To the Editor: Watson-Jones et al. (April 10 issue)1 reportthat 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 facilitiesin northwestern Tanzania. However, this finding is disputable,since treatment with 400 mg of acyclovir twice daily did notsuppress the incidence of HSV-2 infection. Any conclusion regardingthe preventive effect of acyclovir should be based on the analysisof patients in whom the drug was detected, since the study isconfounded because a majority of patients in the acyclovir grouptested negative for acyclovir (>65%) at both 12 months and24 months. Similarly, the data on HIV acquisition should beevaluated according to the suppression of the HSV-2 viral load,as compared with baseline. We believe that the study's methodologiclimitations prevent drawing any conclusions about the effectof 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{at}mail.nih.gov
References
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. [Free Full Text]
Cohen J. AIDS research: promising prevention interventions perform poorly in trials. Science 2007;317:440-440. [Free Full Text]
The authors reply: We do not conclude that HSV-2 suppressionis ineffective in the prevention of HIV acquisition but ratherthat suppressive therapy did not reduce the incidence of HIVacquisition in our study population. Despite intensive adherencesupport, study participants found it difficult to adhere totwice-daily use of acyclovir over a prolonged period. This findingis important, since it shows the limitations of this interventionas a practical measure in HIV control. Our results have beenconfirmed by a further trial showing no effect of acyclovirtherapy on HIV incidence.1
Lisco and Vanpouille suggest that we should have restrictedour analysis to patients in whom acyclovir was detected. Urinetesting for acyclovir was done as a process measure in a smallsample of subjects at selected time points. The presence ofacyclovir at one time point is not a proxy for overall adherenceduring the trial. Similarly, HSV-2 shedding was measured onlyat certain visits, and there were too few subjects with sheddingto 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 possiblein the placebo group, thus resulting in loss of the comparabilityprovided by randomization.
Deborah Watson-Jones, M.D., Ph.D. Helen A. Weiss, Ph.D. RichardHayes, D.Sc. London School of Hygiene and Tropical Medicine London WC1E 7HT, United Kingdom deborah.watson-jones{at}lshtm.ac.uk
References
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][ISI][Medline]
McMahon, M. A., Siliciano, J. D., Lai, J., Liu, J. O., Stivers, J. T., Siliciano, R. F., Kohli, R. M.
(2008). The Antiherpetic Drug Acyclovir Inhibits HIV Replication and Selects the V75I Reverse Transcriptase Multidrug Resistance Mutation. J. Biol. Chem.
283: 31289-31293
[Abstract][Full Text]
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