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(1/330) Molecular mechanisms of resistance: free energy calculations of mutation effects on inhibitor binding to HIV-1 protease.

The changes in the inhibitor binding constants due to the mutation of isoleucine to valine at position 84 of HIV-1 protease are calculated using molecular dynamics simulations. The calculations are done for three potent inhibitors--KNI-272, L-735,524 (indinavir or MK-639), and Ro 31-8959 (saquinavir). The calculations agree with the experimental data both in terms of an overall trend and in the magnitude of the resulting free energy change. HIV-1 protease is a homodimer, so each mutation causes two changes in the enzyme. The decrease in the binding free energy from each mutated side chain differs among the three inhibitors and correlates well with the size of the cavities induced in the protein interior near the mutated residue. The cavities are created as a result of a mutation to a smaller side chain, but the cavities are less than would be predicted from the wild-type structures, indicating that there is significant relaxation to partially fill the cavities.  (+info)

(2/330) Antiviral effect and pharmacokinetic interaction between nevirapine and indinavir in persons infected with human immunodeficiency virus type 1.

Nevirapine and indinavir have the potential of affecting the pharmacokinetics of each other. In a prospective trial, 24 human immunodeficiency virus (HIV)-infected subjects on stable nucleoside or no therapy were treated with 800 mg of indinavir every 8 h. After 7 days, 200 mg of nevirapine a day was added for 14 days and then increased to 200 mg twice a day. At day 7 (before nevirapine), there was a sevenfold difference among the subjects in indinavir area under the curve (AUC), and there was a significant correlation between indinavir AUC (r2=0.378, P=.019), minimum plasma concentration (Cmin; r2=0.359, P=.023), maximum plasma concentration (Cmax; r2=0.340, P=.028), and plasma HIV RNA decline. Nevirapine significantly reduced median indinavir Cmin (47.5%) and AUC (27.4%) and, to a lesser extent, Cmax (11%). Plasma HIV RNA values were +info)

(3/330) Clinical resistance patterns and responses to two sequential protease inhibitor regimens in saquinavir and reverse transcriptase inhibitor-experienced persons.

The efficacy of sequential protease inhibitor therapy was studied in 16 human immunodeficiency virus (HIV) 1-infected persons in whom saquinavir with multiple nucleoside reverse transcriptase (RT) inhibitors (NRTI) had failed. Nelfinavir plus two NRTIs (new or continued) resulted in minimal (0.59 log RNA copies/mL) and transient (8 weeks) suppression of plasma HIV RNA levels. Rapid failure was surprisingly associated with baseline presence of protease gene mutation L90M (P=.04) in the absence of D30N and with RT mutations D67N (P<.01), K70R/S (P=.02), and K219Q/W/R/E (P<.01). Ten patients were subsequently switched to indinavir plus nevirapine and 2 NRTIs, resulting in a median 1.62 log reduction in plasma HIV RNA, with 3 patients maintaining 400 copies/mL for 24 weeks. These results suggest that nelfinavir may have limited utility after saquinavir failure, particularly without potent concomitant therapy. Combining an NRTI with a new protease inhibitor for rescue may improve response.  (+info)

(4/330) Novel four-drug salvage treatment regimens after failure of a human immunodeficiency virus type 1 protease inhibitor-containing regimen: antiviral activity and correlation of baseline phenotypic drug susceptibility with virologic outcome.

Twenty human immunodeficiency virus-infected patients experiencing virologic failure of an indinavir- or ritonavir-containing treatment regimen were evaluated in a prospective, open-label study. Subjects received nelfinavir, saquinavir, abacavir, and either another nucleoside analog (n=10) or nevirapine (n=10). Patients treated with the nevirapine-containing regimen experienced significantly greater virologic suppression at week 24 than those not treated with nevirapine (P=.04). Baseline phenotypic drug susceptibility was strongly correlated with outcome in both treatment arms. Subjects with baseline virus phenotypically sensitive to 2 or 3 drugs in the salvage regimen experienced significantly greater virus load suppression than those with baseline virus sensitive to 0 or 1 drug (median week-24 change=-2.24 log and -0.35 log, respectively; P=.01). In conclusion, non-nucleoside reverse transcriptase inhibitors may represent a potent drug in salvage therapy regimens after failure of an indinavir or ritonavir regimen. Phenotypic resistance testing may provide a useful tool for selecting more effective salvage regimens.  (+info)

(5/330) Cytomegalovirus retinitis after the initiation of highly active antiretroviral therapy: a 2 year prospective study.

BACKGROUND/AIMS: There have been several recent reports suggesting that the natural history of cytomegalovirus retinitis (CMVR) has been significantly modified with the development of highly active antiretroviral therapy (HAART). This 2 year prospective cohort study assesses the effect of HAART on the incidence and progression of CMV retinitis in patients with CD4 cell counts below 50 cells x10(6)/l. METHODS: 63 patients, with CD4 cell counts below 50 cells x10(6)/l, who were recruited to a 2 year prospective cohort study at the commencement of combination antiretroviral therapy including the use of the proteinase inhibitor, indinavir, were reported. The response to HAART was assessed in terms of a rise in the CD4 cell count and fall in HIV viral load. An experienced ophthalmologist performed dilated funduscopy at the time of recruitment and thereafter at 2 weekly intervals and retinal photography was performed at monthly intervals in patients with CMVR. The activity and progression of CMV retinitis was assessed on the basis of the characteristic clinical and photographic findings. RESULTS: 34 patients achieved at least 50 CD4 cells x10(6)/l at 3 months after initiation of therapy. New diagnoses of CMVR were seen only in the non-responder group (p=0. 085). Overall, the relative risk of a new retinitis event in this group was 3.52 (95% CI 1.16, 10.68) at 3 months compared with those patients who were responsive to HAART. 12 of the 63 patients had previous CMVR. Disease progression was associated with non-response to therapy (p=0.182 exact). In patients with CMVR the median time to first progression was 18 days (95% CI 8, 91) in non-responders and 121 days (95% CI 0.59, 3.65) in responders. By the end of the 2 year follow up period all surviving patients had >50 CD4 cells x10(6)/l. No CMV events were seen after 8 months of therapy in either group of patients. CONCLUSIONS: These findings suggest that significant clinical immunorestoration to CMV occurs in response to HAART in patients with CMVR after a lag time of 3-8 months. Initially, a rise in CD4 count is predictive of CMVR response but after the lag period all survivors appear to have developed a clinical immunorestoration to CMV. If HAART is commenced in at risk patients before the development of CMVR the incidence of new disease falls significantly.  (+info)

(6/330) Identification of biased amino acid substitution patterns in human immunodeficiency virus type 1 isolates from patients treated with protease inhibitors.

Human immunodeficiency virus type 1 (HIV-1) amino acid substitutions observed during antiretroviral drug therapy may be caused by drug selection, non-drug-related evolution, or sampling error introduced by the sequencing process. We analyzed HIV-1 sequences from 371 untreated patients and from 178 patients receiving a single protease inhibitor. Amino acid substitution patterns during treatment were compared with inferred substitution patterns arising evolutionarily without treatment. Our results suggest that most treatment-associated amino acid substitutions are caused by selective drug pressure, including substitutions not previously associated with drug resistance.  (+info)

(7/330) Molecular mechanics analysis of drug-resistant mutants of HIV protease.

Drug-resistant mutants of HIV-1 protease limit the long-term effectiveness of current anti-viral therapy. In order to study drug resistance, the wild-type HIV-1 protease and the mutants R8Q, V32I, M46I, V82A, V82I, V82F, I84V, V32I/I84V and M46I/I84V were modeled with the inhibitors saquinavir and indinavir using the program AMMP. A new screen term was introduced to reproduce more correctly the electron distribution of atoms. The atomic partial charge was represented as a delocalized charge distribution instead of a point charge. The calculated protease-saquinavir interaction energies showed the highly significant correlation of 0.79 with free energy differences derived from the measured inhibition constants for all 10 models. Three different protonation states of indinavir were evaluated. The best indinavir model included a sulfate and gave a correlation coefficient of 0.68 between the calculated interaction energies and free energies from inhibition constants for nine models. The exception was R8Q with indinavir, probably due to differences in the solvation energy. No significant correlation was found using the standard molecular mechanics terms. The incorporation of the new screen correction resulted in better prediction of the effects of inhibitors on resistant protease variants and has potential for selecting more effective inhibitors for resistant virus.  (+info)

(8/330) Potent antiretroviral therapy of primary human immunodeficiency virus type 1 (HIV-1) infection: partial normalization of T lymphocyte subsets and limited reduction of HIV-1 DNA despite clearance of plasma viremia.

Antiretroviral therapy commenced during primary human immunodeficiency virus type 1 (HIV-1) infection (PHI) may limit the extent of viral replication and prevent early loss of HIV-specific CD4 lymphocyte function. We studied the effect of current standard therapy (2 nucleoside analogues and a protease inhibitor) in 16 patients with symptomatic PHI. In the 13 patients who completed 1 year of treatment, plasma HIV RNA was <50 copies/mL and median CD4 cell counts were comparable to HIV-uninfected controls, with naive (CD45RA+CD62L+), primed (CD45RO+), and T cell receptor Vbeta subsets all within normal ranges. However, HIV-1 DNA levels in treated and untreated PHI patients were similar. Furthermore, CD8 cell counts remained elevated, including activated (CD38+HLA-DR+), replicating (Ki-67+), and cytotoxic (perforin+CD28-) lymphocytes. In conclusion, early antiretroviral therapy resulted in clearance of viremia and prevented loss of crucial CD4 subsets. The persistence of HIV-1 DNA together with increased CD8 T lymphocyte turnover and activation indicate continued expression of viral antigens.  (+info)