AIDS TREATMENT UPDATE, July 1995
Edward King

Microsporidiosis is infection with the Microsporidia family of gut parasites. No-one knows how the organisms are transmitted from person-to-person, although many people with microsporidiosis have a history of extensive foreign travel or overseas residence.

Microsporidiosis is associated with severe diarrhoea and, because nutrients are not absorbed properly from the gut, weight loss. Other symptoms, which are often intermittent, can include cramping stomach pains, nausea, wind and irregular bowel movements. Occasionally the Microsporidia organisms can spread to other parts of the body, where they can cause problems such as sinusitis.

The link between Microsporidia and diarrhoea isn't clear-cut; the organisms can be found in the gut of some people with HIV who don't have diarrhoea. As there can be many causes of diarrhoea in people with HIV, microsporidiosis is only diagnosed when the organisms can be detected in a sample of faeces. Less commonly, a sample of bowel tissue may be removed and examined under the microscope for the organisms (small bowel biopsy).

TREATMENTS

There is no standard treatment for microsporidiosis. The most promising treatment to date is albendazole, an anti-parasitic drug that can eradicate some species of Microsporidia, but not all of them. The drug metronidazole can also be helpful in reducing the number of organisms and relieving symptoms. However, in cases where the organisms are not eliminated by albendazole treatment, the diarrhoea can often return after treatment is stopped.

A complementary approach is to try to suppress the symptoms using standard anti-diarrhoea medicines such as loperamide (Imodium) or co-phenotrope (Lomotil). Dietary changes may also help, such as reducing the amount of fat in the diet and increasing simple carbohydrates.

NEW RESEARCH

The latest report focuses on the use of thalidomide to relieve the symptoms of microsporidiosis among people who had previously failed to respond to albendazole. Doctors at the Chelsea and Westminster Hospital in London noted that people with microsporidiosis often have high levels of the cytokine tumour necrosis factor (TNF) in their faeces, so tried using thalidomide because the drug reduces TNF levels. The preliminary results were published as a letter to the journal AIDS.

The doctors treated twelve HIV-positive gay men who had had diarrhoea for between 2 months to 2 years and who had no gut infections other than Microsporidia. They were having an average of 6 liquid bowel movements per day, and taking six anti-diarrhoea tablets per day. Thalidomide was given at a dose of 100 mg every night (because it can cause drowsiness) for 3 weeks. Everyone's symptoms improved, often within 3 days of starting treatment.

The average number of bowel movements per day fell to 2.8, as did the average number of anti-diarrhoea tablets, and stools became semi-solid. Before starting treatment, participants had lost an average of 8.4 kg in weight, but after 3 weeks on thalidomide they gained 1.2 kg.

The drug didn't eliminate Microsporidia organisms, although under the microscope the spores did appear to have been damaged. Thalidomide's mode of action in people with microsporidiosis remains unknown. One person developed a rash and stopped treatment, and two people halved their dose due to daytime drowsiness, without recurrence of diarrhoea. Another individual's diarrhoea recurred after a week on thalidomide. No-one developed peripheral neuropathy, another potential side-effect of thalidomide.

The Kobler Centre is now planning a controlled trial, in which people with microsporidiosis will be treated with either thalidomide or a placebo for three weeks. Afterwards, placebo recipients will also be given thalidomide.

ALTERNATIVES

The use of drugs to suppress tumour necrosis factor is controversial because the cytokine plays a part in the normal immune response to infections.

According to Professor Tony Pinching of St Bartholomew's Hospital, "our research group and others have evidence that TNF-alpha is involved in the killing of Pneumocystis [the cause of PCP] and probably other pathogens by macrophages". He suggests that levels of TNF may be high during opportunistic infections purely because the cytokine is produced as part of the immune system's attempt to fight back. Theoretically, reducing TNF levels could suppress the immune response, and thus actually be counter-productive. At the most, anti-TNF treatments need to reduce TNF to normal levels, rather than suppress it completely.

Professor Pinching also feels that if inhibiting TNF is found to be useful, there may be other, safer drugs that could be used, such as oxpentifylline (known as pentoxifylline in the USA, or by its tradename Trental). Formal trials of oxpentifylline are taking place in the USA.

THALIDOMIDE AND AIDS

The use of thalidomide to treat microsporidiosis is just the latest AIDS-related application for the controversial drug. AIDS Treatment Update issue 12 reported in detail how the drug is an established option for treating serious aphthous ulcers in the mouth and is being tested as a means of dampening down over-active parts of the immune system.

More recently, researchers have described its use as a treatment for AIDS-related weight loss. In a small placebo-controlled trial, 8 out of 9 people treated with thalidomide stopped losing or put on weight, compared with only 2 out of 9 placebo recipients. Again, this is thought to be due to thalidomide's suppression of TNF.

The high levels of TNF in people with advanced HIV infection are thought to play a significant role in wasting by reducing the body's ability to store fats, and possibly also by suppressing the appetite.

The Kobler Centre is about to start a new trial of thalidomide, this time recruiting people who have active MAI infection. Infection with MAI can cause a particularly large increase in the amount of TNF produced in the body. It is also often associated with slow, gradual weight loss because the infection often continues to 'grumble on' despite antibiotic treatments. Participants in the study will receive thalidomide or a placebo for one month, and their weight, symptoms and quality of life will be measured.

REFERENCE

The Kobler Centre study was published as Sharpstone D et al. "The treatment of microsporidial diarrhoea with thalidomide". AIDS 9(6):658-659, June 1995.

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