Following on from the results of the KalMo study, presented on Tuesday at the Sixteenth International AIDS Conference in Toronto, three more studies presented in the late breaker session at the conference on Thursday have provided more evidence for a role of monotherapy with ritonavir-boosted lopinavir (Kaletra) in HIV-positive patients.
Due to its long half-life and high genetic barrier to resistance, Kaletra monotherapy is an attractive option for use alone in HIV-positive patients. This may reduce both the cost and side-effects associated with anti-HIV treatment by reducing exposure to HIV drugs.
Two of the studies presented on Thursday – M03-613 and OK40 – had similar designs to the KalMo study, finding that patients whose HIV was controlled with combination therapy could safely switch to Kaletra alone for up to two years, with controlled viral loads and few cases of resistance. In addition, however, the MONARK trial found that starting HIV treatment with Kaletra alone may be safe for some patients, with up to a year's follow-up.
The OK04 study enrolled patients treated with Kaletra and two nucleoside reverse transcriptase inhibitors (NRTIs) and viral loads below 50 copies/ml for at least six months. The patients were randomised to continue on combination therapy or to stop taking their NRTIs. None of the patients had experienced failure of protease inhibitors in the past.
In this study the primary endpoint was the proportion of patients who had experienced virologic failure by week 48. Failure was defined in this study as two consecutive viral load measurements above 500 copies/ml two weeks apart, or a change of any element in the regimen, or treatment discontinuation, or a decrease in viral load of less than 1 log10 four weeks after randomisation.
At week 48, data were available on 89 patients treated with Kaletra monotherapy and 88 patients who received triple combination therapy.
After 48 weeks, the investigators found that the two groups of patients had similar rates of treatment success as measured by intent to treat analysis, defined as a viral load below 500 copies/ml without leaving the study or changing therapy (94 vs. 90%).
All patients who experienced viral load rebound above 500 copies/ml underwent genotypic resistance testing, even if they subsequently resuppressed HIV. Two of the eleven patients in the Kaletra monotherapy arm who experienced rebound had evidence of protease inhibitor resistance mutations, compared to one of ten in the triple combination arm.
The investigators concluded that Kaletra monotherapy was not inferior to combination treatment in patients who had suppressed viral levels on combination anti-HIV treatment, and that a small proportion of the patients needed to re-start NRTIs in order to keep viral loads suppressed.
Study M03-613 involved 155 patients who had never taken anti-HIV drugs before. They were randomised to receive treatment with Kaletra or efavirenz (Sustiva), both with AZT (zidovudine, Retrovir) and 3TC (lamivudine, Epivir). After 24 weeks, the Kaletra-treated patients with three viral load measurements below 50 copies/ml stopped taking AZT and 3TC.
The primary endpoint in this study was the proportion of patients with two consecutive viral load measurements above 50 copies/ml after randomisation.
After 72 weeks of monotherapy, 50% of the 69 patients taking Kaletra alone maintained viral loads below 50 copies/ml, compared to 61% of the patients taking efavirenz-based combination therapy, by intent-to-treat analysis. Although this difference was not statistically significant (p = 0.23), the investigators did find that the patients taking Kaletra alone were less likely to keep viral loads suppressed below 50 copies/ml for the entire duration of the study (84 vs. 95%, p = 0.002).
Nevertheless, twelve out of 14 of the patients with viral load blips between 50 and 500 copies/ml managed to re-suppress their HIV levels while continuing on Kaletra monotherapy. The development of protease inhibitor resistance mutations was seen in only two (13%) of 15 patients tested.
In contrast to the other Kaletra monotherapy studies presented at the conference, investigators co-ordinating the MONARK Trial treated patients who had not taken anti-HIV treatment before with Kaletra alone. The MONARK trial is a 96-week study; Jean-François Delfraissy of the Kremlin-Bicêtre Hospital in Paris presented 48-week data from the study.
Investigators randomised 138 patients with viral loads above 100,000 copies/ml and CD4 cell counts above 100 cells/mm3 to either Kaletra alone or Kaletra plus AZT and 3TC. Similar proportions of each group had ‘sub-optimal’ virological responses (11% vs. 13%). This was defined as a viral load drop of less than 1 log10 after four weeks’ treatment, a viral load above 400 copies/ml after 24 weeks, or at least two viral load measurements above 400 copies/ml after successful suppression of HIV levels. In contrast, the number of patients who discontinued treatment was lower in the monotherapy arm of the trial (19 vs. 30%).
The two groups also had similar CD4 cell count increases (152 vs. 159 cells/mm3).
Two patients in the Kaletra monotherapy arm developed protease inhibitor resistance mutations after viral rebound, while in the triple combination arm one patient who experienced rebound developed resistance, to 3TC.
“Initiating antiretroviral therapy with lopinavir / ritonavir monotherapy demonstrated a sustained virological efficacy,” concluded the investigators.
However, in common with the other studies of Kaletra monotherapy presented today, patients who received Kaletra alone were more likely to experience episodes of viral load between 50 and 400 copies/ml than those who received triple combination therapy.
Jean-François Delfraissy said that it was too early to recommend Kaletra monotherapy for all patients, but said that further analysis might help define the factors that predict which treatment-naive patients might benefit from this strategy.
Cameron W et al. A two-year randomized controlled clinical trial in antiretroviral-naïve subjects using lopinavir/ritonavir (LPV/r) monotherapy after initial induction treatment compared to an efavirenz (EFV) 3-drug regimen (Study M03-613). Sixteenth International AIDS Conference, Toronto, abstract THLB0201, 2006.
Delfraissy JF et al. MONARK trial (MONotherapy Antiretroviral Kaletra): 48-week analysis of lopinavir/ritonavir (LPV/r) monotherapy compared to LPV/r + zidovudine/lamivudine (AZT/3TC) in antiretroviral-naïve patients. Sixteenth International AIDS Conference, Toronto, abstract THLB0202, 2006.
Arribas J et al. 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 (OK40 Study). Sixteenth International AIDS Conference, Toronto, abstract THLB0203, 2006.