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ddI/FTC/ATV QD vs AZT/3TC bid+Efavrienz QD
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Once-Daily Atazanavir-Based Regimen Fails in International Trial
XVII International AIDS Conference
August 3-8, 2008
Mexico City
Mark Mascolini
A once-daily combination of enteric-coated didanosine (ddI), emtricitabine (FTC), and atazanavir without a ritonavir boost did not control HIV as well as an efavirenz-based first-line regimen in a trial that recruited people from eight African, Asian, and Latin American countries and from the United States [1]. An independent safety panel recommended stopping the ddI/FTC/atazanavir part of the study.
AIDS Clinical Trials Group (ACTG) study A5175--the PEARLS trial--enrolled 1571 antiretroviral-naive adults, 1361 of them from Malawi, South Africa, Zimbabwe, India, Thailand, Brazil, Peru, and Haiti, and 210 from the United States. PEARLS stands for prospective evaluation of antiretrovirals in resource-limited settings. The trial is important because it begins filling gaps in the understanding of how well common antiretroviral regimens work in low- and middle-income countries, and because it compares outcomes in those countries with US outcomes.
The trial aimed to evaluate three easy-to-take regimens that should favor good adherence. Notably, the sole atazanavir arm did not use ritonavir to boost concentrations of that protease inhibitor (PI):
- Enteric-coated ddI (400 mg), FTC (200 mg), and atazanavir (400 mg) once daily
- Coformulated FTC/tenofovir (200/300 mg) and efavirenz (600 mg) once daily
- Coformulated zidovudine/lamivudine (AZT/3TC, 300/150 mg) twice daily and efavirenz (600 mg) once daily
All study participants were at least 18 years old and had fewer than 300 CD4 cells. Women could enroll if they took single-dose nevirapine with or without AZT to prevent mother-to-child transmission. The trial included 740 women accounting for 47% of the study population. Half of PEARLS enrollees were black, including one third who were black Africans, 23% were Asian, and 16% were white. Median CD4 count at entry stood at 172 (interquartile range 91 to 231) and median viral load at 5.0 log (100,000 copies, interquartile range 4.6 to 5.5 log).
Enrollment ended in August 2007. Less than a year later, after a median 72 weeks of follow-up, the Data and Safety Monitoring Board recommended disclosing results of the comparison between the atazanavir group and the AZT/3TC/efavirenz group. There were no unexpected safety findings at this point. ACTG A5175 continues in its comparison of the two efavirenz arms.
PEARLS has a three-part primary endpoint: consecutive viral loads at or above 1000 copies at study week 16 or later, or a new AIDS diagnosis, or death from any cause. Loss to follow-up measured only 4% at week 48 and 6% at week 96. After 48 weeks 16.2% in the atazanavir arm reached the primary endpoint, and 23.9% reached the endpoint by week 96. People in the atazanavir group had a two thirds higher risk of failure defined by the combined endpoint than did people taking AZT/3TC/efavirenz (hazard ratio [HR] 1.67, 99.8% confidence interval [CI] 1.02 to 2.75), and that heightened risk did not change over time (P = 0.33).
Compared with the AZT/3TC/efavirenz group, people taking ddI/FTC/atazanavir had a higher risk of virologic failure but not of death.
- Virologic failure: HR 1.77, 99.8% CI 1.04 to 3.03
- AIDS: HR 3.0, 99.8% CI 0.61 to 14.87
- Death: HR 0.99, 99.8% 0.23 to 4.26
Because the confidence interval for the 3 times higher risk of AIDS with atazanavir crossed 1.0, that difference was not statistically significant.
Almost one in five enrollees had a history of TB when PEARLS began. Extrapulmonary TB accounted for 3 new AIDS diagnoses among people taking ddI/FTC/atazanavir and caused 1 death in that group. Cryptococcal meningitis accounted for 2 new AIDS diagnoses and 1 death in the atazanavir arm. Two people in that group had recurrent bacterial pneumonia.
Several factors independently raised the risk of failure in the atazanavir group compared with the AZT/3TC/efavirenz group: male gender (P = 0.02), every 10 fewer years of age (P < 0.001), and a pretreatment CD4 count below 50, between 50 and 99, between 100 and 149, between 150 and 199, or between 200 and 249 versus 250 to 299. Having clinical AIDS when the study began heightened the risk of failure, while a previous AIDS diagnosis lowered the risk.
Treatment outside the United States did not raise the risk of failure among people taking the atazanavir regimen. Indeed, people in Thailand and Brazil had a significantly lower risk of failure with that regimen than did US residents in a multivariate analysis. Failure risk was marginally lower in Haiti and India than in the United States. Principal investigator Thomas Campbell cautioned that the differing failure risks across countries should be interpreted cautiously because statisticians did not control that analysis for multiple comparisons.
French trial planners have proved fond of once-daily ddI/FTC, but they gave it with once-daily efavirenz to 40 previously untreated people [2,3] and to 178 people who controlled viral replication with a PI-based regimen [4]. In both trials this nucleoside duo performed well virologically and caused few serious side effects. Although these studies were small, the results suggest that ddI/FTC is not an inherently weak nucleoside backbone.
A possible disadvantage of the atazanavir regimen in PEARLS was the need to give ddI on an empty stomach and separately from atazanavir because of possible interactions between the drugs. An earlier study recorded an 11% lower atazanavir area under the curve and an 18% lower minimum concentration when unboosted atazanavir is given with enteric-coated ddI [5]. Levels of ddI were slightly higher with than without atazanavir in this study. The ACTG is scrutinizing pharmacology, resistance, and adherence data to help define the higher failure risk with this regimen. The pharmacologic results will be particularly interesting because of the earlier drug-interaction findings. Most clinicians give atazanavir with a ritonavir boost to maintain even levels of the PI. US antiretroviral guidelines list boosted atazanavir--but not unboosted atazanavir--as a preferred element of first-line regimens [6].
References
1. Campbell T, Smeaton L, De Grutolla V, et al. ACTG A5175: a multinational study of ddI-EC, FTC and atazanavir vs. co-formulated AZT/3TC and efavirenz for initial treatment of HIV-1 infection. XVII International AIDS Conference. August 3-8, 2008. Mexico City. Abstract THAB0404.
2. Molina JM, Ferchal F, Rancinan C, et al. Once-daily combination therapy with emtricitabine, didanosine, and efavirenz in human immunodeficiency virus-infected patients. J Infect Dis. 2000;182:599-602.
3. Molina JM, Journot V, Furco A, et al. Five-year follow up of once-daily therapy with emtricitabine, didanosine and efavirenz (Montana ANRS 091 trial). Antivir Ther. 2007;12:417-422.
4. Molina JM, Journot V, Morand-Joubert L, et al. Simplification therapy with once-daily emtricitabine, didanosine, and efavirenz in HIV-1-infected adults with viral suppression receiving a protease inhibitor-based regimen: a randomized trial. J Infect Dis. 2005;191:830-839.
5. Kaul S, Bassi K, Damle B, et al. Pharmacokinetic evaluation of the combination of atazanavir (ATV), enteric coated didanosine (ddI-EC), and tenofovir disoproxil fumarate (TDF) for a once-daily antiretroviral regimen. 43rd International Conference on Antimicrobial Agents and Chemotherapy. September 14-17, 2003. Chicago. Abstract A-1616.
6. Panel on Clinical Practices for Treatment of HIV Infection. Guidelines for the use of
antiretroviral agents in HIV-1 infected adults and adolescents. January 2008.
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