Let’s talk about herpes. To start, if you get genital herpes, you will have it for a lifetime; currently there is no cure. Anti-viral therapy — valacyclovir or famciclovir, both nucleoside DNA polymerase inhibitors — can reduce the frequency and severity of clinical recurrences and have been the standard of care for years. These drugs decrease but do not completely prevent viral shedding, so sexual partners remain at risk. Antiviral resistance may also develop.
A new treatment could change the outlook for genital herpes management. Pritelivir is a first-in-class inhibitor of the herpes helicase-primase complex, which means it can block DNA replication even in patients with resistance to the nucleoside analogues. This week in NEJM, Wald et al. report findings from an innovative study investigating the efficacy of pritelivir as compared to placebo. The results carry important implications for both the treatment of genital herpes and the design of future research.
In this proof-of-concept study, 156 patients with a history of genital herpes and annual clinical recurrences were randomized to receive four weeks of either placebo or pritelivir at one of four possible doses (5, 25, or 75 mg daily; or 400 mg weekly). The goal was to determine the safety and efficacy of pritelivir for reducing viral shedding, as well as the optimal dose. The study design was labor-intensive: daily swabs of genital skin, mucosa, and any lesions were tested by polymerase chain reaction (PCR) for herpes simplex virus (HSV). Patients also kept a diary of signs and symptoms.
The study found that for both men and women, pritelivir reduced the likelihood of genital viral shedding as well as the quantity of virus detected by PCR when shedding did occur. The impact of pritelivir followed a dose response, with 75 mg daily being the most effective dose. Specifically, the rate of shedding was 2.1% among those who received 75 mg daily pritelivir, as compared to 16.6% among placebo recipients. This translates to a relative risk of shedding of 0.13 (p=0.0003). And when virus was detected by PCR, the median log copy number was 2.4 with 75 mg daily of pritelivir, as compared to 5.1 with placebo. The reduction in viral number was significant (p<0.001) for doses of 25 mg or greater.
Pritelivir reduced the frequency of genital lesions, too. Lesions were noted on 1.2% of days for the group receiving 75 mg daily pritelivir, as compared to 9% of days for the group receiving placebo — a significant reduction (relative risk of 0.13; p=0.02).
In an accompanying editorial, Drs. Richard Whitley and Mark Prichard of The University of Alabama at Birmingham write: “The high compliance rates provide statistical power that could not be achieved by simply obtaining cultures three times a week or assessing the effect on clinical disease. The findings were achieved with a relatively small sample size per randomization cell (approximately 30 volunteers per group). Thus, this short-term study shows a proof of concept and allows for the design of additional studies addressing the treatment of genital HSV infections.”
NEJM Deputy Editor Lindsey Baden states: “It is important to develop antiviral therapies with novel mechanisms of action. Efficient study designs, utilizing novel end points such as HSV shedding, may allow a more rapid assessment of potential antiviral activity. Ultimately larger clinical trials will be required to determine the clinical utility and safety.”
For herpes patients and their partners, these study findings represent an exciting development. Pritelivir still has a long way to go before it establishes the reputation of safety and efficacy that valacyclovir and famciclovir enjoy today. For now, though, this new drug offers the hope that after decades of standing still, herpes treatment may finally be moving forward again.
In your practice, what are the main challenges you have faced in treating patients with genital herpes? How do you foresee pritelivir changing your management approach?