AIDS Treatment Update, Issue 54, June 1997
Edward King

For people currently on one of these combinations, the most pressing questions are:

* how to know when the regimen is failing, requiring a change to a new combination

* whether it is worth changing even if you still seem to be responding well to the current regimen

* when switching, which second-line combination to choose to minimise the risk of cross-resistance.

If you are thinking about starting treatment for the first time, you are probably considering issues such as whether to take two drugs or three, and the efficacy and tolerability of the various combinations. But it is important also to think about the impact of your initial choice of NRTIs on your future treatment options.

This perspective on treatment choices is becoming known as 'sequencing' (see AIDS Treatment Update issue 48/49). Its advocates argue that realistically, people with HIV should expect that at some point the treatment regimen they are taking will start to fail, and they will need to be able to switch to another effective regimen. In many cases it may therefore be better to choose a combination which may not be the most potent currently available, but which will leave you as many options as possible for using later. AZT- versus d4T-based combinations

AZT- VERSUS D4T-BASED COMBINATIONS

Until very recently most people starting treatment for the first time will have been prescribed a combination that is based on AZT. Today, though, an alternative is to base the combination on d4T (stavudine). There is now a strong consensus that in cases in which someone needs to change treatment because their current regimen is failing, it is most effective to change both of the nucleoside analogues. That means that someone who starts on an AZT-based combination should expect to switch to a d4T-based combination, and vice versa.

A growing number of clinics are recommending d4T-containing combinations as a possible initial regimen, for two reasons. First, many people with HIV find d4T a particularly easy drug to tolerate (although it can cause reversible peripheral neuropathy in up to 15% of cases).

Secondly, AZT and d4T are the best drugs at penetrating the central nervous system (CNS), and so may help to treat or prevent neurological problems caused by HIV, such as dementia. It therefore makes sense to include either AZT or d4T in any combination. The two should not be combined, since they may reduce each other's effects (see AIDS Treatment Update issue 50).

Several studies have confirmed the antiviral effects of the combination of d4T/ddI. Early concerns that this combination would cause an unacceptably high rate of peripheral neuropathy have turned out to be unfounded; in trials the rate of neuropathy was no greater than with either drug alone. Another possible combination is d4T/ddC but again there is the risk of increased rates of peripheral neuropathy, and there appears to be little or no published evidence on the safety or antiviral effects of this combination.

WHAT ROLE FOR 3TC?

3TC is also a very well-tolerated drug, so also seems an attractive candidate for use as part of an initial treatment regimen. However, there are other arguments that weigh against the early use of 3TC.

First, 3TC may be the most problematic of all the NRTIs in terms of the possible risk of cross-resistance to other NRTIs. Resistance to 3TC emerges very rapidly if HIV replication is continuing at significant levels despite treatment with the drug. 3TC-resistant virus may be somewhat less susceptible to treatment with ddI or ddC, and there is emerging evidence that sometimes it might also be less susceptible to abacavir (1592U89), Glaxo Wellcome's new NRTI that may have a key role in treatment regimens of the future. These concerns may provide grounds to start treatment with a combination such as AZT/ddI or d4T/ddI, saving 3TC for use as part of a future combination.

Secondly, 3TC may be a particularly useful treatment option for AZT-experienced people. The CAESAR trial (see AIDS Treatment Update issue 44), which was published in full in The Lancet this month, showed a substantial clinical benefit of adding 3TC to AZT monotherapy or AZT-based combination regimens, in contrast to studies such as Delta and ACTG 175 in which AZT-experienced people derived relatively little benefit from adding ddI or ddC.

3TC can be effectively combined with either AZT or d4T. Recent studies of d4T/3TC combinations have shown reductions in viral load that seem to be comparable to those achieved with other two-drug nucleoside combinations.

ADDING A THIRD DRUG

In some circumstances, doctors may suggest a three-drug combination when starting or switching treatment. These scenarios include:

1. If your viral load before you start treatment is 'high' suggesting that you may need more antivirals to suppress it to an 'adequate' level (definitions of 'high' and 'adequate' may vary from clinic to clinic)

2. If your CD4 count is below 200, since trials among pre-treated people with CD4 counts below 200 have shown that adding a protease inhibitor (ideally with another new drug as well) is more effective than a two-drug NRTI combination

3. If you have started treatment with two drugs, but after 8 to 12 weeks your viral load has not fallen as anticipated. (This may be more complex if your clinic cannot guarantee prompt access to your viral load results. By the time you get the result, it may be too late simply to add a third drug; instead you may also have change your current two NRTIs. Some activists argue that if your clinic cannot guarantee that the result of your week 8 viral load test will be back by week 12, you should consider starting with three drugs in the first place.)

4. If your current treatment regimen is failing, and you and your doctor are not confident that alternative therapy with only two NRTI drugs will be adequate.

CHOOSING A THIRD DRUG

There are three possibilities for the third drug:

* a non-nucleoside reverse transcriptase inhibitor (NNRTI)

* a protease inhibitor

* a third NRTI

Few studies have investigated the efficacy and tolerability of triple NRTI combinations. But there may be a case for taking three NRTIs if your aim is to reduce viral load as low as possible. Some of the participants in the CAESAR trial were taking AZT/ddI or AZT/ddC when they added 3TC, and like the other group of participants who added 3TC to AZT monotherapy, they experienced a reduced risk of disease progression.

The argument against such combinations is that by 'using up' a third NRTI, it may be harder to assemble an effective combination of two new NRTIs for second-line use later.

There is more evidence about combinations that include an NNRTI or a protease inhibitor. As previous issues of AIDS Treatment Update have reported, several studies have suggested that combinations using a protease inhibitor produce significantly greater reductions in viral load than two-drug NRTI combinations, both when used as initial treatment and when used by pre-treated people. Combinations that include an NNRTI such as nevirapine have given rise to similar conclusions when used as part of an initial treatment regimen, but the effect of switching to a new combination which includes an NNRTI if you have been pre-treated has not been established. Since it is thus possible that your only opportunity to benefit from an NNRTI may be when starting treatment for the first time, this may be an argument for choosing an NNRTI rather than a protease inhibitor if you need a third drug at this stage.

DEFINING TREATMENT FAILURE

If you are currently taking a combination of two nucleosides, how should you judge whether or not they are working adequately?

There are many different views on this, as reflected in the British HIV Association (BHIVA) guidelines on anti-retroviral therapy published in The Lancet in April, but most revolve around viral load measurements. Those who argue that treatment should always aim to reduce viral load to below the limit of detection would add or switch drugs whenever measurable and rising levels of virus are found.

Other doctors would delay a change in therapy until viral load has returned towards or above its baseline (pre-treatment) value. If that baseline value was very high, your doctor may recommend a change of therapy when your viral load increases above a certain 'staging post' level.

A falling CD4 count might also trigger a change of therapy even if your viral load response remains good. Worsening physical health, such as the onset or recurrence of an HIV-related symptom, should also be taken into account; Dr Fiona Boag of the Kobler Centre points out that "if a patient is ill with an HIV-related illness, the treatment clearly isn't working". Putting all these considerations together, for example, Dr Ray Brettle in Edinburgh recommends his patients to switch therapy if their viral load has returned to pre-treatment levels or is above 60,000; or if their CD4 count has returned to pre-treatment levels; or if they develop some clinical indication that treatment is failing.

Researchers on the Delta trial have pointed out that the benefit from an anti-HIV regimen does not abruptly end when your viral load returns to its baseline level or above. In Delta, participants' risk of disease progression remained lower than that of monotherapy recipients long after their viral load had returned to baseline. This is why many doctors recommend taking into account your symptoms and CD4 count, as well as your viral load, when deciding whether you are 'failing' on your current treatment.

Various clinical studies (including the CAESAR trial of 3TC, and the ritonavir clinical endpoint study 247) have suggested that people who do not necessarily appear to be failing on their current nucleoside analogue therapy may benefit from adding further drugs. However, this does not necessarily mean that everyone now only on nucleosides would be well-advised to add additional drugs even if their condition appears to be stable. The results of such trials simply describe the average response seen in a defined group of participants, and not the range of individual responses. On the individual patient level, the benefits of adding an additional drug may well have been greatest among those who were at imminent risk of disease progression, and in the clinic this should often be predictable from viral load, CD4 and clinical indicators.

KEY CONCLUSIONS

* Starting treatment should include consideration of your second- and third-line options.

* Two NRTIs may be adequate to achieve very low or undetectable viral load if your pre-treatment viral load is relatively low.

* Viral load testing is an essential tool - but not the only tool - to help guide treatment choices.

* If you do start with two nucleoside analogues, make sure that you discuss a fail-safe plan for what to do if your viral load response after three months is not satisfactory.

* There may be a case for reserving 3TC for later treatment.

USING NUCLEOSIDES IN DUAL OR TRIPLE COMBINATIONS

Initial Best Risk of Alternative Combination second-line cross-resistance* NRTIs NRTIs

d4T/ddI, or AZT/ddI d4T/3TC ** Low AZT/3TC plus a third drug

d4T/ddI, or AZT/ddC d4T/3TC ** Low AZT/3TC plus a third drug

d4T/3TC AZT/3TC d4T/ddI ** Moderate to low plus a third drug

d4T/ddI AZT/3TC ** Low AZT/ddC ?

AZT/3TC d4T/3TC d4T/ddI ** Moderate to low plus a third drug

* i.e. the risk that the second-line combination will be affected by cross-resistance

** consider also adding an NNRTI, a protease inhibitor or a third nucleoside analogue

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