AIDS TREATMENT UPDATE, November 1995
Edward King

However, the results of Delta were less encouraging for people with prior AZT-experience. AIDS Treatment Update spoke to a range of British clinicians to find out what treatment options they are recommending for people who have already started on AZT.

WHY CHANGE TREATMENT?

Several previous trials have suggested that people who have taken AZT for some time may benefit from changing treatment. The American study ACTG 116B/117 found that people who switched from AZT to ddI after at least four months of AZT were less likely to experience disease progression. More recently, trials have found that AZT-experienced people who add in 3TC in combination with the AZT tend to have reductions in their viral load and increases in their CD4 count over a 6-month period

Researchers believe that it is beneficial to change treatment because during the course of AZT treatment, strains of HIV emerge which are less susceptible to AZT. However, adding or starting another treatment should in theory provide more effective anti-viral treatment of these strains.

ACTG 175 found that AZT-experienced people were less likely to experience new AIDS conditions or die if they either switched to ddI, or added in ddI in combination with AZT. But the results of Delta 2 - the part of the trial for AZT-experienced people - did not provide confirmation of this trend. There was a suggestion that people who added in ddI had a reduced risk of disease progression or death, compared with those who remained on AZT monotherapy, but the differences between the groups were small and were not statistically significant i.e. they could have been due to chance.

Further information is expected to come from longer term follow-up of Delta; the researchers say that with more data, Delta 2 could yet show a benefit for combination therapy. The results of an American trial known as NUCOMBO, which is similar to Delta in design but has enrolled people with more advanced HIV infection, are also expected before the end of the year.

WHEN TO CHANGE TREATMENT

The recent trials suggest that people respond well to combination therapy with ddI or ddC if they are AZT-naive, but derive less benefit if they have already taken AZT for long periods of time. But if you've only taken AZT for a little while, how do you know whether you count as AZT-naive or AZT-experienced?

AZT-experienced people in Delta 2 and ACTG 175 tended to have taken quite a lot of prior AZT - about two-thirds of them had taken AZT for at least one year. All the clinicians we contacted agreed that you should consider yourself AZT-experienced if you have taken AZT for this long - with the implication that you may derive only limited benefits from starting combination therapy by adding in ddI or ddC.

By contrast, Delta 1 - the trial which showed the benefits of combination therapy for AZT-naive people - enrolled people who had taken no AZT at all before. As Professor Tony Pinching points out, "this leaves a gap in-between, in which we don't know the merits of adding in ddI or ddC. We don't strictly know where to draw the line between AZT-naive and AZT-experienced."

Professor Pinching argues that "In my view people who have taken AZT for less than 12 months can perfectly reasonably regard themselves as AZT-naive. In this group I think we should assume that taking the combination will be better than not doing so." The fact that the group who responded best to combination therapy were those who had taken the least prior AZT suggests that an early switch to combination therapy is likely to be better than a later switch.

However, there is no clear consensus about whether people who are responding well to long-term AZT monotherapy, showing no sign of clinical progression and stable CD4 counts, should automatically change their treatment. Dr Ian Williams of the Mortimer Market Centre suggests that such people could quite reasonably remain on AZT monotherapy until further information on fine-tuning treatment strategies becomes available.

WHAT TO CHANGE TO?

If you are AZT-experienced, what treatment options do the trials suggest? In summary, there are three:

- stopping AZT and switching to another drug, such as ddI - starting a combination regime that includes AZT - starting an experimental regime, such as a combination of drugs that doesn't include AZT, or other experimental treatments

Clinicians were not enthusiastic about the first of these options, despite the fact that ACTG 175 suggests that switching to ddI monotherapy may be just as effective as combination therapy with AZT plus ddI. Dr Margaret Johnson recommends that "If you can tolerate AZT I would add, not switch. If you are anaemic or struggling then I would obviously stop the AZT". Professor Pinching agrees, arguing in favour of continuing to take AZT if you can, because it crosses into the brain and helps to prevent HIV-related mental problems much better than ddI. "For someone who's still tolerant of AZT, the benefit in terms of preventing HIV encephalopathy is substantial, and a reason to add in ddI rather than switch."

If you decide to take the second option of starting a combination which contains AZT, clinicians favoured the combination of AZT plus ddI. Trials clearly indicate that for AZT-experienced people this regime may be more effective than the combination of AZT plus ddC. Both ACTG 175 and Delta, as well as the earlier study ACTG 155, found no clinical benefits when AZT-experienced people switched to combination therapy with AZT plus ddC. However, in Delta people who were receiving ddI were more likely to decide to stop treatment because of side-effects than people taking ddC.

Doctors say that there are some AZT-experienced people for whom the AZT plus ddI combination is not recommended - notably, those who have previously had neuropathy or pancreatitis, which could be worsened by ddI. Dr Ian Williams says he would advise such people to join the 3TC expanded access programme. Trials have shown that the combination of AZT and 3TC can reduce viral load and boost CD4 counts in AZT-experienced people, but there's still no information on its effects on clinical endpoints. However, Professor Tony Pinching suggests that in the light of Delta, one can be more confident that a treatment that has a good effect on such markers will also provide clinical benefits.

Protease inhibitor drugs have also shown promising effects on markers in both AZT-naive and AZT-experienced people, particularly when they are used in AZT-based combination regimes. These drugs are still experimental and unapproved, and there are no trials currently recruiting in Britain. But as reported on page 7, two protease inhibitors, saquinavir and indinavir, will shortly be made available to certain people with HIV through expanded access schemes.

COMBINATIONS WITHOUT AZT

Researchers are also planning trials testing the third option, in which AZT-experienced people stop taking AZT but start taking a combination of other drugs. Dr Brian Gazzard argues that "You may get much more benefit from switching to a combination in which you are naive to both drugs, particular if you have developed resistance to AZT. In the future we may determine whether or not to give people a combination containing AZT depending on whether they have high level AZT resistance. Intuitively, I think that would be the right time to stop AZT and try other drugs." Combinations that include AZT are also not an option for people who cannot tolerate AZT.

There are several possible combinations that not based on AZT, but little or nothing is known about their clinical effectiveness. Several clinicians stressed the need to test combinations based on stavudine (d4T), a nucleoside analogue approved in the USA. Research presented at the conference in Copenhagan last month found that the combination of stavudine and ddI did not increase the risk of side-effects such as peripheral neuropathy.

THE NEED FOR TRIALS

Clinical trials will be needed to test the benefits of treatment for AZT-experienced people. However, very few of the currently available studies of anti-HIV drugs will accept people who have already taken AZT. Not only does this narrow the current options for AZT-experienced people; it will also hamper efforts to clarify treatment options for such people in the future. Dr Margaret Johnson points out that "This is a very big group of patients and we need to make sure they don't become a forgotten group. Trials are urgently needed so we do know what to do next."

IN SUMMARY...

- For AZT-experienced people, switching to combination therapy with AZT plus ddI may be more effective.

- Generally, the sooner you switch to combination therapy, the better the effects seem to be. However, people who are doing well on AZT monotherapy may take the view that "if it isn't broken, don't fix it".

- If you can't tolerate ddI, consider an experimental combination such as AZT plus 3TC.

- If you can't tolerate AZT, consider an experimental combination such as d4T plus ddI or 3TC.

- New expanded access schemes may give you the opportunity to try a protease inhibitor such as saquinavir.

- Given the uncertainties, consider joining a trial which may help to prove which treatment choices are most effective for AZT-experienced people.

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