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Thursday, July 26, 2012

More starting treatment, with more options for ART in the pipeline


New updated recommendations for use of antiretroviral therapy (ART) from the International Antiviral Society-USA Panel [1] were released to coincide with the XIX International AIDS Conference (IAC) held in Washington, DC July 22-27. This important set of guidelines now aligns with the DHHS guidelines that since March 2012 have recommended that ART should be initiated in all HIV-infected individuals regardless of CD4+ T-cell counts. This change to universal ART means more asymptomatic people will be treated for longer periods of time, making it more important than ever that ART treatment options are safe, well tolerated, durably effective and convenient to use. New studies of antiretroviral agents (ARVs) and combination ART from the recently concluded XIX IAC identify new treatment options that may soon help fulfill this expanding treatment need.

Dolutegravir (DTG) and elvitegravir (EVG) are two investigational HIV integrase inhibitors (INI) in the late stages of clinical development. Both are administered once daily although EVG requires a pharmacokinetic enhancer to achieve once daily dosing. Both are being studied for treatment-naive patients. EVG is also being investigated for use in treatment-experienced, INI-naive patients, while DTG is being studied in patients that have failed the only currently licensed INI, raltegravir (RAL). A large (n=822) phase III randomized, double dummy trial in treatment naive patients comparing DTG 50 mg once daily to RAL 400mg twice daily, each combined with 2 nucleoside reverse transcriptase inhibitors, was reported during the IAC [2]. After 48 weeks on study, HIV RNA was suppressed to below 50 copies/mL in 88% and 85% in the DTG and RAL arms, respectively (difference between arms 2.5%, 95% CI -2.2, 7.1%) demonstrating the non-inferiority DTG to RAL. In the subset of patients entering with HIV RNA >100,00 copies/mL, efficacy was slightly lower (82% vs. 75%) but did not differ significantly between treatment arms (difference 7.5, 95% CI -3.1, 18.0). Both treatments were well tolerated with no difference between arms in symptomatic adverse events or laboratory abnormalities except for serum creatinine, which rose a mean of 0.15 mg/dL with DTG compared 0.05mg/dL with RAL. The effect of DTG on creatinine is appears to be due to inhibition of tubular secretion of creatinine and not a true loss of GFR. Total cholesterol and triglycerides had only very small increases in both arms. Few viral failures occurred in either arm and fewer still had successful resistance genotyping. Only one patient failed with INI and 4 with NRTI resistance mutations. All were in the RAL arm.

Two poster presentations focused on phase III trials of EVG co-formulated as a single tablet with the pharmacokinetic booster cobicistat, emtricitabine and tenofovir DF, a four drug combination sometimes referred to as the “QUAD” [3,4]. Much of these presentations recapitulated 48 week results already published [5,6] establishing the non-inferiority of this new boosted-INI-based regimen to two regimens that are currently preferred by treatment guidelines for treatment-naive individuals. New subset analyses showed little loss of virologic efficacy when baseline viral loads exceeded 400,000 copies/mL, although moderately lower response rates were seen in both studies when baseline CD4 count was low (74/80% <50 copies/mL when baseline CD4 was <200/mm3 compared 91/90% when baseline CD4 was >350/mm3). In none of the baseline viral load and CD4 subset analyses was there a significant difference between treatment arms. In the comparison to efavirenz, subjects on the “QUAD” experienced more nausea but less rash and CNS symptoms, while in the comparison to boosted atazanavir, nausea was similar but “QUAD” recipients had less hyperbilirubinemia. Use of the “QUAD” was associated with modestly less cholesterol elevation compared to efavirenz and modestly less triglyceride elevation compared with boosted atazanavir. Coincidentally, cobicistat has also been shown to inhibit tubular secretion of creatinine, leading to increases in serum creatinine of 0.12-0.14, similar to those seen with DTG.

Assuming both EVG and DTG receive FDA approval, both will be vying for a spot in the IAS-USA and DHHS guidelines. Both appear highly efficacious, safe, well tolerated and convenient to use. The creatinine elevations seen with DTG and the EVG boosting agent cobicistat may present clinical management problems, especially when there is underlying kidney disease or when other nephrotoxic agents are co-administered, as there is no clinically useful way to differentiate creatinine changes due to inhibition of secretion from true loss of GFR.

References:
1. Thompson MA, Aberg JA, Hoy JF, et al. Antiretroviral treatment of adult HIV infection: 2012 recommendations of the International Antiviral Society-USA panel. JAMA 2012;308:387-402.
2. Raffi F, Rachlis A, Stellbrink HJ, et al. Once-daily dolutegravir (DTG; S/GSK1349572) is non-inferior to raltegravir (RAL) in antiretroviral‑naive adults: 48 week results from SPRING-2 (ING113086). Abstract THLBB04, XIX IAC, Washington DC, July 22-27,2012; http://pag.aids2012.org/Abstracts.aspx?SID=16&AID=20990
3. Sax P, DeJesus E, Mills A, et al. Analysis of efficacy by baseline HIV RNA: week 48 results from a phase 3 study of elvitegravir/cobicistat/emtricitabine/tenofovir DF (Quad) compared to efavirenz/emtricitabine/tenofovir DF in treatment-naïve HIV-1-positive subjects. Abstract TUPE028, XIX IAC, Washington DC, July 22-27,2012; http://pag.aids2012.org/abstracts.aspx?aid=17954
4. DeJesus E, Rockstroh J, Henry K, et al. Analysis of efficacy by baseline viral load: phase 3 study comparing elvitegravir/cobicistat/emtricitabine/tenofovir DF (quad) versus ritonavir-boosted atazanavir plus emtricitabine/tenofovir DF in treatment-naïve HIV-1-positive subjects: week 48 results. Abstract TUPE043, XIX IAC, Washington DC, July 22-27,2012; http://pag.aids2012.org/abstracts.aspx?aid=17993
5. Sax PE, DeJesus E, Mills A, et al. Co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate versus co-formulated efavirenz, emtricitabine and tenofovir disoproxil fumarate for initial treatment of HIV-1 infection: a randomised, double-blind, phase 3 trial,analysis of results after 48 weeks. The Lancet, 2012;379:2439-48.
6. DeJesus E, Rockstroh J, Henry K, et al. Co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate versus ritonavir-boosted atazanavir plus co-formulated emtricitabine and tenofovir disoproxil fumarate for initial treatment of HIV-1 infection: a randomised, double-blind, phase 3 non-inferiority. The Lancet,2012;379:2429-38.


Source: Reporting for the PRN News:David H. Shepp, MD