A pilot study has shown that the nucleoside reverse transcriptase inhibitor (NRTI)-sparing combination of ritonavir-boosted lopinavir (Kaletra) and efavirenz (Sustiva) has a high response rate in HIV-positive patients. The study, published in the 1st July edition of The Journal of Acquired Immune Deficiency Syndromes, suggests that this combination could be useful in avoiding NRTI-related side-effects and resistance.
Although most current HIV treatment guidelines recommend inclusion of at least two NRTIs as part of treatment combinations, several NRTIs have been associated with side-effects such as fat loss and nerve pain. There is also a considerable risk of cross-resistance between some members of this drug class, where the development of resistance to one drug can affect the response to another.
Consequently, experts have become interested in the possibility of treating HIV-positive patients with drug combinations that do not include NRTIs, in order to avoid these side-effects and to save the drug class for subsequent drug combinations. In addition, it is thought that most of the potency and durability of NRTI-containing regimens is driven by the protease inhibitor or non-nucleoside reverse transcriptase inhibitor (NNRTI) component, suggesting that combining two or more of these drugs may allow the design of highly potent anti-HIV regimens.
Investigators from France carried out an open-label pilot study of Kaletra combined with efavirenz in 86 adult HIV-positive patients. The patients took a combination of 600mg efavirenz once a day and 533mg lopinavir boosted with 133mg ritonavir twice daily for 48 weeks. The dose of Kaletra was greater than the standard dose of 400 / 100mg because efavirenz can lower the levels of Kaletra in the blood.
“This pilot study has proven that an NRTI-sparing regimen combining a potent boosted protease inhibitor, lopinavir / ritonavir, and a potent NNRTI, efavirenz, is associated with a high rate of virologic success for up to 48 weeks as well as a sustained immunologic response,” the researchers write. “In addition, the relative lack of drug resistance or virologic failure among the subjects who remained on the medication holds promise for this regimen.”
At the start of the study, the patients’ median viral load was 74,100 copies/ml. However, after 24 weeks, 78% of the patients had a viral load below 400 copies/ml and 69% below 50 copies/ml according to an intent-to-treat analysis. This analysis assumed that any missing data values or treatment discontinuations were due to failure of the treatment.
After 48 weeks of treatment, 73% of the patients still had a viral load below 400 copies/ml and 69% below 50 copies/ml. “These data are within the expected ranges typically seen with most active conventional triple antiretroviral-based combinations,” the investigators explain.
CD4 cell counts increased from 311 cells/mm3 at the start of the study by a mean of 95 cells/mm3 after four weeks, 163 cells/mm3 after 24 weeks and 238 cells/mm3 after 48 weeks.
Sixty-five (76%) of the patients had never taken any anti-HIV drugs before the start of this study, with the remaining 21 (24%) being naïve to NNRTIs but with experience of NRTIs or protease inhibitors, but with no more than three Kaletra-associated resistance mutations. The investigators did not find any significant differences in the drug regimen’s efficacy between these two groups of patients. There was also no significant effect of viral load at the start of the study.
The treatment regimen was generally well tolerated. Twenty-one patients (24%) discontinued the treatment during the 48 weeks of the trial, with seven (33%) of these being due to drug-related adverse events. These included six cases of efavirenz intolerance, characterised by central nervous system effects in three patients and rash in the remaining three. One patient experienced grade four elevations in lipid levels.
“Only one patient stopped the study medication because of a lopinavir / ritonavir -related side-effect,” the researchers explain. “Most discontinuations occurred early, during the first month of treatment, and the main reasons for discontinuation were efavirenz-related adverse events.”
Overall, blood levels of total triglycerides and cholesterol tended to increase over the first eight weeks of the study, but they remained stable thereafter. However, high density lipoprotein (HDL or ‘good’) cholesterol levels increased significantly over the 48-week study from 0.42 to 0.49g/l (p = 0.019), but there was no change in the ratio of total to HDL cholesterol. Three patients required lipid-lowering agents during the study.
The investigators reported six cases of lipodystrophy, five of which were in patients pre-treated with anti-HIV medication and three in patients with a history of body fat redistribution.
Four patients (5%) experienced treatment failure, defined as a viral load above 400 copies/ml on two or more subsequent tests. The investigators found that this was due to adherence below 80% in three patients and development of the K103N NNRTI resistance mutation in the fourth.
The researchers also checked the blood levels of efavirenz and lopinavir in 37 patients during the fourth week of treatment. They found that the levels were similar to concentrations seen in studies combining these drugs with NRTIs.
Due to the success of this treatment regimen in their pilot study, the investigators recommend that it be tested in more robust, comparative trials in the future. “The lopinavir / ritonavir-efavirenz combination is associated with a high rate of virologic response and should be compared with more classic NRTI-containing regimens in randomised and controlled clinical trials,” they suggest.
Allavena C et al. Efficacy and tolerability of a nucleoside reverse transcriptase inhibitor-sparing combination of lopinavir/ritonavir and efavirenz in HIV-1-infected patients. J Acquir Immune Defic Syndr 39: 300-306, 2005.