TY - JOUR
T1 - Effect of daily aciclovir on HIV disease progression in individuals in Rakai, Uganda, co-infected with HIV-1 and herpes simplex virus type 2
T2 - A randomised, double-blind placebo-controlled trial
AU - Reynolds, Steven J.
AU - Makumbi, Fred
AU - Newell, Kevin
AU - Kiwanuka, Noah
AU - Ssebbowa, Paschal
AU - Mondo, George
AU - Boaz, Iga
AU - Wawer, Maria J.
AU - Gray, Ronald H.
AU - Serwadda, David
AU - Quinn, Thomas C.
N1 - Funding Information:
This research was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. This project was funded partly with federal funds from the National Cancer Institute, National Institutes of Health , contract number HHSN261200800001E , and partly through programme project grant PO1 AI-30731-19. The content of this report does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organisations imply endorsement by the US Government. We thank the trial participants, the staff of the Rakai Health Sciences Program, and Larry Corey for his design input and support. We also thank the NIH Data Safety and Monitoring Board and the institutional review boards (Uganda Virus Research Institute Science and Ethics Committee and the National Institute of Allergy and Infectious Diseases institutional review board) for their technical advice and oversight of this study.
PY - 2012/6
Y1 - 2012/6
N2 - Background: Daily suppression of herpes simplex virus type 2 (HSV-2) reduces plasma HIV-1 concentrations and modestly delayed HIV-1 disease progression in one clinical trial. We investigated the effect of daily suppressive aciclovir on HIV-1 disease progression in Rakai, Uganda. Methods: We did a single site, parallel, randomised, controlled trial of HIV-1, HSV-2 dually infected adults with CD4 cell counts of 300-400 cells per μL. We excluded individuals who had an AIDS-defining illness or active genital ulcer disease, and those that were taking antiretroviral therapy. Participants were randomly assigned (1:1) with computer-generated random numbers in blocks of four to receive either aciclovir 400 mg orally twice daily or placebo; participants were followed up for 24 months. All study staff and participants were masked to treatment, except for the two statisticians. The primary outcome was CD4 cell count less than 250 cells per μL or initiation of antiretroviral therapy for WHO stage 4 disease. Our intention-to-treat analysis used Cox proportional hazards models, adjusting for baseline log 10 viral load, CD4 cell count, sex, and age to assess the risk of disease progression. We also investigated the effect of suppressive HSV-2 treatment stratified by baseline HIV viral load with a Cox proportional hazards model. This trial is registered with ClinicalTrials.gov, number NCT00405821. Findings: 440 participants were randomly assigned, 220 to each group. 110 participants in the placebo group and 95 participants in the treatment group reached the primary endpoint (adjusted hazard ratio [HR] 0·75, 95% CI 0·58-0·99; p=0·040). 24 participants in the placebo group and 22 in the treatment group were censored, but all contributed data for the final analysis. In a subanalysis stratified by baseline HIV viral load, participants with a baseline viral load of 50 000 copies mL or more in the treatment group had a reduced HIV disease progression compared with those in the placebo group (0·62, 0·43-0·96; p=0·03). No significant difference in HIV disease progression existed between participants in the treatment group and those in the placebo group who had baseline HIV viral loads of less than 50 000 copies per mL (0·90, 0·54-1·5; p=0·688). No safety issues related to aciclovir treatment were identified. Interpretation: Aciclovir reduces the rate of disease progression, with the greatest effect in individuals with a high baseline viral load. Suppressive aciclovir might be warranted for individuals dually infected with HSV-2 and HIV-1 with viral loads of 50 000 copies per mL or more before initiation of antiretroviral treatment. Funding: National Institute of Allergy and Infectious Diseases, National Cancer Institute (National Institutes of Health, USA).
AB - Background: Daily suppression of herpes simplex virus type 2 (HSV-2) reduces plasma HIV-1 concentrations and modestly delayed HIV-1 disease progression in one clinical trial. We investigated the effect of daily suppressive aciclovir on HIV-1 disease progression in Rakai, Uganda. Methods: We did a single site, parallel, randomised, controlled trial of HIV-1, HSV-2 dually infected adults with CD4 cell counts of 300-400 cells per μL. We excluded individuals who had an AIDS-defining illness or active genital ulcer disease, and those that were taking antiretroviral therapy. Participants were randomly assigned (1:1) with computer-generated random numbers in blocks of four to receive either aciclovir 400 mg orally twice daily or placebo; participants were followed up for 24 months. All study staff and participants were masked to treatment, except for the two statisticians. The primary outcome was CD4 cell count less than 250 cells per μL or initiation of antiretroviral therapy for WHO stage 4 disease. Our intention-to-treat analysis used Cox proportional hazards models, adjusting for baseline log 10 viral load, CD4 cell count, sex, and age to assess the risk of disease progression. We also investigated the effect of suppressive HSV-2 treatment stratified by baseline HIV viral load with a Cox proportional hazards model. This trial is registered with ClinicalTrials.gov, number NCT00405821. Findings: 440 participants were randomly assigned, 220 to each group. 110 participants in the placebo group and 95 participants in the treatment group reached the primary endpoint (adjusted hazard ratio [HR] 0·75, 95% CI 0·58-0·99; p=0·040). 24 participants in the placebo group and 22 in the treatment group were censored, but all contributed data for the final analysis. In a subanalysis stratified by baseline HIV viral load, participants with a baseline viral load of 50 000 copies mL or more in the treatment group had a reduced HIV disease progression compared with those in the placebo group (0·62, 0·43-0·96; p=0·03). No significant difference in HIV disease progression existed between participants in the treatment group and those in the placebo group who had baseline HIV viral loads of less than 50 000 copies per mL (0·90, 0·54-1·5; p=0·688). No safety issues related to aciclovir treatment were identified. Interpretation: Aciclovir reduces the rate of disease progression, with the greatest effect in individuals with a high baseline viral load. Suppressive aciclovir might be warranted for individuals dually infected with HSV-2 and HIV-1 with viral loads of 50 000 copies per mL or more before initiation of antiretroviral treatment. Funding: National Institute of Allergy and Infectious Diseases, National Cancer Institute (National Institutes of Health, USA).
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U2 - 10.1016/S1473-3099(12)70037-3
DO - 10.1016/S1473-3099(12)70037-3
M3 - Article
C2 - 22433279
AN - SCOPUS:84861340082
SN - 1473-3099
VL - 12
SP - 441
EP - 448
JO - The Lancet Infectious Diseases
JF - The Lancet Infectious Diseases
IS - 6
ER -