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Biomedical subjects

Mark Holodniy

Publications and source records attributed to Mark Holodniy.

At least 19 recordsLinked to original sources
PubMed2007

Relationship between antiretroviral prescribing patterns and treatment guidelines in treatment-naive HIV-1-infected US veterans (1992-2004).

OBJECTIVE: To analyze temporal patterns of antiretroviral (ARV) prescribing practices relative to nationally defined guidelines in treatment-naive patients with HIV-1 infection. DESIGN: Retrospective cohort study. METHODS: We evaluated ARV prescribing patterns among ARV treatment-naive veterans who were receiving care within the US Department of Veterans Affairs (VA) from 1992 through 2004 in comparison to evolving adult HIV-1 treatment guidelines. RESULTS: A total of 15,934 patients initiated ARV treatment. Since 1999, >94% of patients initiated at least a 3-ARV medication combination, although the percentage of patients who initiated a guideline "preferred" or "alternative" regimen never rose to greater than 72% and was significantly associated with being black and with region of care. After 1999, 20% of patients started 4 or more active ARV agents in combination, which was significantly associated with lower baseline CD4 cell count, higher viral load, and receiving care in the western United States. The proportion of patients receiving guideline "not recommended" regimens (virologically undesirable or overlapping toxicities) was <1% after 1997. VA prescribing trends generally predated guideline recommendations by 6 to 12 months. CONCLUSIONS: VA prescribing patterns for ARV initiation adhere to treatment guidelines that maximize safety. Guidelines designed to maximize efficacy were not followed as stringently. Evaluating clinical practice patterns against contemporary treatment guidelines can inform guideline development.

Adolescent↗
PubMed2006

HIV-1 load quantitation: a 17-year perspective.

During the past decade and a half, quantitation of plasma-associated human immunodeficiency virus type 1 (HIV-1) RNA level, or HIV-1 load, has been validated in clinical practice and clinical trials as an important surrogate marker of HIV-1 disease progression and of the potency and durability of antiretroviral regimens. This review highlights some of the history, accomplishments, and impact of Tom Merigan's laboratory on the use of HIV-1 load as a marker, as well as on updating technologies for determining HIV-1 load, their performance, interpretation of the results, and their use in clinical practice.

Anti-HIV Agents↗
PubMed2006

Utilization and access to antiretroviral genotypic resistance testing and results within the US Department of Veterans Affairs.

OBJECTIVE: We sought to characterize variation in the use of HIV genotypic resistance tests and how results were reported. METHODS: Clinicians and laboratory managers at all Veterans Affairs (VA) medical centers were asked to complete a survey in March 2003 regarding HIV resistance testing practices. RESULTS: Surveys from 131 of 150 sites were returned. Forty-eight percent of HIV clinicians indicated that US Department of Health and Human Services guidelines were the usual basis for ordering tests. Although between 12% and 31% of respondents indicated that they always, sometimes, seldom, or never ordered resistance tests in patients with acute or chronic HIV infection, >70% ordered tests in adherent patients with treatment failure. Among the 32 centers with >200 patients in care, 13 +/- 8 (mean +/- standard deviation) tests were performed per 100 patients in care during 2002. Forty-nine percent of clinicians said that tests were helpful, but only 33% expressed confidence in using test results. Only 40% of sites entered results in the VA electronic medical record. CONCLUSION: Ordering patterns for HIV resistance tests differed significantly among VA sites. A minority of clinicians indicated confidence in the use of test results. A consistent system to capture and present complete results was absent.

Acquired Immunodeficiency Syndrome↗
PubMed2006

The effect of diagnosis with HIV infection on health-related quality of Life.

We sought to understand how diagnosis with HIV affects health-related quality of life. We assessed health-related quality of life using utility-based measures in a Department of Veterans Affairs (VA) clinic and a University-based clinic. Respondents assessed health-related quality of life regarding their current health, and retrospectively assessed their health 1 month prior to and 2 months after diagnosis with HIV infection. Sixty-six patients completed the study. The overall mean utilities for health 1 month before and 2 months after diagnosis were 0.87 (standard error 0.037), and 0.80 (0.043) (p<0.005 by rank sign test), but the effect of diagnosis differed between the two clinics, with a substantial decrease in the university clinic and a small non-significant decrease in the VA clinic. The overall mean utility for current health was 0.85 (0.034), assessed on average 7.5 years after diagnosis. When asked directly whether diagnosis of HIV decreased health-related quality of life, 47% agreed, but 35% stated that HIV diagnosis positively affected health-related quality of life. Diagnosis with HIV decreased health-related quality of life at 2 months on average, but this effect diminished over time, and differed among patient populations. Years after diagnosis, although half of the patients believed that diagnosis reduced health-related quality of life, one-third reported improved health-related quality of life.

Acquired Immunodeficiency Syndrome↗
PubMed2006

Hepatitis C virus protease gene diversity in patients coinfected with human immunodeficiency virus.

The clonal variability of the hepatitis C virus (HCV) protease gene in 24 individuals with HCV genotypes 1a, 1b, 2b, and 3a who were coinfected with the human immunodeficiency virus was evaluated. Within-genotype variability at the nucleotide and amino acid levels ranged from 6.5 to 8.6% and 2.2 to 3.8%, respectively. After adjustments were made for correlation of intrapatient clonal variation, mixed-model analysis indicated that nucleotide and amino acid variability among patients with different genotypes did not differ significantly. However, within individual patients, clonal variability differed by up to 5.3% and 5.8% at the nucleotide and amino acid levels, respectively, and genotype 1a had significantly greater nucleotide variability than other genotypes (P = 0.01). Significant variability exists within HCV protease gene variants at the patient level and could affect the effectiveness of HCV protease inhibitors.

Adult↗
PubMed2006

Prevention of shingles by varicella zoster virus vaccination.

Herpes zoster is caused by reactivation from previous varicella zoster virus (VZV) infection, and affects millions of people worldwide. It primarily affects older adults and those with immune system dysfunction, most likely as a result of reduced or lost VZV-specific cell-mediated immunity. Complications include post-herpetic neuralgia, a potentially debilitating and chronic pain syndrome. Current treatment of herpes zoster and post-herpetic neuralgia involves antiviral agents and analgesics, and is associated with significant economic cost. Results from several clinical trials have determined that a live, attenuated VZV vaccine using the Oka/Merck strain (Zostavax) is safe, elevates VZV-specific cell-mediated immunity, and significantly reduces the incidence of herpes zoster and post-herpetic neuralgia in people over 60 years of age. Regulatory approval has recently been obtained and once launched, it is expected that this vaccine will significantly reduce the morbidity and financial costs associated with herpes zoster. Durability of vaccine response and possible booster vaccination will still need to be determined.

Aged↗
PubMed2006

The safety and tolerability of Z-100 in patients infected with HIV-1.

Z-100 is an extract of the Mycobacterium tuberculosis strain Aoyama B, which contains various polysaccharides. Aoyama B has previously been shown to induce a T helper 1-type cytokine response in various murine oncological models and has also demonstrated inhibitory activity against HIV-1 in vitro. This multicentre study primarily determined the safety of Z-100 in early HIV-1-infected patients who were treatment naive; were treatment experienced, but had elected to discontinue highly active antiretroviral therapy (HAART) 8 weeks or longer before the study; or were stable on their first or second HAART regimen for at least 12 weeks before the study. Thirty-two individuals participated in this study and self-injected either placebo, 20 microg or 40 microg Z-100 twice a week for 8 weeks. Z-100 was well tolerated and the safety profiles of the Z-100 treatment groups were not meaningfully different compared with the placebo group. Plasma levels of HIV-1 RNA were not statistically significantly different in any treatment group at the end of the treatment period. There were no statistically significant differences among the treatment groups in the change from baseline to week 8 for any of the biological endpoints including plasma levels of HIV-1 RNA; CD4+ and CD8+ T-cell counts; levels of macrophage inflammatory protein 1; soluble tumour necrosis factor receptor 1; C-reactive protein; interleukin-6; and granulocyte colony stimulating factor. Consequently, this trial demonstrates the safety of Z-100 in HIV-1 infected patients without evidence of any activity at the doses administered.

Adult↗
PubMed2005

Accuracy, precision, and consistency of expert HIV type 1 genotype interpretation: an international comparison (The GUESS Study).

BACKGROUND: Resistance testing is considered standard of care in HIV medicine, but there is no standard interpretation system for genotype tests. We sought to determine how much agreement exists within a group of experts in the interpretation of complex genotypes. METHODS: Genotypes from clinical specimens were sent to an international panel of 12 resistance experts. Phenotypic susceptibility testing of these clinical isolates was performed with antivirogram. Experts predicted phenotype fold change category (<2.5-fold change, 2.5-4.0-fold change, >4.0- to 7.0-fold change, >7.0- to 10-fold change, >10- to 20-fold change, or >20-fold change) and predicted expected drug activity for each of 16 antiretroviral drugs. Experts were also asked to make treatment recommendations on the basis of the genotype. RESULTS: The experts predicted the exact phenotype fold change category correctly 44% of the time, but they varied widely by antiretroviral drug (range, 25%-74%). The highest accuracy was observed for lamivudine (74%) and the nonnucleoside reverse transcriptase inhibitors (66%-69%). Experts generally predicted higher levels of resistance to the remaining nucleoside reverse transcriptase inhibitors than what was found by phenotypic testing. Agreement among experts in predicting phenotype fold change category ranged widely depending on the drug (median agreement, 42% [range, 28%-74%]); the same pattern was observed in predicting expected drug activity (median agreement, 45% [range, 32%-87%]). Experts agreed on treatment recommendations in a median of 79% of instances, and recommendations were consistent over time, with blinded retesting. CONCLUSIONS: Although their ability to predict phenotype from a genotype varied for individual antiretroviral drugs, this expert panel had a high degree of agreement in deriving treatment recommendations from the genotype.

Anti-HIV Agents↗
PubMed2005

Cost-effectiveness of screening for HIV in the era of highly active antiretroviral therapy.

BACKGROUND: The costs, benefits, and cost-effectiveness of screening for human immunodeficiency virus (HIV) in health care settings during the era of highly active antiretroviral therapy (HAART) have not been determined. METHODS: We developed a Markov model of costs, quality of life, and survival associated with an HIV-screening program as compared with current practice. In both strategies, symptomatic patients were identified through symptom-based case finding. Identified patients started treatment when their CD4 count dropped to 350 cells per cubic millimeter. Disease progression was defined on the basis of CD4 levels and viral load. The likelihood of sexual transmission was based on viral load, knowledge of HIV status, and efficacy of counseling. RESULTS: Given a 1 percent prevalence of unidentified HIV infection, screening increased life expectancy by 5.48 days, or 4.70 quality-adjusted days, at an estimated cost of 194 dollars per screened patient, for a cost-effectiveness ratio of 15,078 dollars per quality-adjusted life-year. Screening cost less than 50,000 dollars per quality-adjusted life-year if the prevalence of unidentified HIV infection exceeded 0.05 percent. Excluding HIV transmission, the cost-effectiveness of screening was 41,736 dollars per quality-adjusted life-year. Screening every five years, as compared with a one-time screening program, cost 57,138 dollars per quality-adjusted life-year, but was more attractive in settings with a high incidence of infection. Our results were sensitive to the efficacy of behavior modification, the benefit of early identification and therapy, and the prevalence and incidence of HIV infection. CONCLUSIONS: The cost-effectiveness of routine HIV screening in health care settings, even in relatively low-prevalence populations, is similar to that of commonly accepted interventions, and such programs should be expanded.

Adult↗
PubMed2004

Multicenter evaluation of the performance characteristics of the bayer VERSANT HCV RNA 3.0 assay (bDNA).

In this multicenter evaluation, the VERSANT HCV RNA 3.0 Assay (bDNA) (Bayer Diagnostics, Tarrytown, N.Y.) was shown to have excellent reproducibility, linearity, and analytical sensitivity across specimen collection matrices (serum, EDTA, ACD-A), and hepatitis C virus (HCV) genotypes 1 to 6. The VERSANT HCV bDNA Assay has a reportable range of 615 to 7690000 (7.69 x 10(6)) IU/ml. The total coefficient of variation (CV) ranged from 32.4% at 615 IU/ml to 17% at 6.8 x 10(6) IU/ml. The assay was linear across the reportable range. Analytical specificity of 98.8% was determined by testing 999 specimens from volunteer blood donors. Evaluation of HCV genotypes using RNA transcripts of representative clones of 1a, 1b, 2a, 2b, 2c, 3a, 4a, 5a, and 6a and patient specimens showed that the largest difference between genotype 1, upon which the assay is standardized, and non-1 genotypes was within 1.5-fold. Testing of potentially interfering endogenous substances and exogenous substances and conditions found no interference in HCV-positive or HCV-negative specimens except for unconjugated bilirubin at concentrations of >or=20 mg/dl and protein at concentrations of >or=9 g/dl. Biological variability was estimated from 29 clinically stable individuals not on HCV therapy who were tested weekly over an 8-week period. The combined estimate of total (biologic plus assay) variability was 0.15 log(10) standard deviation (CV, 36.1%), a fold change of 2.6. Thus, the observed fold change between any two consecutive HCV RNA measures is expected to be less than 2.6-fold (equivalent to 0.41 log(10) IU/ml) 95% of the time in clinically stable individuals.

Branched DNA Signal Amplification Assay↗
PubMed2003

Inhibition of HIV infectivity by a natural human isolate of Lactobacillus jensenii engineered to express functional two-domain CD4.

The predominant mode of HIV transmission worldwide is via heterosexual contact, with the cervico-vaginal mucosa being the main portal of entry in women. The cervico-vaginal mucosa is naturally colonized with commensal bacteria, primarily lactobacilli. To address the urgent need for female-controlled approaches to block the heterosexual transmission of HIV, we have engineered natural human vaginal isolates of Lactobacillus jensenii to secrete two-domain CD4 (2D CD4) proteins. The secreted 2D CD4 recognized a conformation-dependent anti-CD4 antibody and bound HIV type 1 (HIV-1) gp120, suggesting that the expressed proteins adopted a native conformation. Single-cycle infection assays using HIV-1HxB2 carrying a luciferase reporter gene demonstrated that Lactobacillus-derived 2D CD4 inhibited HIV-1 entry into target cells in a dose-dependent manner. Importantly, coincubation of the engineered bacteria with recombinant HIV-1HxB2 reporter virus led to a significant decrease in virus infectivity of HeLa cells expressing CD4-CXCR4-CCR5. Engineered lactobacilli also caused a modest, but statistically significant, decrease in infectivity of a primary isolate, HIV-1JR-FL. This represents an important first step toward the development of engineered commensal bacteria within the vaginal microflora to inhibit heterosexual transmission of HIV.

Antiviral Agents↗
PubMed2003

High levels of adherence do not prevent accumulation of HIV drug resistance mutations.

OBJECTIVES: To assess the relationship between development of antiretroviral drug resistance and adherence by measured treatment duration, virologic suppression, and the rate of accumulating new drug resistance mutations at different levels of adherence. METHODS: Adherence was measured with unannounced pill counts performed at the participant's usual place of residence in a prospective cohort of HIV-positive urban poor individuals. Two genotypic resistance tests separated by 6 months (G1 and G2) were obtained in individuals on a stable regimen and with detectable viremia (> 50 copies/ml). The primary resistance outcome was the number of new HIV antiretroviral drug resistance mutations occurring over the 6 months between G1 and G2. RESULTS: High levels of adherence were closely associated with greater time on treatment (P < 0.0001) and viral suppression (P < 0.0001) in 148 individuals. In a subset of 57 patients with a plasma viral load > 50 copies/ml on stable therapy, the accumulation of new drug resistance mutations was positively associated with the duration of prior treatment (P = 0.03) and pill count adherence (P = 0.002). Assuming fully suppressed individuals (< 50 copies/ml) do not develop resistance, it was estimated that 23% of all drug resistance occurs in the top quintile of adherence (92-100%), and over 50% of all drug resistance mutations occur in the top two quintiles of adherence (79-100%). CONCLUSION: Increasing rates of viral suppression at high levels of adherence is balanced by increasing rates of drug resistance among viremic patients. Exceptionally high levels of adherence will not prevent population levels of drug resistance.

Adult↗
PubMed2003

An open-label randomized clinical trial of novel therapeutic strategies for HIV-infected patients in whom antiretroviral therapy has failed: rationale and design of the OPTIMA Trial.

OPTIMA (OPTions In Management with Antiretrovirals) is a clinical trial with a factorial randomization to evaluate the hypotheses that mega-antiretroviral therapy (ART) consisting of five or more anti-HIV drugs compared to standard-ART consisting of four or fewer anti-HIV drugs and a 3-month antiretroviral drug-free period (ARDFP) compared to no ARDFP will delay the occurrence of new or recurrent acquired immunodeficiency syndrome events or death, and prove to be more cost-effective in treating human immunodeficiency virus-infected individuals previously exposed to ART drugs from the current three main classes. The aim is to randomize 1,700 participants to four treatment strategy arms: (1) ARDFP+standard-ART; (2) ARDFP+mega-ART; (3) no ARDFP+standard-ART; (4) no ARDFP+mega-ART. The planned study duration is 3.5 years with 2.5 years of intake and a minimum 1 year of follow-up. The OPTIMA Trial was initiated in June 2001 at 30 U.S. Department of Veterans' Affairs hospitals, 22 hospitals in Canada, and 25 hospitals in the United Kingdom. This is the first large-scale, multicenter, randomized controlled trial to compare the relative efficacy of these different therapeutic strategies. We discuss the rationale behind the OPTIMA Trial design as well as the issues arising from the conduct of a trial that involves three national clinical trial agencies.

Adult↗
PubMed2003

Successful management of disseminated Nocardia transvalensis infection in a heart transplant recipient after development of sulfonamide resistance: case report and review.

Nocardia transvalensis is a rarely reported cause of clinically significant disease, and, to our knowledge, has not been reported previously as a cause of infection in the cardiac transplant population. We report a case of N transvalensis new taxon-2 pulmonary infection that disseminated to the brain and skin in a cardiac transplant recipient despite adequate sulfonamide serum levels. Subsequent isolates were resistant to sulfonamides, and molecular ribotyping of the primary and subsequent isolates confirmed that these were the same N transvalensis new taxon-2 strain. The taxonomic and diagnostic considerations, as well as the clinical significance of anti-microbial-resistant nocardia, are reviewed and discussed herein.

Amoxicillin-Potassium Clavulanate Combination↗
PubMed2003

Accuracy of the TRUGENE HIV-1 genotyping kit.

Drug resistance and poor virological responses are associated with well-characterized mutations in the viral reading frames that encode the proteins that are targeted by currently available antiretroviral drugs. An integrated system was developed that includes target gene amplification, DNA sequencing chemistry (TRUGENE HIV-1 Genotyping Kit), and hardware and interpretative software (the OpenGene DNA Sequencing System) for detection of mutations in the human immunodeficiency virus type 1 (HIV-1) protease and reverse transcriptase sequences. The integrated system incorporates reverse transcription-PCR from extracted HIV-1 RNA, a coupled amplification and sequencing step (CLIP), polyacrylamide gel electrophoresis, semiautomated analysis of data, and generation of an interpretative report. To assess the accuracy and robustness of the assay system, 270 coded plasma specimens derived from nine patients were sent to six laboratories for blinded analysis. All specimens contained HIV-1 subtype B viruses. Results of 270 independent assays were compared to "gold standard" consensus sequences of the virus populations determined by sequence analysis of 16 to 20 clones of viral DNA amplicons derived from two independent PCRs using primers not used in the kit. The accuracy of the integrated system for nucleotide base identification was 98.7%, and the accuracy for codon identification at 54 sites associated with drug resistance was 97.6%. In a separate analysis of plasma spiked with infectious molecular clones, the assay reproducibly detected all 72 different drug resistance mutations that were evaluated. There were no significant differences in accuracy between laboratories, between technologists, between kit lots, or between days. This integrated assay system for the detection of HIV-1 drug resistance mutations has a high degree of accuracy and reproducibility in several laboratories.

Anti-HIV Agents↗
PubMed2003

Impact of highly active antiretroviral therapy and immunologic status on hepatitis C virus quasispecies diversity in human immunodeficiency virus/hepatitis C virus-coinfected patients.

This study analyzes the effect of highly active antiretroviral therapy (HAART), and thus immunologic status, on hepatitis C virus (HCV) load and quasispecies diversity in patients coinfected with the human immunodeficiency virus (HIV) and HCV. Three cohorts of coinfected patients were analyzed retrospectively over a period of 7 to 10 months: group A was antiretroviral drug naïve at baseline and then on HAART for the remainder of the study, group B did not receive antiretroviral therapy at any point, and group C was on HAART for the entire study. HCV quasispecies diversity was analyzed by sequencing hypervariable region 1. In a longitudinal analysis, there was no significant change from baseline in any immunologic, virologic, or quasispecies parameter in any of the three groups. However, in comparison to groups A and B, group C had significantly higher CD4+- and CD8+-cell counts, a trend toward a higher HCV load, and significantly increased number of HCV clones, entropy, genetic distance, and ratio of nonsynonymous substitutions per nonsynonymous site to synonymous substitutions per synonymous site (Ka/Ks). In addition, CD4+-cell count was positively correlated with HCV load, genetic distance, and Ka. Interestingly, patients infected with HCV genotype 2 or 3 had a significantly higher CD4+-cell count, HCV load, genetic distance, and Ka/Ks than those infected with genotype 1. These results suggest that there is no immediate effect of HAART on HCV but that, with prolonged HAART, immune restoration results in an increase in HCV load and quasispecies diversity.

Adult↗
PubMed2002

HIV-1 RNA and viral load.

Viral load monitoring has become the standard of care in clinical practice to assess risk for disease progression and to monitor treatment response. Furthermore, viral load monitoring has contributed greatly to the understanding of HIV disease pathogenesis and response to various antiretroviral regimens, and has broadened its applications to include blood bank screening. The assays that are currently available are more sensitive, precise, and robust. There is now a better understanding of their limitations and the clinical scenarios and assay performance issues that result in variations of viral load results.

Disease Progression↗