HIV Treatment Bulletin - November 2003
Graham McKerrow, HIV i-Base

Valacyclovir is a more effective prophylaxis than acyclovir against recurrent herpes simplex in HIV-positive people, according to an international placebo-controlled trial.

The study could have significant influence on clinical practice because the researchers conclude that they have established an important treatment option for the management of genital herpes in HIV-positive patients, in the form of a convenient, twice-daily regimen that is well-tolerated.

Intravenous administration of acyclovir has previously been shown to be effective against mucocutaneous herpes in profoundly immunocompromised patients, and oral acyclovir has been shown to suppress genital herpes in a healthy population. Valacyclovir was developed to improve the bioavaliablity of acyclovir.

Two hundred and ninety-three positive subjects on stable antiretroviral regimens, with histories of symptomatic recurrent genital herpes, were enroled in the randomised, double blind, placebo-controlled, multicentre trial in the United States, Canada and the United Kingdom.

The trial compared valacycolvir administered at 500mg twice daily with placebo, and was conducted between May 1999 and January 2002. Subjects were randomised in a 2:1 allocation (valacyclovir to placebo) to receive treatment for up to six months. They were instructed to return to the clinic monthly and at first recurrence of genital herpes. Study drug was discontinued for subjects with clinically confirmed recurrence and they were treated with valacyclovir (1g twice daily) until they were healed. After treatment, they resumed suppressive therapy with open-label valacyclovir.

Of the 231 subjects who completed the study, 89 had a recurrence of genital herpes during the double blind phase of the study: 56/99 (57%) in the placebo group and 33/134 (17%) in the valacyclovir group. The proportion of subjects who had no recurrence of genital herpes at six months was significantly higher in the valacyclovir group than in the placebo group: 65% versus 26% (relative risk 2.5, 95% confidence interval [CI], 1.8-3.5).

The time to first recurrence of genital herpes was a median 59 days in the placebo group, compared with a median >180 days in the valacyclovir group (hazard ratio [HR] 5.0, 95% CI, 3.30-7.7).

Fifteen per cent (15/99) of subjects who received placebo, compared with 4% (8/194) of subjects who received acyclovir, reported a recurrence of oral herpes during the study.

Adverse event rates per exposure day were similar between treatment groups during the double blind phase: 2.2% for the placebo and 2.0% for valacyclovir; and a Kaplan-Meier plot of the time to first adverse event demonstrated a similar incidence in adverse events over time. Three serious adverse events, all in the same subject, were considered to be attributable to valacyclovir.

Fifty HSV-2 isolates were obtained from 48 subjects who had recurrence of genital herpes (but no pretreatment isolates were collected and no HSV –1 was isolated from genital specimens) and acyclovir resistance isolates were identified in three subjects (6.0%), all of whom had CDC stage C HIV disease. Two subjects in the valacyclovir group had a recurrence of genital herpes caused by a resistant isolate after three and 10 weeks respectively, of valacyclovir. One of these had received suppressive antiherpetic therapy, for about one year prior to the study. The third subject, who was in the placebo group but had received suppressive antiherpetic therapy for about four years prior to study entry, had a recurrence of genital herpes caused by a sensitive isolate after four weeks of doubleblind medication and a second recurrence caused by a resistant isolate after about 18 weeks of open label valacyclovir. All three people responded to a five day course of valacyclovir (1g twice daily).

In their discussion, the authors write: “It is believed that most physicians and patients will be reluctant to initiate long-term suppressive therapy for a low recurrence rate of one or two outbreaks per year. A rate of three or more recurrences per year would probably more resemble the use of long-term suppressive therapy in clinical practice. To increase the probability of reaching an end-point in our six-month study, subjects were required to have had a history of four or more recurrences during the previous year. In addition, when considering patients for suppressive therapy in clinical practice, the decision should not be based on the frequency of recurrences alone. The severity of recurrences and the potential for the activation of HIV in this patient group are also important factors.”

Ref: DeJesus E, Wald A, Warren T et al. Valacyclovir for the suppression of recurrent genital herpes in human immunodeficiency virus infected subjects. The J Infect Dis. 2003 Oct 1;188(7):1009-16.

Comment

Although a head-to-head study has not been performed against acyclovir, valacyclovir has several advantages over acyclovir. It requires fewer pills and is potentially more effective, but is also more expensive than off-patent acyclovir.

Valacyclovir is also active against HIV–associated oral hairy leukoplakia (HLP) and Epstein-Barr virus (EBV) - See J Infect Dis. 2003 Sep 15;188(6):883-90.

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