Herpes simplex virus (HSV) is a member of the herpes virus family which also includes varicella zoster virus (VZV) and cytomegalovirus (CMV).

HSV is common in the population. Once infected, the virus stays in skin and nerve cells for life. Most of the time it is dormant and causes no symptoms, but from time to time it can flare up. This tends to happen when the immune system is weakened, in situations of stress, during a cold or on exposure to strong ultraviolet light, even in people without HIV. Such attacks occur more frequently in children and the elderly, since these groups tend to have less efficient immune systems than adults.

There is some evidence that herpes viruses can act as a co-factor in AIDS, activating HIV and making it easier for HIV to infect certain cells. Genital herpes infection also increases the chances of sexual HIV transmission (Freeman 2004).

Symptoms

There are two main types of HSV. HSV-1, or oral herpes, is the virus which causes cold sores (herpes labialis). These are tingling or painful spots on the edge of the lip where it meets the skin of the face. These can occasionally develop on the nostrils, on the gums or on the roof of the mouth.

HSV-2, or genital herpes, is the major cause of very painful genital or anal ulcers, sometimes accompanied with fever, headache, muscle ache and malaise.

Herpes lesions often start as numbness, tingling or itching. This feeling indicates that the virus is travelling along the nerve to the skin. At the skin it causes small bumps that rapidly develop into small inflamed fluid-filled blisters or vesicles. These burst and crust over, taking around two weeks to heal. The virus can be passed from person to person by contact between these lesions and mucous membranes. Among HIV-positive people, herpes lesions usually also contain large quantities of infectious HIV.

In people with HIV, herpes recurrences tend to be more frequent, more severe and longer lasting. Sometimes the lesions can become infected with other bacteria or fungi. As well as causing large oral and anogenital lesions, herpes can occasionally affect the throat, colon and other organs including the liver, eye and lung. Herpes encephalitis is inflammation of the brain, causing a range of symptoms including headache, nausea, anxiety, depression, confusion, loss of co-ordination, memory loss and seizures (Grover 2004). However, this is rare in people with HIV, possibly because the immune systems ability to mount an inflammatory response is impaired. Herpes encephalitis is potentially fatal if it does occur.

An HIV-positive person who has herpes attacks of the skin and/or mucous membranes which last for four weeks or longer, or herpes in the throat of any duration, is diagnosed as having AIDS.

Diagnosis

HSV is diagnosed by growing or 'culturing' the virus from a swab taken from a lesion, or by using a fluorescent screening test to detect viral antigens. A polymerase chain reaction (PCR) test to look directly for the virus genetic material is available, but not in widespread use. PCR may be useful for diagnosing herpes encephalitis, which otherwise can only be definitively diagnosed by brain biopsy, since HSV cannot be cultured from cerebrospinal fluid (CSF). Herpes in the throat or colon may need to be examined using fibre-optic instruments.

Treatment and prophylaxis

Combination anti-HIV therapy has significantly reduced the prevalence of active herpes among people with HIV (Ceballos-Salobreñ¡ ²000). Effective antiretroviral therapy boosts the immune system and reduce the chances of a herpes outbreak. Patients not taking anti-HIV therapy who are experiencing repeated herpes infections should consider treatment for HIV to strengthen the immune system and to treat or prevent herpes indirectly.

Herpes infections are commonly treated with aciclovir (Zovirax). Although this is available in pharmacies as a cream for preventing cold sores, it is used in tablet form (200 to 800mg fives times a day for five to ten days) to treat serious attacks or genital or anal ulcers. It also comes as an intravenous drip (5 to 10mg/kg every eight hours) for very severe attacks or those involving the brain or eye. Aciclovir has very few side-effects. The use of aciclovir is recommended in the British Association for Sexual Health and HIV's (BASHH's) 2006 guidelines for the management of sexually transmitted infections in people with HIV.

Aciclovir is a very expensive drug in its branded form, but generic forms of aciclovir are becoming available. These are manufactured in a large number of countries, and have made the cost of treating herpes simplex somewhat more affordable in middle and low income countries.

Valaciclovir (Valtrex) is a pro-drug of aciclovir that is broken down to aciclovir in the body. This enables three- to fourfold greater levels of aciclovir to be reached in the blood. Previously such high levels, which are required to treat serious herpes infections, could only be achieved through intravenous infusions of aciclovir. It is licensed for treating single or recurrent outbreaks of herpes simplex or zoster. Valaciclovir is as effective as aciclovir in treating herpes simplex and reducing genital shedding of the virus. It has also been shown to be safe for use in HIV-positive patients (Gupta 2004; Warren 2004).

Occasionally herpes viruses become resistant to these drugs. This may be more likely if someone has been on aciclovir prophylaxis for a long time. Oral valaciclovir or high dose intravenous aciclovir may be useful against mildly resistant HSV. However, intravenous foscarnet (Foscavir) is a licensed treatment for resistant HSV. A topical (ointment) version of foscarnet is also available on a named patient basis and has been used effectively in a number of case reports. Cidofovir gel also appears effective, although the trial results were not convincing enough to win United States Food and Drug Administration approval in May 1997. Intravenous cidofovir (Vistide) may be another option for people with aciclovir-resistant herpes, although it is not licensed as a treatment for drug-resistant herpes in the United Kingdom. One study showed intravenous cidofovir was effective against herpes with resistance to both aciclovir and foscarnet (Saint-Leger 2001). In the United States, topical trifluridine solution is another option for the treatment of drug-resistant herpes.

Various other drugs are also being studied, including trifluorothymidine and sorivudine. Treatments that have failed to show benefit in aciclovir-resistant herpes include vidarabine, BW-348U87 and the bioflavanoid plant extract SP-303.

Aciclovir cannot eliminate latent herpes simplex virus in nerve cells, so herpes attacks may recur after an attack has been treated. It may be possible to delay or prevent some recurrences by taking aciclovir tablets (often 400mg twice daily) as maintenance therapy or 'secondary prophylaxis'. Breakthrough attacks may be due to the development of aciclovir-resistant strains of herpes simplex virus. After taking long-term maintenance therapy it is unwise to stop abruptly, as this may result in a serious herpes outbreak.

Famciclovir (Famvir) and valaciclovir (Valtrex) can also be used to prevent recurrent genital herpes but they are not licensed for this use in the United Kingdom.

An HSV-2 vaccine has been tested, and found to protect women, but not men, from infection. The manufacturer, GlaxoSmithKline is currently conducting a second large phase III study in the United States to confirm this finding.

Despite previously demonstrated associations between low vitamin A levels in the blood and genital shedding of HSV-2, a recent study has shown that vitamin A supplementation does not reduce shedding in HIV-positive women (Baeten 2004).

Research

Freeman (2004) carried out a cross-sectional study of 1000 married HIV-serodiscordant or HIV-positive couples in 4 sub-Saharan cities between 1997 and 1998. The strongest risk factor for both partners being HIV-positive was HSV-2 infection in one or both partners (one partner: odds ratio [OR] 3.4, 95% confidence interval [CI] 0.6, 18.4; both partners: OR 8.6, 95% CI 1.6, 45.0). Significant factors associated with protection from HIV infection were circumcision and duration of marriage.

Gupta (2004) treated 69 HIV-negative women with genital HSV-2 with oral valaciclovir, aciclovir or placebo in a 3-period crossover trial for 7 weeks each. During placebo, the HSV shedding rate in genital swabs was 15% of days by culture. Valaciclovir caused a 97% reduction in shedding (95% confidence interval [CI] 93, 99%) and aciclovir caused a 95% reduction (95% CI 90, 97%). There was no significant difference between drugs

Oral aciclovir is approved for the treatment of HSV-related syndromes and reduces the severity and duration of HSV symptoms. Aciclovir is also effective as primary and secondary prophylaxis against herpes simplex. However, the long-term use of suppressive aciclovir in people with HIV has been associated with the development of thymidine-kinase deficient, aciclovir-resistant herpes simplex infections. Retrospective studies have suggested that 5% to 10% of HSV cases among people with HIV involve aciclovir-resistant strains (Cotarelo).

Conant conducted two studies of valaciclovir versus aciclovir for anogenital herpes in HIV-infected individuals prior to widespread use of highly active antiretroviral therapy (HAART). In Study 1, 1062 patients with CD4 counts above 99 cells/mm³ received either suppressive valaciclovir or aciclovir for one year. In Study 2, 467 patients were treated episodically for at least 5 days with valaciclovir or aciclovir. Valaciclovir was as effective as aciclovir for suppression and episodic treatment of herpes. Compared with aciclovir, the hazard ratios for time to recurrence for valaciclovir 500mg twice daily and 1000mg once daily were 0.73 (confidence interval 0.50-1.06) and 1.31 (CI 0.94-1.82). Twice daily valaciclovir (500mg) was superior to once daily dosing in terms of time to recurrence. In study 2, valaciclovir 1000mg twice daily was comparable to aciclovir on the duration of a herpes episode. Adverse events were similar among treatments.

Javaly treated 20 HIV-infected people with aciclovir resistant herpes lesions with foscarnet cream. Treatment was applied 5 times daily for an average of 34.5 days. 40% (8) had complete resolution of lesions, 20% had an excellent response, 5% had a good response, 25% had a partial response and 15% (3) had no response. Side effects included skin reactions at the site of application.

Mole reported that plasma HIV RNA levels increased 3.4-fold (range 0-10-fold) during active herpes simplex virus infection in 16 HIV-infected people. All subjects were treated for an acute HSV outbreak with aciclovir for 10 days, followed by chronic prophylaxis. 30-45 days after the appearance of lesions, plasma viral load remained above pre-outbreak levels in some subjects.

Saint-Leger reported a case study of an HIV-infected person without AIDS, and CD4 count of 150 and undetectable viral load who was hospitalised for a recurrent genital herpes resistant to aciclovir, valaciclovir and foscarnet. After failure of the standard therapies, the herpes resolved following treatment with intravenous cidofovir.

Vago (2002) reported that the prevalence of HIV encephalitis and brain lesions fell significantly during the 1990s, as antiretroviral therapies were introduced.

Balfour recommended that if HSV lesions fail to respond to aciclovir, doses should be increased to 800 mg five times daily. If there is no response after five to seven days, add topical trifluridine every 8 hours or, if lesions are not accessible, IV foscarnet (60 mg/kg twice daily or 40 mg/kg three times daily) until healing is complete.

Lalezari randomised 30 people with aciclovir-resistant herpes simplex to receive either a placebo or cidofovir gel at 0.1% or 0.3% applied once daily for 5 days followed by observation. Participants median CD4 count was 9. None of the placebo recipients had complete or partial responses or converted to culture negative. However, 30% of cidofovir-treated people had complete responses after a median of 21 days and 87% converted to culture negative after a median of 2 days. There was no difference in adverse events between the groups.

Erlich treated 4 AIDS patients with severe aciclovir-resistant HSV-2 disease with foscarnet (60 mg/kg intravenous every 8 hours) for 12 to 50 days. Dramatic clinical improvement, marked clearing of lesions, and eradication of HSV from mucous membranes were noted.

Tan treated 6 patients with aciclovir-resistant HSV with foscarnet (40 mg/kg intravenous every eight hours for 14 days, followed by 40 mg/kg/day maintenance). Significant or complete healing of lesions occurred in all patients by the end of day 14. Foscarnet maintenance suppressed the recurrence of lesions for up to 10 weeks. Recurrent lesions were successfully treated with re-induction of foscarnet. No significant renal or neurological toxicities were seen. One patient developed persistent penile ulcerations.

Safrin compared foscarnet (40 mg/kg intravenous every 8 hours) to vidarabine (15 mg/kg/day) for aciclovir-resistant mucocutaneous HSV (ACTG 095). 8 patients received foscarnet and 6 received vidarabine. The study was halted due to excessive toxicity and inferior efficacy of vidarabine. No patient healed on vidarabine. Lesions reduced in size and healed more rapidly in foscarnet recipients. Pain resolution and cessation of viral shedding also occurred more quickly in foscarnet recipients. 3/6 vidarabine patients had neurotoxicity (confusion, myoclonus) that required discontinuation of treatment; no foscarnet patients discontinued treatment due to toxicity. All healed patients had a recurrence of aciclovir-resistant HSV (median time to relapse 42.5 days after discontinuation of foscarnet).

Pottage identified 34 clinical isolates of aciclovir-resistant HSV from 25 people, 20 of whom had AIDS. Antiviral drugs included trifluridine (TFT), FIAC, FIAU, FMAU, vidarabine and foscarnet were tested for efficacy in vitro. Foscarnet, vidarabine and trifluridine were the most consistently active agents. The IC₅₀ of trifluridine for 27 of 34 isolates was less than 1.0 µg/ml.

Kessler enrolled 26 people with AIDS in an open-label study (ACTG 172) of topical trifluridine (TFT) for ACV-resistant chronic mucocutaneous HSV. Lesions healed completely in 7/24 participants in a median of 7.1 weeks after a median of 3.4 weeks treatment. Lesions reduced by more than 50% in an additional seven participants. During therapy, eight patients developed new satellite HSV lesions. Lesions were somewhat less likely to respond if they were smaller in size and fewer in number. There were no significant toxicities.

Hovi reported a placebo-controlled study in which 46 HIV-negative adults with oral herpes were treated with topical vitamin C solution. A solution of 100 mg vitamin C dissolved in 3ml water was pressed onto herpes sores on the lips using a cotton wool pad three times at 30 minute intervals. Vitamin C recipients reported significantly faster healing of sores and a reduced rate of scabbing or swelling compared with those given a placebo.

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