However, this intervention may be thought to be less convenient for drug-na?ve subjects due to the necessity for yet another extra tablet of r, which includes to become kept in the refrigerator and produces gastrointestinal disturbances frequently. needed to bring about ATV level of resistance. In drug-na?ve content, regimens predicated on ATV/r have shown non-inferiority compared to lopinavir (LPV)/r (CASTLE study) or fosamprenavir/r (ALERT trial), generally with improved tolerance (less diarrhea and dyslipidemia). Given its good tolerance and convenience, ATV has been proven to be successful as a simplification strategy in switch studies (ie, SWAN and SLOAT) conducted in patients with total virological suppression under other PI-based regimens. Finally, ATV/r-based combinations have shown to be equivalent in terms of viral response to other PI/r-containing regimens, including LPV/r, in rescue interventions in patients failing other PI regimens (ie, studies AI424-045 and NADIS). strong class=”kwd-title” Keywords: atazanavir, HIV, protease inhibitors, drug resistance Introduction The introduction of triple combination therapy following the availability of protease inhibitors (PIs) dramatically changed the natural history of HIV contamination in the Morusin late 1990s. When the first PI (saquinavir) was marketed in 1995, the acknowledgement of significant gains in CD4 counts and dramatic reductions in the incidence of opportunistic events accompanying by unprecedent declines in computer virus replication produced a huge enthusiasm in both patients and clinicians. However, this initial joy was soon tempered when patients began to complain of troubles in pursuing treatment schedules and especially when side effects became clearly manifest. Even worse was the acknowledgement that disturbances in the metabolism of lipids and glucose and disfiguring morphological features due to fat tissue redistribution were a new stigmatizing feature following Hoxa2 prolonged PI exposure. A new generation of PI compounds free of the main limitations of the first-generation PIs has recently joined the HIV armamentarium. ATV, marketed as Reyataz? (Bristol-Myers Squibb), may have an advantage over other PIs because of its favorable effect on lipid profiles, once-daily dosing, low capsule burden and a relatively favorable resistance profile.1 This short article reviews the main pharmacologic and clinical features of Morusin ATV and updates its role in the treatment of HIV infection. Mechanism of action ATV is an azapeptide inhibitor of the HIV-1 protease. The chemical name for ATV sulfate is usually (3S,8S,9S,12S)-3,12-bis(1,1-dimethylethyl)-8-hydroxy-4,11-dioxo-9-(phenylmethyl)-6-((4-(2-pyridinyl)phenyl)methyl)-2,5,6,10,13-pentazatetradecanedioic acid dimethyl ester sulfate (1:1) (Physique 1). The compound inhibits the virus-specific processing of viral Gag and Gag-Pol poliproteins of HIV-1 group M subtype A, B, C, D, AE, AG, F, G, and J in infected cells, thus preventing formation of mature virions.1 As measure of potency, the concentration that inhibits 50% of viral replication (IC50) in the absence of human serum ranged from 0.58 ng/mL to 5.7 ng/mL in a panel of susceptible viruses isolated from 31 PI-na?ve HIV-infected patients.2,3 The presence of 40% human serum in cell cultures increased ATV IC50 by 2.7- to 3.6-fold, as noticed for other PIs. The adjusted IC50 for protein binding was estimated to range from 8 to 20 ng/mL against reference viral strains with a conventional cycle cell contamination and the PhenoSense? single assay (ViroLogic Inc., South San Francisco, CA, USA), respectively.2 Open in a separate window Determine 1 Chemical structure of atazanavir sulfate. Drug resistance Resistance patterns to ATV differ according to the population exposed to the drug being PI-na?ve or -experienced, and to ritonavir (r) boosting. The presence of a single major mutation in the protease gene may result in loss of susceptibility to ATV, but in clinical practice ATV resistance generally occurs when several mutations in the protease gene are present. In PI-na?ve patients, the most frequent mutation at failure under ATV is I50L,4,5 while in PI-experienced patients mutations I84V and N88S are more commonly determined. Of notice, I50L is only selected under ATV pressure and it causes higher susceptibility to other PIs such as amprenavir, darunavir, indinavir, lopinavir (LPV), nelfinavir (NFV) and saquinavir (SQV).6 The prevalence of I50L in large HIV drug resistance mutation databases is generally very low.7 ATV is almost always prescribed boosted with r, but the Food and Drug Administration (FDA) allows also its use unboosted in determined PI-na?ve patients and in simplification strategies. In contrast, the EMEA has not approved yet the use of ATV without r improving. When PIs are used without r improving, drug exposures are significantly lower. In this situation, the resistance barrier may be confined to a single key mutation (eg, I50L). Interpretation of drug resistance mutations is complicated. First, a qualitative approach is usually performed identifying changes that could impact drug susceptibility. As not all changes in the protease gene have the same influence on drug susceptibility, a quantitative score giving.50% dose reduction of diltiazem should be considered.felodipine, nifedipine, nicardipine, verapamil felodipine, nifedipine, nicardipine, verapamilCaution is warranted and ECG monitoring is recommended. br / Dose titration should be considered.Corticosteroidsfluticasone fluticasoneCaution is warranted.Ergot derivativesdihydroergotamine, ergotamine, ergonovine, methylergonovine ergot derivativesContraindicated.GI motility agentcisapridecisaprideContraindicated.Acid suppressive therapyantiacids ATVATV should be adminsitered 2h befote or 1h alter intake of antiacids.H2 receptor antagonists ATVH2 Receptor antagonist should not exceed a 40 mg dose equivalent of famotidine twice daily and ATV should be administered with r simultaneously, with and/or at least 10 hours after the dose of the H2-receptor antagonist.proton pump inhbitors ATVATV/r is recommended. Finally, ATV/r-based combinations have shown to be equivalent in terms of viral response to other PI/r-containing regimens, including LPV/r, in rescue interventions in patients failing other PI regimens (ie, studies AI424-045 and NADIS). strong class=”kwd-title” Keywords: atazanavir, HIV, protease inhibitors, drug resistance Introduction The introduction of triple combination therapy following the availability of protease inhibitors (PIs) dramatically changed the natural history of HIV infection in the late 1990s. When the first PI (saquinavir) was marketed in 1995, the recognition of significant gains in CD4 counts and dramatic reductions in the incidence of opportunistic events accompanying by unprecedent declines in virus replication produced a huge enthusiasm in both patients and clinicians. However, this initial joy was soon tempered when patients began to complain of difficulties in pursuing treatment schedules and especially when side effects became clearly manifest. Even worse was the recognition that disturbances in the metabolism of lipids and glucose and disfiguring morphological features due to fat tissue redistribution were a new stigmatizing feature following Morusin prolonged PI exposure. A new generation of PI compounds free of the main limitations of the first-generation PIs has recently entered the HIV armamentarium. ATV, marketed as Reyataz? (Bristol-Myers Squibb), may have an advantage over other PIs because of its favorable effect on lipid profiles, once-daily dosing, low capsule burden and a relatively favorable resistance profile.1 This article reviews the main pharmacologic and clinical features of ATV and updates its role in the treatment of HIV infection. Mechanism of action ATV is an azapeptide inhibitor of the HIV-1 protease. The chemical name for ATV sulfate is (3S,8S,9S,12S)-3,12-bis(1,1-dimethylethyl)-8-hydroxy-4,11-dioxo-9-(phenylmethyl)-6-((4-(2-pyridinyl)phenyl)methyl)-2,5,6,10,13-pentazatetradecanedioic acid dimethyl ester sulfate (1:1) (Figure 1). The compound inhibits the virus-specific processing of viral Gag and Gag-Pol poliproteins of HIV-1 group M subtype A, B, C, D, AE, AG, F, G, and J in infected cells, thus preventing formation of mature virions.1 As measure of potency, the concentration that inhibits 50% of viral replication (IC50) in the absence of human serum ranged from 0.58 ng/mL to 5.7 ng/mL in a panel of susceptible viruses isolated from 31 PI-na?ve HIV-infected patients.2,3 The presence of 40% human serum in cell cultures increased ATV IC50 by 2.7- to 3.6-fold, as noticed for other PIs. The adjusted IC50 for protein binding was estimated to range from 8 to 20 ng/mL against reference viral strains with a conventional cycle cell infection and the PhenoSense? single assay (ViroLogic Inc., South San Francisco, CA, USA), respectively.2 Open in a separate window Figure 1 Chemical structure of atazanavir sulfate. Drug resistance Resistance patterns to ATV differ according to the population exposed to the drug being PI-na?ve or -experienced, and to ritonavir (r) boosting. The presence of a single major mutation in the protease gene may result in loss of susceptibility to ATV, but in clinical practice ATV resistance generally occurs when several mutations in the protease gene are present. In PI-na?ve patients, the most frequent mutation at failure under ATV is I50L,4,5 while in PI-experienced patients mutations I84V and N88S are more commonly selected. Of note, I50L is only selected under ATV pressure and it causes higher susceptibility to other PIs such as amprenavir, darunavir, indinavir, Morusin lopinavir (LPV), nelfinavir (NFV) and saquinavir (SQV).6 The prevalence of I50L in large HIV drug resistance mutation databases is generally very low.7 ATV is almost always prescribed boosted with r, but the Food and Drug Administration (FDA) allows also its use unboosted in selected PI-na?ve patients and in simplification strategies. In contrast, the EMEA has Morusin not approved yet the use of ATV without r boosting. When PIs are used without r boosting, drug exposures are significantly lower. In this situation, the resistance barrier may be confined to a single key mutation (eg, I50L). Interpretation of drug resistance mutations is complicated. First, a qualitative approach is usually performed identifying changes that could affect drug susceptibility. As not all changes in the protease gene have the same influence on drug susceptibility, a quantitative score giving different weight to each mutation and each drug must be used. The International AIDS Society-USA (IAS-USA) Panel describes a list of mutations in the protease gene that are associated with resistance to ATV. This list include changes at positions 10, 16, 20, 24, 32, 33,.