Biomedical subjects

J M Schapiro

Publications and source records attributed to J M Schapiro.

At least 19 recordsLinked to original sources

PubMed2006

Hepatitis C at the israeli national hemophilia center.

Haemophilia patients who received non-virucidally treated large pool clotting factors before 1987 have a high rate of chronic hepatitis C viral infection (HCV). Some patients are coinfected with HIV. Haemophilia patients and other coagulation disorders were treated at one centre since the beginning of the 1970, and the Israeli National Hemophilia Center (INHC) was officially founded in 1987. To characterize patients with HCV as well as patients with HCV/HIV coinfection at the INHC. Patients with haemophilia and other coagulation disorders positive for HCV antibodies were evaluated between 2001 and 2004. Demographic data, type and severity of coagulation disorder, frequency of coagulation factor usage and treatment with concentrated clotting factors prior to 1987 were recorded. Liver enzymes, viral load, genotype and data supporting advanced liver disease were evaluated. About 179 of 239 haemophilia patients (75%) tested positive for anti-HCV antibodies. Our cohort consisted of 165 patients in whom clinical, biochemical and virological data were available. About 117 patients had active HCV infection with HCV-RNA-positive, and 27 were HCV/HIV coinfected. Twenty-one patients (13%) persistently tested HCV-RNA-negative, hence were considered to clear their HCV infection. There was no former USSR immigrants among HCV/HIV coinfected compared with HCV-infected or HCV-RNA-negative groups (0 vs. 30% and 38%, respectively; P < 0.001). HCV-RNA-negative patients used concentrated coagulation factor less frequently than HCV or HCV/HIV-infected patients (48% vs. 73%; P = 0.023, and 48% vs. 74%; P = 0.043, respectively). The use of concentrated clotting factors before 1987 was significantly more frequent in HCV/HIV than in either HCV-infected or HCV-RNA-negative patients (96% vs. 49% and 48%, respectively; P < 0.001). Compared with HCV/HIV subjects, patients with HCV monoinfection were characterized by a higher proportion of infection with genotype 1 (80% vs. 61%; P = 0.027). The rate of persistently normal liver enzymes in these patients was higher (24% vs. 7%; P = 0.05) than in the HCV/HIV-coinfected patients. Advanced liver disease was significantly more common in patients with HCV/HIV-coinfection than in HCV-monoinfected patients (11% vs. 3%; P = 0.045). The majority of haemophilia patients are infected with HCV. Viral clearance occurred in a minority of these patients. HCV monoinfected and HCV/HIV coinfected differ clinically and prognostically.

Adolescent↗

PubMed2006

Non-invasive biomarkers of liver fibrosis in haemophilia patients with hepatitis C: can you avoid liver biopsy?

Liver biopsy remains the gold standard for the evaluation of fibrosis despite its risks and limitations, especially in haemophilia patients. Recently, non-invasive biomarkers have been used to assess histological features. The most thoroughly evaluated biomarker is the FibroTest (FT) (AUROC 0.80 for fibrosis stages F2F3F4 vs. F0F1). To estimate liver fibrosis in haemophilia patients infected with hepatitis C (HCV) using non-invasive biomarkers without liver biopsy. One hundred and thirty-two haemophilia patients (124 male, mean age 38 +/- 14 years) with anti-HCV antibodies were evaluated. These patients were stratified into several groups: patients with features of advanced liver disease - seven, persistently HCV RNA-negative - 21, persistently normal liver function tests (LFTs)- 24, HCV/HIV co-infected - 27. The following biomarkers of fibrosis were used: FT, AST-to-platelet ratio index (APRI), Forns index, age-platelet index and hyaluronic acid. The obtained scores were correlated with the clinical features of the patients. Estimated by the FT, the distribution of the stage of fibrosis in the 132 patients was F0F1 = 65% (86/132), F2 = 5% (7/132), F3 = 13% (17/132) and F4 = 17% (22/132). Using FT, all patients with clinical suspicion of advanced liver disease were classified as F3F4, whereas patients with persistently HCV RNA-negative were all classified as F0F1. Twenty-one per cent (5/24) of the patients with persistently normal LFTs had fibrosis stage F3F4. The proportion of F3F4 among HCV/HIV co-infected patients was significantly higher than among HCV mono-infected (52% vs. 33%; P = 0.05). Concordance of three or more biomarkers was present in 43% (57/132) of the patients. Liver biopsy could be avoided in 70% (92/132) using a practical assumption that if FT is in concordance with APRI and/or Forns, then we may confidently rely on the biomarker. Concordance rate for patients with presumably advanced or minimal liver disease was excellent (100% and 95% respectively). In our HCV-infected haemophilia patients, FT correctly identified clinically advanced or minimal liver disease. Discordance among the various biomarkers of fibrosis was considerate; nevertheless, practical combination of FT, APRI, and Forns may predict stage of fibrosis with accuracy, potentially avoiding liver biopsy in the majority of the patients.

Adult↗

PubMed2004

Drug-resistant HIV infection among drug-naive patients in Israel.

BACKGROUND: In Israel, <0.06% of the general population is infected with human immunodeficiency virus (HIV), with a much higher prevalence among specific groups. These groups are distinguished demographically by risk behavior category and by virus subtype. We investigated transmission of drug resistance within groups to assess the impact of these factors. METHODS: Plasma samples from >15% of all patients with new diagnoses of HIV infection were randomly collected between June 1999 and June 2003. Sequences from 176 drug-naive patients included 20 of subtype A, 20 of subtype AE, 2 of subtype AC, 29 of subtype B, 100 of subtype C, and 5 of subtype F. RESULTS: Major drug resistance mutations (protease: L90M; reverse transcriptase: M41L, K103N, V106M, M184V, Y181S, G190A, L210W, T215Y/F, and K219R) were detected in 1 subject with A subtype, 3 with subtype B, and 9 with subtype C. In addition, 1 subject with A subtypes, 2 with subtype B, and 10 with subtype C had secondary mutations (protease: M46I; reverse transcriptase: A98G, K101Q, and V108I). Only 1 patient had mutations associated with >1 class of drugs. Among subjects who contracted HIV infection in Israel, 16 of 56 (1 of 7 with subtypes A or AE, 4 of 17 with subtype B, and 11 of 32 with subtype C; P=.7-1.0) carried resistant virus--a significantly higher proportion (P<.001) than in subjects infected in other countries (10 of 120 infected). CONCLUSIONS: Drug-resistant virus was detected in 14.8% of patients with new diagnoses of HIV infection but in 28.6% of patients known to have been infected in Israel. The implications include a need for pretreatment resistance testing and for better programs aimed at prevention of transmission, directed particularly at patients. We did not find significant differences in transmission of resistant virus between those infected with subtypes B and C, despite the different demographic background. A conclusive analysis and interpretation should await a more extensive study.

Adult↗

PubMed2001

Genotypic variation of HIV-1 reverse transcriptase and protease: comparative analysis of clade C and clade B.

OBJECTIVE: To compare drug-resistant variants from untreated (naive) and treated patients infected with clade B or C virus. METHODS: Consecutive samples (165) from patients throughout Israel were analyzed. All those in the treated group were failing highly active antiretroviral therapy. RESULTS: There were 87 clade B (14 naive) and 78 clade C (20 naive) [corrected] with significant differences in the prevalence of known drug-resistance mutations between the clades: in naive patients in the protease region M36I 7% and 95% (P < 0.0001), K20R 0% and 27% (P = 0.063), A71V 18% and 0% (P = 0.063), M46I 0% and 13%, and V77I 18% and 0% (P = 0.063), respectively, and in the reverse transcriptase region A98G/S 0% and 20% (P = 0.12), respectively. Most clade C viruses also showed significant differences from clade B consensus sequence at additional protease sites: R41K 100%, H69K/Q 85%, L89M 95% and I93L 80% (P < 0.0001). There were also significant differences (P < 0.03 to < 0.0001) in treated patients in clades B and C: in the protease region L10I 40% and 12%, M36I 26% and 95%, L63P 67% and 40%, A71I 38% and 7%, G73I and V77I 18% and 0%, I84V 16% and 3%, and L90M 40% and 12%, respectively; in the reverse transcriptase M41L 41% and 17%, D67N 41% and12%, K70R 30% and 7%, T215Y 48% and 29%, K219Q 21% and 7%, and A98G/S 3% and 24%, respectively. CONCLUSION: Significantly differences between clade B and C viruses may be associated with development of differing resistance patterns during therapy and may affect drug utility in patients infected with clade C.

Adolescent↗

PubMed2001

Human Immunodeficiency Virus Reverse Transcriptase and Protease Sequence Database: an expanded data model integrating natural language text and sequence analysis programs.

The HIV Reverse Transcriptase and Protease Sequence Database is an on-line relational database that catalogs evolutionary and drug-related sequence variation in the human immunodeficiency virus (HIV) reverse transcriptase (RT) and protease enzymes, the molecular targets of anti-HIV therapy (http://hivdb.stanford.edu). The database contains a compilation of nearly all published HIV RT and protease sequences, including submissions from International Collaboration databases and sequences published in journal articles. Sequences are linked to data about the source of the sequence sample and the antiretroviral drug treatment history of the individual from whom the isolate was obtained. During the past year 3500 sequences have been added and the data model has been expanded to include drug susceptibility data on sequenced isolates. Database content has also been integrated with didactic text and the output of two sequence analysis programs.

Amino Acid Sequence↗

PubMed2001

Acral purpuric plaques in a woman with asthma: a case of allergic granulomatosis angiitis.

Allergic granulomatosis angiitis (AGA) is a rare systemic vasculitis of unknown etiology. Most patients are adults in their third to fourth decade of life. The combination of asthma, eosinophilia, and necrotizing vasculitis is almost invariably present. Cutaneous lesions are found in up to 70% of the patients and include nodules, hemorrhagic lesions, and erythema multiformelike lesions. We provide a case report of a 30-year-old woman with asthma who presented with acral purpuric plaques and was diagnosed with AGA.

Adult↗

PubMed2001

Understanding protease inhibitor potency: the intersection of exposure, efficacy, and resistance.

Prescribing antiretrovirals has become increasingly complex, not only because of the expanding armamentarium but also because the tools available to measure different aspects of drug efficacy are complicated and interrelated. Potency cannot be viewed as a single unit of data, such as inhibitory concentration, and viral susceptibility to a drug cannot be viewed as a binary choice between "sensitive" and "resistant." Rather, both potency and resistance are continums, and attempts to quantify them in simple terms are often misleading. At the same time, potency and resistance must be considered pieces of a more complex puzzle that also involves drug exposure, metabolism, and pharmacokinetics. Appraising all of these factors simultaneously is difficult but necessary for the optimal care of people with HIV infection.

Drug Resistance, Microbial↗

PubMed2000

Importance of protease inhibitor plasma levels in HIV-infected patients treated with genotypic-guided therapy: pharmacological data from the Viradapt Study.

OBJECTIVE: In a prospective randomized study, the impact of plasma protease inhibitor (PI) trough levels on changes in HIV RNA were assessed in patients treated with genotypic-guided therapy. METHODS: Patients failing combination therapy (HIV-1 RNA > 10,000 copies/ml, and at least 6 months of therapy with nucleoside analogues and 3 months with PI) were randomly assigned into two arms: control group (C) in which the treatment was modified according to the standard of care; genotypic group (G) in which the treatment was modified according to resistance mutation profiles. Serial PI plasma levels were performed in patients throughout the 12 month study. PI levels were determined by high performance liquid chromatography. 'Suboptimal' concentration (SOC) was defined as at least two PI plasma levels below 2 x IC95. Others were defined as 'optimal' concentration (OC). Patients were categorized into four groups: G1 (SOC/control); G2 (OC/control); G3 (SOC/genotype); G4 (OC/genotype). An intent-to-treat analysis was performed with viral load as the primary endpoint. RESULTS: A total of 81 patients [mean age 39.7 +/- 8 years, 59 men, 52.7% Centers for Disease Control and Prevention (CDC) stage C] were included in the pharmacological substudy. The two groups according to randomization arms were comparable in terms of risk factor, age, sex, previous treatments, baseline CD4 cell count, HIV-1 RNA and mean PI plasma concentrations. Linear regression analysis showed a significant relationship between PI concentration and HIV RNA in the plasma. OC and SOC were found in 67.9% (55/81) and 32.1% (26/81) of patients, respectively. Mean changes in HIV RNA from baseline at month 6 were: -0.23 +/- 0.29 log10 copies/ml (G1); -0.97 +/- 0.28 (G2); -0.68 +/- 0.37 (G3); -1.38 +/- 0.20 (G4). Multivariate analysis showed PI plasma concentrations to be an independent predictor of HIV-RNA evolution (P = 0.017). CONCLUSION: Multiple parameters determine the response to antiretroviral therapy and causes other than the development of drug resistance should be considered in the setting of therapeutic failure. Suboptimal concentrations of PI limit the response to antiretroviral therapy. Therapeutic drug monitoring of the PI plasma concentration may therefore prove useful in optimizing antiretroviral therapy.

Adult↗

PubMed2000

Methods for investigation of the relationship between drug-susceptibility phenotype and human immunodeficiency virus type 1 genotype with applications to AIDS clinical trials group 333.

Use of human immunodeficiency virus (HIV) drug-resistance testing in therapeutic decision making may be aided by understanding the relationship between results of genotypic and drug-susceptibility phenotypic assays. We investigated this relationship by applying 3 different statistical methods-cluster analysis, recursive partitioning, and linear discriminant analysis-to results for 72 patients followed in the Adult AIDS Clinical Trials Group (ACTG) protocol 333. ACTG 333 was a multicenter, randomized trial comparing 2 formulations of saquinavir (SQV) to indinavir (IDV) in patients with extensive hard-gel SQV experience. Data include protease amino acid sequences and 50% inhibitory concentrations for SQV and IDV at baseline. The 3 methods give similar results showing the association of mutations at codons 10, 63, 71, and 90 with in vitro resistance to IDV and SQV. Recursive partitioning is especially useful because it can identify interactions among mutations at different codons and accommodates many types of data as well as missing observations.

Adult↗

PubMed2000

Economic evaluation of drug resistance genotyping for the adaptation of treatment in HIV-infected patients in the VIRADAPT study.

BACKGROUND: Costs of antiretroviral therapy for HIV-infected patients have increased at a time when most countries are attempting to contain health care costs. Part of this increase results from HIV drug resistance associated with virologic failure and a subsequent shift to more complex and costly therapies. Genotypic guided treatment is associated with better virologic outcome. However, it is not yet known whether it will be cost effective. METHODS: We present here an economic evaluation based on the results from the VIRADAPT study, a prospective, open-label, randomized trial comparing patients assigned to standard of care (n = 43), versus genotypic guided treatment (n = 64) for 6 months. Total follow-up for the extended trial was 1 year. Costs were computed from the viewpoint of the health care system. Hospitalization data were retrieved from the VIRADAPT study case report forms, costs were estimated from the cost of the corresponding diagnosis-related groups derived from the French national cost data base: these were actual costs and not charges. Data on the volume of tests prescribed, drugs, and clinic visits were retrieved from the VIRADAPT study database. The unit costs of tests and clinic visits were determined using the French national Social Security reimbursement price; costing of drugs used were based upon purchase price by either retail pharmacies or hospitals. Genotyping using TruGene HIV-1 assay was estimated at $500 per test from manufacturer's data (all figures in this paper are expressed in U.S. dollars). RESULTS: Total mean (standard deviation) yearly costs per patients were $20,412 (+/-$10, 129) in the standard of care group and $18,484 (+/-$9,652) in the genotyping group (p =.35). Drug costs represented 55% of total costs. There was a trend toward a decrease in drug costs in the genotyping arm (p =.07), the greatest reduction being in the decreased use of protease inhibitors in the genotyping arm. The additional expense of genotyping appeared to be offset by the savings obtained in drug costs. CONCLUSION: In our study, the cost of drug resistance testing is offset by a reduced use of protease inhibitors and their attendant costs. Although not reaching statistical significance, this trend in the reduction of drug costs and drug use presents a great interest for future trials.

Adult↗

PubMed2000

Persisting long-term benefit of genotype-guided treatment for HIV-infected patients failing HAART. The Viradapt Study: week 48 follow-up.

OBJECTIVE: We report the 12 months follow-up of the patients who participated in the Viradapt study. METHODS: A total of 108 HIV-infected patients failing antiretroviral (ARV) therapy (HIV RNA > 10,000 copies/ml, therapy > 6 months with nucleoside reverse transcriptase inhibitors, > 3 months with protease inhibitors (PIs) were randomized into two arms: standard of care in the control arm, and treatment according to the resistance mutations in the protease and reverse transcriptase genes in the study arm. After the first 6 months of the randomized study, open-label, genotype-guided treatment was offered in both arms. A multivariate analysis was performed to assess the predictive factors of treatment success (HIV RNA < 200 copies/ml). RESULTS: The two arms were comparable in terms of risk factors, age, sex, previous treatments, CD4 cell count and log10 HIV-1 RNA at baseline. At week 24, an interim combined analysis showed a statistically significant difference in the drop in viral load at months 3 and 6 (P = 0.015, repeated measures analysis of variance) in favour of the genotype group. Patients in both arms were then offered open-label genotyping. Genotype analysis was performed every 3 months, and treatment changes could accordingly be made. As some of the patients in the control arm had already progressed to months 9 or 12, only 69% (30/43) of these patients received genotype-guided treatment changes. In the genotype arm, the mean drop in HIV RNA of 1.15 log10 copies/ml, obtained at month 6, persisted at months 9 and 12 (1.15 log10 copies/ml +/- 0.17). In the control arm, an additional drop in HIV RNA to 0.98 log10 +/- 0.22 copies/ml was observed by month 12. In control patients receiving open-label genotype, the percentage of patients with HIV-1 RNA levels below detection limit (200 copies/ml) rose from 14% at month 6 to 30.5% at month 12. This percentage in the study arm remained stable at 31.3% and 30% at months 9 and 12, respectively. Genotype-guided therapy, primary protease mutations and PI plasma concentrations were significantly correlated with virological success. CONCLUSION: In this heavily pretreated patient population, genotype-guided therapy resulted in a sustained reduction in HIV RNA of greater than one log10 throughout a 1 year follow-up period. Performance of genotype-guided therapy may have contributed to the additional viral load reduction seen in patients in the control group who received open-label genotyping after the 6 months point. Multivariate analysis showed that the presence of primary protease mutations, performance of genotype-guided treatment changes and PI plasma concentrations independently affected virological response.

Anti-HIV Agents↗

PubMed1999

Drug-resistance genotyping in HIV-1 therapy: the VIRADAPT randomised controlled trial.

BACKGROUND: Growing evidence has linked HIV-1 resistance mutations and drug failure. The use of genotypic-resistance analysis to assist therapeutic decision-making in patients failing therapy has not been investigated. We assessed the virological and immunological impact of genotypic-resistance testing. METHODS: We did a prospective, open, randomised, controlled study of HIV-1-infected patients in whom combination therapy was not successful. We randomly assigned patients standard care (control, n=43) or treatment according to the resistance mutations in protease and reverse-transcriptase genes (genotypic group, n=65). The major endpoint was the change in HIV-1 RNA viral load. Analysis was by intention to treat. FINDINGS: 108 patients were enrolled. All patients were similar for risk factors, age, sex, previous treatment, CD4-cell count (214/microL [SD14]) and log HIV-1 RNA viral load at baseline (4.7 copies/mL [0.1]). At month 3, the mean change in HIV-1 RNA was -1.04 log (0.14) in the study group compared with -0.46 log (0.17) in the control group (mean difference 0.58 log [95% CI 0.14-1.02], p=0.01). At month 6, changes were -1.15 (0.15) log copies/mL, and -0.67 (0.19) log copies/mL in the genotypic group and the control group, respectively (mean difference 0.48 log [0.01-0.97], p=0.05). Difference in the drop in viral load combined at 3 months and 6 months was significant (p=0.015). At month 3, HIV-1 RNA was lower than detection level (200 copies/mL) in 29% (19/65) of patients in the genotypic group versus 14% (6/43) in the control group (p=0.017). At month 6, the values were 32% (21/65) and 14% (6/43) (p=0.067) for the genotypic group and the control group, respectively. Therapy was generally well tolerated, with ten patients (six in the genotypic group, four in the control group) requiring toxic-effect-related drug modification. INTERPRETATION: We found genotypic-resistance testing to have a significant benefit on the virological response when choosing a therapeutic alternative. Further study of the use of genotypic-resistance testing in assisting clinical decision-making is warranted.

Acquired Immunodeficiency Syndrome↗

PubMed1999

Clinical cross-resistance between the HIV-1 protease inhibitors saquinavir and indinavir and correlations with genotypic mutations.

OBJECTIVES: To determine the clinical efficacy of the HIV-1 protease inhibitor indinavir (IDV) in saquinavir (SQV)-experienced patients and delineate the developing drug-resistance patterns. DESIGN: Open-label prospective clinical trial. SETTING: University hospital research center. PATIENTS: Ten patients who had completed a SQV monotherapy study in which they had received SQV at a dose of 3600 or 7200 mg daily (two and fourfold the standard dose). INTERVENTIONS: At enrollment patients received IDV for 4 weeks as monotherapy, after which zidovudine (ZDV) and lamivudine (3TC) were added to their drug regimen. Patients then received combination therapy (IDV-ZDV-3TC) for an additional 20 weeks to complete a total of 24 weeks of therapy. MAIN OUTCOME MEASURES: Plasma HIV RNA viral load and CD4+ T-cell counts were monitored. Sequencing of the HIV protease gene was performed to determine the development of resistance mutations. Plasma samples for sequencing were taken before initial SQV therapy, after SQV therapy before starting IDV, and after 24 weeks of IDV therapy. RESULTS: The average duration of high-dose SQV before starting IDV was 58+/-29.2 weeks. A 0.58 log10 RNA copies/ml increase was noted during the 3-week washout phase followed by a mean reduction in plasma HIV RNA viral load of 1.2 log10 RNA copies/ml after 4 weeks of IDV. After the addition of ZDV and 3TC at week 4, HIV RNA continued to fall reaching a mean reduction of 1.96 log10 RNA copies/ml at week 24. Plasma HIV RNA was below 400 RNA copies/ml in six out of nine patients at week 24. CD4+ T-cell counts showed a gradual rise from 328 x 10(6)/l to 453 x 10(6)/l by week 24. SQV therapy had resulted in multiple mutations in the protease gene. Six of the patients had developed five or more mutations: L90M in two, G48V in four (of which three also contained L101), and V82A in three. Patients in whom plasma HIV RNA was not durably suppressed by subsequent IDV combination therapy developed multiple (up to four) additional mutations within 24 weeks, including codons 54, 82 and 93 amongst others. No clear correlation was found between the mutations that had developed in individual patients after SQV and the subsequent efficacy of IDV. CONCLUSION: Prolonged use of SQV at potent doses in the presence of elevated viral load levels resulted in the development of multiple resistance mutations. Individual resistance patterns varied greatly between patients, as did their virological response to therapy. Resistance assays may be useful in identifying which patients will benefit from salvage therapy with a second protease inhibitor.

CD4 Lymphocyte Count↗

PubMed1999

Frequency of class I HLA-restricted anti-HIV CD8+ T cells in individuals receiving highly active antiretroviral therapy (HAART).

Peptide/MHC tetrameric complexes were used to enumerate the frequency of HLA class I-restricted epitope-specific CD8+ T cells in 18 HLA-A*0201 HIV type 1-infected asymptomatic patients. HLA-A*0201 molecules were complexed to HIV Gag p17 (amino acids 77-85) and reverse transcriptase (amino acids 464-472) peptides, biotinylated, and bound to streptavidin-phycoerythrin to form tetramers. We show in this study that 17 of 18 HIV-1-infected asymptomatic patients have circulating frequencies of 1/50-1/1000 CD8+ T cells that recognize both Gag and Pol CTL epitopes or either epitope alone. The functional nature of these cells is open to interpretation, as we show that despite relatively high frequencies of fresh epitope-specific CD8+ T cells, variant epitope sequences in viral plasma progeny were rare. In addition, the majority of tetramer-positive cells did not display discernible fresh CTL activity; only after restimulation with specific peptide in culture was there an expansion of epitope-specific CD8+ cells, correlating with high CTL activity. These data suggest that fresh tetramer-stained cells probably represent memory precursors; we demonstrate, with the application of highly active antiretroviral therapy, that the interruption of chronic antigenic stimulation causes significant reductions in the frequency of these cells in five of six patients. In conclusion, this study provides evidence that persistently replicating viral populations are probably required to maintain high frequencies of HIV-1 epitope-specific CD8+ T cells in asymptomatic chronically infected individuals

Amino Acid Sequence↗

PubMed1999

Resistance mutations to zidovudine and saquinavir in patients receiving zidovudine plus saquinavir or zidovudine and zalcitabine plus saquinavir in AIDS clinical trials group 229.

The relationships among treatment regimens, plasma human immunodeficiency virus (HIV) RNA levels, and resistance mutations to saquinavir (codons 48 and 90) and zidovudine (codon 215) were examined in a cohort of 144 patients from the AIDS Clinical Trials Group 229 study. After 24-40 weeks of therapy, no patients who had received the two-drug combination (zidovudine plus saquinavir) had only codon 48 mutations, 45.8% had only codon 90 mutations, and 8.3% had both codon 48 and 90 mutations. Mutations developed by patients who had received the three-drug combination (zidovudine and zalcitabine plus saquinavir) were codon 48 alone in 1.4%, codon 90 alone in 33.3%, and both codons 48 and 90 in 4.2%. The difference between the groups showed a trend toward reduced mutations with three versus two drugs but did not reach significance (P=.11, two-sided chi2). Higher baseline HIV RNA levels correlated with the development of protease mutations. Mutations at codon 215 were present in 82% of all patients at baseline and in 87% after therapy.

Acquired Immunodeficiency Syndrome↗

PubMed1998

Changes in CD4+ and CD8+ T cell subsets in response to highly active antiretroviral therapy in HIV type 1-infected patients with prior protease inhibitor experience.

This study explores whether previous failures on antiretroviral drug regimens preclude the possibility of immune restoration. This was assessed by evaluating T cell subset changes in individuals who received a salvage regimen of highly active antiretroviral therapy (HAART) after initially failing protease inhibitor monotherapy. Ten HIV-1-infected asymptomatic patients received a regimen of indinavir, zidovudine, and 3TC after failing saquinavir monotherapy. Changes in absolute numbers of naive, memory, and activated CD4+ and CD8+ T cells expressing a selection of CD45RA, CD62L, CD45RO, HLA-DR, and CD38 markers were monitored prospectively over 6 months. These measurements were correlated with plasma viral load along with alterations in a selected CD8+ V alpha/Vbeta T cell receptor (TCR) repertoire. Over 6 months there was a progressive increase in numbers of CD4+ memory (CD45RA-CD62L+) and naive (CD45RA+CD62L+) T cells, which displayed a modest inverse correlation with viral load. Two phases of CD8+ memory cell changes were identified, consisting of a transient increase in CD45RA+CD62L- numbers after 2 months and thereafter a progressive rise in CD45RA-CD62L+ cells until 6 months. A strong correlation existed between reduced viral load and loss of activated CD8+CD38+HLA-DR+ cell numbers. There was also a temporary broadening of the CD8+ V alpha/Vbeta TCR repertoire at 8 weeks, which became skewed after 6 months in parallel with reduced viral suppression. Closer analysis of naive and memory cell subset proportions in individual patients revealed that enlarged pools of naive subsets were evident in those patients with rebounds in viral load. Overall, drug-experienced patients responding to HAART displayed increased numbers of naive and memory CD4+ subsets, and reduced CD8+ cell activation with a loss of TCR skewing.

Adult↗

PubMed1998

Lymph node human immunodeficiency virus RNA levels and resistance mutations in patients receiving high-dose saquinavir.

The development of resistance mutations and human immunodeficiency virus (HIV) RNA levels were compared in lymph nodes and plasma of patients receiving antiretroviral therapy. Ten HIV-positive patients receiving high-dose saquinavir monotherapy (3600 or 7200 mg/day) underwent 14 lymph node biopsies before and during therapy. HIV RNA levels and appearance of resistance mutations to saquinavir were determined in simultaneous lymph node and plasma samples. HIV RNA levels were found to be consistently higher (mean, 3.16 log RNA copies; SD, 1.04; range, 2.23-5.59) in lymph nodes than in simultaneous plasma samples. Saquinavir therapy resulted in a reduction in HIV RNA levels in both plasma and lymph nodes. The presence or absence of a resistance mutation to saquinavir at codons 48 or 90 of the HIV-1 protease gene was identical in 13 of 14 biopsies, suggesting that resistance mutations to saquinavir appear within close temporal proximity in lymph nodes and plasma.

Anti-HIV Agents↗

PubMed1998

Human immunodeficiency virus type 1 protease genotypes and in vitro protease inhibitor susceptibilities of isolates from individuals who were switched to other protease inhibitors after long-term saquinavir treatment.

An understanding of the mechanisms of virologic cross-resistance between human immunodeficiency virus type 1 protease inhibitors is important for the establishment of effective treatment strategies for patients who no longer respond to their initial protease inhibitor. Protease gene sequencing results from patients treated with saquinavir showed significant increases in the frequency of the G48V protease mutation in patients receiving higher doses of the drug. In addition, all six patients who developed the G48V mutation during saquinavir therapy developed the V82A mutation either on continued saquinavir or after a switch to nelfinavir or indinavir. In vitro susceptibility assays showed that all 13 isolates with reduced susceptibilities to two or more protease inhibitors had either the G48V or L90M mutation, along with an average of six other protease mutations. Reduced susceptibility to nelfinavir was found in 14 isolates, but only 1 possessed the D30N mutation. These results suggest that mutations selected in vivo by initial saquinavir therapy may provide more cross-resistance to the other protease inhibitors than has been previously reported.

Genome, Viral↗