• Efficacy and Safety of Atazanavir (ATV) With Ritonavir (RTV) or Saquinavir (SQV) Versus Lopinavir/Ritonavir (LPV/RTV) in Combination With Tenofovir (TFV) and One NRTI in Patients Who Have Experienced Virologic Failure to Multiple HAART Regimens: 16-Week Results From BMS AI424-045 (Forum 118)
  Authored by R. Badaro, E. DeJesus, A. Lazzarin, J. Jemsek, B. Clotet, A. Rightmire, A. Thiry, R. Wilber
  

For people who have a history of viral rebound while on a protease inhibitor (PI)-containing regimen, the standard treatment approach has been to switch to a "boosted" PI-based combination containing nucleosides which have been optimized based upon both history and resistance testing. The combination of lopinavir/ritonavir (Kaletra) has become the "standard-of-care" in these cases because of several studies showing its effectiveness.

This study compared two atazanavir (ATV, Reyataz)-based combinations against Kaletra in patients experiencing viral rebound while on their current regimen, and who had a history of rebound while on a PI-containing regimen. The first arm used Kaletra. The second arm used the dual-PI combination of unboosted atazanavir and saquinavir (SQV, Invirase, Fortovase). The third arm used atazanavir "boosted" by 100 mg once daily of ritonavir (RTV, Norvir).

The second arm was justified based on studies showing that atazanavir can boost saquinavir levels -- and that the saquinavir dose selected (1,200 mg once daily) provides the concentration of two PIs, given at a dose sufficient to treat most wild-type, or non-resistant, HIV.

The boosted atazanavir dose was based on studies showing that 300-mg once-a-day atazanavir (instead of the standard 400 mg dose) boosted by 100-mg ritonavir provides about a five to eight-fold higher blood-level concentration than seen with unboosted levels. Thus, this study not only allows us to compare boosted atazanavir to Kaletra, it also allows us to see if two unboosted PIs can be as good as just one boosted PI at reestablishing viral suppression.

About 120 people per arm were followed for 24 weeks. The study design first changed only the PI part of the combination for two weeks. It then switched the nucleoside component to a combination of tenofovir (TDF, Viread) plus one new nucleoside selected by resistance testing.

As this study was getting underway it was noted that tenofovir lowers some PI blood levels, particularly atazanavir's, by about 20 percent. This may have had an impact on the results here, causing the dual "unboosted" PI arm to do worse than it might have done with a different NRTI backbone; boosted atazanavir overcomes much of the effect from tenofovir. However, this effect may also impact the boosted atazanavir arm more than the Kaletra arm. The impact of tenofovir on lopinavir (when boosted by ritonavir), while initially understood to be small but real, is now understood to be much less important -- based on more recent data providing some reassurance about the lack of any significant effect of tenofovir on lopinavir. Therefore, with a different NRTI backbone, the levels of atazanavir, boosted or unboosted, would be even higher, and therefore there could be different results. However, this will need to be assessed in future studies.

The viral loads at entry were about 4.4 log (about 30,000), and the CD4 counts were about 300. The primary results were viral load drops and lipid changes in both arms.

At week 24, the results were a surprise to many. The boosted atazanavir had about the same degree of viral suppression as Kaletra, each getting about 60 percent of participants to a viral load below 400, and about 40 percent below 50 copies. The unboosted dual-PI arm showed lesser degrees of suppression, with about 44 percent of participants reported to have viral loads below 400, and 23 percent below 50 copies. In addition to this impressive showing, boosted atazanavir was well tolerated by the vast majority of those enrolled. Similar numbers of people (22 percent) had adverse events of at least moderate severity in all three arms of the study. The main limiting side effect of atazanavir, jaundice, occurred in only 6 percent of those on boosted atazanavir, and, predictably, this was even lower in the unboosted dual-PI arm (2 percent). While over one third of the patients had elevated bilirubin in the boosted atazanavir arm, this only led to jaundice in a minority of those treated, and very few stopped atazanavir due to this side effect. A lower rate of diarrhea was seen in the atazanavir arms than in the Kaletra arm. Finally, the lipid profile of boosted atazanavir was similar to that of the unboosted dual-PI combination, showing, on average, a 5 percent fall in total cholesterol compared to the prior combination -- there was about a 5 percent increase in this value for those on Kaletra.

These study results were a topic of discussion for many at the conference since all previous studies of atazanavir were done with it as an unboosted drug, and few had anticipated its effectiveness being similar to Kaletra as a result of boosting. These results should be noted as reflecting 24-week data, so follow up for longer periods of time will be of interest.

In addition, it is reasonable to be interested in the outcomes of regimens that use NRTIs other than tenofovir, given that this agent lowers the blood levels of boosted PIs, and therefore these results may underestimate what might be achieved. Finally, subset analyses of these data will also be of interest, since there is hope that resistance testing might suggest that either boosted atazanavir or Kaletra is the better choice for certain resistance profiles, even though the average person did equally well with either selection. Nevertheless, this study clearly established yet another proven option, using boosted atazanavir -- with its favorable aspects, including lower lipid levels -- when faced with someone dealing with viral rebound after taking PI-based combinations.