bluuebunny/crossref_metadata_2025_split huggingface dataset:
Current Status and Future Prospects of Therapeutic Drug Monitoring and Applied Clinical Pharmacology in Antiretroviral Therapy
Authors: Boffito Marta , Acosta Edward , Burger David , Fletcher Courtney V , Flexner Charles , Garaffo Rodolphe , Gatti Giorgio , Kurowski Michael , Perno Carlo Federico , Peytavin Gilles , Regazzi Mario , Back David 
Published: April 2022

The consensus of current international guidelines for the treatment of HIV infection is that data on therapeutic drug monitoring (TDM) of non-nucleoside reverse transcriptase inhibitors and protease inhibitors provide a framework for the implementation of TDM in certain defined scenarios in clinical practice. However, the utility of TDM is considered to be on an individual basis until more data are obtained from large clinical trials showing the benefit of TDM. In April 2004, a panel of experts met in Rome, Italy. This followed an inaugural meeting in Perugia, Italy, in October 2000, which resulted in the article published in AIDS 2002, 16(Suppl 1):S5–S37. The objectives of this second meeting were to review the questions surrounding TDM of antiretroviral drugs and discuss the clinical utility, current concerns and future prospects of drug concentration monitoring in the care of HIV-1-infected individuals. This report, which has been updated to include material published or presented at international conferences up to the end of September 2004, reviews pharmacokinetic and pharmacodynamic data and reports the issues discussed by the panel, offering advice to clinical care providers who may be currently, or are considering incorporating TDM into the routine care of their patients. In addition, the panel formulated a series of position statements that are relevant to the interpretation of current data and can aid the design of future clinical trials. Part 2 of this Special article, Therapeutic drug monitoring and drug–drug interactions involving antiretroviral drugs, will be published in Antiviral Therapy 10(4).
Lack of a Metabolic and Antiviral Drug Interaction between Tenofovir, Abacavir and Lamivudine
Authors: Ray Adrian S , Myrick Florence , Vela Jennifer E , Olson Loren Y , Eisenberg Eugene J , Borroto-Esoda Katyna , Miller Michael D , Fridland Arnold 
Published: April 2022

Objective An anti-HIV regimen composed of the nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) tenofovir (TFV) disoproxil fumarate (TDF), abacavir (ABC) and lamivudine (3TC) has performed poorly in patients. This study evaluated the combination of TFV, ABC and 3TC for metabolic or antiviral antagonism in vitro. Design: Procedures were developed to evaluate the in vitro metabolism and antiviral activity of drug combinations of TFV, ABC and 3TC in cell types relevant for HIV infection. Methods Anabolism of combinations of TFV and ABC were studied over a 24 h period in the human T leukaemic CEM lymphoblast cell line and human primary peripheral blood mononuclear cells (PBMCs) stimulated with human interleukin-2 and phytohaemagglutinin. The anti-HIV activity of combinations of TFV and ABC in the presence or absence of 3TC was studied in stimulated PBMCs infected with the HXB2 strain of HIV-1. Results Levels of the active metabolites produced from TFV and ABC after incubation with CEM or PBMCs showed no significant change upon introduction of the other NRTI. Moreover, the pool sizes for the natural substrates of 2′-deoxyadenosine triphosphate and 2′-deoxyguanosine triphosphate were also unchanged. In anti-HIV assays in PBMCs, the combination of TFV and ABC was found to be additive with respect to inhibition of HIV replication. Addition of 3TC to the combination did not result in synergistic or antagonistic effects. Conclusions The poor efficacy of the triple NRTI regimen of TDF, ABC and 3TC is probably not due to a metabolic drug interaction resulting in antagonism of antiviral activity.
A Randomized, Double-Blind, Placebo-Controlled Dose-Escalation Trial of Merimepodib (VX-497) and Interferon-α in Previously Untreated Patients with Chronic Hepatitis C
Authors: McHutchison John G , Shiffman Mitchell L , Cheung Ramsey C , Gordon Stuart C , Wright Teresa L , Pottage John C , McNair Lindsay , Ette Ene , Moseley Scott , Alam John 
Published: April 2022

Inhibition of inosine monophosphate dehydrogenase (IMPDH) is one of several proposed mechanisms of action for ribavirin (RBV), a critical component of the current treatment for chronic hepatitis C (CHC). This study was a double-blind, placebo-controlled dose-escalation study of a novel, selective, orally active small molecule inhibitor of IMPDH, merimepodib (VX-497 or MMPD) in combination with standard interferon-alpha (IFN-α). Fifty-four treatment-naive patients with genotype-1 CHC were randomized to receive IFN-α 3 MIU subcutaneously three times a week, alone or in combination with 100 mg or 300 mg (every 8 h) of MMPD for 4 weeks. At the end of 4 weeks, all patients were offered 48 weeks of treatment with IFN-α/RBV. The objectives of the study were to evaluate the tolerability of the IFN-α/MMPD combination and to evaluate whether MMPD had an on-treatment effect on HCV-RNA, similar to RBV when added to IFN-α. The drug combination was generally well tolerated; one patient at the higher dose discontinued because of elevated alanine aminotransferase levels. No pharmacokinetic interactions were evident between the two drugs. Analysis of covariance that adjusted for a baseline imbalance in HCV-RNA in the intent-to-treat population did not show any significant differences between the treatment groups, or between MMPD plus IFN-α compared with IFN-α alone. However, the per-protocol primary efficacy analysis based on treatment-compliant patients demonstrated a greater reduction in mean HCV-RNA in the combination of 100 mg MMPD plus IFN-α compared with IFN-α alone (-1.78 log vs -0.86 log, P=0.037). In conclusion, the addition of a selective IMPDH inhibitor to IFN-α was well tolerated. In a low-dose range, the addition of MMPD may have the potential to add to the antiviral efficacy of IFN-α. Larger, longer duration trials incorporating pegylated IFN would be required to determine whether this combination, alone or with RBV, would increase either early or sustained virological response rates.
Low Density Lipoprotein Apolipoprotein B Metabolism in Treatment-Naive HIV Patients and Patients on Antiretroviral Therapy
Authors: Umpleby A Margot , Das Satyajit , Stolinski Michael , Shojaee-Moradie Fariba , Jackson Nicola C , Jefferson William , Crabtree Nicky , Nightingale Peter , Shahmanesh Mohsen 
Published: April 2022

Background Dyslipidaemia and lipodystrophy have been described in treated HIV patients and in a small percentage of untreated HIV patients. Lipodystrophy in these patients has been shown to be associated with a lower expression of low density lipoprotein (LDL) receptors. Methods We have investigated the effect of antiretroviral treatment with either a protease inhibitor (PI) or a non-nucleoside reverse transcriptase inhibitor (NNRTI) on body fat distribution and LDL apolipoprotein B (apoB) kinetics in 12 HIV-negative controls and 52 HIV-infected patients, including antiretroviral treatment-naive (TN) patients ( n=13) and patients taking two nucleoside analogues plus either a PI ( n=15) or an NNRTI ( n=24). Results LDL cholesterol was not different between groups. Compared with the controls, LDL apoB absolute synthetic rate (ASR) and fractional catabolic rate (FCR) were lower and residence time (RT) was higher in the PI and NNRTI groups ( P<0.05). In the TN patients, LDL ASR was lower ( P<0.05) and there was a trend for a lower FCR and higher RT compared with the controls ( P=0.07). LDL apoB pool size was greater in the PI group compared with the controls ( P<0.05). In the PI group, patients on ritonavir (RTV)-containing regimens had a lower LDL apoB ASR ( P=0.009) and a trend to a lower LDL apoB FCR and increased RT compared with non-RTV-containing PI regimens ( P=0.05). There was a positive correlation between LDL apoB FCR and limb fat/lean body mass ( P=0.004) in all subjects. Conclusions Decreased LDL FCR, despite unchanged LDL cholesterol, was demonstrated in both treated and untreated HIV patients. It was more marked with RTV-containing regimens and was associated with reduced limb fat. The increased LDL RT may lead to an increased risk of atherogenesis thus contributing to the risk for cardiovascular disease in these patients.
Impact of Ribavirin Exposure on Early Virological Response to Hepatitis C Therapy in HIV-Infected Patients with Chronic Hepatitis C
Authors: Núnez Marina , Camino Nuria , Ramos Belén , Berdún Miguel Angel , Barreiro Pablo , Losada Elena , Santos Ignacio , Echevarría Santiago , Ocampo Antonio , Miralles Celia , Arazo Piedad , Martín-Carbonero Luz , Romero Miriam , García-Samaniego Javier , Soriano Vincent 
Published: April 2022

Background The use of pegylated interferon (PEG-IFN) plus ribavirin (RBV) is currently the recommended treatment for chronic hepatitis C virus (HCV) infection. Coinfection with HIV is a negative predictor of response, for reasons not well understood. Methods We examined the virological response at weeks 4 and 12 in 198 HCV/HIV-coinfected patients enrolled in a prospective trial in which PEG-IFN alpha 2a (180 μg per week) and RBV (1000-1200 mg daily) were provided. Results In an on-treatment analysis, 52.8% of patients achieved undetectable HCV-RNA (<600 IU/ml) at week 4, while 63% and 77.2% of patients had a decline of at least 2 and 1 log10, respectively. At week 12, 73.1% of patients reached undetectable HCV-RNA, and 83.5% and 89% achieved at least a 2- and 1-log10 drop, respectively. More than 85% of HCV genotypes 2/3 cleared HCV-RNA at week 4, a proportion significantly higher when compared with genotypes 1 (33.8%) and 4 (28.6%). Multivariate logistic regression analysis identified genotype 3 and RBV exposure (mg/kg of body weight) as independent predictors of virological response at week 12 of therapy. Conclusion Early virological response rates to PEG-IFN plus RBV in HCV/HIV-coinfected patients seem to be similar to those reported for HCV-monoinfected subjects. The use of suboptimal doses of RBV in most earlier trials might account for the low response rates seen in coinfected patients. To our knowledge, this is the first report demonstrating that RBV exerts a significant independent effect on early virological response. Therefore, strategies aimed at optimizing doses and adherence to RBV might help to improve responses to HCV therapy in coinfected patients.
Two-Year Interferon Therapy with Or without Ribavirin in Chronic Delta Hepatitis
Authors: Gunsar Fulya , Akarca Ulus Salih , Ersoz Galip , Kobak Arzu Celebi , Karasu Zeki , Yuce Gul , Ilter Tankut , Batur Yucel 
Published: April 2022

The only beneficial agent for the treatment of chronic delta hepatitis (CDH) is interferon (IFN). However, there is no consensus on the best dosage or duration of IFN therapy. As ribavirin (RBV) increases the sustained response when added to IFN in chronic hepatitis C, probably because of its immunomodulatory effect, we aimed to investigate the efficacy of 2-year IFN treatment and whether RBV had any additive effect to IFN in CDH. Methods Patients ( n=31) with CDH were randomized with a 1:2 ratio as 10 patients (3 females/7 males, age 39 ±9) receiving IFN monotherapy (9 MU IFN-α2a three times weekly) and 21 patients (8 females/13 males, age 38 ±11) receiving IFN plus RBV for 2 years (IFN at the same dosage and RBV at 1000–1200 mg/day). Alanine transferase normalization and hepatitis delta virus (HDV) RNA negativity at the end of treatment and at the end of the follow-up period (at least 6 months following 2-year treatment) were primary endpoints of the study. In addition, virological response and biochemical response were determined separately. Results Eight of 31 patients (25%) had cirrhosis in liver biopsies. Six patients from the IFN monotherapy group and 12 patients from the combination group had biochemical response. Five patients from the IFN monotherapy group and 11 patients from the combination group had virological response at the end of therapy. Two patients from the IFN group and five patients from the combination group had sustained biochemical response at the end of the follow-up period. Hepatitis B virus (HBV) activations with HBV DNA positivity were observed in two patients (one from the IFN monotherapy group, one from the combination group). Two patients (20%) in the IFN group and five patients (23.5%) in IFN plus RBV group remained as virological responders at the end of the follow-up period ( P>0.05). None of the patients with liver cirrhosis were responsive at the end of the follow-up period. Conclusion Almost 20% of the patients with CDH were responsive to 2-year IFN treatment at the end of the follow-up period and no additional effect of RBV was observed. Patients with advanced liver disease failed to respond to treatment.
A Randomized Trial to Evaluate Lopinavir/Ritonavir versus Saquinavir/Ritonavir in HIV-1-Infected Patients: The Maxcmin2 Trial
Authors:   for the MaxCmin2 trial group, Belloso W , Ivalo S , Benetucci J , Pugliese D , Garone D , Cahn P , Krolewiecki A , Casiro A , Cassetti I , Bologna R , Duran A , Toibaro J , Rieger A , Vago B , Clumeck N , Kabeya K , Cooper C , Dufresne S , Lalonde R , Walmsley S , Gerstoft J , Mathiesen L , Nielsen H , Obel N , Pedersen C , Lazzarin A , Castagna A , Bruun J N , Gatell J M , Arnaiz J , Blaxhult A , Flamholc L , Gisslén M , Vernazza P , Bingham J , Peters B , Gazzard B , Nelson M , Johnson M , Youle M , Weber J , Scullard G , Brar I , Bouzi V , Brutus A , Jayaweera D T , Mogyoros M , Rodwick B M , Stein D , Wiznia A , Schwartz R , Vandenberg-Wolf M G , Tedaldi E , Dragsted Ulrik B , Gerstoft Jan , Youle Mike , Fox Zoe , Losso Marcello , Benetucci Jorge , Jayaweera Dushyantha T , Rieger Armin , Bruun Johan N , Castagna Antonella , Gazzard Brian , Walmsley Sharon , Hill Andrew , Lundgren Jens D. 
Published: April 2022

Objective To assess the rate of protocol-defined treatment failure and safety of lopinavir/ritonavir (LPV/r) and saquinavir/ritonavir (SAQ/r). Design Open-label, prospective, randomized (1:1), international multi-centre trial. Methods Adult HIV-1-infected patients were assigned LPV/r 400/100 mg twice daily or SAQ/r 1000/100 mg twice daily with two or more nucleoside reverse transcriptase inhibitors (NRTIs)/non-NRTIs. All patients, whether on or off the assigned treatment, were followed for 48 weeks. Results Of 339 randomized patients, 324 initiated assigned treatment (intention-to-treat/exposed [ITT/e] population). At 48 weeks, treatment failure occurred in 29/163 (18%) and 53/161 (33%) of patients in the LPV/r and SAQ/r arms, respectively (ITT/e, P=0.002, log rank test). In an analysis that also considered those patients who discontinued treatment as having failed treatment (ITT/e/discontinuation=failure), 40/161 (25%) LPV/r-treated individuals versus 63/161 (39%) SAQ/R-treated individuals failed treatment ( P=0.005, log rank test). Discontinuation of the assigned treatment occurred in 23/163 (14%) patients in the LPV/r-treated group, compared with 48/161 (30%) in the SAQ/r-treated group (ITT/e; P=0.001). The primary reasons for premature discontinuation were non-fatal adverse events (LPV/r: 12/163; SAQ/r: 21/161) and patients’ choice (LPV/r: 7/163; SAQ/r: 8/161). In the on-treatment analysis of time to treatment failure, no difference was observed between the two arms ( P=0.27, log rank test). Conclusion LPV/r had better antiretroviral effects compared with SAQ/r at the doses and in the formulations studied. This may have been a result of patients’ preferences and ability to adhere to assigned therapy, rather than a result of differences in the intrinsic potency of the study protease inhibitors.
Antiretroviral Drug Resistance among Drug-Naive HIV-1-Infected Individuals in Djibouti (Horn of Africa)
Authors: Maslin Jérôme , Rogier Christophe , Caron Melanie , Grandadam Marc , Koeck Jean-Louis , Nicand Elisabeth 
Published: April 2022

Objective To survey the frequency of genotypic anti-retroviral resistance in drug-naive HIV-1-infected Djiboutians. Methods A national study was conducted in the general population of Djibouti in March 2002 to determine HIV-1 seroprevalence. Blood samples were collected anonymously and plasma samples scoring positive for HIV-1 antibodies were tested for viral load. Genotypic studies were performed with viral RNA from plasma using the consensus technique of the Agence Nationale de Recherche sur le SIDA ( www.hivfrenchresistance.org ). Mutations were identified using the International AIDS Society-USA resistance panel and resistant virus was defined according to the ANRS algorithm. Results A panel of 2423 individuals representing the general population of Djibouti was included. Antibodies were detected in 53 of 2423 samples tested. The HIV-1 seroprevalence in the general population was 2.2%. Genotype C was the most prevalent, and the other isolates were CRF_02 AG, or subtype A or D. Forty-seven of the 53 samples were tested for genotypic resistance, and mutations concerning all three classes of antiretrovirals were found. The most frequent were secondary mutations associated with protease inhibitors (PIs): M36I, R41K and K20I/R. A few strains displayed primary mutations (the non-nucleoside reverse transcriptase inhibitor [NNRTI]-associated mutations K101E, K103T, L100I and G190V; the PI-associated mutation N88D; and the NRTI-associated mutation K65R). The presence of these mutations may be due to the transmission of strains from treated patients. Conclusion Substantial polymorphism and a few primary mutations are found in HIV-1 non-B subtype isolates from Djiboutian antiretroviral-drug-naive individuals. This needs to be taken into account to adapt antiretroviral regimens and prophylactic schedules locally.
Association of the CCR5Δ32 Mutation with Clinical Response and >5-year Survival following Initiation of First Triple Antiretroviral Regimen
Authors: Brumme Zabrina L , Henrick Bethany M , Brumme Chanson J , Hogg Robert S , Montaner Julio SG , Harrigan P Richard 
Published: April 2022

Objective The CCR5Δ32 mutation is associated with slower HIV disease progression in untreated infection. However, it remains controversial as to whether CCR5Δ32 is a relevant prognostic marker in the context of highly active antiretroviral therapy (HAART). Here we investigate associations between CCR5Δ32 and HAART outcomes in a large, population-based cohort of >1000 antiretroviral-naive individuals initiating triple therapy over a median >5 year follow-up. Methods CCR5Δ32 genotypes were determined using PCR and DNA sequencing in a cohort of 1188 antiretroviral-naive individuals initiating triple therapy in British Columbia. Associations between CCR5Δ32 and baseline (pre-therapy) sociodemographic and clinical parameters were investigated in a cross-sectional analysis. Cox proportional hazards regression was used to investigate the effect of CCR5Δ32 on clinical outcomes following therapy initiation. The endpoints that were evaluated included time to plasma viral load (pVL) suppression <400 copies HIV RNA/ml, subsequent time to pVL rebound ≥400 copies/ml, time to CD4+ cell decline below baseline, and time to non-accidental death over a median >5 year follow-up. Results CCR5Δ32 genotypes were available for 1174 of 1188 individuals (98.8%): 171 (14.6%) CCR5wt/Δ32 and 1003 (85.4%) CCR5wt/wt. At baseline, CCR5wt/Δ32 individuals had higher CD4+ cell counts ( P=0.04), lower plasma viral loads ( P=0.06) and were slightly older than CCR5wt/wt individuals ( P=0.04). In multivariate analyses controlling for baseline parameters and adherence estimates, we observed a significant association between CCR5wt/Δ32 and a shorter time to initial pVL suppression <400 copies/ml (multivariate hazard ratio [HR]: 1.20; 95% confidence interval [CI]: 1.01-1.44). No associations were observed between CCR5Δ32 and other clinical outcomes including subsequent time to pVL rebound or time to CD4+ cell decline below baseline. In univariate analyses, we observed a significant association between CCR5wt/Δ32 genotype and improved survival over the median >5 year period following initiation of HAART ( P=0.03). However, this association did not remain significant in multivariate analyses after adjusting for baseline factors including adherence (multivariate HR: 0.64; 95% CI: 0.38-1.07; P=0.09) Conclusion Results indicate that, after controlling for adherence, the CCR5Δ32 mutation is likely not a clinically significant predictor of longer-term clinical responses or survival in the context of HAART.
Efficacy and Safety of Indinavir/Ritonavir 400/100 mg Twice Daily plus Two Nucleoside Analogues in Treatment-Naive HIV-1-Infected Patients with CD4+ T-cell Counts <200 cells/mm3: 96-Week Outcomes
Authors: Mootsikapun Piroon , Chetchotisakd Ploenchan , Anunnatsiri Siriluck , Boonyaprawit Parichat 
Published: April 2022

Objective To evaluate the efficacy and safety of indinavir/ritonavir 400/100 mg plus stavudine and lamivudine twice daily in antiretroviral-therapy-naive Thai HIV-1-infected patients. Methods This was an open-label, non-randomized single arm study. Antiretroviral-naive patients ( n=80) with CD4+ cell count <200x106/l were started on stavudine and lamivudine plus indinavir/ritonavir 400/100mg twice daily. CD4+ cell count and HIV RNA were determined at week 0, 12, 24, 48 and 96. HIV RNA was measured to a level of 50 copies/ml by RT-PCR assay. Primary analysis was statistically performed as intent to treat. The primary endpoint was the percentage of patients with plasma HIV RNA below 50 copies/ml at week 96. Result Eighty antiretroviral-therapy-naive patients with median CD4+ cell count 19x106/l (range: 2-197x106/l) and median baseline plasma HIV RNA of 174,000 copies/ml (range 16,800–750,000 copies/ml) were enrolled. In the intent-to-treat analysis at week 96, the proportion of patients with HIV RNA of <50 copies/ml was 68.8% (95% confidence interval [CI]: 68.3-69.3), whereas it was 88.7% (95% CI: 88.1-89.3) in the on-treatment analysis at week 96. The regimen was well tolerated. Hyperglycaemia, hypercholesterolaemia and hypertriglyceridaemia were found in 8.3, 33.3 and 37.0% of the patients, respectively. Treatment was stopped in 18 patients; two from intolerance, two switched therapy, four as a result of serious adverse event-related death, and ten were lost to follow-up. Conclusion Our study demonstrates that indinavir/ritonavir 400/100 mg plus stavudine and lamivudine twice daily, the least expensive boosted protease inhibitor, appears to be effective and safe up to 96 weeks despite high baseline viraemia and low CD4+ cell count in antiretroviral-naive patients.