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When ^ to stop

Last month in Positive Nation (‘Back to life’), Ian Price told the story of his five-month break from HIV treatment, prompted by a holiday to the US. The results were mixed. He enjoyed the freedom from side effects but his post-holiday checkup revealed that his CD4 count had crashed to a third of its previous level, and, at 230, was close to laying him open to Aids-related illness if he’d continued off the drugs.

Is this the inevitable result of interrupting HIV treatment?

The answer is: not necessarily. But it depends crucially on your treatment history.

signA recent study was reported that seemed to put the nail in the coffin of treatment interruptions.

In the CPCRA 024 study, 244 patients who had burned their way through most HIV regimes took part. They’d taken an average of 12 drugs each and were resistant to pretty well everything (except tenofovir).

Half the patients were put straight on to a new regime. The other half were taken off treatment altogether for four months, with the hope that when they’d started again, non-resistant but stronger ‘wild-type’ HIV would have ‘overgrown’ their resistant virus.

This did happen. The positive result was that the patients who took the break were twice as likely to achieve an undetectable viral load once they were put back on treatment.

But at a price. At the end of the treatment break their average CD4 count was 85 points lower than the other group - taking them into the dangerously immune-deficient area of around 60 T-cells. The consequence was that more people on the treatment break (2.6 times more) were likely to suffer an Aids-defining illness or die during the year the study lasted. In fact, the small numbers of deaths reported in the year after the study was the same for both patient groups (eight each) but those who took the treatment break were 3.5 times more likely to get ill without actually dying.

When to stop, maybe...

signThese results were reported as contradicting the findings of a previous study called GIGHAART that found treatment breaks before starting a ‘salvage’ regime to be beneficial to drug-resistant patients.

However, there were significant differences in the procedures.

The GIGHAART study stopped its patients’ therapy for two rather than four months and the new therapy was more of a kitchen-sink monster-combo of six or even eight drugs than a regular combination therapy. Those in the treatment interruption (TI) group ended up with an average CD4 increase of 51, as opposed to a mere 7 in the non-TI group - at least when measured three months after the trial. This may indicate that a two-month treatment break is short enough to avoid a ‘CD4 crash’ in most cases.

But the overall results were disappointing when it came to the main aim of abolishing drug-resistant virus. Only 45 per cent of TI patients had any of their drug resistance disappear, and only seven per cent saw a complete return to ‘wild-type’ virus.

Benefits versus risks

signThese two studies are only really contradictory when it comes to the CD4 counts. Essentially, the first study was designed to measure the potential risks of a TI for drug-resistant patients, and the second its potential benefits. CPCRA 024 measured whether you were more likely to get ill after a TI; GIGHAART whether you would re-suppress your HIV better.

Aids Treatment Update Editor Edwin J Bernard is one person who has no doubt that a prolonged treatment break he took in similar circumstances benefited him.

“I started treatment early and have a long history of taking sub-optimal regimes. Despite this, and being resistant to all available protease inhibitors and NNRTIs, ddC, 3TC, and possibly AZT, I was doing OK on d4T/3TC with 300 CD4s and a lowish viral load till July 1998.

“At that point, as we later found out, I became resistant to d4T as well. So, with resistance to all available drugs and chemical hepatitis, I decided to come off everything in April 1999. Basically, I had no other options.

“I was off treatment for a year. During that time my CD4s plunged to 30 and my viral load soared to 627,000. Prophylaxis for opportunistic infections stopped me getting life-threateningly ill. But by March 2000 something had to be done.

“So just as in the GIGHAART trial, I creatively recycled the whole medicine cabinet, starting with ddI, 3TC, abacavir and Kaletra, and adding amprenavir, delavirdine (to boost my PIs) and mycophenolate, a drug which may boost abacavir, to get my viral load below 50 copies/ml.

“So I’m currently on seven drugs. But since September 2001 my virus has been undetectable, my CD4s are now a record 460 and although I do have some side effects, I can live with them.

“The treatment interruption was forced on me rather than planned. But I’m convinced that the year’s break, however risky, enabled me to benefit from the mega-combo I eventually took.

“Basically, I’m a walking experiment!”

Hit early, hit...now and then

signThere’s a much larger class of people out there who may be able to risk extended treatment breaks, with resultant savings in side effects - and cost.

UKC Chief Executive Stephen Bitti is one of them. “I probably started therapy too early and am considering taking a treatment break,” he says. “I went straight on treatment as soon as I was diagnosed in 1991 when my CD4s were above 500 and they are now 800, with an undetectable viral load since the test became available.

“I’m on efavirenz, 3TC and d4T and the motive to stop treatment is that I’ve started to get fat loss in the face and legs.

“I’ve talked it through with my doctor and will stop soon. We plan to stop the efavirenz first and stay on the 3TC/d4T with the addition of Kaletra for seven days to guard against efavirenz resistance developing. I’ve only hesitated as long as I have because I recognise that the drugs have been a psychological support over the time I’ve been diagnosed. That crutch will no longer be there.”

People in Stephen’s position who have started therapy early but on an effective combo that has not led to resistance are likely to do well on treatment breaks, where the object of the break is to reduce the time spent on drugs and the resultant side effects and expense.

Two Italian studies presented at the recent ICAAC conference backed this strategy. One stopped people’s HIV treatment when their CD4 count rose above 800, and only resumed it when it fell before 400. This resulted in patients only needing to take the medication 12 per cent of the time - with all that implies for better tolerability and lower cost.

It was found that people were much less likely to have to restart their medication quickly if they had never had CD4 counts below 350. In contrast 80 per cent of patients who had ever had a CD4 count under 200 needed to restart, though they all responded successfully and still had more than half the time off therapy.

The other Italian study produced similar results: see ‘When treatment interruptions work’.

The importance of the lowest-ever CD4 count (the ‘CD4 nadir’) implies a complete rethink about HIV therapy. Current European treatment guidelines recommend waiting till CD4 counts fall to 200 before starting on antiretrovirals. So should the current ‘hit late - but hit hard’ approach be replaced by ‘hit early - but intermittently’? And what does this imply for encouraging early testing?

Resistance is not futile

Even if complete TIs are risky, is there still a place for easing off, rather than intensifying, the treatment?

The answer is that it may sometimes be possible to stay on the same treatment for several years, even with a detectable viral load, rather than jumping into intensified, experimental and possibly toxic regimes - and risk them failing too.

Bernard Forbes, UKC chair, is one of the people who have done this. “I do have a detectable viral load on treatment,” he says. “But despite this, my CD4s keep going up. So I’ve decided to stay on it and preserve my options for when my CD4s do start to go down.

“I’m currently on AZT, 3TC and nevirapine. I stopped an indinavir/d4T/ddI regime in mid-2000 due to fat loss. It started to ‘fail’, ie my viral load became detectable, within 10 months.

“But what that actually means is that my viral load has fluctuated between 3,000 and 4,000 and my CD4s have shown a slight but steady increase from 300 to 400.

“I am resistant to all the drugs I’m taking, and possibly others. But my virus is probably a ‘crippled’ one - they find it impossible to grow it in the lab.

“Something is working though - not perfectly, but it doesn’t seem to be doing me any damage either. When my HIV first rebounded I was shocked and wondered what to do. Well, I did nothing, and nothing has been fantastic.”

Dr. Stephen Deeks of San Francisco has made a study of this kind of viral ‘failure’ - known as discordance - and come to the conclusion that if the ‘right’ kind of resistance can somehow be maintained, the result is a crippled virus that reproduces only slowly. Patients in this situation, like Bernard, have detectable, but consistently low, viral loads.

Stopping some drugs, but not all

In these circumstances, if you are suffering from side effects and want to reduce your treatment burden, you may even be able to ‘shock, horror’ stop some, but not all, of your drugs.

Dr. Deeks took 20 patients who were on a mixed protease/NRTI regime. In 15 patients he stopped the protease inhibitors (PIs) and kept them on the ‘nukes’. With the other five he did the opposite.

The five patients staying on PIs alone experienced rapidly rising viral loads. But 13 of the 15 patients on NRTIs alone had no viral load increase over several months. The two that did turned out to have lost their resistance to PIs.

What was happening was that the NRTIs were holding down the HIV just enough to ensure that only the crippled PI-resistant virus was reproducing (see ‘Trench Warfare’ page 36 for more on this).

The patients off PIs also benefited from reduced PI-related side effects like high cholesterol.

  • Things to think about before starting a treatment break

  • In summary: complete treatment breaks are risky, unless you have a high CD4 count and have never had one below about 350. There are many other options to staying on a toxic or failing regime.
  • Discuss any kind of treatment break with your doctor. Most HIV resistance is caused by unplanned breaks.
  • You may well get a return of acute HIV symptoms that can make you feel unwell for a while.
  • Even after this you may not feel 100 per cent better as HIV causes its own symptoms like night sweats, fatigue and so on.
  • You will probably need to have checkups and blood tests a lot more often - say, monthly - to pick up on sudden falls in CD4 count.
  • You may need to stop the drugs in a particular order rather that all at once. NNRTIs last longer in the body and need to be stopped first so you don’t get resistant to them.
  • IMPORTANT: Remember that you will be more infectious and will need to be more careful about safer sex. Regular partners should be informed of treatment breaks.

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