No new treatments in 20 years
Genital herpes is caused by the herpes simplex virus, usually the type called HSV-2. Lifelong and incurable, it is one of the most frequent sexually transmitted infections worldwide. There have been no new treatments in 20 years.
The next step, Wald said, is to continue testing pritelivir to assess its safety. Although the clinical trials conducted so far in humans have shown no serious side effects, the U.S. Food and Drug Administration put a hold on the drug’s clinical use in 2013 because of skin and blood abnormalities shown in a concurrent animal trial. The hold came while the study published today was underway, forcing it to end early.
The German drug maker AiCuris is working with the FDA to partially lift the hold so that pritelivir can be tested in a new clinical trial on patients who are resistant to drugs in the acyclovir family, which include acyclovir, famciclovir and valacyclovir.
“I hope that if the trial for acyclovir-resistant HSV goes well, we would be able to go back to the general population with further trials,” Wald said. “It’s important to develop new drugs for this incredibly common infection.”
In the U.S., an estimated 16 percent of adults between ages 14 and 49 are infected with HSV-2. The virus spreads through skin-to-skin contact during vaginal or anal sex and can cause painful genital and anal lesions. (Another herpes simplex virus, HSV-1, usually causes cold sores on the lips but can be transmitted through oral sex and cause genital lesions as well.)
The virus can be passed to newborns and cause serious illness or death. In people with suppressed immune systems, such as those undergoing chemotherapy or other cancer treatments, sores can be severe. And HSV-2 infection can increase the risk of getting or transmitting HIV. In sub-Saharan Africa, HSV-2 is one of the main drivers of the HIV pandemic, Wald said.
Once a person is infected, the virus persists in a dormant state, hiding out in nerve cells but frequently reactivating. One of the tricky things about genital herpes is that rapid viral expansion resulting in high viral loads can occur before a sore is visible or without symptoms at all. So even if people avoid sex during visible outbreaks they still spread or contract the virus.
Condoms can lower, but not eliminate, the risk of transmission. Treatment by drugs in the acyclovir family can treat symptoms and — if taken daily — suppress new symptom outbreaks and reduce transmission, but only by about 50 percent.
“Having a new medication would definitely give people more options,” said «Dex,» who created and runs an online community for people with herpes and who, like many on the site, prefers to be identified only by his screen name. “The current options don’t always provide the relief needed. If anything, having new competition might even drive the price down. Unless you have insurance, prescriptions are expensive.”
Pritelivir is in a different class than the older herpes antivirals and acts in a different way. The earlier study, also by Wald and published in the New England Journal of Medicine in 2014, was a small, phase 1 trial testing pritelivir against a placebo to determine safe dosage and identify any side effects.
‘Encouraging’ results, but more trials needed
The new study was conducted in four U.S. cities between October 2012 and July 2013. It was a “crossover” trial, meaning that rather than one group receiving only pritelivir and the other only valacyclovir, each participant received both drugs sequentially for 28 days, with a “washout” period of 28 days in between to make sure the drug taken first was fully eliminated. Because the viral shedding rate is highly variable from person to person but relatively stable within the same person, the trial was designed to compare the two drugs within rather than between people. The order in which the drugs were given was assigned randomly, and neither participants nor researchers knew which drug was given when — considered the “gold standard” of clinical trial design.
Fifty-six participants had completed both treatment periods when the study was terminated due to the FDA hold. Throughout treatment, the participants collected genital swabs four times daily for testing.
HSV was detected in 2.4 percent of swabs during pritelivir treatment compared with 5.3 percent of swabs during valacylovir treatment. Genital lesions were reported on 1.9 percent of days during pritelivir treatment compared with 3.9 percent of days on valacyclovir. The proportion of days with pain was 4 percent with pritelivir and 6.7 percent while taking valacyclovir.
Wald called the results “encouraging.”
“It means we can do better,” she said. “Pritelivir probably is better than valacyclovir, but we need more work on it to understand the safety concerns that have emerged in the animals.”
Pritelivir is under development by AiCuris, which funded the trial.
Other authors on the paper included Fred Hutch researchers Drs. Amalia Magaret and Larry Corey. In the 1980s, Corey worked with biochemist Trudy Elion to show that acyclovir, a then-new type of drug invented by Elion, could control and suppress a viral infection. Acyclovir and its successors had a huge impact, reducing mortality rates for babies born with herpes from 80 to 10 percent. Corey — who went on to found and head the international Fred Hutch-based HIV Vaccine Trials Network — and Wald also studied the daily use of antiretrovirals to prevent herpes transmission.