To the Editor: Nagot et al. (Feb. 22 issue)1 report that treatmentwith valacyclovir (1 g per day) to suppress herpes simplex virus(HSV) reduced human immunodeficiency virus type 1 (HIV-1) RNAlevels in patients in Burkina Faso. This finding raises importantquestions regarding the clinical management of HSV infectionin poor countries. Of the 68 patients receiving valacyclovir,3 (4%) had at least one episode of vesicular or genital ulcerationduring the study period. In another trial,2 which showed a reductionof recurrences of HSV type 2 (HSV-2) with valacyclovir (1 gper day) in HIV-infected patients, 3 (6%) of the 50 HSV-2 isolatescollected were resistant to acyclovir. In Western countries,5 to 6% of the HSV-2 isolates from patients with immunosuppressionare resistant to acyclovir.3 Treatment of such patients is challengingand may require intravenous foscarnet or cidofovir. However,none of these drugs are routinely available in poor countriessuch as Burkina Faso. The risk of emergence of resistant HSVstrains raises important questions that must be considered.
Valérie Martinez, M.D. Eric Caumes, M.D. Groupe Hospitalier Pitié–Salpétrière 75013 Paris, France eric.caumes{at}psl.aphp.fr
References
Nagot N, Ouédraogo A, Foulongne V, et al. Reduction of HIV-1 RNA levels with therapy to suppress herpes simplex virus. N Engl J Med 2007;356:790-799. [Free Full Text]
DeJesus A, Wald T, Warren T, et al. Valacyclovir for the suppression of recurrent genital herpes in human immunodeficiency virus-infected subjects. J Infect Dis 2003;188:1009-1016. [Erratum, J Infect Dis 2003;188:1404.] [CrossRef][Web of Science][Medline]
Tyring SK, Baker D, Snowden W. Valacyclovir for herpes simplex virus infection: long-term safety and sustained efficacy after 20 years' experience with acyclovir. J Infect Dis 2002;186:Suppl 1:S40-S46. [CrossRef][Web of Science][Medline]
To the Editor: In the study by Nagot et al., which showed thattreatment with valacyclovir for HSV infection was associatedwith a reduction in HIV viral load in plasma and the genitaltract, the viral load at baseline was higher in the placebogroup, and the statistical analysis accounted for this factor.However, there was also an increase in the HIV viral load inthe placebo group during the study, and most of the evolvingdifference in viral load between the study groups during treatmentmay have been due to the increase in the placebo group. Thisincrease, in turn, may have been due to other (e.g., gastrointestinal)infections and HIV-unrelated gastrointestinal disorders. (Diarrhea,vomiting, dysphagia, and constipation were reported in 26 patientsin the placebo group vs. 13 in the valacyclovir group; P=0.02.)Breach of the gastrointestinal epithelial barrier with the associatedtranslocation of products of enteric bacteria such as lipopolysaccharideand butyrate1,2 has been associated with systemic immune activation,which amplifies replication of HIV through nuclear factor-B–mediatedstimulation of long terminal repeats induced by tumor necrosisfactor. In future studies, investigators will need to consideradjusting analyses for other concomitant infections, such asthose affecting the gastrointestinal tract, that fuel HIV replication.
Michael Eisenhut, M.D. Luton and Dunstable Hospital National Health Service Foundation Trust Luton LU40DZ, United Kingdom michael_eisenhut{at}yahoo.com
References
Brenchley JM, Price DA, Schacker TW, et al. Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nat Med 2006;12:1365-1371. [Web of Science][Medline]
Stein TP, Koerner B, Schluter MD, et al. Weight loss, the gut and the inflammatory response in AIDS patients. Cytokine 1997;9:143-147. [CrossRef][Web of Science][Medline]
The authors reply: Our study was a proof-of-concept trial andso did not allow prediction of the effect of HSV suppressivetherapy as a public health intervention to prevent the transmissionof HIV. Available data regarding resistance to acyclovir arereassuring. The occurrence of acyclovir-resistant HSV-2 strainsin HIV-infected patients (4 to 7%) has not increased duringthe past two decades in Western countries, despite the frequentuse of acyclovir and valacyclovir.1 Instead, resistance to acyclovircould be declining, since the use of highly active antiretroviraltherapy has become widespread.2 When such resistance occurs,it is not predictive of clinical failure.3 In addition, theoccurrence of genital ulceration during the course of HSV suppressivetherapy does not necessarily mean that the causative strainis resistant to acyclovir. We agree that in the absence of second-linetherapy in resource-constrained countries (and considering thepaucity of data available to date), the importance of resistanceto acyclovir should be investigated further. However, even ifsuch resistance is confirmed, it is unlikely to counterbalancethe potential positive effect of HSV suppressive therapy onHIV-1 disease progression and transmission.
The HIV-1 plasma viral load in the placebo group increased slightlyduring our study, but we doubt this rise was due to HIV-unrelatedgastrointestinal diseases. Several women reported having morethan one symptom, so the P value calculated by Dr. Eisenhutneeds modification. In fact, the proportion of women who reportedat least one gastrointestinal symptom tended to be higher inthe placebo group (38.2%) than in the valacyclovir group (25.0%)but without reaching statistical significance (P=0.10). Valacyclovirand acyclovir have been used for decades with a safety profilesimilar to that of placebo.4 The hypothesis by Brenchley etal.5 that a sustained systemic immune activation is fueled byintestinal bacteria through a translocation mechanism is basedon the commensal enteric flora and not on pathogens. It is unlikelythat this mechanism could be altered or enhanced by the intakeof valacyclovir. It should also be noted that our primary outcomewas genital HIV viral load, and there was little differencein this outcome in the placebo group before randomization andafter randomization (mean number of log10 copies per milliliter,2.97 and 3.02, respectively).
Nicolas Nagot, M.D. Helen Weiss, Ph.D. London School of Hygiene and Tropical Medicine London WC1E 7HT, United Kingdom n_nagot{at}hotmail.com
Philippe Van de Perre, M.D., Ph.D. University Hospital of Montpellier 34295 Montpellier, France
References
Bacon TH, Levin MJ, Leary JJ, Sarisky RT, Sutton D. Herpes simplex virus resistance to acyclovir and penciclovir after two decades of antiviral therapy. Clin Microbiol Rev 2003;16:114-128. [Free Full Text]
Corey L, Wald A, Celum CL, Quinn TC. The effects of herpes simplex virus-2 on HIV-1 acquisition and transmission: a review of two overlapping epidemics. J Acquir Immune Defic Syndr 2004;35:435-445. [CrossRef][Web of Science][Medline]
Lehrman SN, Douglas JM, Corey L, Barry DW. Recurrent genital herpes and suppressive oral acyclovir therapy: relation between clinical outcome and in-vitro drug sensitivity. Ann Intern Med 1986;104:786-790. [Free Full Text]
Tyring SK, Baker D, Snowden W. Valacyclovir for herpes simplex virus infection: long-term safety and sustained efficacy after 20 years' experience with acyclovir. J Infect Dis 2002;186:Suppl 1:S40-S46. [CrossRef][Web of Science][Medline]
Brenchley JM, Price DA, Schacker TW, et al. Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nat Med 2006;12:1365-1371. [Web of Science][Medline]
B–mediated stimulation of long terminal repeats induced by tumor necrosis factor. In future studies, investigators will need to consider adjusting analyses for other concomitant infections, such as those affecting the gastrointestinal tract, that fuel HIV replication. 
Previous
