AIDS Treatment Update, Issue 63, March 1998
Edward King

>>The rationale

Researchers have been keen to explore subtractive therapy for several reasons. Aggressive initial treatment, followed by less aggressive maintenance therapy, is standard practice in many areas of medicine, including the treatment of many cancers and infections such as tuberculosis. It is plausible that once viral load has been driven to very low levels, fewer drugs may be needed to keep the small remaining amount of HIV virus suppressed. If effective, subtractive therapy would allow people with HIV to take fewer drugs, preserving treatment options, minimising the risks from resistance and side-effects, helping compliance and lowering costs.

>>The new study results

The results of two trials were reported in Chicago (abstracts LB15 and LB16). In both trials, participants initially received triple therapy with AZT/3TC/indinavir, then after a period of `undetectable' viral load were randomised either to stay on the triple therapy or to change to dual therapy or (in the case of trial ACTG 343) indinavir monotherapy. Both trials were halted early, after it became clear that significantly higher numbers of people in the subtractive therapy arms were experiencing viral load rebounds, compared with those who remained on triple therapy.

In ACTG 343, people who had not taken anti-HIV drugs before were much more likely to sustain `undetectable' viral load in the maintenance phase compared with participants who had already taken AZT in the past. The researchers also noted that people whose viral load was suppressed to below 50 copies/ml (measured using an ultra-sensitive viral load test) during the initial treatment phase were also less likely to experience a viral rebound during maintenance therapy, although some rebounds occurred even among these people.

The failure of the subtractive therapy approach in these studies does not necessarily mean that the fundamental concept is flawed. It remains plausible, although still unproven, that subtractive therapy could work if it is handled differently, such as:

- Using more aggressive initial therapy - Not switching until participants have had a certain duration of `undetectable' viral load, so residual HIV levels may be lower - Requiring participants to achieve a greater degree of viral suppression before switching (e.g. below 50 using the new ultra-sensitive viral load tests, or waiting until viral load is undetectable in the lymph nodes as well as the blood) - Using more potent maintenance therapy

>>Implications for ProCom

The MRC's ProCom trial is now open for recruitment at clinics throughout the UK. It is different from Trilege and ACTG 343 in two important respects. First, the initial treatment consists of quadruple therapy including two protease inhibitors, nelfinavir and saquinavir in the new, more potent, soft-gel formulation. Secondly, one of the maintenance arms uses a combination of two protease inhibitors (PIs) that is likely to be more potent than any of the maintenance arms in Trilege or ACTG 343.

However, its similarities include the use of standard, rather than ultra-sensitive, viral load tests; the fact that no-one will have had `undetectable' viral load for more than six months before switching; and the use of a dual NRTI combination (d4T/ddI) in one of the maintenance arms.

While people in the dual PI maintenance arm may have the best chance of sustaining their `undetectable' viral load, they also face the greatest risk - that if their viral load rebounds they may develop PI-resistant HIV.

At the time of writing, the MRC is considering what changes need to be made to ProCom to strengthen the design and ensure that subtractive therapy is more thoroughly evaluated. If you are considering joining ProCom, be sure to ask your doctor about the changes and how they affect the trial's pros and cons.

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