Michael J Kozal

Yale-New Haven Hospital, New Haven, Connecticut, United States

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Publications (35)197.28 Total impact

  • Shiven B Chabria, Shaili Gupta, Michael J Kozal
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    ABSTRACT: Human immunodeficiency virus (HIV) exhibits remarkable diversity in its genomic makeup and exists in any given individual as a complex distribution of closely related but nonidentical genomes called a viral quasispecies, which is subject to genetic variation, competition, and selection. This viral diversity clinically manifests as a selection of mutant variants based on viral fitness in treatment-naive individuals and based on drug-selective pressure in those on antiretroviral therapy (ART). The current standard-of-care ART consists of a combination of antiretroviral agents, which ensures maximal viral suppression while preventing the emergence of drug-resistant HIV variants. Unfortunately, transmission of drug-resistant HIV does occur, affecting 5% to >20% of newly infected individuals. To optimize therapy, clinicians rely on viral genotypic information obtained from conventional population sequencing-based assays, which cannot reliably detect viral variants that constitute <20% of the circulating viral quasispecies. These low frequency variants can be detected by highly sensitive genotyping methods collectively grouped under the moniker of deep sequencing. Low-frequency variants have been correlated to treatment failures and HIV transmission, and detection of these variants is helping to inform strategies for vaccine development. Here, we discuss the molecular virology of HIV, viral heterogeneity, drug-resistance mutations, and the application of deep sequencing technologies in research and the clinical care of HIV-infected individuals. Expected final online publication date for the Annual Review of Genomics and Human Genetics Volume 15 is September 01, 2014. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates.
    Annual review of genomics and human genetics 05/2014; · 11.57 Impact Factor
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    ABSTRACT: Low-frequency HIV variants possessing resistance mutations against non‑nucleoside reverse transcriptase inhibitors (NNRTI), especially at HIV reverse transcriptase (RT) amino acid (aa) positions K103 and Y181, have been shown to adversely affect treatment response. Therapeutic failure correlates with both the mutant viral variant frequency and the mutational load. We determined the prevalence of NNRTI resistance mutations at several RT aa positions in viruses from 204 antiretroviral (ARV)-naïve HIV-infected individuals using deep sequencing, and examined the relationship between mutant variant frequency and mutational load for those variants. Deep sequencing to ≥0.4% levels found variants with major NNRTI-resistance mutations having a Stanford-HIVdb algorithm value ≥30 for efavirenz and/or nevirapine in 52/204 (25.5%) ARV-naïve HIV-infected persons. Eighteen different major NNRTI mutations were identified at 11 different positions, with the majority of variants being at frequency >1%. The frequency of these variants correlated strongly with the mutational load, but this correlation weakened at low frequencies. Deep sequencing detected additional major NNRTI-resistant viral variants in treatment-naïve HIV-infected individuals. Our study suggests the significance of screening for mutations at all RT aa positions (in addition to K103 and Y181) to estimate the true burden of pre-treatment NNRTI-resistance. An important finding was that variants at low frequency had a wide range of mutational loads (>100-fold) suggesting that frequency alone may underestimate the impact of specific NNRTI-resistant variants. We recommend further evaluation of all low-frequency NNRTI-drug resistant variants with special attention given to the impact of mutational loads of these variants on treatment outcomes.
    Viruses. 01/2014; 6(9):3428-3437.
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    ABSTRACT: There are few data on the prevalence of WHO transmitted drug resistance mutations (TDRs) that could affect treatment responses to first line antiretroviral therapy (ART) in Hunan Province, China.
    PLoS ONE 01/2014; 9(6):e98740. · 3.53 Impact Factor
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    ABSTRACT: The role of financial incentives in HIV care is not well studied. We conducted a single-site study of monetary incentives for viral load suppression, using each patient as his own control. The incentive size ($100/quarter) was designed to be cost-neutral, offsetting estimated downstream costs averted through reduced HIV transmission. Feasibility outcomes were clinic workflow, patient acceptability, and patient comprehension. Although the study was not powered for effectiveness, we also analyzed viral load suppression. Of 80 eligible patients, 77 consented, and 69 had 12 month follow-up. Feasibility outcomes showed minimal impact on patient workflow, near-unanimous patient acceptability, and satisfactory patient comprehension. Among individuals with detectable viral loads pre-intervention, the proportion of undetectable viral load tests increased from 57 to 69 % before versus after the intervention. It is feasible to use financial incentives to reward ART adherence, and to specify the incentive by requiring cost-neutrality and targeting biological outcomes.
    AIDS and Behavior 02/2013; · 3.49 Impact Factor
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    ABSTRACT: OBJECTIVES:: Antiretroviral (ARV) resistance is of concern. Opioid agonist treatment (ie, methadone or buprenorphine) is effective and decreases HIV transmission risk behaviors and HIV seroconversion. Despite prevention efforts, injection drug use (IDU) and risky sexual behaviors remain prevalent in patients receiving opioid agonist treatment. The purpose of this study is to determine in HIV-infected patients receiving opioid agonist treatment, the prevalence of HIV transmission risk behaviors, the prevalence of ARV resistance, and the prevalence of ARV resistance among those with risk behaviors. METHODS:: The design was a cross-sectional study of patients recruited from opioid treatment programs and outpatient practices. We measured demographic, drug treatment, and HIV clinical information (including ARV adherence), self-reported HIV risk behaviors and drug use, urine toxicologies, and genotype testing for ARV resistance (with both standard assays and ultradeep sequencing). Data analysis included descriptive statistics. RESULTS:: Fifty-nine subjects were enrolled, 64% were male, 24% were white, and mean age was 46 years. Fifty-three percent were receiving methadone, 47% were receiving buprenorphine, and 80% were receiving opioid agonist treatment for 12 weeks or more. Fourteen percent reported unprotected sex, 7% reported sharing needles or works, and 60% had positive urine toxicology for illicit drug use. Fifteen percent had evidence of HIV resistance by standard genotyping; 7% with single class resistance, 3% with double class resistance, and 5% with triple class resistance. Ultradeep sequencing found additional class resistance in 5 subjects. Twenty-two percent of subjects with evidence of transmission risk behaviors versus 14% of subjects without risk behaviors had evidence of ARV resistance. CONCLUSIONS:: Improved prevention and treatment efforts may be needed for HIV-infected, opioid dependent individuals receiving opioid agonist treatment to decrease transmission of ARV resistant virus, especially in resource limited settings.
    Journal of Addiction Medicine 02/2013; · 1.73 Impact Factor
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    ABSTRACT: Drug-resistant HIV-1 minority variants increase the risk of virologic failure for first-line NNRTI-based regimens. We performed a pooled analysis to evaluate the relationship between NNRTI-resistant minority variants and the likelihood and types of resistance mutations detected at virologic failure. In multivariable logistic regression analysis, higher NNRTI minority variant copy numbers, non-white race, and nevirapine use were associated with a higher risk of NNRTI resistance at virologic failure. Among participants on efavirenz, K103N was the most frequently observed resistance mutation at virologic failure regardless of the baseline minority variant. However, the presence of baseline Y181C minority variant was associated with a higher probability of Y181C detection after virologic failure. NNRTI regimen choice and pre-existing NNRTI-resistant minority variants were both associated with the probability and type of resistance mutations detected after virologic failure.
    The Journal of Infectious Diseases 12/2012; · 5.85 Impact Factor
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    ABSTRACT: To evaluate the risk of virologic failure conferred by suboptimal adherence to nonnucleoside reverse transcriptase inhibitors (NNRTIs) and minority NNRTI resistance mutations. Pooled analysis of the risk of virologic failure conferred by minority NNRTI resistance mutations and NNRTI adherence from three studies of treatment-naïve individuals initiating an NNRTI-based regimen. Participants from each study were categorized into both adherence quartiles (Q1-Q4) and four strata: at least 95%, 80-94%, 60-79%, and below 60%. Weighted Cox proportional hazard models were used to estimate the risk of virologic failure. The majority of participants (N = 768) had high measured adherence, but those in the lowest adherence quartile had the highest proportion of participants with virologic failure and the risk of virologic failure increased step-wise with adherence below 95%. Detection of minority NNRTI drug resistance mutations increased the proportion of participants with virologic failure across adherence quartiles (Cochran-Mantel-Haenszel P < 0.001) and adherence strata [Cochran-Mantel-Haenszel P < 0.001; <60% adherence, hazard ratio 1.7 (1.1-2.7), P = 0.02; 60-79% adherence, hazard ratio 1.2 (0.5-3.2), P = 0.67; 80-94% adherence, hazard ratio 2.5 (0.98-6.3), P = 0.06; ≥95% adherence, hazard ratio 3.6 (2.3-5.6), P < 0.001]. On multivariate analysis, the effect of minority variants was also most prominent at higher levels of medication adherence. The presence of minority NNRTI resistance mutations and NNRTI adherence were found to be independent predictors of virologic failure, but also modify each other's effects on virologic failure. In addition to the focus on medication adherence counseling, ultrasensitive HIV-1 drug resistance assays could play a role in optimizing the success rates of first-line antiretroviral therapy.
    AIDS (London, England) 01/2012; 26(2):185-92. · 4.91 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. · 3.53 Impact Factor
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    ABSTRACT: Nucleoside and ritonavir (RTV) toxicities have led to increased interest in nucleoside reverse transcriptase inhibitors (NRTIs) and RTV-sparing antiretroviral regimens. SPARTAN was a multicenter, randomized, open-label, noncomparative pilot study evaluating the efficacy, safety, and resistance profile of an investigational NRTI- and RTV-sparing regimen (experimental atazanavir [ATV] dose 300 mg bid + raltegravir [RAL] 400 mg bid [ATV+RAL]). The reference regimen consisted of ATV 300 mg/RTV 100 mg qd + tenofovir (TDF) 300 mg/emtricitabine (FTC) 200 mg qd (ATV/r+TDF/FTC). Treatment-naïve HIV-infected patients with HIV-RNA ≥5,000 copies/mL were randomized 2:1 to receive twice-daily ATV+RAL (n=63) or once-daily ATV/r+TDF/FTC (n=31). Efficacy at 24 weeks was determined by confirmed virologic response (CVR; HIV-RNA <50 copies/mL) with noncom-pleters counted as failures based on all treated subjects. The proportion of patients with CVR HIV RNA <50 copies/mL at week 24 was 74.6% (47/63) in the ATV+RAL arm and 63.3% (19/30) in the ATV/r+TDF/FTC arm. Systemic exposure to ATV in the ATV+RAL regimen was higher than historically observed with ATV/r+TDF/ FTC. Incidence of Grade 4 hyperbilirubinemia was higher on ATV+RAL (20.6%; 13/63) than on ATV/r+TDF/FTC (0%). The criteria for resistance testing (virologic failure [VF]: HIV-RNA ≥400 copies/mL) was met in 6/63 patients on ATV+RAL, and 1/30 on ATV/r+TDF/FTC; 4 VFs on ATV+RAL developed RAL resistance. ATV+RAL, an experimental NRTI- and RTV-sparing regimen, achieved virologic suppression rates comparable to current standards of care for treatment-naïve patients. The overall profile did not appear optimal for further clinical development given its development of resistance to RAL and higher rates of hyperbilirubinemia with twice-daily ATV compared with ATV/RTV.
    HIV Clinical Trials 01/2012; 13(3):119-30. · 2.30 Impact Factor
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    ABSTRACT: Failure of antiretroviral regimens containing elvitegravir (EVG) and raltegravir (RAL) can result in the appearance of integrase inhibitor (INI) drug-resistance mutations (DRMs). While several INI DRMs have been identified, the evolution of EVG DRMs and the linkage of these DRMs with protease inhibitor (PI) and reverse transcriptase inhibitor (RTI) DRMs have not been studied at the clonal level. We examined the development of INI DRMs in 10 patients failing EVG-containing regimens over time, and the linkage of INI DRMs with PI and RTI DRMs in these patients plus 6 RAL-treated patients. A one-step RT-nested PCR protocol was used to generate a 2.7 kB amplicon that included the PR, RT, and IN coding region, and standard cloning and sequencing techniques were used to determine DRMs in 1,277 clones (mean 21 clones per time point). Results showed all patients had multiple PI, NRTI, and/or NNRTI DRMs at baseline, but no primary INI DRM. EVG-treated patients developed from 2 to 6 strains with different primary INI DRMs as early as 2 weeks after initiation of treatment, predominantly as single mutations. The prevalence of these strains fluctuated and new strains, and/or strains with new combinations of INI DRMs, developed over time. Final failure samples (weeks 14 to 48) typically showed a dominant strain with multiple mutations or N155H alone. Single N155H or multiple mutations were also observed in RAL-treated patients at virologic failure. All patient strains showed evidence of INI DRM co-located with single or multiple PI and/or RTI DRMs on the same viral strand. Our study shows that EVG treatment can select for a number of distinct INI-resistant strains whose prevalence fluctuates over time. Continued appearance of new INI DRMs after initial INI failure suggests a potent, highly dynamic selection of INI resistant strains that is unaffected by co-location with PI and RTI DRMs.
    PLoS ONE 01/2012; 7(7):e40514. · 3.53 Impact Factor
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    ABSTRACT: Presence of low-frequency, or minority, human immunodeficiency virus type 1 (HIV-1) drug resistance mutations may adversely affect response to antiretroviral treatment (ART), but evidence regarding the effects of such mutations on the effectiveness of first-line ART is conflicting. To evaluate the association of preexisting drug-resistant HIV-1 minority variants with risk of first-line nonnucleoside reverse transcriptase inhibitor (NNRTI)-based antiretroviral virologic failure. Systematic review of published and unpublished studies in PubMed (1966 through December 2010), EMBASE (1974 through December 2010), conference abstracts, and article references. Authors of all studies were contacted for detailed laboratory, ART, and adherence data. Studies involving ART-naive participants initiating NNRTI-based regimens were included. Participants were included if all drugs in their ART regimen were fully active by standard HIV drug resistance testing. Cox proportional hazard models using pooled patient-level data were used to estimate the risk of virologic failure based on a Prentice weighted case-cohort analysis stratified by study. Individual data from 10 studies and 985 participants were available for the primary analysis. Low-frequency drug resistance mutations were detected in 187 participants, including 117 of 808 patients in the cohort studies. Low-frequency HIV-1 drug resistance mutations were associated with an increased risk of virologic failure (hazard ratio (HR], 2.3 [95% confidence interval {CI}, 1.7-3.3]; P < .001) after controlling for medication adherence, race/ethnicity, baseline CD4 cell count, and plasma HIV-1 RNA levels. Increased risk of virologic failure was most strongly associated with minority variants resistant to NNRTIs (HR, 2.6 [95% CI, 1.9-3.5]; P < .001). Among participants from the cohort studies, 35% of those with detectable minority variants experienced virologic failure compared with 15% of those without minority variants. The presence of minority variants was associated with 2.5 to 3 times the risk of virologic failure at either 95% or greater or less than 95% overall medication adherence. A dose-dependent increased risk of virologic failure was found in participants with a higher proportion or quantity of drug-resistant variants. In a pooled analysis, low-frequency HIV-1 drug resistance mutations, particularly involving NNRTI resistance, were significantly associated with a dose-dependent increased risk of virologic failure with first-line ART.
    JAMA The Journal of the American Medical Association 04/2011; 305(13):1327-35. · 29.98 Impact Factor
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    ABSTRACT: Penicillium marneffei is an important human immunodeficiency virus (HIV)-associated opportunistic pathogen in Southeast Asia. The epidemiology and the predictors of penicilliosis outcome are poorly understood. We performed a retrospective study of culture-confirmed incident penicilliosis admissions during 1996-2009 at the Hospital for Tropical Diseases in Ho Chi Minh City, Viet Nam. Seasonality of penicilliosis was assessed using cosinor models. Logistic regression was used to assess predictors of death or worsening disease based on 10 predefined covariates, and Cox regression was performed to model time-to-antifungal initiation. A total of 795 patients were identified; hospital charts were obtainable for 513 patients (65%). Cases increased exponentially and peaked in 2007 (156 cases), mirroring the trends in AIDS admissions during the study period. A highly significant seasonality for penicilliosis (P<.001) but not for cryptococcosis (P=.63) or AIDS admissions (P=.83) was observed, with a 27% (95% confidence interval, 14%-41%) increase in incidence during rainy months. All patients were HIV infected; the median CD4 cell count (62 patients) was 7 cells/μL (interquartile range, 4-24 cells/μL). Hospital outcome was an improvement in 347 (68%), death in 101 (20%), worsening in 42 (8%), and nonassessable in 23 (5%) cases. Injection drug use, shorter history, absence of fever or skin lesions, elevated respiratory rates, higher lymphocyte count, and lower platelet count independently predicted poor outcome in both complete-case and multiple-imputation analyses. Time-to-treatment initiation was shorter for patients with skin lesions (hazard ratio, 3.78; 95% confidence interval, 2.96-4.84; P<.001). Penicilliosis incidence correlates with the HIV/AIDS epidemic in Viet nam. The number of cases increases during rainy months. Injection drug use, shorter history, absence of fever or skin lesions, respiratory difficulty, higher lymphocyte count, and lower platelet count predict poor in-hospital outcome.
    Clinical Infectious Diseases 04/2011; 52(7):945-52. · 9.37 Impact Factor
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    ABSTRACT: It has been reported that treatment-naive individuals infected with HIV-1 subtype C may be more likely to harbour viral variants possessing a K65R reverse transcriptase gene mutation. The objectives of this study were to determine the prevalence of low-level K65R variants within different HIV-1 subtypes and to assess the effects of antiretroviral exposure on K65R variant levels. Treatment-naive individuals infected with different HIV-1 subtypes were genotyped by ultra-deep sequencing. Samples were evaluated for low-level variants to 0.4% or 1% levels depending upon viral load. Estimated mutational load was calculated by multiplying the percentage of the variant by the plasma viral load. A total of 411 treatment-naive individuals were evaluated by ultra-deep sequencing to 1% levels; 4 subjects (0.97%) had K65R variants at ≥1% or had a very high mutation load. All four subjects had variants with linked drug resistance mutations suggesting transmitted resistant variants. 147 ARV-naive subjects were sequenced to 0.4% levels; 8.8% (13/147) had K65R low-level variants identified: 2.2% (2/92) in subtype B, 35.7% (10/28) in subtype C (P<0.001 for B versus C) and 3.7% (1/27) in non-B/C subtypes. The 13 ARV-naive subjects with K65R variants at <1% received tenofovir plus emtricitabine plus a ritonavir-boosted protease inhibitor (TDF+FTC+PI/r) and 5 subsequently experienced virological failure. There was no enhancement in K65R levels by percentage or mutational load compared to pre-therapy levels. Low-level K65R variants were more frequently identified in subtype C. K65R variants at >1% levels likely represent transmitted resistant variants. The clinical implication of low-level K65R variants below 1% in treatment-naive subjects who receive TDF+FTC+PI/r remains to be determined as the majority are very low-level and did not increase after antiretroviral exposure.
    Antiviral therapy 01/2011; 16(6):925-9. · 3.07 Impact Factor
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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. · 3.53 Impact Factor
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    ABSTRACT: Common symptoms associated with HIV disease and its management are often underrecognized and undertreated. A clinical decision support tool for symptom management was developed within the Veterans Health Administration electronic medical record (EMR), aiming at increasing provider awareness of and response to common HIV symptoms. Its feasibility was studied in March to May 2007 by implementing it within a weekly HIV clinic, comparing a 4-week intervention period with a 4-week control period. Fifty-six patients and their providers participated in the study. Patients' perceptions of providers' awareness of their symptoms, proportion of progress notes mentioning any symptom(s) and proportion of care plans mentioning any symptom(s) were measured. The clinical decision support tool used portable electronic "tablets" to elicit symptom information at the time of check-in, filtered, and organized that information into a concise and clinically relevant EMR note available at the point of care, and facilitated clinical responses to that information. It appeared to be well accepted by patients and providers and did not substantially impact workflow. Although this pilot study was not powered to detect effectiveness, 25 (93%) patients in the intervention group reported that their providers were very aware of their symptoms versus 27 (75%) control patients (p = 0.07). The proportion of providers' notes listing symptoms was similar in both periods; however, there was a trend toward including a greater number of symptoms in intervention period progress notes. The symptom support tool seemed to be useful in clinical HIV care. The Veterans Health Administration EMR may be an effective "laboratory" for developing and testing decision supports.
    AIDS patient care and STDs 07/2009; 23(7):521-9. · 2.68 Impact Factor
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    ABSTRACT: Minor (i.e., <20% prevalence) drug-resistant human immunodeficiency virus (HIV) variants may go undetected, yet be clinically important. To compare the prevalence of drug-resistant variants detected with standard and ultra-deep sequencing (detection down to 1% prevalence) and to determine the impact of minor resistant variants on virologic failure (VF). The Flexible Initial Retrovirus Suppressive Therapies (FIRST) Study (N = 1397) compared 3 initial antiretroviral therapy (ART) strategies. A random subset (n = 491) had baseline testing for drug-resistance mutations performed by use of standard sequencing methods. Ultra-deep sequencing was performed on samples that had sufficient viral content (N = 264). Proportional hazards models were used to compare rates of VF for those who did and did not have mutations identified. Mutations were detected by standard and ultra-deep sequencing (in 14% and 28% of participants, respectively; P < .001). Among individuals who initiated treatment with an ART regimen that combined nucleoside and nonnucleoside reverse-transcriptase inhibitors (hereafter, "NNRTI strategy"), all individuals who had an NNRTI-resistance mutation identified by ultra-deep sequencing experienced VF. When these individuals were compared with individuals who initiated treatment with the NNRTI strategy but who had no NNRTI-resistance mutations, the risk of VF was higher for those who had an NNRTI-resistance mutation detected by both methods (hazard ratio [HR], 12.40 [95% confidence interval {CI}, 3.41-45.10]) and those who had mutation(s) detected only with ultra-deep sequencing (HR, 2.50 [95% CI, 1.17-5.36]). Ultra-deep sequencing identified a significantly larger proportion of HIV-infected, treatment-naive persons as harboring drug-resistant viral variants. Among participants who initiated treatment with the NNRTI strategy, the risk of VF was significantly greater for participants who had low- and high-prevalence NNRTI-resistant variants.
    The Journal of Infectious Diseases 03/2009; 199(5):693-701. · 5.85 Impact Factor
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    ABSTRACT: Raltegravir (RAL) is an HIV integrase inhibitor characterized by potent antiretroviral activity, few adverse effects, and lack of cross-resistance to other antiretroviral (ARV) agents. RAL is emerging as a component of effective alternative ARV therapy for those who experience therapeutic failure or intolerance to reverse transcriptase inhibitors (NRTI and NNRTI) and ritonavir (RTV)-boosted protease inhibitor (PI) containing regimens. The combination of RAL with atazanavir (ATV) without a concomitant NRTI-based backbone or the inclusion of RTV may provide an alternative strategy for those unable to tolerate these latter ARV agents. In this report the authors present a case series of treatment-experienced patients managed with RAL + ATV given without a boosting dose of RTV. All patients tolerated this regimen over a course of 25 to 82 weeks, and had good virologic and immunologic outcome with a decrease in HIV RNA levels to <50 copies/mL and a mean CD4 count increase of 234 cells/mm(3).
    Journal of the International Association of Physicians in AIDS Care (JIAPAC) 03/2009; 8(2):87-92.
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    M J Kozal
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    ABSTRACT: The development of antiretroviral therapy has led to a major reduction in human immunodeficiency virus (HIV)-related mortality. There are now six antiretroviral drug classes, with more than 20 unique antiretroviral drugs. However, HIV drug resistance occurs with all antiretroviral agents. Drug resistance can affect the response to antiretroviral therapy and is associated with increased mortality. The emergence of resistance in persons on antiretroviral therapy and the transmission of drug-resistant HIV strains to newly infected persons are now major public health concerns. Resistant variants that make up as little as 1% of the viral population in an HIV-infected person are clinically important, as they can rapidly grow under drug selection pressure and lead to therapy failure. However, current resistance assays used in the clinic reliably detect resistant variants only if they make up at least 20% of the circulating viral population. Recently, antiretroviral drugs have been developed that can inhibit HIV replication at new sites within the viral life cycle. These new drugs may improve clinical outcomes in persons infected with multidrug-resistant HIV. This review addresses the epidemiology and biological mechanisms of HIV drug resistance and the new approaches to detect and combat HIV drug resistance.
    Clinical Microbiology and Infection 02/2009; 15 Suppl 1:69-73. · 4.58 Impact Factor
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    ABSTRACT: It is largely unknown how frequently low-abundance HIV drug-resistant variants at levels under limit of detection of conventional genotyping (<20% of quasi-species) are present in antiretroviral-experienced persons experiencing virologic failure. Further, the clinical implications of low-abundance drug-resistant variants at time of virologic failure are unknown. Plasma samples from 22 antiretroviral-experienced subjects collected at time of virologic failure (viral load 1380 to 304,000 copies/mL) were obtained from a specimen bank (from 2004-2007). The prevalence and profile of drug-resistant mutations were determined using Sanger sequencing and ultra-deep pyrosequencing. Genotypes were interpreted using Stanford HIV database algorithm. Antiretroviral treatment histories were obtained by chart review and correlated with drug-resistant mutations. Low-abundance drug-resistant mutations were detected in all 22 subjects by deep sequencing and only in 3 subjects by Sanger sequencing. In total they accounted for 90 of 247 mutations (36%) detected by deep sequencing; the majority of these (95%) were not detected by standard genotyping. A mean of 4 additional mutations per subject were detected by deep sequencing (p<0.0001, 95%CI: 2.85-5.53). The additional low-abundance drug-resistant mutations increased a subject's genotypic resistance to one or more antiretrovirals in 17 of 22 subjects (77%). When correlated with subjects' antiretroviral treatment histories, the additional low-abundance drug-resistant mutations correlated with the failing antiretroviral drugs in 21% subjects and correlated with historical antiretroviral use in 79% subjects (OR, 13.73; 95% CI, 2.5-74.3, p = 0.0016). Low-abundance HIV drug-resistant mutations in antiretroviral-experienced subjects at time of virologic failure can increase a subject's overall burden of resistance, yet commonly go unrecognized by conventional genotyping. The majority of unrecognized resistant mutations correlate with historical antiretroviral use. Ultra-deep sequencing can provide important historical resistance information for clinicians when planning subsequent antiretroviral regimens for highly treatment-experienced patients, particularly when their prior treatment histories and longitudinal genotypes are not available.
    PLoS ONE 01/2009; 4(6):e6079. · 3.53 Impact Factor
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    Gustine Liu-Young, Michael J Kozal
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    ABSTRACT: Hepatitis C infection (HCV) remains a global problem and the current anti-HCV therapies available in the clinic have sustained virologic response rates (SVR) of only about 50%, especially in HCV genotype 1-infected subjects. The SVR is even lower in HIV-HCV co-infected patients, estimated at only about 30-40%. However, exciting new research is under way to find new anti-HCV therapies. Presently, efforts to develop new anti-HCV agents for HCV-infected persons who fail pegylated interferon and ribavirin-based therapies have focused on inhibitors of key HCV enzymes such as the HCV NS3 protease and the NS5B polymerase. There are two protease inhibitors, telaprevir (VX-950, Vertex) and boceprevir (SCH 503034, Schering-Plough); and three polymerase inhibitors, valopicitabine (NM283, Idenix), R1626 (Roche), and HCV-796 (Viropharma) that have advanced to late-stage clinical trials. Of these aforementioned agents, telaprevir is the most advanced in clinical development. Early trial results on efficacy, safety, and HCV drug-resistance profiles of these novel agents will be discussed in this review paper.
    AIDS patient care and STDs 07/2008; 22(6):449-57. · 2.68 Impact Factor

Publication Stats

979 Citations
197.28 Total Impact Points

Institutions

  • 2006–2014
    • Yale-New Haven Hospital
      • Infectious Diseases Program
      New Haven, Connecticut, United States
  • 2011–2012
    • Brigham and Women's Hospital
      • Department of Medicine
      Boston, MA, United States
  • 2010–2012
    • Bristol-Myers Squibb
      • Global Development and Medical Affairs (GDMA)
      New York City, New York, United States
  • 2004–2012
    • Yale University
      • • Section of Infectious Diseases
      • • Department of Internal Medicine
      New Haven, Connecticut, United States
  • 2009
    • 454 Life Sciences
      Branford, Connecticut, United States
  • 2005
    • University of Illinois at Chicago
      Chicago, Illinois, United States