Switch/Intensification Treatment with Combivir (AZT/3TC)

and Abacavir in NRTI-Experienced Individuals

The purpose of this study is to try and identify a population of NRTI-experienced individuals for whom you can spare protease and NNRTI drugs. The concept is that if a person has a low viral load, by adding abacavir and a NRTI the person is naïve to or hasn't taken for a while, you might have enough viral load suppression. If viral load is not reduced to <50 copies/ml, then you can intensify with additional treatment.

Keith Henry, from the Univ of Minnesota, reported preliminary 16 week analysis of this 48 week study which initially enrolled 87 individuals who were taking single or double NRTI therapy prior to study enrollment. Participants were PI naïve and not currently taking AZT, had <50,000 copies/ml of plasma viral load, and had >50 CD4.

On day one of study, participants stopped their current therapy and started Combivir 1 tablet bid and abacavir 300 mg bid for up to 48 weeks. Subjects with >400 copies/ml at week 24 have option to further intensify by adding amprenavir 1200 mg bid. The baseline median viral load and CD4 were 3.10 log (about 1300 copies/ml) and 518 CD4 (range 114-1040). The baseline range of viral load for the 87 participants was 1.04 log (10 copies/ml) to over 5 log (100,000 copies/ml). 69% of the participants were caucasian, 22% black, 8% Hispanic and 1% Asian.

90% of the participants had prior experience with d4T. 79% had prior experience with 3TC. 46% had prior experience with AZT. And, 70% or more had >6 months prior experience with these 3 drugs. 32% had prior experience with DDI and 60% of them had >6 months prior use. 70% started the study currently taking d4T+3TC, 12% taking d4T+ddI, 9% on d4T monotherapy, and 3% on ddI monotherapy. So at least 82% were taking a double NRTI regimen. And, at least 12% were taking NRTI monotherapy.

70 patients currently remain in the study, and 17 have prematurely withdrawn. 10 have withdrawn due to adverse events-2 due to abacavir hypersensitivity, and 8 due to nausea/vomiting/malaise.

Preliminary Viral Load Responses- Most patients had less than 10,000 copies/ml and the ultrasensitive assay was used for them, while for others the regular Roche Amplicor test was used.. At baseline the median viral load was 1259 copies/ml. Using an as-treated analysis, Henry reported by week 2 the median plasma viral load was 68 copies/ml (n=80), at week 16 the median viral load was 50 copies/ml (n=39). The limit of detection using the ultrasensitive was 50 copies/ml. At baseline 12% had viral load <50 copies/ml. At week 4, about 80% (n=75) of the participants had <400 copies/ml and about 50% had <50 copies/ml. At week 16, about 80% (n=39) had <400 copies/ml and 54% had <50 copies/ml. The median CD4 increase at week 16 was 60 cells.

Henry will perform an intent-to-treat analysis at weeks 24 and 48. As well, he intends to perform genotypyng and phenotyping at baseline and at time of failure to detect reasons for failure based on prior NRTI experience.

Henry concluded by saying that despite prior 3TC experience (about 80%), initial response to the combination was good. Of course, it is important to remember that the baseline viral load was low (1300 copies/ml) for the individuals switching to this intensification regimen. So, the approach in this study appears preliminarily successful for individuals with a very low viral load. It remains unclear where a viral load cutoff might be that would make such an intensification approach as explored in this study successful. Would it be successful if a person's viral load was 5,000 or 10,000 copies/ml? The approach used in this study may be risky if a person's viral load is 10,000 copies/ml but the planned intensification by adding amprenavir or another PI regimen by week 24 if viral load is above 400 copies may make this approach successful. I think longer-term data is important to assess durability and if premature resistance emerges.