HIV Treatment Bulletin - Vol. 8, No. 8/9, August-September 2007

Simon Collins, HIV i-Base

Jose Valdez-Madruga from Centro de Referência e Treinamento DST/AIDS, São Paulo presented 48 week results from an international Phase IIItrialcomparing darunavir/ritonavir (DRV/r) with lopinavir/ritonavir(LPV/r) in early treatment-experienced patients.[1, 3]

From April 2005, 594 patients from 26 countries, were randomised to optimum background therapy (OBT) plus either DRV/r or LPV/r, both at standard twice-daily dosing. Patients needed to be on failing therapy that did not contain LPV/r, with viral load >1,000 copies/mL.

Baseline characteristics included: median CD4 of 232 cells/mm³ (range 2-over 800) and viral load of 4.3 logs (range 1.76.7); 79% male; mean age 41 years. 18% had baseline CD4 <100 cells/mm³. Around 30% were PI-naïve and 80% had baseline phenotypic sensitivity to at least four PIs. Half the patients in each arm had used > 4 previous RTIs, 75% were NNRTI-experienced, and just under half were three class experienced. Roughly a third of each group had each used 0, 1, and > 2 PIs. A slightly higher percentage of patients in the DRV/r group used 2 or more sensitive RTIs in the background regimen (65% vs 51%, p-value not given).

At 48 weeks, a significantly greater proportion of patients achieved undetectable viral load: <400 copies/mL (77% vs 67%, p=0.008) and <50 copies/mL (71% vs 60%, p=0.005), in the DRV/r vs LPV/r arms respectively, with mean changes in viral load of -1.95 (±1.24) and -1.72 (±1.34) log (p=0.046).

These results met the pre-defined difference to show non-inferiority and to statistically establish superiority for darunavir/r.

Baseline susceptibility (median fold change and range) to darunavir and lopinavir, was balanced between arms at baseline, The darunavir/r arm had greater viral suppression compared to the LPV/r arm, in patients with low (70% vs 63%) and high (72% vs 28%) level phenotypic resistance to lopinavir (<10-fold and >10-fold respectively). Darunavir/r was also more potent at similar sensitivity cut offs for darunavir: 70% vs 59%, and 60% vs 50%.

CD4 increases (approximately +80-90 cells/mm³, p=NS) and serious side effects/discontinuations (approximately 10%/7%) were similar in each arm. Grade 3/4 lipids were slightly lower in the DRV/r arm: cholesterol 8.3 vs 10.7% patients, triglycerides 9.0 vs 14.5%. Most common side effects (Grade 2 or higher) were diarrhoea (7% vs 14%), nausea (4% vs 4%) and rash 3% vs 1%) of patients in the DRV/r and LPV/r arms respectively. About half the patients with virological failure in each arm experienced viral rebound and half were non-responders (never suppressed <400 copies/mL).

Primary PI and RTI resistance occurred in a higher percentage of LPV/r-receiving patients and were detailed in a second poster presented by Marie-Pierre de Béthune.[2, 3]

These differences remained when baseline drug susceptibility was accounted for.

At baseline over 80% patients had zero DRV-associated mutations. Only 4% patients had >3 DRV mutations and this was associated with a poorer response.

Comment

The results by baseline sensitivity indicate that while lopinavir/r will not rescue patients with loss of sensitivity to darunavir/r, darunavir is certainly more active than lopinavir in patients with loss of sensitivity to lopinavir.

It was also notable that the first presentation of such an important study was full 48 week results, and for this not to have been preceded by earlier presentations of interim results, used for marketing but with underpowered for any real meaning.

This study was published in the 7 July issue of The Lancet. [3]

References

2007-08-10
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