The efficacy of traditional triple-agent highly active antiretroviral therapy (HAART) is offset by cost, toxicity and the development of multi-drug class resistance in patients with virologic failure. Retrospective and prospective studies by Pierone,^1,2 Gathe,³ Ruane⁴ and Arribas⁵ have shown that so-called "monotherapy" with the combination drug lopinavir/ritonavir (LPV/r, Kaletra) can effectively suppress HIV viral loads to undetectable.

The possibility of the rapid development of viral resistance with lopinavir/ritonavir monotherapy has been a major concern with this approach, since this has been seen to occur with other agents. The primary mutations associated with lopinavir resistance in protease inhibitor-naive patients have not been established. This presentation provides genotypic and phenotypic resistance observations from patients who experienced virologic failure while on lopinavir/ritonavir monotherapy and participating in 2 ongoing studies.

Virologic Failure on Lopinavir/Ritonavir Monotherapy

Virologic failure was defined as 2 consecutive HIV-RNA levels above 400 copies/mL or failure to achieve a viral load below 400 copies/mL. Thirty-three patients from 2 ongoing studies of lopinavir/ritonavir monotherapy were evaluated. Eight patients experienced virologic failure; 4 were from a 15-patient retrospective cohort and 4 were from a prospective study of 18 patients switched to lopinavir/ritonavir monotherapy from a non-nucleoside reverse transcriptase inhibitor-based regimen. Five out of 8 failing patients had genetic sequences and phenotypes available for comparison, both from baseline and time of virologic failure.

The 15 patients in the retrospective cohort had been on therapy for a mean of 131 weeks. At the start of this study, 6 of the patients had discontinued and 9 had stayed on therapy. Of the 6 patients discontinuing, 3 were lost to follow-up (1 met virologic failure criteria but no genotype or phenotype was available) and 3 were virologic failures.

Nine patients remained on therapy. Their viral loads were under 400 for a mean of 131 weeks; with 6 patients who had a viral load of under 75 copies/mL and 3 patients who were at 75-400 copies/mL at last lab draw.

The 24-week data from this study was presented at the XV International AIDS Conference in Bangkok;² in this presentation, 48-week data was available on most subjects in the prospective trial. Thirteen out of 18 of the patients were on therapy or were 48-week completers. Ten of them had viral loads under 75 copies/mL at all measurements, 1 had a non-adherence-related blip at week 40, and 2 met criteria for virologic failure secondary to non-adherence, with both resuppressing to under 75 copies/mL after support was provided. No genotype or phenotype was available on these 2 patients. Five discontinued therapy, 3 due to diarrhea and 2 due to virologic failure.

Genotypic and Phenotypic Results

Genotypic and phenotypic data were available on 3 of the 5 patients (referred to as Cases 1 through 3) from the retrospective cohort; their mean time on lopinavir/ritonavir monotherapy was 111 weeks. Data were also available on 2 of the 5 patients (referred to as Cases 4 and 5) from the prospective trial; their mean time on lopinavir/ritonavir monotherapy was 22 weeks.

The results are summarized in the following chart:

These 2 small studies show a rate of virologic failure similar to that seen in larger trials using lopinavir/ritonavir as part of a triple-HAART regimen. When virologic failure occurred, rapid selection of resistance to lopinavir/ritonavir was not observed. In one case with prolonged viremia of 67 weeks, a moderate loss in susceptibility to lopinavir was seen, with the selection of the primary protease mutation I54I/V as well as secondary mutations. In most of the cases, non-adherence was associated with the development of viremia. The lengthy delay in the development of protease resistance mutations in Case 3 despite ongoing viral replication for over a year -- and in the presence of adequate plasma lopinavir levels -- remains unexplained.

Conclusion

These 2 cohort studies add to a small but steadily increasing body of literature showing continued efficacy of lopinavir/ritonavir monotherapy over time. Three issues, however, indicate that this regimen is not yet ready for prime time: the lack of an identified pathway for development of resistance; the need for large clinical trials in multiple, varied populations; and the need to assure adequate drug distribution and lack of compartmental sequestration given that lopinavir is highly protein bound. Still, this promising data -- as well as several other small trials on this monotherapy regimen -- means we're sure to hear more about lopinavir/ritonavir monotherapy in the future. If proven successful, this regimen could potentially decrease the burden of cost and toxicity and improve compliance with HAART.

Footnotes

1. Pierone G, Mieras J, Kantor C, et al. Kaletra (LPV/r) monotherapy for treatment of HIV infection. In: Program and abstracts of HIV DART 2002; December 15-19, 2002; Naples, Fla. Abstract 076.

2. Pierone G, Mieras J, Fontaine L, et al. Simplification to lopinavir/ritonavir monotherapy from NNRTI-based HAART in HIV-infected patients with complete viral suppression; 24-week interim analysis. In: Program and abstracts of the XV International AIDS Conference; July 11-16, 2004; Bangkok, Thailand. Abstract TuPeB4595.

3. Gathe J, Washington M, Mayberry C, et al. IMANI-1 single drug HAART -- proof of concept study. pilot study of the safety and efficacy of Kaletra (LPV/r) as single drug HAART in HIV+ ARV-naive patients -- interim analysis of subjects completing final 48 week data. In: Program and abstracts of the XV International AIDS Conference; July 11-16, 2004; Bangkok, Thailand. Abstract 1057.

4. Ruane P, Luber A, Gaultier C, et al. Maintenance therapy using lopinavir/ritonavir (LPV/r) alone with well-controlled HIV infection. In: Program and abstracts of the XV International AIDS Conference; July 11-16, 2004; Bangkok, Thailand. Abstract TuPeB4577.

5. Arribas J, Pulido F, Lorenzo A, et al. Simplification to lopinavir/r single-drug HAART: 24-week results of a randomized, controlled, open-label, pilot clinical trial (OK Study). In: Program and abstracts of the XV International AIDS Conference; July 11-16, 2004; Bangkok, Thailand. Abstract 4486.