scholarly journals Discrepancies between Protease Inhibitor Concentrations and Viral Load in Reservoirs and Sanctuary Sites in Human Immunodeficiency Virus-Infected Patients

2003 ◽  
Vol 47 (1) ◽  
pp. 238-243 ◽  
Author(s):  
Caroline Solas ◽  
Alain Lafeuillade ◽  
Philippe Halfon ◽  
Stéphane Chadapaud ◽  
Gilles Hittinger ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Drug Resistance ◽  
Lymph Node ◽  
Viral Load ◽  
Lymphoid Tissue ◽  
Drug Penetration ◽  
Hiv Rna ◽  
Drug Concentrations ◽  
Immunodeficiency Virus ◽  
Rna Levels

ABSTRACT The variable penetration of antiretroviral drugs into sanctuary sites may contribute to the differential evolution of human immunodeficiency virus (HIV) and the emergence of drug resistance. We evaluated the penetration of indinavir, nelfinavir, and lopinavir-ritonavir (lopinavir/r) in the central nervous system, genital tract, and lymphoid tissue and assessed the correlation with residual viral replication. Plasma, cerebrospinal fluid (CSF), semen, and lymph node biopsy samples were collected from 41 HIV-infected patients on stable highly active antiretroviral therapy regimens to determine drug concentrations and HIV RNA levels. When HIV RNA was detectable, sequencing of the reverse transcriptase and protease genes was performed. Ratios of the concentration in semen/concentration in plasma were 1.9 for indinavir, 0.08 for nelfinavir, and 0.07 for lopinavir. Only indinavir was detectable in CSF, with a concentration in CSF/concentration in plasma ratio of 0.17. Differential penetration into lymphoid tissue was observed, with concentration in lymph node tissue/concentration in plasma ratios of 2.07, 0.58, and 0.21 for indinavir, nelfinavir, and lopinavir, respectively. HIV RNA levels were <50 copies/ml in all CSF samples of patients in whom HIV RNA was not detectable in plasma. HIV RNA was detectable in the semen of three patients (two patients receiving nelfinavir and one patient receiving lopinavir/r), and its detection was associated with multiple resistance mutations, while the viral load in plasma was undetectable. HIV RNA was detectable in all lymph node tissue samples. Differential drug penetration was observed among the three protease inhibitors in the sanctuary sites, but there was no correlation between drug levels and HIV RNA levels, suggesting that multiple factors are involved in the persistence of viral reservoirs. Further studies are required to clarify the role and clinical relevance of drug penetration in sanctuaries in terms of long-term efficacy and drug resistance.

scholarly journals Comparison of Two Measures of Human Immunodeficiency Virus (HIV) Type 1 Load in HIV Risk Groups

1998 ◽  
Vol 36 (12) ◽  
pp. 3647-3652 ◽  
Author(s):  
Cynthia M. Lyles ◽  
David Vlahov ◽  
Homayoon Farzadegan ◽  
Jacquie Astemborski ◽  
Joseph B. Margolick ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Viral Load ◽  
Risk Group ◽  
Risk Groups ◽  
Homosexual Men ◽  
Hiv Rna ◽  
Viral Burden ◽  
Immunodeficiency Virus ◽  
Rna Levels

Levels of viral burden were compared across risk group and gender populations among 485 human immunodeficiency virus type 1 (HIV-1)-infected participants consisting of 190 male injection drug users (IDUs), 92 female IDUs, and 203 homosexual men. Viral burden was quantified by a microculture technique to determine cell-associated infectious units per 106 peripheral blood mononuclear cells (IUPM) and by reverse transcriptase PCR (Amplicor) to determine plasma HIV RNA levels. Adjusting for CD4+ cell count, females had a lower infectious HIV load than all males combined (0.33 log10 lower; P = 0.004), and homosexual men had a 0.29 log10 higher infectious viral load than all IDUs combined (P = 0.001). For HIV RNA levels, females had lower levels than males (0.19 log10 lower;P = 0.04), but no differences were observed by risk group. After controlling for percent CD4+ cells, no differences were found by risk group for either assay, but females still had a 0.25 log10 lower infectious viral load than males (P = 0.04) and a viral RNA load similar to that of males (P = 0.25). The correlation between infectious viral load and HIV RNA load was 0.58 overall, which did not differ by gender or risk group. Our data suggest that differences in viral load may exist by gender and that any differences observed by risk group are driven predominantly by gender or percent CD4+ cell differences. These data also confirm a moderate correlation between cell-associated infectious viral load and plasma HIV RNA load, which appears to be similar by gender and across risk groups.

scholarly journals Genotypic Changes in Human Immunodeficiency Virus Type 1 Associated with Loss of Suppression of Plasma Viral RNA Levels in Subjects Treated with Ritonavir (Norvir) Monotherapy

1998 ◽  
Vol 72 (6) ◽  
pp. 5154-5164 ◽  
Author(s):  
P. Scott Eastman ◽  
John Mittler ◽  
Reed Kelso ◽  
Chris Gee ◽  
Eric Boyer ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Resistance Mutation ◽  
Virologic Response ◽  
Hiv Rna ◽  
Immunodeficiency Virus ◽  
Plasma Rna ◽  
Doubling Times ◽  
Rna Levels

ABSTRACT Ten subjects received 600 to 1,200 mg of the human immunodeficiency virus type 1 (HIV-1) protease inhibitor ritonavir per day. Following 2 weeks of therapy, plasma HIV RNA levels decreased by a mean of 1.57 (range, 0.89 to 1.96) log units. With continued therapy, HIV RNA levels began to rise in eight subjects. The initial rise in plasma RNA levels was temporally associated with the development and quantitative increase in the V82 resistance mutation. Doubling times of the V82A mutant virus were estimated to be 2.4 to 4.8 days. An L63P/A mutation was commonly present at baseline even in subjects with a durable virologic response. The concomitant acquisition of an L63P/A mutation with the V82A/F mutation at the time when plasma RNA levels rebounded suggests a role for the L63P/A mutation in improving the fitness of the V82A/F mutation. Subsequent additional genotypic changes at codons 54 and 84 were often associated with further increases in plasma RNA levels. Ongoing viral replication in the presence of drugs resulted in the appearance of additional genotypic changes, including the L90M saquinavir resistance mutation, and decreased phenotypic susceptibility. The relative fitness of the protease V82A ritonavir resistance mutation and reverse transcriptase T215Y/F zidovudine resistance mutation following drug withdrawal were estimated to be 96 to 98% that of the wild type. Durability of the virologic response was associated with plasma RNA levels at the nadir. A virologic response beyond 60 days was not observed unless plasma HIV RNA levels were suppressed below 2,000 copies/ml, consistent with estimates from V82A doubling times for selection of a single resistance mutation to dominate the replicating population.

scholarly journals Plasmodium falciparum Infection Does Not Affect Human Immunodeficiency Virus Viral Load in Coinfected Rwandan Adults

2014 ◽  
Vol 1 (2) ◽  
Author(s):  
Krishanthi Subramaniam ◽  
Rebeca M. Plank ◽  
Nina Lin ◽  
Adam Goldman-Yassen ◽  
Emil Ivan ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Drug Resistance ◽  
Plasmodium Falciparum ◽  
Viral Load ◽  
Malaria Infection ◽  
Hiv Transmission ◽  
Falciparum Infection ◽  
Resistance Testing ◽  
Plasmodium Falciparum Infection ◽  
Immunodeficiency Virus

Abstract Background.  Plasmodium falciparum infection has been reported to increase human immunodeficiency virus (HIV) viral load (VL), which can facilitate HIV transmission. We prospectively studied the impact of mild P falciparum coinfection on HIV VL in Rwanda. Methods.  We measured plasma HIV VL at presentation with malaria infection and weekly for 4 weeks after artemether-lumefantrine treatment in Rwandan adults infected with HIV with P falciparum malaria. Regression analyses were used to examine associations between malaria infection and HIV VL changes. Samples with detectable virus underwent genotypic drug-resistance testing. Results.  We enrolled 28 HIV-malaria coinfected patients and observed 27 of them for 5 weeks. Three patients (11%) were newly diagnosed with HIV. Acute P falciparum infection had no significant effect on HIV VL slope over 28 days of follow-up. Ten patients with VL &lt;40 copies/mL at enrollment maintained viral suppression throughout. Seventeen patients had a detectable VL at enrollment including 9 (53%) who reported 100% adherence to ARVs; 3 of these had detectable genotypic drug resistance. Conclusions.  Unlike studies from highly malaria-endemic areas, we did not identify an effect of P falciparum infection on HIV VL; therefore, malaria is not likely to increase HIV-transmission risk in our setting. However, routine HIV testing should be offered to adults presenting with acute malaria in Rwanda. Most importantly, we identified a large percentage of patients with detectable HIV VL despite antiretroviral (ARV) therapy. Some of these patients had HIV genotypic drug resistance. Larger studies are needed to define the prevalence and factors associated with detectable HIV VL in patients prescribed ARVs in Rwanda.

scholarly journals Screening for antiretroviral drug resistance among treatment-naive human immunodeficiency virus type 1-infected individuals in Lebanon

2014 ◽  
Vol 8 (03) ◽  
pp. 339-348
Author(s):  
Jacques M Mokhbat ◽  
Nada M. Melhem ◽  
Ziad El-Khatib ◽  
Pierre Zalloua
Keyword(s):  
Human Immunodeficiency Virus ◽  
Drug Resistance ◽  
Viral Load ◽  
Reverse Transcriptase ◽  
Human Immunodeficiency Virus Type ◽  
Newly Diagnosed ◽  
Reverse Transcriptase Inhibitors ◽  
Immunodeficiency Virus ◽  
Hiv 1

Introduction: Antiretroviral therapy (ART) has been successful at decreasing the morbidity and mortality associated with human immunodeficiency virus type 1 (HIV-1) infection. HIV-1 drug resistance (HIVDR) among ART-naive patients has been documented to compromise the success of initial therapy. This study was conducted to determine the prevalence of HIVDR mutations among newly diagnosed drug-naive HIV-infected individuals in Lebanon. Methodology: Plasma samples from 37 newly diagnosed participants at various stages of HIV-1 infection were used to determine HIV-1 RNA viral load, isolate viral RNA, and amplify DNA by RT-PCR. Purified PCR products were used to perform genotypic resistance tests. Results: The prevalence of resistance mutations to nucleoside reverse transcriptase inhibitors (NRTI), non-nucleoside reverse transcriptase inhibitors (NNRT), and protease inhibitors (PI) were 5.4%, 10.8%, and 8%, respectively. The major mutations detected in the study participants conferred resistance to NRTIs and NNRTIs recommended for HIV-1 treatment.  No significant relationship between HIV-1 viral load of participants and the mode of HIV-1 transmission or between the occurrence of HIVDR and the mode of transmission was found. Conclusions: To our knowledge, this is the first study on HIVDR mutations among newly diagnosed HIV-infected persons in Lebanon. The overall prevalence of HIVDR mutations detected in our study was 16%. Our results are important for evaluating the utility of the standard first-line regimens in use, determining the feasibility of HIVDR testing before the initiation of ART, as well as minimizing the emergence and transmission of HIVDR.

scholarly journals Didanosine Population Pharmacokinetics in West African Human Immunodeficiency Virus-Infected Children Administered Once-Daily Tablets in Relation to Efficacy after One Year of Treatment

2009 ◽  
Vol 53 (10) ◽  
pp. 4399-4406 ◽  
Author(s):  
Déborah Hirt ◽  
Christophe Bardin ◽  
Serge Diagbouga ◽  
Boubacar Nacro ◽  
Hervé Hien ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Viral Load ◽  
Compartment Model ◽  
Volume Of Distribution ◽  
Wilcoxon Test ◽  
Population Pharmacokinetic ◽  
Time Curve ◽  
Drug Concentrations ◽  
Immunodeficiency Virus ◽  
One Year

ABSTRACT Our objective was to study didanosine pharmacokinetics in children after the administration of tablets, the only formulation available in Burkina Faso for which data are missing, and to establish relationships between doses, plasma drug concentrations, and treatment effects (efficacy/toxicity). Didanosine concentrations were measured for 40 children after 2 weeks and for 9 children after 2 to 5 months of treatment with a didanosine-lamivudine-efavirenz combination. A population pharmacokinetic model was developed with NONMEM. The link between the maximal concentration of the drug in plasma (C max), the area under the concentration-time curve (AUC), and the decrease in human immunodeficiency virus (HIV) type 1 RNA levels after 12 months of treatment was evaluated. The threshold AUC that improved efficacy was determined by the use of a Wilcoxon test for HIV RNA, and an optimized dosing schedule was simulated. Didanosine pharmacokinetics was best described by a one-compartment model with first-order absorption and elimination. The apparent clearance and volume of distribution were higher for tablets, probably due to a lower bioavailability with tablets than with pediatric powder. The decrease in the viral load after 12 months of treatment was significantly correlated with the didanosine AUC and C max (P ≤ 0.02) during the first weeks of treatment. An AUC of >0.60 mg/liter·h was significantly linked to a greater decrease in the viral load (a decrease of 3 log10 versus 2.4 log10 copies/ml; P = 0.03) than that with a lower AUC. A didanosine dose of 360 mg/m2 administered as tablets should be a more appropriate dose than 240 mg/m2 to improve efficacy for these children. However, data on adverse events with this dosage are missing.

scholarly journals Expansion of Viral Load Testing and the Potential Impact on Human Immunodeficiency Virus Drug Resistance

2017 ◽  
Vol 216 (suppl_9) ◽  
pp. S808-S811 ◽  
Author(s):  
Helen M Chun ◽  
Yaa F Obeng-Aduasare ◽  
Laura N Broyles ◽  
Dennis Ellenberger
Keyword(s):  
Human Immunodeficiency Virus ◽  
Drug Resistance ◽  
Viral Load ◽  
Load Testing ◽  
Viral Load Testing ◽  
Immunodeficiency Virus ◽  
Potential Impact

scholarly journals High Concentration of Raltegravir in Semen of HIV-Infected Men: Results from a Substudy of the EASIER-ANRS 138 Trial

2009 ◽  
Vol 54 (2) ◽  
pp. 937-939 ◽  
Author(s):  
Caroline Barau ◽  
Constance Delaugerre ◽  
Joséphine Braun ◽  
Nathalie de Castro ◽  
Valérie Furlan ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Highly Active Antiretroviral Therapy ◽  
Plasma Samples ◽  
Drug Penetration ◽  
High Concentration ◽  
Highly Active ◽  
Immunodeficiency Virus ◽  
Hiv 1 ◽  
Rna Levels

ABSTRACT Raltegravir concentrations and human immunodeficiency virus type 1 (HIV-1) RNA levels in semen samples from 10 treatment-experienced HIV-1-infected patients were measured after 24 weeks of raltegravir-based highly active antiretroviral therapy (HAART). Semen and plasma HIV-1 RNA levels were below 100 copies/ml and 50 copies/ml, respectively, in all samples. The median raltegravir concentrations in semen samples (n = 10) and in plasma samples (n = 9) drawn simultaneously were 345 (range, 83 to 707) ng/ml and 206 (range, 106 to 986) ng/ml, respectively. The median semen-to-plasma ratio of raltegravir concentration was 1.42 (range, 0.52 to 6.66), indicating good although variable levels of drug penetration of raltegravir in the seminal compartment.

scholarly journals Phase I and II Study of the Safety, Virologic Effect, and Pharmacokinetics/Pharmacodynamics of Single-Dose 3-O-(3′,3′-Dimethylsuccinyl)Betulinic Acid (Bevirimat) against Human Immunodeficiency Virus Infection

2007 ◽  
Vol 51 (10) ◽  
pp. 3574-3581 ◽  
Author(s):  
Patrick F. Smith ◽  
Abayomi Ogundele ◽  
Alan Forrest ◽  
John Wilton ◽  
Karl Salzwedel ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Betulinic Acid ◽  
Information Criterion ◽  
Cd4 Cells ◽  
Resistance Mutations ◽  
Estimation Model ◽  
Hiv Rna ◽  
Drug Concentrations ◽  
Average Maximum ◽  
Immunodeficiency Virus

ABSTRACT Bevirimat [3-O-(3′,3′-dimethylsuccinyl)betulinic acid] is the first in a new class of anti-human immunodeficiency virus (HIV) drugs that inhibit viral maturation by specifically blocking cleavage of the Gag capsid (CA) precursor, CA-SP1, to mature CA protein, resulting in defective core condensation and release of immature noninfectious virions. Four cohorts of six HIV-infected adults, with CD4 counts of >200 and plasma viral loads of 5,000 to 250,000 transcripts/ml and not currently receiving antiretroviral therapy, were randomized to receive a single oral dose of placebo, 75, 150, or 250 mg of bevirimat. Thirty blood samples for drug concentrations and 20 HIV RNA measures were collected from each subject over a 20-day period. Candidate pharmacokinetic/pharmacodynamic models were fit to individual subjects by maximum likelihood followed by Bayesian estimation; model discrimination was by corrected Akaike's Information Criterion. The bevirimat pharmacokinetics was well described by an oral two-compartment linear model (r 2, 0.98), with a mean (percent coefficient of variation) half-life of 60.3 (13.6) h and apparent oral clearance of bevirimat from the plasma compartment of 0.17 (18) liters/h. HIV RNA was modeled as being produced in infected CD4 cells, with bevirimat inhibiting infection of new CD4 cells thru a Hill-type function (r 2, 0.87). Single oral doses of bevirimat were well tolerated and demonstrated a dose-dependent reduction in viral load. The average maximum reduction from baseline following the 150- and 250-mg doses was greater than 0.45 log10, with individual patients having reductions of greater than 0.7 log10. No bevirimat resistance mutations were detected during the course of the study.

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