Why HIV-positive people need specific treatment guidelines for herpes, by Edwin J Bernard and Adam Legge

The first ever comprehensive set of guidelines for the management of sexually transmitted infections (STIs) in HIV-positive individuals were recently published by the British Association for Sexual Health and HIV (BASHH)¹.

Although many STIs in HIV-positive people can be managed in exactly the same way as those without HIV infection, BASHH singled out genital herpes, as well as genital warts (see ATU 151, November 2005) and syphilis (see ATU 157, June 2006) for special attention. This is because the natural history of untreated genital herpes in HIV-positive individuals is significantly different from HIV-negative individuals in two ways:

• Herpes viruses activate HIV, making it easier for HIV to infect certain cells, which may lead to faster HIV disease progression.
• Genital herpes infection increases the risk of sexual HIV transmission.

Herpes basics

 Herpes simplex virus (HSV) is a member of the herpes virus family, which also includes varicella zoster virus (VZV, which causes chickenpox and shingles) and cytomegalovirus (CMV, which can lead to eye, gut, lung, nerve and brain problems). Once infected, HSV stays in skin and nerve cells for life.

There are two main types of HSV. HSV-1 is the usual cause of cold sores in and around the mouth, also known as oral herpes. HSV-2 is the usual cause of genital herpes, which affects the genital area, including the rectum/anus.

However, HSV-1 can also infect the genital area, and HSV-2 can also infect the mouth area. The BASHH guidelines focus on HSV-2, but they are relevant for anyone who has an herpes infection of any type that affects the genital area.

Although both types of HSV can remain symptom-free for long periods of time, the virus can still be shed – and, therefore, passed on – in genital fluids, even when there are no symptoms. Symptoms appear when HSV becomes activated - when the immune system is weakened; in situations of stress; during a cold; or on exposure to strong ultraviolet light - and this can result in very painful skin eruptions.

Nevertheless, unless the virus infects the brain and causes inflammation, HSV infection is rarely life-threatening. This seldom happens in people with HIV, possibly because the immune system's ability to mount an inflammatory response is impaired.

Does HSV affect me?

Due to the fact that HIV is often sexually transmitted, and genital herpes is always sexually transmitted, HSV infection is a concern for many people living with HIV. Latest figures from the United Kingdom's Health Protection Agency² show that the number of new cases of genital herpes rose four per cent last year, although new diagnoses have remained under 20,000 a year since they dramatically increased at the beginning of this century. There are few UK data on how many people are currently living with genital herpes infection, but United States data suggest that about one in every four women and about one in every five men have an HSV infection. However, it is thought that up to four in every five HIV-positive individuals are also infected with genital herpes³. Unfortunately, many people with genital herpes are unaware of their infection. Data from the US suggest that fewer than one-in-ten people with genital herpes know they have it.⁴

How HIV and HSV interact

There is increasing evidence that the twin epidemics of sexually transmitted HIV infection and HSV infection are linked, primarily because HSV can increase HIV viral loads, and also because the ulcers caused by genital herpes make it easier for HIV to be transmitted during sex.

A 2001 study from Uganda, which examined the factors influencing the transmission of HIV between monogamous partners of different HIV status, found that the two most important factors for HIV transmission were HIV viral load in the HIV-positive partner and the presence of genital ulceration, most commonly caused by HSV⁵.

The following year, an analysis of all the existing data concluded that people infected with genital herpes were more than twice as likely to become infected with HIV than people who didn't have HSV infection⁶.

Other studies have suggested that HSV can activate HIV replication, increasing the amount of HIV in the blood and genitals, and making onward HIV transmission more likely^7,8.

In addition, the course of genital herpes in HIV-positive people with very low CD4 counts (usually below 100 cells/mm³) can be quite severe: ulcers may persist much longer, be more extensive, and more painful. Unfortunately, having a low CD4 count also reduces the chances that anti-HSV drug therapy will work well.

However, people with higher CD4 counts - whether or not they are on anti-HIV therapy- experience HSV infection similar to HIV-negative individuals: the outbreaks tend to be localised, and usually clear up within a week or two.

"Most of the evidence on how HSV interacts with HIV come from the era before effective anti-HIV therapy," explains Dr Rak Nandwani, a consultant physician at the Sandyford Initiative in Glasgow and lead author of the BASHH guidelines. "In fact, genital herpes was considered so severe in those days that genital herpes lesions lasting for longer than a four weeks was made an AIDS-defining condition.

"However," he continues, "now it would be fair to say that if your CD4 counts are good then HSV is likely to be no more a problem for you than for someone who isn't HIV infected."

Treating the first episode

For people with good immune function, the first episode of genital herpes may be symptom-free. However, if symptoms do occur they can be pronounced and usually occur within two weeks of being infected with HSV. They typically appear as one or more blisters on or around the genitals or rectum. These blisters then break, leaving tender ulcers that can take two to four weeks to heal; a second-crop of sores may then appear. The first episode might also include flu-like symptoms, including fever and swollen glands.

The BASHH guidelines recommend that the first episode of genital herpes in HIV-positive people should be treated with aciclovir (Zovirax). Although this is available in pharmacies as a cream for preventing cold sores, it is used here in tablet form (400mg five times a day for seven to ten days). This is higher than the standard recommended dose for HIV-negative individuals.

"We've recommended that all people with HIV get higher doses of aciclovir for the first episode," notes Dr Nandwani, who says that the recommendations are based upon expert opinion and adds that although this intensified treatment "is not currently practised by many doctors," he hopes the guidelines will change that.

Aciclovir has been used to treat genital herpes for almost 20 years, and is considered to be safe and effective, with a very low incidence of side-effects when taken orally. However, the drug needs to be taken so frequently due to its poor bioavailability: only about a fifth of the total amount of the drug taken by mouth makes it into the bloodstream. Adhering to aciclovir five times a day may not be possible for some people, and so the guidelines recommend as alternatives either valaciclovir (Valtrex) 1 gram twice daily for ten days or famciclovir (Famvir) 250-750mg three times a day for ten days. Although studies have found these drugs are equivalent in effectiveness to aciclovir^9,10, and none have significant interactions with anti-HIV drugs, there are cost issues which may mean you wouldn't automatically be prescribed these alternatives unless you specifically asked for them.

"Most people in the UK will be prescribed aciclovir," explains BASHH President, Dr Simon Barton of London's Chelsea & Westminster Hospital, "because that drug is now available in generic form and is, therefore, cheaper." He adds that, "although the other antivirals might be easier to take [due to less pill burden], there's no evidence that they're any better at managing a recurrence."

In severe first-time cases, the guidelines recommend starting intravenous therapy with aciclovir at 5-10mg per kilogram of body weight every eight hours. If new lesions are still forming after three to five days of therapy, the guidelines recommend a repeat viral culture should be taken to test that the HSV is not resistant to medication (see 'Drug-resistant genital herpes').

Episodic or suppressive therapy?

Reactivations of HSV tend to be more frequent and can be more severe in people with HIV- especially in those with CD4 counts of less than 50 cells/mm³, according to Dr Barton. "Optimising the control of HIV is of the utmost importance when managing recurrent genital herpes and once that's been done you can start to look at whether you're going to use anti-herpes drugs for episodic or suppressive therapy," he says.

Episodic treatment involves waiting to take anti-herpes medication as soon as symptoms occur, whereas suppressive therapy may be more effective for people who have more frequent attacks, although this involves taking medication constantly.

"The decision between taking episodic or suppressive therapy is very much dependent on a discussion between doctor and patient," stresses Dr Barton. "If you're getting recurrences once a month, or you're finding the episodes very distressing, then you might well want to consider taking suppressive therapy."

This choice contrasts with current recommendations from the United States, which suggest all HIV-positive people, even those on potent anti-HIV therapy, receive suppressive therapy. "We recommend that HIV-infected patients with HSV-2 coinfection receive counselling about genital herpes and be offered suppressive aciclovir therapy," write Lara Strick and colleagues from the University of Seattle. "Although episodic treatment of symptomatic genital herpes to reduce the duration and severity of the episode is less costly, it is also likely to be less effective than daily suppressive therapy in preventing HSV-2 (and, potentially, HIV-1) transmission and in improving survival, because most HSV-2 reactivation is subclinical. Given the high seroprevalence of HSV-2 among HIV-infected persons, long-term treatment of HSV-2 infection could also have substantial public health benefits." ¹¹

Treating recurrences

If you choose to take episodic treatment, the guidelines state that aciclovir, famciclovir and valaciclovir can all be used.

They recommend one of the following options:

• aciclovir 400mg three times daily for five to ten days
• aciclovir 200mg five ties daily for five to ten days
• famciclovir 500mg twice daily for five to ten days
• valaciclovir 1g twice daily for five to ten days.

Starting anti-HSV therapy as soon as a recurrence is suspected is crucial to success of therapy. Some people with recurrent genital herpes get a tingling sensation where a lesion is going to form, whereas others might not know a recurrence is on the way until they see the characteristic blister start to form.

"You can bet that whenever you get a recurrence that it's going to be at the most awkward time," Dr Nandwani remarks wryly, "usually when you're about to go on holiday or at the start of the weekend when it's impossible to get a clinic appointment. That is why it is important to make sure you have a stash of aciclovir at home so you can start taking it whenever they feel a recurrence coming on."

The new guidelines do not make specific recommendations for suppressive therapy, but BASHH have previously published recommendations in 2001 for the general population with genital herpes:

• aciclovir 400mg twice daily or 200mg four times daily
• or famciclovir 250mg twice daily
• or valaciclovir 500mg daily

Dr Barton recommends that his patients try aciclovir 400mg twice daily or, "for those with very low CD4 counts, 400mg three times daily or valaciclovir 500mg twice daily."

The guidelines make it clear, however, that suppressive anti-herpes therapy in HIV-positive individuals may be less effective than in HIV-negative people. They also recommend that if you decide to try suppressive therapy, it makes sense – especially for people with 'undetectable' HIV viral loads and higher CD4 counts – to interrupt anti-herpes treatment every so often in order to check whether the recurrences are as troublesome as before.

Drug-resistant genital herpes

Occasionally herpes viruses become resistant to anti-HSV drugs. This may be more likely if someone has been on suppressive aciclovir therapy for a long time. Although resistance is rare in people with high CD4 counts, "aciclovir-resistant strains have been found in between five to seven percent of isolates from genital herpes lesions in HIV-infected patients," notes Dr Nandwani, "but these have tended to be people with lower CD4 counts."

Consequently, the guidelines recommend that if lesions are persistent, or recur in someone receiving anti-HSV therapy, then herpes resistance should be suspected and a viral sample taken for sensitivity testing.

Partially resistant HSV strains can sometimes be treated with high-dose intravenous aciclovir but fully aciclovir-resistant strains are also resistant to valaciclovir and another anti-herpes drug, ganciclovir (Cymevene), and are also likely to be resistant to famciclovir.

However, the guidelines make it clear that there are still options for people with resistant HSV. Both topical foscarnet (Foscavir, 1%) cream and cidofovir (Vistide, 1%) gel have been shown to produce significant benefits in healing lesions, reducing pain and suppressing herpes virus in drug-resistant herpes in people with HIV. There is also limited evidence to support the use of the newer antiviral drug trifluorothymidine (trifluridine, TFT) either on its own or in combination with interferon-alpha.

But the preferred treatment for drug-resistant herpes is intravenous cidofovir or foscarnet. Both of these medications are more regularly used to treat CMV infection and have substantial side-effects, notably kidney toxicity. Consequently, these should not normally be given to anyone with pre-existing kidney problems, or those taking drugs that might also cause kidney problems.

The future of herpes therapy

Simon Barton believes that any new drug will have to go some way to better currently available options. "Aciclovir is cheap and very effective if used early enough in herpes infections," he says, "and it is also very safe. We use it at very high doses even in children without substantial problems."

Currently, two helicase-primase inhibitors are being studied by Bayer and Boehringer Ingelheim. These stop HSV replication by blocking the activity of two enzymes - helicase and primase – which work together to make new DNA copies of the virus.

A topical cream is also in development. "There were some very intriguing results from a study of a version of the genital warts treatment imiquimod, called resimiquimod," notes Dr Barton, "which, when applied topically, lengthened the time between herpes recurrences. However, that study was done a few years ago and we're still waiting for further information."

"Of course the Holy Grail is a herpes treatment vaccine," adds Dr Nandwani, "but results so far have been disappointing."

And although GlaxoSmithKline are currently developing a vaccine to prevent HSV infection, it only appears to protect women, and like the recently US-approved HPV vaccine Gardasil, needs to given before sexual maturity to be most effective. Currently, a major trial in young women, called HERPEVAC, is underway, and results are due in 2008.

References

1. Nandwani R et al. available from: www.bashh.org

2. see: www.hpa.org.uk/infections/topics_az/hiv_and_sti/epidemiology/datatables2005.htm

3. see: www.aidsinfonet.org/factsheets/en/docs/508.doc

4. Hook E. An ounce of prevention. Ann Intern Med 143(10): 751-752, 2005.

5. Gray RH et al. Probability of HIV-1 transmission per coital act in monogamous, heterosexual, HIV-1 discordant couples in Rakai, Uganda. Lancet 357: 1149-1153, 2001.

6. Wald A et al. Risk of human immunodeficiency virus infection in herpes simplex virus type-2 seropositive persons: a meta-analysis. JID 185: 42-52, 2002.

7. Gray RH et al. Determinants of HIV-1 load in subjects with early and later HIV infections in a general population cohort of Rakai, Uganda. JID 189:1209-1215, 2004.

8. Schacker T et al. Changes in plasma human immunodeficiency virus type 1 RNA associated with herpes simplex virus reactivation and suppression. JID 186: 1718-1725, 2004.

9. Romanowski B et al. Efficacy and safety of famciclovir for treating mucocutaneous herpes simplex infection in HIV-infected individuals. AIDS 14(9): 1211-1217, 2000.

10. Conant MA et al. Valaciclovir versus aciclovir for herpes simplex virus infection in HIV-infected individuals: two randomized trials. Int J STD AIDS 13(1): 12-21, 2002.

11. Strick LB et al. Management of herpes simplex virus type 2 infection in HIV type 1-infected persons. Clin Infect Dis 43(3): 347-356, 2006.

12. Posavad et al. Frequent reactivation of herpes simplex virus among HIV-1-infected patients treated with highly active antiretroviral therapy. JID 190: 693-696, 2004.