bluuebunny/crossref_metadata_2025 huggingface dataset:
Highly Active Antiretroviral Therapy: Physician Experience and Enhanced Adherence to Prescription Refill
Authors: Delgado Juan , Heath Katherine V , Yip Benita , Marion Stephen , Alfonso Victoria , Montaner Julio SG , O'Shaughnessy Michael V , Hogg Robert S
Published: April 2022

Objective

To identify patient and physician characteristics that may act as determinants of adherence to prescription refill of triple combination antiretroviral therapy.

Methods

A population-based analysis of antiretroviral therapy-naive HIV-positive men and women in British Columbia, Canada, who initiated triple combination therapy between August 1 1996 and October 31 1998. Study participants were considered adherent if they were actually dispensed antiretrovirals ≥95% over the first year of therapy. Log-binomial regression was used to identify patient and physician characteristics associated with adherence to prescription refill.

Results

Of the 886 individuals eligible for analysis, 495 (56%) were ≥95% adherent to prescription refill. In multivariate analysis, adherence was positively associated with increased age [adjusted relative rate (ARR) 1.19; 95% CI: 1.07–1.32], having a diagnosis of AIDS (ARR 1.66; 95% CI: 1.29–2.15), being male (ARR 1.79; 95% CI: 1.27–2.53), and with greater experience of the treating physician (ARR 1.27; 95% CI: 1.13–1.42). History of injection drug use was negatively associated with adherence to prescription refill (ARR 0.65; 95% CI: 0.51–0.83), as was increased pill burden (per pill daily) (ARR 0.95; 95% CI: 0.92–0.99). A sub-analysis of 316 patients who provided additional data regarding psychosocial characteristics indicated that adherence was positively associated with physician experience (ARR: 1.28; 95% CI: 1.09–1.51) and being employed (ARR: 1.55; 95% CI: 1.14–2.21), and negatively associated with a history of injection drug use (ARR: 0.61; 95% CI: 0.43–0.85).

Conclusion

While patient disease stage and personal characteristics may play an important role in patient adherence to prescription refill of complex therapeutic regimens, our findings indicate that HIV-experienced physicians may have greater success in maintaining patients on prescribed therapy.
Effects of Metformin Or Gemfibrozil on the Lipodystrophy of HIV-Infected Patients Receiving Protease Inhibitors
Authors: Martínez Esteban , Domingo Pere , Ribera Esteban , Milinkovic Ana , Arroyo Juan A , Conget Ignacio , Pérez-Cuevas José B , Casamitjana Roser , de Lazzari Elisa , Bianchi Luis , Montserrat Enric , Roca Merce , Burgos Rosa , Arnaiz Juan A , Gatell José M
Published: April 2022

Background

Hypertriglyceridaemia and insulin resistance are common in HIV-infected patients treated with protease inhibitors, particularly in those with lipodystrophy. Whether a therapeutic approach addressed to those metabolic abnormalities may have any impact on body fat is not clear.

Methods

Patients on stable antiretroviral therapy containing protease inhibitors, with abdominal obesity defined by increased waist-to-hip ratio, and plasma triglycerides >200 mg/dl, were randomized to receive blind medication consisting of metformin 850 mg, gemfibrozil 600 mg or placebo every 12 h for 1 year. Weight, height, waist and hip were measured, and fasting blood analyses, including at least CD4 cell count, plasma HIV-1 RNA, lactate, glucose, insulin, triglycerides, total, HDL and LDL cholesterol were performed at baseline and every 3 months. An oral glucose tolerance test, and assessments of total and regional fat by bioimpedance analysis and sonography, respectively, were also done at baseline, 6 and 12 months.

Results

One-hundred-and-eight patients were randomized to placebo ( n=36), gemfibrozil ( n=37) or metformin ( n=35). There was absolute loss of total and regional fat in the three arms without significant changes in the waist-to-hip ratio. However, the loss of fat in patients on gemfibrozil was significantly lower than in patients on placebo. No patient discontinued study drugs due to adverse effects.

Conclusion

In this population of HIV-infected patients, there was a loss of fat along time. The finding of relative preservation of fat associated with gemfibrozil therapy deserves further investigation in the search of potential effective therapies for lipodystrophy in HIV-infected subjects.
Impact of Genotypic Resistance Testing on Selection of Salvage Regimen in Clinical Practice
Authors: Haupts Stefan , Ledergerber Bruno , Böni Jürg , Schüpbach Jörg , Kronenberg Andreas , Opravil Milos , Flepp Markus , Speck Roberto F , Grube Christina , Rentsch Katharina , Weber Rainer , Günthard Huldrych F ,   the Swiss HIV Cohort Study, Bachmann S , Battegay M , Bernasconi E , Bucher H , Bürgisser Ph , Egger M , Erb P , Fierz W , Fischer M , Flepp M , Francioli P , Furrer HJ , Gorgievski M , Günthard H , Grob P , Hirschel B , Kaiser L , Kind C , Klimkait Th , Ledergerber B , Lauper U , Opravil M , Paccaud F , Pantaleo G , Perrin L , Piffaretti J-C , Rickenbach M , Rudin C , Schupbach J , Speck R , Telenti A , Trkola A , Vernazza P , Weber R , Yerly S
Published: April 2022

Objective

To determine whether genotypic resistance testing leads to selection of more potent drug regimens when compared to regimens based on treatment history only.

Design

Prospective, tertiary care centre-based study. Patients: One-hundred-and-forty-five HIV-infected adults on stable antiretroviral therapy (ART) for >6 months experiencing virological failure.

Methods

The physicians’ decision-making process when choosing a salvage regimen was prospectively documented: at time of virological failure, on ‘failing ART’, genotyping was performed and a hypothetical ‘clinical expert ART’ based upon patient's drug history was documented. Subsequently, data on resistance mutations, rating by a decision support software and drug history were used to define ‘genotyping ART’. After discussion with the patient, final treatment, ‘new personalized ART’ was chosen and prescribed. To compare the relative potency of the four ART regimens in a standardized manner, a resistance score ranging from 1 (best) to 8 (worst) based on drug ranking by decision support software was attributed to each ART regimen. Virological and immunological outcomes were analysed based on the magnitude of the resistance score.

Results

Median follow-up was 1.5 years. In all 145 patients, median resistance scores for the stepwise selected ART regimens were: ‘failing ART’: 4.5, ‘clinical expert ART’: 1.8, ‘genotyping ART’: 1.5 and ‘new personalized ART’: 2. The latter was 1.5 in patients who effectively switched to ‘new personalized ART’ ( n=89). Lower resistance scores translated into significantly improved virological response after initiation of ‘new personalized ART’. In multivariable analysis, lower resistance scores, lower baseline HIV RNA levels and use of novel antiretroviral drugs were associated with the probability of reducing plasma viraemia to <50 copies/ml. Conclusions: This study suggests that treatment choices including genotype and decision support software were virologically superior to those based on drug history only.
Sustained Response to Interferon–Ribavirin Combination Therapy Predicted by a Model of Hepatitis C Virus Dynamics Using Both Hcv Rna and Alanine Aminotransferase
Authors: Colombatto Piero , Civitano Luigi , Oliveri Filippo , Coco Barbara , Ciccorossi Pietro , Flichman Diego , Campa Mario , Bonino Ferruccio , Brunetto Maurizia Rossana
Published: April 2022

Background and aims

Standard models simulate the dynamics of hepatitis C virus (HCV) infection using HCV RNA kinetics and show a correlation between the clearance of infected hepatocytes and response to interferon. However, they are unable to predict whether the response will be maintained. The aim of our work was to identify criteria by which sustained responses may be predicted and defined.

Methods

In our model the clearance rate of infected cells is a function of their number and the baseline rate is computed by the alanine aminotransferase (ALT) kinetics during the first month of therapy. We simulated the variations of viral and infected cell loads in 31 consecutive patients treated with IFN-α2b 3–5 MU every other day, with or without ribavirin, for 6 or 12 months depending on HCV genotype.

Results

At baseline the computed (in 28 of 31 cases) percentage of infected cells was lower in seven sustained responders (mean: 11.7%, range: 1–24.6%) than in 14 transient responders (mean: 28.2%, range: 7.4–75.5%) and in seven non-responders (mean: 41%, range: 8.8–86%) ( P=0.036). At the end of therapy the computed infected cell number was <100 cells/ml of extracellular fluid in all sustained responders (mean: 18.4, range: 1.7–48), in three transient responders (mean: 3500, range: 1.52–17500) and in none non-responders (mean: 28500, range: 1200–96000) ( P=0.003). Overall of 10 patients with less than 100 infected cells/ml at the end of therapy seven (six had combination therapy) showed sustained response. All three relapsers received interferon monotherapy.

Conclusion

The analysis of infected cells dynamics using the new model might be useful to tailor treatment duration in patients with combination therapy.
The Potentiating Effect of Ribavirin on Interferon in the Treatment of Hepatitis C: Lack of Evidence for Ribavirin-Induced Viral Mutagenesis
Authors: Schinkel Janke , de Jong Menno D , Bruning Bas , van Hoek Bart , Spaan Willy JM , Kroes Aloys CM
Published: April 2022

The recent finding that ribavirin has a mutagenic capacity in a poliovirus replicon model pushing the virus into error catastrophe, provides a possible explanation for the remarkable synergistic effect of ribavirin when combined with interferon in the treatment of chronic hepatitis C virus (HCV)-infected patients. However, ribavirin-induced hypermutation resulting in loss of vital genetic information and viral clearance, does not occur during treatment of HCV-infected patients, as can be inferred from the lack of viral inhibition when treating HCV-infected patients with ribavirin alone. We therefore hypothesized that ribavirin induces mutations in the C-terminal part of the viral NS5A gene, a region found to be correlated with interferon sensitivity. Ribavirin-induced mutations resulting in the appearance of viral variants more sensitive to interferon would explain the synergistic effect of ribavirin when combined with interferon. To test this hypothesis we retrospectively analysed sequences of the C-terminal half of the NS5A gene before and during treatment in six HCV genotype 1-infected patients who had been treated with combination therapy after initial failure to respond permanently to interferon alone. Our results show that during the early treatment phase mutation rate is not enhanced during combination therapy and that, at least in the major variant, shifts in the NS5A domain resulting in the occurrence of viral variants, which are more interferon-sensitive, do not occur.
Phenotype or Virtual Phenotype for Choosing Antiretroviral Therapy after Failure: A Prospective, Randomized Study
Authors: Perez-Elias María Jesús , Garcia-Arata Isabel , Muñoz Vicente , Santos Ignacio , Sanz José , Abraira Víctor , Arribas José R , González Juan , Moreno Ana , Dronda Fernando , Antela Antonio , Pumares María , Martí-Belda Paloma , Casado Jose L , Geijo Paloma , Moreno Santiago ,   the Realvirfen study group
Published: April 2022

Background

Resistance testing is useful in the management of virological failure patients, although the best method to be used in clinical practice has not been determined.

Methods

A prospective, randomized, double-blind, multicentre, controlled clinical trial was performed to compare the usefulness of drug resistance testing with a recombinant viral phenotype method or with a virtual phenotype, a genotyping interpretation system. Planned 300 HIV-infected adults failing their current antiretroviral therapy (HIV RNA >1000 copies/ml) were centrally randomized 1:1 to resistance testing with a recombinant viral phenotype method or with a virtual phenotype, after stratifying according to previous drug exposure (one or two versus three drug classes). Percent of patients with HIV RNA suppression (% <400 copies/ml) after 24 weeks was the primary outcome variable. Median HIV RNA concentration and change from baseline in HIV RNA concentration were also used to compare effectiveness. An extended analysis was performed at week 48.

Results

Of the 300 patients enrolled, a total of 276 patients could be analysed; 139 patients were randomized to the phenotype group and 137 patients were randomized to the virtual phenotype group. After 24 weeks of follow-up, 46.8 and 56.2% of patients had HIV RNA <400 copies/ml ( P=0.1) in the phenotype and virtual phenotype, respectively. Mean decrease from baseline in viral load was 1.0 and 1.3 log copies/ml in the phenotype and virtual phenotype groups, respectively ( P=0.017). In a multivariate linear regression analysis, after adjusting for baseline HIV RNA and adherence to treatment, the virtual phenotype was associated with a greater mean decrease in plasma HIV RNA ( P=0.0063). The results observed at week 48 were similar.

Conclusions

Virtual phenotype is at least as effective as phenotype when used to select an optimized treatment for patients who have failed one or more antiretroviral regimens.
Nucleoside and Nucleotide Analogue Reverse Transcriptase Inhibitors: A Clinical Review of Antiretroviral Resistance
Authors: Gallant Joel E , Gerondelis Peter Z , Wainberg Mark A , Shulman Nancy S , Haubrich Richard H , Clair Marty St , Lanier Ernest R , Hellmann Nicholas S , Richman Douglas D
Published: April 2022

Although advances in highly active antiretroviral therapy (HAART) have made long-term suppression of HIV an achievable goal of therapy, a substantial proportion of first-line regimens will eventually fail. Successful long-term treatment requires consideration of downstream treatment options at the time of initiating or changing regimens. An understanding of the patterns and interactions of resistance mutations, and the appropriate use of genotypic and phenotypic testing is an important component of successful drug sequencing. Resistance to multiple nucleoside reverse transcriptase inhibitors (NRTIs) may result from several genotypically distinct pathways, including the Q151M (151 complex), the 69 insertion complex, two distinct thymidine analogue mutational pathways and the K65R mutation. Knowledge of the clinical implications of these and other resistance pathways, as well as the antagonism or synergy between mutations, helps guide individualized treatment choices from initial therapy in the treatment-naive patient to salvage therapy in the highly treatment-experienced individual. The development of effective sequencing strategies will depend upon the continued understanding of drug resistance mutation patterns and their associations with specific HAART combinations. This review summarizes research advances that further the understanding of nucleoside and nucleotide analogue resistance mutations, and their interplay.
Efficacy and Safety of Ritonavir/Indinavir 100/400 Mg Twice Daily in Combination with Two Nucleoside Analogues in Antiretroviral Treatment-Naive HIV-Infected Individuals
Authors: Duvivier Claudine , Astriti Myrto , Marcelin Anne-Geneviève , Ghosn Jade , Ait-Mohand Hocine , Schneider Luminita , Agher Rachid , Bricaire François , Costagliola Dominique , Calvez Vincent , Peytavin Gilles , Katlama Christine
Published: April 2022

Objective

To evaluate the efficacy and tolerability of indinavir/ritonavir (IDV/RTV) 400/100 mg twice daily in combination with two nucleoside reverse transcriptase inhibitors in antiretroviral-naive patients.

Design and methods

Antiviral therapy-naive patients with plasma HIV-1 RNA >5000 copies/ml were enrolled in this pilot, single-arm study. CD4 cell count and viral load were evaluated at weeks (W) 4, 12, 24 and every 3 months until W48. The primary end-point was the percentage (%) of patients with viral load <400 copies/ml at W48. Intent-to-treat (ITT) (missing values or change in treatment equalled failure) and on-treatment (OT) analyses were performed.

Results

Forty patients were enrolled. Baseline median viral load was 5.36 log10 copies/ml, median CD4 count was 84 cells/mm3. At W48 by ITT analysis, the % patients with viral load <400 copies/ml was 65% (95% CI: 48–79) and 50% (95% CI: 35–65) with viral load <50 copies/ml, and 96% (26/27) (95% CI: 89–100) and 74% (95% CI: 57–91], respectively, by OT analysis. The median decrease in viral load at W48 was –3.83 log10 copies/ml (–0.1; –5.19) and the median increase in CD4 was +167 cells/mm3 (6–474 cell/mm3). At W4 (34/40), the median IDV Cmin was 500 ng/ml (range 5–8100) with 91% of patients with an adequate IDV Cmin >150 ng/ml. Ten patients discontinued the study treatment before W48: adverse events (eight), patient's will (one) and simplification of therapy (one). Three patients were lost to follow-up. Only one virological failure occurred and was associated with poor compliance and sub-optimal concentrations of IDV/RTV.

Conclusions

IDV/RTV 400/100 mg twice daily is an effective and safe first-line antiretroviral therapy. The simplicity and the low cost of IDV/RTV is of major interest particularly in countries with limited resources.
Hepatitis B Virus Genotypes B and C Do Not Affect the Antiviral Response to Lamivudine
Authors: Yuen Man-Fung , Wong Danny Ka-Ho , Sablon Erwin , Yuan He-Jun , Sum Siu-Man , Hui Chee-Kin , Chan Annie On-On , Wong Benjamin Chun-Yu , Lai Ching-Lung
Published: April 2022

To date, there have been no studies examining the role of hepatitis B virus (HBV) genotypes on the response to lamivudine therapy and the development of YMDD mutations. The present study aimed at determining any differences in the antiviral response and risk of YMDD mutations between lamivudine-treated patients with HBV genotype B and genotype C. Eighty-two patients receiving lamivudine were recruited. HBV genotypes at baseline and YMDD mutations at week 52 were determined by line probe assays (LiPA). HBV DNA levels were determined by the Cobas Amplicor HBV Monitor Test. Seventeen (20.7%) and sixty-four (78%) patients had single genotypes of B and C, respectively. At both week 24 and 52 there were no differences in the median reduction of HBV DNA levels (median 4 logs drop), the median reduction of alanine aminotransferase (ALT) levels, and the proportion with normalization of ALT [8/8 (100%) vs 26/37 (70.3%), P=0.19] between patients with genotypes B and C. The rate of HBeAg seroconversion [3/17 (17.6%) vs 6/64 (9.4%), P=0.39] and the chance of YMDD mutation development [3/17 (17.6%) vs 12/64 (18.8%), P=1.0] at week 52 were also similar between patients with genotype B and C, respectively. In conclusion, there was no difference in the antiviral response and the rate of development of YMDD mutations in Chinese patients with genotype B and C after 1 year of lamivudine. Determination of HBV genotypes before lamivudine therapy was probably not an important pre-treatment investigation to predict antiviral responses in Chinese patients.
A Randomized Trial Comparing Initial Haart Regimens of Nelfinavir/Nevirapine and Ritonavir/Saquinavir in Combination with Two Nucleoside Reverse Transcriptase Inhibitors
Authors: Kirk Ole , Lundgren Jens D , Pedersen Court , Mathiesen Lars R , Nielsen Henrik , Katzenstein Terese L , Obel Niels , Gerstoft Jan
Published: April 2022

Background

A triple-class HAART regimen may be associated with a better virological effect than conventional regimens, but may also lead to toxicity and more profound resistance.

Methods

Randomized, controlled, open-label trial of 233 protease inhibitor- and non-nucleoside reverse transcriptase inhibitor-naive HIV-infected patients allocated to a regimen of nelfinavir and nevirapine (1250/200 mg twice daily; n=118) or ritonavir and saquinavir (400/400 mg twice daily; n=115), both in combination with two nucleoside reverse transcriptase inhibitors. The primary end-point was HIV RNA ≤20 copies/ml after 48 weeks (missing value=failure). Patients remained under follow-up also in case of switch from the randomized therapy.

Results

At baseline, the median CD4 cell counts were 126 (range: 0–942) (nelfinavir/nevirapine) and 150 (0–642) (ritonavir/saquinavir) cells/mm3, and HIV RNA measurements 5.0 copies/ml (1.3–6.4) in both groups. A total of 102 (86%) and 101 (88%) were antiretroviral-naive. Within 48 weeks, 35 and 44% discontinued randomized therapy; P=0.13. Of these, 80 and 73% switched therapy due to adverse events; P=0.99. At week 48, 69 and 56%, respectively, had a HIV RNA ≤20 copies/ml; P=0.037.

Conclusion

A regimen of nelfinavir/nevirapine had a favourable virological effect and tolerability over a 48-week period compared with ritonavir/saquinavir, when administered in combination with two nucleoside reverse transcriptase inhibitors. However, more extensive follow-up is required to determine the long-term consequences of triple class HAART regimens, including the development of broad drug resistance.
Unique Keratinocyte-Specific Effects of Interferon-γ that Protect Skin from Viruses, Identified Using Transcriptional Profiling
Authors: Banno Tomohiro , Adachi Makoto , Mukkamala Lakshmi , Blumenberg Miroslav
Published: April 2022

Interferon (IFN)-γ, is a multifunctional, immunomodulatory cytokine with cell type-specific antiviral activities, particularly important in skin, where it is implicated in many diseases ranging from warts to psoriasis and cancer. Since epidermis is our first line of defence against many viruses, we investigated the molecular processes regulated by IFN-γ in keratinocytes using DNA microarrays. We identified the IFN-γ-regulated keratinocyte-specific genes and antiviral processes. Exclusively in keratinocytes, IFN-γ-induced tight junction proteins, presumably to deny viruses paracellular routes of infection. Furthermore, differing from published data, we find that IFN-γ suppressed the expression of keratinocytes differentiation markers including desmosomal proteins, cornified envelope components and suprabasal cytokeratins. Inhibition of differentiation may interfere with the epidermal tropism of viruses that require differentiating cells for growth, for example, papillomaviruses. As in other cell types, IFN-γ induced HLA, cell adhesion and proteasome proteins, facilitating leukocyte attraction and antigen-presentation by keratinocytes. IFN-γ also induced chemokine/cytokines specific for mononuclear cells. IFN-γ suppressed the expression of over 100 genes responsible for cell cycle, DNA replication and RNA metabolism, thereby shutting down many nuclear processes and denying viruses a healthy cell in which to replicate. Thus, uniquely in keratinocytes, IFN-γ initiates a well-organized molecular programme boosting host antiviral defences, obstructing viral entry, suppressing cell proliferation and impeding differentiation.
Comparison of Antiviral Effect of Lamivudine with Interferon-α2A versus -α2B in Children with Chronic Hepatitis B Infection
Authors: Ozgenc Funda , Dikici Bunyamin , Targan Seref , Doganci Tumay , Akman Sezin , Aydogdu Sema , Yagci Rasit Vural
Published: April 2022

Aim

To compare additive efficacy of combination therapy including interferon (IFN)-α2a+lamivudine (3TC) to IFN-α2b+3TC in children with chronic hepatitis B virus (HBV) infection.

Material and methods

Chronic hepatitis B infection was determined by presence of HBsAg, HBeAg and HBV DNA in serum screened at 3 months intervals for at least 1 year, serum alanine transaminase (ALT) levels more than 1.5-times the upper normal limit and chronic hepatitis with histological activity index (HAI) more than 6 by liver biopsy. Sixty-three children with chronic hepatitis B infection were treated randomly with thrice-weekly subcutaneous injections of 5 MU/m2 recombinant IFN-α2a ( n=29) or recombinant IFN-α2b ( n=34) with the same dose, intervals for 6 months. Patients also received 3TC (4 mg/kg/day, max 100 mg/day) orally daily combined with IFN and continued for 12 months. End of therapy response was defined as ALT normalization, HBV DNA clearance and HBe/anti-HBe seroconversion. Breakthrough infection was determined as re-emergence of HBV DNA in serum after its clearance. Response rate, incidence of side effects and breakthrough infection were compared between IFN-α2a+3TC- and IFN-α2b+3TC-treated patients.

Results

Response rate was 44.8% ( n=13) with IFN-α2a+3TC and 47.1% ( n=16) with IFN-α2b+3TC ( P=1.0). No significant difference was found in respect to the DNA clearance ( P=0.32), anti-HBe ( P=1.0), anti-HBs ( P=0.09) seroconversion and response rates ( P=1.0) between the groups. Breakthrough infection was detected in 1 (3.4%) case on IFN-α2a and none of the cases on IFN-α2b ( P=0.46). All of the patients experienced flu-like symptoms, malaise and fatigue; however, side effect interfering with therapy was not encountered.

Conclusion

No significant difference was found in response rates achieved by combination therapies based on IFN-α2a and IFN-α2b. Clinical efficacy of 3TC and two different IFN subtypes was found similar.
Cost Effectiveness Analysis of Routine Use of Genotypic Antiretroviral Resistance Testing after Failure of Antiretroviral Treatment for HIV
Authors: Corzillius Michael , Mühlberger Nikolai , Sroczynski Gaby , Jaeger Hans , Wasem Jürgen , Siebert Uwe
Published: April 2022

Objectives

Single use of genotypic antiretroviral resistance testing (GART) after first failure of highly active antiretroviral therapy (HAART) was reported to be cost effective; its use prior HAART initiation is unknown. Guidelines recommend GART after each treatment failure. We assessed the cost effectiveness of GART used routinely after first and subsequent treatment failures. Furthermore, we determined the minimum effectiveness required for GART prior to the first HAART to be as cost effective as after treatment failure.

Design and methods

We developed a decision-analytic Markov model to estimate lifetime clinical and economic outcomes in a cohort of HIV patients starting HAART. Rates of treatment failure, estimates of GART effectiveness and data on disease progression were derived from published trials and observational studies. A cost effectiveness analysis was performed from the perspective of the healthcare system using cost data from a Central European healthcare setting. Deterministic and probabilistic sensitivity analyses using Monte Carlo technique were performed.

Results

GART after treatment failures increased life expectancy by 9 months and undiscounted life-time costs per case by €16406. The discounted incremental cost effectiveness ratio was €22510 per life-year gained (€/LY). Best- and worst-case scenarios yielded 16 512 €/LY and 42900 €/LY, respectively. GART prior to the initiation of HAART would be equally cost effective if it could reduce the probability of first HAART failure by at least 36%.

Conclusion

Routine use of GART after treatment failures is cost effective. GART prior to the first HAART would be equally cost effective if it could lower the probability of first HAART failure by approximately a third.
Sequential Switching of Dna Polymerase and Thymidine Kinase-Mediated Hsv-1 Drug Resistance in An Immunocompromised Child
Authors: Stránská Růžena , van Loon Anton M , Bredius Robbert GM , Polman Merjo , Nienhuis Elske , Beersma Matthias FC , Lankester Arjan C , Schuurman Rob
Published: April 2022

Sequential herpes simplex virus type 1 (HSV-1) isolates were obtained from a paediatric haematopoietic stem cell transplant (HSCT) patient who received prolonged therapy with acyclovir (ACV) followed by foscarnet (PFA) and topical cidofovir (HPMPC) for severe persistent mucocutaneous HSV-1 infection. The isolates were retrospectively studied for drug resistance. The first resistant isolate associated with clinical failure of antiviral therapy emerged 44 days post-ACV treatment initiation. Susceptibility testing revealed an ACV-resistant HSV strain that demonstrated cross resistance to PFA in the absence of any previous PFA treatment. The observed cross resistance was conferred by a single amino acid substitution, Ser724Asn, in the HSV DNA polymerase (DNA pol) gene. During the subsequent course of ACV therapy, the ACV/PFA-cross-resistant isolates were replaced by ACV-resistant, PFA-sensitive isolates. These isolates carried no DNA pol mutations, but had an Arg163His substitution in the thymidine kinase gene. Upon subsequent switching of antiviral therapy from ACV to PFA, the original ACV/PFA-cross-resistant DNA pol mutant re-appeared. Our study shows the emergence of different drug-resistant HSV variants during ongoing, unchanged ACV therapy. Furthermore, a rapid re-selection of the original resistant variant was observed after switch. For optimal antiviral management of HSV infections in HSCT recipients, therapeutic decisions should be guided by drug susceptibility results whenever therapeutic failure is observed and/or when changes in antiviral treatment are considered.
Susceptibility of HIV-2, Siv and Shiv to Various Anti-HIV-1 Compounds: Implications for Treatment and Postexposure Prophylaxis
Authors: Witvrouw Myriam , Pannecouque Christophe , Switzer William M , Folks Thomas M , Clercq Erik De , Heneine Walid
Published: April 2022

Limited information is available on the activity of anti-retroviral drugs against human immunodeficiency virus type 2 (HIV-2) and simian immunodeficiency virus (SIV) strains to guide their use in treatment or prophylaxis. We evaluated the antiviral activity of 16 approved drugs and one experimental drug, AMD3100, against two wild-type HIV-2 (ROD and EHO) isolates, two strains of SIV (mac251 and B670), and two strains of simian–human immunodeficiency virus (SHIV) that contain the reverse transcriptase (RTSHIV) or envelope glycoprotein (SHIV89.6) of human immunodeficiency virus type 1 (HIV-1) in a SIV(mac239) background. Drug susceptibility was measured conventionally by the MT-4/MTT assay, and results were analysed as fold changes in 50% effective concentration (EC50) relative to the EC50 for HIV-1(IIIB). The nucleoside reverse transcriptase inhibitors (NRTIs) zidovudine, lamivudine, stavudine, didanosine, zalcitabine and abacavir as well as the nucleotide reverse transcriptase inhibitor tenofovir retained full activity against all six viruses except for SIV and SHIV89.6 that showed low-level resistance to didanosine. The protease inhibitors (PIs) ritonavir, indinavir, saquinavir and nelfinavir were found to be active against some HIV-2 or SIV strains. However, a significant reduction in susceptibility was seen with indinavir against SHIV89.6 (3.3-fold), and with amprenavir against HIV-2(ROD) (8.8-fold). All viruses except for RTSHIV showed a >200-fold decrease in susceptibility for the non-nucleoside reverse transcriptase inhibitors (NNRTIs) nevirapine, delavirdine and efavirenz, indicating high-level resistance. AMD3100, a CXCR4 antagonist, was active against HIV-2 and SHIV89.6, a finding consistent with the use of the CXCR4 co-receptor by these isolates, but was inactive against SIV strains. In contrast, enfuvirtide (T-20) was active against SHIV89.6 but had reduced inhibitory activity against both HIV-2 and SIV strains predicting little therapeutic value against these viruses. These findings support the use of NRTIs, tenofovir, but not NNRTIs, for treating HIV-2-infected persons or for prophylaxis against HIV-2 and SIV. The clinical significance of the low-level resistance of HIV-2 and SIV to some PIs is unclear. Co-receptor antagonists such as AMD3100 show promising anti-HIV-2 therapeutic modalities. Both AMD3100 and enfuvirtide could be used for prophylaxis against SHIV89.6.
Once-Daily Dosing of Saquinavir Soft-Gel Capsules and Ritonavir Combination in HIV-1-Infected Patients (Imea015 Study)
Authors: Lamotte Claire , Landman Roland , Peytavin Gilles , Mentre France , Gerbe Juliette , Brun-Vezinet Françoise , Boue François , Spiridon Gabriella , Valantin Marc-Antoine , Michelet Christian , Farinotti Robert , Yeni Patrick
Published: April 2022

This was a prospective pilot study evaluating a saquinavir (SQV) soft-gel capsules (SGC)/ritonavir (RTV)-containing once-daily regimen over a follow-up of 3 months. The primary end-point was to determine the number of patients both remaining on treatment at month 3 and with trough SQV plasma concentration 24 h after the last intake (C24h) exceeding the inhibition of 95% of viral replication in vitro (IC95). The secondary end-points were to investigate the immuno-virological efficacy and safety of SQV-SGC/RTV once daily, and to explore SQV concentrations in peripheral blood mononuclear cells (PBMCs). Twenty-three antiretroviral-naive and 17 protease inhibitors (PIs) experienced HIV-1-infected patients with plasma HIV-1 RNA level below 200 copies/ml were enrolled. They were assigned to SQV-SGC/RTV (1600/100 mg once daily) combined with nucleoside and/or non-nucleoside reverse transcriptase inhibitors. In a subgroup of 13 patients, both plasma and intracellular SQV concentrations were determined. By intent to treat analysis the percentage of success at month 3 was 87.5% (confidence interval: 73.2–95.8%) with 78.3% in naive and 100% in PI-experienced patients. SQV C24h and intracellular concentrations [median (range, n)] were 241 ng/ml (40–1209, 35) and 323 ng/ml (168–475, 12), respectively. Intracellular concentrations showed an accumulation of SQV in PBMCs persisting during 24 h. Neither immunological nor virological failure was observed. Clinical and biological tolerance was acceptable in all patients but three with adverse effects leading to discontinuation. These data confirmed the short-term efficacy of SQV-SGC/RTV once-daily regimen based on SQV therapeutic drug monitoring.

This work was presented in part at the 2nd International Conference on Clinical Pharmacology of HIV Infection, Noordwijk, the Netherlands, 2-4 April 2001 (Abstract 3.16); and at the 1st International Conference on HIV Pathogenesis & Treatment, Buenos Aires, Argentina, 8–11 July 2001 (Abstract 344).
Probing the Structure of the Sars Coronavirus Using Scanning Electron Microscopy
Authors: Lin Yun , Yan Xiyun , Cao Wuchun , Wang Chaoying , Feng Jing , Duan Jinzhu , Xie Sishen
Published: April 2022

A novel coronavirus, SARS-CoV, has been confirmed to be the aetiological agent of SARS. Transmission electron microscope (TEM) images played an important role in initial identification of the pathogen. In order to obtain greater morphological detail of SARS-CoV than could be obtained by TEM, we used ultra-high resolution scanning electron microscopy (SEM) to image the virus particles. We show here the three-dimensional appearance of SARS-CoV. Enhanced detail of the ultrastructure reveals the trimeric structure of the 10–20 nm spikes on the virion surface. These results contribute to characterization of the SARS agent and development of new antiviral strategies.
Adipocytes Targets and Actors in the Pathogenesis of HIV-Associated Lipodystrophy and Metabolic Alterations
Authors: Gougeon Marie-Lise , Pénicaud Luc , Fromenty Bernard , Leclercq Pascale , Viard Jean-Paul , Capeau Jacqueline
Published: April 2022

The recent clinical use of potent HIV-1 drugs, including nucleoside reverse transcriptase inhibitors (NRTIs) and non-peptidic viral protease inhibitors (PIs), and their combinations, termed highly active antiretroviral therapy (HAART), has dramatically reduced the infection-related mortality of AIDS patients, but it is associated with severe metabolic adverse events such as lipodystrophy syndrome, dyslipidaemia, insulin resistance and diabetes mellitus. The aetiology of this syndrome and metabolic alterations appear to be multifactorial, including HIV drug inhibitory effects on adipocyte differentiation, alteration of mitochondrial functions in adipocytes and altered leptin, adiponectin and cytokine expression in adipose tissue of patients. Adipose tissue may thus be a central regulator in disorganized lipid metabolism and insulin resistance associated with antiretroviral therapy, and we propose in this review to explore how adipose tissue may be a target, but also an actor, in the aetiopathogenesis of the lipodystrophy syndrome.
Safety and Efficacy of a Nrti-Sparing Haart Regimen of Efavirenz and Lopinavir/Ritonavir in HIV-1-Infected Children
Authors: Fraaij Pieter LA , Neubert Jennifer , Bergshoeff Alina S , van Rossum Annemarie MC , Hartwig Nico G , Schroten Horst , Korn Klaus , Burger David M , de Groot Ronald , Niehues Tim
Published: April 2022

We studied a nucleoside reverse transcriptase inhibitor (NRTI)-sparing regimen for the treatment of children infected with NRTI-resistant HIV-1. The combination of lopinavir/ritonavir and efavirenz suppressed HIV-1 levels for a prolonged period and resulted in a significant increase in CD4+ T cell numbers despite an extensive prior treatment with NRTI (>4 years). Observed side effects were transient with the exception of dyslipidaemia.
Impact of Insertions in the HIV-1 P6 Ptapp Region on the Virological Response to Amprenavir
Authors:   the NARVAL Trial Group (ANRS 088), Lastere Stephane , Dalban Cecile , Collin Gilles , Descamps Diane , Girard Pierre-Marie , Clavel Francois , Costagliola Dominique , Brun-Vezinet Francoise , Brun-Vezinet F , Clavel F , Costagliola D , Dalban C , Girard PM , Matheron S , Meynard JL , Morand-Joubert L , Peytavin G , Vray M , Beguinot I , Waldner A , Beumont M , Semaille C , Bentata M , Berlureau P , Gérard L , Molina JM , Hor R , Bayol-Honnet G , Lascoux-Combe C , Drobacheff C , Hoen B , Dupon M , Lacut JY , Goujard C , Rousseau C , Vincent V , Diemer M , Lepeu G , Zerazhi H , de Truchis P , Berthé H , Jeantils V , Tazi C Taleb , Vittecoq D , Escaut L , Dupont B , Nait-Ighil L , Rozenbaum W , Nguyen T Huyen , Boué F , Galanaud P , Kazatchkine M , Piketty C , Bernasconi C , Salmon-Ceron D , Michon C , Chandemerle C , Lascaux AS , Magnier JD , Schneider L , Ait-Mohand H , Simon A , Herson S , Bollens D , Picard O , Tangre P , Bonarek M , Morlat P , Trépo C , Cotte L , Gastaut JA , Poizot-Martin I , Moran G , Masson S , Bennai Y , Belarbi L , Prevot MH , Fournier I , Reynes J , Baillat V , Raffi F , Esnault JL , Ceppi C , Cassuto JP , Arvieux C , Chapplain JM , Rey D , Krantz V , Besnier JM , Bastides F , Obadia M , Aquilina C , Bazin C , Verdon R , Piroth L , Grappin M , Sissoko D , Valette M , May T , Burty C , Debab Y , Caron F , Elharrar B , Launay O , Winter C , Chapuis L , Auperin I , Gilquin J
Published: April 2022

We evaluated the impact of genetic changes within p6Gag gene on the virological response (VR, mean decrease in plasma viral load at week 12) to unboosted amprenavir (APV). Gag-protease fragments, including gag p2, p7, p1, p6 regions and whole protease (PR) were sequenced from baseline plasma specimens of 84 highly pre-treated but APV-naive patients included in the NARVAL (ANRS 088) trial. The correlation between baseline p6Gag polymorphism, PR mutations, baseline characteristics and VR to APV was analysed in univariate analysis. Insertions (P459Ins) within p6 protein, leading to partial or complete duplication of the PTAPP motif, were significantly associated with a decreased VR (P459Ins versus wild-type; –0.3 ±0.8 vs –1.1 ±1.2 log copies/ml, P=0.007) and were more frequent when the V82A/F/T/S PR mutation was present ( P=0.020). In multivariate analysis, after adjustment on the predictive factors of the VR in the NARVAL trial and on the PR mutations linked with response, there was a strong trend to an association ( P=0.058) between the presence of P459Ins and an altered VR. In conclusion, these results suggest that insertions in the p6 region of HIV-1 gag gene may affect the VR, in highly pre-treated patients receiving an unboosted APV-containing regimen.
Antiretroviral Treatment Alters Relationship between Mcp-1 and Neurometabolites in HIV Patients
Authors: Chang Linda , Ernst Thomas , Hillaire Coryse St , Conant Katherine
Published: April 2022

Objective

The relationships between neurometabolites and macrophage chemoattractant protein (MCP-1) in serum and cerebrospinal fluid (CSF) were evaluated in HIV patients before and after antiretroviral treatment. Design: Prior studies found higher CSF MCP-1 levels in patients with HIV-associated dementia compared to those in neuroasymptomatic. We hypothesized that CSF MCP-1 levels would correlate inversely to neuronal metabolites [including N-acetyl compounds, gluta-mate+glutamine, as assessed by principal component analyses (PCA)] and positively to glial metabolites (including myo-inositol and choline compounds).

Methods

Thirty-nine antiretroviral-naive HIV patients were evaluated prospectively with proton magnetic resonance spectroscopy (1H MRS), and serum and CSF MCP-1 measurements prior to highly active antiretroviral therapy (HAART); 31 of these patients completed follow-up studies after 3 months of HAART but only 24 had follow-up CSF studies.

Results

After HAART, brain metabolites and clinical signs showed no change despite improvements in systemic (CD4 counts, plasma viral load, MCP-1) and CSF (viral load and MCP-1) variables. CSF, but not serum, MCP-1 levels correlated inversely with the neuronal component (from PCA) prior to treatment ( r=-0.59, P=0.0008). Conversely, after 3 months of HAART, the glial component (from PCA) correlated positively with CSF MCP-1 levels ( r=0.70, P=0.0002; ANCOVA interaction for treatment status, P=0.003).

Conclusions

These findings suggest that higher CSF MCP-1 levels are associated with neuronal dysfunction in untreated patients. After 3 months of HAART, the decreased systemic factors (viral burden, systemically derived MCP-1) no longer associate with neuronal dysfunction, but subjects with the strongest glial response in the brain continue to produce the highest levels of MCP-1.
Genotypic Determinants of the Virological Response to Tenofovir Disoproxil Fumarate in Nucleoside Reverse Transcriptase Inhibitor-Experienced Patients
Authors:   the ANRS AC11 Resistance study group, Masquelier Bernard , Tamalet Catherine , Montès Brigitte , Descamps Diane , Peytavin Gilles , Bocket Laurence , Wirden Marc , Izopet Jacques , Schneider Véronique , Ferré Virginie , Ruffault Annick , Palmer Pierre , Trylesinski Aldo , Miller Michael , Brun-Vézinet Françoise , Costagliola Dominique
Published: April 2022

Objective

To assess the genotypic determinants of the virological response to tenofovir disoproxil fumarate (TDF) in a multicentre cohort of antiretroviral (ARV)-experienced patients receiving TDF as a part of a salvage therapy.

Methods

HIV-1 genotype was assessed at baseline in a subgroup of 161 patients of the French expanded access program receiving a stable TDF-including regimen for 3 months or more. Reverse transcriptase mutations associated with the viral load decrease at month 3 with a P-value <0.15 were retained for the construction of a mutation score. The score was then validated using a multivariate analysis and bootstrap resampling method.

Results

The strongest association with decrease in viral load was observed with a set of seven mutations (TDF mutation score) that consisted of M41L, E44D, D67N, T69D/N/S, L74V, L210W and T215Y/F RT mutations. The RT K65R mutation and the insertions at codon 69 were not included in the analysis due to low prevalences. A TDF mutation score of ≤2 predicted the absence of resistance to TDF and ≥6 mutations predicted resistance to TDF with corresponding reductions in viral load of –1.3 ±1.1, and +0.1 ±0.7 log10 copies/ml, respectively. In patients with a TDF mutation score of 3–5, the decrease in viral load was –0.8 ±1.0 log10 copies/ml and was considered possibly resistant. In the multivariate analysis, a TDF mutation score ≥6, previous use of amprenavir, indinavir and lopinavir, and co-prescription of didanosine were associated with a worse virological response. The bootstrap analysis showed the robustness of the TDF mutation score.

Conclusion

In ARV-experienced patients receiving TDF-containing regimens, a score derived from seven reverse transcriptase mutations was shown to be independently predictive of the virological response.
Safety and Efficacy of Once-Daily Didanosine, Tenofovir and Nevirapine as a Simplification Antiretroviral Approach
Authors: Negredo Eugènia , Moltó José , Muñoz-Moreno José Antonio , Pedrol Enric , Ribera Esteve , Viciana Pompeyo , Galindo M José , Miralles Celia , Burger David , Fumaz Carmina Rodriguez , Puig Jordi , Gel Sílvia , Rodríguez Eva , Videla Sebastià , Ruiz Lidia , Clotet Bonaventura
Published: April 2022

Objective

To assess the efficacy and safety of a once-daily antiretroviral regimen in HAART-experienced subjects with long-lasting viral suppression.

Methods

One-hundred-and-sixty-nine patients with chronically suppressed viral load (limit of detection <50 copies/ml) were recruited. Based on patient willingness to simplify treatment, 84 of them continued receiving their usual treatment (BID Group) and 85 switched to once-daily didanosine/tenofovir/nevirapine (QD Group) in a non-randomized fashion.

Results

At week 48, the proportion of patients with viral suppression in the QD and in the BID Group, respectively, was 97 vs 100% in the per-protocol analysis ( P=0.497), and 76 vs 86% for the intention-to-treat analysis ( P=0.176). Nevertheless, CD4 count decreased in the QD Group, with a mean decline of 95 cells/mm3 (95% CI: 45–145). Twelve subjects in the QD Group (14%) discontinued treatment due to adverse events, mainly nevirapine-related hepatitis (6%). No significant differences regarding the rate of acute pancreatitis or peripheral neuropathy were observed between both groups. A significant improvement in the lipid profile was only seen in the QD Group. High levels of adherence were observed in both groups during follow-up, as well as a good quality of life. At week 48, a reduction in effort to take medication ( P≤0.001) and an increment in the satisfaction with the treatment ( P<0.001) was only seen in the QD group. No differences were observed in median nevirapine trough levels between patients on twice-daily nevirapine at baseline (4820 ng/ml) and subjects in the QD Group (6090 ng/ml, P=0.30).

Conclusion

Treatment simplification to a once-daily antiretroviral regimen based on didanosine, tenofovir and nevirapine may be a valid approach in HIV-infected subjects with long-lasting viral suppression. Combination of standard doses of didanosine and tenofovir may have contributed to the CD4 cell decline observed with this QD regimen.
Destabilization of the Non-Pathogenic, Cellular Prion-Protein by a Small Molecular Drug
Authors: Ochel Hans-Joachim , Gademann Günther
Published: April 2022

The presence of the normal cellular prion-protein (PrPc) is a prerequisite for the development of fatal, neurodegenerative diseases called transmissible spongiform encephalopathies (TSEs). We discovered a new biological activity of the well-known coumarin antibiotic novobiocin; the treatment of eukaryotic cells with novobiocin induces the rapid depletion of PrPc. This activity is shared by coumermycin A1, another coumarin with a related molecular structure. Novobiocin's effects on the prion-protein are time- and dose-dependent. No permanent damage to the treated cells was observed, which continue to proliferate after cessation of drug exposure. Most of the cellular proteins are unaffected by novobiocin treatment. Pretreatment with geldanamycin, an inhibitor of the aminoterminal ATPase of heat-shock protein 90 (Hsp90) partially antagonizes novobiocin's depletory activity. Concurrent treatment with the protease inhibitor chymostatin completely prevents PrPc loss. Here we show that the stability of the normal cellular prion-protein may be targeted pharmacologically. These findings open up a hitherto unknown avenue to the study of TSEs in general and may have therapeutic implications.