What is the current progress on new herpes simplex virus (HSV) treatments and potential cures?

Current Progress on New HSV Treatments and Potential Cures

No FDA-approved cure for HSV exists, and no new treatment regimens have been approved for suppressive therapy since the last guideline update, but helicase-primase inhibitors represent the most promising novel therapeutic class currently in clinical development. 1

Novel Antiviral Agents in Development

Helicase-Primase Inhibitors (HPIs)

Pritelivir, a helicase-primase inhibitor, is the most advanced investigational agent and has entered an open-label clinical trial (NCT03073967) specifically for immunocompromised patients with acyclovir-resistant HSV infections, with an early-access program already initiated. 1

• HPIs work through a completely novel mechanism of action distinct from nucleoside analogs, targeting the HSV helicase-primase enzyme complex rather than viral DNA polymerase 2, 3, 4
• These agents demonstrate superior efficacy in animal models compared to acyclovir and show low resistance rates in vitro 2, 4
• HPIs have been studied in early-phase clinical trials but have not yet completed phase 3 studies and remain unapproved by the FDA 1
• The high potency and novel mechanism make HPIs particularly promising for overcoming acyclovir resistance, which occurs in approximately 7% of immunocompromised patients 3

Agents for Acyclovir-Resistant HSV

Case reports suggest that brincidofovir, imiquimod, and topical cidofovir may be useful alternatives for acyclovir-resistant HSV infections, though none are FDA-approved for this indication. 1

• Imiquimod is a topically active immune enhancer that stimulates interferon and cytokine production, but it is not FDA-approved for genital herpes treatment 5
• These agents should only be considered when standard antiviral treatments have failed or in cases of confirmed acyclovir resistance 5
• Intravenous foscarnet (40 mg/kg three times daily) remains the treatment of choice for confirmed acyclovir-resistant HSV, with resistance rates below 0.5% in immunocompetent hosts 6

Failed or Ineffective Approaches

Tenofovir Preparations

Tenofovir preparations (intravaginal gel and oral tenofovir disoproxil fumarate) showed no difference in viral shedding or lesion frequency when studied in women with HSV-2 infection. 1

• A crossover study specifically evaluated these agents for prevention of genital shedding and recurrences among HIV-negative women with HSV-2 1
• This represents a failed approach that will not advance to further development 1

Vaccine Development Status

No prophylactic or therapeutic HSV vaccines are currently approved, despite various candidates in preclinical and clinical phases of study. 7, 8

• Vaccine development faces unique challenges due to the complex immunological pathways involved in HSV latency and reactivation 7
• As of 2021, various promising candidates were in development with both preventative and therapeutic focuses, but none have reached approval 7
• The high global prevalence (66.6% for HSV-1 and 13.2% for HSV-2 in ages 15-49) makes vaccine development imperative, but technical obstacles remain substantial 7, 8

Current Standard of Care Remains Unchanged

The nucleoside analogs acyclovir, valacyclovir, and famciclovir remain the only FDA-approved treatments, with no new regimens approved for episodic or suppressive therapy. 1

• These agents partially control symptoms but neither eradicate latent virus nor affect recurrence risk after discontinuation 1
• Suppressive therapy reduces recurrence frequency by ≥75% but does not eliminate subclinical viral shedding 1, 6
• No comparative data exist showing superiority of one nucleoside analog over another for episodic or suppressive therapy 1

Gene Therapy and Future Directions

Gene therapy approaches for HSV remain in early experimental stages and are not yet viable clinical options. 3

• Current research focuses on targeting latent viral reservoirs in neurons, but practical applications remain distant 3
• The complexity of HSV latency in neuronal ganglia presents substantial technical barriers to curative approaches 8

Critical Limitations of Current Progress

• Despite decades of research since acyclovir's development in the late 1970s, no agent has successfully outperformed the nucleoside analog class 4
• Resistance to current therapies is rising, particularly in immunocompromised populations, making new therapeutic development urgent 7, 3
• The inability to eradicate latent infection means that even the most promising new agents (HPIs) will likely suppress rather than cure HSV 3, 4

Clinical Implications

For now, clinicians should continue using standard nucleoside analogs (acyclovir, valacyclovir, famciclovir) as first-line therapy, reserving foscarnet for confirmed acyclovir-resistant cases, and monitoring the progress of pritelivir through its ongoing clinical trials. 1, 6, 5

• Patients asking about cures should be counseled that no curative therapy exists or is imminent, though HPIs may offer improved suppression in the future 3, 8
• The early-access program for pritelivir may provide an option for select immunocompromised patients with resistant infections who have exhausted other alternatives 1