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

Dr Ian Williams suggests that "for a large group of people, it seems unrealistic to expect that they will be able to drive their viral load below 50 even with triple therapy with a PI. If that's going to be your aim, it might be reasonable to delay treatment until we have better drugs. Alternatively, if you feel you need to start therapy now, you might decide to play for time for a year or so with dual NRTIs, and wait until we have better drugs before trying for optimal suppression".

Some suggest that this approach is unwise. Paul Blanchard points out that in a recent study of people taking protease inhibitor containing combinations in San Francisco, the predictors of failure to achieve undetectable viral load included prior NRTI therapy and the duration of prior NRTI therapy. "Those advocating using dual NRTI therapy as a `stop-gap' measure before a subsequent protease inhibitor combination are therefore promoting the very conditions which predict failure on that subsequent regimen."

>>Are future options limited?

Dr Williams disagrees, arguing "I don't actually believe that once you've been on NRTIs you've completely scuppered your chances. People taking d4T/ddI very rarely develop resistance, for example, and there's no evidence that they will respond less well to new regimens in the future. People shouldn't be pilloried if they decide they only want to take two NRTIs."

Likewise, Dr Mike Youle suggests that "there's no research to date which suggests that d4T/ddI will limit your future options, and I would be surprised if it did." An ongoing French study, known as Altiphar, is expected to produce some firm evidence on this question later in 1998. More generally, Professor Brian Gazzard argues "there is no clear evidence that the first chance is the only or best chance for patient treatment".

Another way to hold the protease inhibitors in reserve is to use an NNRTI such as nevirapine as the third drug in a triple therapy regimen. This approach continues to be endorsed by many British doctors. Studies suggest that if your viral load is below 50,000 there is a good chance that triple therapy using nevirapine will suppress it to undetectable levels.

Finally, several studies have provided reassurance that even people with extensive previous treatment with NRTIs can have excellent viral load responses when they later switch to a protease-inhibitor-containing regimen. For example, the Merck 035 trial of AZT/3TC/indinavir enrolled AZT-experienced people, nearly all of whom had developed resistance to AZT. Nevertheless, after 44 weeks about 80% had viral load reductions to below 500.

Likewise, in a study of the combination of ritonavir/saquinavir among people who had received an average of 3 years' prior treatment, 85% had viral load reductions to below 200 after 48 weeks. There is no evidence that NRTI-experienced people have poorer responses to dual PI therapy than previously untreated people.

>>Better to delay treatment?

Paul Blanchard maintains that "obviously the evidence is incomplete, but concerns that dual NRTI therapy fosters cross-resistance, poor durability and poor response to future NRTI-containing regimens means that it should not be used until it has clearly been shown to be safe. The onus is on those who would advocate such an approach to provide data on the safety of such a strategy".

"The person who is considering dual NRTI therapy due to better tolerability and more convenient dosing should think seriously if they should be starting therapy, or whether it would be wiser to delay treatment until they can commit to an optimally suppressive combination. It would be a real shame to start therapy prematurely with a suboptimum approach which may affect subsequent likelihood of success with a later, more potent, combination."

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