Effect of daily aciclovir on HIV disease progression in individuals in Rakai, Uganda, co-infected with HIV-1 and herpes simplex virus type 2: A randomised, double-blind placebo-controlled trial

Steven James Reynolds, Fred Makumbi, Kevin Newell, Noah Kiwanuka, Paschal Ssebbowa, George Mondo, Iga Boaz, Maria J Wawer, Ronald H Gray, David Serwadda, Thomas C Quinn

Research output: Contribution to journalArticle

Abstract

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).

Original languageEnglish (US)
Pages (from-to)441-448
Number of pages8
JournalLancet Infectious Diseases
Volume12
Issue number6
DOIs
StatePublished - Jun 2012

Fingerprint

Human Herpesvirus 2
Uganda
Acyclovir
Disease Progression
HIV-1
Placebos
HIV
Viral Load
CD4 Lymphocyte Count
Therapeutics
Proportional Hazards Models
National Institute of Allergy and Infectious Diseases (U.S.)
Intention to Treat Analysis
National Cancer Institute (U.S.)
National Institutes of Health (U.S.)
Ulcer
Acquired Immunodeficiency Syndrome
Randomized Controlled Trials
Clinical Trials
Safety

ASJC Scopus subject areas

  • Infectious Diseases

Cite this

Effect of daily aciclovir on HIV disease progression in individuals in Rakai, Uganda, co-infected with HIV-1 and herpes simplex virus type 2 : A randomised, double-blind placebo-controlled trial. / Reynolds, Steven James; Makumbi, Fred; Newell, Kevin; Kiwanuka, Noah; Ssebbowa, Paschal; Mondo, George; Boaz, Iga; Wawer, Maria J; Gray, Ronald H; Serwadda, David; Quinn, Thomas C.

In: Lancet Infectious Diseases, Vol. 12, No. 6, 06.2012, p. 441-448.

Research output: Contribution to journalArticle

@article{aa3174b3875342a190ee8d13d8225335,
title = "Effect of daily aciclovir on HIV disease progression in individuals in Rakai, Uganda, co-infected with HIV-1 and herpes simplex virus type 2: A randomised, double-blind placebo-controlled trial",
abstract = "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).",
author = "Reynolds, {Steven James} and Fred Makumbi and Kevin Newell and Noah Kiwanuka and Paschal Ssebbowa and George Mondo and Iga Boaz and Wawer, {Maria J} and Gray, {Ronald H} and David Serwadda and Quinn, {Thomas C}",
year = "2012",
month = "6",
doi = "10.1016/S1473-3099(12)70037-3",
language = "English (US)",
volume = "12",
pages = "441--448",
journal = "The Lancet Infectious Diseases",
issn = "1473-3099",
publisher = "Lancet Publishing Group",
number = "6",

}

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 James

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

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).

UR - http://www.scopus.com/inward/record.url?scp=84861340082&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84861340082&partnerID=8YFLogxK

U2 - 10.1016/S1473-3099(12)70037-3

DO - 10.1016/S1473-3099(12)70037-3

M3 - Article

C2 - 22433279

AN - SCOPUS:84861340082

VL - 12

SP - 441

EP - 448

JO - The Lancet Infectious Diseases

JF - The Lancet Infectious Diseases

SN - 1473-3099

IS - 6

ER -