Lopinavir/ritonavir (Kaletra) alone can suppresses HIV, or maintain viral suppression, in certain patients who achieve good adherence, according to 2 studies presented at the recent 11th European AIDS Conference (EACS) in Madrid Spain (October 24-27, 2007). Another pair of studies, however, showed that once-daily Kaletra may not work as well as twice-daily dosing.

Kaletra Monotherapy

Researchers presented results from 2 studies of Kaletra monotherapy. (The boosting dose of ritonavir is not counted as a separate drug, since it is not active against HIV in such small amounts). The Spanish OK4 study was a treatment simplification trial in which patients with fully suppressed HIV on a Kaletra-based combination regimen switched to monotherapy. In the French MONARK study, by contrast, patients started Kaletra monotherapy as their first regimen. Prior data from these studies indicated that Kaletra alone suppressed HIV to an undetectable level or maintained baseline viral suppression.

In the OK4 study (abstract PS3/1), 198 participants with no prior treatment failures who had an undetectable viral load after taking a traditional Kaletra-based combination regimen containing any 2 nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) for at least 6 months were randomly assigned to either stay on the combination or drop the NRTIs and keep taking Kaletra alone. If viral breakthrough occurred, NRTIs were re-introduced.

After 96 weeks in an intent-to-treat analysis, Kaletra monotherapy and continued combination therapy worked equally well (77% vs 78% with HIV RNA < 50 copies/mL). In an as-treated analysis that included only patients who remained on monotherapy (i.e., those without viral breakthrough), Kaletra monotherapy produced slightly better outcomes (94% vs 86% with HIV RNA < 50 copies/mL), attributable to a higher rate of discontinuations due to NRTI-related adverse events in the combination therapy group (among patients taking d4T or ddI). However, subjects taking Kaletra monotherapy were more likely to experience transient, low-level viral load "blips."

In this study, poor adherence and lower nadir (lowest-ever) CD4 cell count predicted failure to achieve undetectable HIV RNA at 96 weeks. However, no patient with viral breakthrough had evidence of protease-resistance mutations.

In the French MONARK study (abstract PS1/2), 136 previously treatment-naive participants were randomly assigned to receive Kaletra alone or a traditional HAART regimen of Kaletra plus 2 NRTIs (AZT + 3TC).

After 48 weeks in an intent-to-treat analysis (discontinuations and regimen changes counted as failures), Kaletra monotherapy did not suppress HIV as well as the combination HAART regimen (67% vs 75%, respectively, with HIV RNA < 50 copies/mL). In an as-treated analysis, the corresponding figures were 84% and 98%.

In this study, too, poor adherence predicted treatment failure: 31% of patients who did not achieve viral suppression at 48 weeks reported missing doses, compared with 19% of those who achieved undetectable viral load. Baseline viral load and viral suppression < 400 copies/mL at 4 weeks predicted HIV RNA < 50 copies/mL at 48 weeks.

Further, patients with HIV subtypes other than B were less likely to achieve undetectable viral load after 24 weeks using Kaletra monotherapy compared to those with subtype B -- the most common subtype in the U.S. and Western Europe (64% vs 87%, respectively); this may be related to lower adherence in the non-B patients.

Together, these studies suggest that Kaletra monotherapy may be appropriate as a simplification or induction-maintenance strategy for selected patients with suppressed HIV, but monotherapy does not seem to work as well as combination therapy for suppressing HIV in the first place.

Once-daily Kaletra

Another pair of studies presented at the conference looked at once-daily Kaletra used as part of a traditional combination antiretroviral regimen. Current U.S. treatment guidelines list twice-daily Kaletra as a "preferred" HAART component and once-daily Kaletra as an "alternative."

In the ARTEMIS trial (abstract LBPS 7/5), 689 treatment-naive participants were randomly assigned to receive Kaletra once or twice daily or ritonavir-boosted darunavir (Prezista) as part of a combination HAART regimen. In the Kaletra group, 77% took the drug twice-daily, 15% took it once-daily, and 8% switched dosing during the study period (the choice of once-daily or twice-daily dosing in the Kaletra arm was not randomized, but was decided by the patients' physicians).

As previously reported, after 48 weeks, 84% of patients in the darunavir/ritonavir arm achieved a viral load < 50 copies/mL, compared with 78% overall in the Kaletra arms (not a statistically significant difference). Among patients with high baseline viral load (> 100,000 copies/mL), the corresponding response rates were 79% and 67%.

As reported at EACS, further analysis revealed that the lower rate of viral suppression in the Kaletra group was largely attributable to a higher likelihood of treatment failure among participants who received the drug once-daily: 81% with twice-daily dosing vs 71% with once-daily dosing achieved HIV RNA < 50 copies/mL. The difference was especially marked among people with high baseline viral load: 71% with twice-daily dosing vs 56% with once-daily dosing.

Finally, a small pharmacokinetic study (abstract LBPS 7/4) also suggested that once-daily Kaletra may be a risky choice. In this study, 16 participants received once-daily ritonavir-boosted atazanavir (Reyataz), twice-daily Kaletra, and once-daily Kaletra for 10 days. The researchers found that average blood concentrations of lopinavir dropped close to the minimal effective concentration after 24 hours, and fell below this level in 44% of subjects taking the drug once-daily. While it took a mean 40 hours for atazanavir to reach its minimal effective concentration, the mean for once-daily Kaletra was just hours.

These results indicate that once-daily Kaletra may not be able to control HIV if a dose is missed, underlining the importance of optimal adherence and suggesting that twice-daily dosing may be preferable if poor adherence is likely to be an issue.

11/06/07

References

JR Arribas, F Pulido, R Delgado, and others. Lopinavir-ritonavir monotherapy vs. lopinavir-ritonavir and two nucleosides for maintenance therapy of HIV: Ninety-six week results of a randomized, controlled, open label, clinical trials (OK04 Study). 11th European AIDS Conference (EACS). Madrid, Spain. October 24-27, 2007. Abstract PS3/1.

P Flandre, C Delaugerre, J Ghosn, and others. Prognostic factors of virological success in antiretroviral-naïve patients receiving LPV/r monotherapy in the MONARK trial. 11th EACS. Abstract PS1/2.

N Clumeck, J Van Lunzen, P Chiliade, and others. ARTEMIS - efficacy and safety of lopinavir (BiD vs QD) and darunavir (QD) in antiretroviral-naive patients. 11th EACS. Abstract LBPS 7/5.

M Boffito, L Else, D Back, and others. Pharmacokinetics (PK) of atazanavir/ritonavir (ATV/r) once daily (OD) and lopinavir/ritonavir (LPV/r) twice daily (BD) and OD over 72 hours following drug intake cessation. 11th EACS. Abstract LBPS 7/4. 2007.