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The 47th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) was held in Chicago in September, bringing together infectious diseases specialists, fellows, laboratory researchers, microbiologists, doctors of pharmacy, and, as usual, many representatives from private industry (pharmaceutical, diagnostic, and medical education companies). Although ICAAC is not considered the premier venue for HIV-related clinical research, it usually generates at least one major clinical trial.
This year, the most important study presented was the ARTEMIS Study, which was an industry-sponsored comparison between ritonavir-boosted darunavir and fixed-dose lopinavir/ritonavir in treatment-naive patients; study participants also received fixed-dose tenofovir/FTC [Abstract H-718b]. Importantly, the dose of darunavir used in this study was 800 mg once daily, not the 600-mg twice-daily dose that is FDA approved for treatment-experienced patients. Those randomized to lopinavir/r were allowed to take 800 mg once daily if such dosing was approved in their countries; otherwise, they took 400 mg twice daily. A total of 689 patients (30% women) entered the study, having a mean viral load of 4.85 log copies/mL and a median CD4 count of 225 cells/mm3. Forty percent of study participants had CD4 counts <200 cells/mm3, and 36% had viral loads ≥100,000 copies/mL.
In an intent-to-treat analysis at 48 weeks, 84% of the darunavir group and 78% of the lopinavir group had viral loads <50 copies/mL, a significant finding that met the criteria for noninferiority. In addition, among patients with baseline viral loads ≥100,000 copies/mL, darunavir was superior to lopinavir, with 79% and 67% of patients achieving undetectable viral loads, respectively (P<0.05).
Only 4% of the darunavir group and 7% of the lopinavir group experienced adverse drug events that were severe enough to cause study-drug discontinuation. Gastrointestinal (GI) side effects (predominantly diarrhea) were significantly more common with lopinavir than with darunavir (14% vs. 7%). Rash occurred in 3% of darunavir recipients and in 1% of lopinavir recipients. Although triglyceride levels increased more in the lopinavir group, changes in total/HDL cholesterol ratios were similar between the study arms and were quite modest, which suggests that neither regimen had much influence on overall cardiovascular risk. No renal adverse effects were reported, which is an important safety issue given the use of tenofovir/FTC in all participants. Resistance mutations were rare, even in those with virologic failure: No new major PI mutations occurred in either study arm. M184V, the signature resistance mutation of FTC, emerged in one darunavir recipient and two lopinavir recipients. (Of note, this was erroneously reported as zero cases of M184V in both study arms and later corrected.)
These study results are outstanding for both treatment arms and provide a new benchmark for treatment response with PI-based regimens. Furthermore, these findings clearly demonstrate that once-daily ritonavir-boosted darunavir is not inferior to lopinavir/r and, in patients with high baseline viral loads, may well be superior; GI side effects also seem to be less frequent with darunavir than with lopinavir. One limitation of this study is the heterogeneity of lopinavir/r formulations and dosing: Most lopinavir/r recipients switched to tablets during the study, but some remained on capsules for the duration; furthermore, there was some evidence that patients who took once-daily lopinavir/r had a worse outcome than those who took twice-daily doses — a finding also seen in ACTG 5073 [Abstract 138, 14th Retrovirus Conference, 2007]. These limitations notwithstanding, the study certainly provides evidence that ritonavir-boosted darunavir should be considered as another option for initial PI-based therapy when the 400-mg darunavir tablets become available.
Most of the other notable findings presented at ICAAC were updates or further analyses from previously described clinical trials; overall, these results confirmed earlier findings or provided some additional nuances to our understanding of the data. These included 48-week results of the phase III study of maraviroc in treatment-experienced patients [Abstract H-718a; ACC Apr 2 2007], a pooled analysis of the DUET-1 and -2 studies of etravirine [Abstract H-717; ACC Jul 30 2007], a 48-week update from the phase II study of raltegravir in treatment-experienced patients [Abstract H-713; ACC May 7 2007], and an analysis of the elvitegravir phase II study [Abstract H-714; Abstract 143LB, 14th Retrovirus Conference, 2007]. This last analysis demonstrated how important it is, in terms of maintaining durable antiviral response, for regimens to contain at least one other active agent in addition to elvitegravir. In fact, this message has been expressed clearly in every study, to date, of integrase inhibitors, including raltegravir: Clinicians will need to choose accompanying antiretrovirals carefully to maximize the benefits of this exciting new drug class.