N Engl J Med. 2010 Feb 4;362(5):427-39. doi: 10.1056/NEJMoa0904849. Epub 2010 Jan 20.
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;
Partners in Prevention HSV/HIV Transmission Study Team.
Celum C, Wald A, Lingappa J, Magaret A, Hughes JP, Corey L, Baeten JM, McElrath MJ, Bakari B, Barnes LS, Brantley J, Broad J, Durbin S, Farley P, Farrell-Ross M, Flores C, Haugen H, Heffron R, Jackson A, Jonnalagadda SR, Kahle E, Karas J, Karschney R, Kidoguchi L, Kline K, Krows M, Leidholm M, Lennon E, Maddox T, McVarish L, Mobley A, Morrison S, Mugo N, Mujugira A, Nayani V, Ndase P, Nelson K, Newbold T, Panteleeff D, Perera D, Richmond K, Rose A, Shaffer K, Shah H, Sniffen S, Somera D, Stoaks N, Thomas K, Tran C, Wang R, Wang S, Warner-Lubin M, Wilcox E, Wilson C, McKay A, Coetzee D, Kamupira M, de Kock A, Godwana S, Gogo L, Huna J, Khume K, Lee Z, Lindsey S, Mabuto N, Magona P, Makanyiseli M, Makhonza N, Makola N, Mazula Z, Nkompela T, Nkwateni M, Ntshongwana M, Patel S, Tshabalala M, Tshangela L, Tshingana L, Fife K, Were E, Apaka C, Nzioka S, Achieng C, Akhaabi P, Ayuo P, Baliddawa J, Barasa F, Cheruiyot J, Cheruiyot R, Dorothy M, Francis O, Godfrey K, Jaleny O, Kaguiri E, Kamotho H, Kapere C, Kennedy M, Komen A, Kosgei J, Mbowo E, Melli B, Mudogo F, Muga J, Mungai G, Murgor N, Muthui G, Njiru H, Odhiambo C, Ogallo E, Ogolla W, Oketch D, Pierre M, Roseirene M, Rugut J, Saruni J, Sawe J, Seronei S, Sidle J, Simiyu G, Thumbi M, Wafula M, Wamalwa E, Wools-Kaloustian K, Essex M, Makhema J, Ndase P, Dusara-Muzenda P, Owor A, Abel C, Baitseng T, Bome NB, Ekezie C, Hambira R, Iketleng T, Joseph M, Keothepile K, Kgafela M, Kusane A, Madison R, Malamba M, Manyiwa E, Maotwe T, Masike O, Mbazo O, Modise G, Modise G, Mongwa W, Mooketsi U, Mooketsi R, Mosarwe B, Moyo S, Moyo K, Musarira F, Musonda R, Ndungu T, Ntshimane M, Nyawe T, Holme MP, Radinku T, Rammidi K, Sekoto T, Sepako E, Serojane F, Thior I, Widenfelt E, Katabira E, Ronald A, Kavuma L, Bambia F, Brown C, Bulya N, Byabasheija R, Izizinga D, Joloba ML, Kajumba B, Kibuuka E, Kibuuka G, Kikulwe R, Kiranda R, Kirimunda S, Kisekka R, Kizza DM, Kyagaba M, Luzze R, Magala JM, Mugwanya K, Musoke R, Musingunzi AP, Mutyoba J, Muwanguzi J, Muwanguzi P, Nabwire J, Najjta B, Nakanwagi P, Nakku-Joloba E, Nakyanzi A, Namagembe D, Nambi F, Nampala MR, Ntege RP, Odongo P, Okello M, Okwero E, Owor L, Sebikejje R, Ssebbaale A, Tamale ZB, Wasubire J, Allen S, Kayitenkore K, Karita E, Bekan B, Kelley A, Bavana B, Ingabire C, Kabera E, Karangayire P, Linton S, Mudidi E, Mukamuyango J, Mukeshimana J, Mushikiwabo A, Musoni JL, Nsabimana AP, Nshimiyimana A, Nyirabagwiza C, Rufagari J, Sebahungu F, Bukusi E, Cohen C, Nduba V, Odoyo J, Achando J, Achola MA, Adhiambo PP, Adhiambo J, Adipo M, Agot K, Akinyi E, Aluoch AA, Asol F, Bonareri L, Bwoga M, Dacha E, Dola T, Josephine M, Kasyoki J, Kibatha M, Kimani P, Koech D, Kulzer J, Kwach V, Kwena T, Memo LA, Moraa I, Muga C, Mwake P, Mwangi P, Ndichu SN, Ng'oma LA, Njeru E, Nyang'wara L, Nyanjage A, Obiero A, Ochieng D, Ochieng A, Ochuka B, Odera EO, Odhacha J, Odipo C, Odondi J, Odula L, Ogembo S, Ogolo J, Okello D, Okello A, Okeyo R, Okombo M, Okumu LA, Olwenge P, Ombelu FO, Omonge M, Ondiek F, Onyang' J, Onyango P, Onyango B, Ooko H, Opondo C, Orwa J, Osese H, Osir N, Osoo J, Otieno A, Otieno BA, Owiti JA, Raminya J, Rono B, Sharma N, Shiteka R, Wakhungu IN, Wamae N, Wandiga S, Allen S, Kanweka W, Blacher R, Banda A, Beyer A, Bwembya N, Chanda MM, Chanda M, Chibwe H, Chibwe MN, Cluck H, Kaetano L, Kafwaka M, Kapatiso BK, Kasonga W, Kolala I, Lambdin B, Masedza J, Mukuka P, Mulongoti L, Munene C, Musonda GM, Mutiti M, Mutwale D, Namafente C, Ndhlovu J, Nyoni IM, Phiri B, Sakala M, Shah H, Silumesi P, Veal L, Allen S, Vwalika B, Blacher R, Henderson F, Aikayo R, Aikayo F, Besa S, Chitambi A, Chitambi R, Katongo M, Keeling M, Matoba C, Mulenga M, Musonda B, Musonda S, Musulwe L, Mweemba S, Mwila C, Ndhlovu D, Shansonga M, Sharkey T, Shumba H, Kapiga S, Manongi R, Magao P, Imeru A, Swai M, Assenga C, Bamba B, Gonzales AD, Mbwambo MJ, Kessy G, Kidella M, Tillya SM, Makyao H, Maliwa E, Mallya E, Mandao B, Maro V, Maro F, Masaki M, Mbuya E, Bengesi HM, Mlay A, Mosha S, Mrawa M, Mrema H, Mrema G, Msabaa J, Msuya A, Mushi G, Ngilangwa D, Olotu I, Otaru M, Riwa V, Samba T, Tamilwai SS, Temu L, Farquhar C, John-Stewart G, Kiarie J, Tamooh H, Gichuhi S, Kinuthia J, Morrison S, Abkallo H, Akinyi C, Brahmbhatt S, Gitonga E, Idala S, Kamau J, Kamoni R, Karanja J, Kebaara M, Keino S, Keli-Kariithi F, Kibatha M, Kinoti F, Kinyua M, Ludenyo V, Maina S, Makhoha EN, Malubi J, Mose F, Mugo D, Mukundi L, Mulinge L, Mulwa BM, Mureithi J, Mutie L, Mutiso W, Ndungu C, Ngugi M, Nindo F, Njoroge S, Njuguna E, Obara WO, Obuya C, Ogallo J, Okoth NA, Onyanyo R, Opiyo N, Otachi J, Oweya E, Swaleh F, Thiongo A, Timko M, Wachira M, Wafula A, Wairimu M, Wamuyu C, Waweru M, Yegon J, Allen S, Inambao M, Wong F, Bhebhe JB, Chilimboyi K M, Chinyama J, Chinyama L, Chisankuta F, Chileshe P, Cox G, Daka J, Gilbert Y, Kabwe I, Kyakilika E, Linton S, Malauni-Nkhoma P, Maleya C, Masase CH, Mulaisho SC, Mulumbwa W, Mushili T, Mwale M, Shacholi M, Simbala F, Delany-Moretlwe S, 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Campbell MS, Deng W, Raugi D, Sorensen S, Stoddard J, Wong K, Zhao H, Whittington W, Xet-Mull AM, Coombs RW, Dragavon J, Daza G, Ortega JP, Scherrer MC, Corey L, Morrow RA, Kuypers J, Cent A, Diem K, Huang ML, Nguyen P, Pepper G, Sampoleo R, Hayes TS, Selke S, Zimmerman C.
Source
Department of Global Health, University of Washington, Harborview Medical Center, 325 Ninth Ave., Box 359927, Seattle, WA 98104, USA.
Abstract
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.)
2010 Massachusetts Medical Society
- PMID:
- 20089951
- [PubMed - indexed for MEDLINE]
- PMCID:
- PMC2838503
Free PMC ArticleFigure 1Enrollment and Follow-up of Participants
Data are shown for the intention-to-treat cohort, from which the modified intention-to-treat analysis was derived. Seropositivity for HSV-2 at enrollment was determined with the use of the HerpesSelect-2 immunoassay (Focus Technologies) at the site laboratory (a cutoff index value for seropositivity of >3.4 was used to improve specificity [see Laboratory Procedures in the Supplementary Appendix]); inclusion in the primary analysis was based on positive results of Western blotting for HSV-2 performed at the University of Washington (see the Supplementary Appendix). The numbers for follow-up visits include only participants who attended scheduled visits; in the case of partners not infected with HIV-1, visits with HIV-1 tests up to and including the first visit in which a positive HIV-1 test result was recorded were included. The total study populations include all participants who were expected to attend visits (in the case of partners not infected with HIV-1, this included visits up to and including the first visit in which a positive HIV-1 test result was recorded) and reflect a staged close-out of the sites after 12 months. During the follow-up period, three participants who were seropositive for HIV-1 were given a drug kit that was incorrect for their randomization group; the follow-up time for their HIV-1–uninfected partner was censored at that point.
N Engl J Med. 2010 February 4;362(5):427-439.
Figure 3Kaplan-Meier Curves for the Modified Intention-to-Treat Analysis
The cumulative probability of genetically linked transmission of HIV-1 is shown for the two study groups.
N Engl J Med. 2010 February 4;362(5):427-439.
Figure 5Plasma HIV-1 RNA Levels in Participants Infected with HIV-1, According to Study Group
The values represent the mean plasma viral load during the 24-month follow-up period. Enrollment values were adjusted for a difference of 0.12 log10 copies per milliliter in the average plasma HIV-1 RNA level that arose from validating the HIV-1 RNA measurements in the two laboratories that performed the viral load measurements at enrollment and follow-up.
N Engl J Med. 2010 February 4;362(5):427-439.
Figure 2End Points with Respect to Transmission of HIV-1, According to the Study Group, in the Modified Intention-to-Treat and the Intention-to-Treat Populations
The 132 seroconversions to HIV-1 excluded 19 in partners who, during confirmatory testing, were found to be seronegative for HIV-1 (i.e., negative for HIV-1 antibodies) but who were infected with HIV-1 (i.e., positive for HIV-1 RNA) at study enrollment and were infected therefore with HIV-1 before their HIV-1–infected partner received acyclovir or placebo. Determination of linkage for transmission pairs was based on viral sequencing in the partner who was originally infected with HIV-1 and that person's partner who underwent seroconversion to HIV-1; linkage data were reviewed by an expert adjudication committee. The modified intention-to-treat analysis excluded HIV-1 transmissions among male partners who underwent seroconversion when their HIV-1–infected female partners were pregnant and not taking the study drug as specified by the protocol (two in the acyclovir group and four in the placebo group).
N Engl J Med. 2010 February 4;362(5):427-439.
Figure 4HIV-1 Seroconversion Events, Overall and within Subgroups
The intention-to-treat analysis included all HIV-1 transmissions; the modified intention-to-treat analysis included only genetically linked HIV-1 transmissions. Subgroup analyses were performed on the modified intention-to-treat data set. P values are for the effect of acyclovir overall and in subgroup analyses. Hazard ratios less than 1.0 are consistent with a protective effect of acyclovir.
N Engl J Med. 2010 February 4;362(5):427-439.
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