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Antiretroviral pre-exposure prophylaxis (PrEP) for preventing HIV in high-risk individuals

  1. Charles I Okwundu1,2,*,
  2. Olalekan A Uthman1,
  3. Christy AN Okoromah3

Editorial Group: Cochrane HIV/AIDS Group

Published Online: 11 JUL 2012

Assessed as up-to-date: 17 OCT 2012

DOI: 10.1002/14651858.CD007189.pub3


How to Cite

Okwundu CI, Uthman OA, Okoromah CAN. Antiretroviral pre-exposure prophylaxis (PrEP) for preventing HIV in high-risk individuals. Cochrane Database of Systematic Reviews 2012, Issue 7. Art. No.: CD007189. DOI: 10.1002/14651858.CD007189.pub3.

Author Information

  1. 1

    Faculty of Health Sciences, Stellenbosch University, Centre for Evidence-Based Health Care, Tygerberg, South Africa

  2. 2

    South African Medical Research Council, South African Cochrane Centre, Tygerberg, Western Cape, South Africa

  3. 3

    College of Medicine, University of Lagos, Department of Paediatrics and Child Health, Lagos, Lagos, Nigeria

*Charles I Okwundu, ciokwundu@sun.ac.za.

Publication History

  1. Publication Status: Edited (no change to conclusions), comment added to review
  2. Published Online: 11 JUL 2012

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Characteristics of included studies [ordered by study ID]
Baeten 2012

MethodsRandomized controlled trial


ParticipantsHIV-1 uninfected individuals within HIV-1 discordant partnerships (men and women age 18 Years to 69 Years)

Inclusion Criteria for HIV-1 uninfected partner:

  • Partner within an HIV-1 discordant heterosexual relationship
  • One partner meets study eligibility for HIV-1 uninfected study participant and the other partner meets study eligibility criteria for HIV-1 infected participant
  • Plan to remain in the relationship for the duration of the study period
  • Adequate renal, hepatic & hematologic function
  • Negative Hepatitis B surface antigen test
  • Willing and able to provide written informed consent & locator information


Exclusion Criteria for HIV-1 uninfected partner:

  • Current pregnancy, or planning to become pregnant during the study period
  • Currently breastfeeding
  • Concurrent enrolment in another HIV-1 vaccine or prevention trial
  • Receiving ongoing antiretroviral therapy
  • Repeated positive urine dipstick tests for glycosuria or proteinuria
  • Active and serious infections
  • History of pathological bone fractures not related to trauma


Inclusion Criteria for HIV-1 infected partner:

  • Partner within an HIV-1 discordant heterosexual relationship
  • One partner meets study eligibility for HIV-1 uninfected study participant and the other partner meets study eligibility criteria for HIV-1 infected participant
  • HIV-1 infected based on positive EIA
  • No history of any clinical AIDS-defining diagnoses
  • Plan to remain in the relationship for the duration of the study period
  • Willing and able to provide written informed consent & locator information


Exclusion Criteria for HIV-1 infected partner:

  • Current use of antiretroviral therapy
  • Concurrent enrolment in another HIV-1 treatment trial


InterventionsDaily Tenofovir Disoproxil Fumarate 300 mg vs. placebo
Daily Tenofovir Disoproxil Fumarate 300 mg + Emtricitabine 200 mg vs. placebo


OutcomesPrimary Outcome Measures:

  • Efficacy of once daily PrEP in preventing HIV-1 acquisition among uninfected heterosexual HIV-1 discordant couples.


  • Safety of daily TDF or FTC/TDF among HIV-1 uninfected individuals randomised to TDF or FTC/TDF to those randomised to placebo.


Secondary Outcome Measures:

  • Reported risk behaviours, STI prevalence, pill counts and reported adherence.


  • HIV-1 drug resistance, plasma HIV-1 RNA levels and CD4 T cell counts among HIV-1 seroconverters.


  • Congenital abnormalities, growth and development among infants born to female participants taking study drug


NotesThe study was conducted in Kenya and Uganda


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskHIV-1 uninfected partners were assigned in a 1:1:1 ratio to one of three study arms: once-daily TDF, TDF-FTC, or placebo, using a fixed-size block randomisation, stratified by site.

Allocation concealment (selection bias)Low riskA telephonic interactive voice response system was used to assign study drug kits. The investigators, except for statistical staff at the central coordinating center, remained unaware of the randomisation assignments

Blinding (performance bias and detection bias)
All outcomes
Low riskThere was blinding of participants and investigators. Active and placebo TDF were indistinguishable, as were active and placebo TDF-FTC

Incomplete outcome data (attrition bias)Low riskRetention rates were similar in the different study arms

Selective reporting (reporting bias)Low riskNo evidence of selective outcome reporting

Other biasLow riskNo other potential sources of bias identified

Grant 2010

MethodsRandomized controlled trial


ParticipantsMen who have sex with men

Inclusion Criteria:

  • Male sex (at birth)
  • HIV uninfected
  • Age having reached the local age of consent
  • High risk for HIV infection including any of the following: 1) No condom use during anal intercourse with a male HIV-uninfected partner or a male partner of unknown HIV status during the last 6 months; (2) anal intercourse with more than 3 male sex partners during the last 6 months; (3) exchange of money, gifts, shelter, or drugs for anal sex with a male partner during the last 6 months; (4) sex with a male partner and STI diagnosis during the last 6 months or at screening, or (5) sexual partner of an HIV-infected man with whom condoms are not consistently used in the last 6 months.
  • Able to provide a street address of residence for themselves and one personal contact who would know their whereabouts during the study period
  • Healthy enough to work, as indicated by score of 80 or greater on the Karnofsky scale
  • Certain laboratory values
  • A urine dipstick with a negative or trace result for both glucose and protein within 28 days of enrolment.
  • Ability to understand and local language for which an informed consent form has been approved by a local IRB and registered with the study sponsor.


Inclusion Criteria for Open-Label Extension:

  • Participated in a randomised, placebo-controlled, PrEP trail
  • Has been unblinded
  • Has provided informed consent


Exclusion Criteria:

  • Previously diagnosed active and serious infections, including tuberculosis infection, osteomyelitis, or infections requiring parenteral antibiotic therapy
  • Active clinically significant medical problems including heart disease (e.g., symptoms of ischemia, congestive heart failure, arrhythmia), lung disease (steroid-dependent chronic obstructive pulmonary disease), diabetes requiring hypoglycemic medication, or previously diagnosed cancer expected to require further treatment
  • Acute HBV infection at the screening visit or presence of treatment indications for hepatitis B based on local practice standards; or clinical signs of hepatic cirrhosis
  • History of pathological bone fractures not related to trauma
  • Receiving ongoing therapy with certain HIV/AIDS-related medications or other medications as determined by the investigator
  • Definitely or possibly received an anti-HIV vaccine while participating in a blinded clinical trial
  • Current alcohol or drug use that, in the opinion of the investigator, may interfere with the study
  • Current participation in a clinical trial or cohort study other than sub-studies of this protocol
  • Any condition at enrolment that, in the opinion of the investigator, would make participation in the study unsafe or would interfere with the study
  • Sites may utilize additional criteria that restrict enrolment to a subset of people who meet the protocol-defined enrolment criteria.


Exclusion Criteria for Open-Label Extension:

- Site leadership believes participant will have difficulty completing requirements


InterventionsDaily Tenofovir Disoproxil Fumarate 300 mg + Emtricitabine 200 mg vs. placebo


OutcomesPrimary Outcome:

  • Anti-HIV seroconversion


  • Safety endpoints, including Grade 1 or higher creatinine toxicity; Grade 3 or higher phosphorous toxicity; Grade 2, 3, or 4 laboratory adverse events; or Grade 2, 3, or 4 clinical adverse events; or HIV seroconversion


Secondary Outcome Measures:

  • Hepatitis flares among hepatitis B virus (HBV) infected persons during and after chemoprophylaxis


  • Changes in bone mineral density, body fat distribution, or fasting triglyceride and cholesterol levels


  • Among HIV infected participants: viral load, drug resistance, and CD4 count


  • Proportion of missed doses by pill count and by estimate during CASI interview


  • Risk behavior, including number of sexual partners with HIV positive or unknown status, total number of sexual partners, and condom use before, during, and after use of study medication


  • Prevalence of sexually transmitted infections (STIs) before, during, and after use of study medication


NotesThis is a multinational trial conducted in Peru, Ecuador, South Africa, Brazil, Thailand and the United States


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskSubject codes were randomly assigned in blocks of 10, stratified according to site

Allocation concealment (selection bias)Unclear riskThe method used for allocation concealment is not described

Blinding (performance bias and detection bias)
All outcomes
Low riskThere was blinding of participants and investigators

Incomplete outcome data (attrition bias)Low riskIncomplete outcome data were properly addressed

Selective reporting (reporting bias)Low riskNo evidence of selective outcome reporting

Other biasLow riskNo other potential sources of bias identified

Mutua 2010

MethodsRandomized controlled trial


ParticipantsHIV negative men and women aged 18 to 49 Years

Inclusion Criteria:

  • Willing to comply with the requirements of the protocol and available for follow-up for the planned duration of the study
  • Has understood the information provided and has provided written informed consent before any study-related procedures are performed
  • Willing to undergo HIV testing, STI screening, HIV counselling and receive HIV and STI test results
  • At risk for HIV infection as defined by at least one of the following:Current sexually-transmitted infection (STI) or STI in the previous 3 monthsIn the past 3 months had multiple episodes of unprotected vaginal sexIn the past 3 months had multiple episodes of unprotected anal sexIn the past 3 months engaged in sex work for money or drugs
  • If a female of childbearing potential (i.e., not post-menopausal or surgically sterile), using an effective method of non-barrier contraception (hormonal contraceptive; intrauterine device (IUD); surgical sterility) from 7 days prior to randomisation until the end of the study. All female volunteers must be willing to undergo urine pregnancy tests


Exclusion Criteria:

  • Confirmed HIV-1 or HIV-2 infection
  • Any clinically significant acute or chronic medical condition that is considered progressive or in the opinion of the investigator would make the volunteer unsuitable for the study, including severe infections requiring treatment such as tuberculosis, and alcohol or drug abuse
  • Any of the following abnormal laboratory parameters:Haemoglobin <9.0 g/dLCreatinine clearance <80mL/min, as calculated by Cockcroft-Gault equationAST: >2.5 x ULNALT: >2.5 x ULNTotal bilirubin >1.5 x ULNSerum amylase >1.5 x ULNSerum phosphorus <2.4 mg/dLUrinalysis: Two abnormal dipsticks showing any of the following:blood = 2+ or more (not due to menses)protein = 1+ or more leucocytes = 2+ or more glucose= 1+ or more
  • Confirmed diagnosis of chronic hepatitis B infection (HBsAg positive)
  • If female, pregnant or planning a pregnancy within 4 months after enrolment or lactating
  • Participation in another clinical study of an investigational product currently, within the 3 months prior to enrolment or expected participation during this study


InterventionsDaily vs intermittent Tenofovir Disoproxil Fumarate plus Emtricitabine (FTC/TDF) 


OutcomesPrimary Outcome Measures:

  • Safety and tolerability: The proportion of volunteers with moderate and greater severity clinical adverse events; mild, moderate and greater severity of renal toxicities, and other moderate and severe laboratory abnormalities.


  • Acceptability: The proportion of volunteers who report willingness to use the study regimen


  • Intracellular drug concentrations: The mean intracellular drug concentration for each group assigned to FTC/TDF


  • Adherence: Proportion of volunteers who took, by MEMS data, at least 80% of expected doses of the IP; Proportion of volunteers assigned to FTC/TDF who have detectable drug plasma levels within 48 hrs of use.


  • Behavioral: Reported number of steady and casual sex partners; Frequency of unprotected vaginal and/or anal intercourse; Substance use prior to or during sex.


Secondary Outcome Measures:

  • Proportion of volunteers who report somewhat high or high levels of burden in using electronic medication monitoring to measure adherence, and using cell phone communication to measure sexual activity


  • The proportion of study days with missing SMS sexual activity data


  • The proportion of volunteers who report sharing medications


  • The proportion of volunteers assigned to placebo who have detectable intracellular drug levels


  • The proportion of volunteers with HIV-specific immune responses as measured by analysis of cellular or humoral immune response, or changes in gene regulation as measured by microarray or proteomic techniques.


NotesThe study was conducted in Kenya


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskA random allocation sequence was generated by an external data coordinating centre. Investigators at the study sites enrolled
participants via an electronic enrolment system where allocation codes were assigned consecutively to eligible volunteers at the time of first dispensation of study drug.

Allocation concealment (selection bias)Low riskAllocation was done by an external centre.

Blinding (performance bias and detection bias)
All outcomes
Low riskThere was blinding of participants and investigators to the study medications. However, the allocation to daily or intermittent dosing was not blinded.

Incomplete outcome data (attrition bias)Low riskThere was no loss to follow up.

Selective reporting (reporting bias)Low riskNo evidence of selective outcome reporting

Other biasLow riskNo other potential source of bias

Peterson 2007

MethodsRandomized controlled trial


ParticipantsWomen aged 18 to 35 years

Inclusion Criteria:

  • HIV seronegative
  • Willing and able to give informed consent
  • 18 years to 35 years old, inclusive
  • Sexually active (on average, coitus 3 times per week)
  • Have had more than three sexual partners in the last month
  • Willing to use study product as directed
  • Willing to adhere to follow-up schedule
  • Willing to participate in the study for up to 12 months
  • Not pregnant, breast feeding, or desiring a pregnancy during the 12 months of participation
  • Have adequate renal function (serum creatinine < 1.5 mg/dL)
  • Have adequate liver function (hepatic transaminases [ALT and AST] < 43 U/L)
  • Have adequate serum phosphorus (greater than or equal to 2.2 mg/dL)
  • In general good health


InterventionsDaily 300 mg tenofovir disoproxil fumarate versus placebo


OutcomesPrimary Outcome Measures:

  • Effectiveness endpoint: conversion for antibodies to HIV 1 or 2


  • Laboratory safety endpoints including serum creatinine and phosphorus for kidney function, and AST and ALT for hepatic function.
  • Reported adverse events


NotesThis is a multinational study conducted in Ghana, Cameroon and Nigeria


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskA random allocation sequence was generated using a computer random number generator.

Allocation concealment (selection bias)Low riskAllocation was concealed by the use of sealed opaque envelopes. The randomisation envelopes were maintained in a secure office. They were not available to the study counsellors until the immediate moment of randomisation.

Blinding (performance bias and detection bias)
All outcomes
Low riskPlacebo tablets were made to match the TDF tablets, and contained denatonium benzoate to provide a bitter taste to resemble the active tablets.

Incomplete outcome data (attrition bias)High riskSome data were discarded (Nigeria-safety data)

Selective reporting (reporting bias)Low riskNo evidence of selective outcome reporting

Other biasHigh riskThere was premature stoppage of the trial at the Cameroon and Nigeria sites.

Thigpen 2012

MethodsRandomized controlled trial


Participants1200 HIV uninfected, sexually active healthy male and female volunteers

Inclusion Criteria:

  • citizen of Botswana 18-29 years old
  • sexually active
  • HIV uninfected
  • Hepatitis B and C uninfected
  • Calculated creatinine clearance >= 60 mL/min
  • hemoglobin >= 8 gm/dL
  • ALT and AST <= 2x ULN
  • total bilirubin <= 1.5 mg/dL
  • total serum amylase <= 1.5x ULN
  • Serum phosphorus >= 2.2 mg/dL
  • willing to use hormonal contraception (females)
  • living within 1 hours travel of study clinic
  • pass comprehension test
  • willing and able to give informed consent


Exclusion Criteria:

  • 18-20 without parent/guardian consent
  • history of significant renal or bone disease
  • any chronic illness requiring ongoing prescription medication
  • pregnant or breastfeeding
  • planning to move away from site in the next year
  • participating in another HIV prevention or vaccine safety trial
  • any other clinical condition or prior therapy that, in the opinion of the study physician, would make the volunteer unsuitable for the study or unable to comply with the dosing requirements


InterventionsTenofovir Disoproxil Fumarate 300 mg + Emtricitabine 200 mg daily


OutcomesPrimary Outcome Measures:

  • Adverse drug reactions


  • HIV incidence in the tenofovir/emtricitabine and placebo arms


Secondary Outcome Measures:

  • Changes in levels of unprotected sex during the trial;


  • Adherence to medication;


  • Antiretroviral (ARV) resistance patterns in seroconverters;


  • Viral set point in seroconverters


NotesThe study was conducted in Botswana


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskParticipants were randomised in a 1:1 ratio using random, permuted blocks of six, stratified by site and gender

Allocation concealment (selection bias)Low riskThe randomisation was done randomly centrally

Blinding (performance bias and detection bias)
All outcomes
Low riskNeither researchers nor participants knew an individual’s group assignment

Incomplete outcome data (attrition bias)Low riskSimilar rates of attrition in both groups and all participants were accounted for

Selective reporting (reporting bias)Low riskNo evidence of selective outcome reporting

Other biasLow riskWe did not identify any other potential source of bias

Van Damme 2012

MethodsRandomized controlled trial


ParticipantsHIV-antibody-negative women between the ages of 18-35 who were at risk of HIV acquisition through sexual intercourse

Inclusion Criteria:

  • Willing and able to provide written informed consent to be screened for and to participate in the trial


  • Able to answer a percentage of informed consent screening (75%) and enrolment (100%) comprehension quiz questions correctly


  • Between 18-35 years old, inclusive


  • At higher risk of becoming HIV infected


  • Have a final negative result according to the site-specific screening HIV testing algorithm and a final negative result at enrolment according to the study HIV testing algorithm


  • Willing to participate in all aspects of the study and to comply with study procedures, for up to 60 weeks, including:


  • Not intending to relocate out of the area for the duration of the study participation and does not have a job or other obligations that may require long absences from the area ( > 1 month at a time)


  • In general good health and have no condition (social or medical) which, in the opinion of the Site Investigator, would make study participation unsafe or complicate data interpretation


  • Not pregnant or breastfeeding, and does not anticipate a desire for pregnancy during the 52 weeks of on-product participation


  • Not received or receiving an experimental HIV vaccine, participating in another HIV prevention study or participating in any other clinical trial with a biomedical intervention


  • No clinical signs of liver disease (e.g., ascites, spider angiomata, hepatomegaly, jaundice)


  • No definite evidence of glycosuria or proteinuria (i.e., no repeated positive [ ≥ + 1 ] urine dipstick). If a urine dipstick is positive for either glucose and/or protein at the first test, a second urine sample will be tested.


  • No history of pathological bone fractures


  • No history of adverse reaction to latex


  • Not taking any of the following medications: nephrotoxic agents; aminoglycoside antibiotics (including gentamicin); intravenous (IV) amphotericin B; cidofovir; cisplatin; foscarnet; IV pentamidine; oral or IV vancomycin; oral or IV gancyclovir; other agents with significant nephrotoxic potential; drugs that slow renal excretion; probenecid; immune system modulators; systemic chemotherapeutic agents (i.e. cancer treatment medications); systemic corticosteroids; interleukin-2 (IL-2); immunomodulators; interferon (alpha, beta, or gamma); other antiretrovirals (including nucleoside analogs, non-nucleoside reverse transcriptase inhibitors, protease inhibitors or investigational antiretroviral agents)


InterventionsDaily Tenofovir Disoproxil Fumarate 300 mg + Emtricitabine 200 mg vs placebo


OutcomesPrimary Outcome Measures:

  • Combined incidence of HIV-1 and HIV-2 infection


  • Incidence of confirmed Grade 2 or higher serum creatinine toxicity, and Grade 3 or higher AST, ALT, or phosphorus toxicity during and 4 weeks after study product administration


  • Frequency and nature of adverse events (AEs) during and within 4 weeks after study product administration


Secondary Outcome Measures:

  • Viral load and CD4+ T cell counts at the time of HIV diagnosis and at 4, 8, 12, 16, 24, 36 and 52 weeks later


  • FTC and/or tenofovir resistance at the time of HIV diagnosis and 4 weeks later.


  • Incidence of pregnancy loss, prematurity, low birth weight, and congenital abnormalities


  • Pill counts and participant report of adherence to once-daily pill taking


  • Participant report of the number of sexual partners and frequency of unprotected sexual acts over time


  • Participant report of sexual behaviours and sex partner characteristics by participants who seroconvert and HIV negative participants


NotesThe study was conducted in Kenya, South Africa, Tanzania and Zimbabwe.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskThe authors described the use of block randomization

Allocation concealment (selection bias)Low riskEnvelopes were used to conceal the assignment of participants 

Blinding (performance bias and detection bias)
All outcomes
Low riskThere was blinding of participants and investigators

Incomplete outcome data (attrition bias)Low riskSimilar rates of attrition in both groups and all participants were accounted for

Selective reporting (reporting bias)Low riskNo evidence of selective outcome reporting

Other biasLow riskNo other potential sources of bias identified

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Brooks 2003Phase І trial with no control group

 
Characteristics of ongoing studies [ordered by study ID]
Chirenje 2012

Trial name or titleSafety and Effectiveness of Tenofovir 1% Gel, Tenofovir Disproxil Fumarate, and Emtricitabine/Tenofovir Disoproxil Fumarate Tablets in Preventing HIV in Women. MTN-003 (VOICE).

MethodsRandomised controlled trial

ParticipantsSexually active women in South Africa, Uganda and Zimbabwe

Inclusion Criteria:

  • Willing to provide adequate locator information
  • Sexually active, defined as having vaginal intercourse at least once in the 3 months prior to screening
  • Agree to not participate in other research studies involving drugs, medical devices, or vaginal products for duration of study.
  • Agree to use effective method of contraception. More information on this criterion can be found in the protocol.


Exclusion Criteria:

  • HIV infected
  • Known adverse reaction to any of the study products
  • Known adverse reaction to latex
  • Pathologic bone fracture not related to trauma
  • Non-therapeutic injection drug use in the 12 months prior to screening
  • Post-exposure prophylaxis for HIV exposure within 6 months prior to enrolment
  • Last pregnancy outcome 42 days or less prior to enrolment
  • Gynecologic or genital procedure 42 days or less prior to enrolment
  • Participation in any other research study involving drugs, medical devices, or vaginal products 30 days or less prior to enrolment
  • Currently using spermicide, interferon or interleukin therapy, or certain medications. More information on this criterion can be found in the protocol.
  • Any significant uncontrolled active or chronic disease. More information on this criterion can be found in the protocol.
  • Certain abnormal laboratory values. More information on this criterion can be found in the protocol.
  • Intends to become pregnant in the 24 months after enrolment
  • Plans to relocate or travel away from the study site for more than 8 consecutive weeks in the 24 months after enrolment
  • Urinary tract infection
  • Pelvic inflammatory disease, an STI, or reproductive tract infection requiring treatment
  • Grade 2 or higher pelvic exam finding
  • Any condition that, in the opinion of the investigator, would interfere with the study
  • Pregnant or breastfeeding

Interventions200 mg/300 mg tablet TDF-FTC versus placebo

300 mg tablet TDF versus placebo

OutcomesPrimary Outcome Measures:

  • Effectiveness of oral TDF and oral FTC/TDF versus oral placebo measured by HIV seroconversion


Secondary Outcome Measures:

  • Adherence


  • Change in sexual activity, condom use, and intravaginal practices


  • Frequency of HIV-1 drug resistance in women who acquire HIV-1 infection while using study product


  • Reported HIV seroconversion, toxicity, viral resistance, cervicovaginal inflammation, or adverse events


  • Incidence of HIV seroconversion in each study product group

Starting dateSeptember 2009

Contact informationZvavahera M. Chirenje, MD, FRCOG. UZ-UCSF Collaborative Research Programme. Jeanne Marrazzo, MD, MPH. University of Washington, Division of Allergy and Infectious Disease

NotesClinicalTrials.gov Identifier:

Choopanya 2010

Trial name or titleBangkok Tenofovir Study

MethodsRandomised controlled trial

ParticipantsInjection drug users aged between 20 and 60 (both gender)

Inclusion Criteria:

  • Report injection drug use in the 6 months before screening
  • Possess a Thai National Identification Card
  • Laboratory values as follows within 2 weeks before enrolment:
  • HIV oral fluid test non-reactive at screening and pre-enrollment visits
  • Hemoglobin 9 gm/dL
  • ALT and AST 2.5 x upper limit of normal (ULN)
  • Total bilirubin 1.5 mg/dL
  • Serum amylase 1.5 x ULN
  • Serum phosphorus 2.2 mg/dL
  • No evidence of current or chronic Hepatitis B infection by serology
  • Calculated creatinine clearance 60 mL/min by the Cockcroft-Gault formula where creatinine clearance in mL/min = Male: (140 - age in years) x (wt in kg)/72 x (serum creatinine in mg/dL) Female:(140 - age in years) x (wt in kg) x 0.85/72 x (serum creatinine in mg/dL)
  • Willing to abstain from sexual intercourse or use effective contraception during the trial (oral, injection, or barrier), for women
  • Willing and able to provide informed consent for study participation
  • Available and committed to DOT or monthly follow-up for at least 12 months


Exclusion Criteria:

  • Clinic physicians will determine if a subject with chronic illness requiring prescription medication can not enroll (medication used for drug treatment is allowed)
  • Positive urine pregnancy test
  • Breastfeeding
  • History of significant renal, liver, or bone disease
  • Any other clinical condition or prior therapy that, in the opinion of the clinic physician, would make the subject unsuitable for the study or unable to comply with the dosing requirements
  • Concurrent participation in any other HIV prevention trial or drug/vaccine safety trial. AIDSVAX B/E HIV vaccine trial (CDC protocol #2076) participants and Extension Study (CDC protocol #3750) participants may be screened for enrolment in the Bangkok Tenofovir Study.

InterventionsOral tenofovir 300 mg versus placebo

OutcomesPrimary Outcome Measures:

  • Adverse events
  • Rates of HIV seroconversion


  • Frequency of grade 3 or 4 renal or hepatic function laboratory toxicities or clinical toxicities


  • Frequency of adverse clinical events in tenofovir and placebo arm


Secondary Outcome Measures:

  • Rates of injecting and needle sharing


  • adherence to study drug/placebo


  • HIV viral load and CD4 counts


  • antiretroviral resistance


  • genetic characteristics of infecting


  • the number of unprotected sexual acts over the course of the trial


  • number of reported sexual partners over the course of the trial


  • proportional use of condoms during sexual intercourse

Starting dateJune 2005

Contact informationPrincipal Investigator: Kachit Choopanya, Bangkok Tenofovir Study Group.

Study director: Michael T Martin, Centers for Disease Control and Prevention

NotesStudy location: Bangkok

Grant 2012

Trial name or titleUse of Emtricitabine and Tenofovir Disoproxil Fumarate for Pre-Exposure Prophylaxis (ADAPT)

MethodsRandomised controlled trial (open label)

ParticipantsMen and women aged 18 years and older

Inclusion Criteria:

  • Literacy in one of the study languages (Thai, Xhosa and/or English)
  • Able to provide written informed consent
  • Able to provide weekly telephonic updates
  • Certain lab valued within 70 days of enrolment
  • Willing and able to provide adequate locator information


Inclusion Criteria for Men Who Have Sex With Men (MSM):

  • Male at birth
  • Reporting anal intercourse with at least one man in the past 6 months
  • Presence of one or more of the following risk factors for HIV acquisition in the past 6 months: sexual intercourse with more than one man; history of an acute sexually transmitted disease (STI); sex in exchange for money, goods, or favors; condom-less intercourse (oral, anal, or vaginal) with a partner known to be HIV-infected or of unknown HIV infection status according to self report


Inclusion Criteria for Women Who Have Sex With Men (WSM):

  • Female at birth or self identify as female
  • Not pregnant or breastfeeding
  • Not able to or not intending to become pregnant during the next year
  • If able to become pregnant, self reported use of an effective method of contraception at Enrollment, and intending to use an effective method for the next 34 weeks
  • One or more of the following risk factors for HIV acquisition in the past six months according to self report: sexual intercourse with more than one man; history of an acute STI; sex in exchange for money, goods or favors; condomless intercourse (oral, anal or vaginal) with a partner known to be HIV-infected or of unknown HIV infection status


Exclusion Criteria:

  • Proteinuria 2+ or greater at screening
  • Glucosuria 2+ or greater at screening
  • Serious and active medical or mental illness
  • One or both HIV rapid tests is reactive at screening or enrolment, regardless of subsequent HIV diagnostic test results
  • Signs or symptoms suggestive of acute HIV infection
  • Use of hypoglycemic agents for diabetes or agents with known nephrotoxic potential
  • Serum phosphate level below site laboratory LLN (lower limit of normal)
  • Current participation (or participation within three months of screening) in any HIV prevention study
  • Previous or current participation in the active arm of an HIV vaccine trial
  • Acute or chronic HBV infection
  • Presence of a psychological or social condition or an addictive disorder that would preclude compliance with the protocol
  • Any other reason or condition that in the opinion of the investigator would interfere with participation, complicate interpretation of study outcome data, or otherwise interfere with achieving the study objectives

InterventionsEmtricitabine/Tenofovir Disoproxil Fumarate (FTC/TDF): daily, time-based, and event-based dosing

OutcomesPrimary Outcome Measures:

  • Proportion of sexual exposures covered by pre- and post-exposure dosing


  • Minimum total number of pills needed for 100% coverage


  • Total number of pills used over the follow-up period


  • Self-reported side effect or symptom scores


Secondary Outcome Measures:

  • Amount of tenofovir diphosphate (TFV-DP) in peripheral blood mononuclear cell (PBMC)


  • Listing of adverse events (AEs) by grade


  • Drug resistance test results and plasma HIV RNA levels among all participants who seroconvert while enrolled in the study


  • Proportion of participants who self-report acceptability of assigned study arm, as collected on computer assisted self interview (CASI) assessment


  • Perceptions of advantages and disadvantages of different regimens as reported by participants and clinical personnel [


  • Percentage of adherence and correctly timed adherence, measured by weekly interviews and electronic drug monitoring data


  • Percentage of adherence, based on pill counts


  • Proportion of participants who discontinue all pre-exposure prophylaxis (PrEP) use as assessed by self-report via CASI or weekly interviews


  • Information related to PrEP use, motivation, and behavioral skills as assessed by self-report via CASI


  • Frequency of unprotected sex acts as assessed via CASI


  • Planning for sex as assessed via CASI


  • Results of safer sex planning survey as assessed via CASI


  • Perceived vulnerability as assessed via CASI


  • PrEP optimism as assessed via CASI


  • General optimism as assessed via CASI


  • Demographic factors

Starting dateSeptember 2012

Contact informationStudy chair: Robert M. Grant, MD, MPH. University of California, San Francisco

NotesStudy location: South Africa and Thailand

Molina 2012

Trial name or titleOn Demand Antiretroviral Pre-exposure Prophylaxis for HIV Infection in Men Who Have Sex With Men (IPERGAY)

MethodsRandomised controlled trial

ParticipantsMen who have sex with men aged 18 years and older

Inclusion Criteria:

  • Age ≥ 18 years old
  • Male (or transgender) having sex with men
  • Not infected with HIV-1 or HIV-2
  • Elevated risk of HIV contamination : anal sexual relations with at least 2 different sexual partners within the past 6 months without the systematic use of a condom
  • Satisfactory kidney function with a clearance of more than 60 mL/min (Cockcroft formula)
  • ALT < 2.5 ULN,
  • Neutrophil granulocytes ≥ 1 000/mm3, haemoglobin ≥ 10 g/dL, platelets ≥ 150 000/mm3
  • Negative HBs antigen and negative HCV serology (or negative HCV PCR if positive serology)
  • Agrees to be contacted personally, if possible by telephone, SMS or e-mail
  • Agrees to the constraints imposed by the trial (visits every 2 months)
  • Subjects enrolled in or a beneficiary of a Social Security program (State Medical Aid or AME is not a Social Security program).
  • Signature of the informed consent form.


Exclusion Criteria:

  • Subject in a stable and exclusive relationship with a person
  • Systematic use of a condom during sexual relations
  • Expected to go abroad for more than 3 consecutive months or move expected to a city where the study is not being conducted.
  • Presence of significant glycosuria or proteinuria > 1+ in the urine dipstick, in the absence of infection.
  • Presence of significant haematuria or leukocyturia > 2+ in the urine dipstick, in the absence of infection.
  • History of chronic kidney disease, osteoporosis, osteopaenia
  • History of pathological bone fracture not related to trauma
  • Treatment with Interferon, Interleukin, corticosteroids or antiretrovirals
  • Treatment that could inhibit or compete with the tubular secretion of antiretrovirals
  • Treatment undergoing investigation
  • Intravenous toxicomania
  • Subject who is currently receiving or going to receive a potentially nephrotoxic treatment (long-term anti-inflammatory)
  • Gastro-intestinal disease (or chronic nausea or vomiting) disrupting the absorption of treatments
  • Positive HBs antigen
  • Positive HCV serology with positive HCV PCR
  • Life-threatening disease (lymphoma) or other serious disease (cardiovascular, renal, pulmonary, unstable diabetes) that could require treatment that could disrupt adherence to the treatment
  • Subject potentially non-compliant.

InterventionsTDF-FTC versus placebo (taken at the time of intercourse)

OutcomesPrimary Outcome Measures:

  • Contamination with HIV-1 or -2


Secondary Outcome Measures:

  • Evolution of sexual behavior and potential at-risk behavior


  • Treatment adherence


  • Incidence of hepatitis B


  • Incidence of other sexually transmitted diseases


  • Frequency of HIV resistance to antiretrovirals in HIV infected subjects


  • Emtricitabine and tenofovir concentrations in plasma, saliva and rectal samples


  • Costs evaluation

Starting dateJanuary 2012

Contact informationJean-Michel MOLINA, Hôpital Saint-Louis Paris FRANCE

NotesStudy location: France

NIAID 2012

Trial name or titleEvaluating the Safety and Tolerability of Antiretroviral Drug Regimens Used as Pre-Exposure Prophylaxis to Prevent HIV Infection in Men Who Have Sex With Men (HPTN 069)

MethodsRandomised controlled trial

ParticipantsMen who have sex with men, 18 years and older

Inclusion Criteria:

  • Born male and age 18 years or older at the time of screening
  • Willing to provide informed consent for the study
  • Able to read at a level required for the study components (e.g., computer-assisted self-interview [CASI] and short message service [SMS], per the judgment of the study investigator
  • History of receptive or insertive anal intercourse without use of condoms with at least one HIV-infected male partner or male partner of unknown HIV serostatus within 3 months of study entry (provided by self-report)
  • The following laboratory values must be from specimens obtained within 30 days prior to study enrolment: Nonreactive HIV test results (more information on this criterion can be found in the protocol); hemoglobin greater than 11 g/dL; absolute neutrophil count greater than 750 cells/mm^3 and platelet count greater than 100,000/mm^3; calculated creatinine clearance at least 70 mL/minute using the Cockcroft-Gault equation; alanine aminotransferase (ALT) and aspartate aminotransferase (AST) less than 3 times the upper limit of normal (ULN); total bilirubin less than 2.5 ULN; urine protein less than 2+; and hepatitis B surface antigen (HBsAg) negative.
  • No alcohol or substance use that, in the opinion of the study investigator, would interfere with the conduct of the study (e.g., provided by self-report or found upon medical history and examination or in available medical records)
  • No medical condition that, in the opinion of the study investigator, would interfere with the conduct of the study (e.g., provided by self-report or found upon medical history and examination or in available medical records
  • Willing to undergo all required study procedures (including sexual assessment by CASI, use of the drug monitoring device, and SMS [i.e., texting])
  • For the Tissue Subset: Willing to abstain from receptive anal intercourse and practices involving insertion of anything in the rectum (drug, enema, penis, or sex toy) for 48 hours prior to rectal biopsy and for 14 days post-biopsy to minimize risk of HIV-1 infection and bleeding complications after each flexible sigmoidoscopy procedure.


Exclusion Criteria:

  • One or more reactive HIV test results at screening or enrolment, even if HIV infection is not confirmed
  • Coenrollment in any other HIV interventional research study (provided by self-report or other available documentation) or prior enrolment and receipt of active arm (i.e., NOT a placebo) of an HIV vaccine trial (provided by available documentation)
  • Use of ARV therapy (e.g., for post-exposure prophylaxis [PEP] or PrEP) in the 90 days prior to study entry
  • Prior history of a gastrectomy, colostomy, ileostomy, or any other procedure altering the gastrointestinal tract or drug absorption (provided by self-report or obtained from medical history or records)
  • Receipt of prohibited medications as described in the study drug package inserts or listed in the Study-Specific Populations (SSP) Manual (provided by self-report or obtained from medical history or medical records)
  • Ongoing intravenous drug use: episodic use or any use in the past 3 months (as assessed by the study investigator)
  • Known medical history of allergy to soy (soya or soybeans) or peanuts
  • For the Tissue Subset: Abnormalities of the colorectal mucosa or significant colorectal symptom(s) that, in the opinion of the clinician, represent a contraindication to biopsy (including but not limited to presence of any unresolved injury, infectious or inflammatory condition of the local mucosa, and presence of symptomatic external hemorrhoids)
  • For the Tissue Subset: Per participant report at screening, anticipated use and/or unwillingness to abstain from the following medications during the period of study participation: heparin, including lovenox; warfarin; plavix (clopidogrel bisulfate); rectally administered medications (including over-the-counter products); aspirin; non-steroidal anti-inflammatory drugs (NSAIDS); any other drugs that are associated with increased risk of bleeding following biopsy procedures
  • Abnormal laboratory results for coagulation tests that may indicate an increased risk of bleeding (in the opinion of the investigators)
  • Active untreated syphilis, gonorrhea, or chlamydia infection

InterventionsFour ARV regimens: maraviroc (MVC), MVC plus emtricitabine, MVC plus tenofovir disoproxil fumarate (TDF), and TDF plus FTC.

OutcomesPrimary Outcome Measures:

  • Safety as assessed by the occurrence of Grade 3 or higher adverse events
  • Tolerability as assessed by time to permanent discontinuation of treatment


Secondary Outcome Measures:

  • Safety as assessed by the occurrence of Grade 2 or higher adverse events


  • Changes in creatinine clearance and fractional excretion of phosphate


  • Changes in total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL) (calculated or measured), and triglycerides 48 ]


  • Changes in peripheral blood and gut-associated lymphoid tissue (GALT) T cell phenotype


  • Pre-dose and post-dose concentrations of MVC, FTC, and tenofovir (TFV) in plasma (Drug Interaction Subset)


  • Pre-dose concentrations of drugs (MVC, FTC, TFV, and their phosphorylated derivatives), in plasma, peripheral blood mononuclear cells (PBMCs), and rectal samples (Tissue Subset)


  • PrEP adherence as assessed by proportion of daily doses taken, measured by electronic drug monitoring (EDM)


  • Self-reported number of doses missed in last 30 days and self-reported adherence rating scale


  • Proportion of doses taken as measured by EDM the day of and day prior to a sexual exposure as detected by SMS assessment


  • Selected drug concentration measurements in stored plasma samples


  • Self-reported quality of life indicators over time using a standardized assessment tool


  • Self-reported sexual behavior over time using a standardized assessment tool

Starting date2012

Contact informationNational Institute of Allergy and Infectious Diseases (NIAID)

NotesStudy location: USA

Paxton 2007

Trial name or titleBotswana TDF/FTC Oral HIV Prophylaxis Trial

MethodsRandomised controlled trial

ParticipantsSexually-active men and women aged 18 to 29 years

Inclusion Criteria:

  • citizen of Botswana 18-29 years old
  • sexually active
  • HIV uninfected
  • Hepatitis B and C uninfected
  • Calculated creatinine clearance >= 60 mL/min
  • hemoglobin >= 8 gm/dL
  • ALT and AST <= 2x ULN
  • total bilirubin <= 1.5 mg/dL
  • total serum amylase <= 1.5x ULN
  • Serum phosphorus >= 2.2 mg/dL
  • willing to use hormonal contraception (females)
  • living within 1 hours travel of study clinic
  • pass comprehension test
  • willing and able to give informed consent


Exclusion Criteria:

  • 18-20 without parent/guardian consent
  • history of significant renal or bone disease
  • any chronic illness requiring ongoing prescription medication
  • pregnant or breastfeeding
  • planning to move away from site in the next year
  • participating in another HIV prevention or vaccine safety trial
  • any other clinical condition or prior therapy that, in the opinion of the study physician, would make the volunteer unsuitable for the study or unable to comply with the dosing requirements

InterventionsDaily Tenofovir Disoproxil Fumarate 300 mg + Emtricitabine 200 mg daily versus placebo

OutcomesPrimary Outcome Measures:

  • Adverse drug reactions in the tenofovir/emtricitabine and placebo arms;


  • HIV incidence in the tenofovir/emtricitabine and placebo arms


Secondary Outcome Measures:Secondary:

  • Changes in levels of unprotected sex during the trial;


  • Adherence to medication;


  • Antiretroviral (ARV) resistance patterns in seroconverters;


  • Viral set point in seroconverters

Starting dateMarch 2007

Contact informationLynn A Paxton, MD, MPH. Centers for Disease Control and Prevention

NotesStudy location: Botswana

 
Comparison 1. TDF+ FTC vs placebo

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 HIV infection (by risk group)48918Risk Ratio (M-H, Random, 95% CI)0.49 [0.28, 0.85]

    1.1 Heterosexual group
36419Risk Ratio (M-H, Random, 95% CI)0.46 [0.19, 1.10]

    1.2 MSM group
12499Risk Ratio (M-H, Random, 95% CI)0.56 [0.38, 0.84]

 2 HIV infection (by gender)24354Risk Ratio (M-H, Random, 95% CI)0.31 [0.19, 0.50]

    2.1 Women
21729Risk Ratio (M-H, Random, 95% CI)0.40 [0.23, 0.71]

    2.2 Men
22625Risk Ratio (M-H, Random, 95% CI)0.17 [0.07, 0.41]

 3 Serious adverse events36862Risk Ratio (M-H, Random, 95% CI)1.00 [0.83, 1.19]

 
Comparison 2. TDF vs placebo

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 HIV infection24027Risk Ratio (M-H, Random, 95% CI)0.33 [0.20, 0.55]

 2 Serious adverse events13168Risk Ratio (M-H, Random, 95% CI)1.03 [0.79, 1.33]

 
Comparison 3. TDF-FTC vs TDF alone

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 HIV infection1Risk Ratio (M-H, Random, 95% CI)Totals not selected

 2 Serious adverse events1Risk Ratio (M-H, Random, 95% CI)Totals not selected

 
Summary of findings for the main comparison. TDF+ FTC compared to placebo for preventing HIV in high-risk individuals

Tenofovir + Emtricitabine compared to placebo for preventing HIV in high-risk individuals

Patient or population: High-risk HIV-uninfected individuals (including serodiscordant couples, men who have sex with men and sex workers)
Settings: High, middle and low income settings
Intervention: Oral Tenofovir + Emtricitabine
Comparison: placebo

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

PlaceboTDF+ FTC

HIV infectionStudy populationRR 0.49
(0.28 to 0.85)
8813
(4 studies)
⊕⊕⊕⊝
Moderate1

39 per 100019 per 1000
(11 to 33)

Serious adverse eventsStudy populationRR 1

(0.83 to 1.19)
6862
(3)
⊕⊕⊕⊝
Moderate1

65 per 100065 per 1000
(54 to 77)

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio;

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1 We downgraded the quality of evidence by one level on account of instability of results since there are fewer than 200 events per arm.
 
Summary of findings 2. TDF compared to placebo for preventing HIV in high-risk individuals

Tenofovir compared to placebo for preventing HIV in high-risk individuals

Patient or population: High-risk individuals (including serodiscordant couples, men who have sex with men and sex workers)
Settings: High, middle and low income settings
Intervention: Oral Tenofovir
Comparison: placebo

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

PlaceboTDF

HIV infectionStudy populationRR 0.33
(0.20 to 0.55)
4027
(2 studies)
⊕⊕⊕⊝
Moderate1

29 per 10009 per 1000
(6 to 16)

Serious adverse eventsStudy populationRR 1.03
(0.79 to 1.33)
3168
(1)
⊕⊕⊕⊕
Moderate1

66 per 100068 per 1000
(52 to 88)

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio;

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1 We downgraded the quality of evidence by one level on account of instability of results since there are fewer than 200 events per arm.
 
Table 1. Search Strategy: PubMed

SearchMost Recent Queries

#7Search #6 NOT pregnan*

#6Search #1 AND #2 AND #5

#5Search #3 OR #4

#4Search tenofovir OR TNF OR TDF OR PMPA OR viread OR emtricitabine OR EMC OR truvada OR emtriva OR coviracil

#3Search pre-exposure prophylaxis[tiab] OR preexposure prophylaxis[tiab] OR PREP[tiab] OR anti-retroviral chemoprophylaxis[tiab] OR antiretroviral chemoprophylaxis[tiab] OR chemoprevention[mh] OR chemoprevention[tiab] OR HIV prophylaxis[tiab]

#2Search (randomised controlled trial [pt] OR controlled clinical trial [pt] OR randomised [tiab] OR placebo [tiab] OR drug therapy [sh] OR randomly [tiab] OR trial [tiab] OR groups [tiab]) NOT (animals [mh] NOT humans [mh])

#1Search HIV Infections[MeSH] OR HIV[MeSH] OR HIV[tw] OR hiv-1*[tw] OR hiv-2*[tw] OR hiv1[tw] OR hiv2[tw] OR HIV infect*[tw] OR human immunodeficiency virus[tw] OR human immunedeficiency virus[tw] OR human immuno-deficiency virus[tw] OR human immune-deficiency virus[tw] OR ((human immun*) AND (deficiency virus[tw])) OR acquired immunodeficiency syndrome[tw] OR acquired immunedeficiency syndrome[tw] OR acquired immuno-deficiency syndrome[tw] OR acquired immune-deficiency syndrome[tw] OR ((acquired immun*) AND (deficiency syndrome[tw])) OR "sexually transmitted diseases, viral"[MESH:NoExp]

 
Table 3. EMBASE Search strategy

No.Query

#8 #6 NOT pregnan*

#7 #6 NOT pregnan*

#6 #1 AND #2 AND #5

#5 #3 OR #4

#4 'tenofovir'/syn OR tnf OR tdf OR 'pmpa'/syn OR 'viread'/syn OR 'emtricitabine'/syn OR emc OR 'truvada'/syn OR 'emtriva'/syn OR 'coviracil'/syn

#3 'pre-exposure prophylaxis' OR 'preexposure prophylaxis' OR prep OR 'anti-retroviral chemoprophylaxis' OR 'antiretroviral chemoprophylaxis' OR 'chemoprevention'/syn OR 'hiv prophylaxis' OR 'chemoprophylaxis'/syn

#2 random*:ti OR random*:ab OR factorial*:ti OR factorial*:ab OR cross?over*:ti OR cross?over:ab OR crossover*:ti OR crossover*:ab OR placebo*:ti OR placebo*:ab OR (doubl*:ti AND blind*:ti) OR (doubl*:ab AND blind*:ab) OR (singl*:ti AND blind*:ti) OR (singl*:ab AND blind*:ab) OR assign*:ti OR assign*:ab OR volunteer*:ti OR volunteer*:ab OR 'crossover procedure'/de OR 'crossover procedure' OR 'double-blind procedure'/de OR 'double-blind procedure' OR 'single-blind procedure'/de OR 'single-blind procedure' OR 'randomised controlled trial'/de OR 'randomised controlled trial' OR allocat*:ti OR allocat*:ab

#1 'human immunodeficiency virus infection'/exp OR 'human immunodeficiency virus infection'/de OR 'human immunodeficiency virus infection' OR 'human immunodeficiency virus'/exp OR 'human immunodeficiency virus'/de OR 'human immunodeficiency virus' OR hiv:ti OR hiv:ab OR 'hiv-1':ti OR 'hiv-1':ab OR 'hiv-2':ti OR 'hiv-2':ab OR 'human immunodeficiency virus':ti OR 'human immunodeficiency virus':ab OR 'human immuno-deficiency virus':ti OR 'human immuno-deficiency virus':ab OR 'human immunedeficiency virus':ti OR 'human immunedeficiency virus':ab OR 'human immune-deficiency virus':ti OR 'human immune-deficiency virus':ab OR 'acquired immune-deficiency syndrome':ti OR 'acquired immune-deficiency syndrome':ab OR 'acquired immunedeficiency syndrome':ti OR 'acquired immunedeficiency syndrome':ab OR 'acquired immunodeficiency syndrome':ti OR 'acquired immunodeficiency syndrome':ab OR 'acquired immuno-deficiency syndrome':ti OR 'acquired immuno-deficiency syndrome':ab