AIDS TREATMENT UPDATE, December 1995
Edward King

* The theory of early intervention

One important question is whether it is more advisable to start treatment early, before HIV-related symptoms occur, or to delay treatment until you develop symptoms or a low CD4 count. There are several theoretical reasons for thinking that early anti-HIV therapy should be better than later therapy. On average, the longer someone is infected with HIV, the more the virus reproduces and spreads throughout the body, impairing the immune system. It is possible that some of the immune damage caused by the virus is irreversible, so it makes sense to try to limit the spread of the virus and prevent the damage, rather than to delay treatment until after the harm is done. Moreover, medicines usually cause fewer side-effects in healthy HIV-positive people than in people with advanced HIV disease.

But for some years doctors have debated whether the available anti-HIV drugs are effective enough to translate this theory into practice. The earliest trial of AZT took place in people who had already developed AIDS, and found that the drug prolonged life in the short term. Later trials suggested that the drug also worked in people with early HIV-related symptoms or no symptoms, boosting their CD4 counts and reducing the risk of developing AIDS in the short-term. However, these trials did not directly compare the effects of AZT at different stages of HIV infection, to see whether taking AZT early was more or less effective than taking AZT late.

This was the question investigated by the Concorde trial. Concorde found that there was no clinical advantage in starting AZT monotherapy early (by people who had not yet developed HIV-related symptoms) as opposed to taking it later (by people who had developed symptoms or been diagnosed with AIDS). As a result many people with HIV and their doctors concluded that there was no point in starting treatment early.

* Implications of Delta

The latest trials were an advance in that they did prove that alternative treatment regimes - combination therapy with AZT/ddC or AZT/ddI in Delta, and the same combinations or ddI monotherapy in ACTG 175 - were able to delay the onset of AIDS in symptom-free people, as compared with AZT monotherapy.

However, Delta did not compare the effects of early treatment versus late treatment, as Concorde did. This means that it does not provide any guidance on whether people with HIV are best advised to start taking combination therapy before they develop symptoms, or to wait until after symptoms occur.

"Delta doesn't tell you the optimum time to start treatment", Dr Brian Gazzard, Delta's UK Principal Investigator, told AIDS Treatment Update. "But it does tell you that if you do start with no symptoms then you will benefit, which we didn't know before."

ACTG 175 did look at the differences between 'immediate' versus 'deferred' combination therapy. The 'immediate' group was composed of people who were allocated to take one of the combination regimes as soon as they joined the trial. The 'deferred' group was actually composed of people who started with monotherapy then switched later to a combination, not people who started treatment with a combination. The results found no significant differences between the groups in terms of the risk of developing AIDS or dying. This suggests that there is no major advantage to starting combination therapy early rather than switching to it later, although it is possible that there was a difference but it was simply too small for the trial to detect.

* Starting with ddI

The most unexpected finding of ACTG 175 was that ddI monotherapy seemed to be more effective than AZT monotherapy for people just starting treatment. This contradicts a previous trial, ACTG 116A, which compared the two drugs. There was also no significant difference between the effectiveness of ddI monotherapy and combination therapy with AZT/ddI or AZT/ddC. Delta did not have a ddI monotherapy arm, so it sheds no light on this question.

Does this mean that HIV-positive people should consider ddI monotherapy as their initial treatment? Dr Janet Darbyshire, head of the Medical Research Council's HIV Trials Centre, argues that "it would be very rash to do that at this stage". The American researchers are currently looking to see if there are other reasons why ddI did unexpectedly well, and Dr Darbyshire recommends waiting for more data to become available before drawing any firm conclusions.

Dr Gazzard agrees, pointing out that "in ACTG 175, people on AZT monotherapy responded particularly poorly, with much smaller CD4 count increases than you would expect. That could be why ddI was better in comparison. The data simply isn't clear."

* Treatment choices

Although Delta clearly showed that combination therapy was more effective than AZT monotherapy for people starting treatment for the first time, it also raised other concerns. Participants who had already taken AZT monotherapy before they joined the trial seemed to derive little or no benefit from starting combination therapy, as opposed to staying on AZT alone. One possibility is that Delta participants who had already taken AZT monotherapy for a long time had developed resistance to the drug, blocking its effects, so when they switched to AZT/ddI or AZT/ddC they were still only receiving one effective drug. The results of ACTG 175 differed from Delta on this point; in the American study, AZT-experienced people had a reduced risk of dying if they switched to ddI monotherapy or to AZT/ddI combination therapy.

The important implication of Delta is that the treatment(s) you take today may have a direct bearing on your ability to benefit from the treatment regimes of the future. Dr Gazzard describes this dilemma as "one of the complex issues that we raise in discussions with patients - that you probably will benefit from a combination therapy now, but that may mean you'll benefit less from a subsequent combination."

The difficult decision for people thinking of starting treatment is to choose between two options: - to take advantage of the proven benefits of combination therapy now, but risk being less able to benefit from future treatments - to delay starting treatment in case even more effective regimes become available, but risk suffering further (possibly irreversible) immune damage.

* Future options

"You don't want to miss the boat, but what you start with is probably of critical importance", says Dr Margaret Johnson of the Royal Free Hospital in London. "For the person who has no symptoms and a stable CD4 count above 200-250, there may be merit in waiting until more potent combinations are available before starting treatment."

On the other hand, Dr Mike Youle of the Kobler Centre argues in favour of early treatment. "I would suggest starting combination therapy at a CD4 count between 300 and 350, to try to keep your count above the danger level of 200. The aim is to prevent disease progression, rather than wait until it's happened and then try to treat it. If you do progress, other drugs like 3TC and saquinavir are available so you can change one or more components of your combination."

In the future, the growing number of available anti-HIV drugs may allow people to start with one combination regimen then switch to a completely different combination. Dr Gazzard says "We urgently need to know whether people who have taken one combination but are apparently experiencing disease progression will respond well to a different combination containing two different drugs. That's an unknown question. If they do respond then there's a lot in favour of starting combination therapy early. If not, perhaps people should 'keep their powder dry' and wait until there's a triple or quadruple drug combination available to them."

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