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Biomedical subjects

Nancy Shulman

Publications and source records attributed to Nancy Shulman.

5 recordsLinked to original sources
PubMed2005

NNRTI hypersusceptibility.

Hypersusceptibility to the nonnucleoside reverse transcriptase inhibitors (NNRTIs) is a recently described observation in which approximately 30% of HIV isolates with resistance to nucleoside reverse transcriptase inhibitors exhibit greater phenotypic susceptibility to the NNRTI class than does wild-type HIV. This increased susceptibility has been associated with better virologic outcomes in several clinical trials and observational cohorts in which NNRTI-based regimens were used. Nucleoside mutations at positions 215, 208, and 118 are associated with efavirenz hypersusceptibility, but to date, there have been no reported biochemical or structural studies on the effect of these mutations on NNRTI binding or on binding pocket conformational changes. There is currently no basis for the practical use of NNRTI hypersusceptibility to guide HIV therapeutic strategies, but it theoretically could affect the evolution of resistance in antiretroviral-naive patients who begin NNRTIs with various nucleoside backbones.

Alkynes↗
PubMed2003

A review of HIV-1 resistance to the nucleoside and nucleotide inhibitors.

The nucleoside reverse transcriptase inhibitors (NRTIs) were the first class of agents used for the treatment of HIV and remain an important component of combination antiretroviral therapy. Resistance to the NRTIs occurs by the acquisition of mutations in the reverse transcriptase gene that result in a structural change that either decreases the NRTI incorporation into the extending nucleotide chain or enhances removal of the NRTI from the terminated chain, also known as primer unblocking or pyrophosphorylysis. There are several major genetic mutational patterns of resistance and cross-resistance that evolve with the NRTIs including the thymidine analog mutations M41L, D67N, K70R, L210W, T215Y, and K219Q/E/W, the non-thymidine mutations M184V, L74V, and K65R, and the multidrug resistant Q151M complex, as well as others. Increasing knowledge of resistance and cross-resistance patterns that evolve on the NRTIs as well as the other antiretroviral classes will help optimize antiretroviral treatment strategies. Advancing knowledge of the biochemical and structural basis of resistance will aid in the design of newer compounds that are active against HIV resistant to the currently available drugs, ultimately prolonging virologic suppression and life in the millions of people who are infected with HIV.

Drug Resistance, Viral↗
PubMed2002

Virtual inhibitory quotient predicts response to ritonavir boosting of indinavir-based therapy in human immunodeficiency virus-infected patients with ongoing viremia.

Depending on the degree of underlying resistance present, optimization of the pharmacokinetics of protease inhibitors may result in improved virologic suppression. Thirty-seven human immunodeficiency virus (HIV)-infected subjects who had chronic detectable viremia and who were receiving 800 mg of indinavir three times a day (TID) were switched to 400 mg of indinavir BID with 400 mg of ritonavir two times a day (BID) for 48 weeks. Full pharmacokinetic evaluations were obtained for 12 subjects before the switch and 3 weeks after the switch. Combination therapy increased the indinavir predose concentrations in plasma by 6.47-fold, increased the minimum concentration in serum by 3.41-fold, and reduced the maximum concentration in serum by 57% without significantly changing the area under the plasma concentration-time curve at 24 h. At week 3, 58% (21 of 36) of the subjects for whom postbaseline measurements were available achieved a viral load in plasma of <50 copies/ml or a reduction from the baseline load of > or =0.5 log(10) copies/ml. Of these subjects, 82% (14 of 17) whose viruses had three or fewer protease inhibitor mutations and 88% (14 of 16) whose viruses had an indinavir virtual phenotypic susceptibility test of more than sixfold less than that for the baseline isolate were considered virologic responders. The indinavir virtual inhibitory quotient, which is a function of baseline indinavir phenotypic resistance (estimated by virtual phenotype) and the indinavir predose concentration in plasma achieved with indinavir-ritonavir combination therapy, was the best predictor of a viral load reduction. Sixteen subjects discontinued the study by week 48 due to adverse events, predominantly related to hyperlipidemia. Pharmacokinetic intensification of indinavir-based therapy with ritonavir reduced the viral loads in subjects but added toxicity. The virtual inhibitory quotient, which incorporates both baseline viral resistance and the level of drug exposure in plasma, was superior to either baseline resistance or drug exposure alone in predicting the virologic response.

Adult↗
PubMed2002

Evolution of primary protease inhibitor resistance mutations during protease inhibitor salvage therapy.

In order to track the evolution of primary protease inhibitor (PI) resistance mutations in human immunodeficiency virus type 1 (HIV-1) isolates, baseline and follow-up protease sequences were obtained from patients undergoing salvage PI therapy who presented initially with isolates containing a single primary PI resistance mutation. Among 78 patients meeting study selection criteria, baseline primary PI resistance mutations included L90M (42% of patients), V82A/F/T (27%), D30N (21%), G48V (6%), and I84V (4%). Despite the switching of treatment to a new PI, primary PI resistance mutations present at the baseline persisted in 66 of 78 (85%) patients. D30N persisted less frequently than L90M (50% versus 100%, respectively; P < 0.001) and V82A/F/T (50% versus 81%, respectively; P = 0.05). HIV-1 isolates from 38 (49%) patients failing PI salvage therapy developed new primary PI resistance mutations including L90M, I84V, V82A, and G48V. Common combinations of primary and secondary PI resistance mutations after salvage therapy included mutations at amino acid positions 10, 82, and 46 and/or 54 in 16 patients; 10, 90, and 71 and/or 73 in 14 patients; 10, 73, 84, 90, and 46 and/or 54 in 5 patients; 10, 48, and 82 in 5 patients; and 30, 88 and 90 in 5 patients. In summary, during salvage PI therapy, most HIV-1 isolates with a single primary PI resistance mutation maintained their original mutations, and 49% developed additional primary PI resistance mutations. The persistence of L90M, V82A/F/T, G48V, and I84V during salvage therapy suggests that these mutations play a role in clinical resistance to multiple PIs.

Drug Resistance, Microbial↗