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Guideline Summary
Guideline Title
Interim guidance for clinicians considering the use of preexposure prophylaxis for the prevention of HIV infection in heterosexually active adults.
Bibliographic Source(s)
Centers for Disease Control and Prevention (CDC). Interim guidance for clinicians considering the use of preexposure prophylaxis for the prevention of HIV infection in heterosexually active adults. MMWR Morb Mortal Wkly Rep. 2012 Aug 10;61(31):586-9. [11 references] PubMed External Web Site Policy
Guideline Status

Note: This guideline has been updated. The National Guideline Clearinghouse (NGC) is working to update this summary.

Scope

Disease/Condition(s)

Human immunodeficiency virus (HIV) infection

Guideline Category
Counseling
Prevention
Risk Assessment
Clinical Specialty
Family Practice
Infectious Diseases
Internal Medicine
Obstetrics and Gynecology
Preventive Medicine
Intended Users
Advanced Practice Nurses
Health Care Providers
Physician Assistants
Physicians
Public Health Departments
Guideline Objective(s)
  • To provide interim guidance for health-care providers electing to provide preexposure prophylaxis (PrEP) for the prevention of human immunodeficiency virus (HIV) infection in heterosexually active adults who are at ongoing, very high risk for sexual acquisition of HIV infection
  • To consider new information and address pregnancy and safety issues for heterosexually active adults at very high risk for sexual HIV acquisition that were not discussed in the previous interim guidance for the use of PrEP in men who have sex with men (MSM)
Target Population

Heterosexually active adults who are at ongoing, very high risk for sexual acquisition of human immunodeficiency virus (HIV) infection (e.g., those with partners known to have HIV infection)

Interventions and Practices Considered
  1. Determining eligibility for preexposure prophylaxis (PrEP) medication
    • Documenting negative human immunodeficiency virus (HIV) antibody test
    • Testing for acute HIV infection
    • Determining pregnancy and breastfeeding status
    • Confirming high risk for HIV infection
    • Linking HIV-infected partners to care
    • Calculation of creatinine clearance
  2. Screening for hepatitis B infection and treating active hepatitis B infection
  3. Vaccination against hepatitis B infection
  4. Treating other sexually transmitted infections
  5. Discussing safety of PrEP for infants exposed during pregnancy
  6. Avoiding PrEP in women who are breastfeeding
  7. Beginning PrEP medication regimen (tenofovir disoproxil fumarate 300 mg plus emtricitabine 200 mg [i.e., one Truvada tablet] daily)
  8. Providing risk-reduction and PrEP medication–adherence counseling and condoms
  9. Follow-up while PrEP medication is being taken
  10. Discontinuing PrEP (at patient request, for safety concerns, or if HIV infection is acquired)
Major Outcomes Considered
  • Risk for human immunodeficiency virus (HIV) acquisition
  • Rate of acquisition of HIV infection among uninfected but exposed heterosexually active adults
  • Safety and effectiveness of preexposure prophylaxis (PrEP)
  • Medication adherence

Methodology

Methods Used to Collect/Select the Evidence
Hand-searches of Published Literature (Primary Sources)
Hand-searches of Published Literature (Secondary Sources)
Searches of Electronic Databases
Searches of Patient Registry Data
Description of Methods Used to Collect/Select the Evidence

The evidence base for these recommendations is derived from a systematic search and review of published literature. To identify all preexposure prophylaxis (PrEP) safety and efficacy trials pertaining to prevention of sexual acquisition of human immunodeficiency virus (HIV), a search of the clinical trials registry (www.clinicaltrials.gov External Web Site Policy) was performed using combinations search terms (preexposure prophylaxis, pre-exposure prophylaxis, PrEP, HIV, Truvada, Tenofovir, and antiretroviral). In addition, the same search terms were used to search conference abstracts for major HIV conferences (annual International AIDS Society Conference, annual Conference on Retroviruses and Opportunistic Infections) for the years 2009-2012. Using the same search terms, a search of PubMed and Web of Science databases was done for the years 2006-2012. Finally, references from published PrEP trial data were reviewed and the data summary prepared by Food and Drug Administration (FDA) for its approval decision, and both confirmed no additional trial results were available.

Number of Source Documents

Four randomized, double-blind, placebo-controlled, clinical trials

Methods Used to Assess the Quality and Strength of the Evidence
Not stated
Rating Scheme for the Strength of the Evidence

Not applicable

Methods Used to Analyze the Evidence
Systematic Review with Evidence Tables
Description of the Methods Used to Analyze the Evidence

Data from the four randomized, double-blind, placebo-controlled, clinical trials of oral preexposure prophylaxis (PrEP) with tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) that have been conducted in human immunodeficiency virus (HIV)-uninfected, heterosexually active adults were reviewed.

Methods Used to Formulate the Recommendations
Expert Consensus
Description of Methods Used to Formulate the Recommendations

Medical epidemiologists in the Division of HIV/AIDS Prevention of the National Center for HIV, Viral Hepatitis, Sexually Transmitted Disease (STD), and Tuberculosis (TB) Prevention at the Centers for Disease Control and Prevention (CDC) developed this interim guidance. Subject matter experts at other federal health agencies, academic researchers, health department HIV policy stakeholders, and community representatives have participated in working groups and consultations to inform content for comprehensive U.S. Public Health Service (PHS) guidelines for preexposure prophylaxis (PrEP) use currently in development; those ideas also were used in developing this interim guidance.

Rating Scheme for the Strength of the Recommendations

Not applicable

Cost Analysis

A formal cost analysis was not performed and published cost analyses were not reviewed.

Method of Guideline Validation
Not stated
Description of Method of Guideline Validation

Not applicable

Recommendations

Major Recommendations

Note: This guideline has been updated. The National Guideline Clearinghouse (NGC) is working to update this summary. The recommendations that follow are based on the previous version of the guideline.

Recommendation for Clinicians

Daily oral tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) use in two studies has been shown to be safe in reducing the risk for sexual human immunodeficiency virus (HIV) acquisition by heterosexual women and men when consistently used. In a third study with heterosexual women, preexposure prophylaxis (PrEP) was not found to be effective, and results are pending in a fourth study. The conflicting trial results for efficacy of TDF/FTC in heterosexual women can be partially explained by the low medication adherence in FEM-PrEP compared with the higher adherence in Partners PrEP and TDF2. As yet unidentified factors also might have influenced the results. (Note: The Partners PrEP trial evaluated a daily dose of a fixed-dose combination of 300 mg TDF and 200 mg FTC, and daily TDF alone [300 mg], for the HIV-uninfected male or female partner in HIV-discordant couples [where one partner is infected with HIV and the other is not] in Kenya and Uganda. The TDF2 trial evaluated daily TDF/FTC in adult women and men in Botswana, and the FEM-PrEP study evaluated daily TDF/FTC in women in Kenya, South Africa, and Tanzania.)

Until comprehensive Public Health Service (PHS) guidelines are available, the Centers for Disease Control and Prevention's (CDC) January 2011 interim recommendations should help guide the use of PrEP in men who have sex with men (MSM.) On the basis of the new data regarding PrEP use in heterosexually active adults, CDC now provides the following interim guidance for clinicians considering the use of PrEP for adults at very high risk for HIV acquisition through heterosexual sex (e.g., those with partners known to have HIV infection): 1) TDF/FTC is contraindicated for PrEP in persons with unknown or positive HIV status; 2) in women and men at very high risk for acquiring HIV from penile-vaginal sex, daily doses of TDF/FTC can be safe and effective in reducing the risk of HIV infection; 3) PrEP use may be one of several options to help protect the HIV-negative partner in discordant couples during attempts to conceive; and 4) women of reproductive age should have a documented pregnancy test before beginning PrEP and if not pregnant at initiation, at regular intervals while being prescribed PrEP. If women are either pregnant before initiating PrEP or become pregnant while being prescribed PrEP, health-care providers should discuss currently available information regarding potential risks and benefits of continuing PrEP so that an informed decision can be made. If a woman takes PrEP while pregnant, providers are encouraged to prospectively and anonymously submit information about the pregnancy to the Antiretroviral Use in Pregnancy Registry.

Health-care providers should be aware, and should inform their patients that 1) the efficacy of TDF/FTC for HIV prevention is highly dependent on adherence to daily doses of medication, and 2) its long-term safety in HIV-uninfected adults or following fetal exposure is not yet determined. Health-care providers should report any serious adverse events resulting from prescribed TDF/FTC for PrEP to the U.S. Food and Drug Administration's (FDA) MedWatch External Web Site Policy.

CDC and other PHS agencies are developing PHS guidelines on the use of PrEP as part of a comprehensive set of HIV prevention services that will include specific recommendations for use with MSM and heterosexually active adults at very high risk for HIV acquisition. The guidelines will be updated as information about factors affecting efficacy and safety for all transmission risk groups becomes available from additional studies.

Important Reminders

PrEP has the potential to contribute to safe and effective HIV prevention for heterosexually active adults as well as MSM. CDC advises clinicians and patients to use this interim guidance as a basis to prescribe or use PrEP for heterosexually active patients until full PHS guidelines are available. When PrEP is used by heterosexually active adults, it is important to ensure that 1) PrEP is targeted to persons at very high risk for HIV acquisition, especially uninfected persons whose regular sexual partners are known to have HIV infection; 2) the importance of adherence to daily medication and its influence on efficacy is clearly discussed; 3) couples understand that although no adverse effects have been found among infants exposed to TDF/FTC during pregnancy and breastfeeding, these data are incomplete for women in HIV-discordant couples using TDF/FTC to prevent acquisition of HIV; 4) PrEP is delivered as part of a comprehensive set of prevention services, including risk-reduction, PrEP medication adherence counseling, and ready access to condoms; 5) sexually transmitted infection treatment is provided when indicated by laboratory screening tests conducted at least every 6 months; and 6) PrEP is accompanied by monitoring of HIV status, pregnancy status, side effects, adherence, and risk behaviors at each quarterly follow-up visit.

Interim Guidance for Health-Care Providers Electing to Provide Preexposure Prophylaxis (PrEP) for the Prevention of Human Immunodeficiency Virus (HIV) Infection in Heterosexually Active Adults Who Are at Ongoing, Very High Risk for Sexual Acquisition of HIV Infection*

Before Initiating PrEP

Determine Eligibility

  • Document negative HIV antibody test immediately before starting PrEP medication.
  • Test for acute HIV infection if patient has symptoms consistent with acute HIV infection or reports unprotected sex with an HIV-positive person in the preceding month.
  • Determine if women are planning to become pregnant, are currently pregnant, or are breastfeeding.
  • Confirm that patient is at ongoing, very high risk for acquiring HIV infection.
  • If any sexual partner is known to be HIV-infected, determine whether receiving antiretroviral therapy; assist with linkage to care if not in care or not receiving antiretroviral therapy.
  • Confirm that calculated creatinine clearance is ≥60 mL per minute (Cockcroft-Gault formula†).

Other Recommended Actions

  • Screen for hepatitis B infection; vaccinate against hepatitis B if susceptible, or treat if active infection exists, regardless of decision regarding prescribing PrEP.
  • Screen and treat as needed for sexually transmitted infections (STIs).
  • Disclose to women that safety for infants exposed during pregnancy is not fully assessed but no harm has been reported.
  • Do not prescribe PrEP to women who are breastfeeding.

Beginning PrEP Medication Regimen

  • Prescribe TDF 300 mg plus FTC 200 mg (i.e., one Truvada [Gilead Sciences] tablet) daily.
  • In general, prescribe no more than a 90-day supply, renewable only after HIV testing confirms that patient remains HIV-uninfected. For women, ensure that pregnancy test is negative or, if pregnant, that the patient has been informed about use during pregnancy.
  • If active hepatitis B infection is diagnosed, consider using TDF/FTC, which may serve as both treatment of active hepatitis B infection and HIV prevention.
  • Provide risk-reduction and PrEP medication–adherence counseling and condoms.

Follow-Up While PrEP Medication Is Being Taken

  • Every 2–3 months, perform an HIV antibody test (or fourth generation antibody/antigen test) and document negative result.
  • At each follow-up visit for women, conduct a pregnancy test and document results; if pregnant, discuss continued use of PrEP with patient and prenatal-care provider.
  • Evaluate and support PrEP medication adherence at each follow-up visit, more often if inconsistent adherence is identified.
  • Every 2–3 months, assess risk behaviors and provide risk-reduction counseling and condoms. Assess STI symptoms and, if present, test and treat for STIs as needed.
  • Every 6 months, test for bacterial STIs, even if asymptomatic, and treat as needed.
  • Three months after initiation, then every 6 months while on PrEP medication, check serum creatinine and calculate creatinine clearance.

On Discontinuing PrEP (at Patient Request, for Safety Concerns, or If HIV Infection Is Acquired)

  • Perform HIV test(s) to confirm whether HIV infection has occurred.
  • If HIV-positive, order and document results of resistance testing, establish linkage to HIV care.
  • If HIV-negative, establish linkage to risk reduction support services as indicated.
  • If active hepatitis B is diagnosed at initiation of PrEP, consider appropriate medication for continued treatment of hepatitis B infection.
  • If pregnant, inform prenatal-care provider of TDF/FTC use in early pregnancy and coordinate care to maintain HIV prevention during pregnancy and breastfeeding.

*Those with partners known to have HIV infection.

†Additional information available at Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976;16:31–41.

Clinical Algorithm(s)

None provided

Evidence Supporting the Recommendations

Type of Evidence Supporting the Recommendations

The recommendations are supported chiefly by data from the four randomized, double-blind, placebo-controlled, clinical trials.

Benefits/Harms of Implementing the Guideline Recommendations

Potential Benefits

Appropriate interim guidance for clinicians considering the use of preexposure prophylaxis for the prevention of human immunodeficiency virus (HIV) infection in heterosexually active adults

Potential Harms
  • No serious toxicities were identified in any of the four trials comparing participants receiving daily oral tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) with those receiving placebo pills; however, in the first 1–2 months on medication, nausea and vomiting were more common in those receiving TDF/FTC than in those receiving placebo.
  • If women are either pregnant before initiating preexposure prophylaxis (PrEP) or become pregnant while being prescribed PrEP, health-care providers should discuss currently available information regarding potential risks and benefits of continuing PrEP so that an informed decision can be made. If a woman takes PrEP while pregnant, providers are encouraged to prospectively and anonymously submit information about the pregnancy to the Antiretroviral Use in Pregnancy Registry.

Contraindications

Contraindications
  • Tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) is contraindicated for preexposure prophylaxis (PrEP) in persons with unknown or positive human immunodeficiency virus (HIV) status.
  • PrEP should not be prescribed to women who are breastfeeding.

Qualifying Statements

Qualifying Statements
  • The findings in this report are subject to at least three limitations. First, the assessment of adherence by drug-level testing currently is incomplete in trials with heterosexually active adults and is likely to provide important additional information regarding the relationship of efficacy to medication adherence that will need to be addressed in clinical practice. Second, women who became pregnant during the preexposure prophylaxis (PrEP) trials described in this report were discontinued promptly from medication, so the safety of chronic fetal exposure could not be assessed adequately. Therefore, decisions to continue PrEP during pregnancy require additional consideration. Both tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) have been used among human immunodeficiency virus (HIV)-infected pregnant women to prevent perinatal transmission, have been studied for use by discordant couples attempting conception, and have been examined in antiretroviral treatment trials that included HIV-infected women who continued therapy during their pregnancies. Data from these sources and the Antiretroviral Use in Pregnancy Registry indicate no evidence of adverse effects among fetuses exposed to TDF or FTC. In addition, the higher risk for HIV transmission to uninfected women during pregnancy (compared with uninfected women who are not pregnant) might indicate an added value to continuing PrEP during pregnancy. Finally, sexual risk behaviors and adherence to PrEP medications among persons taking TDF/FTC for PrEP in clinical practice, when users are made aware of trial results, might be different from adherence by heterosexually active adults in PrEP trials who were unaware of their assignment to active drug or placebo and could not know the impact of adherence on efficacy.
  • Use of trade names and commercial sources is for identification only and does not imply endorsement by the U.S. Department of Health and Human Services.
  • References to non-Centers for Disease Control and Prevention (CDC) sites on the Internet are provided as a service to MMWR readers and do not constitute or imply endorsement of these organizations or their programs by CDC or the U.S. Department of Health and Human Services. CDC is not responsible for the content of pages found at these sites. URL addresses listed in MMWR were current as of the date of publication.

Implementation of the Guideline

Description of Implementation Strategy

An implementation strategy was not provided.

Implementation Tools
Resources
For information about availability, see the Availability of Companion Documents and Patient Resources fields below.

Institute of Medicine (IOM) National Healthcare Quality Report Categories

IOM Care Need
Staying Healthy
IOM Domain
Effectiveness
Patient-centeredness

Identifying Information and Availability

Bibliographic Source(s)
Centers for Disease Control and Prevention (CDC). Interim guidance for clinicians considering the use of preexposure prophylaxis for the prevention of HIV infection in heterosexually active adults. MMWR Morb Mortal Wkly Rep. 2012 Aug 10;61(31):586-9. [11 references] PubMed External Web Site Policy
Adaptation

Not applicable: The guideline was not adapted from another source.

Date Released
2012 Aug 10
Guideline Developer(s)
Centers for Disease Control and Prevention - Federal Government Agency [U.S.]
Source(s) of Funding

United States Government

Guideline Committee

Not stated

Composition of Group That Authored the Guideline

Authors: DK Smith, MD; Michael C. Thigpen, MD; Steven R. Nesheim, MD; Margaret A. Lampe, MPH; Lynn A. Paxton, MD; Taraz Samandari, MD; Amy Lansky, PhD; Jonathan Mermin, MD; Kevin Fenton, MD; National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, CDC

Financial Disclosures/Conflicts of Interest

Not stated

Guideline Status

Note: This guideline has been updated. The National Guideline Clearinghouse (NGC) is working to update this summary.

Guideline Availability

Electronic copies of the updated guideline: Available from the Centers for Disease Control and Prevention (CDC) Web site External Web Site Policy.

Print copies: Available from the Centers for Disease Control and Prevention, MMWR, Atlanta, GA 30333. Additional copies can be purchased from the Superintendent of Documents, U.S. Government Printing Office, Washington, DC 20402-9325; (202) 783-3238.

Availability of Companion Documents

The following is available:

Patient Resources

None available

NGC Status

This NGC summary was completed by ECRI Institute on May 3, 2013.

Copyright Statement

No copyright restrictions apply.

Disclaimer

NGC Disclaimer

The National Guideline Clearinghouse™ (NGC) does not develop, produce, approve, or endorse the guidelines represented on this site.

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