Pre-Exposure Prophylaxis to Prevent the Acquisition of HIV-1 Infection (PROUD): Effectiveness Results from the Pilot Phase of a Pragmatic Open-Label Randomised Trial

Nicole Venezia, Pharm.D., Mercer University College of Pharmacy

Tenofovir-emtricitabine (Truvada®) is a once daily medication approved for the use of pre-exposure prophylaxis (PrEP) to reduce the risk of sexually acquired human immunodeficiency virus (HIV) in adults at high risk. According to the manufacturer, this indication was approved based on clinical trials in men who have sex with men (MSM) at high risk for HIV infection and heterosexual serodiscordant couples. 1

According to a 2014 report from the Public Health England, gay, bisexual, and men who have sex with men are at highest risk for HIV infection in the United Kingdom (UK). Despite reported promotion of HIV testing, condom usage, and earlier treatment in those with HIV infection to help prevent transmission, data suggests HIV incidence continues to increase in the UK. 2

A recent, published study in The Lancet assessed the net effectiveness of PrEP with tenofovir-emtricitabine (Truvada®) for safety, adherence, and risk compensation.3

Pre-Exposure Prophylaxis to Prevent the Acquisition of HIV-1 Infection (PROUD): Effectiveness Results from the Pilot Phase of a Pragmatic Open-Label Randomised Trial 3
Design Pragmatic, open-label, randomised [randomized] controlled trial at 13 sexual health clinics in England; neither investigators or patients were blinded from treatment group to assess risk compensation

(N = 544)

Objective To assess the net effectiveness of PrEP with tenofovir-emtricitabine (Truvada®). Net effectiveness included assessment of safety, adherence, and risk compensation.
Study Groups 1:1 randomization

Immediate group: PrEP at enrollment (n = 275)

·         One tablet by mouth once daily- tenofovir disoproxil fumarate 245 mg and emtricitabine 200 mg

Deferred group: Deferral of PrEP for 1 year (n = 269)

 

Regular sexual partners were encouraged to enroll together and both partners allocated to the same group — minimize the possibility of drug sharing

 

All eligible patients must be HIV-negative at enrollment.

Methods HIV infection was defined as a reactive HIV antigen–antibody test result, confirmed by the detection of HIV ribonucleic acid (RNA), in participants without HIV infection at enrollment. Participants were asked to complete monthly questionnaires and daily diaries about sexual behavior and adherence to PrEP. A more detailed questionnaire was administered at enrollment and yearly visits.
Duration November 29, 2012 – October 13, 2014
Primary Outcome Measure The primary outcome was time to accrual of 500 participants and retention. The secondary outcomes were HIV infection, safety, adherence, and risk compensation.
Baseline Characteristics Eligible patients were male at birth and 18 years of age or older.

 

Immediate group:

Average age (35 years), Caucasian (81%), No partner (53%), circumcised (28%), any sexually transmitted infection (STI) diagnosis in past 12 months (63%), number of HIV tests in past 12 months (3), Use of post-exposure prophylaxis in past 12 months (35%)

 

Deferral group:

Average age (35 years), Caucasian (83%), No partner (55%), circumcised (30%), any STI diagnosis in past 12 months (65%), number of HIV tests in past 12 months (3), Use of post-exposure prophylaxis in past 12 months (37%)

Results   Immediate Group

(n = 275)

Deferral Group

(n = 269)

HIV incidence 1.2 cases/100 patient-years (90% CI, 0.4-2.9) 9.0 cases/100 patient-years (90% CI, 6.1-12.8) (p=0.0001)
The data monitoring committee considered the interim results on October 6, 2014. The monitoring committee notified the steering committee of the significantly increased risk of HIV infection in the deferred group. On October 13, 2014, the principal investigators were requested to offer PrEP to all participants in the deferred group (n = 163).
Resistance Two of the five HIV+ participants showed resistance for emtricitabine  
Post-exposure prophylaxis 14 courses prescribed to 12 participants 174 courses prescribed to 85 participants
Reported receptive anal sex without a condom with ten or more partners 21% (p = 0.03) 12%
One or more other STI diagnosis 152 (57%) of 265 participants 124 (50%) of 247 participants
Bacterial Sexual Transmitted Infections

*Infections were diagnosed during deferral phase of follow-up. Odds ratio (OR) adjusted for the number of screens for specific infection. Detection of STI in throat, urethra, or rectum.

STI Immediate Group Deferral Group Odds Ratio, 90% CI, p value
Any STI 152/265 (57%) 124/247 (50%) OR 1.07 (CI 0.78-1.46, p=0.74)
Gonorrhea 103/261 (39%) 89/242 (37%) OR 0.86 ( CI 0.62-1.20, p=0.46)
Chlamydia 77/261 (30%) 54/242 (22%) OR 1.27 (CI 0.89-1.80, p=0.27)
Syphilis 30/263 (11%) 22/247 (9%) OR 1.29 (CI 0.79-1.29, p=0.39)
Rectal gonorrhea or chlamydia 93/258 (36%) 77/238 (32%) OR 1.00 (CI 0.72-1.38, p=0.99)
Adverse Events Common Adverse Events: nausea, headache, arthralgia

21 (8%) of 275 participants interrupted or missed doses of PrEP due to adverse event episodes – 13 episodes were attributed to study drug

Serious Adverse Events: 29 serious adverse events, including 1 death – 0 were attributed to study drug
Percentage that Discontinued due to Adverse Events: 0%; Three of 21 participants interrupted therapy due to elevated SCr.
Study Author Conclusions Use of PrEP is not compromised in the real-world setting, and resulted in decreased incidence of HIV infections. Other sexually transmitted infections, including rectal gonorrhea and chlamydia, did not differ significantly between the groups. Use of an open-label design, rather than placebo-controlled, allowed for appropriate assessment of risk compensation. A disadvantage to PrEP could produce subsequent drug-resistant viruses.

The study summarized above suggests that utilization of HIV PrEP therapy with tenofovir-emtricitabine (Truvada®) can decrease the incidence of HIV infections in high-risk patients. However, a potential disadvantage of PrEP is the production of resistant virus strains to tenofovir, emtricitabine, or both. 3

According to the Centers for Disease Control and Prevention (CDC), approximately 50,000 people in the United States (US) are newly infected with HIV each year. In 2010 (the most recent year that data are available), there were an estimated 47,500 new HIV infections. Nearly two thirds of these new infections occurred in gay and bisexual men. 4

Although the study summarized above analyzed men from the UK, information pertaining to the usage of HIV PrEP therapy with tenofovir-emtricitabine could be potentially useful in the US as well.

 

References:

  1. Gilead Sciences, Inc. http://start.truvada.com/hcp?_ga=1.211594013.924958036.1448298126#. Accessed November 23, 2015.
  2. Yin Z, Brown A, Hughes G, Nardone A, Gill ON, Delpech V. HIV in the United Kingdom: 2014 Report. Public Health England. https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/401662/2014_PHE_HIV_annual_report_draft_Final_07-01-2015.pdf. Accessed November 23, 2015.
  3. McCormack S et al. Pre-exposure prophylaxis to prevent the acquisition of HIV-1 infection (PROUD): effectiveness results from the pilot phase of a pragmatic open-label randomised trial. Lancet. 2015; [Epub ahead of print].
  4. Centers for Disease Control and Prevention (CDC). HIV/AIDS. http://www.cdc.gov/hiv/statistics/overview/index.html. Updated September 11, 2015. Accessed November 16, 2015.
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