Orkin C, Dejesus E, Khanlou H, Stoehr A, Supparatpinyo K, Lathouwers E, et al. Final 192-week efficacy and safety of once-daily darunavir/ritonavir compared with lopinavir/ritonavir in HIV-1-infected treatment-naïve patients in the ARTEMIS trial. HIV Med. 2012 Oct 23. doi: 10.1111/j.1468-1293.2012.01060.x.
The "AntiRetroviral Therapy with TMC114 ExaMined In naïve Subjects" (ARTEMIS) trial's initial primary objective was to demonstrate the non-inferiority of the protease inhibitor (PI) ritonavir-boosted darunavir (DRV/r), taken once-daily, compared to the PI ritonavir-boosted lopinavir (LPV/r), taken either once- or twice-daily, both with tenofovir (TDF) and emtricitabrine (FTC) for initial treatment of HIV infection on the proportion of patients with HIV-1 RNA <50 copies/mL at week 48. Secondary objectives of the trial, examined in the current paper, were to evaluate the durability of virologic response over 192 weeks, and the statistical superiority of DRV/r to LPV/r in virologic response. Other secondary objectives in the current paper include evaluating long-term safety and tolerability, and evaluating change from baseline in HIV-1 RNA levels.
Clinics in 26 countries (Argentina, Australia, Austria, Belgium, Canada, Chile, Costa Rica, Denmark, France, Germany, Greece, Guatemala, Italy, Malaysia, Mexico, Panama, Puerto Rico, Russia, Singapore, South Africa, Spain, Switzerland, Taiwan, Thailand, United Kingdom, and the United States).
Phase III, open-label randomized controlled trial (RCT).
ART-naïve adults initiating antiretroviral therapy (ART) with plasma HIV-1 RNA of at least 5000 copies/mL. Patients with the following conditions were excluded: active AIDS-defining illness; any clinically significant disease; clinical or laboratory evidence of significantly impaired hepatic or nephritic function. Individuals with primary HIV infection (i.e. those recently-infected) or those pregnant or breastfeeding were also excluded. Patients with grade 3 or 4 laboratory abnormalities were not eligible with some exceptions. Patients coinfected with chronic hepatitis B (HBV) or hepatitis C (HCV) were enrolled if their condition was clinically stable and they did not require treatment for these conditions during the study period.
Virologic response; adverse events (AE); virologic resistance; adherence.
Patients were stratified by HIV-1 RNA and CD4 cell count and randomized to receive DRV/r 800/100 mg once-daily, or a total daily dose (once- or twice-daily) of LPV/r 800/200 mg. All patients also received a fixed-dose combination of TDF and FTC. Follow-up was for 192 weeks.
Of 843 patients screened, 689 were randomized and treated with DRV/r 800/100 mg once daily (n=343) or LPV/r 800/200 mg once- or twice-daily (n=346). Of patients in the LPV/r arm, 260 (75.1%) received LPV/r twice daily, 50 (14.5%) received LPV/r once daily and 36 (10.4%) switched from LPV/r twice daily to once daily. Baseline characteristics were well balanced across treatment arms and stratification factors. At baseline, 234 (34%) patients had HIV-1 RNA ≥100,000 copies/mL and 289 (42%) had CD4 cell count of <200 cells/µL.
At 192 weeks, once-daily DRV/r 800/100mg plus TDF/FTC provided sustained and durable virologic response rates in treatment-naïve adult patients. In the DRV/r arm, 236/343 (68.8%) achieved HIV-1 RNA <50 copies/mL, compared to 198/346 (57.2%) in the LPV/r arm (response difference [RD] 11.6%, 95% confidence interval [CI] 4.4% to 18.8%). In the DRV/r arm, 258/343 (75.2%) patients had a confirmed HIV-1 RNA <400 copies/mL, compared to 225/346 (65.0%) in the LPV/r arm (RD 10.1%, 95% CI 3.2% to 16.9%). This demonstrates the statistical superiority of DRV/r to LPV/r (p=0.004). Non-inferiority of DRV/r to LPV/r was demonstrated in the trial's 48-week and 96-week analyses.(1, 2)
Stratifying the analysis by baseline HIV-1 RNA levels (<100,000 copies/mL or ≥100,000 copies/mL), patients in both strata of the DRV/r arm achieved statistically superior virologic response rates compared to those in the LPV/r arm. For the stratum with baseline HIV-1 RNA <100,000 copies/mL, the difference was 9.3% (95% CI 0.5% to 18.1%). For the stratum with baseline HIV-1 RNA ≥100,000 copies/mL, the difference was 15.9% (95% CI 3.5% to 28.3%).
Stratifying the analysis by baseline CD4 levels (<200 cells/µL or ≥200 cells/µL), patients in both strata of the DRV/r arm achieved statistically superior virologic response rates compared to those in the LPV/r arm (RD 11.7%, 95% CI 2.4% to 21.0%).
The rate of patients experiencing at least one AE was similar across treatment arms, 326/343 (95.0%) in the DRV/r arm and 333/346 (96.2%) in the LPV/r arm. Permanent discontinuation of treatment because of AEs (including pregnancies; nine in the DRV/r arm and six in the LPV/r arm) was significantly less frequent in the DRV/r arm (n=26, 7.6%) than in the LPV/r arm (n=50, 14.5%) (p = 0.005). Serious AEs regardless of causality were reported in 55 (16.0%) patients in the DRV/r arm and 72 (20.8%) patients in the LPV/r arm. By week 192
, four patients (1.2%) in the DRV/r arm and seven patients (2.0%) in the LPV/r arm had died during treatment. None of these deaths was considered by the investigators to be treatment related.
Paired baseline/endpoint genotypes were available for 43 (78.3%) DRV/r and 57 (80.2%) LPV/r VFs. At endpoint (i.e. the last available time-point with a genotype/phenotype during the treatment period), PI resistance-associated mutations (RAMs)(3) were identified in four (9.3%) patients in the DRV/r arm and nine (15.8%) VF patients in the LPV/r arm. None of these PI RAMs were major (primary) PI mutations. One or two nucleoside reverse transcriptase inhibitor (NRTI) RAMs were identified in four (9.3%) VFs in the DRV/r group and seven (12.3%) in the LPV/r group.
Paired baseline/endpoint phenotype data were available for 39 (70.1%) patients in the DRV/r arm and 52 (73.2%) patients in the LPV/r arm. All samples from these patients remained susceptible to DRV, LPV and other PIs at endpoint. Of these VFs, four (10.5%) patients in the DRV/r arm and five (9.8%) patients in the LPV/r arm lost susceptibility to FTC. In addition, a loss of susceptibility to TDF was observed in two patients in the DRV/r arm; this was not correlated with the development of NRTI RAMs and may have been a result of assay variation (the endpoint fold-change value was just above the biological cut-off).
There was no statistically significant difference between treatment arms in the percentage of patients reporting >95% adherence to treatment (p=0.102). Virologic response for adherent patients receiving DRV/r was better than it was in patients receiving LPV/r (RD 12.2%, 95% CI 4.2% to 20.2%). This was also the tendency in suboptimally adherent patients, though the difference was not statistically significant (RD 10.3%, 95% CI -7.6% to 28.1%).
The authors conclude that DRV/r has an efficacy, resistance and safety profile favorable for long-term use in ART-naïve patients.
The risk of bias in this trial is low. Randomization was performed by means of a predefined randomization list, using a central randomization system to ensure balance across treatments groups in each stratum. Allocation was not concealed and the trial was not blinding. The follow-up period was quite long, however, and investigators used statistical methods to control for potential confounders. Loss to follow-up was low and was accounted for appropriately. The trial compares favorably to its registration documents.(4)
Current World Health Organization (WHO) guidelines(5) recommend a boosted PI plus two nucleoside reverse transcriptase inhibitors (NRTIs) for second-line ART (i.e. after treatment failure). Boosted PIs are not presently recommended for use in first-line therapy. Another commonly used PI is atazanavir (ATV), which has also been evaluated head-to-head with LPV/r in ART-naïve patients and found to be non-inferior.(6) DRV/r has fewer gastrointestinal side effects than LPV/r and can be taken once daily (although LPV/r now has once daily dosing as well). The primary limitation to the greater use of DRV/r is cost. The current pricing of generic 300 mg ATV/r for developing countries is $304 per patient per year (ppy) and $368 ppy for 200 mg LPV/r. DRV (unboosted) is still on patent and the 300 mg dose is currently at least $803 ppy, even without the ritonavir necessary to its use (DRV/r is not available as fixed-dose combination).(7)
Clinicians should follow current national and WHO guidelines on ART. New guidelines are expected to be released in mid-2013.
- Ortiz R, Dejesus E, Khanlou H et al. Efficacy and safety of once-daily darunavir/ritonavir versus lopinavir/ritonavir in treatment-naïve HIV-1-infected patients at week 48. AIDS 2008; 22: 1389-1397
- Mills A, Nelson M, Jayaweera D et al. Once-daily darunavir/ritonavir vs lopinavir/ritonavir in treatment-naïve, HIV-1-infected patients: 96-week analysis. AIDS 2009; 23: 1679-1688.
- International Antiviral Society-USA (formerly International AIDS Society-USA). HIV Drug Resistance Mutations. [accessed November 4, 2012]
- ClinicalTrials.gov. TMC114-C211: Trial of an Investigational Protease Inhibitor TMC114 With Ritonavir ("TMC114/r") in HIV-1 Infected Patients Who Have Never Been Treated With Antiretroviral Medications (NCT00258557). [accessed November 4, 2012]
- WHO. Antiretroviral therapy for HIV infection in adults and adolescents. Recommendations for a public health approach: 2010 revision. [accessed November 4, 2012]
- Molina J-M, Andrade-Villanueva J, Echevarria J, et al. Once-daily atazanavir/ritonavir compared with twice-daily lopinavir/ritonavir, each in combination with tenofovir and emtricitabrine, for management of antiretroviral naïve HIV-1-infected patients: 96-week efficacy and safety results of the CASTLE study. JAIDS 2010; 53:323-332.
- Médecins Sans Frontières. Untangling the web of antiretroviral price reductions (15th edition, July 2012). [accessed 10 November 2012]