of various health care professionals to provide HIV risk-reduction and adherence counseling. The frequency and content of HIV risk-reduction and adherence counseling differed among the various trials and published articles were not detailed in their descriptions of counseling content; although the clinical trial participants were given condoms (Chou et al., 2019; Chou et al., 2022). The USPSTF recognizes that further research is needed on factors associated with adherence to PrEP and methods to increase uptake and adherence, especially in populations with lower use of and adherence to PrEP, such as younger persons and racial/ethnic minorities (Owens et al., 2019). The FDA also recognizes that education materials for prescribers and patients and treatment guidelines for PrEP to prevent HIV infection are readily available from the CDC (see https://www.cdc.gov/hiv/effective-interventions/prevent/prep/index.html; https://www.cdc.gov/hiv/pdf/risk/prep/cdc-hiv-prep-provider-supplement-2021.pdf?page=1). The CDC also has a compendium of evidence-based and evidence informed interventions and best practices for HIV prevention, with a list of PrEP best practices: https://www.cdc.gov/hiv/research/interventionresearch/compendium/prep/complete-list.html. (also see NCD 210.10 Screening for STIs and HIBC to prevent STIs for a review of evidence and analysis of counseling for adults at increased risk for STIs).
We agree with the USPSTF recommendation and CDC guidelines, which convey that PrEP is a comprehensive intervention comprised of ART and certain support services in order to ensure that PrEP is administered safely and effectively. Therefore, CMS proposes to cover up to seven 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 and individuals must be competent and alert at the time that counseling is provided.
Therefore, the evidence is sufficient to determine that offering PrEP with effective ART for persons at high risk of HIV acquisition is reasonable and necessary for the prevention or early detection of illness or disability. The PrEP using ART to prevent HIV infection policy addresses the concerns about harm by including HIV risk reduction and medication adherence counseling and monitoring of potential adverse events through laboratory testing, such as screening for hepatitis B virus and HIV infection.
Question 3: Is the evidence sufficient to determine that offering PrEP with effective ART for persons at high risk of HIV acquisition is appropriate for Medicare beneficiaries under Part A or Part B?
While those aged 50 and older comprise the majority of people in the United States living with HIV, new infections in older adults also occur (NIA, 2021). In 2019, approximately 11% of new HIV infections occurred in adults age 55 and older (CDC, 2021b). Between 2015 and 2019, among people 55 years and older, there was a 40% increase (from 289,900 to 407,100) in prevalence and a 15% increase (from 2700 to 3100) in incidence—the largest increases of any age group (CDC, 2021a; Justice et al., 2022). Despite these numbers, HIV prevention in older adults is often not discussed and late discovery of HIV infection is common throughout the United States, across age groups and irrespective of known risk for HIV acquisition (Justice et al., 2022). More than half of older people with HIV are diagnosed at a late stage of disease and many develop AIDS-defining illnesses, such as tuberculosis, Kaposi’s sarcoma, and other opportunistic infections like fungal infections, within one year of diagnosis (HHS, 2023; Justice et al., 2022; Lee et al., 2022) (also see discussion of late HIV diagnosis in the NCD 210.7 Screening for HIV Infection).
The majority of clinical trials on PrEP to prevent HIV infection did not include a large number of older participants (≥65 years old). Older adults may have greater risks of adverse effects from PrEP using ART related to the presence of multiple comorbidities, including decreased renal and hepatic function, and polypharmacy. Yet, the large sample sizes and the diversity of the participants in the PrEP to prevent HIV infection clinical trials demonstrate statistically and clinically significant outcomes that contribute to our proposed conclusion that the evidence is sufficient to determine that PrEP to prevent HIV infection is appropriate for Medicare beneficiaries. In addition, the prevention of HIV infection in order to decrease the morbidity and mortality of the disease, as well as to decrease its transmission, is applicable to any age group. Although the majority of Medicare beneficiaries are over the age of 65, approximately 13% of the Medicare population is younger and are either disabled or receiving benefits due to a diagnosis of end stage renal disease or amyotrophic lateral sclerosis (CMS Fast Facts, 2023).
A meta-analysis demonstrated no difference in the proportion of adverse events in the clinical trials comparing oral PrEP to placebo, with no differences seen in a priori subgroup analysis that included mode of acquisition, adherence, gender, drug regimen, dosing or age; and no differences were seen in grade 3 or 4 adverse events (Fonner et al., 2016). Although age was only stratified as ≤25 and ≥25 years old. Chou et al. (2019; 2022) found that the clinical trials examining PrEP for HIV infection prevention demonstrated that PrEP was effective across population subgroups, including populations defined by age, geographic setting and sex.
Subgroup Analyses
Age
Chou et al. (2022) notes that in four trials that performed within-study stratified analyses of oral PrEP vs. placebo or no PrEP effectiveness, it was found that there were no clear differences in populations defined by age (Baeten et al., 2012; Choopanya et al., 2013; Grant et al., 2010; Van Damme et al., 2012). The clinical trials examining oral PrEP versus placebo or no PrEP had a mean age that was less than 40 years old and no trial enrolled persons below 18 years old (Chou et al., 2022). The iPrEx pivotal trial included participants ranging from 18 to 67 years old; 137 participants (11%) in the intervention arm were over the age of 40. The DISCOVER trial comparing TAF-FTC versus TDF-FTC found no statistically significant interactions between effects on HIV infection risk and age when comparing <25 vs. ≥25 years (Mayer et al., 2020). Two trials (HPTN trials 083 and 084) compared long-acting injectable cabotegravir versus daily oral TDF-FTC (Landovitz et al., 2021; Delany-Moretlwe et al., 2022). Cabotegravir was found to have less toxicities. Findings for decreased risk for HIV acquisition were also similar when results were stratified by age (≤30 vs. >30 years) and geographic region. There were 123 participants (67 in the cabotegravir group) over age 50 among cisgender men and transgender women in the HPTN 083 trial. HPTN 084 decreased HIV acquisition results were also similar in stratified analyses based on age (<25 vs. ≥25 years). To note, all PrEP using ART to prevent HIV infection is FDA approved for adolescents and adults who are 35 kilograms or greater, and is not restricted by age.
Seven trials comparing oral PrEP versus placebo or no PrEP were conducted in Africa (Baeten et al., 2012; Marrazzo et al., 2015; Peterson et al., 2007; Mutua et al., 2012; Kibengo et al., 2013; Thigpen et al., 2012; Van Damme et al., 2012), one in Thailand (Choopanya et al., 2013), two in Europe or Canada (Molina et al., 2015; McCormack et al., 2016), one in the United States (Grohskopf et al., 2013) and one trial was international (~10% of patients from US sites) (Grant et al., 2010). Chou et al. (2022) found that PrEP was more effective at preventing HIV infection in trials conducted in the United States, Europe, or Canada than in trials conducted in Africa, Asia, or internationally. Chou et al. (2022) surmised this could be related to high adherence in the North American and European trials or differences across countries in HIV epidemiology and management (e.g., differences in the proportion of partners with HIV treated with ART).
Chou et al. (2022) found that there were no statistically significant interactions between effects on HIV infection risk and region (United States vs. other) for the DISCOVER trial comparing TAF-FTC and TDF-FTC; although they stated that stratified estimates were imprecise.
The HPTN 083 trial was conducted in the United States (37% of the study population), Latin America (43%), Asia (16%), and Africa (3.3%) (Landovitz et al., 2021). Chou et
al. (2022) reported that findings were similar when results were stratified by geographic region, where cabotegravir was associated with a statistically significant decreased risk of HIV acquisition versus oral TDF-FTC.
Gender
There are two major studies of PrEP in women, the FEM-PrEP trial (Van Damme et al., 2012) and the VOICE study (Marrazzo et al, 2015). The participants in these studies did not adhere to taking the medication as prescribed. A later study HPTN 067, demonstrated adherence among women in Cape Town, South Africa (Bekker et al., 2018). Chou et al. (2022) found that in three trials that performed within-study stratified analyses of oral PrEP vs. placebo or no PrEP effectiveness, it was found that there were no clear differences in the effect of PrEP between men and women (Baeten et al., 2012; Choopanya et al., 2013; Thigpen et al., 2012).
Evidence on safety of HIV treatment
Since TDF and TAF are common backbone therapy for HIV and HBV infection long-term treatment, we searched the literature for evidence on the safety of the medications for
treatment in people age 65 and older. The medications are considered to be highly effective and, in the vast majority of patients, well tolerated (Franconi & Guaraldi, 2018; Pilkington et al., 2020; Roade et al., 2021). A systematic review found that RCTs of TDF-FTC and TAF-FTC used as treatment and prevention of HIV infection demonstrated efficacy and safety (Pilkington et al., 2020). Yet, as an editorial commentary on Pilkington’s review stated, the RCTs reviewed do not thoroughly examine efficacy and safety in populations over age 50 years or individuals with multiple comorbidities (Wood, 2020). Similar to the evidence on PrEP for HIV prevention, the evidence on these treatments and their safety for older adults is scarce. Lengthier real-world studies are needed to examine these drugs in individuals with concomitant conditions who are at higher risk of developing treatment related adverse events, including older adults (Roade et al., 2021). The International Antiviral Society – USA Panel recommendations for ART for treatment and prevention of HIV infection are noteworthy for the discussion of treatment challenges that older adults (age 65 and older) with HIV face, including a greater risk of serious non-AIDS complications, co-morbidities, drug-drug interactions, and polypharmacy (Gandhi et al., 2023). They also
recognize that studies of the pharmacokinetics of ART are limited in older people with HIV and state that regardless of this limitation, they do not recommend dose adjustments in older people with HIV in reference to such pharmacokinetic changes and potential increased toxicity associated with aging. Similarly, HHS (2023b) also
recognizes that care of people with HIV will increasingly involve adults aged ≥60 years and that data from clinical trials or pharmacokinetic studies are very limited for this population. The patient evaluations and ongoing monitoring for people who are prescribed PrEP to prevent HIV previously discussed are important for these reasons.
Conclusion
Based on the discussion above, CMS proposes that PrEP using ART to prevent HIV infection for persons at high risk of HIV acquisition is appropriate for Medicare beneficiaries.
Health Disparities
HIV infection disproportionately affects racial/ethnic minorities, transgender women, and MSM and equitable provision of PrEP to populations at highest risk of HIV acquisition is not occurring. According to the CDC, black and Hispanic/Latinx people have the lowest rates of PrEP use compared to other racial/ethnic groups (CDC, 2021g). In 2021, the CDC reported that approximately 11% of black/African American and 20.5% of Hispanic/Latino people who were eligible to receive PrEP actually received a prescription, while 78% of white people eligible to receive PrEP obtained a prescription for PrEP (CDC, 2022c). Additionally, the CDC reports that approximately 38% of those in the US that have indications for PrEP are black persons; yet, in 2021, the number of white people prescribed PrEP was around five times greater than the number of
black people prescribed PrEP. Barriers to PrEP among adolescent black and Hispanic/Latinx people and young adult MSM include low awareness and low uptake of PrEP (Macapagal et al., 2020). Similarly, there is low PrEP utilization among the transgender population. According to a study based on a national probability sample, 72% of transgender persons supported the use of PrEP; however, only 3% of those at risk for HIV infection were presently taking PrEP (Sevelius et al., 2020).
Clinical trials found PrEP to be effective in diverse racial/ethnic populations and across various risk groups worldwide (Chou et al., 2022). The iPrEX trial included approximately 99% MSM and 1% transgender women who have sex with men. Approximately 72.3% Hispanic, 69.1% mixed race/other, 17.2% white, 8.6% black and 5.1% Asian people participated within this trial. In the iPrEx study, a sub-analysis of efficacy of PrEP in Hispanic versus non-Hispanic participants found no difference in efficacy. The
Partners PrEP Study focused on heterosexual HIV-1-serodiscordant couples. Participants’ racial/ethnic demographics were not reported for this trial. In other pivotal trials that showed effectiveness for PrEP, approximately 98.6% of participants in the DISCOVER trial were cisgender men who have sex with men and 1.4% were transgender women who have sex with men. Participants were 84% white, 24% Hispanic/Latinx, 9% black, and 4% Asian. In the HPTN 084 trial, subjects included approximately 99.8% female, 0.1% male, and 0.1% transgender male. Participants were 96.8% black, 0.2% Asian, 0.03% white, 0.3% mixed race, and 2.6% identified as other. Participants of the HPTN 083 trial consisted of 87.4% MSM, 12.5% transgender women who have sex with men, and 0.1% who preferred not to provide this information. 0.3% of the participants were age 60 years and older. The portion of the HPTN 083 trial that was conducted within the United States consisted of 49.8% black and 50.1% non-black participants.
Summary
Approximately 1.2 million people in the United States are living with HIV infection and over half of the people diagnosed with HIV are over the age of 50. Life-long treatment with HIV medicines has transformed HIV from a terminal illness into a chronic condition. Early initiation of ART is important for older individuals diagnosed with HIV because they have a greater risk of serious non-AIDS complications. Pre-exposure prophylaxis (PrEP) is a key component of HIV prevention. People who are at high risk of acquiring HIV face cultural, social and structural barriers to the uptake and effective use of PrEP, although their options for PrEP, such as the long-acting injectable cabotegravir, may help to overcome such barriers by allowing people to choose their preferred regimen. The evidence is considered to be good quality and demonstrates that PrEP using ART, when used according to the FDA label, can reduce the risk of acquiring HIV for those at high risk of HIV infection. Generally, the evidence also reveals that the benefits from PrEP to prevent HIV infection outweigh the risks. Equitable provision of PrEP to populations at highest risk of HIV acquisition is not occurring. Public health approaches to implementing the use of PrEP to prevent HIV will need to continue to consider effectiveness, acceptability, feasibility and resource needs across a variety of settings.
Based on our analysis, CMS proposes that the evidence is adequate to conclude that PrEP using ART to prevent HIV infection to people of high risk provides direct benefit to the Medicare population. Ongoing patient assessment, counseling and monitoring is important and appropriate for individuals prescribed PrEP for HIV prevention.
IX. Conclusion
CMS proposes that the evidence is adequate to conclude that the United States Preventive Services Task Force (USPSTF) recommends offering Pre-Exposure Prophylaxis (PrEP) with effective antiretroviral therapy (ART) to persons at high risk of Human Immunodeficiency Virus (HIV) acquisition with a grade of A recommendation, is reasonable and necessary for the prevention or early detection of illness or disability under §1861(ddd)(1) of the Social Security Act (the Act), and is appropriate for individuals entitled to benefits under Part A or enrolled under Part B.
CMS proposes to cover PrEP using antiretroviral drugs (whether oral or injectable) approved by the US Food and Drug Administration (FDA) to prevent HIV infection in individuals at high risk of HIV acquisition. The determination of whether an individual is at high risk for HIV infection is made by the physician or health care practitioner who assesses the individual’s history. In addition, CMS proposes to also cover the administration of injectable PrEP using antiretroviral drugs to prevent HIV infection.
CMS also proposes to cover up to seven 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 and individuals must be competent and alert at the time that counseling is provided.
Additionally, for individuals being assessed for or who are taking PrEP using ART to prevent HIV infection, CMS proposes to cover HIV screening up to seven times annually and a single screening for hepatitis B virus (HBV). These screening tests are proposed to be covered with the appropriate FDA approved laboratory tests and point of care tests, used consistent with FDA approved labeling and in compliance with the Clinical Laboratory Improvement Act (CLIA) regulations.
See Appendix B for the proposed manual language.
CMS is seeking comments on our proposed decision pursuant to § 1862(l)(3)(B) of the Social Security Act.
APPENDIX A
General Methodological Principles of Study Design
(Section VI of the Decision Memorandum)
When making national coverage determinations, CMS evaluates relevant clinical evidence to determine whether or not the evidence is of sufficient quality to support a finding that an item or service is reasonable and necessary. The overall objective for the critical appraisal of the evidence is to determine to what degree we are confident that: 1) the specific assessment questions can be answered conclusively; and 2) the intervention will improve health outcomes for patients.
We divide the assessment of clinical evidence into three stages: 1) the quality of the individual studies; 2) the generalizability of findings from individual studies to the Medicare population; and 3) overarching conclusions that can be drawn from the body of the evidence on the direction and magnitude of the intervention’s potential risks and benefits.
The methodological principles described below represent a broad discussion of the issues we consider when reviewing clinical evidence. However, it should be noted that each coverage determination has its unique methodological aspects.
Assessing Individual Studies
Methodologists have developed criteria to determine weaknesses and strengths of clinical research. Strength of evidence generally refers to: 1) the scientific validity underlying study findings regarding causal relationships between health care interventions and health outcomes; and 2) the reduction of bias. In general, some of the methodological attributes associated with stronger evidence include those listed below:
- Use of randomization (allocation of patients to either intervention or control group) in order to minimize bias.
- Use of contemporaneous control groups (rather than historical controls) in order to ensure comparability between the intervention and control groups.
- Prospective (rather than retrospective) studies to ensure a more thorough and systematical assessment of factors related to outcomes.
- Larger sample sizes in studies to demonstrate both statistically significant as well as clinically significant outcomes that can be extrapolated to the Medicare population. Sample size should be large enough to make chance an unlikely explanation for what was found.
- Masking (blinding) to ensure patients and investigators do not know to that group patients were assigned (intervention or control). This is important especially in subjective outcomes, such as pain or quality of life, where enthusiasm and psychological factors may lead to an improved perceived outcome by either the patient or assessor.
Regardless of whether the design of a study is a randomized controlled trial, a non-randomized controlled trial, a cohort study or a case-control study, the primary criterion for methodological strength or quality is to the extent that differences between intervention and control groups can be attributed to the intervention studied. This is known as internal validity. Various types of bias can undermine internal validity. These include:
- Different characteristics between patients participating and those theoretically eligible for study but not participating (selection bias).
- Co-interventions or provision of care apart from the intervention under evaluation (performance bias).
- Differential assessment of outcome (detection bias).
- Occurrence and reporting of patients who do not complete the study (attrition bias).
In principle, rankings of research design have been based on the ability of each study design category to minimize these biases. A randomized controlled trial minimizes systematic bias (in theory) by selecting a sample of participants from a particular population and allocating them randomly to the intervention and control groups. Thus, in general, randomized controlled studies have been typically assigned the greatest strength, followed by non-randomized clinical trials and controlled observational studies. The design, conduct and analysis of trials are important factors as well. For example, a well-designed and conducted observational study with a large sample size may provide stronger evidence than a poorly designed and conducted randomized controlled trial with a small sample size. The following is a representative list of study designs (some of that have alternative names) ranked from most to least methodologically rigorous in their potential ability to minimize systematic bias:
Randomized controlled trials
Non-randomized controlled trials
Prospective cohort studies
Retrospective case control studies
Cross-sectional studies
Surveillance studies (e. g. , using registries or surveys)
Consecutive case series
Single case reports
When there are merely associations but not causal relationships between a study’s variables and outcomes, it is important not to draw causal inferences. Confounding refers to independent variables that systematically vary with the causal variable. This distorts measurement of the outcome of interest because its effect size is mixed with the effects of other extraneous factors. For observational, and in some cases randomized controlled trials, the method in that confounding factors are handled (either through stratification or appropriate statistical modeling) are of particular concern. For example, in order to interpret and generalize conclusions to our population of Medicare patients, it may be necessary for studies to match or stratify their intervention and control groups by patient age or co-morbidities.
Methodological strength is, therefore, a multidimensional concept that relates to the design, implementation and analysis of a clinical study. In addition, thorough documentation of the conduct of the research, particularly study selection criteria, rate of attrition and process for data collection, is essential for CMS to adequately assess and consider the evidence.
Generalizability of Clinical Evidence to the Medicare Population
The applicability of the results of a study to other populations, settings, treatment regimens and outcomes assessed is known as external validity. Even well-designed and well-conducted trials may not supply the evidence needed if the results of a study are not applicable to the Medicare population. Evidence that provides accurate information about a population or setting not well represented in the Medicare program would be considered but would suffer from limited generalizability.
The extent to that the results of a trial are applicable to other circumstances is often a matter of judgment that depends on specific study characteristics, primarily the patient population studied (age, sex, severity of disease and presence of co-morbidities) and the care setting (primary to tertiary level of care, as well as the experience and specialization of the care provider). Additional relevant variables are treatment regimens (dosage, timing and route of administration), co-interventions or concomitant therapies, and type of outcome and length of follow-up.
The level of care and the experience of the providers in the study are other crucial elements in assessing a study’s external validity. Trial participants in an academic medical center may receive more or different attention than is typically available in non-tertiary settings. For example, an investigator’s lengthy and detailed explanations of the potential benefits of the intervention and/or the use of new equipment provided to the academic center by the study sponsor may raise doubts about the applicability of study findings to community practice.
Given the evidence available in the research literature, some degree of generalization about an intervention’s potential benefits and harms is invariably required in making coverage determinations for the Medicare population. Conditions that assist us in making reasonable generalizations are biologic plausibility, similarities between the populations studied and Medicare patients (age, sex, ethnicity and clinical presentation) and similarities of the intervention studied to those that would be routinely available in community practice.
A study’s selected outcomes are an important consideration in generalizing available clinical evidence to Medicare coverage determinations. One of the goals of our determination process is to assess health outcomes. These outcomes include resultant risks and benefits such as increased or decreased morbidity and mortality. In order to make this determination, it is often necessary to evaluate whether the strength of the evidence is adequate to draw conclusions about the direction and magnitude of each individual outcome relevant to the intervention under study. In addition, it is important that an intervention’s benefits are clinically significant and durable, rather than marginal or short-lived. Generally, an intervention is not reasonable and necessary if its risks outweigh its benefits.
If key health outcomes have not been studied or the direction of clinical effect is inconclusive, we may also evaluate the strength and adequacy of indirect evidence linking intermediate or surrogate outcomes to our outcomes of interest.
Assessing the Relative Magnitude of Risks and Benefits
Generally, an intervention is not reasonable and necessary if its risks outweigh its benefits. Health outcomes are one of several considerations in determining whether an item or service is reasonable and necessary. CMS places greater emphasis on health outcomes actually experienced by patients, such as quality of life, functional status, duration of disability, morbidity and mortality, and less emphasis on outcomes that patients do not directly experience, such as intermediate outcomes, surrogate outcomes, and laboratory or radiographic responses. The direction, magnitude, and consistency of the risks and benefits across studies are also important considerations. Based on the analysis of the strength of the evidence, CMS assesses the relative magnitude of an intervention or technology’s benefits and risk of harm to Medicare beneficiaries.
APPENDIX B
Medicare National Coverage Determinations Manual
Draft
We are seeking public comments on the proposed language that we would include in the Medicare National Coverage Determinations Manual. This proposed language does not reflect public comments that will be received on the proposed decision memorandum, and which may be revised in response to those comments.
Table of Contents
(Rev.)
NCD 210.15 – Pre-Exposure Prophylaxis (PrEP) for Human Immunodeficiency Virus (HIV) Infection Prevention
A. General
Human immunodeficiency virus (HIV) continues to be a serious public health issue, with an estimated 1.2 million people aged 13 and older living with HIV in the United States. Due to continuing medical advances and earlier initiation and expanded access to medications, HIV is now considered a chronic condition rather than a terminal
illness. Antiretroviral therapy (ART) is known to reduce HIV-related morbidity and mortality. Nearly half of the people in the United States diagnosed with HIV are aged 50 and older. Pre-exposure prophylaxis (PrEP) involves the use of ART on an ongoing basis (e.g., daily or bimonthly) or before and after HIV exposure events (“on-demand” or “event-driven” PrEP) to decrease the risk of acquiring HIV infection. When taken as prescribed, PrEP is highly effective for preventing HIV. PrEP can be an oral medication or an injection. Under §1861(ddd)(1) of the Social Security Act (the Act), the Centers for Medicare & Medicaid Services (CMS) has the authority to add coverage of “additional preventive services” through the Medicare national coverage determination (NCD) process if certain statutory requirements are met: (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 (USPSTF), and (3) appropriate for individuals entitled to benefits under Part A or enrolled under Part B.
B. Nationally Covered Indications
Effective for claims with dates of service on or after xx/xx/xx, CMS proposes that the evidence is adequate to conclude that the United States Preventive Services Task Force (USPSTF) recommends offering Pre-Exposure Prophylaxis (PrEP) with effective antiretroviral therapy (ART) to persons at high risk of Human Immunodeficiency Virus (HIV) acquisition with a grade of A recommendation, is reasonable and necessary for the prevention or early detection of illness or disability under §1861(ddd)(1) of the Social Security Act (the Act), and is appropriate for individuals entitled to benefits under Part A or enrolled under Part B.
CMS proposes to cover PrEP using antiretroviral drugs (whether oral or injectable) approved by the US Food and Drug Administration (FDA) to prevent HIV infection in individuals at high risk of HIV acquisition. The determination of whether an individual is at high risk for HIV infection is made by the physician or health care practitioner who assesses the individual’s history. In addition, CMS proposes to also cover the administration of injectable PrEP using antiretroviral drugs to prevent HIV infection.
CMS also proposes to cover up to seven 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 and individuals must be competent and alert at the time that counseling is provided.
Additionally, for individuals being assessed for or who are taking PrEP using ART to prevent HIV infection, CMS proposes to cover HIV screening up to seven times annually and a single screening for hepatitis B virus (HBV). These screening tests are proposed to be covered with the appropriate FDA approved laboratory tests and point of care tests, used consistent with FDA approved labeling and in compliance with the Clinical Laboratory Improvement Act (CLIA) regulations.
C. Nationally Non-Covered Indications
Preventive services are non-covered by Medicare unless specifically covered in this NCD, any other NCD or in statute or regulations.
D. Other
Medicare Part B coinsurance and deductible are waived for this preventive service.
