Darunavir Effective in Resistant HIV

BARCELONA, Spain, April 5 -- The third-generation protease inhibitor darunavir (Prezista) is highly effective in combating highly resistant HIV, according to researchers here.

In two parallel phase IIB randomized trials, darunavir, augmented by the protease inhibitor ritonavir, was better at reducing viral load than control drugs, said Bonaventura Clotet, M.D., of the Hospital Universitari Germans Trias i Pujol.

After 48 weeks, 67 of 110 (61%) of darunavir patients had seen their viral load drop by a factor of 10, compared with 18 of 120 (15%) of patients getting control protease inhibitors, Dr. Clotet and colleagues reported online in The Lancet. The difference in response was 46%, which was significant at P<0.0001.

On the basis of a logistic regression model including stratification factors (baseline number of primary protease inhibitor mutations, use of enfuvirtide, baseline viral load) as covariates, the difference in response was 50% (odds ratio 1172, 95% CI 575-2389).

Patients in the darunavir group also had a significantly greater chance of having a viral load of less than 50 copies of viral RNA per cubic milliliter of blood - the lower limit of detectability.

That finding underscores the possibility of reaching such a low HIV level, even in patients whose virus is resistant to multiple drugs, Dr. Clotet and colleagues said.

The target is a "stringent yet realistic therapeutic goal" whose benefit is that it may delay or prevent the emergence of resistance, they said.

The finding comes from the two POWER studies, which began with 24 weeks of dose-finding and primary efficacy analyses. Some of the data were presented at the International AIDS Conference in Toronto in 2006. IAC: Prezista (darunavir) Suppresses HIV for Patients Out of Options

At 24 weeks, the researchers settled on a twice-daily dose of 600 mg of darunavir and 100 mg of ritonavir and patients getting other doses were switched.

For this 48-week analysis, only patients who had been on the twice-daily 600/100 dose from the beginning were included. They were compared with patients in the control arm - getting an optimized background regimen, including a protease inhibitor - who simply continued on this therapy.

The researchers found:

• At all time points, more patients getting darunavir had undetectable viral loads, below 50 copies per milliliter, than those in the control PI group.
• At week 48, 50 darunavir patients (45%) reached a viral load of less than 50 copies per mL, compared with 12 (10%) of the patients receiving control protease inhibitors. The difference was 37%, which was significant at P<0.0001.
• Darunavir patients also saw greater gains in CD4 cells - a mean increase of 102 cells per microliter, compared with 19. The difference was significant at P<0.0001.

The latter finding is important, said Rodger MacArthur, M.D., of Wayne State in Detroit, in an accompanying comment article, because the CD4 response is a better predictor of risk of disease progression than HIV RNA levels.

In the darunavir-ritonavir group, rates of adverse events were mostly lower than, or similar to, those in the control group when corrected for treatment exposure.

Dr. MacArthur said clinicians "will probably rejoice" at the availability of darunavir -- approved by the FDA in 2006 -- but the current study has some limitations.

Chiefly, he said, the combined trials are short and relatively small, so that it is unclear how long the benefits of darunavir will last in this group of treatment-experienced patients.

It is also not clear, he said, how darunavir compares in this population with tipranavir (Aptivus), another relatively new protease inhibitor boosted with ritonavir and aimed at patients with highly resistant virus.

Because tipranavir had not been approved when the POWER trials started, it was not included as a comparator. But some cross-resistance has been seen between the two drugs, Dr. MacArthur said, so that it's not clear how or in what order they should be used.

Dr. MacArthur reported that he had no conflicts to disclose.