Correspondence

HSV-2 Suppression and the Incidence of HIV

N Engl J Med 2008; 359:535July 31, 2008

Article

To the Editor:

Watson-Jones et al. (April 10 issue)1 report that the suppression of herpes simplex virus type 2 (HSV-2) does not decrease the incidence of human immunodeficiency virus (HIV) infection in female workers at recreational facilities in northwestern Tanzania. However, this finding is disputable, since treatment with 400 mg of acyclovir twice daily did not suppress the incidence of HSV-2 infection. Any conclusion regarding the preventive effect of acyclovir should be based on the analysis of patients in whom the drug was detected, since the study is confounded because a majority of patients in the acyclovir group tested negative for acyclovir (>65%) at both 12 months and 24 months. Similarly, the data on HIV acquisition should be evaluated according to the suppression of the HSV-2 viral load, as compared with baseline. We believe that the study's methodologic limitations prevent drawing any conclusions about the effect of acyclovir on HIV acquisition.2

Andrea Lisco, M.D., Ph.D.
Christophe Vanpouille, Ph.D.
Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD 20892
liscoa@mail.nih.gov

2 References

1. 1

   Watson-Jones D, Weiss HA, Rusizoka M, et al. Effect of herpes simplex suppression on incidence of HIV among women in Tanzania. N Engl J Med 2008;358:1560-1571
   Full Text | Web of Science | Medline

2. 2

   Cohen J. AIDS research: promising prevention interventions perform poorly in trials. Science 2007;317:440-440
   CrossRef | Web of Science | Medline

Author/Editor Response

We do not conclude that HSV-2 suppression is ineffective in the prevention of HIV acquisition but rather that suppressive therapy did not reduce the incidence of HIV acquisition in our study population. Despite intensive adherence support, study participants found it difficult to adhere to twice-daily use of acyclovir over a prolonged period. This finding is important, since it shows the limitations of this intervention as a practical measure in HIV control. Our results have been confirmed by a further trial showing no effect of acyclovir therapy on HIV incidence.1

Lisco and Vanpouille suggest that we should have restricted our analysis to patients in whom acyclovir was detected. Urine testing for acyclovir was done as a process measure in a small sample of subjects at selected time points. The presence of acyclovir at one time point is not a proxy for overall adherence during the trial. Similarly, HSV-2 shedding was measured only at certain visits, and there were too few subjects with shedding to conduct a subgroup analysis of HIV incidence. In any case, such analyses would have been subject to severe confounding, since an equivalent restriction would not have been possible in the placebo group, thus resulting in loss of the comparability provided by randomization.

Deborah Watson-Jones, M.D., Ph.D.
Helen A. Weiss, Ph.D.
Richard Hayes, D.Sc.
London School of Hygiene and Tropical Medicine, London WC1E 7HT, United Kingdom
deborah.watson-jones@lshtm.ac.uk

1 References

1. 1

   Celum C, Wald A, Hughes J, et al. Effect of acyclovir on HIV-1 acquisition in herpes simplex virus 2 seropositive women and men who have sex with men: a randomised, double-blind, placebo-controlled trial. Lancet 2008;371:2109-2119
   CrossRef | Web of Science | Medline

Citing Articles (4)

Citing Articles

1. 1

   Andrea Lisco, Christophe Vanpouille, Leonid Margolis. (2009) A missed point in deciphering the viral synergy between herpes simplex virus and HIV. The Lancet Infectious Diseases 9:9, 522-523
   CrossRef

2. 2

   SJ van Hal, DE Dwyer. 2009. Herpes Simplex: Viruses and Infections. .
   CrossRef

3. 3

   Christophe Vanpouille, Andrea Lisco, Leonid Margolis. (2009) Off-label indication: acyclovir as an anti-HIV drug?. Future Virology 4:1, 1-5
   CrossRef

4. 4

   Andrea Lisco, Christophe Vanpouille, Egor P. Tchesnokov, Jean-Charles Grivel, Angélique Biancotto, Beda Brichacek, Julie Elliott, Emilie Fromentin, Robin Shattock, Peter Anton, Robert Gorelick, Jan Balzarini, Christopher McGuigan, Marco Derudas, Matthias Götte, Raymond F. Schinazi, Leonid Margolis. (2008) Acyclovir Is Activated into a HIV-1 Reverse Transcriptase Inhibitor in Herpesvirus-Infected Human Tissues. Cell Host & Microbe 4:3, 260-270
   CrossRef