Tenofovir, Used to Combat HIV, Also Acts on Herpes

Having genital herpes (HSV) increases the risk that someone will contract or spread HIV during sexual intercourse, and it also can lead to worse health outcomes for those already infected with HIV. Because herpes is a cofactor for HIV, scientists are eager to develop strategies that will target both HIV and HSV in one fell swoop.

Several clinical trials investigating tenofovir for the prevention of HIV and HSV have been conducted, with varying results. The CAPRISA 004 study found that a vaginal microbicide gel containing tenofovir reduced HIV acquisition by 39% and reduced HSV acquisition by 51%. The VOICE study, which utilized oral tenofovir as well as vaginal microbicide gel, was halted ahead of schedule due to an inability to show that tenofovir reduced disease transmission rates, possibly due to low adherence. Two other studies that had subjects take a form of tenofovir were unable to demonstrate a reduction in transmission rates for HIV and HSV.

These mixed clinical results led a group of Belgian researchers to conduct an in vitro trial to see how tenofovir (a first-line candidate against HIV) and PMEO-DAPy (an investigational antiviral agent) affected the herpes virus.

“Tenofovir inhibits the action of the enzyme reverse transcriptase in HIV, but HSV does not have that enzyme so the drug must be affecting something else,” Contagion ^® Editorial Board Member Kirk E. Hevener, PharmD, PhD, assistant professor in the Department of Pharmaceutical Sciences at the University of Tennessee, College of Pharmacy in Memphis, who was not part of the study, told Contagion ^®. “The team hypothesized that the target of these drugs in HSV was the DNA polymerase enzyme, a common HSV drug target. To prove this, they exposed human embryonic lung cells infected with the herpes virus to both drugs. The selective pressure resulted in the emergence of resistant viral mutants.”

The scientists then performed sequencing on the gene encoding the HSV DNA polymerase enzyme in the mutants to show that the resistance was due to amino acid changes (mutations) in the DNA polymerase enzyme that impacted the drugs’ ability to bind to the enzyme. “They confirmed this by testing both drugs against the lab- and clinic-derived viruses with known DNA polymerase mutations to show that the two drugs were also less effective against these,” Dr. Hevener said.

The scientific community is eager to come up with new strategies that can prevent both viruses in humans. “Genital herpes, a highly prevalent sexually transmitted disease, is recognized as one of the most common causes of genital ulcers in developed and developing countries,” the authors wrote. However, while herpes presents its own risks, one of its most insidious aspects is its association with HIV. “Because infection with HSV-2 has been associated with an increased risk for HIV-1 infection and often worsen(s) the clinical outcome of HIV disease, strategies to prevent transmission of both HIV-1 and HSV are highly desirable,” the authors wrote.

The researchers noted that because clinical study subjects seem to have difficulty adhering to a regimen that includes microbicide gels, scientists are in the early stages of developing intravaginal rings that offer easy delivery of tenofovir. More work is needed, however. “Taking into account that the target of all approved anti-HSV drugs is the DNA pol[ymerase] and that a single mutation in this viral enzyme may confer resistance to many anti-HSV drugs, there is an urgent need to develop novel classes of anti-HSV drugs,” they wrote.

While this study is encouraging, the fact that it was conducted in vitro does not necessarily translate to success in human subjects. “There is no evidence provided here that inhibiting HSV by these drugs translates into clinical efficacy,” Dr. Hevener said.

He also pointed out that the study team could have gone further than sequencing only the enzyme DNA polymerase under the assumption that this was the drugs’ target: “It did turn out to have mutations in the HSV resistant virus, so they were probably right, but they should have confirmed this by sequencing the rest of the virus’ genome to make sure there were no mutations elsewhere—which could indicate another possible drug target. I suspect we’ll be seeing some follow-up studies on this soon.”

Laurie Saloman, MS, is a health writer with more than 20 years of experience working for both consumer- and physician-focused publications. She is a graduate of Brandeis University and the Medill School of Journalism at Northwestern University. She lives in New Jersey with her family.