AIDS Treatment Update, Issue 60, December 1997
Edward King

The concerns stem from a letter sent by the US Food and Drug Administration to American doctors in July 1996. It reported 15 cases of spontaneous bleeding episodes among people with haemophilia in Europe who were being treated with saquinavir, indinavir or ritonavir at the time. Since then, a total of 55 cases of unusual bleeding have been reported world-wide among haemophiliacs receiving protease inhibitor therapy.

Most of the bleeds have been of a type known as haematomas, in which the bleeding occurs into body tissues, causing a swelling. Only a minority of these bleeds have been haemarthroses (bleeding into a joint), the type that is most common among people with haemophilia.

**Cause or coincidence?

The FDA stressed that there is no conclusive evidence that these unexpected bleeds were caused by the protease inhibitors (PIs). It is possible that it was simply a coincidence that these people were taking a PI.

There were no reports of increases in bleeding or blood clotting problems among haemophiliac or non-haemophiliac participants in clinical trials of protease inhibitors. However, in a study reported at the annual Retroviruses conference in Washington in Spring 1997, French researchers reported that two out of 21 non-haemophiliac people showed signs of blood clotting abnormalities after they started treatment with ritonavir or indinavir (abstract 201).

Dr Keeling, a consultant at the Haemophilia Centre at Oxford's Churchill Hospital, agrees that "the evidence is really anecdotal. If there is a real link with protease inhibitor treatment, we don't know whether it's something that will only affect a small minority of patients, or whether everyone is at an increased risk of bleeds. No-one has come up with any explanation of how the protease inhibitors might cause an increase in bleeding. I still remain slightly sceptical."

Dr Keeling expressed concern that the reports might be used as a pretext to deny PI therapy to people with haemophilia. "If someone with haemophilia needs treatment with a protease inhibitor they should receive it, and be monitored carefully. These reports shouldn't be used just as an excuse not to give expensive drugs to haemophiliacs."

Nevertheless, there continue to be reports of bleeding problems apparently related to PIs. At the recent Hamburg conference, Spanish doctors reported that 5 out of 17 haemophiliacs who were treated with indinavir as part of their combination therapy developed bleeding episodes; the three major bleeds were all haematomas (abstract 380).

Irish doctors also reported on their experience of treating 20 haemophiliacs with protease inhibitors. While there was no statistically significant increase in the number of bleeding episodes or in patients' requirements for the blood clotting factor used to treat and prevent bleeds, two individuals with severe haemophilia did report unusual haematomas (abstract 564).

While the majority of people with haemophilia have not experienced problems with protease inhibitors, the uncertainty has left many either very cautious about or already decided against taking a protease inhibitor.

**Hepatitis co-infection

People who were infected with HIV through contaminated blood products are very likely also to have been infected with hepatitis B virus (HBV) and/or hepatitis C virus (HCV). Most people who were infected with HIV through injecting drug use are also co-infected with HBV and HCV. There is no convincing evidence that co-infection with HBV or HCV affects the rate of HIV disease progression - at least during the first decade after infection.

However, in a proportion of infected people, HBV or HCV can cause chronic (long-term) infection, which may result in liver damage. HCV may also infect cells elsewhere in the body, such as in the lymphoid tissue. There is some evidence that HIV-positive people who also have HCV are more likely to suffer liver damage than HIV-negative people with HCV. Among those who do develop liver damage, it can have a significant impact on their HIV treatment options.

The liver helps to filter foreign substances - including some drugs - out of the blood. If the liver has been severely damaged by chronic hepatitis virus infection, it may be less efficient at filtering the blood. This may allow drugs to reach higher levels for longer, increasing the risk of toxicities. Liver damage may show up in the form of unusually high levels of liver enzymes in the blood, although some people with HCV-related liver disease may not show any signs of abnormalities in these blood tests. Viral load tests for HBV and HCV have also been developed, although these are not yet widely used, and their usefulness remains unclear. The clearest way to detect liver damage is to examine a sample of liver tissue, taken using a needle through the skin.

Treatment with certain anti-HIV drugs may not be recommended for people with high liver enzyme levels. For example, protease inhibitors may worsen the liver damage. In a Canadian study of the combination of ritonavir and saquinavir, HIV-positive people who were co-infected with HBV or HCV were more likely to suffer liver toxicity, and a quarter of co-infected people have had to stop treatment because of it.

Dr Ray Brettle of Edinburgh's City Hospital treats a large group of injecting drugs users who are co-infected with HIV and hepatitis viruses. "I have never withheld anti-HIV treatment from a patient because of their liver disease", he told us. "My approach is to offer treatment to people who need it and then monitor their liver enzymes carefully. People taking nucleoside analogues alone hardly ever have problems, but since we've started to use protease inhibitors we've had to stop therapy in quite a few case, and try to restart it later when the liver settles down."

The main treatment for HBV or HCV is alpha interferon, which causes severe flu-like side-effects. Its benefits are limited even among HIV-negative people and it appears to be even less effective among people who are also HIV-positive. The anti-HIV drug 3TC also inhibits HBV and is far easier to take than interferon, so may be a particularly attractive option for co-infected people. However, there is one caveat: in September 1997 3TC's manufacturer, Glaxo Wellcome, warned that people with HBV-related liver damage who stop 3TC may experience `flare-ups' of hepatitis that may be serious enough to require hospitalisation, or may even be fatal.

**BOX: Hepatitis A and anti-HIV therapy

There have been recent reports of an increase in cases of hepatitis A, a less serious form of viral hepatitis than HBV or HCV, among gay men in London and Brighton. Hepatitis A is transmitted by contact with faeces, either from contaminated food or water, or during sexual contact such as rimming.

Hepatitis A may be of particular concern to HIV-positive people, since it can cause a period of acute illness during which the liver may not be able to handle anti-HIV drugs properly. At worst, people on combination therapy may have to stop treatment until the hepatitis resolves.

Genito-urinary medicine (GUM) clinics can offer a blood test to see whether you have already been exposed to hepatitis A. Government guidelines on immunisation recommend that gay men who have not been exposed should be given a vaccine to protect them against hepatitis A infection. This vaccine is safe for people with HIV to receive.

Despite the Government guidance, however, some GUM clinics are not immunising gay men. Others will only vaccinate gay men who have been referred to the clinic by their GP.

**References

The FDA letter to doctors about protease inhibitors and bleeding can be read on the Internet at http://www.fda.gov/medwatch/safety/protease.htm

Glaxo Wellcome's letter warning of hepatitis B flare-ups after stopping 3TC can be read at http://www.fda.gov/medwatch/safety/1997/lamivu.htm

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