Daily acyclovir for HIV-1 disease progression in people dually infected with HIV-1 and herpes simplex virus type 2: a randomised placebo-controlled trial.
BACKGROUND
Most people infected with HIV-1 are dually infected with herpes simplex virus type 2. Daily suppression of this herpes virus reduces plasma HIV-1 concentrations, but whether it delays HIV-1 disease progression is unknown. We investigated the effect of acyclovir on HIV-1 progression.


METHODS
In a trial with 14 sites in southern Africa and east Africa, 3381 heterosexual people who were dually infected with herpes simplex virus type 2 and HIV-1 were randomly assigned in a 1:1 ratio to acyclovir 400 mg orally twice daily or placebo, and were followed up for up to 24 months. Eligible participants had CD4 cell counts of 250 cells per mL or higher and were not taking antiretroviral therapy. We used block randomisation, and patients and investigators were masked to treatment allocation. Effect of acyclovir on HIV-1 disease progression was defined by a primary composite endpoint of first occurrence of CD4 cell counts of fewer than 200 cells per microL, antiretroviral therapy initiation, or non-trauma related death. As an exploratory analysis, we assessed the endpoint of CD4 falling to <350 cells per microL. Analysis was by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00194519.


RESULTS
At enrollment, the median CD4 cell count was 462 cells per microL and median HIV-1 plasma RNA was 4.1 log(10) copies per microL. Acyclovir reduced risk of HIV-1 disease progression by 16%; 284 participants assigned acyclovir versus 324 assigned placebo reached the primary endpoint (hazard ratio [HR] 0.84, 95% CI 0.71-0.98, p=0.03). In those with CD4 counts >or=350 cells per microL, aciclovir delayed risk of CD4 cell counts falling to <350 cells per microL by 19% (0.81, 0.71-0.93, p=0.002)


CONCLUSIONS
The role of suppression of herpes simplex virus type 2 in reduction of HIV-1 disease progression before initiation of antiretroviral therapy warrants consideration.


BACKGROUND
Bill & Melinda Gates Foundation.
Lingappa
Jairam R
JR
Department of Global Health, Seattle, WA, USA. lingappa@u.washington.edu
Baeten
Jared M
JM
Wald
Anna
A
Hughes
James P
JP
Thomas
Katherine K
KK
Mujugira
Andrew
A
Mugo
Nelly
N
Bukusi
Elizabeth A
EA
Cohen
Craig R
CR
Katabira
Elly
E
Ronald
Allan
A
Kiarie
James
J
Farquhar
Carey
C
Stewart
Grace John
GJ
Makhema
Joseph
J
Essex
Myron
M
Were
Edwin
E
Fife
Kenneth H
KH
de Bruyn
Guy
G
Gray
Glenda E
GE
McIntyre
James A
JA
Manongi
Rachel
R
Kapiga
Saidi
S
Coetzee
David
D
Allen
Susan
S
Inambao
Mubiana
M
Kayitenkore
Kayitesi
K
Karita
Etienne
E
Kanweka
William
W
Delany
Sinead
S
Rees
Helen
H
Vwalika
Bellington
B
Magaret
Amalia S
AS
Wang
Richard S
RS
Kidoguchi
Lara
L
Barnes
Linda
L
Ridzon
Renee
R
Corey
Lawrence
L
Celum
Connie
C
D000212:Acyclovir / Q000627:therapeutic use*; D000328:Adult; D000998:Antiviral Agents / Q000627:therapeutic use*; D018791:CD4 Lymphocyte Count; D018450:Disease Progression; D004311:Double-Blind Method; D005260:Female; D015658:HIV Infections / Q000150:complications / Q000188:drug therapy* / Q000276:immunology / Q000821:virology; D015497:HIV-1 / Q000302:isolation & purification; D006558:Herpes Genitalis / Q000150:complications / Q000188:drug therapy* / Q000821:virology; D018258:Herpesvirus 2, Human / Q000302:isolation & purification; D006801:Humans; D008297:Male; D019562:Viral Load
D000998:Antiviral Agents; D000212:Acyclovir