AIDS TREATMENT UPDATE, Issue 37, January 1996
Edward King

The symptoms they cause are often generalised, non-specific and of gradual onset, such as fever, weight loss, night sweats, diarrhoea and tiredness. Once it has developed, MAI is relatively hard to treat, requiring a combination of several different antibiotics. It is slow to respond to therapy, resulting in reduced quality of life for long periods, and is an increasingly common cause of AIDS-related death.

For nearly two years, the drug rifabutin has been licensed as primary prophylaxis against MAI i.e. to prevent the onset of the condition. In the USA, it is recommended for all HIV-positive people with CD4 counts below 75. However, in March 1994 AIDS Treatment Update found that many doctors in the UK were not encouraging their patients to take rifabutin, because of doubts over its effectiveness and concerns about resistance. Because more research has accumulated since then, we repeated our survey of clinicians to find out whether their thinking has changed. Concerns

The original trials of rifabutin were conducted among HIV-positive people with CD4 counts below 100. They found that those who took rifabutin were significantly less likely to develop detectable levels of the MAI organisms in their blood - a condition called MAI bacteraemia. However, the trials were only designed to test the effectiveness of rifabutin using this blood test - and like many other blood tests, the significance of MAI bacteraemia has been controversial. The trials were not large enough to be able to tell whether rifabutin could reduce the risk of developing symptoms of MAI, improve quality of life or prolong survival. In the absence of this information, many British doctors remained unconvinced about the value of rifabutin.

The other concern related to resistance. Rifabutin is related to other drugs used to treat tuberculosis, which is also caused by a member of the Mycobacteria family of organisms, Mycobacterium tuberculosis (M.Tb). Some doctors were worried that widespread use of rifabutin could lead to the development of drug-resistant strains of MAI and M.Tb, ultimately perhaps doing more harm than good. Current guidelines stress that people should be screened to ensure that they do not have active MAI or tuberculosis before they start rifabutin, to avoid inducing drug-resistant strains. The evidence to date suggests that the widespread use of rifabutin in countries such as the USA has not resulted in significant problems with resistance.

NEW TRIAL RESULTS

Over the last year, more information has become available that is generally reassuring about the merits of MAI prophylaxis in general and rifabutin in particular. In November 1995, researchers from the original rifabutin trials reported the results of a new analysis of the trials, in which the data from the two studies were pooled and analysed as one, with a longer period of follow-up. Although such unplanned analyses need to be interpreted with caution, it suggested that among the 1146 participants, rifabutin recipients were significantly less likely to die than people who received no MAI prophylaxis.

More evidence came from a trial of a different drug as MAI prophylaxis, the antibiotic clarithromycin (made by Abbott under the trade-name Biaxin). A US/European/Canadian trial reported at the ICAAC conference in November 1995 found that people who took clarithromycin were 69% less likely to develop MAI symptoms than people given a placebo, and 31% less likely to die.

Moreover, placebo recipients who developed MAI bacteraemia had a significantly greater risk of death than placebo recipients who remained free of MAI organisms in the blood, providing a clear rationale for trying to prevent the onset of bacteraemia. On 27th December 1995, the US Food and Drug Administration approved clarithromycin for prescription as MAI prophylaxis.

Despite this promising result, many researchers do not think that clarithromycin is a good choice of drug for MAI prophylaxis because MAI organisms develop resistance to clarithromycin more readily than to rifabutin. Clarithromycin or a related antibiotic, azithromycin, are recommended components of combination regimes for treating people who do develop MAI, and the effect of these regimes is likely to be reduced in people who have already become resistant to clarithromycin. In the trial described above, 60% of people who developed MAI despite taking clarithromycin were found to have developed clarithromycin-resistant strains.

CLINICIANS' VIEWS

AIDS Treatment Update asked clinicians at treatment centres around the UK about their attitudes to MAI prophylaxis. The results showed that opinions remain divided. About half of the clinics actively encourage patients with CD4 counts below 75-100 to take rifabutin, while the remaining clinics still had concerns about the wisdom of such a policy.

Dr Ian Williams of the Mortimer Market argued that the evidence for the clinical benefits of rifabutin remains uncertain. "The original trials were never set up to analyse survival so you can't be sure that the re-analysis is reliable." He and others suggested that it would be hard to justify the routine use of rifabutin because in the UK most people with low CD4 counts are unlikely to develop MAI even if they receive no prophylaxis. "It is a risk-benefit problem" said Dr Williams. "There probably is some benefit from the use of rifabutin but is it sufficient to warrant its widespread use?"

On the other hand, Professor Tony Pinching of St Bartholomew's Hospital routinely offers rifabutin to people with CD4 counts below 100. He argues that "the rationale is to improve patients' quality of life, even if it doesn't prolong survival".

Other clinicians mentioned rifabutin's side-effects and interactions with other drugs. At high doses, rifabutin has been associated with eye inflammation, although this appears to be rare at the dose of 300 mg/day now usually used. Other side-effects can include discoloured urine, stomach upsets, rashes and blood abnormalities, but generally rifabutin is well tolerated. In trials, about 16% of recipients stopped taking it because of toxicities. Rifabutin also interacts with a number of other drugs commonly used by people with HIV; most particularly, it decreases blood levels of the anti-fungals dapsone, itraconazole and ketoconazole. But Professor Pinching argues that with care these interactions are easily managed.

TRIAL

A pan-European trial known as ENTA10 is currently investigating MAI prophylaxis. Participants are randomly assigned either to receive rifabutin or no prophylaxis. They are also sub-divided again - half have routine blood tests for MAI every two months, while the others only have MAI blood tests if they develop symptoms that suggest MAI. Anyone who is found to have MAI bacteraemia will receive combination antibiotic treatment. With this split design, the trial aims to assess and compare the benefits of two different approaches to preventing MAI:

- Is regular monitoring and prompt treatment of MAI more effective at reducing illness and death than only treating when symptoms are apparent?

- Is rifabutin more effective than no treatment at reducing illness and death?

Dr Brian Gazzard of the Kobler Centre in London suggested that the results of this trial should shed light on one of the main issues still to be decided - "Is it better to give prophylaxis to everyone with low CD4 counts prophylaxis, even though the majority are unlikely to develop MAI anyway? Or because MAI is much more treatable than hitherto, is it better to monitor very closely for MAI and treat early those who get it?"

British clinics currently recruiting participants for this trial are the Kobler Centre and the Royal Free Hospital.

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