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Another Small Study Suggests Viability of
Unboosted Atazanavir/Raltegravir Maintenance
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49th ICAAC (Interscience Conference on Antimicrobial Agents and Chemotherapy), September 12-15, 2009, San Francisco
Mark Mascolini
from Jules: in the study presented today in a poster by Peter Ruane, he used Reyataz 400 mg once daily plus raltegravir 400 mg twice daily. BMS is studying both drugs in a nukesparing regimen twice daily, the Ruane dosing regimen could be suspect to low blood levels of Reyataz. I recall the dosing in the BMS study is 400 RAL + 300 Reyataz both twice daily. Taking one drug once daily and the second drug twice daily creates a situation where it's possible that patients could forget a dose of the twice daily drug. We have yet to study if there are negative consequences regarding CSF regarding NRTI-sparing regimens, 2 protease inhibitor monotherapy studies have observed neurologic disorders emerging in a few patients.
Adding to results of other pilot studies [1,2], Los Angeles clinicians reported good 24-week results with unboosted atazanavir plus the integrase inhibitor raltegravir as maintenance therapy for people responding virologically to regimens they can no longer tolerate [3]. Two of 30 people (7%) had to stop the novel two-drug combo, one because of side effects and one with virologic rebound.
This combination intrigues HIV clinicians and pharmacologists because both drugs are potent, both have relatively good safety profiles, and their use would avoid side effects related to nucleoside and nonnucleoside reverse transcriptase inhibitors and to ritonavir.
Pharmacologists in Italy [1] and Spain [2] tested interactions between unboosted atazanavir and raltegravir at different doses. The Italian study involved 21 people with no atazanavir-related mutations switching from a boosted protease inhibitor (PI) to atazanavir/raltegravir at a dose of 200/400 mg twice daily. Concentrations of both drugs were generally comparable to those in earlier studies. After 5 to 7 months of follow-up, everyone had a viral load below 50 copies, no one had a grade 3 or 4 lab toxicity, and no one dropped out of the study.
The Spanish study involved 15 people who had taken 400 mg of atazanavir once daily for at least 2 weeks and had a viral load under 50 copies [2]. They stopped other antiretrovirals, continued the atazanavir, and added 800 mg of raltegravir once daily. That dose yielded a higher raltegravir maximum concentration, a lower trough concentration, and a similar area under the curve compared with a single 400-mg dose of raltegravir taken by HIV-negative people after a high-fat meal.
Los Angeles clinicians switched 30 people to atazanavir/raltegravir at doses of 400 mg once daily (with food) and 400 mg twice daily (with or without food) [3]. Everyone was older than 18 and had taken a stable antiretroviral regimen for at least 2 months, had maintained a viral load below 400 copies for more than 4 months, and had fewer than 50 copies at screening for this study. No one had a history of resistance to PIs or failure of a PI regimen. No one had tried raltegravir, and everyone had adequate kidney and liver function.
Twenty-two people (73%) switched from a PI regimen, 27 (90%) had PI experience, and 19 (63%) had taken atazanavir. Everyone had consistent long-term viral suppression on their current regimen but wanted to switch because of side effects including body fat changes and abnormal lipids. Twenty-nine study participants were men, 24 were white, and median age was 47 years (range 39 to 70). Fourteen people (47%) had an AIDS diagnosis. The highest-ever viral load in the group ranged from 504 to 985,099 copies. Median CD4 count when follow-up began stood at 699 (range 301 to 1286) and median lowest-ever CD4 count at 199 (range 3 to 354).
At the time of this report, 27 people (90%) continued the regimen for a median of 36 weeks. Two people stopped atazanavir/raltegravir after 8 weeks. One of them, who was also taking the anticonvulsant phenytoin, had a virologic rebound. Phenytoin lowers concentrations of some PIs. No PI resistance mutations emerged during this rebound. The other person stopped because of elevated creatinine, which then resolved. One person died of newly diagnosed lung cancer after week 36 with a viral load below 48 copies.
Raltegravir pill count determined that 90% of study participants had better than 85% adherence. Median 24-hour atazanavir concentration, measured in 18 people, was 62.8 ng/mL (range 0 to 158). Atazanavir concentrations in 4 people were below 20 ng/mL, including 2 with unmeasurable levels. But all 4 people had viral loads below 48 copies with no blips.
In missing-data-equals failure analyses, 27 of 29 people (93%) had a viral load below 400 copies at week 24 and 24 (83%) had a load below 48 copies. Seven people had viremic blips ranging from 48 to 83 copies through week 24. CD4 counts remained largely unchanged throughout follow-up.
Total cholesterol and "bad" low-density lipoprotein cholesterol fell significantly from week 0 to week 24 (P < 0.05). The percentage of people with lipid levels outside US national guidelines fell for total cholesterol, triglycerides, LDL cholesterol, and "good" high-density lipoprotein cholesterol. Everyone who continued raltegravir/atazanavir for 24 weeks tolerated the combination well.
References
1. Ripamonti D, Maggiolo F, d'Avolio A, et al. Steady-state pharmacokinetics of atazanavir (200mg BID) when combined with raltegravir (400mg BID) in HIV-1 infected adults. 10th International Workshop on Clinical Pharmacology of HIV Therapy. April 15-17, 2009. Amsterdam. Abstract O_14. http://www.natap.org/2009/PK/PK_08.htm
2. Molto J, Valle M, Mothe B, et al. Pharmacokinetics and safety of once-daily raltegravir (800 mg) plus atazanavir (400 mg) in HIV-infected patients. 10th International Workshop on Clinical Pharmacology of HIV Therapy. April 15-17, 2009. Amsterdam. Abstract O_13.
3. Ruane PJ, Alas B. Dual maintenance therapy with raltegravir bid with atazanavir qd in patients with no prior pi resistance and intolerance to other ARV regimens: Preliminary Report. 49th ICAAC (Interscience Conference on Antimicrobial Agents and Chemotherapy). September 12-15, 2009. San Francisco. Abstract H-914.
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