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Faster Viral Decay With Nevirapine Than Atazanavir/Ritonavir in ARTEN Trial
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49th ICAAC (Interscience Conference on Antimicrobial Agents and Chemotherapy), September 12-15, 2009, San Francisco
Mark Mascolini
Viral load fell faster in the first 4 weeks of treatment with nevirapine than with atazanavir/ritonavir (both with tenofovir/emtricitabine), according to a subanalysis of the randomized ARTEN trial [1]. The trial established that once- or twice-daily nevirapine is not inferior to atazanavir/ritonavir in previously untreated people [2]; the faster viral decay detected in the new study did not translate into a longer-term virologic or CD4 benefit.
The international ARTEN trial randomized 569 previously untreated people to once-daily nevirapine, twice-daily nevirapine, or once-daily atazanavir/ritonavir. All men who enrolled had a CD4 count below 400 and all women had a count below 250. The study excluded people with hepatic cirrhosis or active HBV or HCV infection. The primary endpoint was a viral load below 50 copies at weeks 24 and 36 without a rebound by week 48 in the combined nevirapine groups versus the atazanavir group. Almost two thirds of study participants had a pretreatment viral load above 100,000 copies. Pretreatment viral load averaged 5.12 log in both groups.
Earlier, ARTEN investigators reported virologic response rates of 66.8% in the combined nevirapine arms versus 65.3% in the atazanavir arm, a result that established the noninferiority of nevirapine [2]. Overall side effect rates were similar in the nevirapine and atazanavir groups, though a substantially higher proportion of people taking nevirapine dropped out because of a side effects (13.6% versus 3.6%), often rash with nevirapine. Through 48 weeks of follow-up, people taking nevirapine had a significantly better total-to-high-density lipoprotein (HDL) cholesterol ratio (P = 0.0001) and a significantly greater gain in "good" HDL cholesterol (P < 0.0001), while people taking atazanavir had a significantly higher jump in triglycerides (P < 0.0001).
The early-response analysis involved 376 people taking nevirapine and 193 taking atazanavir. ARTEN investigators measured their change in viral load and CD4 count at weeks 4, 8, and 12 and figured time to treatment response as the time from starting therapy until the first measurement of a confirmed viral load below 50 copies.
After 4 weeks of treatment 9.6% in the combined nevirapine arms and 8.3% in the atazanavir/ritonavir arm had a viral load below 50 copies. At week 8 those rates were 26.6% for nevirapine and 23.8% for atazanavir, and at week-12 rates were 44.4% for nevirapine and 39.4% for atazanavir. However, the groups did differ significantly in change from pretreatment viral load to week 4: -2.32 log with nevirapine versus -2.16 log with atazanavir (P = 0.005). By week 8 the change in viral load was equivalent with nevirapine (-2.74 log) and atazanavir (-2.71 log). At week 12, change in viral load remained equivalent with nevirapine (-2.98 log) and atazanavir (-2.94 log).
Time to treatment response was significantly better with nevirapine than with atazanavir (hazard ratio 0.74, P = 0.003). CD4-cell gains did not differ significantly between the two groups at weeks 4, 8, and 12.
The faster viral decay with nevirapine than with atazanavir had no apparent impact on longer-term virologic response or on clinical outcomes to date. Faster viral decay has also been seen in comparisons of other drugs, including raltegravir versus efavirenz [3], with no apparent clinical impact. The ARTEN team argues, though, that "early predictors of long-term treatment response can be used to prevent the accumulation of drug-resistance-associated mutations and the development of drug-related adverse events, by avoiding unnecessary exposure to ineffective regimens."
References
1. Johnson M, Soriano V, Brockmeyer N, et al. Early virological and immunological response is comparable for nevirapine and RTV-boosted atazanavir: an ARTEN sub-analysis. 49th ICAAC (Interscience Conference on Antimicrobial Agents and Chemotherapy). September 12-15, 2009. San Francisco. Abstract H-924c.
2. Soriano V, Koppe S, Mingrone H, et al. Prospective comparison of nevirapine and atazanavir/ritonavir both combined with tenofovir DF/emtricitabine in treatment-naïve HIV-1 infected patients: ARTEN study week 48 results. 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention. July 19-22, 2009. Cape Town. Abstract LBPEB07. http://www.ias2009.org/pag/PDF/3709.pdf
3. Markowitz M, Nguyen BY, Gotuzzo E, et al. Rapid and durable antiretroviral effect of the HIV-1 Integrase inhibitor raltegravir as part of combination therapy in treatment-naive patients with HIV-1 infection: results of a 48-week controlled study. J Acquir Immune Defic Syndr. 2007;46:125-133.
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