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

Connie Celum, Anna Wald, Jairam R. Lingappa, Amalia S. Magaret, Richard S. Wang, Nelly Mugo, Andrew Mujugira, Jared M. Baeten, James I. Mullins, James P. Hughes, Elizabeth A. Bukusi, Craig R. Cohen, Elly Katabira, Allan Ronald, James Kiarie, Carey Farquhar, Grace John Stewart, Joseph Makhema, Myron Essex, Edwin WereKenneth Fife, Guy De Bruyn, Glenda E. Gray, James A. McIntyre, Rachel Manongi, Saide Kapiga, David Coetzee, Susan Allen, Mumbiana Inambao, Kayitesi Kayitenkore, Etienne Karita, William Kanweka, Sinead Delany, Helen Rees, Bellington Vwalika, Wendy Stevens, Mary S. Campbell, Katherine K. Thomas, Roberts W. Coombs, Rhoda Morrow, William L H Whittington, M. Juliana McElrath, Linda Barnes, Renee Ridzon, Lawrence Corey

Research output: Contribution to journalArticle

387 Citations (Scopus)

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, ≥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 log10 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.).

Original languageEnglish
Pages (from-to)427-439
Number of pages13
JournalNew England Journal of Medicine
Volume362
Issue number5
DOIs
StatePublished - Feb 4 2010

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Human Herpesvirus 2
Acyclovir
HIV-1
Confidence Intervals
CD4 Lymphocyte Count
Ulcer
Placebos
Therapeutics
Random Allocation

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Celum, C., Wald, A., Lingappa, J. R., Magaret, A. S., Wang, R. S., Mugo, N., ... Corey, L. (2010). Acyclovir and transmission of HIV-1 from persons infected with HIV-1 and HSV-2. New England Journal of Medicine, 362(5), 427-439. https://doi.org/10.1056/NEJMoa0904849

Acyclovir and transmission of HIV-1 from persons infected with HIV-1 and HSV-2. / Celum, Connie; Wald, Anna; Lingappa, Jairam R.; Magaret, Amalia S.; Wang, Richard S.; Mugo, Nelly; Mujugira, Andrew; Baeten, Jared M.; Mullins, James I.; Hughes, James P.; Bukusi, Elizabeth A.; Cohen, Craig R.; Katabira, Elly; Ronald, Allan; Kiarie, James; Farquhar, Carey; Stewart, Grace John; Makhema, Joseph; Essex, Myron; Were, Edwin; Fife, Kenneth; De Bruyn, Guy; Gray, Glenda E.; McIntyre, James A.; Manongi, Rachel; Kapiga, Saide; Coetzee, David; Allen, Susan; Inambao, Mumbiana; Kayitenkore, Kayitesi; Karita, Etienne; Kanweka, William; Delany, Sinead; Rees, Helen; Vwalika, Bellington; Stevens, Wendy; Campbell, Mary S.; Thomas, Katherine K.; Coombs, Roberts W.; Morrow, Rhoda; Whittington, William L H; McElrath, M. Juliana; Barnes, Linda; Ridzon, Renee; Corey, Lawrence.

In: New England Journal of Medicine, Vol. 362, No. 5, 04.02.2010, p. 427-439.

Research output: Contribution to journalArticle

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, K, 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, WLH, McElrath, MJ, Barnes, L, Ridzon, R & Corey, L 2010, 'Acyclovir and transmission of HIV-1 from persons infected with HIV-1 and HSV-2', New England Journal of Medicine, vol. 362, no. 5, pp. 427-439. https://doi.org/10.1056/NEJMoa0904849
Celum, Connie ; Wald, Anna ; Lingappa, Jairam R. ; Magaret, Amalia S. ; Wang, Richard S. ; Mugo, Nelly ; Mujugira, Andrew ; Baeten, Jared M. ; Mullins, James I. ; Hughes, James P. ; Bukusi, Elizabeth A. ; Cohen, Craig R. ; Katabira, Elly ; Ronald, Allan ; Kiarie, James ; Farquhar, Carey ; Stewart, Grace John ; Makhema, Joseph ; Essex, Myron ; Were, Edwin ; Fife, Kenneth ; De Bruyn, Guy ; Gray, Glenda E. ; McIntyre, James A. ; Manongi, Rachel ; Kapiga, Saide ; Coetzee, David ; Allen, Susan ; Inambao, Mumbiana ; Kayitenkore, Kayitesi ; Karita, Etienne ; Kanweka, William ; Delany, Sinead ; Rees, Helen ; Vwalika, Bellington ; Stevens, Wendy ; Campbell, Mary S. ; Thomas, Katherine K. ; Coombs, Roberts W. ; Morrow, Rhoda ; Whittington, William L H ; McElrath, M. Juliana ; Barnes, Linda ; Ridzon, Renee ; Corey, Lawrence. / Acyclovir and transmission of HIV-1 from persons infected with HIV-1 and HSV-2. In: New England Journal of Medicine. 2010 ; Vol. 362, No. 5. pp. 427-439.
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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, ≥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 log10 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.).",
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T1 - Acyclovir and transmission of HIV-1 from persons infected with HIV-1 and HSV-2

AU - Celum, Connie

AU - Wald, Anna

AU - Lingappa, Jairam R.

AU - Magaret, Amalia S.

AU - Wang, Richard S.

AU - Mugo, Nelly

AU - Mujugira, Andrew

AU - Baeten, Jared M.

AU - Mullins, James I.

AU - Hughes, James P.

AU - Bukusi, Elizabeth A.

AU - Cohen, Craig R.

AU - Katabira, Elly

AU - Ronald, Allan

AU - Kiarie, James

AU - Farquhar, Carey

AU - Stewart, Grace John

AU - Makhema, Joseph

AU - Essex, Myron

AU - Were, Edwin

AU - Fife, Kenneth

AU - De Bruyn, Guy

AU - Gray, Glenda E.

AU - McIntyre, James A.

AU - Manongi, Rachel

AU - Kapiga, Saide

AU - Coetzee, David

AU - Allen, Susan

AU - Inambao, Mumbiana

AU - Kayitenkore, Kayitesi

AU - Karita, Etienne

AU - Kanweka, William

AU - Delany, Sinead

AU - Rees, Helen

AU - Vwalika, Bellington

AU - Stevens, Wendy

AU - Campbell, Mary S.

AU - Thomas, Katherine K.

AU - Coombs, Roberts W.

AU - Morrow, Rhoda

AU - Whittington, William L H

AU - McElrath, M. Juliana

AU - Barnes, Linda

AU - Ridzon, Renee

AU - Corey, Lawrence

PY - 2010/2/4

Y1 - 2010/2/4

N2 - 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, ≥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 log10 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.).

AB - 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, ≥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 log10 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.).

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