bluuebunny/crossref_metadata_2025 huggingface dataset:
Simplification of Protease Inhibitor-Containing Regimens with Efavirenz, Nevirapine or Abacavir: Safety and Efficacy Outcomes
Authors: Chiesa Elisabetta , Bini Teresa , Adorni Fulvio , Capetti Amedeo , Rizzardini Giuliano , Faggion Ivano , Mussini Cristina , Sollima Salvatore , Melzi Sara , Bongiovanni Marco , Tordato Federica , Cicconi Paola , Castelnuovo Barbara , Rusconi Stefano , Monforte Antonella d'Arminio
Published: April 2022

Objective

To describe the immunological and virological outcome, and the factors associated to discontinuation in patients switching to a regimen containing efavirenz (EFV), nevirapine (NVP) or abacavir (ABC) after long-term viral suppression under protease inhibitor-including HAART.

Design

Observational study at three outpatient clinics for HIV care in Italy.

Methods

Patients with HIV RNA <80 copies/ml and CD4 >200 cells/ml for at least 6 months on a protease inhibitor-containing treatment who switched to NVP, EFV or ABC were included in the study. End-points were immunological failure, virological failure and discontinuation due to toxicity. Survival analyses were performed to find out any independent variables predictive of reaching the end-points.

Results

177 patients were enrolled; 85 started EFV, 54 NVP and 38 ABC as part of the simplification regimen. 16/159 patients experienced immunological failure: the variables associated to CD4 count decrease were HIV RNA set point value (HR 2.32 for each log10 copies more, P=0.040) and intolerance/toxicity as reason for simplification (HR 3.96, P=0.05). 13/151 subjects showed virological failure; an AIDS diagnosis (HR 6.04, P=0.021) and the use of NVP (HR 7.98, P=0.027) were associated to a worse virological outcome, while patients naive before HAART showed a lower risk of failure (HR 0.008, P=0.007). 16/177 patients discontinued simplification regimen due to toxicity; longer HAART duration before switch was associated to risk reduction (HR 0.92, P=0.004).

Conclusions

Simplification is safe and effective, but it should be offered to patients with shorter treatment duration, and in good clinical and immunovirological conditions.
Low versus High CD4 Cell Count as Starting Point for Introduction of Antiretroviral Treatment in Resource-Poor Settings: A Scenario-Based Analysis
Authors: Bogaards Johannes A , Weverling Gerrit Jan , Geskus Ronald B , Miedema Frank , Lange Joep MA , Bossuyt Patrick MM , Goudsmit Jaap
Published: April 2022

Objective

To evaluate CD4 cell count-driven strategies for the initiation of highly active antiretroviral therapy (HAART) in terms of the reduction of the incidence of AIDS-defining events in resource-poor settings.

Methods

Data from the Amsterdam Cohort Study on HIV infection and AIDS were used to estimate the hazard of AIDS in untreated HIV-1 infection and after initiation of HAART, respectively, conditional on CD4 cell count. Different strategies for initiating therapy were compared by calculating the expected HAART administration rate and 1-year cumulative AIDS incidence in three different population settings, varying in the stage of HIV-1 infection at the time of presentation.

Results

Among 695 HIV-1-infected cohort participants, the 1-year AIDS incidence density (ID) ranged from 3.2 per 100 person-years for CD4 cell counts 600–700 cells/mm3, to 31.9 per 100 person-years for CD4 cell counts 100–200 cells/mm3 and 77.9 per 100 person-years for CD4 cell counts below 100 cells/mm3. Upon initiation of HAART, the ID in the lowest CD4 strata declined to 13.3 and 16.3 per 100 person-years, respectively. Extrapolated to developing countries, supply of HAART to patients presenting with HIV-1 infection below 200 CD4 cells/mm3 is expected to give an administration rate of 67%, while the AIDS incidence will drop from over 30% to almost 10%.

Conclusions

Introduction of HAART in populations with advanced HIV-1 infection can accomplish a threefold reduction of the AIDS incidence when HAART is administered to patients with CD4 cell counts below 200 cells/mm3. In a hospital-based setting in resource-poor environments this ensures an efficient treatment allocation.
Anti-HIV-1 Activity of Enfuvirtide (T-20) by Inhibition of Bystander Cell Death
Authors: Barretina Jordi , Blanco Julià , Armand-Ugón Mercedes , Gutiérrez Arantxa , Clotet Bonaventura , Esté José A
Published: April 2022

Infection by human immunodeficiency virus type 1 (HIV-1) has been associated with increased cell death of both infected and bystander cells. The envelope glycoprotein complex appears to play an active role in HIV-induced death of bystander cells. We quantified cell-to-cell fusion, single cell death and membrane lipid mixing in cocultures of effector, HIV-1 envelope-expressing cells with peripheral blood mononuclear cells or purified CD4 T lymphocytes from HIV-negative donors, in the presence or the absence of the fusion inhibitor enfuvirtide (T-20, pentafuside, Fuzeon™). T-20, which blocks gp41-dependent virus-cell fusion, showed a complete and dose-dependent inhibition of syncytium formation in cocultures of envelope-expressing cells with uninfected cells. Similarly, T-20 totally abrogated death of single bystander CD4 T cells with an IC50 of 0.04 μg/ml. Membrane lipid mixing, as a measure of interaction between envelope-expressing cells and CD4 cells, was also dose-dependently inhibited by T-20. Moreover, effector cells chronically infected with a T-20-resistant virus recovered the ability to induce bystander cell death in the presence of the drug, supporting the role of gp41 in single cell death. In conclusion, T-20 is able to protect CD4 T cells from envelope presentation with a dual effect: inhibition of virus replication and blockade of HIV-1 envelope-induced cell death of bystander CD4 T cells. Protection of cells prior to infection from HIV envelope-dependent bystander effect could lead to a better immune restoration of HIV-1-infected patients that are treated with T-20.
Triple Nucleoside Combination Zidovudine/Lamivudine/Abacavir versus Zidovudine/Lamivudine/Nelfinavir as First-Line Therapy in HIV-1-Infected Adults: A Randomized Trial
Authors: Matheron Sophie , Descamps Diane , Boué François , Livrozet Jean-Michel , Lafeuillade Alain , Aquilina Christian , Troisvallets Didier , Goetschel Agnès , Brun-Vezinet Françoise , Mamet Jean-Philippe , Thiaux Cécile ,   CNAF3007 study group, Allegre T , Bataille P , Bazin C , Bentata M , Bergmann JF , Beytout J , Bicart-See A , Bodard L , Brottier-Mancini E , Caron F , Cassuto JP , Chousterman M , Counillon E , Delfraissy JF , Dellamonica P , Doll J , Faller JP , Gallais H , Garre M , Gastaut JA , Gilquin J , Herson S , Hoen B , Jarousse B. , Katlama C , Lacoste D , Lange JM , Lecomte I , Lepeu G , Lucht F , Malkin JE , Massip P , Mechali D , Molina JM , Mouton Y , Pathe JP , Peyramond D , Philibert P , Plaisance N , Polomenie P , Remy G , Rispal P , Roue R , de Saint Martin L , Sereni D , Sicard D , Sobel A , Stahl JP , Trepo C , De Truchis P , Vermersch A , Welker Y , Izopet J , Vabret A , Peytavin. G
Published: April 2022

Objective

To compare the efficacy and safety of a triple nucleoside combination to a protease inhibitor-containing triple regimen as first-line antiretroviral therapy (ART) in HIV-1-infected patients.

Design

Open-label study in HIV-1-infected ART-naive adults, randomized to receive either Combivir® (lamivudine 150 mg/zidovudine 300 mg twice daily) + abacavir (300 mg twice daily), or Combivir® + nelfinavir (750 mg every 8 h) for 48 weeks. Plasma HIV-1 RNA, CD4 cell count and adverse events were assessed at baseline and weeks 4, 8, 16, 24, 32, 40 and 48.

Results

195 subjects (131 men, 64 women), median age 34 years, were randomized: 98 received combivir/abacavir and 97 combivir/nelfinavir. Baseline median plasma HIV-1 RNA was 4.2 log10 copies/ml [Interquartile range (IQR): 3.7-4.5.2] and 4.1 log10 copies/ml (IQR: 3.8–4.6), respectively. Baseline median CD4 cell count was 387 cells/mm3 (IQR: 194–501) and 449 cells/mm3 (IQR: 334–605), respectively. Nine patients (3 vs 6, respectively) did not start treatment or did not have any available efficacy data. At week 48, using the intent to treat analysis (switch/missing equals failure), plasma HIV-1 RNA was <50 copies/ml in 54/95 (57%) and 53/91 (58%) of subjects, respectively. Median CD4 increase was +110 and +120 cells/mm3, respectively. Possible hypersensitivity reactions to abacavir were reported in four subjects (4%).

Conclusion

The triple nucleoside combination combivir/abacavir is well tolerated as a first-line ART regimen in HIV-1-infected adults, with comparable antiviral activity to a nelfinavir-containing regimen at week 48.
Comparison of Nine Resistance Interpretation Systems for HIV-1 Genotyping
Authors: Stürmer Martin , Doerr Hans Wilhelm , Staszewski Schlomo , Preiser Wolfgang
Published: April 2022

HIV-1 genotyping has become a widely accepted tool for monitoring antiretroviral therapy. However, the benefit of genotyping is limited by the need to interpret the mutation pattern in order to obtain a prediction regarding susceptibility to each antiretroviral drug. Several different interpretation systems are currently available, commercially or free of charge; some are in combination with the genotyping test system used. In this study, we compared the results obtained on patient samples, using nine different resistance interpretation systems for HIV-1 genotype, and identified mutation patterns responsible for discordances between these systems. HIV-1 genotypes from 26 patients were obtained using the ViroSeq™ HIV-1 Genotyping System (Applied Biosystems). Nine resistance interpretation systems were used: the ‘virtual phenotype’ systems VirtualPhenotype™ (Virco) and Geno2Pheno ( http://cartan.gmd.de/geno2pheno.html ), the rule-based resistance algorithms Antiretroviral Drug Resistance Report (Applied Biosystems), Stanford HIV-SEQ program ( http://hivdb.stanford.edu/ ) and the ViroScorer™ system (ABL; including ANRS AC11, Detroit Medical Center, Grupo de Aconselhamento Virológico, CHL, and Rega). Discordance was defined as the same sequence being interpreted as resistant and sensitive to a substance by different systems, with intermediate scores being regarded as neutral. Results for lopinavir were not available from some interpretation systems. None of the 26 patient samples had concordant results for all drugs. The highest degree of concordance was found for the resistance scoring of lamivudine (25/26), followed by nelfinavir (23/26), indinavir, ritonavir, saquinavir (all 22/26), zidovudine, nevirapine (all 21/26), lopinavir, efavirenz (all 18/26), amprenavir, delavirdine (all 17/26), stavudine, abacavir (all 13/26), zalcitabine (7/26) and didanosine (5/26). In most cases, it was only one interpretation system that gave an interpretation different from the others. If this interpretation system was omitted, the overall discordance rate decreased by a statistically significant degree. There exists, therefore, an urgent need for standardization of interpretation algorithms for HIV-1 genotyping.
Pharmacokinetics of Lower Doses of Saquinavir Soft-Gel Caps (800 and 1200 Mg Twice Daily) Boosted with Itraconazole in HIV-1-Positive Patients
Authors: Cardiello Peter G , Samor Tarika , Burger David , Hoetelmans Richard , Mahanontharit Apicha , Ruxrungtham Kiat , Lange Joep M , Cooper David A , Phanuphak Praphan
Published: April 2022

Objective

The pharmacokinetics of 800 mg and 1200 mg of saquinavir soft-gel caps (SQV-SGC) twice daily plus 100 mg itraconazole once daily were compared to 1400 mg SQV-SGC twice daily without itraconazole.

Methods

The pharmacokinetics of SQV were determined in 17 randomly selected patients on 1400 mg twice daily SQV-SGC without itraconazole and after 2 weeks with lower SQV-SGC doses plus itraconazole. SQV plasma concentrations were determined by HPLC. Pharmacokinetic parameters were calculated by a non-compartmental model.

Results

Median (+IQR) area under plasma concentration-versus-time curve (AUC0–12h) were 3.33 (1.96–7.34), 4.29 (3.14–7.67) and 4.07 (2.76–4.49) mg/l.h for SQV 1400 mg without itraconazole, SQV 1200 mg with itraconazole and SQV 800 mg with itraconazole, respectively. These differences were not statistically significant. The median Cmin was above the proposed minimum effective concentration of 0.05 mg/l for all three regimens.

Conclusion

SQV-SGC 800 mg or 1200 mg twice daily boosted with 100 mg of itraconazole once daily resulted in adequate SQV pharmacokinetics not significantly different from SQV-SGC 1400 mg twice daily.
Polyphenotypic Expression of Mitochondrial Toxicity Caused by Nucleoside Reverse Transcriptase Inhibitors
Authors: Miller Robert F , Shahmanesh Maryam , Hanna Michael G , Unwin Robert J , Schapira Anthony HV , Weller Ian VD
Published: April 2022

An HIV-infected man taking long-term zidovudine and didanosine presented with a polyphenotypic expression of nucleoside reverse transcriptase inhibitor (NRTI)-induced mitochondrial toxicity. Clinical features included lactic acidosis, myopathy, Fanconi-type proximal tubulopathy, pancreatic dysfunction, pseudo-obstruction, mega-oesophagus, peripheral sensory neuropathy and osteoporosis. A muscle biopsy showed morphologically abnormal mitochondria and respiratory chain biochemistry revealed marked reductions in the activity of respiratory chain enzymes containing mitochondrial DNA-encoded subunits. Southern blotting showed no mitochondrial DNA depletion and long PCR revealed only minor deletions. Following withdrawal of NRTI therapy, the lactic acidosis, pancreatic dysfunction and Fanconi's tubulopathy rapidly improved. Over the next 6 months there was marked improvement in osteoporosis, myopathy and neuropathy. At this stage, dual protease inhibitors and nevirapine were started. A repeat muscle biopsy 14 months after presentation showed normal morphology and respiratory chain biochemistry was almost normal.
Predictors of the Virological Response to a Change in the Antiretroviral Treatment Regimen in HIV-1-Infected Patients Enrolled in a Randomized Trial Comparing Genotyping, Phenotyping and Standard of Care (Narval Trial, Anrs 088)
Authors: Vray Muriel , Meynard Jean-Luc , Dalban Cécile , Morand-Joubert Laurence , Clavel François , Brun-Vézinet Françoise , Peytavin Gilles , Costagliola Dominique , Girard Pierre-Marie ,   the Narval Trial Group
Published: April 2022

Objective

To identify predictors of the virological response to antiretroviral therapy in patients in whom initial therapy has failed.

Methods

The Narval trial was designed to compare phenotyping, genotyping and standard of care for the choice of antiretroviral therapy in patients in whom a protease inhibitor (PI)-containing regimen had failed. Virological success was defined as viral load below 200 copies/ml at week 12. Baseline variables including demographic, clinical and biological characteristics, HIV reverse transcriptase and protease mutations, the randomization arm, the drugs prescribed, as well as adherence to treatment and plasma concentrations of PIs and non-nucleoside reverse transcriptase inhibitors (NNRTIs) at week 12 were tested in the model. Variables that were significantly associated with virological success in univariate analysis were included in a logistic regression model.

Results

Five-hundred-and-forty-one patients were randomized. Virological success at week 12 was obtained in 200 patients. In multivariate analysis, the following factors were significantly associated with virological success: prescription of efavirenz to NNRTI-naive patients (OR=4.37; 95% CI: 2.76–6.90), randomization to the genotyping arm (OR=2.13, 1.20–3.79), prescription of lamivudine (OR=1.69, 1.01–2.83) and prescription of abacavir to abacavir-naive patients (OR=1.66, 1.02–2.72). Factors significantly associated with virological failure were prescription of nelfinavir (OR=0.30, 0.13–0.68), a high baseline viral load (OR=0.37, 0.28–0.50), the presence of at least five PI mutations (OR=0.42, 0.26–0.66), the presence of at least three thymidine analogue mutations (OR=0.61, 0.39–0.97) and at least 30 months of prior PI exposure (OR=0.64, 0.41–0.99).

Conclusions

These results confirm that among heavily pretreated patients, prescription of efavirenz to NNRTI-naive patients is associated with a good virological response, while a high baseline viral load, a large number of PI mutations and nelfinavir prescription at baseline are associated with a poor virological response. Genotyping was found to be beneficial, while this was not the case for phenotyping. This work was presented at the XI International HIV Drug Resistance Workshop, Sevilla, Spain, July 3–6 2002 (Abstract N°133); and at the XIV International Conference on AIDS, Barcelona, Spain, July 7–11 2002 (Abstract N°ThOrB138).
Age, Adherence and Injection Drug use Predict Virological Suppression among Men and Women Enrolled in a Population-Based Antiretroviral Drug Treatment Programme
Authors: O'Connell Jacqueline M , Braitstein Paula , Hogg Robert S , Yip Benita , Craib Kevin JP , O'Shaughnessy Michael V , Montaner Julio SG , Burdge David R
Published: April 2022

Objectives

To characterize 1-year virological response to antiretroviral therapy and its determinants by sex.

Methods

This is a population-based analysis of anti-retroviral therapy naive HIV-positive adult men and women. Factors associated with sex and with plasma HIV RNA viral load suppression to below 500 copies/ml were examined using non-parametric tests and logistic regression analyses.

Results

A total of 739 subjects (92 women and 647 men) were eligible. Female participants were younger (34 vs 37 years; P<0.001), less likely to have AIDS (6.5 vs 14.4%; P=0.039), more frequently injection drug users (44.6 vs 25.2%; P=0.001) and were less likely to be adherent to therapy (34.8 vs 62.9%; P<0.001) than male participants. There was no difference in baseline median CD4 count ( P=0.424) or HIV RNA levels ( P=0.140), physician experience ( P=0.057), or with respect to antiretroviral regimens containing protease inhibitors or non-nucleoside reverse transcriptase inhibitors ( P=0.911). With treatment, 46.7% (43/92) of women and 64.8% (419/647) of men ( P=0.001) suppressed HIV RNA viral load to below 500 copies/ml at 1 year. In a multivariate analysis, the association of sex with HIV RNA response to antiretroviral therapy fell from statistical significance (odds ratio 1.18; 95% CI: 0.72–1.95) after adjusting for adherence, injection drug use and age.

Conclusion

Our data indicate that in this population-based setting, sex differences in 1-year virological response to antiretroviral therapy are explained by age, adherence and injection drug use.
Changes in Body Fat Composition after 1 Year of Salvage Therapy with Lopinavir/Ritonavir-Containing Regimens and Its Relationship with Lopinavir Plasma Concentrations
Authors: Gutiérrez Félix , Padilla Sergio , Masiá Mar , Navarro Andrés , Gallego Juan , Hernández Ildefonso , Ramos José Manuel , Martin-Hidalgo Alberto
Published: April 2022

Objective

To determine whether an association existed between lopinavir (LPV) plasma concentrations and changes in body fat composition.

Design

A prospective, non-randomized study.

Setting

HIV clinic of a University Hospital. Subjects, participants: HIV-infected subjects who had virological failure on protease inhibitor-containing regimens. Twenty-two consecutive patients were enrolled, 19 completed 24 weeks of treatment and 16 completed the full 48-week study period. Intervention: Patients were treated with LPV/ritonavir (LPV/r) in combination with other antiretroviral agents. LPV trough plasma concentrations were measured at baseline and weeks 4, 8, 12, 24, 36 and 48. Body fat composition was quantified by computerized tomographic scanning at baseline, and weeks 24 and 48.

Results

LPV trough concentrations correlated with absolute and proportional changes in limb fat from baseline to week 48. Significant differences were found in mean LPV trough concentrations between patients losing less than 5% of limb fat, those experiencing a limb fat loss between 5 and 20%, and those losing more than 20% at week 24 [mean (SD), 4.67 (1.67); 8.57 (1.77); 9.49 (2.67) μg/ml, respectively; P=0.013] and week 48 [mean (SD), 4.5 (2.24); 7.04 (1.77); 9.7 (2.8) μg/ml, respectively; P=0.027]. Most patients losing more than 5% of limb fat during LPV/r therapy had mean LPV trough concentrations ≥8 μg/ml.

Conclusions

In patients receiving salvage therapy with LPV/r there was an association between LPV plasma trough concentrations and limb fat loss. The risk of peripheral limb fat loss may be greater among patients achieving higher LPV trough concentrations.
Meta-Analysis of Mutations in the Ns5A Gene and Hepatitis C Virus Resistance to Interferon Therapy: Uniting Discordant Conclusions
Authors: Schinkel Janke , Spaan Willy JM , Kroes Aloys CM
Published: April 2022

Background

Hepatitis C virus genotype 1B responds poorly to treatment with interferon, in contrast to the more interferon-sensitive genotypes 2 and 3. Studies on combination therapy regimens with PEG-interferon and ribavirin report sustained response rates that generally do not exceed 50%, in contrast to sustained response rates of 80% for genotype 2 and 3. In Japan, a correlation was found between the number of mutations in an ‘interferon sensitivity determining region’ (ISDR) and outcome of interferon treatment in genotype 1B-infected patients. However, an ongoing controversy on the existence of an ISDR in non-Japanese isolates resulted, as non-Japanese studies failed to confirm this association. The present study approached this issue by carrying out a meta-analysis of ISDR sequences and response to interferon treatment.

Methods

Twenty-seven studies were included, reporting 1351 ISDR sequence data of genotype 1B-infected patients and their virological response to interferon treatment. Both summary statistics and individual patient data were used systematically to explore the association between ISDR mutations and response to interferon.

Results

The ISDR effect on response was universally present but appeared to be stronger in Japan, with a relative risk of 5.73 for mutant viruses as compared to 4.66 for non-Japanese isolates. High interferon dose, in Japan administered more frequently, was associated with an increase in response rate only among patients infected with mutant isolates. Interaction between dose and ISDR type was confirmed in a logistic regression model. After stratifying for dose, differences in response rate between Japanese and non-Japanese patients were no longer present.

Conclusion

This study puts an end to a longstanding controversy by confirming the universal existence of an ISDR in genotype 1B-infected patients. Apparent discrepant findings from Japanese and non-Japanese studies can be explained by differences in dosing regimens and a dose-dependent differential effect of ISDR mutations on response to treatment.
Relative Prognostic Value of Self-Reported Adherence and Plasma Nnrti/Pi Concentrations to Predict Virological Rebound in Patients Initially Responding to Haart
Authors:   the AdICoNA Study Group, Antinori Andrea , Cozzi-Lepri Alessandro , Ammassari Adriana , Trotta Maria Paola , Nauwelaers David , Hoetelmans Richard , Murri Rita , Melzi Sara , Narciso Pasquale , Nasta Paola , Zaccarelli Mauro , Santopadre Paola , Vecchiet Jacopo , Izzo Crescenzo Maria , Monforte Antonella d'Arminio , Tirelli U , Nasti G , Carosi G , Nasta P , Manconi PE , Piano P , Pizzigallo E , Dalessandro M , Vecchiet J , Mazzotta F , Caputo S Lo , Soscia F , Tacconi L , Scasso A , Vincenti A , Scalzini A , Fibbia GC , Moroni M , Manforte A d'Arminio , Melzi S , Esposito R , Mussini C , Piazza M , Abrescia N , Izzo MC , Marco M De , Manzillo E , Nappa S , Alberici F , Sisti M , Baldelli F , Loso K , Mele P , Acinapura R , Ammassari A , Antinori A , Antonucci G , Ciardi M , Delia S , Longis P De , D'Offizi G , Ippolito G , Lichtner M , Marconi P , Murri R , Narciso P , Noto P , Petrosillo N , Pezzotti P , Santopadre P , Trotta MP , Vullo V , Zaccarelli M , Caramello P , Orofino GC , Cozzi-Lepri A , Baltimore MD. , Wu AW
Published: April 2022

We studied the predictive value of self-reported adherence and plasma drug concentrations on virological rebound to HAART. Among 238 participants in the AdICoNA study who had viral load ≤500 copies/ml, 42 (17.6%) experienced virological rebound by 96 weeks. Both self-reported non-adherence and sub-optimal concentration were independently associated with a higher risk of virological rebound.
Persistence of Multidrug-Resistant HIV-1 without Antiretroviral Treatment 2 Years after Sexual Transmission
Authors: Delaugerre Constance , Morand-Joubert Laurence , Chaix Marie-Laure , Picard Odile , Marcelin Anne-Genevieve , Schneider Veronique , Krivine Anne , Compagnucci Alexandra , Katlama Christine , Girard Pierre-Marie , Calvez Vincent
Published: April 2022

Objectives

To understand the virological mechanisms of 2-year persistence of multidrug-resistant virus without selective antiretroviral pressure in HIV-1-infected patients.

Patients and Methods

Two patients were contaminated recently by their HIV-1-infected partners, who had received, before the transmission, all available antiretroviral drugs and who exhibited a severe therapeutic failure. The resistance mutations analysis was performed by clonal sequencing of 1.2 kb of pol gene in plasma of index and sources patients. Sequencing of HIV-1 DNA was performed in PBMCs of index patients.

Results

Genotypic testing performed in index patients at time of seroconversion showed resistance mutations to three classes of drugs. All mutations were linked on the same viral genome and all quasispecies carried all mutations. No wild-type virus was detected. The same results were found in source patients and showed that all mutations were transmitted. In the index patients, all mutations persisted over 2 years without antiretroviral treatment. Moreover, the resistance mutations were all archived in the cellular reservoir. Viral load and CD4 count of index patients remained unchanged during 2 years of follow-up.

Discussion

Only multidrug-resistant viruses were detected in the source patients and could be transmitted in index patients. In the latter, an expansion of predominant multidrug-resistant quasispecies and the ‘archival’ of all mutations were observed. These results explain the persistence of mutations and suggest that it is highly difficult to return to a wild-type viral population, sensitive to an antiretroviral treatment. The treatment of index patients is limited and the major risk is the transmission of these multidrug-resistant viruses. This work was presented in part in the XII International HIV Drug Resistance Workshop, Los Cabos, Mexico, June 2003; and in the 2nd IAS Conference on HIV Pathogenesis & Treatment, Paris, France, July 2003.
The Influence of Protease Inhibitor Resistance Profiles on Selection of HIV Therapy in Treatment-Naive Patients
Authors: Turner Dan , Schapiro Jonathan M , Brenner Bluma G , Wainberg Mark A
Published: April 2022

Although protease inhibitors (PIs) have dramatically improved outcomes in HIV-infected patients, half still fail treatment with PI-based combination therapy. Genetic pressure from incomplete viral suppression rapidly selects for HIV variants with protease gene mutations that confer reduced susceptibility to PI drugs. A number of specific amino acid substitutions have been associated with PI resistance. However, high-level resistance to individual PIs requires the accumulation of several primary and secondary mutations, developing along drug-specific, step-wise pathways. HIV variants resistant to saquinavir and ritonavir usually contain L90M and V82A substitutions, respectively. Indinavir resistance may be linked to substitutions at positions 46 or 82. Resistance to nelfinavir is primarily associated with D30N but may alternatively be found with L90M. Resistance during exposure to amprenavir can follow development of I50V, which also may confer resistance to lopinavir. Failure during treatment with atazanavir is closely linked to I50L. The overlapping of these pathways can lead to multiple-PI resistance, limiting therapeutic options in antiretroviral-experienced patients. Reduced susceptibility to more than one PI is most likely to be associated with amino acid substitutions at six positions: 10, 46, 54, 82, 84 and 90. Other mutations (D30N, G48V, I50V or I50L) are relatively specific for particular PIs and are less likely to produce cross resistance. Certain resistance mutations selected by exposure to one PI may actually increase susceptibility to others. Patients newly diagnosed with HIV infection are increasingly found to harbour virus that is resistant to the more commonly used drugs. Newer PIs may select for mutations that result in less cross resistance with older agents.
Simplified Volumetric Flow Cytometry Allows Feasible and Accurate Determination of Cd4 T Lymphocytes in Immunodeficient Patients Worldwide
Authors: Cassens Uwe , Göhde Wolfgang , Kuling Gudrun , Gröning Arndt , Schlenke Peter , Lehman Leopold Gustave , Traoré Yves , Servais Jean , Henin Yvette , Reichelt Doris , Greve Burkhard
Published: April 2022

The determination of CD4 cells is of crucial clinical importance for patients with AIDS. However, the high costs involved represent limitations for CD4 cell counting in developing countries. In order to provide an affordable technique, we introduced a simplified volumetric counting (SVC) technique without sample manipulations and investigated it in a multicentre study. Blood samples from 434 healthy donors and immunodeficient patients were tested in eight hospital laboratories in Europe, Africa and Asia. CD4 cell counts were compared using inhouse flow cytometric methods and the SVC technique. The SVC method was performed on a low-cost flow cytometer (CyFlow SL, Partec, Münster, Germany) after 15 min antibody incubation without pre-analytic manipulations, such as washing or erythrocyte lysing procedures. Linear regression analysis demonstrated a correlation of r=0.942 (Europe), r=0.952 (Africa) and r=0.989 (Asia) between the SVC technique and the in-house methods. Bland Altman plot analysis of all patient data showed a mean bias between the two methods of +26 CD4 cells in favour of the SVC technique (measured range: 6–1905 cells/μl; median CD4 cell count: 388/μl). Three centres used the FACS-count technique (Becton-Dickinson, San José, Calif., USA) as an in-house method dispensing with pre-analytic manipulations. The comparison of SVC and FACS-count method revealed a mean bias of +32 CD4 cells/μl (median CD4 cell count: 349/μl). The accuracy of the SVC was tested on standards with known CD4 cell counts ( n=6) and was shown to be 95.2%. The low-cost device and the simplified no-lyse, no-wash test procedure reduces the costs per determination and facilitates the use of flow cytometry in developing countries.
Infrequent Transmission of HIV-1 Drug-Resistant Variants
Authors:   the Swiss HIV Cohort Study (SHCS), Yerly Sabine , Jost Stéphanie , Telenti Amalio , Flepp Markus , Kaiser Laurent , Chave Jean-Philippe , Vernazza Pietro , Battegay Manuel , Furrer Hansjakob , Chanzy Bruno , Burgisser Philippe , Rickenbach Martin , Gebhardt Martin , Bernard Marie-Charlotte , Perneger Thomas , Hirschel Bernard , Perrin Luc
Published: April 2022

Transmission of drug-resistant variants is influenced by several factors, including the prevalence of drug resistance in the population of HIV-1-infected patients, HIV-1 RNA levels and transmission by recently infected patients. In order to evaluate the impact of these factors on the transmission of drug-resistant variants, we have defined the population of potential transmitters and compared their resistance profiles to those of newly infected patients. Sequencing of pol gene was performed in 220 recently infected patients and in 373 chronically infected patients with HIV-1 RNA >1000 copies/ml. Minimal and maximal drug-resistance profiles of potential transmitters were estimated by weighting resistance profiles of chronically infected patients with estimates of the Swiss HIV-1-infected population, the prevalence of exposure to antiviral drugs and the proportion of infections attributed to primary HIV infections. The drug-resistance prevalence in recently infected patients was 10.5% (one class drug resistance: 9.1%; two classes: 1.4%; three classes: 0%). Phylogenetic analysis revealed significant clustering for 30% of recent infections. The drug-resistance prevalence in chronically infected patients was 72.4% (one class: 29%; two classes: 27.6%; three classes: 15.8%). After adjustment, the risk of transmission relative to wild-type was reduced both for one class drug resistance (minimal and maximal estimates: odds ratio: 0.39, P<0.001; and odds ratio: 0.55, P=0.011, respectively), and for two to three class drug resistance (odds ratios: 0.05 and 0.07, respectively, P<0.001). Neither sexual behaviour nor HIV-1 RNA levels explained the low transmission of drug-resistant variants.

These data suggest that drug-resistant variants and in particular multidrug-resistant variants have a substantially reduced transmission capacity.
Prevalence of Lipoatrophy and Mitochondrial DNA Content of Blood and Subcutaneous Fat in HIV-1-Infected Patients Randomly Allocated to Zidovudine- or Stavudine-Based Therapy
Authors: van der Valk Marc , Casula Miriam , Weverling Gerrit-Jan , van Kuijk Kees , van Eck-Smit Berthe , Hulsebosch Hendrick-Jan , Nieuwkerk Pythia , van Eeden Arne , Brinkman Kees , Lange Joep , de Ronde Anthony , Reiss Peter
Published: April 2022

Introduction

Mitochondrial toxicity resulting from mitochondrial DNA (mtDNA) depletion is suggested to be involved in the pathogenesis of lipodystrophy.

Methods

We cross-sectionally assessed lipodystrophy both clinically and radiographically in patients who, 4 years before, had been enrolled in a randomized comparative trial of stavudine- or zidovudine-based therapy. mtDNA content was measured in peripheral blood mononuclear cells (PBMCs) and subcutaneous adipose tissue from the thigh and back.

Results

Twenty-eight of the 45 patients enrolled in the original trial were included. Despite comparable exposure to stavudine or zidovudine (51 and 50 months, respectively), lipoatrophy prevalence by intent-to-treat analysis was significantly greater in stavudine recipients (82 vs 9%, P=0.0001). Likewise, those allocated to stavudine had significantly less peripheral fat. In an analysis restricted to patients who had remained on randomly allocated nucleoside reverse transcriptase inhibitors (NRTIs), mtDNA in PBMCs decreased after the start of treatment in both groups ( P<0.0001) (-73% for stavudine and -67% for zidovudine, P=0.11), resulting in significantly lower levels in patients with lipoatrophy ( P=0.007). The mtDNA content in subcutaneous adipose tissue from the thigh, but not from the back, was significantly lower in patients allocated to stavudine compared to zidovudine ( P=0.01). mtDNA in adipose tissue from either location did not differ significantly between those with or without lipoatrophy.

Discussion

This study objectively confirms that regimens containing stavudine are associated with a greater risk of lipoatrophy than those containing zidovudine. mtDNA in PBMCs markedly declined with both treatments and was lowest in patients with lipoatrophy. The lack of difference in mtDNA in adipose tissue from patients with as opposed to without lipoatrophy may have been masked by a relative preponderance of stromal and vascular tissue in the subcutaneous tissue samples from these patients, combined with compensatory mitochondrial proliferation in remaining adipocytes. However, our findings may also suggest that the different risk of lipoatrophy observed between NRTIs cannot solely be explained by differences in mtDNA depletion directly at the level of peripheral adipose tissue.
Atp Binding Cassette Multidrug Transporters Limit the Anti-HIV Activity of Zidovudine and Indinavir in Infected Human Macrophages
Authors: Jorajuria Sylvie , Dereuddre-Bosquet Nathalie , Becher François , Martin Solenne , Porcheray Fabrice , Garrigues Alexia , Mabondzo Aloise , Benech Henri , Grassi Jacques , Orlowski Stéphane , Dormont Dominique , Clayette Pascal
Published: April 2022

Objectives

To investigate whether P-glycoprotein (P-gp) and multidrug resistance proteins (MRPs), which limit the bioavailability of HIV protease inhibitors (PIs) and nucleoside reverse transcriptase inhibitors (NRTIs), modulate the anti-HIV activity of NRTIs, non-NRTIs and PIs in vitro. Design: We used primary cultures of major HIV target cells: human monocyte-derived macrophages (MDMs) and lymphocytes.

Methods

P-gp and MRP expression in response to long-term zidovudine (3′-azido-3′-deoxythymidine; AZT) or indinavir treatment was quantified by RT-PCR. MDM and lymphocytes were infected in vitro with HIV-1/Ba-L and HIV-1-LAI, respectively, and treated with antiretroviral drugs. We evaluated the activity of these drugs in combination with PSC833, a P-gp inhibitor, and/or probenecid, an MRP1 inhibitor. Intracellular AZT triphosphate derivative (AZT-TP) was quantified by HPLC-MSMS. P-gp ATPase activity was measured with inside-out native membrane vesicles enriched in P-gp.

Results

Levels of MDR1, mrp4 and mrp5 mRNA were high following AZT treatment. In infected MDM, PSC833 and probenecid increased the anti-HIV activity of AZT and indinavir. AZT (5 nM) decreased HIV replication by 34% alone and by 72% in combination with P-gp/MRP inhibitors. Indinavir (10 nM) gave 14% inhibition alone and 81% in combination. The increase in anti-HIV activity of AZT was correlated with an increase in intracellular AZT-TP concentration. However, unlike PIs, neither AZT nor its metabolites interacted with P-gp.

Conclusion

AZT increases the expression of multidrug transporters, thereby decreasing its pharmacological activity. The cellular efflux of AZT probably involves MRP4 or MRP5. In contrast, increases in indinavir anti-HIV activity require the inhibition of both P-gp and MRP1.
Altered Fat Differentiation and Adipocytokine Expression are Inter-Related and Linked to Morphological Changes and Insulin Resistance in HIV-1-Infected Lipodystrophic Patients
Authors: Jan Véronique , Cervera Pascale , Maachi Mustapha , Baudrimont Marielle , Kim Minji , Vidal Hubert , Girard Pierre-Marie , Levan Philippe , Rozenbaum Willy , Lombès Anne , Capeau Jacqueline , Bastard Jean-Philippe
Published: April 2022

Objective

To achieve a better understand of the pathophysiology of HIV-related lipoatrophy, we compared the mRNA expression of adipocytokines in fat samples from patients and healthy HIV-seronegative controls together with fat morphology and we studied the relationship between changes in fat morphology, adipocytokine expression, markers of adipose tissue differentiation and whole body insulin sensitivity.

Design

Cross-sectional analytical study.

Subjects and methods

The mRNA expression of adipocytokines and transcriptional factors in fat samples from 26 patients with peripheral lipoatrophy (all under anti-retroviral therapy associating protease inhibitor and nucleoside-analogue reverse transcriptase inhibitors) and from 16 non-HIV-infected controls was measured by real time quantitative RT-PCR. Fat morphology was assessed histologically on a subgroup of 10 patients and six controls: collagen fibres by Sirius Red staining, apoptosis by the TUNEL technique, vessels by smooth muscle α-actin staining and macrophages by CD68 staining. Insulin resistance was assessed by using the homeostasis model assessment.

Results

The patients’ fat showed higher values of apoptosis ( P=0.005), fibrosis ( P<0.05), vessel density ( P=0.001) and macrophage infiltration ( P<0.05) than the controls’ fat, together with lower adiponectin and leptin mRNA levels and higher interleukin (IL)-6 and tumour necrosis factor (TNF)α mRNA levels. TNFα and IL-6 expression correlated positively with the level of apoptosis ( P=0.05 and P<0.05, respectively) and negatively with CCAAT-enhancer binding protein (C/EBP)α ( P<0.001 and P<0.05, respectively). Apoptosis correlated negatively with the expression level of sterol-regulatory-element-binding-protein-1c (SREBP1c) ( P=0.01) and C/EBPα ( P=0.01) whilst the vessel density correlated negatively with SREBP1c ( P<0.005), C/EBPα ( P=0.001) and β ( P=0.001). Adiponectin and leptin expression correlated positively with each other, and also with adipogenic marker expression and overall insulin sensitivity. These relationships were also present when the patient group was studied separately. Finally, fat morphological abnormalities correlated positively with whole body insulin resistance.

Conclusions

Adipose tissue from patients with HIV-1-related lipoatrophy shows increased apoptosis, together with decreased adipocyte differentiation. Increased TNFα and IL-6 expression could be a major phenomenon linking these alterations. Decreased adiponectin and leptin expression, which may result from decreased adipocyte differentiation, could be involved in the observed whole body insulin resistance.
Genotypic and Phenotypic Characterization of Acyclovir-Resistant Herpes Simplex Viruses Isolated from Haematopoietic Stem Cell Transplant Recipients
Authors: Stránská Růžena , van Loon Anton M , Polman Merjo , Beersma Matthias FC , Bredius Robbert GM , Lankester Arjan C , Meijer Ellen , Schuurman Rob
Published: April 2022

Thirty-one herpes simplex virus type one (HSV-1) isolates from 12 haematopoietic stem cell transplant recipients with persistent HSV infections despite acyclovir (ACV) prophylaxis or treatment, were genotypically and phenotypically characterized. The relationship between drug susceptibility of the isolates and mutations in thymidine kinase (TK) and DNA polymerase (DNA pol) genes was examined. In all 12 patients, HSV infections were due to ACV-resistant, foscarnet-sensitive viruses. Out of 31 isolates examined, 23 were resistant and eight were sensitive to ACV; eight patients carried viruses with frameshift mutations in the TK gene (due to addition or deletion of single nucleotides in homopolymeric repeats). These mutations were found at codon 61 (G deletion, one patient), 146 (G insertion, five patients) and 153 or 185 (C deletion, one patient each). In four patients, viruses were selected during ACV therapy that contained novel amino acid substitutions in the TK gene (H58R, G129D, A189V, R216H, R220C). Their possible role in ACV resistance was further confirmed phenotypically and by the absence of any resistance-associated mutations in the DNA pol gene. These substitutions were located in ATP- or nucleoside-binding sites or in conserved regions of the TK gene. In addition, a single mutation, Q570R, in the δ-region C of the DNA pol gene, was identified in an isolate from a single patient with resistance to ACV. Our study confirms and expands previous data on genotypic changes associated with ACV resistance of HSV-1 clinical isolates.
Use of Pegylated Interferons is Associated with An Increased Incidence of Infections during Combination Treatment of Chronic Hepatitis C: A Side Effect of Pegylation?
Authors: Puoti Massimo , Babudieri Sergio , Rezza Giovanni , Viale Pierluigi , Antonini Maria Giulia , Maida Ivana , Rossi Stefania , Zanini Barbara , Putzolu Valeria , Fenu Luisa , Baiguera Chiara , Sassu Salvatore , Carosi Giampiero , Mura Maria Stella
Published: April 2022

Standard interferon treatment is known to increase the risk of infections; this risk also needs to be evaluated in clinical practice for pegylated interferon. To this end, we studied 255 patients treated with standard (103) or pegylated (152) interferon, in combination with ribavirin, for hepatitis C. Overall, 31 anti-hepatitis C virus treatment-related infections were observed. Neutropenia (neutrophil counts below 1x103 cells/ml) was observed in a significantly higher proportion of patients treated with pegylated interferons (48% vs 9%; P=0.0009). Of the 31 infections, eight were respiratory infections and were observed only in patients with neutropenia. None of the non-respiratory infections was observed in patients with neutropenia. Multivariate analysis, using Cox's proportional hazards regression model, found a higher risk of all infections associated with both use of pegylated interferons [hazard ratio (HR) 4.6] and neutropenia (HR 2.46). However, neutropenia was independently associated with acute respiratory infections only and use of pegylated interferons with non-respiratory infections. In summary, use of pegylated interferon appears to increase the risk of non-respiratory infections independently from neutropenia.
Immunomodulation Induced by Tucaresol in HIV Infection: Results of a 16 Week Pilot Phase I/II Trial
Authors: Gori Andrea , Trabattoni Daria , Bandera Alessandra , Saresella Marina , Marchetti Giulia , Gazzola Lidia , Biasin Mara , Rhodes John , McDade Hugh , Panebianco Ruggero , Galli Massimo , Moroni Mauro , Ferrante Pasquale , Thomas Nicola , Franzetti Fabio , Bray Dorothy , Clerici Mario
Published: April 2022

Objective

Immune reconstitution in highly active anti-retroviral therapy (HAART)-treated individuals is incomplete and immunomodulatory compounds are needed to improve the outcome of HIV therapy. In a Phase I/II clinical trial performed on HIV-positive patients we analysed the safety and immunomodulating effects of tucaresol, a novel compound that has previously been described to enhance cell-mediated immune responses.

Patients and methods

Sixteen weeks pulse dose escalation protocol. Four groups of HIV-positive patients were enrolled: group A ( n=6): HAART, CD4+ 300–500 cells/μl, HIV RNA <80 copies/ml; group B ( n=6): HAART-naive, CD4+ <500 cells/μl, HIV RNA >10 000 copies/ml; group C ( n=3): HAART-naive, CD4+ >500 cells/μl, HIV RNA <10 000 copies/ml; and group D ( n=6): HAART, CD4+ <200 cells/μl, HIV RNA <80 copies/ml. Tucaresol was added to HAART in group A and D patients; group B patients started tucaresol with HAART, group C patients received tucaresol alone. Clinical and immunological analyses were performed at different time points.

Results

Tucaresol-related serious adverse events were observed in the first week of therapy in 2/21 patients who were viraemic when commencing treatment, but did not occur in patients on stable HAART. Tucaresol did not affect HIV viraemia whereas increases in CD4+ percentages, mainly supported by naive CD4+ cells, were observed. CD8+/28-/45RA+ cells and HIV-specific CD8+ IFNγ- and perforin-producing cells improved whereas IL-10 mRNA diminished in tucaresol-treated patients. The effects were greater with 25 mg given every other day for 1 week.

Conclusion

In HAART-receiving patients with proper virus suppression, tucaresol was not associated with serious adverse events and resulted in qualitative and quantitative stimulation of HIV-specific cytotoxic T lymphocyte activity and generation of naive T cells. These data may support further exploration of tucaresol use in reconstitution of immune system parameters in HIV patients with proper virus suppression while on HAART.