AIDS Treatment Update, Issue 45, September 1996
Edward King

- switching to combination therapy with AZT plus ddI may be more effective than remaining on AZT alone

- 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"

Nearly a year later, there is more evidence about the effects of different combinations, including newer options such as AZT/3TC, d4T/ddI, d4T/3TC and protease inhibitors. Viral load testing also potentially offers a new way of assessing whether you need to consider changing your treatment. AIDS Treatment Update asked leading clinicians to explain their current advice to people who are already taking anti-HIV drugs.

* When to change?

All the doctors agreed that in most cases people with HIV should not now be taking AZT monotherapy. Professor Tony Pinching of St Bartholomew's Hospital reported that "patients who previously chose to remain on monotherapy are increasingly saying they want to be doing more". At most clinics, the majority of people who are taking anti-HIV drugs are now likely to be receiving AZT/ddI, although there is a significant number of people who are using AZT/3TC.

There are two main issues to consider if you are already on treatment - do you need to change treatment at all, and if so, what should you change to?

All the doctors agreed that there is no need to look for new options if you are currently taking a standard combination of two nucleoside analogues such as AZT plus ddI, ddC or 3TC, are tolerating the drugs and are not experiencing a falling CD4 count or worsening symptoms. "At present I'd advise patients who are doing all right to carry on treatment until there's some deterioration," said Dr Brian Gazzard of the Chelsea and Westminster Hospital.

"The most important consideration is to ensure that the CD4 count remains up so that the risk of opportunistic infections is as low as possible. If there's no indicator to change therapy, I wouldn't," agreed Dr Ian Williams of the Mortimer Market Centre.

People with very low CD4 counts may be the only exceptions to this rule. Several clinicians pointed out that in the Abbott trial 247 whose results were released last January, people with counts below 100 (the average was about 20) who added the protease inhibitor ritonavir to whatever other anti-HIV therapy they were taking had a significantly reduced risk of developing a new opportunistic infection or dying. "Anyone with a low CD4 count on therapy should be offered a protease inhibitor, irrespective of whether they seem to be failing," said Dr Gazzard.

Others felt that if their CD4 counts are stable, even people with low CD4 counts might be well advised to delay any change. "In a few months' time we'll know more about the combination of saquinavir and ritonavir for people with advanced disease," said Dr Margaret Johnson of the Royal Free Hospital. "If you're not progressing it may be better to wait for that combination, rather than to start on just one protease inhibitor now".

* Using viral load

Some researchers argue that measuring viral load may help to reveal when a treatment regimen is failing. If your virus levels increase until they are close to or above the baseline level (the level just before you started treatment), that could indicate that the drugs are no longer inhibiting the virus effectively, perhaps due to the emergence of resistance. But this isn't proven; Dr Johnson pointed out that in the Delta trial, participants' viral load tended to return to baseline long before the clinical benefit of treatment became apparent. "I'm worried that viral load tests might prompt patients to jump from one regimen to the next before they have got the best out of it".

What's more, viral load testing is a new procedure in the UK, so even if they have their viral load measured now, most people currently on treatment won't know what their baseline level was.

Nevertheless, it is possible - but unproven - that monitoring change in your viral load over time may help to guide treatment decisions. "If your viral load is rising while you're on therapy, does that predict that your CD4 count will fall?" wondered Dr Williams. "We don't yet know, but I suspect it does."

* What to change to?

If you are going to change therapy, the current thinking is that it's best to add or switch to at least two new drugs which are unlikely to be cross-resistant to those you took before. Adding only one drug can have benefits - recent trials have shown significant reductions in disease progression from adding ritonavir alone, ddI alone, or 3TC alone - but a growing number of researchers feel that in the long-term the impact of only one new drug may be too small, so that significant levels of virus replication may continue and resistance to the new drug may emerge more rapidly (see the article 'Preventing resistance' in AIDS Treatment Update issue 44).

"If people are definitely failing, I would always switch them to a new combination," said Dr Williams. "Why tinker around with a regimen that's failing?"

One advantage of AZT is that it passes into the central nervous system (CNS) and helps to prevent AIDS-related dementia. Dr Johnson stressed that when changing treatment, the new combination should ideally be one that would continue to protect the CNS. Little is known about the ability of other drugs to prevent neurological complications, so if you are still tolerating AZT it may make sense to stay on it and add two new drugs.

There's little clear-cut evidence from trials to help you and your doctor decide which new drugs to add. Until recently, most trials of options for people on treatment have only looked at the effects of switching to another monotherapy (such as ddI in the Alpha trial) or adding one new drug (such as ddI in Delta), not two.

At the Vancouver conference, increases in CD4 count and reductions in viral load were reported from many trials in which AZT-experienced people added or switched to different two drug combinations, such as ddI/nevirapine, d4T/ddI, d4T/3TC, or combinations involving a protease inhibitor. If you are going to stop AZT, the best results to date have been seen from switching to saquinavir plus ddC. This combination has been shown to reduce disease progression and prolong life compared with switching to with either ddC monotherapy or saquinavir monotherapy (see box below).

But given the lack of evidence in favour of any specific regimen, doctors told AIDS Treatment Update that it was impossible to recommend specific drugs. The choice will depend on the treatments you have previously used (so as to minimise the risk of cross-resistance), other drugs you currently need (to avoid interactions) and your preferences about possible side-effects, the ease of taking the drugs, and how aggressively you want to treat.

BOX - Recent trial results in summary

Two trials looking at the effect of changes in treatment on clinical endpoints were reported recently.

The CAESAR trial, whose interim results were announced last month, looked at the addition of only 3TC, or both 3TC and loviride. 61% of people in CAESAR had never taken anti-HIV drugs before or had only taken AZT monotherapy for less than three months (the 'naive' group), but the other 39% (the 'experienced' group) had already been taking either AZT monotherapy, or combination therapy with AZT/ddI or AZT/ddC, for at least three months. Overall, the study concluded that adding 3TC (with or without loviride) resulted in about a 50% reduction in the risk of disease progression and/or death (from 14% to 7%), and that this benefit was seen both among people taking AZT monotherapy and those taking a combination. However, the researchers have not yet specifically analysed the effects of adding 3TC depending on whether participants were 'naive' or 'experienced' when they joined, so the implications of CAESAR for people who are currently on treatments aren't clear.

The NV14256 trial, mentioned in AIDS Treatment Update issue 42, enrolled people with CD4 counts between 50 and 350 who had previously taken AZT but had stopped. It found that only 15% people who took the combination of ddC plus saquinavir developed AIDS or died, compared with 27% of people who took ddC alone and 24% of those who took saquinavir alone. Looking just at deaths, the rates were 3% (combination), 9% (ddC alone) and 11% (saquinavir alone). These results mean that at present this combination is the best proven option for AZT-intolerant people. However, the trial did not compare other combination options, and it is plausible that many of the other potential two-drug regimens could have equally good results.

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