Could monotherapy with Kaletra become an option for HIV treatment?

The protease inhibitor lopinavir boosted with ritonavir (Kaletra) could become a viable option for monotherapy in treating HIV-infection in treatment-naïve patients or in patients wishing to simplify a successful antiretroviral drug regime, according to a range of studies presented this week at the Fifteenth International AIDS Conference in Bangkok.

While three-drug antiretroviral regimens are currently the recommended option for suppressing HIV in most patients, the high incidence of drug-related toxicities, plus the cost associated with multi-drug regimens, is fuelling interest in potent regimens containing fewer drugs.

Most antiretroviral drugs are not potent enough to be used alone to treat HIV infection. However, ‘monotherapy’ with ritonavir-boosted lopinavir, which is produced in a single tablet, is currently being investigated as an HIV treatment, since it has high potency and a long half life in the body, and because resistance to the drug develops slowly.

Following on from an early phase II study showing that three weeks’ treatment with lopinavir/ritonavir alone brought about a rapid decline in viral load to a similar degree to liponavir/ritonavir taken alongside two nucleoside analogues, the three studies presented at this week's conference set the ground for future trials into ritonavir-boosted lopinavir monotherapy.

Although their protocols differ in terms of the patient selection criteria and drug dosing, all three studies report promising findings in terms of effective virological suppression. Adverse events and the development of genotypic or phenotypic resistance to the drug were also rare across the three studies, suggesting that use of ritonavir-boosted lopinavir may become an option for simpler antiretroviral therapy in the future.

Lopinavir/ritonavir in treatment-naïve patients

The results of IMANI-1, a 48-week open-label study of the safety and efficacy of lopinavir/ritonavir alone in treatment-naïve patients were presented on Monday by Dr. Joseph Gathe. Thirty adult patients (28 male) with a mean viral load of 262,000 copies/ml and CD4 count of 170 cells/mm³ were recruited for the study. They received lopinavir/ritonavir 533/133mg twice daily (or 400/100mg if body weight was below 70kg).

After 48 weeks of treatment, the 20 patients remaining in the study showed a mean viral load decrease of 3.71 log₁₀ copies/ml. All of the patients had viral load below 400 copies/ml at this time point, and 18 (90%) had viral load below 50 copies/ml. This was accompanied by a mean increase in CD4 cell count of 317 cells/mm³.

Three of the four patients who did not achieve undetectable viral loads after 48 weeks of therapy were found to have poor adherence due to loss of health insurance during the study. However, these patients exhibited modest reductions in viral load, which was enhanced after intensification of their drug regimen with nucleoside analogues.

Of the ten patients who left the study, two were lost to follow-up, another two left because of gastrointestinal side effects, a further two did not adhere to the study regimen, two experienced virological failure, one was deported from the United States and one was found to be coinfected with hepatitis B.

None of the patients taking lopinavir/ritonavir experienced adverse events, and genotypic and phenotypic analysis of virus extracted from the patients failed to reveal the development of any resistance mutations, despite receiving only one (boosted) drug.

However, despite his promising findings, Dr. Gathe emphasised that monotherapy with lopinavir/ritonavir should not become a routine treatment option on the basis of this pilot study. He did acknowledge, however, that the use of lopinavir/ritonavir may eventually become a viable option in first-line therapy, if controlled trials uphold these preliminary observations.

Lopinavir/ritonavir monotherapy in treatment simplification

In addition to the findings in treatment-naïve patients, two posters presented at the conference on Tuesday suggest that lopinavir/ritonavir monotherapy may be a suitable option for maintenance therapy in patients with controlled viral load.

In the first presentation, Dr. José Arribas from Hospital La Paz in Madrid, Spain, presented 24-week results from the Only Kaletra (OK) trial. In this study, 42 patients with undetectable viral loads (below 50 copies/ml) after at least four weeks taking lopinavir/ritonavir plus two nucleoside analogues, were randomised to receive lopinavir/ritonavir (400/100mg twice daily) alone, or to continue with the triple drug regimen.

Patients in both groups maintained viral suppression and CD4 cell counts over 24 weeks. Although three of the patients in the lopinavir/ritonavir-only arm experienced virological failure, genotypic analysis revealed that this was not due to the development of protease inhibitor resistance mutations. The authors did not have an explanation for these patients' failure in the absence of genotypic resistance, speculating that it may be due to the presence of 'minority populations' of drug-resistant virus, or host issues, such as anatomical sites protected fom protease inhibitors or efficient pumping of the drugs out of cells.

The presenters also demonstrated a significant increase in the number of red blood cells (the haematocrit) in the patients who stopped taking nucleoside analogues (p = 0.031). In congtrast, there was no such increase in the patients still taking a the triple-drug regimen. This, they argue, may be due to the loss of the deleterious effects of nucleoside analogues on bone marrow. In an accompanying poster presentation on Wednesday, however, they show that stopping the nucleoside analogues did not have any significant impact on lipid levels. This trial is continuing up to 48 weeks, results of which will be available at the end of this month.

In Tuesday's second poster, Dr. Gerald Pierone presented similar findings from a pilot study of patients switching from a non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimen to lopinavir/ritonavir monotherapy.

The investigators recruited 18 patients for their study. At baseline, all of the patients had undetectable viral loads and were taking one NNRTI and two nucleoside analogues. Two weeks after replacing the NNRTI with twice-daily lopinavir/ritonavir (400/100mg) the nucleoside analogues were stopped, leaving only lopinavir/ritonavir. Twenty-four weeks later, 14 (78%) of the patients remained in the study, 13 (72%) of whom had maintained their viral load below 75 copies/ml.

Of the remaining four patients, three left the study due to diarrhoea, while the fourth developed the protease inhibitor resistance mutation M36I and withdrew. Five of the patients remaining within the trial for 24 weeks exhibited a rise in blood lipids that required the addition or increased dosing of lipid-lowering agents. This study is continuing for another 48 weeks.