Acyclovir and transmission of HIV-1 from persons infected with HIV-1 and HSV-2

Celum,C.; Wald,A.; Lingappa,J.R.; Magaret,A.S.; Wang,R.S.; Mugo,N.; Mujugira,A.; Baeten,J.M.; Mullins,J.I.; Hughes,J.P.; Bukusi,E.A.; Cohen,C.R.; Katabira,E.; Ronald,A.; Kiarie,J.; Farquhar,C.; Stewart,G.J.; Makhema,J.; Essex,M.; Were,E.; Fife,K.H.; de,Bruyn G.; Gray,G.E.; McIntyre,J.A.; Manongi,R.; Kapiga,S.; Coetzee,D.; Allen,S.; Inambao,M.; Kayitenkore,K.; Karita,E.; Kanweka,W.; Delany,S.; Rees,H.; Vwalika,B.; Stevens,W.; Campbell,M.S.; Thomas,K.K.; Coombs,R.W.; Morrow,R. Whittington,W.L.; McElrath,M.J.; Barnes,L.; Ridzon,R.; Corey,L. N Engl J Med. 2010 Feb 4;362(5):427-39.
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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.