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Biomedical subjects

Daniel Kuritzkes

Publications and source records attributed to Daniel Kuritzkes.

12 recordsLinked to original sources
PubMed2005

Safety of enfuvirtide in combination with an optimized background of antiretrovirals in treatment-experienced HIV-1-infected adults over 48 weeks.

BACKGROUND: Antiretroviral tolerability is a critical factor contributing to treatment outcome. The T-20 Versus Optimized Background Regimen Only (TORO) studies assessed the safety and efficacy of enfuvirtide in treatment-experienced HIV-1-infected patients. METHODS: A total of 997 patients were randomized at a 2:1 ratio to an optimized background antiretroviral regimen plus enfuvirtide (n = 663) or an optimized background regimen alone (control group; n = 334). Control patients could switch to enfuvirtide on virologic failure. RESULTS: In total, 26.5% of patients randomized to enfuvirtide and 36.6% to the control group discontinued study treatment before week 48; the percentage of patients withdrawn for safety reasons (including adverse events [AEs], deaths, and laboratory abnormalities) was 14.0% in the enfuvirtide group and 11.6% in the control group. Injection site reactions (ISRs) occurred in 98% of enfuvirtide patients and led to treatment discontinuation in 4.4%. Treatment-related (defined as possibly, probably, or remotely) AE rates per 100 patient-years were lower with enfuvirtide (96.2) than in the control group (149.9); diarrhea, nausea, and fatigue, the most frequently reported AEs, were significantly less frequent with enfuvirtide than in the control group. Pneumonia was significantly more frequent in patients treated with enfuvirtide (6.7 vs. 0.6 events per 100 patient-years), although the incidence was within expected ranges for this population. Lymphadenopathy was also higher in enfuvirtide-treated patients (7.1 vs. 1.2 events per 100 patient-years) for control patients. CONCLUSION: The addition of enfuvirtide to an optimized background regimen does not exacerbate AEs commonly associated with antiretrovirals. ISRs limited treatment in <5% of patients.

Adult↗
PubMed2004

Long-term changes in circulating CD4 T lymphocytes in virologically suppressed patients after 6 years of highly active antiretroviral therapy.

Highly active antiretroviral therapy (HAART) initiated in advanced HIV disease is associated with CD4 lymphocyte increases (200-300 cells/mm3 after 2-4 years), although longer-term cellular dynamics have not been studied. We observed a significant median CD4 lymphocyte increase of 126 cells/mm3 and 54 naive CD4 lymphocytes from year 3 to 6 of HAART among 20 individuals with pre-HAART CD4 cell counts of 100-300 cells/mm3. This cohort represents the longest prospective immunological follow-up of virologically suppressed patients on HAART.

Antiretroviral Therapy, Highly Active↗
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

Immune reconstitution is comparable in antiretroviral-naive subjects after 1 year of successful therapy with a nucleoside reverse-transcriptase inhibitor- or protease inhibitor-containing antiretroviral regimen.

We compared immune restoration in patients who suppressed human immunodeficiency virus type 1 replication after treatment with a protease inhibitor (PI) plus nevirapine or with 3 nucleoside reverse-transcriptase inhibitors (NRTIs) plus nevirapine. Changes in total and memory CD4 and CD8 cells were similar in the groups, as were decreases in immune activation (e.g., CD38 and HLA-DR) and increases in CD28 expression. Increases in naive CD4 and CD8 cells tended to be greater in the NRTI-treated group, with differences in naive CD4 cells significant at weeks 8 and 12 (P<.05) but not at week 48. Lymphocyte apoptosis decreased in both groups, but the week-1 decrease was greater in the PI-treated group (P<.02). Lymphocyte proliferation and skin-test responses were comparable. We find little evidence for differences in the major direct immunologic effect of PI versus NRTI regimens and propose that effects observed elsewhere were indirect, mediated through antiviral activity or adaptation of the virus to selection pressure.

Adult↗
PubMed2003

MDR1 gene polymorphisms and phase 1 viral decay during HIV-1 infection: an adult AIDS Clinical Trials Group study.

Human CD4+ T cells express P-glycoprotein (P-gp), the ATP binding cassette efflux transporter encoded by MDR1. A common MDR1 single-nucleotide polymorphism in exon 26 (C3435T), which is linked to an exon 21 polymorphism (G2677T/A) and reportedly alters expression, has been associated with greater CD4+ T-cell increases during antiretroviral therapy. P-gp overexpression prevents apoptosis and inhibits HIV-1 replication in model systems, suggesting a potential effect on T-cell turnover. This study explored relationships between MDR1 polymorphisms and phase 1 viral decay among 31 HIV-infected individuals initiating antiretroviral therapy. Position 3435 genotypes were CC in 7 (23%), CT in 14 (45%), and TT in 10 (32%). Position 2677 genotypes were GG in 8 (26%), GT in 18 (58%), and TT in 5 (16%). There was no significant relationship between allelic variants in either exon 26 or 21 and phase 1 or phase 2 viral decay, changes in lymphocyte subsets over time, or plasma trough ritonavir concentrations. It is concluded with 95% confidence that phase 1 viral decay differences between exon 26 TT and CC groups are unlikely to exceed 18%.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2003

Adipocyte-derived hormone levels in HIV lipodystrophy.

OBJECTIVE: Despite evidence for the role of adipocyte-derived hormones in insulin resistance, little is known about their levels in human lipodystrophic states. We examined the relationships of plasma leptin and adiponectin levels to fat distribution and insulin sensitivity in the HIV lipodystrophy syndrome. DESIGN: Cross-sectional study SETTING: HIV primary care practices PATIENTS: HIV-infected men with (n=13) and without (12) lipodystrophy and healthy uninfected controls (12). MAIN OUTCOME MEASURES: Plasma adiponectin and leptin levels were measured in the fasting state. Body composition was assessed by physical examination, dual-energy x-ray absorptiometry and computed tomography. Insulin sensitivity (S(I)) was measured using the insulin-modified frequently sampled intravenous glucose tolerance test. RESULTS: Leptin levels were significantly higher in HIV-infected men with lipodystrophy as compared to HIV-infected controls (5.2 vs 3.0 ng/ml, P=0.01). Across the entire study population, leptin levels were positively correlated with measures of general adiposity. In the HIV-infected patients, leptin levels were negatively correlated with S(I) after adjustment for fat mass (r=-0.38, P=0.07). Adiponectin levels were significantly lower in HIV-infected men with lipodystrophy as compared to both HIV-infected and healthy controls (1.6 vs 3.4 microg/ml, P<0.05 and 1.6 vs 6.7 microg/ml, P<0.001, respectively). Adiponectin levels, after adjustment for fat mass, were correlated with measures of fat distribution. Finally, in the HIV-infected patients, adiponectin levels were significantly and positively correlated with S(I) after adjustment for fat mass (r=0.75, P < or = 0.001), and adiponectin level was also an independent determinant of S(I). CONCLUSIONS: Plasma leptin and adiponectin levels are altered in the HIV lipodystrophy syndrome. Adiponectin deficiency may play a role in the insulin resistance associated with HIV lipodystrophy.

Adipocytes↗
PubMed2002

Drug resistance. Navigating resistance pathways.

Treatment failure due to the rise of drug-resistant viral strains remains a serious problem confronting HIV treaters and patients alike. Among patients receiving antiretroviral therapy for HIV infection, new mutations associated with drug resistance continue to emerge, as do new patterns of cross-resistance and multidrug resistance. Drug-resistant HIV variants are now becoming so widespread that an increasing number of patients are experiencing "primary" resistance, having been infected with drug-resistant and sometimes multidrug-resistant strains. Drug-specific resistance mutations, in some cases, show resistance to a number of anti-retroviral drugs in the same class. Recent data have shown that there is more cross-resistance among the nucleoside reverse transcriptase inhibitors than initially thought. The growing complexity of the HIV-1 resistance spectrum calls for more sophisticated testing and clinical expertise, in addition to more effective drugs.

Anti-HIV Agents↗