A5031539588- HIV/AIDS drug development and treatment
- HIV Research and Treatment
- HIV/AIDS Research and Interventions
- Pancreatic function and diabetes
- HIV-related health complications and treatments
- Diabetes Management and Research
- Mycobacterium research and diagnosis
- Pneumocystis jirovecii pneumonia detection and treatment
- Cytomegalovirus and herpesvirus research
- T-cell and Retrovirus Studies
- Pharmacological Effects and Toxicity Studies
- Herpesvirus Infections and Treatments
- Cannabis and Cannabinoid Research
- Fatty Acid Research and Health
- Eicosanoids and Hypertension Pharmacology
- Vitamin K Research Studies
- Tuberculosis Research and Epidemiology
- Diabetes and associated disorders
- Lipoproteins and Cardiovascular Health
- Chronic Lymphocytic Leukemia Research
- Parvovirus B19 Infection Studies
- Alcoholism and Thiamine Deficiency
- Hepatitis C virus research
Scientific Consulting Group
2020-2021
Abbott Fund
1998-2003
University of Chicago Medical Center
2003
Abbott (United Kingdom)
1998-2002
Northwestern University
2001
University of Amsterdam
2001
Beth Israel Deaconess Hospital
1991-1998
Harvard University
1983-1998
Beth Israel Deaconess Medical Center
1994-1998
Harvard University Press
1997
Lopinavir is a newly developed inhibitor of human immunodeficiency virus (HIV) protease that, when formulated with ritonavir, yields mean trough plasma lopinavir concentrations that are at least 75 times as high needed to inhibit replication wild-type HIV by 50 percent.
We studied measures of human immunodeficiency virus (HIV) replication, the viral phenotype, and immune function (CD4 cell counts) relation changes in these indicators to clinical outcomes a subgroup patients controlled trial early antiretroviral treatment for HIV, AIDS Clinical Trials Group Study 175.
ABSTRACT The valine at position 82 (Val 82) in the active site of human immunodeficiency virus (HIV) protease mutates response to therapy with inhibitor ritonavir. By using X-ray crystal structure complex HIV and ritonavir, potent ABT-378, which has a diminished interaction Val 82, was designed. ABT-378 potently inhibited wild-type mutant ( K i = 1.3 3.6 pM), blocked replication laboratory clinical strains type 1 (50% effective concentration [EC 50 ], 0.006 0.017 μM), maintained high potency...
To evaluate the safety and antiviral activity of different dose levels HIV protease inhibitor ABT-378 combined with low-dose ritonavir, plus stavudine lamivudine in antiretroviral-naive individuals.Prospective, randomized, double-blind, multicenter.Eligible patients plasma HIV-1 RNA > 5000 copies/ml received 200 or 400 mg ritonavir 100 every 12 h; after 3 weeks 40 150 h were added (group I, n = 32). A second group initiated treatment II, 68).Mean baseline was 4.9 log10 both groups CD4 cell...
ABSTRACT The association of genotypic changes in human immunodeficiency virus (HIV) protease with reduced vitro susceptibility to the new inhibitor lopinavir (previously ABT-378) was explored using a panel viral isolates from subjects failing therapy other inhibitors. Two statistical tests showed that specific mutations at 11 amino acid positions (L10F/I/R/V, K20M/R, L24I, M46I/L, F53L, I54L/T/V, L63P, A71I/L/T/V, V82A/F/T, I84V, and L90M) were associated susceptibility. Mutations 82, 54,...
Objective: To determine markers that are associated with the durability of virologic response to therapy HIV protease inhibitors in HIV-infected individuals. Design: This study encompassed two retrospective analyses duration inhibitor therapy. The first analysis included 29 patients receiving either monotherapy or combination ritonavir whose plasma RNA levels rebounded from point greatest decline mutations resistance ritonavir. second a cohort 102 who initially responded randomized treatment...
Objective: To evaluate the safety and antiretroviral activity of ritonavir (NorvirTM) saquinavir (InviraseTM) combination therapy in patients with HIV infection. Design: A multicenter, randomized, open-label clinical trial. Setting: Seven research units USA Canada. Patients: group 141 adults infection, CD4 T lymphocyte counts 100-500×106 cells/l, whether treated previously or not reverse transcriptase inhibitor therapy, but without previous protease drug therapy. Interventions: After...
Changes in body fat distribution are an adverse effect of therapy with HIV protease inhibitors (PI). It has been suggested that nucleoside analogue reverse transcriptase (NRTI) may also contribute to this so-called lipodystrophy syndrome, but the relative contribution two drug classes is unclear as they usually administered concomitantly.The occurrence lipodystrophy, reported by physicians using no standardized criteria, was followed patients randomly assigned treatment either a PI alone or...
Human immunodeficiency virus (HIV)-1 RNA level in plasma was evaluated as a surrogate marker for disease progression clinical trial of advanced HIV-1 infection. Baseline HIV-l an independent predictor (relative hazard [RH] each doubling level, 1.26; 95% confidence interval [CI], 1.03-1.54; P = .02), after adjusting the week 4 change baseline CD4 cell count, syncytium-inducing phenotype, status at study entry, and therapy randomization. A 50% reduction associated with 27% decrease adjusted...
ABSTRACT The pharmacokinetic interaction between indinavir and ritonavir was evaluated in five groups of healthy adult volunteers to explore the potential for twice-daily (b.i.d.) dosing this combination. All subjects received 800 mg every 8 h (q8h) on day 2. In addition, group I one dose 1 q8h 17. Subjects Groups II IV each 600 days 17, III V 400 During 3 placebo or at 200, 300, q12h given I, II, III, IV, V, respectively. Ritonavir steady state probably inhibited cytochrome P-450 3A...
The safety and antiviral activity of lopinavir (Lpv), a protease inhibitor (PI) coformulated with ritonavir (Rtv) to enhance its pharmacokinetic properties, were evaluated in 70 patients plasma human immunodeficiency virus type 1 (HIV-1) RNA levels 1000–100,000 copies/mL on first PI-containing regimen. Patients randomized substitute only the PI Lpv/Rtv, 400/100 mg or 400/200 twice daily. On day 15, nevirapine (200 2×/day) was added, nucleoside reverse-transcriptase inhibitors changed....
Zidovudine resistance mutations at reverse transcriptase codons 215 or 41 were found in two-thirds of human immunodeficiency virus type 1 (HIV-1) isolates obtained baseline from patients enrolled an AIDS Clinical Trials Group (ACTG) protocol that compared didanosine with continued zidovudine > = 16 weeks previous therapy (ACTG 116B/117). The combined presence both and conferred increased risk for progression (relative hazard, 1.82; 95% confidence interval [CI], 1.02-3.26) death (RH, 5.42;...
Objective: To examine the patterns of vertical transmission zidovudine (ZDV) resistance mutations. Design: HIV-1 reverse transcriptase codons 10–250 were sequenced from 24 pairs ZDV-exposed women and their HIV-infected infants as part Women Infants Transmission Study. Methods: Viral RNA was extracted tissue culture supernatants using fluorescent dye-primer chemistry an automated sequencer. Results: For 17 these pairs, maternal infant sequences identical to one another lacking known ZDV The...
Objectives Although the treatment of pregnant women and their infants with zidovudine (ZDV) has been remarkably effective in preventing perinatal transmission human HIV-1, many potentially preventable infections still occur. To examine whether risk infection is increased among who carry ZDV-resistant role genotypic ZDV resistance was evaluated. Methods The reverse transcriptase (RT) region clinical isolates from culture supernatants 142 HIV-1-infected enrolled Women Infants Transmission...
Islet allotransplantation in the United States (US) is facing an imminent demise. Despite nearly three decades of progress field, archaic regulatory framework has stymied US clinical practice. Current regulations do not reflect state-of-the-art or technical practices. In US, islets are considered biologic drugs and "more than minimally manipulated" human cell tissue products (HCT/Ps). contrast, across world, appropriately defined as "minimally manipulated tissue" regulated a drug, which led...
The association of plasma human immunodeficiency virus type 1 (HIV-1) RNA level at study entry and over time with clinical progression was evaluated in 187 patients from AIDS Clinical Trials Group protocol 116A who had little or no prior zidovudine treatment. Three-fold-higher HIV-1 levels 3-fold increases by week 8 were associated (relative hazard [RH], 1.67; 95% confidence limits [CLl, 1.20,2.32; RH, 1.45; CL, 1.02,2.05, respectively). Having 3-fold-higher CD4 cell count independently a...
A standardized assay in 96-well microtiter plates for syncytium-inducing (SI) human immunodeficiency virus type 1 phenotype detection using MT-2 cells has been developed. SI variants were found 67% of the patients with advanced disease. The occurrence increased lower CD4+ counts. There was no association between p24 antigenemia and phenotype.
A quantitative rapid assay to detect resistant clinical human immunodeficiency virus type 1 (HIV-1) strains remains an important medical goal. system incorporating a RNA.RNA hybridization that measures the amount of intracellular HIV-1-specific RNA has been employed level inhibition by nucleoside analogues in sensitive and HIV-1 strains. The readily distinguished previously published zidovudine (ZDV; 3'-azido-3'-deoxythymidine)-resistant isolates from ZDV-sensitive HIV-1. 50% inhibitory...
Human immunodeficiency virus type 1 (HIV-1) isolates resistant to zidovudine (ZDV) have previously been demonstrated exhibit in vitro cross-resistance other similar dideoxynucleoside agents which contain a 3'-azido group. However, didanosine (ddI) or dideoxycytidine (ddC) has less well documented. ZDV, ddI, and ddC susceptibility data collected from clinical HIV-1 obtained by five centers their respective retrovirology laboratories. All subjects were treated only with ZDV. Clinical isolated,...
Protease inhibitor (PI) therapy for patients infected with the human immunodeficiency virus has been associated lipid disorders and insulin resistance. We compared incidence of myocardial infarction (MI) among participants receiving treatment PIs or without nucleoside reverse transcriptase inhibitors (nRTIs) to nRTI alone in 30 phase II/III double-blind, randomized studies conducted before 1999 first 4 PI drugs. In most trials included this analysis, could receive combination a plus nRTIs...
Summary: A phase-I study was conducted to examine the safety, pharmacokinetics, and activity of combination 2',3'-dideoxyinosine (ddI) ribavirin against human immunodeficiency virus type 1 (HIV-1)-positive individuals with CD4+ cell counts ≤500/μl. Nineteen patients were enrolled into in which ddI monotherapy (200 mg p.o. b.i.d.) administered for first 4 weeks, followed by coadministration (600 q.d.) 8 or 20 additional weeks. The regimen safe well tolerated. Three did not complete 12 weeks...
Virologic measurements are increasingly used to evaluate prognosis and treatment responses in human immunodeficiency virus (HIV) type 1 infection. Markers of HIV-1 replication, including infectious titer from peripheral blood mononuclear cells, serum p24 antigen, plasma RNA, CD4 cell numbers, viral syncytium-inducing (SI) phenotype, were determined 391 virology substudy participants AIDS Clinical Trials Group study 175. The subjects had 200–500 cells/mm3. All markers replication...
Objective To evaluate the effect of treatment with ritonavir (RTV)/saquinavir (SQV)/stavudine (D4T) or RTV/SQV alone, intensification if needed, in protease inhibitor- and D4T-naïve HIV-1-infected individuals. Design Multicentre, open-label, randomized controlled trial. Two-hundred eight patients were to receive RTV 400 mg/SQV mg twice daily mg/D4T 40 daily. Intensification study medication reverse transcriptase inhibitors was permitted serum HIV-RNA remained > copies/ml after 12 weeks...
Human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) displays a characteristic poor processivity during DNA polymerization. Structural elements of RT that determine are poorly understood. The three-dimensional structure HIV-1 RT, which assumes hand-like structure, shows the fingers, palm, and thumb subdomains form template-binding cleft may be involved in determining degree processivity. To assess influence fingers subdomain polymerase processivity, two insertions were...