July 14, 2003
This poster falls into the broad category of switch studies. Switch studies take patients who are doing well and suppressed on a regimen, usually a protease inhibitor (PI)-based regimen, and switch them to a regimen that might be easier or less toxic in the long term.
Long-term therapy with PI-based regimens often results in the elevation of lipids. While the benefits of suppressing HIV far outweigh any potential risk of heart disease associated with these changes in cholesterol, the evidence is building that the long-term elevation of lipids may increase a patient's chances of developing heart disease, including heart attacks. This is one of the motivations behind the interest in switch studies.
Adherence to antiviral therapy is critical to success. Several studies at this meeting and the recent resistance workshop showed that contrary to what most people would think, it is actually the patients with moderate breakdowns in adherence who have the highest risk of selecting for resistance. And over time even the most adherent patients can have breakdowns in adherence.
The idea behind this study was to take patients who had been doing well on a standard PI-based regimen for three to five years and switch them to a once-daily regimen based on atazanavir (ATV, Reyataz), 3TC (lamivudine, Epivir) and extended-release d4T (stavudine, Zerit XR). The switch to atazanavir, it was hoped, would improve blood lipids. It was hypothesized that the switch to a potent once-daily regimen might increase the long-term loss of latently infected memory T cells. This would be manifest as a decay in the amount of proviral DNA, as studied using a modified PCR method for quantifying proviral DNA.
This was a pilot study that enrolled 22 subjects. Eighteen people completed 48 weeks of therapy. Two were lost to follow-up, one dropped out due to worsening lipoatrophy, and one had viral rebound with evidence of 3TC resistance. All of the remainder people in the study maintained viral loads of less than 50 copies/mL. Cholesterol dropped by an average of about 15 mg/dL at 24 weeks, and the drop in triglycerides was proportionally greater. Adherence and tolerability were excellent. As expected, increased bilirubin was the major side effect but it did not lead to any breaks in therapy.
Proviral DNA decay was neither better nor worse than expected or measured by the group on other regimens. They concluded that a switch to once-daily atazanavir, 3TC and extended-release d4T was safe, effective and resulted in improved lipids, but once-daily therapy did not lead to accelerated proviral DNA clearance.
These findings are consistent with those of other studies in which patients were switched to atazanavir from other PIs. Last year, results were reported on patients in one of the registrational trials of atazanavir who were originally randomized to nelfinavir. After the end of the initial study period, they switched to atazanavir and had substantial improvements in lipids. It is also not surprising that the once-daily regimen did not perform better than other fully suppressive regimens in adherent patients when it came to clearing the proviral reservoirs. It might be more interesting to compare decay rates among patients on a twice-daily regimen with adherence problems and those on a once-daily regimen. It is possible that that is where a difference would be seen.
We now understand from the comparison of tenofovir (TDF, Viread) to d4T in Gilead's GS903 trial that d4T by itself can have some unfavorable effects on lipids, particularly on triglycerides. It is only speculation, but perhaps the lipid improvement would have been greater had ddI (didanosine, Videx) or abacavir been used instead of d4T.