AIDS Treatment Update, Issue 61-62, January-February 1998
Edward King

However, others remain unconvinced that such an aggressive approach to therapy is justified or achievable with the currently available drugs. We talked to advocates of `hitting hard' to define precisely what they are recommending and why. We then asked a number of leading British doctors whether they endorse this approach and recommend it to patients at their clinics.

>>The case for hitting hard

Advocates of `hitting hard' propose that this approach is the only logical one, on the basis of recent scientific studies. They make three main arguments:

- that when you start treatment, you should always choose a combination that is likely to suppress viral load to below the limit of detection

- that dual combinations consisting of two nucleoside analogue drugs are inadequate to achieve this and will limit your future choices

- that viral load ideally needs to be suppressed below the limit of the new ultra-sensitive viral load test, which is 50 copies/ml

Paul Blanchard of the AIDS Treatment Project argues that current research studies "all inform positive people of the necessity, once treatment is started, of using all available means to prevent viral resistance and thereby preserve durability of their chosen regimen. This means attempting to achieve an `undetectable' viral load with your first regimen."

Blanchard argues that "studies show that, compared with people who are taking anti-HIV drugs for the first time, previously treated people have worse viral load responses to anti-HIV therapy, even when the specific drugs are all new to them. Virological control is easiest with the first regimen chosen. It therefore makes sense that this first regimen should be optimal. This may mean using four or five drug combinations if your viral load is high, and using no less than a triple therapy regimen in all others." [Editor's note: This view was not shared by all our medical advisory panel - see the box on page 2.]

According to Blanchard, dual therapy with nucleoside analogue reverse transcriptase inhibitors (NRTIs), such as AZT/3TC or d4T/ddI, "should be discouraged on safety grounds, because these regimens are less active than triple therapy and the risk of developing resistance to the drugs is greater than if they are used as part of triple therapy regimens. 3TC in particular is extremely potent but has the disadvantage that resistance arises easily and rapidly, making it doubly important that its use is reserved for the attempt at complete suppression, where its potency will most usefully support a protease inhibitor and the combined potency will prevent resistance to either drug.

"Cross-resistance among NRTIs may mean that even with three completely new drugs in a subsequent regimen, you could still be resistant to components of that new combination. Studies suggest that HIV viral load in lymph tissue is unaffected by dual NRTIs, but declines with a protease inhibitor-containing regimen. Studies also suggest that the immune system rebuilds itself more effectively with PI-containing triple therapy when compared to dual NRTIs."

Blanchard argues that whenever anti-HIV therapy is taken, one of the main priorities should be to prolong the efficacy of the drugs for as long as possible. "When viral load is only partially suppressed, suppression will not be sustained for long, because resistance to the drugs will emerge. Studies suggest that we see the greatest durability of suppression if viral load is maximally suppressed to below 50." It also follows, he argues, that viral load needs to be monitored frequently (such as 6 to 8 weekly during treatment) and the results need to be available quickly, so that treatment can be changed promptly if viral load shows a sustained rebound.

Finally, advocates of `hitting hard' are concerned that it may not be enough for viral load to be suppressed to below the limit of the tests now widely used in clinics, which is 400 or 500 copies/ml. As evidence, they point to studies presented at the International Workshop on HIV Drug Resistance, Treatment Strategies and Eradication in Florida last June. One study found that HIV can eventually develop resistance to anti-HIV drugs even after viral load has been suppressed to below 500 (abstract 63). Another found that viral suppression was relatively short-lived among people whose lowest viral load after starting protease inhibitor therapy was in the range 200 to 1000, compared with people whose viral load did fall below 200 (abstract 62). Similarly, the INCAS study of AZT/ddI/nevirapine found that the average duration of suppression was 154 days for people whose viral load fell to below 20, compared with only 7 days for people whose viral load never fell below 20 (Hamburg, abstract 105).

A newer viral load test made by Roche, called the ultra-sensitive test, has a limit of detection of only 50 copies/ml; other companies are also developing more sensitive tests. Advocates of `hitting hard' argue that the aim of treatment should be to suppress viral load sufficiently to be `undetectable' using such a test. According to Paul Blanchard, "resistance does not evolve and durability is prolonged in those who achieve less than 50 copies/ml".

>>Has dual therapy had its day?

When we last covered this subject in issue 53/54, our medical advisors all agreed that triple therapy regimens offered a better chance of achieving undetectable viral load than dual therapy. However, some pointed out that dual therapy regimens may cause fewer side-effects and be more convenient to take than more complex combinations, and that for some people with HIV, these considerations may be more important than striving for maximal viral suppression. Dual therapy may also be an effective way of `playing for time' and reducing your risk of disease progression while you wait for more effective anti-HIV drugs to become available (see box opposite).

Nevertheless, all our respondents now agreed that there is a very strong case for trying to achieve undetectable viral load when starting treatment - and therefore, as Dr Graeme Moyle of the Chelsea & Westminster Hospital puts it, "choosing a regimen that's likely to get you to where you want to be". In early 1998, amendments to the British HIV Association guidelines on anti-HIV therapy will also encourage doctors and people with HIV to opt for regimens capable of achieving undetectable viral load.

While agreeing that "maximal viral suppression is a perfectly reasonable target", Professor Tony Pinching of St Bartholomew's Hospital sounds a note of caution. "We have to remember that not everyone may be able to achieve `undetectable' viral load. If one doesn't achieve it, one may have to review whether that really is a realistic target for that patient. It may not be prudent to keep adding and switching drugs in an attempt to reach undetectable levels, since in the process you may use up many of the available drugs in a relatively short time. I see quite a lot of patients whose viral load we can get down to the 2,000 to 3,000 level, but no further. Many of them have stayed at that level for six to nine months, which suggests that they are not seeing the rapid emergence of resistance that some have predicted."

>>`Undetectable' - a moving target?

No sooner has UK expert opinion moved in favour of aiming for `undetectable' viral load, than the goalposts have shifted again. Now, advocates of `hitting hard' argue that simply being `undetectable' by today's standard tests may not be enough. Instead, they suggest that the aim of treatment should be to suppress viral load so much that it is `undetectable' by the ultra-sensitive viral load test, with its lower limit of detection of only 50.

At present, the ultra-sensitive viral load test is not routinely available at British clinics. However, several centres told us that they expect to have access to it in March or April 1998, and the rest of this article examines the choices that people with HIV may face when they do have access to the test. The ultra-sensitive test won't simply replace current tests because although it is more accurate at measuring very low viral load, it is less accurate at measuring high viral load.

Although there is currently little firm evidence, Dr Moyle believes that the ultra-sensitive test will be an important tool for treatment decision-making. "I think it's plausible that patients whose viral load remains in the 50 to 400 band are likely to develop resistance to their current regimen sooner than those whose viral load does fall below 50. That does provide a rationale for not settling for `undetectable' with the standard tests."

However, he also points out that "we don't know how long it may take for resistance to develop among people with viral load in the 50 to 400 range - in some cases it might take many years. For some people, just getting below 400 for a prolonged period may be good enough to buy the additional life so that you die of old age before you fail on therapy."

Professor Pinching remains unconvinced that there is a real difference between `below 400' and `below 50'. "That might be true if your regimen includes an NNRTI, because they are particularly liable for the emergence of resistance, but we don't know if that is applicable to other agents such as protease inhibitors. While it may be plausible that these patients will do even better if they go below the 50 cut-off, it's still unproven."

Professor Pinching argues that there are so many unanswered questions about the ultra-sensitive assay that it is too early to start using the ultra-sensitive test in day-to-day treatment choices. "We would simply be adding a process in the clinic, without really knowing how to use the information. We need more research to identify that it has value and utility." That view is shared by the authors of the current US guidelines on anti-HIV therapy, reviewed in AIDS Treatment Update issue 60, and is also likely to be endorsed in the updated BHIVA guidelines.

Dr Moyle suggests that the picture may be clearer by this summer, when studies using the ultra-sensitive assay are due to be presented at the World AIDS Conference in Geneva.

There also practical questions about the use of the ultra-sensitive assay, including how realistic it is to expect such profound viral suppression and what duration of treatment might be required to achieve it among those for whim it is possible. These are discussed in the two boxes on this page.

>>A treatment dilemma

Given all these uncertainties, most of our medical advisors felt that it was too early to base treatment decisions on the ultra-sensitive test. Instead, they felt the priority should be to achieve `undetectable' viral load using the standard test.

But what are the practical implications for those who do decide that their treatment aim will be to suppress viral load to below 50?

First, all the evidence suggests that the initial priority should be to achieve undetectable viral load using standard tests (i.e. below 400) during the first 16 to 24 weeks of treatment. For most people, it certainly seems to be unrealistic to hope for any better virological response during this early stage of treatment.

After two consecutive viral load tests that are below 400, it may be worth asking your clinic to perform an ultra-sensitive test next time. That will tell you whether your viral load is below 50, or in the 50 to 400 range.

If it is in the 50 to 400 range, you face a dilemma. On the hand, it might be unwise to change therapy during the first year of treatment solely because your viral load remains above 50, since given a little longer it might fall to below 50 without using up any more of the available drugs. On the other hand, by doing nothing and waiting to see what happens, you are probably running a small risk that resistance may start to develop, which would also limit your long-term treatment options. That's why advocates of `hitting hard' argue that the most cautious response is to monitor viral load closely and regularly, with rapid access to the test results, and to modify treatment as soon as there is any sign of an increase.

Different doctors are likely to offer different advice about this dilemma. Dr Moyle, for example, suggests that "people whose viral load is between 50 and 400 should wait a few weeks and have a second test done, to see whether it just needs a little longer to get below 50. The chance that resistance will develop in the meantime is very low; it would be taking a greater risk to change treatment prematurely. But if it remains above 50, I would suggest promptly adding an extra drug, to try to drive it that little bit further down. When the viral load is so low, you can probably get away with just adding a single extra drug. If you wait longer and the viral load rises into the hundreds or thousands, you may need to change all your drugs."

However, he acknowledges that with this strategy too, you may end up changing treatment (and using up drugs) unnecessarily. Several of our respondents gave accounts of patients whose viral load increased from `undetectable' into the few hundreds or thousands, but after a couple of months it had returned to `undetectable' without any change in treatment. For this reason, other doctors would not recommend changing treatment unless repeated tests over several months indicated that the rise in viral load was real and persistent. At that point, most would be worried that adding or changing only one drug might lead to resistance, and instead they would switch at least two components of the combination.

>>Keeping a sense of perspective

As Professor Brian Gazzard of the Chelsea & Westminster Hospital points out, "The lasting lesson of AIDS research has been that it is important to rely on scientific data for the development of treatment strategies. When there is little data, as in this case, opinions flourish. My strongest plea would be for the tolerance of other people's viewpoints in a debate which does not preclude further rational thought."

Meanwhile, people with HIV and their doctors are experimenting with different treatment strategies based on incomplete research. However, it seems clear that (at least with today's drugs) some people may not be able to achieve viral load below 50 - nor, as Professor Pinching noted, may it be wise for them to strive to achieve it at all costs.

As Paul Blanchard points out "It's important to remember that although total suppression may be a good aim of treatment, failure to achieve it is not total failure. Even if they only achieve partial suppression, or if the drugs eventually fail, many people have derived tremendous benefit. Of course we want to believe that we might derive a normal life-span from their use. But don't be disappointed if they only stave off disease and death for a few years. That in itself is a considerable achievement."

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