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Victor DeGruttola

Publications and source records attributed to Victor DeGruttola.

10 recordsLinked to original sources
PubMed2006

Longitudinal analysis of clinical markers following antiretroviral therapy initiated during acute or early HIV type 1 infection.

BACKGROUND: Treatment of acute human immunodeficiency virus type 1 (HIV-1) infection may have unique immunologic, virological, and clinical benefits. However, the timing of treatment, optimal starting regimens, and expected response to therapy have not been defined.Methods. One hundred two subjects treated during acute and early HIV-1 infection were observed prospectively to determine the effect of time elapsed before initiation of therapy on time to virological suppression and absolute CD4+ cell count. Subjects were divided into pre- and postseroconversion groups on the basis of HIV-1 antibody status at the time of initiation of treatment. Absolute CD4+ cell counts were compared between these groups and with those of historical untreated persons who had experienced seroconversion. Potential predictors of time to virological suppression and CD4+ cell count at > or =12 months were assessed. RESULTS: Ninety-nine (97%) of 102 subjects achieved virological suppression. The median time to suppression was 11.1 weeks (95% confidence interval, 9.4-14.9) and was independent of initial regimen. The mean CD4+ cell count at 12 months was 702 cells/mm3 (95% confidence interval, 654-750 cells/mm3) and showed an increasing trend over 60 months. Treated subjects demonstrated a statistically significant gain in the CD4+ cell count, compared with untreated historical control subjects, at > or =12 months. Comparable virological and immunologic outcomes were seen in the pre- and postseroconversion groups. Baseline virus load and nadir CD4+ cell count predicted time to virological suppression and CD4+ cell count at > or =12 months, respectively. CONCLUSIONS: Early treatment of HIV-1 infection is well tolerated and results in rapid and sustained virological suppression. Preservation of CD4+ cell counts may be achieved with early therapy, independent of seroconversion status. Protease inhibitor-based and nonnucleoside reverse-transcriptase inhibitor-based regimens show comparable performance in tolerability, time to virological suppression, and CD4+ cell count when used as a first regimen.

Acquired Immunodeficiency Syndrome↗
PubMed2006

Host immune status and incidence of hepatocellular carcinoma among subjects infected with hepatitis C virus: a nested case-control study in Japan.

A nested case-control study was conducted to examine the association between host immune status, as characterized by serum immune marker levels, and the development of hepatocellular carcinoma (HCC) up to 8 years later in persons with chronic hepatitis C virus (HCV) infection. Cases (n = 39) and matched controls (n = 117) were selected from participants of the Town C HCV Study in Japan between 1996 and 2004 and matched on age at first available sample (+/-1 year), gender, and length of follow-up. Separate analyses were done for each of three serum immune markers: soluble tumor necrosis factor-receptor II (sTNF-R2) and soluble intercellular adhesion molecule-1 (sICAM-1), as indicators of type 1, cell-mediated immune response, and soluble CD30 (sCD30), as an indicator of type 2, humoral immune response. The median concentrations of sTNF-R2, sICAM-1, and sCD30 among controls were 3,170 pg/mL, 305 ng/mL, and 3.0 units/mL, respectively, and were higher among cases (3,870 pg/mL, 372 ng/mL, and 3.3 units/mL, respectively). The risk of developing HCC among subjects with immune marker concentrations above the median levels of the controls was >2-fold greater than among subjects with lower concentrations for all three markers [sTNF-R2: odds ratio (OR), 6.9; 95% confidence interval (95% CI), 2.4-20.5; sICAM-1: OR, 2.0; 95% CI, 0.9-4.1; and sCD30: OR, 2.1; 95% CI, 1.0-4.7]. Simultaneous adjustment for all three markers revealed only sTNF-R2 to be associated with HCC risk (OR, 6.4; 95% CI, 2.0-20.6). Adjustment for alcohol consumption and HCV serotype did not materially alter these associations. Results from this prospective, community-based study suggest that a dysregulation in both type 1-related and type 2-related host immunity contributes to the development of HCV-associated HCC.

Aged↗
PubMed2005

A flexible B-spline model for multiple longitudinal biomarkers and survival.

Often when jointly modeling longitudinal and survival data, we are interested in a multivariate longitudinal measure that may not fit well by linear models. To overcome this problem, we propose a joint longitudinal and survival model that has a nonparametric model for the longitudinal markers. We use cubic B-splines to specify the longitudinal model and a proportional hazards model to link the longitudinal measures to the hazard. To fit the model, we use a Markov chain Monte Carlo algorithm. We select the number of knots for the cubic B-spline model using the Conditional Predictive Ordinate (CPO) and the Deviance Information Criterion (DIC). The method and model selection approach are validated in a simulation. We apply this method to examine the link between viral load, CD4 count, and time to event in data from an AIDS clinical trial. The cubic B-spline model provides a good fit to the longitudinal data that could not be obtained with simple parametric models.

Acquired Immunodeficiency Syndrome↗
PubMed2004

Immunophenotypic markers and antiretroviral therapy (IMART): T cell activation and maturation help predict treatment response.

To determine whether markers of T cell activation and maturation are independently predictive of the response to potent antiretroviral therapy, the Immunophenotypic Markers and Antiretroviral Therapy study applied a novel data-sharing strategy across 5 Adult AIDS Clinical Trial Group trials that counted naive and activated CD4(+) and CD8(+) T cells in 324 subjects. Regression models--adjustment for baseline CD4 cell count, human immunodeficiency virus (HIV) RNA, and study--revealed that high pretreatment CD8(+) T cell activation predicted virologic failure (P=.046). Additional models showed the greatest increase in CD4(+) T cell counts in subjects with highest pretreatment naive CD4(+) T cell counts (P<.0001), which was enhanced by high CD4(+) and low CD8(+) T cell activation. Total lymphocyte count also predicted a subsequent CD4(+) T cell change. These results document the utility of T cell markers in predicting treatment outcome and their potential value for the study and management of HIV-1 infection.

Adult↗
PubMed2004

Clinically validated genotype analysis: guiding principles and statistical concerns.

Whereas previously the output of HIV resistance tests has been based on therapeutically arbitrary criteria, there is now an ongoing move towards correlating test interpretation with virological outcomes on treatment. This approach is undeniably superior, in principle, for tests intended to guide drug choices. However the predictive accuracy of a given stratagem that links genotype or phenotype to drug response is strongly influenced by the study design, data capture and analytical methodology used to derive it. For genotyping, the most widely used resistance tool in clinical practice, these considerations are further complicated by the range of mutational patterns present in the treated population. There is no definitively superior methodology for generating a genotype-response association for use in interpreting a resistance test, and the various approaches used to date all have their strengths and weaknesses. This review discusses the processes involved in constructing such tools, with particular emphasis on establishing validated mutation score rules, and examines the key issues and confounding factors that influence predictive accuracy outside the originating dataset. Since the size of the sample is a key influence on the statistical power to determine an effect, it is hoped that a greater understanding of the influence of study design and methodology will assist the development of standardized outcome measures and reporting formats that allow data pooling at the international level.

Anti-HIV Agents↗
PubMed2003

Assessing resistance costs of antiretroviral therapies via measures of future drug options.

The emergence of drug-resistant human immunodeficiency virus (HIV) type 1 in the setting of antiretroviral therapy failure limits the number of drugs available for use in subsequent therapy regimens. To quantify the relative HIV-1-resistance costs associated with various antiretroviral therapy strategies, we developed 2 related measures of future drug options (FDOs) by use of rule-based genotype-interpretation systems. The FDO1 metric assesses the number of drug classes that remain useful; the FDO2 metric assesses the number of drug classes that remain useful and the number of active drugs within each class. Application of these methods is illustrated with data from a randomized study of 3 therapy regimens in nucleoside analog-experienced patients. Each therapy regimen resulted in a unique pattern of drug-resistance (and cross-resistance) mutations. The regimen with the highest virologic failure rate preserved greater future drug options. Quantification of future drug options as an outcome of antiretroviral therapy trials may complement traditional clinical, virologic, and immunologic end points, thereby providing novel insights.

Anti-HIV Agents↗
PubMed2003

Non-parametric methods to predict HIV drug susceptibility phenotype from genotype.

Medical management of HIV infection requires an understanding of the relationship between viral genetic sequences and viral susceptibility to antiretroviral drugs. Because of the high dimensionality of the data on viral genotype, traditional statistical methods are not well suited for investigating this relationship. We develop non-parametric methods specifically for the setting where high-dimensional data provides a basis for predicting a low-dimensional response variable. Our non-recursive methods proceed in three stages: (i) build models, in a forward-stepwise manner, that predict phenotype response from genotype sequence; (ii) identify specific patterns of amino acid sequence that are most influential in predicting phenotype, and (iii) identify combinations of codons that have either a concordant or a discordant association in the occurrence of a mutation. The methods are applied to a data set provided by the Virco Group that contains protease genome sequences and IC50 measurements on a drug from the protease inhibitor class, amprenavir, for 2747 patient samples. From these methods, we were able to identify eight codons from the protease region of the HIV genome that predict resistance to amprenavir, and to determine pairs of codons that tend either to occur together or to preclude the occurrence of the other member of the pair.

Anti-HIV Agents↗
PubMed2003

Design and analysis of clinical trials with a bivariate failure time endpoint, with application to AIDS Clinical Trials Group Study A5142.

This paper investigates the use of a bivariate endpoint in clinical trials of antiretroviral drugs to treat infection with the HIV. While they provide the most reliable information about treatment effects, clinical events such AIDS or death are relatively rare among newly treated patients with HIV infection. As a result, surrogate endpoints, such as time to virological failure and time to regimen termination, are generally used in place of clinical endpoints in studies that enroll patients without previous treatment experience. Because no surrogate endpoint has been completely validated (i.e., shown to capture the full effect of treatment on clinical endpoint), it may be preferable to base treatment decisions on more than one surrogate. In this paper, we consider the bivariate endpoint of time to virological failure and time to regimen termination. Analysis of a bivariate endpoint requires appropriate statistical methods that maintain the experimentwise type I error rate when making simultaneous inference with respect to each endpoint. This article outlines such methods and compares their small sample properties using the simulation study that was executed for the purpose of designing a current AIDS clinical trial.

Anti-HIV Agents↗
PubMed2002

Dual vs single protease inhibitor therapy following antiretroviral treatment failure: a randomized trial.

CONTEXT: Management of antiretroviral treatment failure in patients receiving protease inhibitor (PI)-containing regimens is a therapeutic challenge. OBJECTIVE: To assess whether adding a second PI improves antiviral efficacy of a 4-drug combination in patients with virologic failure while taking a PI-containing regimen. DESIGN: Multicenter, randomized, 4-arm trial, double-blind and placebo-controlled for second PI, conducted between October 1998 and April 2000, for which there was a 24-week primary analysis with extension to 48 weeks. SETTING: Thirty-one participating AIDS (acquired immunodeficiency syndrome) Clinical Trials Units in the United States. PARTICIPANTS: A total of 481 human immunodeficiency virus (HIV)-infected persons with prior exposure to a maximum of 3 PIs and viral load above 1000 copies/mL. INTERVENTION: Selectively randomized assignment (per prior PI exposure) to saquinavir (n = 116); indinavir (n = 69); nelfinavir (n = 139); or placebo twice per day (n = 157); in combination with amprenavir, abacavir, efavirenz, and adefovir dipivoxil. MAIN OUTCOME MEASURES: Primary efficacy analysis involved the proportion with viral load below 200 copies/mL at 24 weeks. Other measures were changes in viral load and CD4 cell count from baseline, adverse events, and HIV drug susceptibility. RESULTS: Of 481 patients, 148 (31%) had a viral load below 200 copies/mL at week 24. The proportions of patients with a viral load below 200 copies/mL in the saquinavir, indinavir, nelfinavir, and placebo arms were 34% (40/116), 36% (25/69), 34% (47/139), and 23% (36/157), respectively. The proportion in the combined dual-PI arms was higher than in the amprenavir-plus-placebo arm (35% [112/324] vs 23% [36/157], respectively; P =.002). Overall, a higher proportion of nonnucleoside reverse transcriptase inhibitor (NNRTI)-naive patients had a viral load below 200 copies/mL compared with NNRTI-experienced patients (43% [115/270] vs 16% [33/211], respectively; P<.001). Baseline HIV-1 hypersusceptibility to efavirenz (< or = 0.4-fold difference in susceptibility compared with reference virus) was associated with suppression of viral load at 24 weeks to below 200 copies/mL (odds ratio [OR], 3.49; 95% confidence interval [CI], 1.62-7.33; P =.001), and more than 10-fold reduction in efavirenz susceptibility, with less likelihood of suppression at 24 weeks (OR, 0.28; 95% CI, 0.09-0.87; P =.03). CONCLUSIONS: In this study of antiretroviral-experienced patients with advanced immunodeficiency, viral load suppression to below 200 copies/mL was achieved in 31% of patients with regimens containing 4 or 5 new drugs. Use of 2 PIs, being naive to NNRTIs, and baseline hypersusceptibility to efavirenz were associated with a favorable outcome.

Adenine↗