AIDS Treatment Update, Issue 45, September 1996
Edward King & Keith Alcorn

Since then, many further trials involving a greater range of drugs have been completed. Viral load testing has also emerged as a potential tool for helping to guide treatment decisions. What is the impact of these advances on decisions about starting treatment?

It's important to recognise that none of the recent research has specifically addressed the questions 'when to start' and 'what to start with', so there are still no firm answers. None of the newly completed trials has compared the effectiveness of early versus late treatment, so they don't prove whether it is better to start treatment before you develop symptoms or other signs of immune damage, or to wait until later.

* In favour of early treatment

However, we do now have improved knowledge in two areas. First, it is now established that anti-HIV drugs can have tangible clinical benefits when they are taken by people who have no symptoms.

Prior to the combination therapy era, there was no clear-cut evidence that it was worth taking AZT monotherapy before the onset of AIDS, as it did not delay the onset of AIDS but did cause side-effects for people who otherwise felt perfectly well. But the Delta and ACTG 175 trials showed that the combination of AZT plus ddI did delay the development of AIDS and prolong life compared with AZT alone, among asymptomatic or mildly symptomatic people with CD4 counts below 350. Other studies suggest that adding 3TC or ritonavir to other anti-HIV drugs also delays disease progression significantly.

At the Vancouver AIDS conference, it was clear that new understandings of HIV's activity in the body are also shifting the balance of expert opinion in favour of earlier and more aggressive treatment. The arguments can be simplified as follows:

- HIV damages the immune system, eventually leading to the development of AIDS

- stop HIV from damaging the immune system and you stop (or at least slow) the disease process

- the less damage HIV is allowed to do to the immune system the better, as some immune damage may be irreversible

- so the best time to start treatment is before the CD4 count has fallen too low, and long before the development of any symptoms.

Dr Brian Gazzard of the Chelsea & Westminster Hospital argued that "It's very difficult to sustain the view that you should wait until an opportunistic infection (OI) before starting treatment. We don't know at what stage HIV's damage to the bone marrow, the thymus, the lymph nodes or the T-cells becomes irreversible, but we do know that serious immune damage has already occurred by the time a patient develops an OI. Everyone is moving towards earlier treatment."

Studies of viral load in recently infected people who are not taking anti-HIV treatments are partly responsible for the new enthusiasm for early aggressive therapy. These studies show that people with the lowest viral load one to three years after infection have the least chance of progressing to AIDS within ten years. It has been assumed that suppressing viral load to similar levels with drugs will have similar effects on health and survival, but this has not yet been definitively proven.

But there is indeed growing evidence that treatments that significantly suppress viral load may have a beneficial effect on health and survival. The American study of combination therapy, ACTG 175, showed that for every 1 log fall in viral load, the chance that individuals would develop AIDS or die fell by two-thirds. In other words, people who had a 2 log fall in viral load were two-thirds less likely to die than their counterparts who had a fall in viral load of 1 log, and they in turn were two-thirds less likely to die than their counterparts who didn't experience a fall of this amount. If the same effect holds true for other studies, this finding suggests that aggressive treatment which reduces viral load to the lowest possible level holds out the greatest hope of prolonging life.

As discussed in AIDS Treatment Update issue 44, some researchers argue that the aim of treatment with anti-HIV drugs should be to reduce viral load to as low a level as possible; this is likely to minimise the risk that HIV strains that are resistant to the drugs will evolve. Thus, some argue that a regimen that doesn't reduce viral load to levels that are undetectable with current tests should be considered to be inadequate treatment.

This perspective would also favour early treatment, because:

- the lower your viral load when you start treatment, the greater the chance that your virus levels will be reduced below the limit of detection

- the higher your viral load when you begin treatment, the greater the chance that your virus levels will remain detectable on treatment, and the greater the chance that you will develop resistance to the drugs with which you are being treated.

A final argument in favour of early use of treatments is that people with high CD4 counts are less likely to develop side-effects than people with more advanced HIV infection taking the same dose of the same drug.

* Against early treatment

One of the most convincing arguments against early treatment is the incomplete state of our knowledge. No-one really knows when is the best time to start treatment, and while we do know that some drug regimens are better than others, no-one knows which of the currently available combinations is the best or for how long they will be effective.

Quite apart from psychological considerations - some people find that taking anti-HIV drugs while they are well is an unwelcome reminder of their HIV status - starting treatment means embarking on a course that will affect your future choices too. People who have already taken one drug may be less able to benefit from other drugs in the future, leading some doctors to argue that the choice of initial treatment may be the most important. The dilemma posed in issue 36 remains unchanged:

- do you take advantage of the proven benefits of combination therapy now, but risk being less able to benefit from future treatments, or

- do you delay starting treatment in case even more effective regimens become available, but risk suffering (possibly irreversible) immune damage?

The rapid pace of research means that there may be more facts on which to base your decision if you wait even just for a few months. For example, the anti-HIV effect of triple combinations has only been studied in the short-term so far. "In a few months we may well have better information about which triple combination has the most durable effects on virus load," said Professor Tony Pinching of St Bartholomew's Hospital. "Patients shouldn't race to make a decision if there's no imperative to decide today rather than in two, four or six months' time".

Dr Gazzard agreed that "There's no need to panic about any of this; most patients can afford to take their time to make a mature, sensible decision".

In the past it was often argued that the limited number of drugs available meant that people without symptoms might be wise to delay treatment until they really needed it, rather than 'burning the light-bulb at noon'. However, the growing number of approved treatments makes this argument less persuasive. Already, six anti-HIV drugs are approved in the UK (AZT, ddI, ddC, d4T, 3TC and ritonavir), and two more (indinavir and saquinavir) will be licensed this autumn. Someone starting treatment with a two- or three-drug combination could potentially look forward to several years of benefit, and still be able to switch to a new combination of entirely different drugs afterwards.

* Making the decision

Doctors told AIDS Treatment Update that your CD4 count is still the most important thing to consider when deciding whether and when to start treatment.

Dr Ian Williams of the Mortimer Market Centre stressed that "the aim of treatment is to keep people well. Keeping people's CD4 count above 200 is going to be as important as keeping their viral load down, but suppressing viral load may be the way to preserve the CD4 count. We recommend that patients consider starting treatment when their CD4 count is between 200 and 350."

"Once someone's CD4 count falls below 500 you can be pretty sure that without treatments they will eventually get ill," said Dr Gazzard. "It's at that point that we would start discussing treatment."

There is good evidence that among untreated people, low viral load predicts a better prognosis and high viral load predicts a poorer prognosis. Viral load testing will increasingly become available to people who are thinking of starting treatment. Professor Pinching suggested that "For example, viral load may help to identify the subsets of patients in whom the CD4 count does not have its usual predictive value: the subset with high CD4 counts whom we should be worried about because they progress surprisingly quickly, and the subset with low CD4 counts whom we can be more relaxed about who do remarkably well without treatment."

It remains unclear whether people with a high CD4 count and high viral load should start treatment. A high viral load may mean that you are relatively 'late' in the disease course, not 'early'. Dr Williams pointed out that people with a high viral load are more likely to have a rapid fall in CD4 count than people with lower viral load. "People with a high CD4 count and a high viral load are not necessarily in immediate need of treatment because their immune systems are still relatively intact. But I would monitor their CD4 count more frequently and discuss treatment, so that they could start promptly if their count did fall rapidly. When people with high viral load do start treatment, it may help to use a more aggressive regimen, such as a combination that includes a protease inhibitor, to try to get a good reduction in virus levels."

Dr Janet Darbyshire, head of the Medical Research Council's HIV Clinical Trials Centre, suggested that "the change in your CD4 count or viral load, rather than its absolute value, may be the better guide to when you might think about treatment". She pointed out that some people have CD4 counts that remain stable at, say, 250 for long periods; they may be in less urgent need of treatment than someone with a higher count that has started to fall rapidly.

It's also important to recognise that starting treatment involves a serious commitment. Anti-HIV drugs should be taken at the right dose and the right time each day to maximise their effect and minimise the risk of resistance. Taking the drugs wrongly may well be worse than not taking them at all. People who feel that they cannot commit themselves to such a regimen at present may be advised to delay starting treatment until a time when they can.

* Two drugs or three?

Dr Darbyshire argued that during the last year "we haven't learned anything new about when to start treatment, but we've a learned a lot about what to start with". All the clinicians agreed that the minimum anyone should be offered is a two-drug combination such as AZT/ddI, AZT/ddC or AZT/3TC. However, the protease inhibitors are about to hit the market - ritonavir was finally approved throughout Europe on August 27th, to be followed within a couple of months by saquinavir and indinavir - and several clinics are keen to use triple-drug combinations as initial treatment as soon as the drugs (and, critically, the money to pay for them) are available.

Whether two, three or more drugs are used, "it is very attractive to aim for undetectable viral load," said Dr Gazzard. "There are two options - either you start with a couple of drugs then add more if the initial response has not been great enough, or you start with many drugs and then try to stop some of them while keeping viral load below detectable levels." The latter approach is due to be tested in the Medical Research Council's upcoming PROCOM trial.

Some doctors argue that two drugs may be enough to achieve a good anti-HIV effect, and currently advise against using a protease inhibitor when starting treatment, because:

- using a protease inhibitor early may lead to the emergence of resistant HIV strains and these could also be resistant to the other protease inhibitors, severely limiting your future options

- the trial of AZT, 3TC and indinavir showed that triple combinations can be just as effective at suppressing viral load if they are reserved for later use; even people with AZT-resistant HIV responded well to this regimen

- to date only two trials looking at the effects of protease inhibitors on disease progression and survival have been completed, and neither of them enrolled people who were starting treatment for the first time.

Dr Williams recommended starting treatment with only two drugs such as AZT/ddI, but stressed the importance of using a viral load test after two to three months to check that there has been an adequate response. However, he noted that "No-one has clearly defined what an adequate response to treatment might be. Personally, I would want to see at least a one log (ten-fold) drop in viral load, or a very good CD4 response with a smaller drop in viral load." For people who have a very high viral load, or whose CD4 count is already very low (e.g. 50), he would suggest starting treatment more aggressively with a combination of one nucleoside analogue plus a protease inhibitor.

Other doctors now feel that initial treatment should always be as aggressive as possible, using triple-drug combinations. "I feel that when you start treatment, you should use what you perceive to be the best regimen you can access. If we're going to treat we should treat hard," said Dr Margaret Johnson of the Royal Free Hospital.

In every comparison to date, three-drug combinations which include a protease inhibitor have proved superior to two drug combinations in reducing viral load and boosting the CD4 count. The general trend is for viral load to fall below the level of detection in 60 to 90% of triple-combination recipients, and to stay undetectable for as long as follow-up has continued, which so far is a maximum of one year.

Professor Jonathan Weber of St Mary's Hospital, for example, favours the combination of AZT, 3TC and saquinavir for anyone starting treatment. He pointed out that side-effects from 3TC and saquinavir are rare, and even if saquinavir-resistant HIV strains emerge, these may well still be susceptible to indinavir or ritonavir. Some other clinics favour AZT/3TC/indinavir, because indinavir appears to be more potent than saquinavir. No-one advocated ritonavir for people starting treatment because of the unpleasant side-effects it causes for the first month.

Professor Pinching drew attention to the promising results seen using nevirapine (see AIDS Treatment Update issue 43). "For patients who want to take a more aggressive approach, adding nevirapine as the third drug may be just as valid as adding a protease inhibitor." Several clinics reported that many people are choosing to join the trial of nevirapine in which everyone receives a triple combination of AZT/ddI/3TC or AZT/ddC/3TC and are randomly assigned to receive additional nevirapine or a placebo.

Joining a study in which a drug company rather than your clinic pays for some or all of the drugs may be the best way of obtaining a triple combination at present, because there is still no Government commitment to fund the increased costs of viral load testing and multi-drug regimens. "The reality of the situation is that no matter how much we'd like to, at the moment we simply can't afford to prescribe three drugs for everyone," said Dr Johnson.

* Avoiding AZT

Although most of the two- and three-drug combinations which have been studied include AZT, this does not mean that you have to take AZT in order to get the anti-viral benefit of combination therapy. Combinations of 3TC/stavudine, ddI/stavudine or ddI/3TC are all possible, and a protease inhibitor or a non-nucleoside such as nevirapine could also be added to increase the antiviral effects.

Each combination will have a slightly different range of side-effects, and as ever, it is important to avoid combinations of drugs with overlapping toxicities. For example, Dr Mike Youle of the Kobler Centre said that he has seen several patients who developed a rapid and severe form of peripheral neuropathy from the triple combination of stavudine/ddI/3TC.

In the USA, preliminary studies are looking at combinations of two protease inhibitors. The short-term results of a trial combining ritonavir and saquinavir suggest that the combination is safe and has a strong anti-viral impact. Another trial later this year will test the combination of indinavir and saquinavir. In the future, these might be considered options for initial treatment.

BOX - Combining AZT with other nucleosides

* AZT/ddI or AZT/ddC

Delta and ACTG 175 showed that compared with AZT monotherapy, two drug combinations of AZT/ddI or AZT/ddC reduce the risk of death or illness in people who have never received treatment before by around 50% over two years.

AZT/ddI is probably marginally more effective than AZT/ddC at delaying disease progression, although at the cost of a higher rate of gastrointestinal side-effects such as diarrhoea.

For some people this two-drug combination may be enough to reduce viral load to very low levels (especially among those whose viral load is not already very high). Among previously untreated people in the Delta study, about a third had their viral loads reduced below the level of detection after 12 weeks of treatment on AZT/ddI, but only 16% on AZT/ddC. After two years the two arms appeared similar, at around 14% each.

The average reduction in viral load was one log (or ten-fold) after eight weeks.

* AZT/3TC

In July 3TC was licensed in the UK, making the combination of AZT/3TC a possible choice. It is an attractive drug because it rarely causes side-effects, and in test-tube studies makes it harder for HIV to develop resistance against AZT (and possibly other drugs too). It is unclear whether 3TC resistance has this effect in real people; some people taking AZT and 3TC develop strains that are resistant to both drugs.

It is not possible to compare AZT/3TC directly against AZT/ddI or AZT/ddC because they have not been studied as initial therapy within a single trial.

The meta-analysis of 3TC trials presented in Vancouver pooled the results of two trials in which people were starting treatment for the first time, and two trials which enrolled AZT-experienced people. It found that people taking AZT/3TC were less likely to develop symptoms than people taking AZT alone, or AZT/ddC. In general, the effect of this combination on viral load is about the same as AZT/ddI.

* AZT/ddI/3TC

There's no clear evidence about the effectiveness of this regimen as initial treatment. However, the CAESAR study found that among people who started treatment with AZT/ddI or AZT/ddC, or had already been on those combinations for some time, adding 3TC reduced disease progression and prolonged life.

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