Formal Alliances, 1816-1965: an Extension of the Basic Data

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/69121/2/10.1177_002234336900600305.pd

Durability of response to treatment among antiretroviral-experienced subjects: 48-week results from AIDS Clinical Trials Group Protocol 359

The 24-week extension of AIDS Clinical Trials Group Protocol 359, a study of human immunodeficiency virus (HIV)-infected, indinavir-experienced patients, was designed to study the durability of "salvage" treatment regimens. Patients received saquinavir in combination with either ritonavir or nelfinavir and, in addition, delavirdine, adefovir, or both. Patients who demonstrated a virologic response at weeks 12-16 were eligible to continue therapy in the extension through week 48. Of the 105 eligible subjects who were enrolled in the extension, 86 (82%) completed 48 weeks, and 49 (57%) of those 86 had HIV RNA levels <or=500 copies/mL at week 48. For these 86 subjects who completed 48 weeks, the median change in CD4 cell count from baseline was +72 cells/mm(3). Greater body weight, higher CD4 cell count, and greater degree of phenotypic susceptibility to indinavir and saquinavir at baseline were significantly associated with durable virologic suppression. These results show that some patients who experience treatment failure can demonstrate durable virologic and immunologic responses with salvage antiretroviral regimens

Pharmacogenetics of plasma efavirenz exposure after treatment discontinuation: an Adult AIDS Clinical Trials Group Study

Efavirenz has a long plasma half-life and a low genetic barrier to resistance. Simultaneously stopping treatment with all agents in efavirenz-containing regimens may result in functional efavirenz monotherapy that selects for drug-resistant human immunodeficiency virus type 1. Lower plasma efavirenz clearance is associated with a cytochrome P450 2B6 gene (CYP2B6) polymorphism (516G--&gt;T) that is more frequent among African American individuals than among European American individuals.; We characterized relationships between this polymorphism and predicted plasma efavirenz concentration-time profiles after discontinuation of therapy with use of data obtained from subjects receiving therapy. Pharmacokinetic parameters were estimated using population-based methods. Concentrations after discontinuation of therapy were predicted from subject-specific estimates. RESULTS. Median estimated efavirenz half-lives were 23, 27, and 48 h for patients with CYP2B6 position 516 GG (78 patients), GT (60), and TT (14) genotypes, respectively (P&lt;.001). After therapy was stopped, plasma efavirenz concentrations in patients with GG, GT, and TT genotypes were predicted to exceed 46.7 ng/mL (the estimated protein-adjusted 95% inhibitory concentration for wild-type virus) for a median of 5.8 days (interquartile range [IQR], 4.4-8.3 days), 7.0 days (IQR, 5.0-8.0 days), and 14 days (IQR, 11.1-21.2 days), respectively (P&lt;.001). Plasma efavirenz levels were predicted to exceed 46.7 ng/mL for &gt;21 days in 5% of subjects with GG genotype, 5% of subjects with GT genotype, and 29% of subjects with TT genotype.; The CYP2B6 position 516 TT genotype or a prolonged measured elimination half-life may predict increased risk of developing drug resistance among patients who discontinue efavirenz-containing regimens. This has implications for strategies to safely discontinue antiretroviral regimens while avoiding the emergence of drug resistance

The major genetic determinants of HIV-1 control affect HLA class I peptide presentation.

Infectious and inflammatory diseases have repeatedly shown strong genetic associations within the major histocompatibility complex (MHC); however, the basis for these associations remains elusive. To define host genetic effects on the outcome of a chronic viral infection, we performed genome-wide association analysis in a multiethnic cohort of HIV-1 controllers and progressors, and we analyzed the effects of individual amino acids within the classical human leukocyte antigen (HLA) proteins. We identified &gt;300 genome-wide significant single-nucleotide polymorphisms (SNPs) within the MHC and none elsewhere. Specific amino acids in the HLA-B peptide binding groove, as well as an independent HLA-C effect, explain the SNP associations and reconcile both protective and risk HLA alleles. These results implicate the nature of the HLA-viral peptide interaction as the major factor modulating durable control of HIV infection