Antiviral Treatments Prescribed by UK Doctors

Herpes simplex virus exists as two types: HSV-1, traditionally associated with orolabial infection (cold sores), and HSV-2, primarily causing genital herpes.

This distinction has blurred — HSV-1 now accounts for 50-70% of new genital herpes diagnoses in the UK, driven by changing sexual practices.

Epidemiology in the UK:

• HSV-1 seroprevalence: approximately 60-70% of adults (many acquired in childhood)
• HSV-2 seroprevalence: approximately 12% of adults aged 16-49
• Annual new diagnoses of genital herpes: approximately 33,000 per year through sexual health clinics
• 80% of HSV-2 infected individuals are unaware of their status due to mild or unrecognised symptoms

Pathophysiology: After primary infection of mucosal epithelial cells, HSV travels retrogradely along sensory nerve axons to the dorsal root ganglion (sacral ganglia for genital HSV, trigeminal ganglion for orolabial HSV), where it establishes lifelong latency.

Periodic reactivation occurs when the virus travels anterogradely back to the skin surface, producing clinical recurrence or subclinical viral shedding.

Primary genital herpes presents 2-14 days after exposure with painful grouped vesicles on an erythematous base, ulcerating within 24-48 hours.

Systemic symptoms (fever, malaise, inguinal lymphadenopathy) are common. Dysuria may occur if lesions involve the urethra or vulva. The first episode lasts 2-4 weeks untreated.

Recurrent genital herpes is milder and shorter (5-10 days untreated).

Prodromal symptoms — tingling, burning, itching, or shooting pain in the affected dermatome — precede visible lesions by 12-48 hours in approximately 50% of patients.

Recurrence frequency varies enormously: some patients have monthly episodes, others have one and never recur.

HSV-2 recurs more frequently (average 4-6 times per year) than genital HSV-1 (average 1-2 times per year).

Triggers for reactivation include:

• Physical or emotional stress
• UV exposure (particularly orolabial HSV)
• Menstruation
• Febrile illness
• Immunosuppression
• Local skin trauma or friction

Antiviral nucleoside analogues do not eradicate HSV from the ganglia but suppress viral replication, reducing symptom severity, outbreak duration, and transmission risk.

Treatment follows BASHH (British Association for Sexual Health and HIV) and NICE guidelines.

Aciclovir is the first-generation antiviral for HSV.

It is phosphorylated by viral thymidine kinase and then by cellular kinases to aciclovir triphosphate, which inhibits viral DNA polymerase with high selectivity for virus-infected cells — explaining its excellent safety profile.

Dosing regimens:

• First episode genital herpes: aciclovir 400 mg three times daily for 5-10 days (or 200 mg five times daily — equally effective but less convenient)
• Recurrent genital herpes (episodic): aciclovir 800 mg three times daily for 2 days (ultrashort course) or 400 mg three times daily for 3-5 days
• Suppressive therapy: aciclovir 400 mg twice daily continuously
• Cold sores: aciclovir cream 5% applied 5 times daily for 5-10 days; oral aciclovir is more effective for severe or frequent episodes

Valaciclovir is the L-valyl ester prodrug of aciclovir, offering 3-5 fold greater oral bioavailability (54% vs 15-20%).

This allows less frequent dosing with equivalent or superior tissue drug levels.

Dosing regimens:

• First episode genital herpes: valaciclovir 500 mg twice daily for 5-10 days
• Recurrent genital herpes (episodic): valaciclovir 500 mg twice daily for 3 days
• Suppressive therapy: valaciclovir 500 mg once daily (standard), or 1 g once daily if breakthrough recurrences occur on 500 mg
• Transmission reduction: valaciclovir 500 mg daily reduces HSV-2 transmission to serodiscordant partners by 48% (Corey et al, NEJM 2004)

Patient-initiated episodic therapy (PIET): Providing a prescription in advance allows the patient to start treatment immediately at the first sign of prodromal symptoms, maximising efficacy.

Delaying treatment by more than 48 hours after lesion onset significantly reduces benefit.

Suppressive versus episodic approach: Suppressive therapy is recommended for patients with:

• 6 or more recurrences per year
• Significant psychological distress from recurrences
• Desire to reduce transmission to a seronegative partner
• Recurrences that are severe or prolonged despite episodic treatment

Aciclovir and valaciclovir have an exceptionally well-established safety profile, having been in clinical use since the 1980s and 1990s respectively.

Serious adverse effects are rare at standard oral doses.

Common side effects (occurring in 1-10% of patients):

• Nausea and abdominal discomfort: 2-5%, usually mild and self-limiting
• Headache: 2-3%
• Dizziness: 1-2%

Renal considerations: Both drugs are renally excreted. Aciclovir crystalluria can cause acute kidney injury at high intravenous doses or in dehydrated patients.

At standard oral doses, the risk is negligible in patients with normal renal function.

• Aciclovir: reduce to 400 mg twice daily for suppression
• Valaciclovir: reduce to 500 mg daily for suppression; 500 mg twice daily for episodic treatment

Pregnancy: Aciclovir has been used extensively in pregnancy with no evidence of teratogenicity in over 1,000 first-trimester exposures documented in the aciclovir pregnancy registry.

BASHH recommends suppressive aciclovir 400 mg three times daily from 36 weeks' gestation in women with genital HSV to reduce the risk of neonatal herpes (which carries a 30% mortality rate if disseminated).

Breastfeeding: Aciclovir is excreted in breast milk at low concentrations (0.6-4.1 times plasma levels).

The infant dose is estimated at under 1% of the therapeutic paediatric dose, making it compatible with breastfeeding.

Drug interactions are minimal. Probenecid reduces renal clearance, increasing aciclovir levels.

Concurrent use with nephrotoxic drugs (aminoglycosides, ciclosporin, tacrolimus) requires renal function monitoring.

Antiviral resistance: Aciclovir resistance occurs through thymidine kinase mutations and affects fewer than 1% of immunocompetent patients.

It is a greater concern in immunocompromised individuals (5-10%), for whom intravenous foscarnet is the alternative.

Resistance does not develop more frequently with long-term suppressive therapy than with episodic use.

Long-term suppressive use: Safety data spanning over 6 years of continuous aciclovir use shows no cumulative toxicity, no increased risk of malignancy, and no effects on fertility.

Annual review is recommended to reassess the need for continued suppression, as recurrence frequency naturally declines over time.

A herpes diagnosis carries significant psychological impact for many patients, often disproportionate to the physical severity of the condition.

Evidence-based counselling and practical management strategies help patients regain control and reduce both physical and emotional burden.

Psychological impact: Studies show that the psychological distress following a genital herpes diagnosis can exceed the physical morbidity.

Feelings of shame, anxiety about disclosure, and fear of rejection are extremely common.

Normalising the diagnosis is an important clinical role — HSV is one of the most prevalent infections globally, carried by the majority of the adult population.

Disclosure and relationships: BASHH provides guidance on discussing HSV with partners. Key points:

• Transmission risk per sexual act with condom use, suppressive therapy, and avoiding intercourse during outbreaks is approximately 1-2% per year for discordant heterosexual couples
• Combination of condoms plus suppressive valaciclovir reduces transmission by approximately 75%
• Asymptomatic viral shedding accounts for over 70% of HSV-2 transmission, which is why suppressive therapy has value beyond symptom control

Outbreak management tips:

• Keep the affected area clean and dry; saline bathing (1 teaspoon salt per 500 mL water) soothes ulcerated lesions
• Wear loose cotton underwear to minimise friction and allow air circulation
• Lidocaine 2% gel applied to ulcerated areas provides topical anaesthesia for 30-60 minutes
• Oral analgesia (paracetamol, ibuprofen) manages systemic discomfort during primary episodes
• Avoid sexual contact from the onset of prodromal symptoms until lesions have fully re-epithelialised

Natural history: The frequency and severity of HSV recurrences typically decline over 5-10 years as immune surveillance strengthens.

Patients experiencing 6 episodes in the first year may see this fall to 1-2 per year by year 5. This natural decline should inform decisions about long-term suppressive therapy.

Immune support measures:

• Adequate sleep (7-9 hours) and stress management reduce reactivation triggers
• L-lysine supplementation (1-3 g daily) has limited evidence from small RCTs suggesting modest reduction in recurrence frequency — results are inconsistent
• Arginine-rich foods (nuts, chocolate, seeds) have been theoretically linked to HSV reactivation, but clinical evidence does not support dietary arginine restriction
• Sun protection (SPF 30+ lip balm) prevents UV-triggered orolabial HSV reactivation