← AAUS Clinical GuidelinesSexually Transmitted Infections

Genital herpes

Authors

Vishal Gupta (Department of Dermatology and Venereology, All India Institute of Medical Sciences, New Delhi, India)

Neetu Bhari (Department of Dermatology and Venereology, All India Institute of Medical Sciences, New Delhi, India)

Somesh Gupta (Department of Dermatology and Venereology, All India Institute of Medical Sciences, New Delhi, India)

Executive Summary

Prevention

1. Regular male condom usage is effective in reducing the transmission risk of genital HSV-2 infection (LE: 2A, GR: B), there is no added advantage of vaginal diaphragm (LE: 1B, GR: A).

2. Circumcision can be used as an effective preventive measure in males (LE: 1A). Circumcision in spouses seems to confer protection from acquiring genital herpes in their wives (LE: 3, GR: B).

3. Oral valacyclovir and acyclovir and tenofovir1% gel can reduce the risk of sexual transmission in susceptible partners (LE: 1B, GR: A).

4. Limited data on the use of anti-HSV vaccines suggests that it is not significantly effective in preventing genital herpes (LE: 1B, GR: B).

Diagnosis

1. Tzanck smear is a rapid point-of-care test. (LE: 3)

2. Virus antigen can be detected using either DIF or antigen capture EIA. (LE: 3). It is important to perform HSV typing in patients with first-episode genital herpes. (LE: 3)

3. Viral culture has been traditionally considered as ‘Gold standard’ in the diagnosis of genital herpes. (LE: 4)

4. PCR is more sensitive than viral culture. (LE: 1B) It is widely regarded as the test of choice for the diagnosis of genital herpes in symptomatic patients. (LE: 4)

4. Serology: Seroconversion or a rising titre of antibodies has diagnostic significance. (LE: 2A)

Type-specific assays which detect antibodies against antigenically unique glycoproteins G1 and G2 should be used. (LE: 3)

Treatment

First episode genital herpes

1. Oral acyclovir, valacyclovir and famciclovir are effective in reducing the severity and duration of symptoms (LE: 1B, GR: A). Topical antivirals are less effective than systemic agents (LE: 1B, GR: A) and topical acyclovir has been shown to be associated with resistance to oral acyclovir (LE: 3, GR:B).

Recurrent genital herpes

1. Episodic therapy with oral acyclovir, valacyclovir and famciclovir can be utilised to treat recurrent episodes (LE:IB, GR:A).

2. Suppressive therapy with all the three antiviral agents (acyclovir, valacyclovir and famciclovir) has been found to reduce the frequency of recurrences significantly in patients having six or more recurrent episodes per year (LE: 1B, GR: A), though it can benefit patients with fewer recurrences as well.

3. The suppressive therapy may be discontinued after a year to assess the recurrence frequency.

It may be reasonable to re-start suppressive therapy for patients who continue to have high recurrence rates. (LE: 4, GR: C)

4. Suppressive therapy with valacyclovir is more effective than episodic therapy in reducing the frequency of recurrent episodes and improving the quality-of-life (LE: 1B, GR: A).

Management of partner

1. Adequate sexual history and history of genital herpes should be taken. Examination of the partner should be done (LE: 4, GR: C).

Genital herpes and HIV

1. There is epidemiological synergy between HSV and HIV. HSV infection is associated with increased HIV shedding and increases the risk of acquiring HIV infection (LE: 1A). HIV infection may lead to increased severity of genital herpes (LE: 3) and is associated with increased genital HSV shedding (LE 3).

2. First episode genital herpes can be treated with the same doses of antivirals as for non-HIV infected patients, but has to continued till complete resolution of lesions (LE:IIB, GR:B). Twice the standard doses for 10 days have also been recommended by some experts (LE: 4, GR: C).

3. Episodic therapy for recurrent genital herpes comprises of the standard doses as for HIVnegative patients if no significant immunosuppression; or double-the-standard dosage, if advanced HIV disease (LE: 1B, GR: A).

4. Standard doses of acyclovir and valacyclovir have been used effectively in suppressing recurrent episodes (LE: 1B, GR: A). If inadequate response, double the dose or use famciclovir 500mg twice daily (LE: 2A, GR: B).

Drug resistance

1. Drug resistant HSV-2 is more common in HIV co-infected patients in comparison to HIVnegative individuals (LE: 3).

2. Intravenous foscarnet 40 mg/kg every 8 hours has been found to be effective in treating drugresistance genital herpes (LE: 1B, GR: A).

3. Intravenous cidofovir has also been found to be useful in treating drug-resistant cases, even in foscarnet resistance (LE: 4, GR: C).

4. Topical cidofovir gel 0.3, 1% (LE: 1B, GR: A) and foscarnet 1% cream (LE: 2A, GR: B) have shown good response in treating drug-resistant genital herpes.

Introduction

The present guidelines aim to provide comprehensiveinformation on genital herpes, including the epidemiology, clinical features, diagnosis and management. The guidelines provide evidencebased recommendations on the prevention and treatment of genital herpes in adults in Asia, including patients with HIV co-infection.

Methodology

A PubMed search last performed on March 23, 2014, using the terms “genital herpes”, “herpes genitalis”, “human herpes virus type 2” and “HSV-2” was carried out. A careful review of the titles and abstracts was done to find all the studies pertaining to epidemiology, clinical features, diagnosis, treatment and prevention of genital herpes. In addition, the 2007 British Association for Sexual Health and HIV (BASHH) National Guideline for the Management of Genital Herpes, the 2010 European guidelines for management of genital herpes and the 2010 US Centers for Disease Control and Prevention (CDC) Sexually Transmitted Disease Guidelines were reviewed in detail.

Epidemiology

According to 2003 WHO estimates, the number of people aged 15–49 years who were living with HSV-2 worldwide was 536 million, or roughly 16% of the world’s population in this age range. The prevalence of HSV-2 infection varies greatly with different geographic regions. Generally, the prevalence was found to be higher in developing countries as compared to developed countries.

The lowest prevalence was seen in Western Europe (18% in women, 13% in men) while the highest was seen in Sub-Saharan Africa (70% and 55% in women and men, respectively).[1] Because of larger population size, Asian countries contribute more prevalent infections to the global total as compared to countries with a smaller population.

Though globally, women were found to have a higher prevalence than men, a sub-data analysis suggests that men are more commonly infected with HSV-2 in South and South-East Asia. This difference from the global scenario is more likely to be due to fewer seroprevalence studies in Asia than a true result.[1] The prevalence of HSV-2 infection increases with age and reaches a peak in the age-group 35-39 years, after which it decreases slightly.[1] Genital herpes infection is primarily caused by HSV-2, but the causative role of HSV-1 has increased over the years. In a study conducted in British Columbia, the proportion of genital herpes due to HSV-1 increased over time from 31.4% to 42.8% over a period of 8 years (1997-2005). Additionally, HSV-1 infection was more likely in females, younger age groups, and later time periods.[2] In an Australian study, cases of first-episode anogenital herpes the proportion attributable to HSV-1 increased from 29% to 42% over a 15-year period, this increase being statistically significant for heterosexual women and MSM younger than 28 years of age.[3] In the developing countries, the proportion of genital herpes caused by HSV-1 is not known, but is presumed to be low.[4] The sero-prevalence of HSV-2 in Asian countries is around 10-30% in general population,[5]with the prevalence being highest in Eastern Asian countries. The prevalence has been found to be lowest in Japan and countries of the pacific region.[1] In India, a cross-sectional study conducted in 2006, the prevalence of HSV-2 infection was found to be 10.1% with significant differences in geographical prevalence. Females (11.3%) had a higher prevalence than males (8.9%), but the difference was not statistically significant.[6] In a cross-sectional study, the prevalence of HSV-2 infection among males in six major cities of Pakistan was 3.4%.[7]

Special population groups

In a retrospective analysis done on 500 pregnant women in Goyang, Korea, the HSV-2 seroprevalence rate was found to be 17%,[8] while in North-East India the overall prevalence was 8.7% in pregnant women.[9]

The incidence rates for HSV-2 infection in female sex workers in Yunnan, China was found to be 21.9 per 100 person years (95% confidence interval 17.8-26.3) in an open cohort study.[10] The prevalence rates for HSV-2 infection in female sex workers in the border area between China and Vietnam was 58.3%.[11]

In a seroprevalence study done in India among 170 STI clinic attendees, 15.88% of the patients tested positive for HSV-2 IgM serology.[12] HSV-2 seroprevalence in HIV-positive individuals has been found to vary from 55-70%.[13][14][15][16][17] However, only about 20-30% of the cases manifest themselves clinically in HIV infected patients.[18][19] In MSM population, the rate of coinfection with HIV was found to be 3.2% in a Chinese study.[20] A Chinese study found that the prevalence of HSV-2 infection in MSM population was 16%.[20]

Risk factors and Prevention

Risk factors

The risk of acquiring HSV-2 infection increases with age and number of sexual partners, including sex partner concurrency. HSV-2 infection occurs more frequently in individuals with a history of other sexually acquired infections including HIV. Women and men who have sex with men (MSM) have been found to have a higher prevalence of HSV-2 infection.

Prevention

Barrier contraceptives

In a large pooled analysis of six prospective studies with individual-level condom use data, it was found that consistent condom users (those who used condom 100% of the time) had a 30% lower risk of HSV-2 acquisition as compared to those who never used condoms (p = 0.01) (IIA).

Risk for HSV-2 acquisition increased steadily and significantly with each unprotected sex act. There was no gender difference in condom efficacy.[21] In a case-crossover study where data was pooled from six prospective studies, it was found that each unprotected act leads to a 3.6% increase in the odds of HSV-2 acquisition (odds ratio = 1.036; 95% confidence interval: 1.021-1.052), but no increase in the odds of acquisition associated with protected acts (odds ratio = 1.008; 95% confidence interval: 0.987-1.030).[22] In another study, more frequent use of condoms was found to be protective against HSV-2 acquisition, but not against HSV-1 acquisition.[23]

Additional use of vaginal diaphragm and lubricating gel has not been found to offer any additional benefit in preventing HSV-2 transmission as compared to male condom use only (LE:1B).[24]

Circumcision

In a meta-analysis of observational studies, the reduced risk of HSV-2 acquisition among circumcised males was only borderline statistically significant (RR=0.88, 95% CI 0.77-1.01) (IA).[25] Similary, in an Indian prospective cohort study, no statistically significant protection against HSV2 was found to be conferred on circumcised males.[26] However, in a RCT (immediate circumcision versus delayed circumcision at 24 months) done on rural Ugandan population, circumcision was found to prevent HSV-2 infection by 28% (LE: 1B).[27] In another study, male circumcision was found to reduce the HSV-2 sero-incidence by about 55%.[28]

In a small study on 40 patients, (therapeutic) circumcision appeared to reduce the frequency of recurrent genital herpes episode and prolong the disease-free interval between the two recurrences.[29] In a study done in North-east India to determine the efficacy of male circumcision in HSV-2 acquisition by spouses, the seroprevalence of HSV-2 in women with circumcised spouses (1.7%) was found to be significantly lower than those with uncircumcised spouses (9.2%).[30]

Antivirals

Valacyclovir 500mg once daily has been demonstrated to significantly reduce the risk of HSV-2 transmission among serodiscordant couples by 48% and clinical disease in the susceptible partner by 75%.[31] In another study, daily acyclovir 400mg twice daily in HIV-1/HSV-2 discordant couples failed to decrease the risk of HSV-2 transmission in susceptible partners.[32] A doubleblind RCT (CAPRISA-004 trial) found vaginal tenofovir1% gel to reduce the acquisition of HSV-2 by 51% in females.[33] In another prospective trial, daily oral emtricitabine/tenofovir did not prevent HSV-2 transmission in MSMs, but reduced the proportion of patients with moderatesevere genital ulcer by half.[34]

Anti-HSV Vaccines

In a RCT, a vaccine consisting of 20 μg of glycoprotein D from HSV-2 with alum and 3-Odeacylated monophosphoryl lipid A as an adjuvant given at 0, 1 and 6 months was found to be only 20% efficacious in preventing genital herpes disease. It was more effective in preventing HSV-1 infection and disease as compared to HSV-2, though it was able to generate a humoral response against HSV-2.[35]

Classifications and Natural history

Genital herpes manifest as grouped vesicles which later become pustular and ulcerate. The erosions are superficial and have characteristic polycyclic margins. New lesions may continue to form for a few days. Complete re-epithelisation can take 1-3 weeks and usually occurs without scarring.

First episode

This is the first time an individual develops genital herpes. It can be further subdivided into true primary and non-primary.

True primary episode

The first episode is considered a true primary episode if the patient does not have antibodies against both HSV-1 and HSV-2, that is in a seronegative individual. It is usually more severe, prolonged (lasting 2-4 weeks) and associated with systemic symptoms.

Non-primary episode

The first episode is considered a non-primary episode if the patient is infected by one HSV type and has antibodies against other type. For example, a patient who has antibodies against HSV-1 and gets infected with HSV-2. Previous infection with HSV-1 reduces the severity of clinical manifestations due to HSV-2 and increases the likelihood of asymptomatic seroconversion by a factor of 2.6 (p<0.001).[36]

Recurrent episode

A recurrent episode is said to occur in an individual if he/she has a past history of genital herpes lesions. It is shorter than the first episode, lasting for 7-12 days before spontaneously resolving.

Sometimes, a patient may have an asymptomatic first episode and may manifest as recurrent episode for the first time.

Etiology

Genital herpes is caused by a DNA virus, Herpesvirus hominis. The genital lesions are usually caused by HSV-2, though the incidence of genital HSV-1 infections is increasing.[2][3]

Natural history

The incubation period ranges from 5-14 days. Transmission often occurs in the absence of clinically detectable lesions, with asymptomatic shedding accounting for majority of viral transmission.[37][38]

HSV establishes a latent infection in the sensory ganglia which is re-activated by a trigger leading to a recurrence. The recurrence may not be clinically detectable (asymptomatic recurrence).

Asymptomatic recurrence or asymptomatic viral shedding is usually more following a clinical episode and during the initial years of infection. PCR-based studies (which are more sensitive than culture-based studies) suggest that asymptomatic viral shedding occurs 12-25% of days.[39][40]Another study suggests that only 7% of anogenital viral reactivation may manifest itself clinically. About half of such viral reactivation lasts for 12 hours or less.[41]

Clinical recurrences are more common and earlier in HSV-2 infections than HSV-1 infections.

Ninety percent patients with HSV-2 infection have atleast one recurrence during the first year.

Though the average number of recurrences is 4-5 per year in HSV-2 infections, it is quite variable with upto 20% patients experiencing more than 10 recurrences. Men were found to have about 20% more recurrences than women.[42] In a cohort study, the rate of HSV-1 recurrences was found to be 1.3/year in the first year of infection which fell to 0.7/year in the second year.[43] The number of recurrences gradually decreases with time at a variable rate.

Diagnosis

Genital herpetic infection is usually diagnosed clinically, especially when the clinical picture is classical, with the presence of polycyclic erosions associated with local adenitis and in recurrent cases preceded by prodrome. However, clinical diagnosis of genital herpes is not a 100% accurate and is highly dependent on clinician’ skill and experience.

Tzanck smear

It is a point-of-care test which does not require expensive equipments, can be easily done in the clinician’s office and yields rapid results, but is highly operator skill-dependant. In a study, the sensitivity of tzanck smear (viral culture as gold standard) in diagnosing anogenital lesions of herpes was found to be 79% for skin lesions and 81% for mucous membrane lesions in men and 52% in women. The specificity was 93%.[44] (LE: 3)

Virus antigen detection

As the natural course of HSV-2 infection is different from that of HSV-1, it is important to perform HSV typing in patients with first-episode genital herpes. (LE: 3)

HSV antigen can be detected and typed by DIF assay using fluorescein-labelled type-specific monoclonal antibodies on smears. It can be classified as a rapid diagnostic test and performs satisfactorily in symptomatic patients. However, its sensitivity may drop to less than 50% (viral culture as ‘gold standard’) when testing asymptomatic patients.[45][46] In a study to determine the utility of DIF test in genital herpes, there was concordance between DIF and viral culture in 85% patients whereas in about 15% patients DIF was positive when viral culture was negative. This method proved to be highly sensitive (97%) in patients with clinically suspected infection. High negative predictive value (99%) proves the clinical utility of the DIF in this group of patients. (LE:3)[47]

Antigen capture EIA is another method which can be used to detect HSV antigen, however unlike DIF test, most of the commercially available assays do not differentiate HSV-1 from -2. The sensitivity of this method, as compared to viral culture, is atleast 95% while specificity ranges from 62-100% in symptomatic patients.[48][49][50] (LE: 3)

Viral culture

Viral culture has traditionally been considered as the ‘Gold standard’ in diagnosis of genital herpes (LE: 4). The sensitivity depends on the nature of the lesion, being 90% from vesicular/pustular lesions, 70% from ulcerative lesions and 27% from crusted lesions. The sensitivity further depends upon the transport and storage facilities.[51] The characteristic cytopathic effect usually appears in 24-72 hours but may take as long as 5 days. The specificity is virtually 100%. Though it is labour-intensive and takes time, the advantage is it can be used for performing anti-viral sensitivity testing. Commonly used cells, sensitive to different viruses, include mainly primary human diploid fibroblasts, such as MRC-5 cells, and cell lines, such as Vero cells (monkey kidney), HEp-2 cells (laryngeal squamous cell carcin-oma), baby hamster kidney and rabbit kidney cells. The CAM of chick embryo has been found to be a simple, cheap and efficient method of cultivation of HSV and can be used in settings where cell culture facilities are not available. (LE: 3).[52] In a study on correlating pock sizes produced on CAM with HSV typing, a 100% concordance of small pock sizes with HSV-1, and of large pock sizes with HSV-2 was found. (LE: 3)[53]

Molecular methods

PCR allows multiplication and detection of the HSV genome in clinical samples. Not only the sensitivity of PCR has been shown to be better than that of viral culture (11-71% superior to viral culture), another advantage is the requirement of less stringent transport conditions as compared to that for viral culture.[54][55][56] (LE: 1B) It is widely regarded as the test of choice for the diagnosis of genital herpes in symptomatic patients. (LE: 4) Compared with traditional PCR, rtPCR is faster, less labor-intensive with minimal technical hands-on time and a lower risk of molecular contamination.[57] A rapid quantitative rt-PCR was found to give the result in 2 hours (range 1.5-3.5 hours). The correlation between the rapid test and conventional TaqMan PCR was excellent (R=0.96, P<.001). (LE: 2B).[58]

Serology

Serological tests detect antibodies in the serum against the virus and have traditionally plated a limited role in the management of genital herpes. They are unreliable in differentiating a primary infection from a recurrent infection as IgM antibodies are not always increased in a primary infection. Conversely, IgG antibodies can be sometimes elevated in a recent infection posing a diagnostic difficulty. In such a setting, a seroconversion or a rising titre of antibodies can help in resolving the issue. (LE: 2A) Additionally, as it is important to know whether the patient has HSV1 or -2 infection, the serology tests which are not type-specific are not useful in the management of genital herpes. Type-specific assays which detect antibodies against antigenically unique glycoproteins G1 and G2 should be used.[59] (LE: 3)

Western blot is considered as the serological gold standard, but is not commercially available. ELISAs, which are commercially available, have about 95% sensitivity and specificity when compared to western blots.[59][60] However, the specificity of the tests varies with the population being tested, as even a highly specific test can have a poor predictive value in a population with a low prevalence. Hence, the test results should be interpreted keeping in mind the local epidemiology and the patient demographic profile. (LE: 3)

Three FDA approved kits are available now to perform type-specific serology. Diagnology's POCkittrade mark HSV-2 is a point of care test for herpes simplex virus type 2 (HSV-2) antibodies. Focus Technologies' HerpeSelect ELISAs can be used for distinguishing between HSV1 and HSV-2. Focus Technologies' HerpeSelect Immunoblot is a novel strip immunoblot test.

Treatment

First-episode genital herpes

First-episode genital herpes can be quite severe, prolonged and usually associated with constitutional symptoms. Additionally, there is an increased risk of local and systemic complications as compared to the recurrent episodes.

All patients presenting within 3-5 days of disease onset or if still forming new lesions should be started treatment with oral antivirals.[61] Antiviral therapy does not alter the natural course of infection. Acyclovir, valacyclovir and famciclovir have been found to be effective in reducing the severity as well as the duration of symptoms.[62][63] (LE: 1B) Intravenous therapy is indicated only in certain situations, when the patient is not able to swallow, has vomiting or has a complicated infection. Topical antivirals are inferior to oral antiviral drugs.(LE: 1B) Moreover, topical acyclovir has been shown to be associated with resistance to oral acyclovir in HIV-negative individuals.[62][64] (LE: 3)

All the recommended regimens are for 7-10 days. These are:

The choice of an antiviral agent should be based upon the cost and compliance of the therapy.

The duration of therapy can be extended depending on the clinical response. Maintain hygiene by saline bathing and local anaesthetics like lignocaine can be used to alleviate pain. Benzocaine should be avoided as it is a potential sensitizer. Hospitalisation may be required in cases complicated by urinary retention, meningismus or severe constitutional symptoms. If catheterisation is necessary for urinary retention, a supra-pubic approach may be preferred over the per-urethral approach as it prevents the risk of ascending urinary tract infection.

Recurrent genital herpes

The recurrent episodes of genital herpes tend to be milder and shorter. Many episodes can be managed with supportive therapy alone.Other treatment options include episodic therapy and suppressive therapy. Treatment for the patient should be individualised taking into account patients’ symptoms, frequency of recurrences and concerns.

Episodic antiviral treatment

Starting therapy within 48 hours of the onset of lesions has been shown to have a greater clinical benefit than initiating treatment later in the disease.[65] Oral acyclovir, valacyclovir and famciclovir have been found to be effective in reducing the severity and the duration of symptoms, with no advantage of one drug over the other. (LE: 1B) The mean reduction in the duration of symptoms is 1-2 days.[66][67][68] Ultra-short treatment course (1-3 days) not only has similar degree of clinical improvement as the 5-day course, but is also more convenient for the patient.[69][70] The reegimens include[71]:

Five-day regimens

Ultra-short regimens

Suppressive antiviral therapy

Most of the earlier studies evaluating the efficacy of suppressive antiviral therapy were done on patients having six or more recurrences per year; this number has been chosen arbitrarily. Suppressive therapy may reduce the number of recurrences even in patients experiencing less frequent episodes. The decision to start suppressive therapy is a subjective one, and should be made in consultation with the patient considering the patient’s needs, concerns, compliance and cost of therapy.

About half of patients on suppressive therapy become symptom-free while the other half experience a significant reduction in the frequency of recurrent episodes (by 70-80%).[61][72] Suppressive therapy with valacyclovir leads to a better QOL than episodic therapy.[73][74][75] (LE:1B) If a patient develops a breakthrough lesion while on being suppressive therapy, the dose of antiviral should be increased to that of the episodic therapy till the lesion lasts, following which the patient is continued on the suppressive doses.

The suppressive therapy should be discontinued after a year to assess the recurrence frequency.

The minimum time to assess the clinical benefit should be two recurrences. It is reasonable to restart suppressive therapy for patients who continue to have high recurrence rates. (LE: 4)

All the three agents seem to have comparable clinical efficacy.[72][76] (LE: 1B) The recommended regimens are

Counselling

As genital herpes is a recurrent disease and has a significant psycho-social burden on the affected patients, medical treatment should be supplemented with counselling. The patients should be educatedregarding the natural course of disease, available treatment options, sexual route of transmission, sexual abstinence during active lesions and safe sexual practices including promotion of condom use to prevent transmission to partner.

Management of partners

There is no evidence on which recommendations for partner notification can be based. However, we recommend examining the partner for any genital lesionsand taking history of genital herpes as it can help in the counselling process (LE: 4).

Genital herpes in HIV

There is epidemiological synergy between HSV and HIV infections. Epidemiological studies demonstrate that the seroprevalence of HSV-2 infection is disproportionately higher in HIV patients as compared to HIV-negative individuals with comparable demographic profile and a similar risk-behaviour for HSV-2 acquisition.

HSV is known to activate the replication of HIV and is associated with increased HIV shedding.

This is supported by the fact that valacyclovir suppressive therapy for HSV-2 significantly reduced the plasma and genital HIV RNA levels.[77] In addition, genital HSV infection increases the risk for HIV acquisition by 2-3 times[78] as it can facilitate HIV transmission, possibly due to a local inflammatory response at the site of herpetic lesions and breach in the genital epithelium. (LE:1A) Conversely, increased HSV shedding has been documented in HIV positive patients, thus HIV infection can lead to an increased risk of sexual transmission of HSV.[79] HIV-associated immunosuppression can also lead to increased severity of infection, more clinical reactivations, persistence of lesions and atypical manifestations of reactivation episodes.[80][81][82] (LE: 3) The degree of immunosuppression due to HIV dictates the clinical morphology, healing time and the degree of recurrence. In untreated HIV patients, herpetic lesions can be severe, prolonged and can develop into chronic non-healing anogenital ulcers with a verrucous morphology, sometimes simulating a tumour.[83][84][85] Genital herpes can also be a manifestation of immune reconstitution inflammatory syndrome (IRIS) following initiation of anti-retroviral therapy.[86]

Though systemic antiviral drugs are effective in treating genital herpes in HIV patients as well, drug resistance is encountered more frequently in PLHIV. In a study, about 5% of HIV-patients had acyclovir-resistant HSV-2 isolates, in contrast to 0.2% in HIV-negative individuals.[64]

First-episode

Controlled trials on the optimum antiviral dose and duration are lacking for patients with genital herpes and HIV co-infection. The antiviral dose for acyclovir, valacyclovir and famciclovir is the same, but given till complete resolution of lesions.[87] (LE: 2B) If the lesions continue to persist or new lesions continue to appear after 3-5 days of treatment, increase the antiviral dose and rule out drug resistance by performing viral culture and drug-susceptibility testing.[71] Some researchers recommend using twice-the-standard dose of antivirals for a 10-day period, especially in advanced HIV infection with low CD4 counts.[88] (LE: 4) In severe cases, intravenous acyclovir 5 mg/kg thrice daily may be required for the initial few days followed by oral acyclovir to complete a minimum of 10-day course.[71]

Recurrent episode

Genital herpes recurrences are more frequent in PLHIV. Initiation of ART decreases the recurrent episodes but has less effect on the asymptomatic viral shedding. Recurrent episodes can be managed with episodic or suppressive treatment. There are no clinical trials comparing the two strategies.

Episodic treatment

Standard doses of antivirals for 5 days can be effective in patients without profound immunosuppression. The dose may have to be doubled and may have to be given for more than 5 days in patients with advanced immunosuppression.[88] (LE: 1B)

Suppressive treatment

All three antivirals have been tried for HSV suppression in PLHIV with good effect. Standard suppressive dose of acyclovir (400 mg BD) has been found to be effective. Valacyclovir 500 mg BD has been found to be better than 1g OD, while 500 mg OD has not been tried in PLHIV. It has been suggested to double the standard dose of these agents if patient continues to develop recurrences. (LE: 1B) If the suppression is still inadequate, famciclovir 500 mg twice daily can be tried.[88] (LE: 2A)

An advantage of suppressive therapy is that it has been shown to decrease not only the plasma HIV levels, but also limit the HIV disease progression in patients with dual infection. In a RCT, suppressive acyclovir therapy (400mg twice daily) was shown to reduce the risk of HIV disease progression (i.e., sustaining the CD4 count above the levels necessitating the initiation of ART) by 16% at 2 years.[89] But we feel that the data is insufficient for it to be routinely preferred over episodic therapy. The decision should be made on a case-to-case basis.

Genital herpes and drug-resistance

Drug resistance to common antiviral agents used to treat genital herpes (acyclovir, valacyclovir, famciclovir) is rare in immunocompetent individuals, but is increasingly becoming common in immunosuppressed patients. A study demonstrated that only about 0.18% HIV-negative patients had drug-resistant HSV-2, in contrast to 5.3% in HIV positive patients.[64] (LE: 3)

Acyclovir is a nucleoside analogue which is phosphorylated by the viral-thymidine kinase to form acyclovir monophosphate. This monophosphate derivative of acyclovir is then converted to acyclovir triphosphate, which in turn causes competitive inhibition of the viral DNA polymerase.

Thus, HSV lacking thymidine kinase (TK-deficient strains) would demonstrate drug resistance.

Because valacyclovir and famciclovir are also nucleoside analogs, acyclovir resistance confers resistance against these agents as well.

The TK-deficient viral strains have been shown to be less virulent as compared to drug-sensitive strains. The clinical reactivation of TK-deficient strains is less frequent, possibly due to a less effective establishment of latent infection.[90][91] Hence further clinical reactivations are likely to be acyclovir sensitive, despite the previous episode being acyclovir resistant (episodic drug resistance).

Drug resistant HSV isolates have shown to be associated with history of prior oral acyclovir use (especially in sub-optimal doses), persistent lesions, recurrent episodes and a low CD4 count.[64]

Drug-resistance should be suspected if lesions are not improving or the patient continues to develop new lesions while on therapy, especially in the setting of immunosuppression.

How to document and manage drug resistance?

If drug-resistance is suspected clinically, a sample should be sent for viral culture and drugsensitivity testing. Simultaneously, a sample for viral PCR should also be sent to document HSV infection. Currently, a molecular method to test drug resistance is not available.

As partially-resistant strains can respond to higher doses of acyclovir, one approach is to treat the patient with high doses of intravenous acyclovir while waiting for the sensitivity report. Once resistance is confirmed, switching to an alternative agent like foscarnet or cidofovir is required.

Foscarnet 40mg/kg every 8 hourly until complete clinical resolution has been shown to be effective in treating acyclovir-resistant genital herpes.[92] (LE: 1B) Intravenous cidofovir 5mg/kg over 1-2 hours till complete healing of lesions is another agent which has been found to be useful. It may even be effective in cases of foscarnet resistance.[93][94][95] (LE: 4) Topical cidofovir gel (0.3%, 1%) once daily for 5 days was found improve lesions of acyclovir-resistant genital herpes in HIV patients in a RCT.[96] (LE: 1B) Fifty percent (10 out of 20) patients in cidofovir arm had >50% improvement, out of which 30% (6 out of 20) had experienced complete subsidence.

In an open-label non-randomised trial, topical foscarnet 1% five times a day for a mean duration of 34.5 days led to improvement in 65% (13/20) of lesions in AIDS patients with acyclovir unresponsive genital herpes.[97] (LE: 2A) There are anecdotal reports of beneficial response with topical foscarnet 2.4%,[98] topical imiquimod 5%,[99] intralesional cidofovir[100] and oral thalidomide[101][102] in drug-resistant herpes. (LE: 3)

Abbreviations

AIDS: Acquired immunodeficiency syndrome, ART: Anti-retroviral therapy, CAM: Chorioallantoic membrane, EIA: Enzyme immunoassay, ELISA: Enzyme linked immunosorbent assay, DIF: Direct immunofluorescence, FDA: Food and drug administration, HIV: Human immunodeficiency virus, HSV: Herpes simplex virus, IRIS: Immune reconstitution inflammatory syndrome, MSM: Men having sex with men, PCR: Polymerase chain reaction, PLHIV: People living with HIV, RCT:Randomised controlled trial, rt-PCR: Real time PCR, TK: Thymidine kinase, QOL: Quality of life, WHO: World Health Organisation

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