HIV This Week

Acyclovir and Transmission of HIV-1 from Persons Infected with HIV-1 and HSV-2.

Celum C, Wald A, Lingappa JR, Magaret AS, Wang RS, Mugo N, Mujugira A, Baeten JM, Mullins JI, Hughes JP, Bukusi EA, Cohen CR, Katabira E, Ronald A, Kiarie J, Farquhar C, Stewart GJ, Makhema J, Essex M, Were E, Fife KH, de Bruyn G, Gray GE, McIntyre JA, 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 MS, Thomas  KK, Coombs RW, Morrow R, Whittington WL, McElrath MJ, Barnes L, Ridzon R, Corey L; the Partners in Prevention HSV/HIV Transmission Study Team. N Engl J Med. 2010 362(5):427-39.

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. Celum et al 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, >/=250 cells per cubic millimetre) and that partner was also infected with HSV-2 and was not taking antiretroviral therapy at the time of enrolment. 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. 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 millimetre. 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 millilitre (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. 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 millilitre and a 73% reduction in the occurrence of genital ulcers due to HSV-2.

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Editors’ note: Given that the majority of people with HIV infection also have herpes simplex-2 (HSV-2) infection, genital shedding of herpes occurs on up to 30% of days in co-infected people living with HIV even when they have no symptoms, and HSV-2 reactivation without symptoms has been associated with increased HIV viral load in the blood plasma and genital tract, there was good reason to conduct a large trial of serodiscordant couples to see if herpes suppression would reduce HIV transmission. After all, five trials had already shown that daily suppressive therapy for HSV-2 reduced plasma HIV viral load. Of 6543 HIV-discordant couples screened, 3408 were enrolled at 14 sites in Botswana, South Africa, Zambia, Kenya, Rwanda, Tanzania, and Uganda. With adherence to acyclovir/placebo high and HIV infections acquired outside the couple excluded from the final analysis through genotyping to link transmitted viruses, this well-powered trial gave an unequivocal answer. Despite reductions in HIV viral load, acyclovir did not reduce HIV transmission. However, this study documented a 16% reduction in disease progression for those in the acyclovir arm, all of whom started the study with CD4+ counts above 250. This suggests that, for their own health, co-infected people who are not yet eligible for antiretroviral treatment may benefit from daily acyclovir – it is off-patent and cheap and has few side effects.