Genital Herpes: Key Issues for the Next 50 Years

This is the authors' abstract. We don't add key points for this paper.

Over the past 50 years, our understanding and management of genital herpes infections has grown exponentially. We have learned that not only herpes simplex virus (HSV) causes recurrent genital lesions, but also viral shedding occurs frequently during asymptomatic intervals, leading to transmission, and genital HSV-2 causes chronic genital inflammation, increasing susceptibility to HIV acquisition.1–3 Sensitive type-specific virologic diagnosis from lesions and type-specific serologic tests have revolutionized our understanding of the epidemiology of HSV-1 and HSV-2.4 We now have nucleoside analogues that can be used daily to suppress viral reactivation or to treat genital herpes recurrences. Natural history studies have informed our ability to provide prognosis and counseling to patients. Despite this progress, we need improved diagnostics, treatments, and prevention strategies to control this prevalent infection. Here, we address 6 specific domains of HSV issues that remain highly problematic. DIAGNOSIS Many studies have shown that visual “syndromic” diagnosis of genital herpes, still used in most of the world, is unreliable, even by expert clinicians. In addition, it does not provide information about whether the infection is caused by HSV-1 or HSV-2, an important distinction as prognosis differs by viral type. The development of HSV DNA polymerase chain reaction was an important advance, as this test is ~4 times as sensitive as viral culture. Yet, most persons with HSV-2 do not have a history of genital herpes, so diagnostics need to rely on antibody testing. Here, we have failed to develop and commercialize an accurate serologic assay that can correctly identify HSV-1 and HSV-2 infection.5 The problematic nature of the commercial IgG assays was recently acknowledged by the Food and Drug Administration; the criterion standard assay, the HSV Western blot, is available only at a single academic center in the United States. Partly based on the poor performance of these assays, testing for HSV-2 as part of sexual health assessment is not recommended. Some people who obtain commercially available assays without confirmatory testing carry an incorrect—false positive—diagnosis of HSV-2 infection. ANTIVIRAL TREATMENT Nucleoside analogues, developed in the 1970s by the Nobel prize winning Dr. Getrude Elion, led to the revolution in development of novel antivirals to treat chronic viral infections. Nucleoside analogues remain the only Food and Drug Administration–approved oral antiviral therapy for treatment of HSV infections.6 Uniquely safe because of its mechanism of action, acyclovir (and its relatives, valacyclovir and famciclovir) can be taken daily for decades with little concern for toxicity or development of resistance. The drug is quite effective for ameliorating symptomatic disease and prevents most recurrence. However, even at a high dose, it does not eliminate viral shedding and thus has limited effect on prevention of the transmission to sexual partners.7,8 Twenty years ago, when the valacyclovir transmission study showed that daily valacyclovir reduced the risk for HSV-2 transmission to HSV-2 seronegative partners by 48%,7 making it the first study to demonstrate the potential for antivirals to reduce sexual transmission of a chronic viral infection, the glass seemed half-full. Now, potent antivirals that fully suppress HIV infection are proven to prevent HIV transmission (“undetectable = untransmittable, U = U”) currently available therapies for HSV, which decrease but do not eliminate the risk of transmission, clearly fall short. Can we do better? The helicase-primase inhibitors are a new class of drugs that seem effective in preclinical and early clinical studies. The efficacy of pritelivir, evaluated most thoroughly to date, to suppress HSV seems higher than nucleoside analogues, and new helicase-primase inhibitors are in preclinical development: these compounds need urgent evaluation in well-designed clinical trials. Unfortunately, the development of pritelivir has been stalled because of concerns about toxicity. In the last 3 decades, we have learned that viral shedding is the appropriate endpoint during clinical development to establish the most effective dose. The dose-ranging studies of nucleoside analogues used clinical endpoints such as lesion healing, failing to differentiate accurately between doses. An important goal of antiviral therapy is prevention of transmission to sex partners; the potential for transmission is measured in viral shedding, not recurrences. People with HSV advocate for better therapeutics to prevent transmission. Potent and safe medication to suppress viral shedding and prevent transmission would revolutionize genital herpes management. VACCINES Despite a handful of attempts, no vaccine has been shown to be adequately effective for HSV infection. Two types of vaccines are possible. Ideally, we would have a prophylactic vaccine for HSV-2, akin to the human papillomavirus vaccine, which could be administered to prevent HSV-2 infection before initiation of sexual activity. Furthermore, if it also protected against HSV-1 acquisition, then the vaccine could be incorporated into the newborn vaccination schedule. A therapeutic vaccine for HSV would also be desirable. This vaccine would be administered for people with HSV-2 infection to improve the immunological control of the infection. Immunization of persons who already have latent varicella-zoster virus to prevent shingles is highly effective, so there is hope that a similar approach might be found for HSV. The progress for vaccines is slow as neither an immune correlate of protection from acquisition nor for control of latent infection has been identified—and we tried! As such, trials to test a product as a preventative vaccine need to rely on HSV-2 acquisition as an endpoint; this requires large studies with populations at risk for acquiring HSV-2 infection, followed over a long period of time. For therapeutic vaccines, viral shedding is the appropriate endpoint to measure efficacy—providing insight as to whether a vaccine that is effective in controlling recurrent disease may also reduce the risk for transmission to partners. STIGMA Genital herpes results in stigma and shame. People with genital herpes often feel marked by disease, as illustrated in the 1982 Time cover “Herpes, the New Scarlet Letter,” and not infrequently claim that having genital herpes defines their identity.9 Disclosure is feared because of concern both for rejection from sexual partners and for potential “outing” in the community. Herpes remains a topic for jokes, adding to the stigma. Just a few months ago, Saturday Night Live carried a news segment about “pigeon herpes.” FRAUD Given the distress caused by the diagnosis of an incurable sexually transmitted infection, many people fantasize about a cure. Internet searches reveal many outfits selling a variety of proprietary products that promise a cure. Most rely on a combination of herbal remedies that assure the customer that, for a hefty price, they can be free of HSV. Although some fraudulent sites disappear, presumably following regulatory response, new ones appear. Patients who are scammed are (understandably) reluctant to admit to investing into these fraudulent products and the scope of the problem is hard to assess. Health care providers can help fight against this fraud by providing accurate information to patients upon diagnosis of genital herpes. CURE Can we cure people infected with HSV? Early work has shown the possibility of destruction of HSV at its site of latency. Mega-nucleases have been used to eliminate 98% of latent HSV in mice ganglia.10 An early report from a Chinese company claims elimination of HSV in people with herpetic keratitis.11 It is likely that these novel approaches will be successful, but potential toxicity, pathway to regulatory approval, and timeline for accessibility remain unclear. Progress in HSV has lagged substantially behind other chronic viral infections: antivirals for HIV and hepatitis C have transformed the approach to these infections. Although we have made substantial strides in the past 50 years, patients continue to tell us that management and control of this infection remain suboptimal, and if anything, stigma is increasing. We must create new tools to diagnose, prevent, treat, and, aspirationally, cure HSV infection.