Acyclovir and transmission of HIV-1 from persons infected with HIV-1 and HSV-2.
BACKGROUND
Most persons who are infected with human immunodeficiency virus type 1 (HIV-1) are also infected with herpes simplex virus type 2 (HSV-2), which is frequently reactivated and is associated with increased plasma and genital levels of HIV-1. Therapy to suppress HSV-2 reduces the frequency of reactivation of HSV-2 as well as HIV-1 levels, suggesting that suppression of HSV-2 may reduce the risk of transmission of HIV-1.


METHODS
We conducted a randomized, placebo-controlled trial of suppressive therapy for HSV-2 (acyclovir at a dose of 400 mg orally twice daily) in couples in which only one of the partners was seropositive for HIV-1 (CD4 count, > or = 250 cells per cubic millimeter) and that partner was also infected with HSV-2 and was not taking antiretroviral therapy at the time of enrollment. The primary end point was transmission of HIV-1 to the partner who was not initially infected with HIV-1; linkage of transmissions was assessed by means of genetic sequencing of viruses.


RESULTS
A total of 3408 couples were enrolled at 14 sites in Africa. Of the partners who were infected with HIV-1, 68% were women, and the baseline median CD4 count was 462 cells per cubic millimeter. Of 132 HIV-1 seroconversions that occurred after randomization (an incidence of 2.7 per 100 person-years), 84 were linked within couples by viral sequencing: 41 in the acyclovir group and 43 in the placebo group (hazard ratio with acyclovir, 0.92, 95% confidence interval [CI], 0.60 to 1.41; P=0.69). Suppression with acyclovir reduced the mean plasma concentration of HIV-1 by 0.25 log(10) copies per milliliter (95% CI, 0.22 to 0.29; P<0.001) and the occurrence of HSV-2-positive genital ulcers by 73% (risk ratio, 0.27; 95% CI, 0.20 to 0.36; P<0.001). A total of 92% of the partners infected with HIV-1 and 84% of the partners not infected with HIV-1 remained in the study for 24 months. The level of adherence to the dispensed study drug was 96%. No serious adverse events related to acyclovir were observed.


CONCLUSIONS
Daily acyclovir therapy did not reduce the risk of transmission of HIV-1, despite a reduction in plasma HIV-1 RNA of 0.25 log(10) copies per milliliter and a 73% reduction in the occurrence of genital ulcers due to HSV-2. (ClinicalTrials.gov number, NCT00194519.)
Celum
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Department of Global Health, University of Washington, Harborview Medical Center, 325 Ninth Ave., Box 359927, Seattle, WA 98104, USA.
Wald
A
A
Lingappa
J R
JR
Magaret
A S
AS
Wang
R S
RS
Mugo
N
N
Mujugira
A
A
Baeten
J M
JM
Mullins
J I
JI
Hughes
J P
JP
Bukusi
E A
EA
Cohen
C R
CR
Katabira
E
E
Ronald
A
A
Kiarie
J
J
Farquhar
C
C
Stewart
G J
GJ
Makhema
J
J
Essex
M
M
Were
E
E
Fife
K H
KH
de Bruyn
G
G
Gray
G E
GE
McIntyre
J A
JA
Manongi
R
R
Kapiga
S
S
Coetzee
D
D
Allen
S
S
Inambao
M
M
Kayitenkore
K
K
Karita
E
E
Kanweka
W
W
Delany
S
S
Rees
H
H
Vwalika
B
B
Stevens
W
W
Campbell
M S
MS
Thomas
K K
KK
Coombs
R W
RW
Morrow
R
R
Whittington
W L H
WL
McElrath
M J
MJ
Barnes
L
L
Ridzon
R
R
Corey
L
L
D017088:AIDS-Related Opportunistic Infections / Q000188:drug therapy*; D000212:Acyclovir / Q000009:adverse effects / Q000627:therapeutic use*; D000293:Adolescent; D000328:Adult; D000998:Antiviral Agents / Q000009:adverse effects / Q000627:therapeutic use*; D018791:CD4 Lymphocyte Count; D005260:Female; D005500:Follow-Up Studies; D015658:HIV Infections / Q000150:complications / Q000635:transmission*; D015497:HIV-1 / Q000235:genetics / Q000302:isolation & purification; D006558:Herpes Genitalis / Q000150:complications / Q000188:drug therapy*; D018258:Herpesvirus 2, Human; D006801:Humans; D057194:Intention to Treat Analysis; D053208:Kaplan-Meier Estimate; D008297:Male; D010349:Patient Compliance; D011247:Pregnancy; D012367:RNA, Viral / Q000097:blood; D047568:Unsafe Sex / Q000706:statistics & numerical data; D055815:Young Adult
D000998:Antiviral Agents; D012367:RNA, Viral; D000212:Acyclovir