Current management of herpes skin infections in general practice

Transcription

1 Drug review Viral skin infections Current management of herpes skin infections in general practice Gayti Islam MB ChB and Goura Kudesia MBA(Hlth Mgt), FRCPath Herpes viruses are a common cause of viral skin infection ranging from chickenpox in children to shingles in older patients. Our Drug review discusses current management of herpes simplex and varicella-zoster infections, followed by a review of prescription data and sources of further information. Herpes simplex virus (HSV) types 1 and 2 and varicella-zoster virus (VZV) are members of the subfamily Alphaherpesvirinae. Their genome contains double-stranded DNA and their unique viral DNA polymerase provides a target for antiviral drugs. These viruses are recognised as causing a diversity of clinical syndromes ranging from minor cutaneous lesions to life-threatening illnesses, particularly in the immunocompromised host. An important property of all herpes viruses is their ability to cause lifelong latent infection within the dorsal root and trigeminal sensor y ganglia. Recrud - escences affecting the same dermatome may occur in an unpredictable fashion. The clinical management of viral skin infection poses a significant challenge. Background knowledge of the changing epidemiology of such infections allows us a greater understanding of the population burden of disease and the substantial associated morbidity. Trials conducted to evaluate potential antiviral agents may then be designed to identify subgroups that may benefit most from advances in chemotherapy. Properties of nucleoside analogues The nucleoside analogue aciclovir is an antiviral agent that has been available for more than 20 years. Aciclovir has unique antiherpes virus specificity. The compounds are phosphorylated inside infected cells by herpes virus thymidine kinase; once inside the cell, the aciclovir molecule cannot emerge because of the charged phosphate group that has been added. This leads to accumulation of the drug only in infected CPD questions available for this article. See page 34 Prescriber 19 March

2 Figure 1. Adults with orofacial infection may be treated with aciclovir five times daily, famciclovir three times daily or vala - ciclovir twice daily cells, thus limiting its tissue distribution and toxicity. The triphosphate active moiety then acts as a competitive substrate for viral DNA polymerase, but has little effect on cellular DNA polymerase and consequently maintains low toxicity. The drug also acts as a chain terminator preventing further elongation of the viral DNA chain. Valaciclovir (Valtrex) is the 1-valyl ester prodrug of aciclovir. The valine side-chain enhances GI absorption and tissue penetration. The drug is rapidly cleaved to aciclovir in the liver and intestine, resulting in three- to fivefold enhanced bioavailabilty when compared to oral aciclovir. 2 This means that dosing frequency may be reduced, and an early switch from intravenous to oral therapy can be a realistic option in patients with more severe clinical manifestations, enabling earlier discharge and management at home. Penciclovir (Vectavir) has a similar mechanism of action to aciclovir. Penciclovir triphosphate has a lower affinity for viral DNA polymerase but is able to be accumulated in high concentrations. This, together with a longer half-life, means it produces similar clinical effects to aciclovir. 1 Similarly, famciclovir (Famvir) is a prodrug of penciclovir. Drug resistance is not a significant clinical problem in immunocompetent patients, although severe infections due to resistance strains have been described in patients who are immunocompromised. The commonest form of resistance is due to loss of the thymidine kinase enzyme (TK minus strains) so the drug is not phosphorylated to its active form in the infected cells. Virus strains with drug-resistant DNA polymerase have also been described. These drugs are eliminated primarily by the kidneys, but dose adjustment is not required for patients with mild renal impairment. Bioavailability is not affected by food and there are no notable drug interactions. Side-effects are rarely encountered but include GI upset, hypersensitivity reactions and neurological reactions including dizziness, confusion and hallucination. There may be reduction in haematological indices. Local inflammation may occur at the site of intravenous infusion. Antiviral drugs are not licensed for use in pregnancy; however, the potential seriousness of infection with herpes viruses, including chickenpox, in pregnancy means that risk-benefit issues must be carefully considered. The Aciclovir and Valaciclovir Pregnancy Registry followed over a thousand exposed pregnancies and found the rate of birth defects to be no greater than the general population, with no pattern of birth defects or laboratory evidence of drug toxicity seen. Similarly, a Danish study that followed 1804 pregnancies exposed to aciclovir and valaciclovir in first trimester showed no association of birth defects with either. There was also no adverse outcome with famciclovir use although the numbers followed up were small. 3 Herpes simplex infection The two types of herpes simplex virus can be easily differentiated by laboratory tests, but share common clinical features. As a general rule, HSV-1 causes orolabial infection, whereas HSV-2 is more usually associated with genital infection. There is little cross-protection between the two types. The rise in numbers of HSV-1- associated genital herpes is thought to be related to increased orogenital contact. 4 One study of seroprevalence data in low-risk groups found that worldwide prevalence of HSV-1 was higher than HSV-2 in most geographic areas. In contrast, high-risk groups such as HIV-positive people and commercial sex workers had HSV-2 seroprevalence of >65 per cent. 5 Orofacial infection HSV-1 infection is often acquired at an early age, when a susceptible child is kissed by an older person who may be asymptomatically shedding the virus in saliva. The resulting primary infection is usually asymptomatic, but severe gingivostomatitis may ensue. Vesicles appear on the buccal mucosa, which easily de-roof forming painful, shallow ulcers. The lips and circum- 28 Prescriber 19 March

3 oral skin are involved, in contrast to vesicles caused by Coxsackie virus that typically affect the soft palate, tonsillar fauces and uvula. 6 The child may be unwell with inability to feed, resulting in dehydration. Severe cases may require hospitalisation. Autoinoculation may result in herpetic whitlow, conjunctivitis and keratitis. Untreated lesions may take more than two weeks to heal. In children, aciclovir suspension at 15mg per kg five times daily for seven days, started within the first three days of symptom onset, shortens the duration of all clinical manifestations by about 50 per cent. 7 The suspension is palatable and easily swallowed. Valaciclovir is not available in a stable suspension as it is hydrolysed on contact with water. It is not recommended, therefore, to crush tablets in water. Valaciclovir in tablet form is licensed for use in children aged 12 years and above. Adults with orofacial infection (see Figure 1) may be given oral treatment for five days with aciclovir five times a day, valaciclovir 500mg twice a day or fam - ciclovir 250mg three times a day. Recurrent facial herpes results from reactivation of the virus. Episodes may be triggered by stimuli such as cold weather, menstruation, fever, stress or UV light. Lesions commonly begin on the vermillion border of the lips but may extend into the mouth or onto the nasal septum. There is typically a prodromal sensation of tingling, burning or itching at the affected site, which is thought to be due to early viral replication at sensory nerve endings and in the epidermis or mucosa. 8 Ease of access to over-the-counter topical antiviral preparations has made these a popular focus in treating facial herpes. However, creams may be far from ideal in some patients, eg those with difficult-to-reach lesions in the nose or mouth, and application may promote autoinoculation. In addition, topical treatments need to be applied frequently and can be easily removed by eating or drinking. Nevertheless, modest benefit has been demonstrated from both aciclovir and penciclovir creams, with reduction in the duration of episodes, faster lesion healing and pain resolution. 9 Use of prophylactic oral aciclovir for danger periods has been shown to have a more pronounced effect. This is particularly useful for those who have clear-cut trigger factors 10 or frequent episodes, but most people would probably opt for self-initiating medication at the onset of prodromal symptoms, which in addition may be more economical than long courses of suppressive therapy. Should a course of suppressive therapy be the preferred option, oral aciclovir 400mg twice daily is useful in preventing recurrent cold sores. It is often more convenient for the patient, however, to take valaciclovir at a dose of 500mg once daily. Studies have demonstrated that this regimen, continued for four months, effectively suppresses recurrent herpes labialis outbreaks. 11 The problem with self-initiation of therapy is that, following a trigger, vesicles develop rapidly in association with a strong secondary (cell-mediated) immune response. Hence, the narrow therapeutic window means that treatment has the best impact when started as early as possible, during the initial phase of viral replication before the skin and mucosa are damaged. 12 A Scandinavian group studied the effects of early oral valaciclovir therapy on facial herpes. They found that more than half of their patients achieved an aborted or partially-aborted lesion after treatment with either of two regimens: 500mg twice daily for three days or 1g twice daily for one day. 13 The study also showed a significant reduction in time to episode and pain resolution when compared with earlier data. They concluded that further work was needed to determine the best dose and duration for this treatment. Figure 2. Uncomplicated chickenpox in immunocompetent children rarely requires treatment Prescriber 19 March

4 Eczema herpeticum Mucocutaneous herpes simplex lesions in patients with uncontrolled atopic eczema may spread extensively (eczema herpeticum) and may lead to disseminated infection. Therapy with intravenous aciclovir is indicated in such cases for the prompt control of infection. Herpes gladiatorum Herpes gladiatorum is another cutaneous form of herpes infection, which may be troublesome in those who engage in contact sports such as rugby, wrestling or water polo. Primary infection arises due to inoculation of chafed skin by contact with another competitor, or from contaminated mats or towels. Infective lesions may take up to two weeks to appear. As years pass by, recurrences may become milder, more localised and of shorter duration than the primary episode. Prophylactic use of valaciclovir (500 or 1000mg) once or twice daily during the sporting season may be beneficial. It has been suggested that the higher dose is best reserved for cases with more recent primary acquisition. 6 Genital herpes Genital herpes is a sexually transmitted disease. Infection occurs with both HSV-2 and HSV-1 and manifests as a painful vesicular eruption of the penis, vulva, vagina and surrounding skin. Symptomatic primary infection may last as long as two to three weeks, although recurrences are associated with a shorter duration of symptoms. Management includes education about safe sexual practice, analgesia and antiviral therapy. Other herpes simplex infections Neonatal herpes simplex Neonatal herpes simplex infection is a rare but potentially life-threatening infection that occurs in 1 in live births in the UK. It is most commonly acquired at or near time of delivery as a result of primary maternal infection and can generate a clinical spectrum of disease ranging from localised cutaneous manifestations to skin or mouth to severe CNS infection with encephalitis. Herpes encephalitis Herpes simplex virus is the most common cause of sporadic viral encephalitis with an incidence of 1 in to population per year. If untreated it has high mortality and morbidity in terms of severe neurological sequelae. Patients present with fever, confusion, disorientation, personality changes and headache. Prompt treatment with high dose intravenous aciclovir (10mg per kg body weight eight hourly) for three weeks is indicated. Ophthalmic herpes simplex infections may present as conjunctivitis, blepharitis or keratitis. HSV keratitis Figure 3. Uncomplicated chickenpox in adults is usually treated with 800mg aciclovir tablets five times daily typically presents with acute onset of pain and blurred vision, and dendritic corneal ulcers are present on examination. If untreated, blindness may occur due to corneal scarring. Rarely HSV may cause acute necrotising retinitis leading to painless visual loss in both immunocompetent and immunocompromised patients. Patients should be referred to a specialist for treatment of HSV eye infections. Varicella-zoster virus infection Two clinically distinct forms of VZV infection exist. Chickenpox results from primary infection and typically occurs in outbreaks among young children (see Figure 2). The two-week incubation period (range days) is followed by a prodrome of fever and posterior cervical lymphadenopathy. A characteristic widespread rash ensues, more dense on the trunk than on the face and limbs. Lesions evolve through papular, vesicular, pustular and crusting stages. Cropping means that, at any one time, there may be lesions at different stages of evolution. Infectivity is related to both the presence of the virus in the nasopharynx and 30 Prescriber 19 March

5 viral shedding from skin lesions; patients are infectious from two days before to the later of five days after the appearance of the rash or until the lesions have crusted. The episode generates production of IgG antibody that is protective against further chickenpox; however, following infection, the virus establishes lifelong latency in neural tissue. Reactivation of latent VZV from dorsal root ganglia occurs much less often than with HSV and is associated with waning T-cell immunity. This results in herpes zoster (shingles), which is a painful, localised, cutaneous eruption, of which there is usually only one life-time episode that most often occurs in those over 50 years. Recurrent shingles or shingles occurring in younger people should raise suspicion of poor T-cell immunity, and the possibility of HIV infection may need to be addressed. In contrast to chickenpox there is no nasopharyngeal carriage and so infectivity is much lower, requiring contact with vesicle fluid for transmission. Chickenpox Uncomplicated chickenpox, in immunocompetent children, rarely requires treatment. Antivirals should be considered in the immunocompromised, those with severe disease or complications and adults (see Figure 3), and should be commenced within two days of onset. Intravenous aciclovir 10mg per kg body weight eight hourly is indicated in the immunocompromised and those with chickenpox complications, under hospitalisation. Oral treatment with 800mg aciclovir five times per day generally suffices for uncomplicated chickenpox in adults. Zoster hyperimmune globulin is indicated for susceptible at-risk groups within 10 days of a significant varicella exposure. (Significant exposure is defined as face-to-face contact or being in the same room for 15 minutes or longer with an infectious person.) These ar-risk groups include the immunocompromised, premature neonates or those weighing less than 1kg whose mothers lack VZV IgG antibodies, susceptible pregnant women, or babies of mothers who develop chickenpox from seven days before to seven days after delivery. VZV IgG antibodies should be checked in exposed immunocompromised and pregnant patients to assess their risk prior to administering VZV IgG. There are two live, attenuated varicella vaccines (Varilrix and Varivax) that have been licensed for use in the UK. Both vaccines are contraindicated in pregnancy and in immunocompromised individuals. In the UK, the DoH recommends varicella vaccination of susceptible healthcare workers in direct patient contact. Localised or occasionally generalised vesicular rash may occur due to the vaccine virus, rarely resulting in horizontal transmission to close contacts. Varivax is also licensed for postexposure prophylaxis. The vaccine may be administered to susceptible individuals within three days of exposure when it may prevent onset of chickenpox or modify the course of illness. It may be given within five days of exposure purely to modify the illness in those at risk of severe disease. Of note, universal childhood varicella immunisation has been introduced in other countries, including the USA; however, there are no current plans to undertake a similar programme in the UK. Herpes zoster The rash of zoster is typically unilateral (see Figure 4), may affect any dermatome and lasts two to four weeks, the lesions evolving in a similar manner to those of chickenpox. The skin of the trunk is most commonly affected, with the first division of the trigeminal nerve next in line (ophthalmic zoster). The latter presentation is often compounded by the complication of keratitis or iritis. The pain of herpes zoster is the most debilitating symptom and typically occurs as a prodrome to the Figure 4. Valaciclovir 1g three times daily has been shown to be more effective in herpes zoster than aciclovir 800mg five times daily Prescriber 19 March

6 rash, but may persist for weeks or months. It is described as burning or lancinating and may be associated with allodynia (pain induced by trivial stimuli such as light touch). Pain present before or during the rash is called acute neuritis, whereas chronic pain, persisting for more than four weeks after the appearance of lesions, is termed postherpetic neuralgia (PHN). Up to 10 per cent of patients may have pain one year later, after which time the chance of spontaneous resolution is limited. 14 Since neuropathic pain mechanisms in herpes zoster begin very early after nerve damage, the most appropriate means of minimising pain is prevention of further damage by the use of antiviral agents that stop VZV replication. In order to target antiviral therapy at those who will receive most benefit, factors that may predict higher risk of prolonged pain should be assessed at presentation. These include: age at presentation (more likely with advanced years) prodromal pain severe acute pain rash severity pre-existing neurological disorders ophthalmic involvement. The nucleoside analogues have demonstrable benefit in improving cutaneous healing of acute zoster and also reduce ocular complications in ophthalmic zoster. A meta-analysis of four studies showed that aciclovir at 800mg five times daily in acute zoster reduced the duration of zoster-associated pain, particularly in older people. 15 Studies investigating the use of valaciclovir, at a dose of 1g three times daily for seven days, showed statistically significant advantages over aciclovir, with a smaller proportion having pain at six months. Famciclovir has at least equivalent efficacy to aciclovir at doses of 500mg three times daily. This high dose is usually reserved for severe zoster in those who are immunocompromised. In mild-to-moderate disease, 250mg three times daily should suffice. Of the two prodrugs, valaciclovir is the more cost-effective option in the UK at present. 16 Useful adjuvants in herpes zoster therapy Patients with severe PHN should be referred to specialist clinics for pain management. TCAs exert an analgesic effect in chronic neuropathic pain that is independent of their antidepressive effect. Nortriptyline is as effective as amitriptyline at reducing PHN but is better tolerated. Anticonvulsants such as gabapentin and pregabalin (Lyrica) have been shown to produce a statistically significant reduction in daily pain score and improvement in quality of life. They are as effective as the tricyclics, are more expensive but probably have a better adverse event profile and fewer drug interactions, which may be a consideration when prescribing in older patients. Other analgesic options shown to be of benefit include topical anaesthetic application in the form of lidocaine plasters (Versatis) and opioid analgesia. Despite these options patients may ultimately need specialist pain clinic input. In addition, clinicians must recognise the role of psychosocial input as many older PHN sufferers live alone and have experienced negative life events, such as failing mobility and independence or loss of a loved one. Anxiety and depression are associated with a worse outcome in herpes zoster infection. 7 Herpes zoster vaccine Herpes zoster may be prevented by immunisation with a vaccine (Zostavax) containing higher titres of herpes zoster vaccine than the childhood vaccine. The Shingles Prevention Study Group has demonstrated that herpes zoster vaccination can significantly reduce the incidence, morbidity and postherpetic neuralgia associated with zoster infection in older adults, ie those over The Joint Committee on Vaccine and Immunisation (JCVI) states that a universal herpes zoster vaccination programme for adults aged 70 years up to and including 79 years is recommended provided that a licensed vaccine is available at a cost-effective price. Zostavax has been licensed in the UK but is not currently available for use. Conclusion A common theme linking the many manifestations of herpes virus infections is the intimate relationship between the virus and the host s sensory nervous system. Aciclovir is highly specific for herpes virus-infected cells and sets the standards in terms of its efficacy, tolerability and safety profiles, and remains the drug of choice when severe infection warrants intravenous administration. When oral therapy is appropriate, in most instances the use of valaciclovir should ensure a less onerous treatment schedule, thus promoting compliance. This in turn allows better bioavailability, yet with the preser vation of the aciclovir standards already mentioned. Future research developments may focus on immunomodulation and ideally should target viral replication and control at the level of the sensory ganglia. 32 Prescriber 19 March

7 References 1. Collier L, et al. Mode of action of aciclovir and related compounds. In: Human virology: a text for students of medicine, dentistry and microbiology. 2nd ed. Oxford: Oxford University Press, Weller S, et al. Clin Pharmacol Ther 1993;54: Pasternak B, et al. JAMA 2010;304(8): Cunningham AL, et al. Global epidemiology of STD. In: Stanberry LR, et al, eds. Sexually transmitted diseases: vaccines, prevention and control. San Diego; London: Academic Press, Smith JS, et al. J Infect Dis 2002;186(suppl 1):S3 S Simmons A. J Infect Dis 2002;186(suppl 1):S71 S Amir J, et al. BMJ 1997;314: Huff JC, et al. J Am Ac Dermatol 1981;5: Fiddian AP, et al. BMJ 1983;286: Spruance SL, et al. JAMA 1988;260; Baker DA, et al. Valaciclovir effective for suppression of recurrent HSV-I herpes labialis [abstract 464]. In: Program and abstracts of the 40th Interscience Conference on Antimicrobial Agents and Chemotherapy. Toronto: American Society for Microbiology, Esmann J. J Antimicrob Chemother 2001;47(suppl T1): Laiskonis A, et al. J Infect Dis 2002;186(suppl 1):S66 S Bhala BB, et al. Clin J Pain 1988;4: Wood MJ, et al. Clin Infect Dis 1996;22: Wood M. J Infect Dis 2002;186(suppl 1):s78 s Johnson RW. J Infect Dis 2002;186(suppl 1):s83 s Oxman MN, et al. N Engl J Med 2005;352(22): Dr Islam is a specialty registrar in microbiology, and Goura Kudesia is honorary professor of clinical virology and lead consultant virologist at Sheffield Teaching Hospitals NHS Trust Prescription review In 2009, GPs in England wrote prescriptions for oral antivirals for the treatment of herpes simplex and varicella-zoster at a total cost of 12 million. This represents a 9 per cent increase in volume and a 6 per cent fall in spending. Aciclovir still accounts for the majority of prescribing (91 per cent) almost all generic but less than half of costs (40 per cent). By contrast, only 5 per cent of prescribing but almost half of spending (45 per cent) was for famciclovir tablets, with the average cost of a prescription ranging from 65 to 400. Fewer than 4 per cent of prescriptions were for valaciclovir, which accounted for 15 per cent of spending. Use of inosine pranobex (Imunovir) has changed little despite the BNF s designation of less suitable for prescribing due to lack of evidence of efficacy. In 2009 there were 600 prescriptions for this agent at a cost of No. scrips (000s) Cost ( 000s) aciclovir famciclovir valaciclovir inosine pranobex Table 1. Number and cost of prescriptions for antiviral agents for herpes simplex and varicella zoster. England, 2009 Resources Patient information Information leaflets: Cold Sores, Cold Sores Primary Infection, Chickenpox in Children, Chickenpox in Adults, Chickenpox Contact and Pregnancy, Shingles and Postherpetic Neuralgia from Patient UK: www. patient.co.uk. Booklets including Herpes Simplex A Guide, Transmission, Pregnancy and Childbirth, Talking to a New Partner and Summary of Tips to Prevent Recurrences from the Herpes Viruses Association (see details below). Patient support groups Herpes Viruses Association, 41 North Road, London N7 9DP. Tel: (doctors), (public). Website: Provides information for the public and professionals on herpes skin infections. Subscribers receive leaflets, articles and a quarterly journal Sphere. Shingles Support Society. Subgroup of the Herpes Viruses Association supplying information on shingles and postherpetic neuralgia for patients and GPs. Contact details as above. Prescriber 19 March

8 CPD: Viral skin infections Answer these questions online at Prescriber.co.uk and receive a certificate of completion for your CPD portfolio. Utilise the Learning into Practice form to record how your learning has contributed to your professional development. 1. One of these statements about nucleoside analogues is false which is it? a. They accumulate only in infected cells, limiting tissue distribution and toxicity b. Valaciclovir is a prodrug of aciclovir c. Famciclovir is a prodrug of penciclovir d. Penciclovir triphosphate has a lower affinity for viral DNA polymerase and is less effective than aciclovir 2. Which one of these statements about herpes simplex infection and its treatment is false? a. HSV-1 may cause genital infection b. In children, aciclovir suspension at 15mg per kg five times daily for seven days, started within the first three days of symptom onset, shortens the duration of all clinical manifestations by about 50 per cent c. Over-the-counter aciclovir and penciclovir creams do not reduce the duration of episodes or produce faster lesion healing d. Oral aciclovir 400mg twice daily or valaciclovir 500mg once daily is useful for preventing recurrent cold sores 3. Which one of these statements about herpes virus infections is false? a. The seroprevalence of HSV-2 in high-risk groups such as HIV-positive people and commercial sex workers is >65 per cent b. The dose of valaciclovir for prophylaxis of herpes gladiatorum is 500 or 1000mg once or twice daily during the sporting season c. Topical aciclovir is indicated for the treatment of eczema herpeticum d. Patients with HSV eye infection should be referred to a specialist for treatment with topical and/or systemic antivirals 4. Which one of these statements about varicella-zoster virus infection is false? a. Recurrent shingles or shingles occurring in younger people should raise suspicion of poor T-cell immunity b. Antiviral treatment for an adult with chickenpox should begin within seven days of symptom onset c. Oral treatment with 800mg aciclovir five times per day generally suffices for uncomplicated chickenpox in adults d. Zoster hyperimmune globulin is indicated for susceptible at-risk groups within 10 days of a significant varicella exposure 5. One of these statements about varicella-zoster virus infection is false which is it? a. The rash of zoster is typically unilateral and lasts two to four days b. Rash severity is a risk factor for higher risk of prolonged pain c. The most appropriate way to minimise pain is to prevent further damage by the use of antiviral agents that stop varicella-zoster virus replication d. Valaciclovir has been shown to be superior to aciclovir in reducing the proportion of patients with pain after six months 6. One of these statements is false which is it? a. Nortriptyline is as effective as amitriptyline at reducing post - herpetic neuralgia but is better tolerated b. Anticonvulsants such as gabapentin and pregabalin are not as effective as the tricyclics in the treatment of postherpetic neuralgia c. Anxiety and depression are associated with a worse outcome in herpes zoster infection d. Herpes zoster vaccination can significantly reduce the incidence, morbidity and postherpetic neuralgia associated with zoster infection in adults aged over Prescriber 19 March