AIDS Treatment Update, Issue 65, May 1998
Edward King

HHV-8 stands for human herpes virus 8; another name for the same virus is Kaposi's sarcoma-associated herpes virus (KSHV). Fragments of its genetic material were first isolated from KS lesions in 1994. Since then, researchers around the world have been investigating its possible role.

* WHO GETS KS?

KS lesions were first observed in elderly Mediterranean men in the 1860s. Since earlier this century, the lesions have been observed among a significant minority of people of all ages in Africa. In more recent times, KS has been seen among some organ transplant recipients whose immune systems have been deliberately suppressed to prevent the organ from being rejected. Since 1981 KS lesions have been among the symptoms experienced by people with AIDS (especially gay men and Africans).

Among people with HIV, KS on the skin can occur at relatively high CD4 counts. At this stage it rarely causes health problems and may not require treatment, although the psychological impact of having visible signs of HIV infection can be immense. At lower CD4 counts, KS is more likely to cause widespread skin lesions and to affect the internal organs, making treatment essential. KS is one of the diseases included in the definition of AIDS, so any HIV-positive person who develops KS is diagnosed as having AIDS. AIDS-related KS is often much more aggressive than the types of KS seen in HIV-negative people, which rarely cause significant illness (except in babies).

KS is much more common among HIV-infected gay men and Africans than among other groups of people with HIV (such as non-Africans infected through heterosexual sex, or people infected through contaminated blood products or injecting drug use). This has long led researchers to suspect that KS may be caused, at least in part, by something other than HIV itself.

* EVIDENCE LINKING HHV-8 AND KS

The discovery of HHV-8 in KS lesions does not prove that the virus causes the lesions _ it could simply be a common, harmless virus that happens to flourish in the abnormal tissue of KS lesions.

However, recent studies have confirmed that HHV-8 can almost always be found in KS lesions _ including non-HIV-related KS _ but is very rare in other body tissues (except for one other rare type of cancer). It is also rare among people who do not have KS. Scientists have uncovered a number of different ways in which HHV-8's genes, alone or combined with HIV (and perhaps other undiscovered factors), may trigger abnormal blood vessel growth.

Experimental blood tests for antibodies to HHV-8 have been developed for use in research studies _ but there remain serious question marks over their ability accurately to detect HHV-8 among people who do not have KS lesions, and the results of surveys to date should be viewed with caution. These tests are not currently available through clinics.

Tests on stored blood samples from a large group of American gay men found that among men who were infected with both HIV and HHV-8 in the early- to mid-1980s, 50% had developed KS lesions within ten years. The more sexual partners and the more sexually transmitted diseases a man had, the more likely he was to have HHV-8, providing further evidence that it may be sexually transmitted. 48% of HIV-positive gay men had HHV-8 _ as did 17% of HIV-negative gay men.

A different American study found that among a group of HIV-positive gay men, the proportion who tested positive for HHV-8 increased steadily over time, from 14% in 1984 to 36% in 1997. These figures mean that each year, 6% of the men became infected with HHV-8. There was some evidence that men who became infected with HHV-8 when they were already HIV-positive were at even higher risk of developing KS than those who acquired HHV-8 before HIV.

Among a group of HIV-positive Danish gay men followed since 1981, infection with HHV-8 was most likely to occur before 1985. Everyone who developed KS lesions had already been infected with HHV-8. In another study among gay men, the average time between infection with HHV-8 and the appearance of KS lesions was 33 months.

Last month, results of blood tests for HHV-8 on 2,718 people attending STD clinics in London were reported. 19.4% of heterosexuals born in Africa,18.2% of the gay men but only 4.6% of heterosexuals not born in Africa were infected with HHV-8. The study did not look at HIV-positive and negative people separately.

Finally, a PCR viral load test for HHV-8 has recently been developed. Preliminary research found that people with KS lesions had higher levels of HHV-8. High or rising levels were seen in people whose KS was progressing. HHV-8 levels fell when KS was treated with chemotherapy. All these points are similar to the relationship between HIV viral load and HIV disease progression, reinforcing the evidence that HHV-8 and KS are linked.

* HOW IS HHV-8 TRANSMITTED?

No-one knows precisely how HHV-8 is passed from one person to another. In studies of people with HIV in the USA, the risk of infection with HHV-8 increases significantly at around the time when people become sexually active. However, some infection seems to occur at younger ages, suggesting that transmission may sometimes be possible through certain types of day-to-day contact.

For many years, epidemiological studies have suggested that among HIV-positive gay men, those who report regular oral-anal sex (rimming) are the most likely to develop KS. This suggests that HHV-8 might be most easily transmitted through contact with faeces. HHV-8 can only rarely be detected in semen, even among people with KS lesions.

In the USA there is little evidence of mother-to-baby transmission of HHV-8 _ although this may be because very few HIV-positive American women are infected with HHV-8 in the first place. In African countries, where a far higher proportion of HIV-infected women also have HHV-8, HHV-8 has been detected among a significant proportion of their children, suggesting that mother-to-baby transmission can occur.

* COULD ANTI-HHV-8 DRUGS HELP?

Current treatments for KS range from therapies designed to destroy individual skin lesions, such as radiation or injections with anti-tumour drugs, through to drugs that act throughout the body such as chemotherapy.

More recently, researchers have started to look for drugs that inhibit HHV-8, and to test whether these are effective at reducing the number or size of KS lesions. There is also interest in whether these drugs can prevent KS from appearing in the first place.

HHV-8 belongs to the herpes virus family, so anti-viral drugs such as ganciclovir, foscarnet and cidofovir (used to treat CMV) and acyclovir (used to treat herpes simplex) have been tested against HHV-8. In test-tube studies, acyclovir has no effects against HHV-8, ganciclovir and foscarnet have only modest effects, and cidofovir has quite strong effects. Trials of cidofovir as a treatment for KS are now taking place in the USA.

Other evidence that the anti-CMV drugs may be effective against KS has come from studies of people who received foscarnet or ganciclovir as treatment for CMV retinitis _ although not all of these studies agree. In a study of over 20,000 HIV-positive Americans, people who received foscarnet at any time were 70% less likely to develop KS than people who never received foscarnet. Receiving ganciclovir did not seem to affect the risk of developing KS. In a French study of over 16,000 people, neither foscarnet or ganciclovir was linked to a reduced risk of KS. Lastly, in a study of over 3,500 people in the UK, people who received foscarnet or ganciclovir seemed less likely to develop KS.

A pilot study in which people with KS were treated with intravenous foscarnet found that lesions did decrease during treatment. However, all the IV anti-CMV drugs are very toxic, and are unlikely to be feasible therapies for KS. Several better-tolerated broad-spectrum anti-viral drugs are in development, such as adefovir or lobucavir, but there is no information yet about effects against HHV-8.

Dramatic recoveries from KS have been seen in many cases during anti-HIV therapy that includes a protease inhibitor. This is thought to be due to improvements in the immune system. However, one recent test-tube study has suggested that HIV protease inhibitors may also have anti-HHV-8 effects.

The positive outcome is the same _ a recent reduction in cases of KS. In a study of 6,700 HIV-positive gay men in the USA, no new cases of KS were seen in 1996 _ a dramatic reduction from 1993-1995 that coincides with the widespread use of protease inhibitors.

* Sidebar: LATEST RESEARCH

Much of the newest research on HHV-8 described in this article was presented at the Second National AIDS Malignancy Conference in Bethesda in April 1998. Detailed daily summaries and the conference abstracts can be read on the Internet at http://www.healthcg.com/hiv/2ndnciconf

The US study of HHV-8 in US gay men was published in the New England Journal of Medicine 338:948-954, 2nd April 1998.

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