Atazanavir/efavirenz NRTI-sparing regimen effective, but raises lipid levels

Overview of class-sparing regimens

In a “mini-lecture” the following day at the conference, Richard Haubrich of the University of California at San Diego (who was also pressed into service as an impromptu session moderator) gave an overview of current knowledge about class-sparing regimens.

In addition to NRTI-sparing regimens such as the one mentioned above, he also discussed all-NRTI regimens (such as the one used in the ACTION study presented Wednesday), and regimens that consist solely of a single boosted PI.

Overall, he noted, “Adding more classes doesn’t necessarily mean better results.”

The benefits of class-sparing regimens include avoidance of specific toxicities, saving more therapeutic options for later use, and reduced monetary cost. Among the drawbacks, there are less data available concerning these strategies, some class-sparing regimens appear less potent (in particular, triple-NRTI regimens in patients with high viral loads and boosted PI monotherapy), and some may trade one set of side effects for another.

Haubrich noted that when considering whether to eliminate an antiretroviral class, clinicians should try to keep some drugs in a regimen that penetrate various body compartments such as the central nervous system and the genital tract, in order to prevent HIV breakthrough in these areas.

Today, he concluded, it is “much more difficult, if not impossible” to put together class-sparing regimens for heavily treatment-experienced patients, compared with those new to therapy. However, he added, as new classes of antiretroviral drugs are approved in the coming years – such as integrase inhibitors and CCR5 blockers – “we may be able to break out of this paradigm” of having all approved regimens consist of a PI or NNRTI plus a NRTI backbone.

Indeed, he said, as these novel drugs come on line, “It’s not hard to think that in the future, we’ll be able to put together regimens without any of our current three classes.”

Nucleoside-sparing regimens consisting of ritonavir-boosted atazanavir (Reyataz) plus efavirenz (Sustiva, Stocrin) demonstrated potent antiviral activity in treatment-naive patients, but raised levels of triglycerides and both LDL and HDL cholesterol, according to a study presented on Thursday at the Forty-Sixth Interscience Conference on Antimicrobial Agents and Chemotherapy in San Francisco

Given concerns about long-term side effects such as lipoatrophy and mitochondrial toxicity associated with certain nucleoside reverse transcriptase inhibitors (NRTIs), researchers have explored the use of “NRTI-sparing” regimens that include only non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs).

However, NRTI-sparing regimens may cause toxicities of their own, in particular elevated blood fat levels. In studies to date, atazanavir has been shown to cause fewer lipid abnormalities than other drugs in the PI class.

Gary Thal of Bristol-Myers Squibb presented data on one such regimen. In the multicentre, open-label BMS-121 study, 61 participants receiving anti-HIV therapy for the first time were randomised and began treatment with one of two doses of atazanavir boosted with ritonavir (300/100 mg or 400/100 mg once daily) plus 600 mg efavirenz for 48 weeks. No NRTIs were used.

Most participants were men (85%), nearly half (49%) were white, 43% were black, and the mean age was 37 years. At study entry, participants had CD4 cell counts of at least 50 cells/mm³ (median 305 cells/mm³), HIV RNA levels of 1000 copies/mL or higher (median 4.97 log₁₀copies/mL), and fasting triglyceride levels below 200 mg/dL (considered the upper limit of normal).

Overall, HIV viral load fell by a mean 3.24 log₁₀ copies/mL by Week 48. In an intention-to-treat analysis (drop-outs counted as failures), 75% of patients in the 300/100 mg atazanavir arm and 67% in the 400/100 mg arm achieved viral suppression below 400 copies/mL; 63% and 61%, respectively, had viral loads below 50 copies/mL. Mean CD4 counts increased by 271 cells/mm³ in the 300/100 mg group and 250 cells/mm³ in the 400/100 mg arm.

In an observed/as-treated analysis (looking only at patients who successfully completed the study), 92% and 96% in the 300/100 mg and 400/100 mg arms, respectively, reached HIV RNA levels below 400 copies/mL, whilst 77% and 87% had viral load below 50 copies/mL.

With regard to side effects, moderate to severe (grade 2-4) treatment-related adverse events were seen in nearly one-third of participants (26% in the 300/100 mg arm and 30% in the 400/100 mg arm), with the most common being insomnia, skin rash, diarrhoea, and dizziness. A total of 12 patients stopped treatment prematurely, but only two discontinuations were due to adverse events.

Grade 3-4 bilirubin elevation – a known side effect of atazanavir – was observed in 13% of patients in the 300/100 mg arm and 40% in the 400/100 mg arm, though none discontinued for this reason. For grade 3-4 liver enzyme elevations, the rates were 10% and 7%, respectively, for alanine aminotransferase (ALT), and 7% and 3% for aspartate aminotransferase (AST).

Looking at lipid changes, fasting triglyceride levels rose by 48% from baseline in the 300/100 mg arm and by 63% in the 400/100 mg arm. These elevations were greater than those observed in most studies of atazanavir or efavirenz to date, although none were worse than grade 2.

Total cholesterol (TC) increased by 29% and 32% from baseline in the 300/100 mg and 400/100 mg arms, respectively. From a clinical perspective, it is more useful to consider the different types of cholesterol separately. LDL (low-density lipoprotein) is a risk factor for cardiovascular disease, while HDL (high-density lipoprotein) has a protective effect. LDL increased by 11% in the 300/100 mg arm and by 13% in the 400/100 mg arm, while HDL rose by 54% and 45%, respectively.

None of the TC or LDL elevations were considered severe (grade 3-4), whilst the HDL increases were greater than those observed in most previous studies of these drugs. Further, the ratios of total cholesterol to HDL and of LDL to HDL (TC:HDL and LDL:HDL) decreased in both dose arms, which is considered to be a more favorable.

The researchers concluded that both dosing regimens of atazanavir/ritonavir plus efavirenz “were generally safe, well-tolerated and demonstrated potent antiretroviral efficacy through 48 weeks.” They added that, “Increases in triglycerides, total cholesterol and LDL cholesterol were observed in both arms and were accompanied by robust increases in HDL cholesterol and decreases in TC:HDL and LDL:HDL ratios.”

Because both potentially dangerous triglycerides and LDL and protective HDL increased simultaneously, the researchers acknowledged that the long-term implications for cardiovascular health could not be determined.