Atazanavir/ritonavir as potent over two years as Kaletra, but has better side-effects profile

Atazanavir (Reyataz) with low dose ritonavir is as effective as Kaletra (lopinavir/ritonavir) at suppressing viral load over two years in treatment-experienced patients when combined with tenofovir (Viread) and an NRTI, according to results from a study conducted by atazanavir’s manufacturer published in the March 21^st edition of AIDS.

A favourable safety profile for atazanavir also emerged in the study. The investigators found that patients taking atazanavir were less likely to experience diarrhoea than individuals taking Kaletra and that atazanavir-treated patients had an improvement in their lipid profile from baseline whereas individuals on Kaletra experienced an increase in their blood fats and sugars.

BMS Study 045

Analysis of the first 48 weeks of the BMS Study 045 has been previously published. This showed that, in treatment- experienced individuals who had experienced virological failure on two earlier potent antiretroviral combinations, a regimen based on atazanavir/ritonavir was likely to achieve as large and durable a reduction in viral load as an antiretroviral regimen based upon Kaletra. Patients in both arms of the study also took tenofovir (Viread) and an NRTI, which, whenever possible, was selected by resistance testing. The trial was randomised, open-label and involved 347 individuals.

The investigators extended their analysis to 96 weeks. Once again, they wished to see if atazanavir/ritonavir achieved and maintained suppression of HIV comparable to Kaletra. They also had a number of secondary objectives. These included the number of patients in each arm of the study with a viral load below 400 copies/ml and 50 copies/ml after two years of treatment; and, the increase in CD4 cell count from baseline. They also wished to compare the safety and side-effect profile of the two study drugs.

96-week results

Over two years, atazanavir/ritonavir had comparable virologic efficacy to Kaletra. The mean reduction in viral load from baseline was – 2.29 log₁₀ copies/ml amongst patients taking atazanavir/ritonavir and – 2.08 log₁₀ amongst individuals randomised to take Kaletra. Similar proportions of patients in both arms of the study achieved a viral load below 400 copies/ml and 50 copies/ml.

Further analysis was conducted to see if the number of baseline protease inhibitor resistance mutations influenced the effectiveness of the two study medications. The investigators found that amongst patients with fewer than four resistance mutations, the median fall in viral load was – 2.47 log₁₀ copies/ml in the atazanavir/ritonavir arm and – 2.21 log₁₀ copies/ml in the Kaletra arm. If a patient had four or more protease inhibitor resistance mutations, the median reduction in viral load was – 1.71 log₁₀ copies/ml if they were taking atazanavir/ritonavir and – 1.81 log¹⁰ copies/ml if they were taking Kaletra.

After 96 weeks of treatment, CD4 cell count had increased from baseline by 160 cells/mm³ in the atazanavir/ritonavir arm and by 142 cells/mm³ in the Kaletra arm. All differences were non-significant.

Safety and side-effects

The investigators then looked at the safety profile of the two drugs. Over the 96 weeks of the study, a severe adverse event was experienced by 13% of patients taking atazanavir/ritonavir and 11% of patients taking Kaletra. Two people taking Kaletra died as did one person taking atazanavir/ritonavir, but none of these deaths were related to the study medications.

Significantly more patients taking Kaletra (19%) experienced mild to severe gastrointestinal problems than those taking atazanavir/ritonavir (9%, p Kaletra-treated patients (13% vs 3%, p

Attention was then turned to the effect of the two study medications on patients’ lipid profiles. Two years of treatment with Kaletra resulted in a mean 9% increase in total cholesterol and a 30% increase in fasting triglycerides, whereas atazanavir/ritonavir-treated patients experienced a mean fall from baseline in total cholesterol of 3% and a 13% fall in fasting triglycerides (p

As expected, jaundice and increases in bilirubin were associated with atazanavir treatment. A total of 53% of those taking atazanavir experienced a moderate to severe increase in their bilirubin compared to less than 1% of patients taking Kaletra. However, although there were a total of 29 cases of hyperbilirubinaemia amongst patients taking atazanavir, only five occurred during the second year of therapy with the drug, and nobody stopped treatment because of it.

The higher incidence of diarrhoea and lipid increases amongst the Kaletra-treated patients meant that these individuals were much more likely to require anti-diarrhoea treatment (25%) than those taking atazanavir/ritonavir (6%, p Kaletra were also significantly more likely to require lipid lowering therapy than individuals taking atazanavir/ritonavir (20% vs 9%, p

The investigators conclude that atazanavir/ritonavir showed comparable “durable efficacy to Kaletra and was not associated with unexpected or late-emerging adverse events” when used in combination with tenofovir and an NRTI in treatment-experienced patients. They add “the long-term use of atazanavir/ritonavir may decrease pill burden, improve tolerability and provide sustained virologic suppression for antiretroviral-experienced patients with HIV infection.”