| Clinical Use|
As with all antiretrovirals, atazanavir should be used only in combination regimens.
| Use in Initial vs Subsequent Therapy|
Adult and adolescent treatment guidelines of the U.S. Department of Health and Human Services include ritonavir-boosted atazanavir in combination with tenofovir/emtricitabine as a "preferred" regimen for initial treatment of HIV infection regardless of pretreatment HIV RNA level and boosted atazanavir in combination with abacavir/lamivudine as a "preferred" regimen for patients with pretreatment HIV RNA <100,000 copies/mL. The guidelines state that unboosted atazanavir in combination with nucleoside analogues is "not recommended" for initial treatment.
Atazanavir has been studied in both initial and salvage therapy. In the Phase II comparison (1) between atazanavir (at 3 dose levels) and nelfinavir, each combined with stavudine + didanosine in initial therapy, similar rates of viral suppression to <50 HIV copies/mL were seen in the 4 treatment arms (28-42% in intention-to-treat analysis [ITT], 33-52% in on-treatment analysis [OT]). A second study comparing atazanavir (at 2 dose levels) with nelfinavir, each combined with stavudine + lamivudine in treatment-naive subjects, demonstrated comparable rates of viral suppression to <50 HIV copies/mL at 48 weeks (31-38% in ITT, 39-42% in OT).(2) In an ongoing follow-up of these subjects, approximately 50% of those on atazanavir had viral loads of <50 copies/mL at a mean of 108 weeks (ITT), whereas subjects switched from nelfinavir to atazanavir had comparable rates of viral suppression.(4) In these studies, CD4 responses were comparable across treatment arms.
A randomized, controlled comparison of atazanavir + zidovudine + lamivudine with efavirenz + zidovudine + lamivudine in treatment-naive subjects showed comparable rates of viral suppression to <50 copies/mL (32% vs 37%) and CD4 increase (approximately 170 cells/µL) at 48 weeks in ITT analysis.(3)
A randomized open-label study compared ritonavir-boosted atazanavir with lopinavir/ritonavir (dosed twice daily), each in combination with tenofovir/emtricitabine. At week 48, rates of HIV suppression to <50 copies/mL were not significantly different: 78% and 73% for the two groups, respectively. CD4 cell count increases were similar.(5)
In treatment-naive individuals, atazanavir + ritonavir was compared with raltegravir and with darunavir-ritonavir, with each given in combination with tenofovir/emtricitabine. At week 96 (the primary endpoint), by intention to treat (snapshot) analysis, the rate of virologic suppression to <50 copies/mL was, 63% in the atazanavir group, 80% in the raltegravir group, and 73% in the darunavir group; the difference with each comparator was statistically significant. The differences in efficacy were driven primarily by differences in rates of adverse effects in the three groups; discontinuations owing to adverse effects were more common in the atazanavir group. Mean increases in CD4 cell counts were similar in all treatment groups.(6)
Also in initial therapy, atazanavir + ritonavir with tenofovir/emtricitabine was compared with the coformulation of elvitegravir + cobicistat + tenofovir + emtricitabine. At 48 weeks, rates of virologic suppression to <50 were 87% and 90%, respectively; the difference was not statistically significant.(7)
In a Phase III study of initial treatment, atazanavir was boosted either by cobicistat or by ritonavir, and each combination was given with tenofovir and emtricitabine. At week 48, by snapshot analysis, rates of HIV suppression to <50 copies/mL were 85% in the atazanavir + cobicistat group and 87% in the atazanavir + ritonavir group; the difference was not statistically significant.(8)
In patients with prior treatment failure on protease inhibitor-based therapy, treatment with unboosted atazanavir plus 2 nucleoside analogues was found to be less effective at 48 weeks than treatment with lopinavir/ritonavir plus 2 nucleoside analogues.(9)
In a cohort with multiple virologic failures and prior exposure to 3 classes of antiretrovirals, patients treated with ritonavir-boosted atazanavir (combined with tenofovir and 1 nucleoside analogue) achieved rates of viral suppression and CD4 increase at 48 weeks statistically similar to those observed in patients treated with lopinavir/ritonavir + tenofovir + 1 nucleoside analogue (by ITT analysis, viral load <400 copies/mL in approximately 57% in both groups; CD4 increase 110-121 cells/µL).(10) However, patients with ≥4 primary protease inhibitor mutations had a poorer response to atazanavir + ritonavir (by ITT analysis, 28% in the atazanavir + ritonavir group vs 40% in the lopinavir/ritonavir group). The response rates in the atazanavir + ritonavir and lopinavir/ritonavir arms were significantly better than those in a third treatment arm, atazanavir + saquinavir + tenofovir + 1 nucleoside analogue.
| Adverse Effects|
Symptomatic side effects may include jaundice (in approximately 10% of individuals), nausea, diarrhea, and rash. Kidney stones and gallstones have been reported. The most common laboratory abnormality is isolated elevation in unconjugated bilirubin caused by inhibition of UDP-glucuronosyltransferase; this resolves upon discontinuation of atazanavir. Elevations of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) may occur. Unlike most other protease inhibitors, atazanavir does not typically cause significant elevations in total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglyceride levels. Cardiac conduction abnormalities (particularly PR prolongation) have been observed, as have decreases in bone mineral density.
It is important to assess patient motivation and discuss possible side effects and strategies for their management before treatment with atazanavir is initiated.
| Interactions with Other Drugs|
Atazanavir is a substrate of the cytochrome P450 3A4 isoenzyme, and may alter serum concentrations of other drugs metabolized by this pathway, such as rifabutin, clarithromycin, lipid-lowering agents, and others. Similarly, drugs that induce or inhibit the action of this isoenzyme may cause therapeutically significant alterations in atazanavir levels. For example, coadministration with ritonavir increases atazanavir levels, whereas coadministration with efavirenz decreases atazanavir levels.(11) Coadministration of atazanavir with tenofovir has been found to lower serum atazanavir concentrations and to raise tenofovir concentrations; the mechanism of this interaction is not clear.(12) Coadministering atazanavir with low-dose ritonavir (or cobicistat) may boost serum atazanavir levels enough to compensate for interactions with tenofovir or with certain nonnucleoside reverse transcriptase inhibitors.
Some antacids, particularly proton pump inhibitors and H2 receptor antagonists, significantly interfere with the absorption of atazanavir and can cause subtherapeutic serum atazanavir levels; coadministration of atazanavir with ritonavir or cobicistat does not fully compensate for this adverse interaction. These agents should be avoided in persons taking atazanavir, if possible. If they are used together, dosage modifications of both atazanavir and the acid-lowering agent may be required, and the medication must be given at specific times; see prescribing information for dosing recommendations.(11)
Information on drug interactions should be consulted, as dosage adjustments are frequently required, and certain combinations are contraindicated.
Resistance to atazanavir is associated with the selection of 1 or more of several resistance mutations.
| Implications of atazanavir resistance for treatment with other antiretrovirals|
Resistance to atazanavir has been associated with various known protease inhibitor mutations as well as with the novel I50L substitution. Some atazanavir resistance mutations have been associated, in vitro, with decreased susceptibility to other protease inhibitors, while the I50L mutation has been associated with increased susceptibility to other protease inhibitors.(13) Results from clinical studies are needed to elucidate atazanavir resistance and its implications for subsequent therapy. Genotypic or phenotypic testing may be useful in predicting the likelihood of response to other protease inhibitors following failure of regimens containing atazanavir.
| Implications of resistance to other antiretrovirals for atazanavir treatment|
Resistance mutations selected by other protease inhibitors may confer or contribute to resistance to atazanavir. Substitutions at a number of specific sites (including the mutations M46I/L, G48V, I54V, A71V/T, G73S/T/C, V82A/F/T/S/I, I84V, and L90M) have been associated with decreased susceptibility to atazanavir. Both the specific mutations and the number of mutations affects response to atazanavir, and the accumulation of 3 or more of key mutations predicted sharply reduced susceptibility.(14)
Genotypic or phenotypic testing may be useful in predicting the likelihood of response to atazanavir following failure of regimens containing other antiretrovirals.
|| || Sanne I, Piliero P, Squires K, Thiry A, Schnittman S; AI424-007 Clinical Trial Group. Results of a phase 2 clinical trial at 48 weeks (AI424-007): a dose-ranging, safety, and efficacy comparative trial of atazanavir at three doses in combination with didanosine and stavudine in antiretroviral-naive subjects. J Acquir Immune Defic Syndr. 2003 Jan 1;32(1):18-29.|
|| || Murphy RL, Sanne I, Cahn P, Phanuphak P, Percival L, Kelleher T, Giordano M. Dose-ranging, randomized, clinical trial of atazanavir with lamivudine and stavudine in antiretroviral-naive subjects: 48-week results. AIDS. 2003 Dec 5;17(18):2603-14.|
|| || Squires K, Lazzarin A, Gatell JM, Powderly WG, Pokrovskiy V, Delfraissy JF, Jemsek J, Rivero A, Rozenbaum W, Schrader S, Sension M, Vibhagool A, Thiry A, Giordano M. Comparison of Once-Daily Atazanavir With Efavirenz, Each in Combination With Fixed-Dose Zidovudine and Lamivudine, As Initial Therapy for Patients Infected With HIV. J Acquir Immune Defic Syndr. 2004 Aug 15;36(5):1011-1019.|
|| || Wood R, Phanuphak P, Cahn P, Pokrovskiy V, Rozenbaum W, Pantaleo G, Sension M, Murphy R, Mancini M, Kelleher T, Giordano M. Long-term efficacy and safety of atazanavir with stavudine and lamivudine in patients previously treated with nelfinavir or atazanavir. J Acquir Immune Defic Syndr. 2004 Jun 1;36(2):684-92.|
|| || Molina JM, Andrade-Villanueva J, Echevarria J, Chetchotisakd P, Corral J, David N, Moyle G, Mancini M, Percival L, Yang R, Thiry A, McGrath D; CASTLE Study Team. Once-daily atazanavir/ritonavir versus twice-daily lopinavir/ritonavir, each in combination with tenofovir and emtricitabine, for management of antiretroviral-naive HIV-1-infected patients: 48 week efficacy and safety results of the CASTLE study. Lancet. 2008 Aug 23;372(9639):646-55.|
|| ||Landovitz RJ, Ribaudo HJ, Ofotokun I, et al. Efficacy and tolerability of atazanavir, raltegravir, or darunavir with FTC/Tenofovir: ACTG 5257. In: Program and abstracts of the 21st Conference on Retroviruses and Opportunistic Infections; March 3-6, 2014; Boston. Abstract #85.|
|| || DeJesus E, Rockstroh JK, Henry K, et al; GS-236-0103 Study Team. 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 trial. Lancet. 2012 Jun 30;379(9835):2429-38.|
|| ||Gallant J, Koenig E, Andrade-Villanueva J, et al. Cobicistat versus ritonavir as pharmacoenhancers in combination with atazanavir plus tenofovir disoproxil fumarate/emtricitabine: phase 3 randomized, double blind, active-controlled trial, week 48 results. In: Program and abstracts of the XIX International AIDS Conference; July 22-27, 2012; Washington. Abstract TUAB0103.|
|| || Cohen C, Nieto-Cisneros L, Zala C, Fessel WJ, Gonzalez-Garcia J, Gladysz A, McGovern R, Adler E, McLaren C; BMS AI424-043 Study Group. Comparison of atazanavir with lopinavir/ritonavir in patients with prior protease inhibitor failure: a randomized multinational trial. Curr Med Res Opin. 2005 Oct;21(10):1683-92.|
|| || Johnson M, Grinsztejn B, Rodriguez C, Coco J, DeJesus E, Lazzarin A, Lichtenstein K, Rightmire A, Sankoh S, Wilber R. Atazanavir plus ritonavir or saquinavir, and lopinavir/ritonavir in patients experiencing multiple virological failures. AIDS. 2005 Apr 29;19(7):685-94.|
|| ||Reyetaz Prescribing Information. Princeton, NJ: Bristol-Myers Squibb Company Princeton, NJ. June 2014. Available at Drugs@FDA, www.fda.gov/Drugs|
|| || Taburet AM, Piketty C, Chazallon C, Vincent I, Gerard L, Calvez V, Clavel F, Aboulker JP, Girard PM. Interactions between atazanavir-ritonavir and tenofovir in heavily pretreated human immunodeficiency virus-infected patients. Antimicrob Agents Chemother. 2004 Jun;48(6):2091-6.|
|| || Colonno R, Rose R, McLaren C, Thiry A, Parkin N, Friborg J. Identification of I50L as the signature atazanavir (ATV)-resistance mutation in treatment-naive HIV-1-infected patients receiving ATV-containing regimens. J Infect Dis. 2004 May 15;189(10):1802-10.|
|| || Naeger LK, Struble KA. Effect of baseline protease genotype and phenotype on HIV response to atazanavir/ritonavir in treatment-experienced patients. AIDS. 2006 Apr 4;20(6):847-53.|