bluuebunny/crossref_metadata_2025 huggingface dataset:
Lifetime Cost of HIV Care in France during the Era of Highly Active Antiretroviral Therapy
Authors: Yazdanpanah Yazdan , Goldie Sue J , Losina Elena , Weinstein Milton C , Lebrun Thérèse , Paltiel A David , Seage George R , Leblanc Garmenick , Ajana Faisa , Kimmel April D , Zhang Hong , Salamon Roger , Mouton Yves , Freedberg Kenneth A
Published: April 2022

Objective

To estimate the treatment and health care costs of HIV infection or AIDS in France during the era of highly active antiretroviral therapy (HAART).

Design

We used a clinical database of HIV-infected patients to calculate the resource use and cost of care for different stages of HIV infection. Costs were incorporated into a computer-based, probabilistic simulation model of the natural history and treatment of HIV infection to estimate the lifetime cost of treating patients with HIV disease.

Setting

A northern France HIV clinical cohort.

Participants

1232 HIV-infected patients followed from January 1994 through July 1998.

Results

In the absence of an AIDS-defining event, the average total cost of care ranged from 670 euros (1 euro=US $1.19) per person-month in the highest CD4 stratum (>500/μl) to 1060 euros per person-month in the lowest CD4 stratum (≤50/μl). The mean cost of care was estimated at 3370 euros per person-month during the initial months around the occurrence of an AIDS-defining event; at 1750 euros per person-month during the period spanning from 2 months after the diagnosis of specific AIDS-defining event to 1 month prior to death; and at 13 010 euros per person-month in the final month prior to death. If clinical management of HIV infection began at a CD4 cell count of 378/μl, as in this cohort, the discounted lifetime cost of treating an HIV-infected French patient was estimated at 214 000 euros. The undiscounted costs were 309 000 euros over a projected life expectancy of 16.4 years.

Conclusion

The cost of HIV disease varies widely depending upon the stage of illness. These estimates of stage-specific and lifetime costs of HIV care will assist health policy planners in assessing the burden of disease in the era of HAART and projecting future resource requirements.
No Protective Effect of Acyclovir on HIV Disease Progression in a Cohort of Hsv-2–HIV-Infected Individuals
Authors:   the Italian Seroconversion Study (see acknowledgements for list of individuals and centres), Suligoi Barbara , Dorrucci Maria , Volpi Antonio , Andreoni Massimo , Rezza Giovanni , Rezza Giovanni , Pezzotti Patrizio , Dorrucci Maria , Sinicco Alessandro , Zerboni Roberto , Angarano Gioacchino , Lazzarin Adriano , Aiuti Fernando , Zaccarelli Mauro , Salassa Bernardino , Castelli Francesco , Alberici Francesco , Mazzarello Giovanni , Barbanera Mauro , Colangeli Vincenzo , Ortona Luigi , Pristerà Raffaele , Ursitti Maria A. , Tirelli Umberto , Giuliani Massimo
Published: April 2022

The efficacy of anti-herpetic drugs in decreasing HIV disease progression has not been clarified. We studied a cohort of 126 HIV-positive individuals with known date of seroconversion who were HSV-2-seropositive to determine if progression to AIDS was influenced by treatment with acyclovir. In the multivariate analysis, being homosexual and low CD4 count were associated with a faster progression to AIDS, whereas treatment with acyclovir showed a 37.0% protective effect compared to those who did not receive it when antiretroviral treatment was not included in the model. When including antiretroviral therapy, the protective effect of acyclovir decreased to 9.0% and that of antiretroviral therapy was 43.0% for monotherapy and 36.0% for double therapy, suggesting that most of the protective effect of acyclovir in the previous model was due to antiretroviral therapy. In conclusion, treatment with acyclovir does not seem to prolong significantly survival to AIDS among HIV-positive individuals who are HSV-2-infected.
Dynamics of the Pool of Infected Resting Cd4 Hla-Dr- T Lymphocytes in Patients Who Started a Triple Class Five-Drug Antiretroviral Regimen During Primary HIV-1 Infection
Authors: Sankatsing Sanjay UC , van Praag Rieneke ME , van Rij Ronald P , Rientsma Ronald , Jurriaans Suzanne , Lange Joep MA , Prins Jan M , Schuitemaker Hanneke
Published: April 2022

Starting standard antiretroviral therapy within 10 days after the onset of a primary HIV-1 infection cannot prevent the establishment of a reservoir of HIV-1-infected memory CD4 T cells. Here we studied the reservoir of HIV-1-infected memory CD4 T cells in four patients who started a triple class, five-drug regimen during primary HIV-1 infection. There was a strong correlation between the proportion of productively infected CD4 HLA-DR- T lymphocytes and plasma HIV-1 RNA levels (r=0.852; P<0.001) during the first 24 weeks of therapy. Within 45 weeks of treatment, in three of the four patients the proportion of productively infected CD4 HLA-DR- T lymphocytes was reduced below the level of quantification. In the fourth patient the cellular reservoir remained quantifiable. In two patients who stopped therapy 44 weeks after initiation an immediate rebound of the plasma HIV-1 RNA level and the proportion of productively infected CD4 HLA-DR– T lymphocytes occurred.

In conclusion, initiation of a potent five-drug, triple class regimen during primary HIV-1 infection does not result in virus-specific immune control upon discontinuation of therapy after 44 weeks. Therefore, longer or even stronger suppression of viral replication might be necessary to achieve this goal in primary HIV-1 infection.
Nucleotide Analogue Binding, Catalysis and Primer Unblocking in the Mechanisms of HIV-1 Reverse Transcriptase-Mediated Resistance to Nucleoside Analogues
Authors: Selmi Boulbaba , Deval Jérôme , Boretto Joëlle , Canard Bruno
Published: April 2022

Nucleoside analogues play a key role in the fight against HIV-1. Unfortunately, under therapeutic pressure, HIV-1 inevitably develops resistance to these inhibitors. This resistance correlates with specific pol gene mutations giving rise to specific substitutions in reverse transcriptase that are responsible for the loss of efficacy of the corresponding analogue. This work is an overview of the molecular mechanisms of HIV-1 drug resistance as judged by the analysis of chemical reactions at play at the reverse transcriptase active site. One class of mechanism involves nucleotide analogue discrimination either at the binding step or at the catalytic step, the latter being by far the most common mechanism. The other class of mechanism involves repair of the analogue-terminated DNA chain. The mechanisms were elucidated using purified reverse transcriptase and biochemical assays aimed at correlating resistant HIV-1 phenotypes to enzymatic data. The elucidation of these molecular mechanisms of drug-resistant reverse transcriptase is important for effective and rational combination therapies as well as for the conception of second-generation drugs that do not confer nucleotide resistance to reverse transcriptase or are active against pre-existing resistant viruses.
Virological Success of Lopinavir/Ritonavir Salvage Regimen is Affected by an Increasing Number of Lopinavir/Ritonavir-Related Mutations
Authors: Bongiovanni Marco , Bini Teresa , Adorni Fulvio , Meraviglia Paola , Capetti Amedeo , Tordato Federica , Cicconi Paola , Chiesa Elisabetta , Cordier Laura , Cargnel Antonietta , Landonio Simona , Rusconi Stefano , Monforte Antonella d'Arminio
Published: April 2022

We evaluated the virological outcome of lopinavir/ritonavir (LPV/RTV) in 224 HIV-1-infected and protease inhibitor (PI)-experienced patients showing virological failure to a highly active antiretroviral therapy (HAART) regimen and followed up for at least 3 months. At baseline, the median level of plasma viraemia was 4.61 log10 copies/ml (range 3–6.48) and the median CD4 cell count was 219 cells/mm3 (range 1–836). During a median follow-up of 272 days (range 92–635), we observed an increase in the number of CD4 cells (P=0.02) and a dramatic decrease in plasma viraemia levels (P=0.0001), which became undetectable in 122 patients (54.5%). The closely related predictive factors were baseline plasma viraemia levels and the number of mutations known to reduce susceptibility to LPV/RTV. Thirty-one patients (13.8%) discontinued LPV/RTV during the follow-up, and one AIDS event and three deaths were recorded. Of the 134 patients (59.8%) who underwent a baseline genotype resistance test, 22 (16.4%) had ≥6 mutations known to reduce LPV/RTV susceptibility; plasma viraemia became undetectable in 76 patients (56.7%), only five of whom harboured ≥6 mutations at baseline (P=0.0001). The independent predictive factors related to virological success were plasma viraemia levels and the number of mutations reducing susceptibility to LPV/RTV at baseline; each additional log10 copies/ml of HIV RNA reduced the probability of virological success by 34.0% and each extra mutation by 14.5%.
Vasodilator Agents Protect against Indinavir Nephrotoxicity
Authors: de Araujo Magali , Seguro Antonio Carlos
Published: April 2022

Indinavir (IDV) is a protease inhibitor widely used in AIDS treatment. A sustained elevation of creatinine was identified in IDV-treated patients. We have previously demonstrated that IDV causes renal vasoconstriction in rats. The objective of this study was to investigate the mechanism of IDV-induced vasoconstriction and the effect that the vasodilator agents L-arginine (LA), nifedipine (NF), as well as magnesium supplementation (Mg), have on IDV-induced nephrotoxicity. Male Wistar rats were kept on fast overnight and given free access to water. IDV (80 mg/kg BW) and NF (3 mg/kg BW) were given by gavage for 15 days. LA (1.5%) and MgCl2.6H2O (1%) were added to drinking water. Six groups were studied: Control ( n=6): normal rats treated with vehicle, a 0.05 M citric acid solution; IDV ( n=7): IDV-treated rats; IDV+LA ( n=6): IDV- and LA-treated rats; IDV+NF ( n=7): IDV- and NF-treated rats; IDV+Mg ( n=7): IDV- and MgCl2-treated rats; IDV+Mg+L-NAME ( n=9): IDV- and MgCl2-treated rats, supplemented with L-NAME (2.5 mg/l in drinking water). Clearance studies and evaluations of urinary nitrite (NO2) excretion were performed on day 16. No changes in blood pressure were observed. NO2 excretion decreased in IDV-treated rats. LA and NF protected against IDV effects, improving GFR (IDV+LA, 1.95 ±0.10; IDV+NF, 1.94 ±0.07 vs IDV, 1.15 ±0.07 ml/min, P<0.001) and RBF (IDV+LA, 7.83 ±0.09; IDV+NF, 7.63 ±0.14 vs IDV, 6.17 ±0.25 ml/min, P<0.001). These results suggest that IDV-induced vasoconstriction is mediated by NO and Ca2+ channels. Magnesium also ameliorated GFR and RBF in IDV-treated rats (GFR IDV+Mg, 1.77 ±0.08 ml/min, P<0.001; RBF IDV+Mg, 7.35 ±0.158 ml/min, P<0.001). Magnesium protection is not NO-mediated since it was not blocked by L-NAME. In conclusion, LA, NF and Mg protect against IDV-induced nephrotoxicity in rats. This study may have potential clinical implications for prevention of IDV-induced nephrotoxicity.
Administration of Indinavir and Low-Dose Ritonavir (800/100 Mg Twice Daily) with Food Reduces Nephrotoxic Peak Plasma Levels of Indinavir
Authors: Aarnoutse Rob E , Wasmuth Jan-Christian , Fätkenheuer Gerd , Schneider Katrin , Schmitz Karina , de Boo Theo M , Reiss Peter , Hekster Yechiel A , Burger David M , Rockstroh Jürgen K
Published: April 2022

Background

The objective of this study was to compare indinavir peak plasma (Cmax) values after administration of indinavir/ritonavir 800/100 mg on an empty stomach or with food. High indinavir Cmax values have been associated with indinavir-related nephrotoxicity.

Methods

This was an open-label, randomized, two-treatment, two-period, cross-over pharmacokinetic study performed at steady state. HIV-infected patients who had been using indinavir/ritonavir 800/100 mg twice daily for at least 4 weeks were randomized to take this combination with a light breakfast (two filled rolls and 130 ml of fluid) on a first study day, and without food on a second day, or in the reverse order. The pharmacokinetics of indinavir and ritonavir were assessed after plasma and urine sampling during 12 h.

Results

Data for nine patients were evaluated. Administration of indinavir/ritonavir 800/100 mg on an empty stomach resulted in a higher indinavir Cmax [geometric mean (GM) ratio – fasting/fed and 95% confidence interval (CI): 1.28 (1.08–1.52), P=0.01] and a trend to a shorter indinavir tmax ( P=0.07) compared to administration with food. The mode of administration of indinavir/ritonavir did not affect plasma indinavir Cmin and AUC values, parameters that have been associated with the antiviral efficacy of indinavir, nor the urinary excretion of indinavir.

Conclusions

Administration of indinavir/ritonavir 800/100 mg on an empty stomach results in a higher indinavir Cmax compared to ingestion with a light meal. Stated the other way round, intake with a light meal reduces indinavir Cmax, which probably reflects a food-induced delay in the absorption of indinavir. It is recommended to administer indinavir/ritonavir 800/100 mg with food, as a possible means to prevent indinavir-related nephrotoxicity in patients who start or continue with this regimen.
Modest Decreases in Nnrti Susceptibility Do Not Influence Virological Outcome in Patients Receiving Initial Nnrti-Containing Triple Therapy
Authors: Harrigan P Richard , Hertogs Kurt , Verbiest Werner , Larder Brendan , Yip Benita , Brumme Zabrina L , Alexander Christopher , Tilley Jessica , O'Shaughnessy Michael V , Montaner Julio SG
Published: April 2022

Objective

To assess the prevalence of modest (<10-fold) decreases in baseline non-nucleoside reverse transcriptase inhibitor (NNRTI) susceptibility and their impact on virological response to NNRTI-containing triple therapy in drug-naive individuals.

Methods

Baseline HIV resistance phenotype, genotype and response to therapy were examined retrospectively for all antiretroviral-naive individuals initiating therapy with two nucleoside analogues and an NNRTI in British Columbia, Canada, between 05/1997 and 08/1999 ( n=279), followed until July 31 2001. Time to viral suppression (first of at least two consecutive plasma viral loads <400 copies HIV RNA copies/ml) and viral rebound (to ≥400 copies/ml after first pVL <400 copies HIV RNA copies/ml), were estimated by Kaplan-Meier methods. Multivariate analyses were performed using Cox proportional hazards regression.

Results

Nevirapine was the most commonly prescribed NNRTI (96%). Four- to 10-fold decreased susceptibility to NNRTIs was observed in >30% of untreated individuals at baseline, an observation strongly driven by decreased susceptibility to delavirdine (22.4%). A >10-fold decrease in susceptibility to any NNRTI was observed only rarely (<2%). There was no association between four- and 10-fold decreased baseline susceptibility to NNRTIs and virological outcome ( P>0.05). In multivariate analyses, the strongest predictors of poor virological response to NNRTI-based therapy were baseline plasma viral load and the proportion of time on therapy in the first year of follow-up. There was no relationship between the presence of previously reported mutations associated with decreased NNRTI susceptibility (at codons 135 and 283 in HIV reverse transcriptase) and virological response.

Conclusions

These data suggest that the clinically significant level of resistance to NNRTIs, particularly nevirapine, in drug-naive individuals is likely greater than four- to 10-fold.
Intracellular Disposition and Metabolic Effects of Zidovudine, Stavudine and Four Protease Inhibitors in Cultured Adipocytes
Authors: Janneh Omar , Hoggard Patrick G , Tjia John F , Jones Simon P , Khoo Saye H , Maher Bridget , Back David J , Pirmohamed Munir
Published: April 2022

Objective

The pathogenesis of lipodystrophy caused by the HIV protease inhibitors (PIs) and nucleoside reverse transcriptase inhibitors (NRTIs) is unclear. We have investigated the disposition of these drugs in adipocytes and the consequent effect on adipocyte metabolism and viability.

Design

Laboratory study utilizing two murine cell lines, 3T3-L1 and 3T3-F442A.

Methods

Intracellular NRTI phosphate and PI concentrations were determined by HPLC and HPLC-MS/MS, respectively. The cytotoxicity of the drugs was examined on the different adipogenic stages together with their effects on glucose uptake plus or minus insulin, and on glycerol and triglyceride levels.

Results

There was rapid intracellular accumulation and phosphorylation of [3H]-zidovudine and -stavudine to their phosphate metabolites in adipocytes. The NRTIs were not cytotoxic, did not affect preadipocyte protein synthesis and did not inhibit adipogenesis or induce lipolysis. PIs accumulated in adipocytes (nelfinavir>saquinavir>ritonavir>indinavir). All PIs, except indinavir, were cytotoxic and inhibited adipogenesis, increased lipolysis and impaired preadipocyte protein synthesis. PIs inhibited glucose uptake in the rank order: indinavir>saquinavir>ritonavir>nelfinavir.

Conclusion

These data demonstrate that PIs may play a role in the insulin resistance observed in lipodystrophy by affecting glucose uptake, adipogenesis and lipolysis. NRTIs alone do not seem to have any effect on adipocyte metabolism despite undergoing phosphorylation to their triphosphorylated anabolites, although their effects in combination with PIs in perturbing adipocyte metabolism warrants further investigation.
Uridine Abrogates Mitochondrial Toxicity Related to Nucleoside Analogue Reverse Transcriptase Inhibitors in Hepg2 Cells
Authors: Walker Ulrich A , Venhoff Nils , Koch Eva C , Olschewski Manfred , Schneider Josef , Setzer Bernhard
Published: April 2022

Objective

To assess in vitro if uridine may be suitable to prevent or treat mitochondrial toxicity related to nucleoside analogue reverse transcriptase inhibitors (NRTIs).

Methods

Human HepG2-hepatocytes were exposed to NRTIs with or without uridine for 25 days. Cell growth, lactate production, intracellular lipids, mitochondrial DNA (mtDNA) and the ratio between the respiratory chain components COX II (mtDNA-encoded) and COX IV (nuclear-encoded) were measured.

Results

HepG2 cells exposed to zalcitabine (177 nM) without uridine developed a severe depletion of mtDNA (to 8% of wild-type mtDNA levels), resulting in a decline of cell proliferation and COX II levels, with increased lactate and lipid accumulation. Uridine fully abrogated the adverse effects of zalcitabine on hepatocyte proliferation and normalized lactate synthesis, intracellular lipids and COX II levels by adjusting mtDNA levels to about 65% of NRTI-unexposed control cells. This effect was dose-dependent, with a maximum at 200 μM of uridine. Uridine also rapidly and fully restored cell function when added to cells with established mitochondrial dysfunction (zalcitabine for 15 days) despite continued zalcitabine exposure. Uridine also normalized cell proliferation in HepG2 cells exposed to 36 μM of stavudine and protected HepG2-cells exposed to 7 μM of zidovudine + 8 μM of lamivudine (pyrimidine analogues), but failed to improve cell function or mtDNA in cells exposed to 11.8 or 118 μM of didanosine (a purine analogue).

Conclusions

The pyrimidine precursor uridine may attenuate the mitochondrial toxicity of antiretroviral pyrimidine NRTIs in vitro, and its supplementation may represent a promising strategy in the prevention or treatment of mitochondrial toxicities in HIV-infected patients.
Proteasome Inhibitors: A Novel Tool to Suppress Human Cytomegalovirus Replication and Virus-Induced Immune Modulation
Authors: Prösch Susanna , Priemer Christina , Höflich Conny , Liebenthal Christa , Babel Nina , Krüger Detlev H , Volk Hans-Dieter
Published: April 2022

Recently, we like others, demonstrated that systemic inflammation is the most important mechanism involved in (re)activation of human cytomegalovirus (HCMV) in both immunocompromised and immunocompetent patients. By in vitro studies the eukaryotic transcription factor NF-κB could be identified as the key mediator of TNF-α- and IE1-dependent stimulation of the HCMV IE1/2 enhancer/promoter activity, which is crucial for initiation of viral gene expression during reactivation from latency as well as productive infection. The enzymatic proteasome complex plays a central role in regulating intracellular processes, including the activation of NF-κB. As present antiviral strategies target mainly late events in HCMV replication (DNA replication, virus assembly) that do not completely prevent virus mediated immunopathogenesis, we wondered whether proteasome inhibitors might be a novel tool for targeting the interaction between inflammation and HCMV (re)activation. Here, proteasome inhibitors like MG132, PSI, II and III (MG262) have been shown to block both TNF-α-associated up-regulation of the HCMV IE1/2 enhancer/promoter in monocytic cells in an in vitro transient transfection system and HCMV replication in permissive human embryonal lung fibroblasts. Importantly, ganciclovir-resistant HCMV strains are sensitive to proteasome inhibitors. The effect of proteasome inhibitors on HCMV replication was found to be specific as replication of other herpes viruses, like HSV-1 and HSV-2, under identical experimental conditions was not influenced. Inhibition of HCMV replication correlated with a delayed and significantly reduced expression of IE proteins, particularly of the IE2 protein, suggesting that MG132 blocks HCMV replication at an immediate early stage of infection. Early and late protein synthesis as shown exemplary for the pp52 (DNA-binding protein) and p68 (structural protein) protein production and viral DNA synthesis were also inhibited. Suppression of HCMV replication could be correlated with an increased cytosolic accumulation of IκB as well as a reduced NF-κB binding activity in nuclear extracts of MG132-treated cells, which mainly regards NF-κB p50. MG132 also reduced the immune modulatory activity of the virus by abrogating virus-induced up-regulation of cellular ICAM-1. These data suggest that short-term therapy with proteasome inhibitors might be an alternative strategy to prevent (re)activation, replication and immune modulatory activity of HCMV in patients with systemic inflammation.
Monitoring the Emergence of Hepatitis B Virus Polymerase Gene Variants during Lamivudine Therapy in Human Immunodeficiency Virus Coinfected Patients: Performance of Clip™ Sequencing and Line Probe Assay
Authors: Roque-Afonso Anne-Marie , Férey Marie-Pierre , Mackiewicz Vincent , Fki Lamia , Dussaix Elisabeth
Published: April 2022

Sera from 12 patients infected with human immunodeficiency virus and hepatitis B virus (HBV), on lamivudine as part of an antiretroviral therapy, were retrospectively analysed for the presence of HBV polymerase mutations by the line probe assay, INNO-LiPA HBV DR, and by the direct sequencing assay, TRUGENE™ HBV genotyping kit. Results at codons 180, 204 and 207 were compared for 44 samples. Full concordance was observed for 81.4% of the 129 analysed codons. Discordance involved only mixed populations: LiPA detected additional species in 19 codons and TRUGENE in five. Viral breakthrough occurred in seven patients, 12-33 months after lamivudine initiation. In five cases with close sampling available, both assays detected mutations before the rise in viral load, although earlier by LiPA for three patients. The time interval between the first mutant detection and viral escape ranged from 2 to 22 months. Mutations were detected in four of the five remaining patients: 1) at therapy initiation in a primary non-responder; 2) after 37 months, but replication became undetectable after tenofovir introduction; 3) transiently at 6 months by LiPA but treatment was ceased thereafter; 4) after 23 months but replication levels remained low during a 5-year follow-up. Interestingly, TRUGENE sequencing identified on late samples from three patients a variant carrying rtV173L plus rtL180M plus M204V mutations, having the in vitro characteristics of ‘vaccine escape’ mutants.

Both assays appear to be valuable tools for the early detection of mutated HBV strains. The detection of genotypic resistance could improve therapeutic decision-making, although clinical or other virological factors may determine the rapidity of the viral breakthrough.
Predictors of Tonsillar Tissue HIV-1 Viral Burden at Baseline and after 1 Year of Antiretroviral Therapy
Authors: Navarrete Pilar , Morente Vanessa , García Felipe , Alós Lluçia , Arnedo Mireia , Plana Montserrat , Gil Cristina , Caballero Miguel , Miró José M , Martínez Esteban , Fumero Emilio , Castro Pedro , Blanco José L , Mallolas Josep , Blanch José L , Cruceta Anna , Mestre Gabriel , Pumarola Tomás , Gallart Teresa , Gatell José M
Published: April 2022

In 81 antiretroviral-naive HIV-1 chronic-infected patients, we found a correlation among tonsillar tissue viral load, and virological and immunological measures in blood at baseline. No correlation was observed after 1 year of antiretroviral therapy. A protease inhibitor-containing regimen was the best predictor of good tonsillar tissue virological response.
A Randomized Trial of Nelfinavir and Abacavir in Combination with Efavirenz and Adefovir Dipivoxil in HIV-1-Infected Persons with Virological Failure Receiving Indinavir
Authors: Hammer Scott M , Bassett Roland , Squires Kathleen E , Fischl Margaret A , Demeter Lisa M , Currier Judith S , Mellors John W , Morse Gene D , Eron Joseph J , Santana Jorge L , DeGruttola Victor ,   for the ACTG 372B/D Study Team
Published: April 2022

Objectives

(1) To determine the efficacy and safety of nelfinavir versus placebo and abacavir versus other approved nucleoside reverse transcriptase inhibitors (NRTIs), in combination with efavirenz and adefovir dipovoxil, in subjects experiencing virological failure on an indinavir-containing regimen. (2) To determine the relationship of baseline viral drug resistance genotype and phenotype to virological outcome.

Design and methods

A prospective, randomized, controlled, multicentre study in non-nucleoside reverse transcriptase inhibitor (NNRTI)-naive subjects conducted by the Adult AIDS Clinical Trials Group (ACTG 372B) and an open-label, single-arm, multicentre study in NNRTI-experienced subjects (ACTG 372D). Ninety-four subjects were randomized in ACTG 372B, which used a factorial design. All subjects received efavirenz and adefovir dipivoxil, and were randomly assigned to nelfinavir versus nelfinavir placebo and abacavir versus previously FDA-approved NRTIs. Twenty subjects received abacavir, efavirenz, adefovir dipivoxil and nelfinavir in ACTG 372D. Primary analysis time-point was at 16 weeks with follow-up through 48 weeks. Measures of efficacy were plasma HIV-1 RNA levels and CD4 cell counts. Adverse events were recorded according to ACTG criteria. Baseline reverse transcriptase and protease genotype, and drug susceptibility phenotype were determined. Resistance analyses were combined for ACTG 372B and D.

Results

At 16 weeks in ACTG 372B, 67% of subjects reached a primary study treatment failure end-point. In factorial analyses, nelfinavir was superior to nelfinavir placebo in rate of this failure end-point (56 vs 78%, P=0.02), but abacavir was not different from other NRTIs. No differences by nelfinavir or abacavir factor were noted at week 48. The failure end-point rate was significantly lower in those with baseline RNA levels ≤15000 copies/ml versus those with >15000 copies/ml (42 vs 79%, P<0.001). Higher genotypic and phenotypic sensitivity scores were significantly correlated with better virological responses ( P=0.003 and 0.030, respectively). Conclusions: (1) Treatment responses were low in this trial of nelfinavir, abacavir, efavirenz and adefovir dipivoxil for subjects experiencing virological failure on an indinavir-containing regimen. (2) Subjects with plasma HIV-1 RNA levels ≤15000 copies/ml had a significantly better virological response than those with >15000 copies/ml at baseline. Switching at lower, rather than higher, viral load levels improved response rates in treatment-experienced subjects. (3) Summary measures of regimen sensitivity (such as, genotypic and phenotypic sensitivity scores) are useful in the evaluation of multidrug combination regimens.
Effect of Individual Cognitive Behaviour Intervention on Adherence to Antiretroviral Therapy: Prospective Randomized Trial
Authors:   the Swiss HIV Cohort Study, Weber Rainer , Christen Lisanne , Christen Stephan , Tschopp Simone , Znoj Hansjoerg , Schneider Christine , Schmitt Joachim , Opravil Milos , Günthard Huldrych F , Ledergerber Bruno , 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 , Wagels Th , Weber R , Yerly S
Published: April 2022

Objective

A high level of adherence to antiretroviral therapy is required for complete suppression of HIV replication, immunological and clinical effectiveness. We investigated whether cognitive behaviour therapy can improve medication adherence.

Design

Prospective randomized 1-year trial.

Setting

Collaboration of HIV university outpatient clinic and psychotherapists in private practice.

Participants

60 HIV-infected persons on stable anti-retroviral combination therapy and viral load below 50 copies/ml.

Intervention

Cognitive behaviour intervention in individual patients, in addition to standard of care.

Main outcome measures

Feasibility and acceptance of intervention; adherence to therapy assessed using medication event monitoring system (MEMS) and self-report questionnaire; virological failure; psychosocial measures.

Results

The median number of sessions for cognitive behaviour intervention per patient during the 1-year trial was 11 (range 2–25). At months 10–12, mean adherence to therapy as assessed using MEMS was 92.8% in the intervention and 88.9% in the control group ( P=0.2); the proportion of patients with adherence ≥95% was 70 and 50.0% ( P=0.014), respectively. While there was no significant deterioration of adherence during the study in the intervention arm, adherence decreased by 8.7% per year ( P=0.006) in the control arm. No differences between the intervention group and standard of care group were found regarding virological outcome. Compared with the control group, participants in the intervention group perceived a significant improvement of their mental health during the study period.

Conclusions

Cognitive behavioural support in addition to standard of care of HIV-infected persons is feasible in routine practice, and can improve medication adherence and mental health.
The Impact of HIV Antiviral Therapy on Human Papillomavirus (Hpv) Infections and Hpv-Related Diseases
Authors: Heard Isabelle , Palefsky Joel M , Kazatchkine Michel D
Published: April 2022

Human papillomavirus (HPV) infections play an important role in the pathogenesis of anogenital cancer and its precursors. HIV-infected individuals exhibit a high prevalence of HPV DNA. Several studies have further shown that HIV-infected individuals have an increased prevalence of squamous intraepithelial lesions (SIL) of the cervix, vulva and anus. The incidence of invasive cervical cancer is also elevated in HIV-positive women as well as that of anal cancer in HIV-positive women and men. Given the relationship between HIV-induced immunosuppression and HPV-associated disease, treatment with highly active antiretroviral therapy (HAART) has the potential, through immune reconstitution of the host, to alter the natural history of HPV infection and SIL. However, data on the impact of HAART on HPV disease are sparse and mixed results have been reported.
No Benefit to Continue Lamivudine Therapy after Emergence of Ymdd Mutations
Authors: Liaw Yun-Fan , Chien Rong-Nan , Yeh Chau-Ting
Published: April 2022

Background

Mutations in the sequence of the conserved tyrosine-methionine-aspartate-aspartate (YMDD) locus of the HBV RNA-dependent DNA polymerase (rt M 204 I/V) may develop after 6–9 months of lamivudine therapy. The current practice of continuing lamivudine therapy has been associated with hepatitis flares or even hepatic decompensation. In addition, experiments have shown that the defective replication competency of rt M 204 I/V restores upon addition of lamivudine.

Aim

To evaluate whether continuing lamivudine therapy after emergence of rt M 204 I/V is appropriate.

Patients and methods

The clinical courses of 66 patients with continuing lamivudine therapy (continued group) and 68 patients who discontinued lamivudine therapy (discontinued group) were monitored monthly or more frequently if condition required. Hepatitis flare, jaundice, hepatic decompensation and hepatitis B e antigen (HBeAg) seroconversion in HBeAg-positive patients were documented as events.

Results

In a 12-month period, hepatitis flares and decompensations occurred in 67 and 11%, respectively, in patients who continued lamivudine therapy, as compared with 54 and 7%, respectively ( P>0.05), in those who stopped therapy. HBeAg seroconversion rate was 19% in continued group and 35% in discontinued group ( P=0.08). Serum HBV DNA increased in 48 (73%) of the continued group, and the median level increased from 46 pg/ml upon first detection of mutation to 330 pg/ml ( P<0.001) at the end of 12 months continuing therapy. In contrast, serum HBV DNA level in the discontinued group increased in 22 (33%) patients but decreased in 39 patients, and median level decreased from 172 to 55 pg/ml at the end of 12 months after stopping lamivudine.

Conclusion

These results suggest that there is no benefit to continued lamivudine therapy after emergence of rt M 204 I/V. Presented in part at the Digestive Disease Week, San Francisco, Calif., USA, May 2002.
Interferon–Lamivudine Combination is No Better than Lamivudine Alone in Anti-Hbe-Positive Chronic Hepatitis B
Authors: Akarca Ulus Salih , Ersoz Galip , Gunsar Fulya , Karasu Zeki , Saritas Elif , Yuce Gul , Batur Yucel
Published: April 2022

Background and aims

Results of studies using lamivudine and interferon combination in the treatment of chronic hepatitis B are not consistent or conclusive. This study aimed to evaluate the efficacy of interferon plus lamivudine use versus single lamivudine in anti-HBe-positive chronic hepatitis B.

Methods

Eighty patients were treated with either lamivudine or lamivudine plus simultaneously started interferon. Patients were assigned in groups according to random allocation rule. Lamivudine was given 150 mg/day for 96 weeks in each group; interferon was administered 10 MU three times a week for 24 weeks in the combination therapy group.

Results

Alanine aminotransferase (ALT) normalization was achieved earlier in patients treated with lamivudine alone. At the end of treatment, there was no difference between the groups with respect to HBV DNA negativity, ALT normalization and breakthrough rate. Histological improvement was remarkable in each group, but fibrosis score and necro-inflammatory activity were much lower in lamivudine-treated patients.

Conclusions

Addition of interferon to the lamivudine regimen does not increase the effectiveness of the treatment. Considering the side effects of interferon treatment, this combination seems not to be convenient for anti-HBe-positive chronic hepatitis B.
Simple Linear Model Provides Highly Accurate Genotypic Predictions of HIV-1 Drug Resistance
Authors: Wang Kai , Jenwitheesuk Ekachai , Samudrala Ram , Mittler John E
Published: April 2022

Drug resistance is a major obstacle to the successful treatment of HIV-1 infection. Genotypic assays are used widely to provide indirect evidence of drug resistance, but the performance of these assays has been mixed. We used standard stepwise linear regression to construct drug resistance models for seven protease inhibitors and 10 reverse transcriptase inhibitors using data obtained from the Stanford HIV drug resistance database. We evaluated these models by hold-one-out experiments and by tests on an independent dataset. Our linear model out-performed other publicly available genotypic interpretation algorithms, including decision tree, support vector machine and four rules-based algorithms (HIVdb, VGI, ANRS and Rega) under both tests. Interestingly, our model did well despite the absence of any terms for interactions between different residues in protease or reverse transcriptase. The resulting linear models are easy to understand and can potentially assist in choosing combination therapy regimens.
Prophylactic and Therapeutic Effects of Small Interfering Rna Targeting Sars-Coronavirus
Authors: Zheng Bo-jian , Guan Yi , Tang Qingquan , Cheng Du , Xie Frank Y , He Ming-Liang , Chan Kwok-Wah , Wong Kin-Ling , Lader Eric , Woodle Martin C , Lu Patrick Y , Li Baojian , Zhong Nanshan
Published: April 2022

Objectives

To identify and characterize the siRNA duplexes that are effective for inhibition of SARS-CoV infection and replication in the non-human primate cells. This in vitro study will serve as the foundation for development of novel anti-SARS therapeutics.

Methods

48 siRNA sequences were designed for targeting regions throughout entire SARS-CoV genome RNA including open-reading frames for several key proteins. Chemically synthesized siRNA duplexes were transfected into foetal rhesus kidney (FRhK-4) cells prior to or after SARS-CoV infection. The inhibitory effects of the siRNAs were evaluated for reductions of intracellular viral genome copy number and viral titres in the cell culture medium measured by Q-RT-PCR and CPE-based titration, respectively. Four siRNA duplexes were found to achieve potent inhibition of SARS-CoV infection and replication. A prolonged prophylactic effect of siRNA duplexes with up to 90% inhibition that lasted for at least 72 h was observed. Combination of active siRNA duplexes targeting different regions of the viral genome resulted in therapeutic activity of up to 80% inhibition.

Conclusion

Chemically synthesized siRNA duplexes targeting SARS-CoV genomic RNA are potent agents for inhibition of the viral infection and replication. The location effects of siRNAs were revealed at both genome sequence and open-reading frame levels. The rapid development of siRNA-based SARS-CoV inhibitors marked a novel approach for combating newly emergent infectious diseases.
Epstein–Barr Virus Load Correlating with Clinical Manifestation and Treatment Response in a Patient with Angioimmunoblastic T-Cell Lymphoma
Authors: Battegay Manuel , Berger Christoph , Rochlitz Christoph , Hurwitz Nina , Hirsch Hans H , Geyter Christian De , Haque Tanzina , Nadal David
Published: April 2022

Epstein–Barr virus (EBV)-associated lymphoma may arise secondary to angioimmunoblastic T-cell lymphoma (AITL). The prognosis is poor despite chemotherapy and experimental therapies. We report on a 40-year-old woman with AITL without obvious immunodeficiency in which EBV-associated lymphoma developed. The occurrence and size of enlarged lymph nodes correlated strongly with the EBV load in serum (EBVL). Treatment with valacyclovir at the early stage resulted in a drastic more than 3 log10 decrease of EBVL and complete remission. However, valacyclovir had to be stopped after 6 months due to side effects, and the lymphoma reoccurred 3 months later associated with increasing EBVL. Eventually started cytotoxic chemo- and anti-CD20 therapy resulted only in partial remission. The lymphoma progressed and 33 months after it was diagnosed the patient died. This case report demonstrates the close association of EBVL and AITL and a beneficial effect of antiviral therapy at an initial stage of disease manifestation.
Peginterferon Alpha-2B plus Ribavirin with or without Amantidine for the Treatment of Non-Responders to Standard Interferon and Ribavirin
Authors: Hasan Fuad , Al-Khaldi Jameela , Asker Haifa , Al-Ajmi Misfer , Owayed Salem , Varghese Rosh , Siddique Iqbal , Al-Nakib Basil
Published: April 2022

Background

A significant proportion of hepatitis C patients treated with unmodified interferon plus ribavirin fail to respond. The optimal therapy for these patients has not been established yet. The objective of this study was to assess the efficacy and safety of peginterferon plus ribavirin with or without amantidine in such patients.

Methods

In this open-label, prospective controlled trial, a total of 63 patients were randomly divided into groups A and B with a ratio of 1:2. Group A (21 patients) received weekly peginterferon alpha-2b, 1.5 μg/kg concomitantly with ribavirin 1000–1200 mg per day. Group B (42 patients) received peginterferon and ribavirin as in group A, plus amantidine 200 mg per day.

Results

At the completion of treatment, serum levels of hepatitis C virus RNA were undetectable in 14% and 12% of patients in groups A and B, respectively ( P=NS). Hepatitis C virus RNA remained undetectable 24 weeks after the end of treatment in one patient (5%) in group A and three patients (7%) in group B ( P=NS). Sustained viral clearance was associated with sustained normalization of serum alanine aminotransferase level. Both drug regimens had similar side effect profiles.

Conclusion

Peginterferon plus ribavirin therapy with or without amantidine is associated with a low sustained virological response in patients who failed interferon and ribavirin combination therapy.
Hepatitis C Virus-Rna Clearance in HIV-Coinfected Patients with Chronic Hepatitis C Treated with Pegylated Interferon plus Ribavirin
Authors: Soriano Vincent , Núñez Marina , Camino Nuria , Maida Ivana , Barreiro Pablo , Romero Miriam , Martín-Carbonero Luz , Garcia-Samaniego Javier , González-Lahoz Juan
Published: April 2022

Hepatitis C virus (HCV)-RNA clearance seems to occur more slowly in HIV/HCV-coinfected patients than in HCV-monoinfected subjects treated with pegylated interferon alpha (peg-IFN) plus ribavirin (RBV). As a consequence, concern has arisen over the feasibility of following the treatment rules applied to HIV-negative patients with chronic hepatitis C. A total of 89 HIV/HCV-coinfected patients who had fully completed a course of peg-IFN plus RBV were analysed. Of these, 29 (32.6%) reached sustained virological response (SVR). Reductions >2 logs in plasma HCV-RNA occurred in 52 (58%) patients at week 12 of treatment (early virological response; EVR). None of patients who showed HCV-RNA drops <2 logs at week 12 reached SVR (negative predictive value: 100%). The positive predictive value of EVR was 56%. On the other hand, relapses occurred in 19 (39.6%) out of the 48 patients who had negative HCV-RNA at the end of treatment, and there were no differences noted when comparing patients with HCV genotypes 2/3 and 1/4. In summary, the quantitative assessment of plasma HCV-RNA at week 12 predicts the chance of SVR using peg-IFN plus RBV in HIV-positive patients with chronic hepatitis C, as it does in HIV-negative individuals. Thus, discontinuation of anti-HCV therapy, which is associated with frequent side effects, might be warranted in HIV/HCV-coinfected patients showing HCV-RNA reductions <2 logs at week 12 of treatment. On the other hand, relapses in virological responders were unexpectedly high in HIV/HCV-coinfected patients when treatment was provided following the rules applied to HIV-negative subjects. This is particularly relevant for HCV genotypes 2/3, which only rarely relapse in HIV-negative patients. Therefore, extending therapy (for 12 months in HCV genotypes 2/3 and perhaps for 18 months in HCV genotypes 1/4) might be warranted in HIV/HCV-coinfected patients showing EVR.
Predictive Value of HIV-1 Protease Genotype and Virtual Phenotype on the Virological Response to Lopinavir/Ritonavir-Containing Salvage Regimens
Authors: Loutfy Mona R , Raboud Janet M , Walmsley Sharon L , Saskin Refik , Montaner Julio S , Hogg Robert S , Thompson Courtney A , Harrigan P Richard
Published: April 2022

The predictive values of HIV-1 protease genotype and virtual phenotype (vPhenotype) results on the HIV-1 RNA response to lopinavir/ritonavir (LPV/r)-containing salvage regimens were assessed. Data were evaluated from patients with antiretroviral (ARV) resistance testing prior to initiating an LPV/r-containing salvage ARV regimen, from two independent cohorts from Toronto, Ontario and British Columbia, Canada. Multivariate logistic regression models controlling for previous non-nucleoside reverse transcriptase inhibitor use, baseline viral load and AIDS-defining illness were used to assess the impact of different protease genotypic mutations (individual and in combination) and lopinavir vPhenotyping on virological suppression to <50 copies/ml by 12 months. We confirmed that the 11-mutation ‘lopinavir mutation score’ (LMS) was significantly inversely associated with the probability of virological suppression within 12 months [odds ratio (OR)=0.91; P=0.02]. The only single specific protease mutation found to predict virological response in multivariate analyses was 46I (OR=0.55; P=0.02). The most predictive three-mutation combination was 10F/I/R/V, 46I, 82A/F/T (OR=0.18; P=0.0004). We confirmed that a 10-fold increase of lopinavir IC50 is an appropriate clinical cut–off for lopinavir vPhenotype. In univariate analyses, a cut-off of the LMS as low as 3 was significantly associated with a lack of virological suppression ( P=0.04). This finding, which is in contrast to those of other studies, may be due to the high degree of ARV experience of our population and lack of active agents in the salvage regimen. Selecting the 11 specific mutations to make the LMS is potentially arbitrary; we determined that when different combinations of 11 protease mutations were chosen randomly from a set of 30, similar associations with virological response were found, probably due to the co-linearity of these mutations.