In Abbott study M03-613¹ lopinavir/ritonavir (LPV/r, Kaletra) monotherapy after an induction treatment of lopinavir/ritonavir + zidovudine/lamivudine (AZT/3TC, Combivir) was compared with a standard regimen of zidovudine/lamivudine + efavirenz (EFV, Sustiva, Stocrin). Data presented at the XVI International AIDS Conference in Toronto in 2006 revealed that the lopinavir/ritonavir monotherapy arm was associated with a higher rate of confirmed virologic rebound to more than 50 copies/mL.

The OK studies (OK and OK04) had a similar study design, but included only patients with long-term (more than six months) virologic suppression before starting lopinavir/ritonavir maintenance therapy; in the OK04 study, low-level virologic rebound on the lopinavir/ritonavir-alone arm also occurred more frequently than in the triple-therapy group, with reintensification successful in regaining virologic suppression.²

Analyses presented at the 14th Conference on Retroviruses and Opportunistic Infections by R. Campo of the M03-613 study and by Federico Pulido of the OK and OK04 studies, evaluated the predictors of this virologic rebound.^3,4

In study M03-613, 155 treatment-naive patients entered the study, and were randomized 2:1 to the lopinavir/ritonavir monotherapy arm and the zidovudine/lamivudine arm, respectively.³ Among the 104 patients in the lopinavir/ritonavir group, 32 patients demonstrated confirmed virologic rebound to more than 50 copies/mL, generally between 50 and 500 copies/mL. By multivariate analysis, study participants reporting at least one missed lopinavir/ritonavir dose had a 2.7 fold higher risk of rebound than those who were fully adherent (P = .01). In addition, patients with higher baseline CD4+ cell counts were more likely to maintain full virologic suppression. Baseline HIV RNA and demographic factors were not significantly associated with virologic failure.

In the OK studies, 121 patients received lopinavir/ritonavir monotherapy, with 15 of the 121 showing loss of virologic suppression (defined as an HIV RNA greater than 50 copies/mL).⁴ Again, a multivariate analysis found that low adherence was the most important factor predicting virologic rebound, with a nadir CD4+ cell count less than 100 cells/mm³ and a lower baseline hemoglobin also independently associated with loss of viral control. In contrast to the OK pilot study, the amount of time with undetectable HIV RNA before maintenance therapy was not a predictor of rebound.

These results suggest that the lopinavir/ritonavir monotherapy arm is less "tolerant" of suboptimal adherence than a standard two NRTI + lopinavir/ritonavir regimen, as lopinavir has a relatively short terminal half life compared with the intracellular half life of NRTIs. In addition, the results add to a body of data showing that better immune status is associated with improved virologic control -- a phenomenon widely observed in studies of treatment-experienced patients. These data reinforce that triple-drug therapy remains the standard of care for patients with HIV in general, and that boosted-PI monotherapy should generally not be used outside of a clinical trial.

Footnotes

1. Cameron W, da Silva B, Arribas J, et al. A two-year randomized controlled clinical trial in antiretroviral-naive subjects using lopinavir/ritonavir (LPV/r) monotherapy after initial induction treatment compared to an efavirenz (EFV) 3-drug regimen (Study M03-613). In: Program and abstracts of the XVI International AIDS Conference; August 13-18, 2006; Toronto, Canada. Abstract THLB0201.

2. Arribas J, Pulido F, Delgado R, et al, and the OK04 Study Group. Lopinavir/ritonavir as single-drug maintenance therapy in patients with HIV-1 viral suppression: forty eight week results of a randomized, controlled, open label, clinical trial (OK04 Study). In: Program and abstracts of the XVI International AIDS Conference; August 13-18, 2006; Toronto, Canada. Abstract THLB0203.

3. Campo R, da Silva B, Cotte L, et al. Predictors of loss of virologic response in subjects who deintensified to lopinavir/ritonavir monotherapy after achieving plasma HIV-1 RNA <50 copies/mL on LPV/r plus zidovudine/lamivudine. In: Program and abstracts of the 14th Conference on Retroviruses and Opportunistic Infections; February 25-28, 2007; Los Angeles, Calif. Abstract 514.
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4. Pulido F, Arribas J, González-Garcia J, et al, and OK/OK04 Study Groups. Risk factors for loss of virological suppression at 48 weeks in patients receiving lopinavir/ritonavir monotherapy in 2 clinical trials comparing LPV/r monotherapy vs triple therapy with LPV/r (OK and OK04 Trials). In: Program and abstracts of the 14th Conference on Retroviruses and Opportunistic Infections; February 25-28, 2007; Los Angeles, Calif. Abstract 513.
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