ICAAC: Boosted darunavir non-inferior to boosted lopinavir after 48 weeks in treatment-naïve

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Results from the ARTEMIS trial have shown that ritonavir-boosted darunavir is virologically non-inferior to boosted lopinavir in treatment-naïve patients after 48 weeks of treatment, and that patients with viral loads greater than 100,000 copies/ml were more likely to achieve undetectable viral loads with darunavir than with lopinavir.

Lead investigator Edwin DeJesus presented the findings as a late-breaker session at the 47th Interscience Conference on Antimicrobial Agents and Chemotherapy in Chicago on Tuesday.

The ARTEMIS study randomised 689 treatment-naïve participants to receive either darunavir or lopinavir, ritonavir-boosted in either case, with a dual NRTI backbone of once-daily tenofovir and FTC (emtricitabine).

Glossary

boosting agent

Booster drugs are used to ‘boost’ the effects of protease inhibitors and some other antiretrovirals. Adding a small dose of a booster drug to an antiretroviral makes the liver break down the primary drug more slowly, which means that it stays in the body for longer times or at higher levels. Without the boosting agent, the prescribed dose of the primary drug would be ineffective.

first-line therapy

The regimen used when starting treatment for the first time.

intent to treat analysis

All participants in a clinical trial are included in the final analysis, in the groups they were originally assigned to, whether or not they actually completed their course of treatment. This method provides a better estimate of the real-world effect of a treatment than an ‘on treatment’ analysis.

naive

In HIV, an individual who is ‘treatment naive’ has never taken anti-HIV treatment before.

cholesterol

A waxy substance, mostly made by the body and used to produce steroid hormones. High levels can be associated with atherosclerosis. There are two main types of cholesterol: low-density lipoprotein (LDL) or ‘bad’ cholesterol (which may put people at risk for heart disease and other serious conditions), and high-density lipoprotein (HDL) or ‘good’ cholesterol (which helps get rid of LDL).

The 343 participants in the boosted darunavir arm received 800 mg darunavir (Prezista) plus 100 mg ritonavir, once daily (Prezista was dosed in the form of two 400mg tablets). The 346 in the boosted lopinavir (lopinavir/r, Kaletra) arm received Kaletra (400 mg lopinavir/100 mg ritonavir) dosed twice daily (except in the United States, where participants were allowed to take a once-daily 800/200 mg dose).

At the beginning of the study participants received soft-gel Kaletra capsules, but as the study went on, most were rolled over to receive the better-tolerated Kaletra tablets. By week 48 of the study 80% of participants were receiving tablets. (Analyses are underway to identify any differences due to the different Kaletra formulations; data are not yet available.)

The study population was broadly reflective of individuals who might be starting treatment today: 40% had CD4 cell counts below 200 cells/mm3 and 36% had a baseline viral load above 100,000 copies/ml. The average baseline CD4 cell count was 228 cells/mm3 in the darunavir group and 218 in the lopinavir group. Around one in ten in each arm had CDC stage C HIV disease (AIDS-defining illness), and 13-14% had hepatitis B or C coinfection. 30% were women.

The study was designed to test whether darunavir/ritonavir was non-inferior to lopinavir/ritonavir when judged by the primary endpoint: the proportion of patients with a viral load below 50 copies/ml at week 48. (Statistically, “non-inferiority” means proving that an experimental treatment is not less effective than a comparison treatment – in this case, Kaletra. True “equivalence” is, statistically, more difficult to prove than non-inferiority.)

At week 48, 84% of the darunavir group had viral load below 50 copies/ml, compared to 78% of the Kaletra group, by intent to treat analysis, demonstrating the goal of non-inferiority.

In those with a baseline viral load of 100,000 copies/ml or more, darunavir/ritonavir was clearly more potent than Kaletra: 79% achieved viral load below 50 copies/ml, compared with 67% of the Kaletra group. (p

A smaller sub-group analysis, which looked at patients with baseline viral load above 100,000 copies/ml and a CD4 count below 50 cells/mm3, also found a strong trend favouring darunavir. Seventy-seven per cent of the darunavir group (n=82) had viral load below 50 copies/ml, compared to 63% of the Kaletra group (n=79), but this difference was not statistically significant.

The difference in outcomes was chiefly due to a higher rate of virologic failure in the Kaletra arm (10% vs 6%, p=0.038). Adverse events leading to treatment discontinuation were somewhat more frequent in the Kaletra arm (8% vs 5%), but the difference was non-significant; total discontinuations were 12% with darunavir and 16% with Kaletra. Gastrointestinal side-effects of grade 2 or greater severity such as diarrhoea, nausea and vomiting were more frequent in the Kaletra arm (14% vs 7%, p

Three cases (9%) of serious rash were seen in the darunavir group, versus one (4%) in the Kaletra arm. One of these cases of rash was a Stevens-Johnson syndrome, a serious life threatening side-effect, which was determined to be due to dapsone rather than darunavir.

Darunavir/ritonavir had a less pronounced effect on triglycerides than Kaletra. Despite an elevation after starting treatment, the mean triglyceride level did not rise above the 150mg/dl intervention threshold in the darunavir group. Cholesterol levels rose in both treatment groups, but rose higher in the Kaletra group – although not to a level that would require cholesterol-lowering treatment.

On the basis of these 48-week results, Tibotec expects to file an application for a US marketing license for the use of Prezista in first-line treatment as a once-daily drug, at a dose of 800mg, before the end of this year. The study will need to continue to 96 weeks of follow-up before an application for first-line treatment will be reviewed in Europe. This means that Prezista will not be available for first-line use in the United Kingdom or other European countries for at least two years.

References

DeJesus E et al. Efficacy and safety of darunavir/ritonavir versus lopinavir/ritonavir in ARV treatment-naïve HIV-1-infected patients at week 48: ARTEMIS. 47th Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, late breaker abstract H-718b, 2007.