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ABSTRACT: CASTLE was a randomized 96-week study that demonstrated that atazanavir/ritonavir (ATV/r) was noninferior to lopinavir/ritonavir (LPV/r) in treatment-naïve HIV-infected patients. Analyses were carried out among patients who received ATV/r in the CASTLE study to better understand the clinical significance of unconjugated hyperbilirubinemia associated with administration of boosted ATV. Hyperbilirubinemia was defined as total bilirubin (conjugated and unconjugated) elevation greater than 2.5 times the upper limit of normal (grade 3-4). Patients in the ATV/r arm were assessed based on the presence or absence of hyperbilirubinemia through week 96. Analyses included number of confirmed virologic responders (CVR; HIV RNA<50 copies per milliliter), impact of hyperbilirubinemia on symptoms, elevations in liver enzymes, patient quality of life, and medication adherence. Through 96 weeks in the CASTLE study, 44% of patients who received ATV/r had hyperbilirubinemia at any time point, and between 12.5% and 21.6% had hyperbilirubinemia at any single study visit. At 96 weeks, 74% of patients overall and 84% and 69% of patients with and without hyperbilirubinemia, respectively, achieved CVR. Symptoms of jaundice or scleral icterus occurred in 5% of patients overall and in 11% with hyperbilirubinemia and 0% without hyperbilirubinemia. Four percent of patients with and 3% of patients without hyperbilirubinemia had grade 3-4 elevations in liver transaminases. Less than 1% of patients discontinued treatment due to hyperbilirubinemia. There were no differences in quality of life or adherence between patients with or without hyperbilirubinemia. In the CASTLE study, hyperbilirubinemia observed in the ATV/r group did not negatively impact clinical outcomes in HIV-infected patients.
AIDS patient care and STDs 03/2012; 26(5):259-64. · 2.68 Impact Factor
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ABSTRACT: It is unknown whether HIV-positive patients experiencing virologic failure (VF) on boosted-PI (PI/r) regimens without drug resistant mutations (DRM) by standard genotyping harbor low-level PI resistant variants. CASTLE compared the efficacy of atazanavir/ritonavir (ATV/r) with lopinavir/ritonavir (LPV/r), each in combination with TVD in ARV-naïve subjects.
To determine if VF on an initial PI/r-based regimen possess low-level resistant variants that may affect a subsequent PI-containing regimen.
Patients experiencing VF on a Tenofovir/Emtricitabine+PI/r regimen were evaluated by ultra deep sequencing (UDS) for mutations classified/weighted by Stanford HIVdb. Samples were evaluated for variants to 0.4% levels. 36 VF subjects were evaluated by UDS; 24 had UDS for PI and RT DRMs. Of these 24, 19 (79.2%) had any DRM by UDS. The most common UDS-detected DRM were NRTI in 18 subjects: M184V/I (11), TAMs(7) & K65R(4); PI DRMs were detected in 9 subjects: M46I/V(5), F53L(2), I50V(1), D30N(1), and N88S(1). The remaining 12 subjects, all with VLs<10,000, had protease gene UDS, and 4 had low-level PI DRMs: F53L(2), L76V(1), I54S(1), G73S(1). Overall, 3/36(8.3%) subjects had DRMs identified with Stanford-HIVdb weights >12 for ATV or LPV: N88S (at 0.43% level-mutational load 1,828) in 1 subject on ATV; I50V (0.44%-mutational load 110) and L76V (0.52%-mutational load 20) in 1 subject each, both on LPV. All VF samples remained phenotypically susceptible to the treatment PI/r.
Among persons experiencing VF without PI DRMs with standard genotyping on an initial PI/r regimen, low-level variants possessing major PI DRMs were present in a minority of cases, occurred in isolation, and did not result in phenotypic resistance. NRTI DRMs were detected in a high proportion of subjects. These data suggest that PIs may remain effective in subjects experiencing VF on a PI/r-based regimen when PI DRMs are not detected by standard or UDS genotyping.
PLoS ONE 01/2012; 7(2):e30118. · 4.09 Impact Factor
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ABSTRACT: Current guidelines for HIV therapy recommend initiating treatment at a CD4 cell count of 500 cells/mm(3). However, a large proportion of patients with HIV infection begin antiretroviral treatment at a more advanced stage. In the CASTLE study, patients with the most advanced HIV disease (CD4 cell count <50 cells/mm(3)) showed that 78% (45/58) vs. 58% (28/48) of the patients achieved HIV RNA <50 copies/mL in the intent-to-treat analysis at week 96 for atazanavir/ritonavir and lopinavir/ritonavir, respectively. This current sub-analysis of the CASTLE study describes demographics, virologic failure, discontinuations, safety, tolerability, immunologic response, and clinical outcomes for the following baseline strata: CD4 cell count (cells/mm(3)) <50, 50 to <100, 100 to <200, and ≥200 and HIV RNA (copies/mL) <100,000, 100,000 to <500,000, and ≥500,000. In the lowest CD4 cell count stratum (<50 cells/mm(3)), the proportion of discontinuations was 2-fold greater for the lopinavir/ritonavir arm (33%) than for the atazanavir/ritonavir arm (16%) with a similar rate of virologic failure between the two groups. Also in this CD4 cell count stratum, grades 2-4 treatment-related adverse events occurred in 25% in the atazanavir/ritonavir group and in 43% of lopinavir/ritonavir group, and the rate was also higher than in the higher CD4 cell count strata within the lopinavir/ritonavir treatment group (range: 29-34%). Grades 2-4 treatment-related diarrhea and nausea occurred in more patients receiving lopinavir/ritonavir than atazanavir/ritonavir in all strata. The atazanavir/ritonavir group had more grades 2-4 treatment-related jaundice than in the lopinavir/ritonavir group. These results highlight the importance of tolerability of antiretroviral therapy (ART) in the patients at greatest risk of morbidity and mortality when using regimens of similar potency.
AIDS Care 07/2011; 23(11):1500-4. · 1.60 Impact Factor
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ABSTRACT: To examine whether the overall results of the CASTLE study pertain to both genders, we analysed the efficacy and safety of atazanavir/ritonavir and lopinavir/ritonavir in 277 female and 606 male patients in the open-label, multinational trial over 96 weeks. The trial is registered with ClinicalTrials.gov, number NCT00272779.
Treatment-naive patients aged ≥ 18 years with HIV-1 RNA ≥ 5000 copies/mL were randomized to receive either atazanavir/ritonavir 300/100 mg once daily or lopinavir/ritonavir 400/100 mg twice daily, with fixed-dose tenofovir/emtricitabine 300/200 mg once daily.
At week 96, confirmed virological response rates (HIV RNA <50 copies/mL; intent-to-treat analysis) were higher in women and men receiving atazanavir/ritonavir than those receiving lopinavir/ritonavir and lower in women than men in both treatment arms (67% of women and 77% of men on atazanavir/ritonavir and 63% of women and 71% of men on lopinavir/ritonavir). These differences were not observed in the on-treatment analysis. Mean change in CD4 cell count from baseline to week 96 was 265 cells/mm(3) for women and 269 cells/mm(3) for men on atazanavir/ritonavir and 298 cells/mm(3) for women and 286 cells/mm(3) for men on lopinavir/ritonavir. Discontinuation rates were higher in women than men in each treatment arm (22% of women and 15% of men on atazanavir/ritonavir and 29% of women and 18% of men on lopinavir/ritonavir). In women and men, grade 2-4 nausea and diarrhoea were more frequent in the lopinavir/ritonavir group; jaundice and hyperbilirubinaemia occurred more frequently in the atazanavir/ritonavir group.
Once-daily atazanavir/ritonavir is an effective and well-tolerated therapeutic option for women and men with HIV-1 infection. The sex-based differences in response may be due to higher discontinuation rates in women.
Journal of Antimicrobial Chemotherapy 12/2010; 66(2):363-70. · 5.07 Impact Factor
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Max Lataillade,
Jennifer Chiarella,
Rong Yang,
Steven Schnittman,
Victoria Wirtz, Jonathan Uy,
Daniel Seekins,
Mark Krystal,
Marco Mancini,
Donnie McGrath,
Birgitte Simen,
Michael Egholm,
Michael Kozal
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ABSTRACT: Background
CASTLE compared the efficacy of atazanavir/ritonavir with lopinavir/ritonavir, each in combination with tenofovir-emtricitabine in ARV-naïve subjects from 5 continents.
Objectives
Determine the baseline rate and clinical significance of TDR mutations using ultra-deep sequencing (UDS) in ARV-naïve subjects in CASTLE.
Methods
A case control study was performed on baseline samples for all 53 subjects with virologic failures (VF) at Week 48 and 95 subjects with virologic successes (VS) randomly selected and matched by CD4 count and viral load. UDS was performed using 454 Life Sciences/Roche technology.
Results
Of 148 samples, 141 had successful UDS (86 subtype B, 55 non-B subtypes). Overall, 30.5% of subjects had a TDR mutation at baseline; 15.6% only had TDR(s) at
PLoS ONE 06/2010; 5(6). · 4.09 Impact Factor
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Max Lataillade,
Jennifer Chiarella,
Rong Yang,
Steven Schnittman,
Victoria Wirtz, Jonathan Uy,
Daniel Seekins,
Mark Krystal,
Marco Mancini,
Donnie McGrath,
Birgitte Simen,
Michael Egholm,
Michael Kozal
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ABSTRACT: CASTLE compared the efficacy of atazanavir/ritonavir with lopinavir/ritonavir, each in combination with tenofovir-emtricitabine in ARV-naïve subjects from 5 continents.
Determine the baseline rate and clinical significance of TDR mutations using ultra-deep sequencing (UDS) in ARV-naïve subjects in CASTLE.
A case control study was performed on baseline samples for all 53 subjects with virologic failures (VF) at Week 48 and 95 subjects with virologic successes (VS) randomly selected and matched by CD4 count and viral load. UDS was performed using 454 Life Sciences/Roche technology.
Of 148 samples, 141 had successful UDS (86 subtype B, 55 non-B subtypes). Overall, 30.5% of subjects had a TDR mutation at baseline; 15.6% only had TDR(s) at <20% of the viral population. There was no difference in the rate of TDRs by B (30.2%) or non-B subtypes (30.9%). VF (51) and VS (90) had similar rates of any TDRs (25.5% vs. 33.3%), NNRTI TDRs (11.1% vs.11.8%) and NRTI TDRs (24.4% vs. 25.5%). Of 9 (6.4%) subjects with M184V/I (7 at <20% levels), 6 experienced VF. 16 (11.3%) subjects had multiple TAMs, and 7 experienced VF. 3 (2.1%) subjects had both multiple TAMs+M184V, and all experienced VF. Of 14 (9.9%) subjects with PI TDRs (11 at <20% levels): only 1 experienced virologic failure. The majority of PI TDRs were found in isolation (e.g. 46I) at <20% levels, and had low resistance algorithm scores.
Among a representative sample of ARV-naïve subjects in CASTLE, TDR mutations were common (30.5%); B and non-B subtypes had similar rates of TDRs. Subjects with multiple PI TDRs were infrequent. Overall, TDRs did not affect virologic response for subjects on a boosted PI by week 48; however, a small subset of subjects with extensive NRTI backbone TDR patterns experienced virologic failure.
PLoS ONE 01/2010; 5(6):e10952. · 4.09 Impact Factor
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ABSTRACT: There are limited data on the risk of developing HIV drug resistance based on the CD4 cell count at which highly active antiretroviral therapy (HAART) is initiated.
We examined data from participants in the HIV Outpatient Study who initiated antiretroviral therapy with HAART in 1999 or later (when genotypic resistance testing became more commonly used in clinical practice and in the HIV Outpatient Study), achieved virologic suppression, and subsequently experienced virologic failure and received a genotypic assay for antiretroviral resistance mutations. We assessed the frequency of resistance mutations at virologic failure and the differences in the frequencies of mutations by the CD4 stratum at which HAART was initiated using the Cochran-Armitage exact test.
Of 683 patients who achieved virologic suppression on a first HAART regimen, 243 had virologic failure and 78 of these had a genotype resistance test done. Among these patients, the frequency of any HIV resistance mutations was 50% among patients who started HAART at 0-199 CD4 cells per cubic millimeter or 200-349 CD4 cells per cubic millimeter compared with 22% among patients who started HAART at >or=350 CD4 cells per cubic millimeter (P = 0.062). The frequency of nucleoside reverse transcriptase inhibitor-associated mutations was 48%, 31%, and 11% among persons who initiated nucleoside reverse transcriptase inhibitor-containing HAART within these respective CD4 cell count strata (P = 0.005). We observed similar trends for nonnucleoside reverse transcriptase inhibitor-associated (P = 0.040) and protease inhibitor-associated (P = 0.063) mutations among persons initiating HAART containing these agents.
Patients failing HAART that was initiated at <350 CD4 cells per cubic millimeter had higher frequencies of resistance mutations to the classes of antiretrovirals to which they had been exposed than failing patients who initiated at >or=350 CD4 cells per cubic millimeter. Initiating HAART at higher CD4 cell counts may decrease the risk of developing treatment-limiting antiretroviral resistance.
JAIDS Journal of Acquired Immune Deficiency Syndromes 06/2009; 51(4):450-3. · 4.43 Impact Factor
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ABSTRACT: Clinical utilization of genotype resistance testing is evolving. We examined the extent to which HIV care providers requesting genotype resistance tests used the information appropriately and the impact of inappropriate utilization.
Data from a prospective cohort of HIV-infected patients (the HIV Outpatient Study) were used in the analysis. We analysed the frequency with which patients were prescribed any non-nucleoside reverse transcriptase inhibitor after identification of the K103N mutation in reverse transcriptase and the frequency of prescription of nelfinavir after identification of the D30N mutation in HIV protease; the short-term impact of this action on HIV viral load and CD4+ T-cell count was assessed.
Among 441 patients demonstrating either mutation, 18% who were taking the resistant antiretroviral at the time of the test were continued on the medication for >6 months after this finding. In 33% of these instances, prescribers reported these actions were erroneous oversights. For persons taking the resistant antiretroviral at the time of the genotype test, stopping this medication within 6 months of the test produced greater decreases in viral load (-1.35 versus -0.43 log copies/ml, P = 0.025) and a greater likelihood of achieving an undetectable viral load (25.3% versus 7.3%, P = 0.012) at 9 months. Changes in CD4+ T-cell count differed (+22.8 versus -23.0 cells/mm3), but not significantly (P = 0.167).
Following evidence of definitive resistance by genotype testing, a substantial fraction of antiretroviral prescriptions were continued in error leading to an attenuated therapeutic response. These data highlight the need to consider better systems to manage genotype resistance testing data in the clinical setting.
Antiviral therapy 01/2007; 12(6):957-62. · 3.16 Impact Factor
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Richard M Novak,
Li Chen,
Rodger D MacArthur,
John D Baxter,
Kathy Huppler Hullsiek,
Grace Peng,
Ying Xiang,
Christopher Henely,
Barry Schmetter, Jonathan Uy,
Mary van den Berg-Wolf,
Michael Kozal
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ABSTRACT: The prevalence of drug resistance among persons with newly acquired human immunodeficiency virus (HIV) infection is well documented. However, it is unclear to what extent these mutations persist in chronically infected, treatment-naive patients.
Prevalence of and factors associated with genotypic drug resistance were analyzed retrospectively in a subset of 491 chronically HIV-infected, antiretroviral-naive patients enrolled at 25 cities in the Terry Beirn Community Programs for Clinical Research on Acquired Immune Deficiency Syndrome (AIDS) Flexible Initial Retrovirus Suppressive Therapies trial during 1999-2001. Resistance was defined on the basis of the International AIDS Society 2003 definition, as well as the presence of additional mutations at codons 215 (C/D/E/S) and 69 (A/N/S) in the pol gene. Prevalence of mutations was estimated by use of techniques for stratified random samples. Logistic regression models were used to determine factors associated with resistance.
Among the 491 chronically HIV-infected patients (mean CD4 cell count, 269 cells/mm(3); 31% of patients had a prior AIDS diagnosis), 57 (11.6%) had >or=1 resistance mutation, resulting in an estimated prevalence for the cohort of 10.8% (95% confidence interval [CI], 9.5%-12.1%). The prevalence was 8.8% if the 118I mutation was excluded. By drug class, the estimated prevalence of mutations conferring resistance to nucleoside reverse-transcriptase inhibitors was 7.8%, and the prevalence was 3.0% for nonnucleoside reverse-transcriptase inhibitors and 0.7% for protease inhibitors. In a multiple logistic regression analysis, non-Hispanic white subjects were twice as likely than African American subjects to have resistance (odds ratio [OR], 2.1; 95% CI, 1.1-4.1; P=.03), and there was a 40% increase per year in prevalence of mutations by later year of enrollment (OR, 1.4; 95% CI, 1.0-2.1; P=.05).
These results demonstrate the persistence of drug resistance mutations in chronically HIV-infected patients and an increasing prevalence of resistance over time, and they support genotyping of virus at baseline for chronically HIV-infected patients.
Clinical Infectious Diseases 03/2005; 40(3):468-74. · 9.15 Impact Factor
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ABSTRACT: Mutations at reverse transcriptase codons 44, 118, 207, and 208 were significantly correlated with reduced zidovudine susceptibility in biologically cloned human immunodeficiency virus type 1 (HIV-1) isolates. Sequences from the Stanford HIV RT and Protease Sequence Database showed that these mutations were more common in HIV-1 isolates from patients treated with zidovudine and lamivudine than in patients not treated with these drugs.
Antimicrobial Agents and Chemotherapy 01/2003; 46(12):4000-3. · 4.84 Impact Factor
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Jonathan Uy
Positively aware: the monthly journal of the Test Positive Aware Network 14(1):32-3.
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ABSTRACT: Treatment-naïve participants were randomized to three antiretroviral strategies (all with nucleoside reverse transcriptase inhibitor [NRTI] background): protease inhibitor (PI), non-nucleoside reverse transcriptase inhibitor (NNRTI), or PI+NNRTI. The strategies were compared for drug resistance at first virologic failure (VF; HIV RNA >1000 copies/mL). The impact of resistance on AIDS or death was determined.
Drug resistance was determined by genotype. Cox models were used to compare the strategies for VF with resistance and to determine the impact of resistance on AIDS or death.
Of 1,360 participants, 866 experienced VF; 226 experienced AIDS or death (median follow-up 5 years). Rates (per 100 personyears) for VF with resistance were 14.9 (PI), 10.8 (NNRTI), and 11.5 (PI+NNRTI); hazard ratio (HR) was 0.78 (95% CI 0.61-0.99) for NNRTI versus PI. Compared to those with no VF, there was a significantly increased risk of AIDS or death for participants with solitary NNRTI resistance (HR 2.31, 95% CI 1.46-3.66) and for those failing with no known resistance (HR 1.78, 95% CI 1.18-2.68). Participants failing with solitary NNRTI resistance and with no resistance had the lowest percent of time on antiretroviral treatment (ART) and the lowest cumulative mean adherence scores.
For treatment-naïve participants, the risk of AIDS or death is increased for those who failed virologically with solitary NNRTI resistance and those who failed with no known drug resistance compared to those with no virologic failure. Both the lack of ART exposure in nonadherent participants and the development of NNRTI resistance among those who take and fail their ART regimen predict poor clinical outcomes.
HIV Clinical Trials 8(6):357-70. · 1.64 Impact Factor
