Aciclovir shows lower efficacy outside US in global trial

Michael Carter
Published: 19 March 2010

Aciclovir’s efficacy in preventing genital ulcers and lowering herpes simplex virus-2 load varied significantly between the US and resource poor countries, investigators from a large international clinical trial report in the April 15th edition of the Journal of Infectious Diseases.

The randomised study showed that individuals taking aciclovir were less likely to develop genital ulcers than those who received the placebo. In addition, when ulcers did develop, herpes simplex virus-2 (HSV-2) load was lower amongst patients taking aciclovir.

But there were important regional differences. Gay and other men who have sex with men recruited to the study in the US were less likely to develop genital ulcers and have lower HSV-2 load than individuals recruited in the study’s two other research regions: Peruvian men who have sex with men and African women.

HSV-2 is the most common cause of genital ulcer disease, and this has been associated with a significantly increased risk of acquisition of HIV. Genital herpes is commonly treated with aciclovir (known as acyclovir in the United States).

Randomised placebo-controlled trials were recently undertaken to see if preventative HSV-2 therapy, consisting of 400 mg of aciclovir twice-daily, reduced the risk of HIV infection. The trials failed to show any protective effect.

One of the studies, the HIV Prevention Trials Network 039 trial, also examined the efficacy of aciclovir at preventing genital ulcer disease and lowering HSV-2 load in ulcers when they did occur.

A total of 3127 HIV-negative individuals were included in the study. They were recruited from three regions: 459 gay and other men who have sex with men in the US; 1335 gay and other men who have sex with men in Peru; and 1358 women in Africa.

At baseline, 29% of patients in the US, 17% of patients in Peru and 33% of African patients reported anogenital lesions in the previous three months.

During the 18 months of the study, 29% of patients were diagnosed with genital ulcers after physical examination, with a total of 1664 episodes of the disease being recorded.

Treatment with aciclovir reduced the rate of genital ulcers. The number of cases was 55 per 100 person years amongst those receiving the placebo compared to 30 per 100 person-years amongst those taking aciclovir.

However, regional differences were apparent.

In the US, the rate was 53 cases per 100 person years for the placebo versus 15 per 100 person-years for aciclovir. In Peru, the placebo rate was 34 cases per 100 person-years compared to 16 per 100 cases for those treated with aciclovir. For African women, the rate was 75 cases per 100 person-years in the placebo arm and 46 cases per 100 person-years in the treatment arm.

Overall, aciclovir was associated with a 47% reduction in incidence of genital reductions. For US men the reduction was 77%, compared to a 53% reduction for men in Peru and a 39% reduction for African women. This difference was significant (p < 0.001).

The investigators then looked at HSV-2 viral load in 1468 swab specimens collected from genital ulcers.

They found that the swabs taken from the ulcers of those who were taking aciclovir were significantly less likely to contain detectable HSV-2 than those collected from patients who received the placebo (p < 0.001).

But once again there were regional differences.

Overall, taking aciclovir reduced the risk of genital ulcers having detectable HSV-2 by 63%. The greatest reduction was seen in the US (88%), followed by Peru (61%) and Africa (57%).

There were also regional differences in the reductions of HSV-2 load in ulcers achieved by aciclovir therapy.

Consistent with the other study findings, the biggest drops were seen in the US (1.07 log10, p = 0.004), followed by Peru (0.68 log10, p = 0.04), and Africa (0.32 log10, p = 0.05).

These regional differences persisted when the researchers restricted their analysis to patients with at least 90% adherence.

“Possible explanations for the lower efficacy of aciclovir on genital ulcer disease-associated HSV-2 shedding outside the United States, particularly in Africa, include strain variation, resulting in inherent aciclovir resistance among HSV strains from Africa, or unappreciated differences in aciclovir absorption or pharmacokinetics,” write the investigators. “Detailed studies with frequent assessment of genital shedding combined with drug level evaluation may elucidate the mechanisms underlying our observations.”

Reference

Fuchs J et al. Clinical and virologic efficacy of herpes simplex virus type 2 suppression by acyclovir in a multicontinent clinical trial. J Infect Dis 201: 1164-68, 2010.

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