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Original Research |

Daily Oral Tenofovir and Emtricitabine–Tenofovir Preexposure Prophylaxis Reduces Herpes Simplex Virus Type 2 Acquisition Among Heterosexual HIV-1–Uninfected Men and Women: A Subgroup Analysis of a Randomized TrialHSV-2 Protection With Tenofovir-Based Preexposure Prophylaxis

Connie Celum, MD, MPH; Rhoda A. Morrow, PhD; Deborah Donnell, PhD; Ting Hong, MD, PhD; Craig W. Hendrix, MD, PhD; Katherine K. Thomas, MS; Kenneth H. Fife, MD, PhD; Edith Nakku-Joloba, MBChB, PhD; Andrew Mujugira, MBChB, MPH; Jared M. Baeten, MD, PhD, for the Partners PrEP Study Team*
[+] Article, Author, and Disclosure Information

* For a list of the members of the Partners PrEP Study Team, see the Appendix.

From University of Washington and Fred Hutchinson Cancer Research Center, Seattle, Washington; Johns Hopkins University, Baltimore, Maryland; Indiana University, Indianapolis, Indiana; and Makerere University, Kampala, Uganda.

Note: All authors vouch for the completeness and accuracy of the data presented.

Acknowledgment: The authors thank the study participants and the study team.

Grant Support: By the Bill & Melinda Gates Foundation (OOP47674).

Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M13-2471.

Reproducible Research Statement: Study protocol and statistical code: Available from Dr. Celum (e-mail, ccelum@uw.edu). Data set: Portions of the analytic data set are available to approved individuals through written agreement with Dr. Celum (e-mail, ccelum@uw.edu).

Requests for Single Reprints: Connie Celum, MD, MPH, University of Washington, 325 Ninth Avenue, UW Box 359927, Seattle, WA 98104.

Current Author Addresses: Drs. Celum, Donnell, Hong, and Baeten; Ms. Thomas; and Mr. Mujugira: University of Washington, 325 Ninth Avenue, UW Box 359927, Seattle, WA 98104.

Dr. Morrow: Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, LE-500, Seattle, WA 98109.

Dr. Hendrix: Department of Medicine, Johns Hopkins University, 600 North Wolfe Street, Harvey 502, Baltimore, MD 21287-5554.

Dr. Fife: Department of Medicine, Indiana University, Emerson H/Room 435, 545 Barnhill Drive, Indianapolis, IN 46202.

Dr. Nakku-Joloba: School of Public Health, Makerere University, PO Box 22418, Plot 106, Block 213, Bukoto, Kampala, Uganda.

Author Contributions: Conception and design: C. Celum, D. Donnell, J.M. Baeten.

Analysis and interpretation of the data: C. Celum, R.A. Morrow, D. Donnell, T. Hong, C.W. Hendrix, K.K. Thomas, K.H. Fife, J.M. Baeten.

Drafting of the article: C. Celum, D. Donnell, J.M. Baeten.

Critical revision of the article for important intellectual content: C. Celum, D. Donnell, K.H. Fife, E. Nakku-Joloba, J.M. Baeten.

Final approval of the article: C. Celum, R.A. Morrow, D. Donnell, C.W. Hendrix, K.H. Fife, E. Nakku-Joloba, A. Mujugira, J.M. Baeten.

Provision of study materials or patients: K.H. Fife, A. Mujugira, J.M. Baeten.

Statistical expertise: D. Donnell, T. Hong, K.K. Thomas.

Obtaining of funding: C. Celum, J.M. Baeten.

Administrative, technical, or logistic support: E. Nakku-Joloba, A. Mujugira, J.M. Baeten.

Collection and assembly of data: C. Celum, R.A. Morrow, D. Donnell, C.W. Hendrix, K.H. Fife, E. Nakku-Joloba, A. Mujugira, J.M. Baeten.

Ann Intern Med. 2014;161(1):11-19. doi:10.7326/M13-2471
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Background: Daily oral preexposure prophylaxis (PrEP) using the antiretroviral tenofovir disoproxil fumarate (TDF) alone or in combination with emtricitabine (FTC–TDF) reduces the risk for HIV-1 acquisition. Tenofovir has in vitro activity against herpes simplex virus type 2 (HSV-2).

Objective: To assess the efficacy of daily oral PrEP with tenofovir and FTC–TDF in the prevention of HSV-2 acquisition.

Design: Subgroup analysis of data from a randomized, placebo-controlled trial with concealed allocation. (ClinicalTrials.gov: NCT00557245)

Setting: Multiple sites in Kenya and Uganda.

Participants: Heterosexual men and women who were seronegative for HIV-1 and HSV-2 and at high risk for HIV-1 acquisition due to having an HIV-1–infected partner.

Measurements: HSV-2 seroconversion.

Results: A total of 131 participants seroconverted to HSV-2 (79 of 1041 assigned to tenofovir or FTC–TDF PrEP [HSV-2 incidence, 5.6 per 100 person-years] and 52 of 481 assigned to placebo [HSV-2 incidence, 7.7 per 100 person-years]). The hazard ratio (HR) for HSV-2 acquisition with daily oral PrEP was 0.70 (95% CI, 0.49 to 0.99; P = 0.047) compared with placebo, and the absolute risk reduction was 2.1 per 100 person-years. Among the 1044 participants with HSV-2–infected partners, the HR for PrEP was 0.67 (CI, 0.46 to 0.98; P = 0.038) compared with placebo, and the absolute risk reduction was 3.1 per 100 person-years.

Limitation: Randomization was not stratified by HSV-2 status, and diagnostic tests to exclude participants with acute HSV-2 at baseline are not available.

Conclusion: Daily oral tenofovir-based PrEP significantly reduced the risk for HSV-2 acquisition among heterosexual men and women. Modest protection against HSV-2 is an added benefit of HIV-1 prevention with oral tenofovir-based PrEP.

Primary Funding Source: Bill & Melinda Gates Foundation.


Grahic Jump Location
Figure 1.

Study flow diagram.

Retention of partners who were seronegative for HIV-1 and HSV-2 was calculated as cumulative retention, which was defined as remaining in follow-up and having available HSV-2 serostatus information. A total of 131 participants seroconverted to HSV-2 (42 in the tenofovir group, 37 in the FTC–TDF group, and 52 in the placebo group) and were included in the intention-to-treat analysis. FTC–TDF = emtricitabine in combination with tenofovir disoproxil fumarate; HSV-2 = herpes simplex virus type 2; TDF = tenofovir disoproxil fumarate.

Grahic Jump Location
Grahic Jump Location
Figure 2.

Cumulative probability of HSV-2 seroconversion in the active PrEP (tenofovir and FTC–TDF) versus placebo groups.

FTC–TDF = emtricitabine in combination with tenofovir disoproxil fumarate; HSV-2 = herpes simplex virus type 2; PrEP = preexposure prophylaxis.

Grahic Jump Location




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