October 27, 2001
Despite the aggressive antiretroviral regimens currently in use, only half of the patients attain plasma HIV RNA levels <50 copies/mL by week 24 of therapy. Two approaches have been suggested to address this problem. The first strategy uses more aggressive initial regimens with four or more different antiretroviral drugs, especially in patients with relatively high baseline plasma HIV-1 RNA levels. Obviously that approach has a significant economic and toxicity cost. The second strategy involves early intensification (adding a single new drug to an existing regimen) in patients who are at risk for attaining incomplete viral suppression by week 24 of therapy.
This study is about "early intensification." This group in New Orleans looked at their outpatient clinic and at 1,755 patients who started HAART during the years 1997 to 2000. They examined viral loads at six months after patients started antiretroviral therapy and classified the patients as: complete responders, if they had an undetectable viral load; incomplete responders, if they had at least a 0.5 log10 decrease in viral load but their viral load was still over 400 copies/mL; or non-responders, if their decay of viral load had decreased less than 0.5 logs.
Then they looked at predictors of subsequent virologic failure. Not surprisingly, they found that patients with lower CD4 counts were more likely to fail, something that had been observed before. Baseline viral load was also a strong predictor of virologic failure. Their classification at six months of treatment was also a strong predictor of subsequent virologic failure. Patients with an intermediate response were three times more likely to fail than the ones who had a complete response.
This study is not original in the sense that its main conclusions are already known and have been shown in many previous studies. Its merit lies in its very large size, which supports its conclusions.
The authors propose that patients with incomplete responses at six months are candidates for intensification because they are at an increased risk of failure.
It is not the first time that this has been proposed. This strategy has been tried on a couple of occasions: the PROMETHEUS study, published in AIDS last year, and the ACTG trial 5064, which hopefully will be presented during the next Retrovirus meeting. In the PROMETHEUS study, patients were randomized to receive d4T and RTV/SQV or RTV/SQV alone. Patients on RTV/SQV alone who did not become undetectable by week 12 could then add d4T or other nucleosides to their regimen. This occurred in 17 subjects with a viral load greater than 1,000 at week 12 of therapy; they found that all patients had plasma HIV RNA levels <50 copies/mL at week 24. The study found no difference between starting the initial therapy with two drugs (ritonavir and saquinavir) or three drugs (ritonavir, saquinavir and stavudine) in the number of patients attaining plasma HIV RNA levels <50 copies/mL at week 24.
The idea of intensification is tempting. The problem is to identify patients as candidates early enough so that any long-term response is not compromised. This is an uphill battle: Zeng et al. demonstrated in a different paper that it is very difficult to identify these patients.
I think we will continue to see studies around this idea. It is difficult to design studies in a way that makes them feasible. Maybe this is something that will be tackled by an investigator in the developing world.
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