bluuebunny/crossref_metadata_2025 huggingface dataset:
Using Live Pathogens to Treat Infectious Diseases: A Historical Perspective on the Relationship between Gb Virus C and HIV
Authors: Aronoff David M
Published: April 2022

Recent reports that co-infection with GB virus C (GBV-C) is associated with a reduced mortality in HIV-infected individuals, a slower progression to AIDS, and lower HIV viral loads, suggest a potential role of GBV-C as therapy for HIV infection. Although not known to cause any human disease, GBV-C was only recently discovered and prospective studies assessing long-term consequences of infection have not been completed. Our understanding of the host-viral interactions between humans and GBV-C is in its infancy. Further research into the intriguing relationship between GBV-C and HIV is needed before intentional inoculation of GBV-C into individuals infected with HIV should proceed. This essay explores the history of the once-popular treatment of paretic tertiary syphilis with the blood-borne pathogen Plasmodium vivax, providing a historical perspective on the current state of affairs between GBV-C and HIV. A brief review of GBV-C biology and human infection is followed by a discussion of the current challenges facing the use of this organism to treat HIV.
Residual Cell-Associated Unspliced HIV-1 Rna in Peripheral Blood of Patients on Potent Antiretroviral Therapy Represents Intracellular Transcripts
Authors:   for the Swiss HIV Cohort Study (members listed in Acknowledgements), Fischer Marek , Wong Joseph K , Russenberger Doris , Joos Beda , Opravil Milos , Hirschel Bernhard , Trkola Alexandra , Kuster Herbert , Weber Rainer , Günthard Huldrych F
Published: April 2022

Unspliced HIV-RNA (HIV-UsRNA) associated with peripheral blood mononuclear cells (PBMCs) persists in patients on potent antiretroviral therapy even in the absence of detectable plasma HIV-RNA. To further characterize such residual HIV-RNA, cell-associated virion-encapsidated HIV and intracellular unspliced HIV-RNA were differentiated and monitored using a novel highly sensitive method. In addition, expression of HIV-mRNA encoding tat and rev was assessed. PBMCs of patients with unsuppressed plasma viraemia harboured an extracellular fraction of HIV-UsRNA, which correlated highly with intracellular HIV-RNA levels. Thus, extracellular PBMC-associated HIV-RNA may, to a significant extent, reflect nascent virions attached to productively infected cells. Upon treatment with potent antiretroviral therapy resulting in plasma viraemia <50 copies/ml, expression of cell-associated viral particles was hardly discernible in PBMCs but transcription of unspliced HIV-RNA persisted. Given the virtual absence of rev-mRNA, translation of residual HIV-UsRNA was probably precluded by retention of these transcripts in the nucleus. As shown by limiting dilution analysis, HIV-1 infected cells with such a repressed viral transcription pattern were observed at high frequencies in PBMC from untreated patients.
Baseline Thymic Volume is a Predictor for CD4 T Cell Repopulation in Adult HIV-Infected Patients under Highly Active Antiretroviral Therapy
Authors: de la Rosa Rafael , Leal Manuel , Rubio Amalia , Martínez-Moya Manuel , Delgado Juan , Ruíz-Mateos Ezequiel , Merchante Elena , Sánchez-Quijano Armando , Lissen Eduardo ,   (Viral Hepatitis and AIDS Study Group)
Published: April 2022

The objective of the present study was to assess the impact of baseline thymic volume on the CD4 cell repopulation induced by highly active antiretroviral therapy (HAART) in HIV-infected adults. Therefore, 37 previously untreated HIV-1-infected adults were prospectively followed from August 1998 to September 2001. All patients underwent a thorax CT scan at starting HAART to measure thymic volume. The median follow-up time was 189 [87.5–498.5] days. CD4 cell repopulation was considered as an increase ≥200 cells/mm3 above baseline count. Twenty-one (57%) patients achieved this CD4 repopulation. Baseline thymic volume was the main independent factor associated with CD4 repopulation ( P=0.016); this factor was a positive predictor (adjusted hazard ratio: 1.25 [95% confidence interval 1.1–1.4]). Although, CD4 cell count and non-AIDS diagnosis at baseline were associated with CD4 cell repopulation on the univariate analysis ( P=0.03 and P=0.02, respectively), no statistical signification was found on the multivariate test. In summary, baseline thymic volume is a predictor of early CD4 cell repopulation in adult HIV-1-infected patients taking HAART.
Trimethoprim-Sulfamethoxazole (Tmp/Smx) Potentiates Indinavir Nephrotoxicity
Authors: de Araujo Magali , Seguro Antonio Carlos
Published: April 2022

Objectives

Indinavir is a widely prescribed protease inhibitor in the treatment of HIV infection. It has been associated with nephrolithiasis, crystalluria and tubulointerstitial nephritis. Nelfinavir is another protease inhibitor used successfully in AIDS treatment. The objective of this study was to evaluate the effect of both indinavir and nelfinavir individually, and in association with trimethoprim-sulfamethoxazole (TMP/SMX), on renal function in Wistar rats.

Methods

Doses of indinavir (80 mg/kg body weight [BW] daily), nelfinavir (75 mg/kg BW daily) and TMP/SMX (100 mg TMP/kg BW daily) were given by gavage for 15 days. Seven groups were studied: control, vehicle, TMP/SMX, indinavir, indinavir+TMP/SMX, nelfinavir, and nelfinavir+TMP/SMX.

Results

No changes were observed in body weight, urine volume and blood pressure. The vehicle group did not differ from the control group. TMP/SMX induced a small decrease in inulin clearance with no tubular alterations. Indinavir decreased inulin clearance (indinavir: 0.48 ±0.03 vs control: 0.93 ±0.08, P<0.001) and renal blood flow (indinavir: 6.2 ±0.2 vs control: 8.0 ±0.3, P<0.05). These effects were potentiated by TMP/SMX, which produced high vasoconstriction associated with alterations in tubular functions, characterised by increased fractional excretion of sodium (indinavir+TMP/SMX: 1.14 ±0.16 vs control: 0.39 ±0.07, P<0.01). Nelfinavir either alone or in combination with TMP/SMX did not change the renal function of the rats.

Conclusion

These results suggest that indinavir nephrotoxicity in rats is potentiated by TMP/SMX and that nelfinavir alone or in combination with TMP/SMX is not nephrotoxic.
Long-Term Virological Outcome in Patients Infected with Multi-Nucleoside Analogue-Resistant HIV-1
Authors: Clevenbergh Philippe , Kirstetter Myriam , Liotier Jean-Yves , Dupon Michel , Philibert Patrick , Jacomet Christine , Cua Eric , Montagne Nathalie , Schmit Jean Claude , Dellamonica Pierre
Published: April 2022

The emergence of HIV strains that are resistant to anti-retroviral drugs is a major cause of treatment failure. Two sets of mutations: the Q151M complex and the 69 insert, cause resistance to multiple nucleoside analogues. We report the response to treatment in 12 patients with multiple NRTI-resistant HIV-1 strains. Seven of 12 patients (58%) were able to maintain a viral load below 200 copies/ml at week 48. The patients most likely to obtain therapeutic success were those having no or low-level resistance to non-nucleoside reverse transcriptase inhibitors and/or protease inhibitors. New and more effective drugs are needed for patients with HIV-1 that is resistant to more than one of the current three classes of HIV drugs.
Long-Term Efficacy and Safety of Twice-Daily Saquinavir Soft Gelatin Capsules (SGC), with or without Nelfinavir, and Three Times Daily Saquinavir-SGC, in Triple Combination Therapy for HIV Infection: 100-Week Follow-Up
Authors: Greenberg Richard N , Feinberg Judith , Goodrich James , Pilson Robert S , Siemon-Hryczyk Peggy
Published: April 2022

Objectives

To evaluate the long-term efficacy and safety of saquinavir soft gelatin capsules (SQV-SGC) (Fortovase®) in twice-daily, with or without nelfinavir (NFV), and three-times-daily regimens. This was an extension of a 48-week study, with follow-up to 100 weeks.

Design

Patients were randomized to one of three treatment arms: arm A, SQV-SGC 1200 mg three times daily plus two nucleoside reverse transcriptase inhibitors (NRTIs); arm B, SQV-SGC 1600 mg twice daily plus two NRTIs; or arm C, SQV-SGC 1200 mg twice daily plus NFV 1250 mg twice daily plus one NRTI. At week 48, patients could either withdraw or continue in the study to the common study closure date. Antiretroviral activity was assessed by changes in HIV-1 RNA values and CD4 cell counts from 48 weeks until 100 weeks.

Results

In the modified intention-to-treat population, the proportion of patients with HIV-1 RNA values <400 copies/ml was statistically different between arms A and C (49 vs 28%, P=0.017), and arms B and C (48 vs 28%, P=0.027). Continued suppression of HIV-1 replication (HIV-1 RNA <400 copies/ml) was observed through 100 weeks in 83% (30/36), 73% (29/40) and 62% (16/26) of patients in treatment arms A, B and C, respectively, in the on-treatment (OT) population. At 100 weeks, sustained increases were achieved in mean CD4 cell counts of +361, +273 and +309 cells/mm3, respectively (OT population). No additional adverse events or increase in the proportion of patients reporting adverse events were observed from 48 weeks to 100 weeks.

Conclusions

This study demonstrates the long-term efficacy and safety of SQV-SGC twice daily, with or without NFV, and three times daily, in triple combination therapy for HIV-1-infected patients. However, the evidence suggests that long-term treatment with SQV-SGC plus NFV may be less acceptable to patients.
Paternal Exposure to Ribavirin: Pregnancy and Neonatal Outcome
Authors: De Santis Marco , Carducci Brigida , Cavaliere Anna Franca , Santis Lidia De , Lucchese Angela , Straface Gianluca , Caruso Alessandro
Published: April 2022

We report seven cases of newborns conceived within 6 months from the end or during paternal ribavirin exposure.
Antiviral Agents from Plants and Herbs: A Systematic Review
Authors: Martin Karen W , Ernst Edzard
Published: April 2022

Background and aims

Many antiviral compounds presently in clinical use have a narrow spectrum of activity, limited therapeutic usefulness and variable toxicity. There is also an emerging problem of resistant viral strains. This study was undertaken to examine the published literature on herbs and plants with antiviral activity, their laboratory evaluation in vitro and in vivo, and evidence of human clinical efficacy.

Methods

Independent literature searches were performed on MEDLINE, EMBASE, CISCOM, AMED and Cochrane Library for information on plants and herbs with antiviral activity. There was no restriction on the language of publication. Data from clinical trials of single herb preparations used to treat uncomplicated viral infections were extracted in a standardized, predefined manner.

Results

Many hundreds of herbal preparations with antiviral activity were identified and the results of one search presented as an example. Yet extracts from only 11 species met the inclusion criteria of this review and have been tested in clinical trials. They have been used in a total of 33 randomized, and a further eight non-randomized, clinical trials. Fourteen of these trials described the use of Phyllanthus spp. for treatment of hepatitis B, seven reporting positive and seven reporting negative results. The other 10 herbal medicines had each been tested in between one and nine clinical trials. Only four of these 26 trials reported no benefit from the herbal product.

Conclusions

Though most of the clinical trials located reported some benefits from use of antiviral herbal medicines, negative trials may not be published at all. There remains a need for larger, stringently designed, randomized clinical trials to provide conclusive evidence of their efficacy.
Prevalence and clinical implications of insertions in the HIV-1 p6Gag N-terminal region in drug-naive individuals initiating antiretroviral therapy
Authors: Brumme Zabrina L , Chan Keith J , Dong Winnie WY , Wynhoven Brian , Mo Theresa , Hogg Robert S , Montaner Julio SG , O'Shaughnessy Michael V , Harrigan P Richard
Published: April 2022

We assessed the prevalence and clinical impact of insertions within the HIV-1 p6Gag proline-rich (PTAP) region on initial antiretroviral therapy response in 461 HIV-infected, drug-naive individuals initiating therapy in British Columbia, Canada between June 1996 and August 1998. HIV p6Gag insertions were detected by nested RT-PCR of extracted patient plasma followed by direct DNA sequencing. Insertions were observed in 70 of 423 successfully genotyped samples (16.5%). HIV p6Gag insertions were significantly associated with a lower baseline CD4 cell count (P<<0.05) and the presence of basic amino acids at key positions in the HIV envelope V3 loop linked to a syncytium-inducing phenotype (P<<0.05). After adjusting for baseline factors, no effect of HIV p6Gag insertions was observed on time to virological success (pVL ≤500 copies/ml), virological failure (subsequent confirmed pVL ≥500 copies/ml) or immunological failure (confirmed CD4 count below baseline), as evaluated by Kaplan-Meier methods and Cox proportional hazard regression (P>0.1). The data suggest that HIV p6Gag insertions are not exclusively related to drug resistance and may not influence response to antiretroviral therapy, but may be linked to sequence variations in the HIV envelope.
Fat Distribution and Metabolic Abnormalities in HIV-Infected Patients on First Combination Antiretroviral Therapy Including Stavudine or Zidovudine: Role of Physical Activity as a Protective Factor
Authors: Domingo Pere , Sambeat María A , Pérez Antonio , Ordoñez Jordi , Rodríguez José , Vázquez Guillermo
Published: April 2022

Objective

To compare body composition, serum lipid profile, parameters of insulin secretion and endocrine measurements in HIV-1-infected patients whose first combination antiretroviral regimen differed only in a nucleoside reverse transcriptase inhibitor (NRTI).

Design and setting

Cross-sectional study in an AIDS clinic of a university hospital.

Patients

One-hundred-and-fifty HIV-infected patients on long-term first highly active antiretroviral therapy including stavudine (n=75) or zidovudine (n=75).

Main outcome measure

Fat wasting was assessed by physical examination. Regional fat distribution was estimated using calliper measurements of skinfold thickness at four sites. Central adiposity was assessed by measurement of waist–hip ratio. Fasting glucose, insulin, triglyceride, cholesterol and its fractions, testosterone, follicle stimulating hormone, luteinizing hormone levels, CD4 cell count and HIV viral load were determined. Daily caloric intake and physical activity level were also calculated.

Results

Total body fat was significantly lower in patients taking stavudine, whereas the lean body mass was not statistically different amongst both groups. Ninety-four patients (62.7%; 95% CI: 54.9–70.4%) had fat redistribution, being isolated lipoatrophy in 20 (13.3%; 95% CI: 7.9–18.8%), isolated lipohypertrophy in 33 (22.0%; 95% CI: 15.4–28.6%) and mixed syndrome in 41 (27.3%; 95% CI: 20.2–34.5%). There were not statistically significant differences between stavudine- and zidovudine-treated patients with respect to the overall prevalence of fat redistribution syndromes (P=0.34). The prevalence of lipoatrophy (OR=1.86; 95% CI: 0.58–6.33, P=0.37), lipohypertrophy (OR=0.65; 95% CI: 0.25–1.69, P=0.45) and mixed syndromes (OR=1.05; 95% CI: 0.43–2.54, P=0.93) was not statistically different in both groups of patients. The only independent predictor for the appearance of mixed syndrome and lipoatrophy was sedentarism (OR=4.418; 95% CI: 1.565–12.472, P=0.005) and (OR=4.515; 95% CI: 1.148–17.761, P=0.03), respectively. Independent predictors of lipohypertrophy were age (OR=1.138; 95% CI: 1.061–1.220, P<0.0001) and prior AIDS (OR=0.305; 95% CI: 0.100–0.931, P=0.04). There were no statistically significant differences between stavudine and zidovudine-based groups with respect to metabolic and hormonal parameters.

Conclusion

The use of stavudine or zidovudine in the context of the first combination antiretroviral therapy is not associated either with an increased likelihood of lipid or gonadal hormones abnormalities, and although there was a trend to a lesser body fat content in the stavudine group, there was no increase in the overall likelihood of fat redistribution syndromes with respect to zidovudine group. Physical activity is a protective factor for the development of fat redistribution syndromes.
Comparison of Thymic Function-Related Markers to Predict Early Cd4 T-Cell Repopulation in Adult HIV-Infected Patients on Haart
Authors: Ruiz-Mateos Ezequiel , de la Rosa Rafael , Soriano Natalia , Martinez-Moya Manuel , Rubio Amalia , Sánchez-Quijano Armando , Lissen Eduardo , Leal Manuel
Published: April 2022

The aim of this work was to compare thymic function-related markers for predicting early CD4 T-cell repopulation in adult HIV-infected patients under HAART. Forty-three consecutive antiretroviral-naive patients were prospectively analysed for clinical, biochemical, immunological and virological parameters at starting HAART, and followed for 4 weeks and every 12 weeks thereafter. At baseline, all patients underwent a thoracic computer tomography scan, in order to measure thymic volume, as well, T-cell phenotype (naive CD4 and CD8 T cells) and the number of TREC-bearing cells were obtained. CD4 cell repopulation was considered as an increase ≥200 cells/mm3 above baseline count. Twenty-seven patients (62.8%) increased ≥200 cells/mm3 above baseline levels during the follow-up. The median time to event was 182 days (84–537 days). On the univariate analysis, to be younger than 36 years, showing a CD4 cell count ≥272 cells/mm3, a total naive T-cell count ≥128 cells/mm3, a TREC-bearing cell count ≥0.74 cells/mm3, and a thymic volume ≥3.07 cc at baseline were statistically associated to the event studied. However, when the multivariate analysis was performed, only thymic volume at baseline was independently associated ( P=0.002) to CD4 cell recovery. This co-variable was identified as a positive predictor [hazard ratio, 1.22 (95% confidence interval: 1.16–1.28)]. In summary, data presented herewith show that thymic volume is the best thymic function-related marker for predicting early CD4 T-cell recovery in adult HIV-infected patients under HAART.
Natural History Models for Hepatitis C-Related Liver Disease: Different Disease Progression Parameters for Different Settings
Authors: Dore Gregory J , Freeman Anthony J , Law Matthew , Kaldor John M
Published: April 2022

An understanding of the natural history of hepatitis C virus (HCV) infection has improved in recent years. Estimates of liver disease progression among people with chronic hepatitis C have been developed from various study populations, including liver clinics, post-transfusion hepatitis C cohorts and community-based cohorts. These estimates can be used in hepatitis C natural history models; however, they need to be matched to differing requirements. Estimation and projection of liver disease burden at the population level requires estimates of HCV prevalence and incidence, and disease progression among all people with chronic hepatitis C. Liver disease progression based on community cohorts would appear the most appropriate for a population level model. In contrast, models that examine the cost-effectiveness of antiviral therapy for people with chronic hepatitis C require disease progression estimates from the treatment setting. Further models are required to determine individual prognosis and should be based on an assessment of cofactors for liver disease progression.
A Once-Daily Haart Regimen Containing Indinavir + Ritonavir plus One Or Two Nucleoside Reverse Transcriptase Inhibitors (Pipo Study)
Authors: Burger David M , Aarnoutse Rob E , Dieleman Jeanne P , Gyssens Inge C , Nouwen Jan , de Marie Siem , Koopmans Peter P , Stek Michael , van der Ende Marcina E
Published: April 2022

Introduction

There is an increased interest in developing once-daily regimens for the treatment of HIV-infected patients. A Phase II study was conducted to investigate the pharmacokinetics, and short-term safety and efficacy of an indinavir/ritonavir combination as part of a once-daily regimen.

Methods

HIV-infected patients with either proven poor compliance to HAART regimens in the past or an anticipated poor compliance to such a regimen in the future were eligible for this study. They received a once-daily regimen consisting of indinavir 1200 mg, ritonavir 400 mg, and one or two nucleoside reverse transcriptase inhibitors (NRTIs), also administered once daily with food. A 24 h pharmacokinetic profile was constructed in a subset of patients. Short-term safety and efficacy were evaluated at 4, 12 and 24 weeks after initiation of treatment.

Results

A total of 64 patients were included in this study, of whom 27 (42.2%) were treatment-naive. The geometric mean (+95% CI) of indinavir AUC0–24h, Cmax and Cmin as determined in an unselected group of 16 patients were 84.9 (69.7–103.5) mg/l.h, 12.0 (10.2–14.1) mg/l and 0.15 (0.09–0.26) mg/l, respectively. A large interpatient variability was observed, with five out of the 16 subjects having a Cmin value below the minimum effective concentration of 0.10 mg/l. During the 24 weeks of follow-up nine patients (14.1%) discontinued study medication, two due to medication-related toxicity. Gastrointestinal adverse events were reported most frequently (50.0%), followed by skin effects (45.3%), joint pain (9.4%) and urological complaints (7.8%). No patient developed nephrolithiasis. The median (+interquartile range) serum creatinine level in the 64 patients increased slightly from 74 (63–88) μmol/l to 79 (66–92) μmol/l during the 24 weeks of follow-up. One new patient reached a grade 1 elevation in serum creatinine, which normalized during the follow-up; five other patients with elevated serum creatinine at baseline remained stable. During the 24 weeks of follow-up, the proportion of patients with a viral load <500 copies/ml increased from 35.1% at baseline to 71.4% (ITT NC=F analysis) or 83.3% (OT analysis), and from 0% at baseline to 76.2% (ITT NC=F analysis) or 100.0% (OT analysis) in treatment-experienced and -naive patients, respectively. This was accompanied by a mean increase in CD4 cell count of 52 and 220 cells/mm3 in these two sub-groups, respectively.

Conclusion

The 24-week follow-up data of this study indicate favourable pharmacokinetics of an indinavir/ritonavir 1200/400 mg combination as part of a once-daily regimen consisting also of one or two NRTIs. Short-term safety and efficacy were also satisfactory. Long-term follow up is planned to evaluate the durability of these results.
Contribution of Nucleoside-Analogue Reverse Transcriptase Inhibitor Therapy to Lipoatrophy from the Population to the Cellular Level
Authors: Nolan David , Hammond Emma , James Ian , McKinnon Elizabeth , Mallal Simon
Published: April 2022

Objectives

It has been proposed that the contribution of nucleoside-analogue reverse transcriptase inhibitor (NRTI) therapy to subcutaneous fat wasting involves adipose tissue-specific mitochondrial DNA toxicity. We have investigated the relationships between NRTI therapy, adipocyte mitochondrial DNA content, evidence of toxicity in adipose tissue and fat wasting in Caucasian male Western Australian HIV Cohort study participants. Methods: Longitudinal mixed effects analysis of fat wasting was undertaken in individuals receiving initial stavudine- or zidovudine-containing highly active anti-retroviral therapy (HAART) ( n=49, 149 DEXA measurements). Adipocyte mitochondrial DNA (mtDNA) depletion was also assessed according to current NRTI therapy in 92 subcutaneous fat biopsies from 69 HIV-positive individuals and seven healthy controls, and results were correlated with fat wasting among a subset of patients with biopsy data receiving initial stavudine-or zidovudine-containing HAART ( n=22, 103 DEXA measurements). Confocal microscopy was performed in 22 biopsy samples obtained before and after initiating/switching NRTI therapy.

Results

Stavudine therapy was associated with more severe adipocyte mitochondrial DNA depletion ( P<0.001) and fat wasting over time ( P=0.002) compared with zidovudine therapy in independent analyses. Among patients with concurrent biopsy and longitudinal DEXA data, fat wasting was associated with duration of NRTI therapy ( P=0.001) and adipocyte mtDNA copies/cell ( P=0.01). In this analysis, the significant association between choice of stavudine versus zidovudine and fat wasting ( P=0.03) was lost after adjustment for the effect of mtDNA depletion ( P=0.13). Confocal analysis provided direct evidence of a relationship between severity of adipose tissue toxicity and mitochondrial DNA depletion. No significant effects of HIV protease inhibitor therapy were detected in these analyses.

Conclusions

Severity of subcutaneous fat wasting is primarily determined by choice of NRTI therapy (stavudine versus zidovudine) and by duration of exposure to the relevant NRTI. At the cellular level, evidence is provided that this effect manifests through NRTI-induced mitochondrial DNA depletion.
Mitochondrial Effects of Antiretroviral Therapies in Asymptomatic Patients
Authors: López Sònia , Miró Òscar , Martínez Esteban , Pedrol Enric , Rodríguez-Santiago Benjamín , Milinkovic Ana , Soler Anna , García-Viejo Miguel A , Nunes Virginia , Casademont Jordi , Gatell Josep M , Cardellach Francesc
Published: April 2022

Background

A decrease in the mitochondrial (mt) DNA to nuclear DNA ratio has gained acceptance as a marker of mitochondrial toxicity in treated HIV-infected patients, but the functional meaning of this alteration is unclear.

Methods

We assessed mtDNA content, mitochondrial content and function in peripheral blood mononuclear cells (PBMCs) of consecutive asymptomatic HIV-infected patients. Patients selected had been receiving a first-line highly active antiretroviral therapy (HAART) regimen for at least 6 months, consisting of zidovudine plus lamivudine or stavudine plus didanosine plus either nelfinavir or nevirapine, or were antiretroviral-naive. The mtDNA content was assessed by quantitative real-time PCR, mitochondrial content by citrate synthase activity, enzyme activity of complexes III and IV (both partially encoded by mtDNA) of the electron transport chain by spectrophotometry, oxygen consumption by polarography, and oxidative damage in cell membranes by monitoring cis-parinaric acid fluorescence.

Results

Mitochondrial content was significantly lower in all treated groups. Patients receiving stavudine plus didanosine had mtDNA depletion and a decrease in complex IV activity. However, oxygen consumption capacity and lipid peroxidation were unaffected in all groups.

Conclusion

Long-term HAART may induce mitochondrial abnormalities in PBMC mitochondria, which do not necessarily translate into functional abnormalities, at least in asymptomatic patients. This study was presented in the 4th International Workshop on Adverse Drug Reactions & Lipodystrophy in HIV (San Diego, Calif., USA, September 2002) and in ‘Late Breakers & Hot Topics’ session in the 6th International Congress on Drug Therapy in HIV Infection (Glasgow, UK, November 2002).
Immune Restoration in HIV-Positive, Antiretroviral-Naive Patients after 1 Year of Zidovudine/Lamivudine plus Nelfinavir or Nevirapine
Authors: Plana Montserrat , Ferrer Elena , Martínez Catalina , Podzamczer Daniel , García Felipe , Maleno María J , Barceló Juan J , García Ana , Barberá María J , Lacarcel Montserrat , Miró José M , Gallart Teresa , Gatell José M
Published: April 2022

Objectives

To evaluate the immunological response in HIV-1-infected, antiretroviral-naive patients receiving highly active antiretroviral therapy regimen of two nucleosides plus a protease inhibitor or a non-nucleoside reverse transcriptase inhibitor.

Design and methods

Of 142 patients included in a randomized, open, multicentre trial comparing zidovudine/lamivudine plus nelfinavir (NFV) or nevirapine (NVP), 36 patients (16 NFV, 20 NVP) were enrolled in an immunological substudy. Mean baseline CD4 T-cell counts was 360/mm3 (range: 11–679) and mean baseline plasma viral load >50 000 copies/ml (range: 2240–1468210). Viral load (VL), T-cell subsets and T-cell functions were analysed at baseline and after 1 year of treatment.

Results

After 12 months of follow-up, plasma viral load was reduced similarly in both groups, with 78% (NFV) and 83% (NVP) of patients achieving a VL <200 copies/ml. A significant increase in CD4 T cells was observed in both groups (mean: +182 cells, P=0.001). Both regimens were similarly effective in reducing activated T cells (CD38 and DR). A significant increase of both CD4 and CD8 CD28 T cells occurred in both arms of treatment. Patients of both regimens showed a significant decrease of activated memory (CD45RA–CD45RO+) CD8 T cells and a clear increase of naive (CD45RA+CD45RO-) CD8 T cells. Peripheral blood mononuclear cell proliferative responses to polyclonal stimuli (CD3 and CD3 +CD28) as well as to ubiquitous cytomegalovirus antigen increased significantly in both groups after 12 months of follow-up. Nevertheless, neither at baseline nor after 1 year of treatment, these patients showed any significant T-cell responsiveness to HIV-1 recombinant proteins gp160 or p24.

Conclusions

Our data indicate that immune restoration achieved after 1 year of therapy with either NFV or NVP was similar. This reinforces the role of NVP-containing regimens as a valid option for initiating antiretroviral therapy. Nevertheless, additional therapeutic approaches should be envisaged to restore HIV-1-specific T-cell responses.
Comparison of Two Reduced-Dose Regimens of Indinavir (600 Mg Vs 400 Mg Twice Daily) and Ritonavir (100 Mg Twice Daily) in Healthy Volunteers (Coredir)
Authors: Wasmuth Jan-Christian , la Porte Charles JL , Schneider Katrin , Burger David M , Rockstroh Juergen K
Published: April 2022

Objective

To assess the pharmacokinetics and tolerability of reduced dosages of twice daily indinavir (IDV) boosted by low-dose ritonavir (RTV) in healthy volunteers.

Methods

Pharmacokinetics and tolerability of IDV/RTV twice daily (600/100 mg and 400/100 mg) were assessed in a randomized crossover design in 16 healthy volunteers. Each dosage was taken twice daily for 2 weeks before 12 h pharmacokinetics were obtained.

Results

Sixteen subjects were included, with a mean age ±SD of 30 ±4 years; seven female, nine male. Fifteen subjects completed the study. After dose reduction of IDV AUC, Cmax and Cmin decreased significantly. In the 400 mg group three out of 15 subjects had IDV levels below 0.10 mg/l vs none in the 600 mg group. All subjects reported mild to moderate side effects throughout the study period, which were more severe in the 600 mg group (mostly renal, dry skin/lips, paresthesias/oral discomfort). In the 600 mg group four subjects reported dysuria and one subject discontinued because of flank pain, whereas two subjects reported dysuria and no subject discontinued in the 400 mg group, respectively. Eight subjects developed crystalluria without a significant difference between both groups. No significant change in serum creatinine was observed.

Conclusions

IDV/RTV 400/100 mg twice daily resulted in significant lower IDV exposure, with three out of 15 subjects revealing Cmin values below the recommended threshold for wild-type virus of 0.10 mg/l. Tolerability, however, was lower in the 600 mg IDV group. Therapeutic drug monitoring in the individual patient appears to be necessary to guarantee appropriate drug levels and simultaneously minimize toxicity. Presented in part at the 6th International Congress on Drug Therapy in HIV Infection. Glasgow, Scotland, UK, November 2002. Abstract P182.
Long-Term Virological Response to Multiple Sequential Regimens of Highly Active Antiretroviral Therapy for HIV Infection
Authors:   the Study Swiss HIV Cohort, Kaufmann Gilbert R , Khanna Nina , Weber Rainer , Perrin Luc , Furrer Hansjakob , Cavassini Matthias , Ledergerber Bruno , Vernazza Pietro , Bernasconi Enos , Rickenbach Martin , Hirschel Bernard , Battegay Manuel , Bachmann S , Battegay M , Bernasconi E , Bucher H , Burgisser Ph , Cattacin S , Egger M , Erb P , Fierz W , Fischer M , Flepp M , Fontana A , Francioli P , Furrer HJ , Gorgievski M , Gunthard H , Hirschel B , Kaiser L , Kind C , Klimkait Th , Ledergerber B , Lauper U , Opravil M , Paccaud F , Pantaleo G , Perrin L , Piffaretti C , Rickenbach M , Rudin C , Schupbach J , Speck R , Telenti A , Trkola A , Vernazza P , Weber R , Yerly S
Published: April 2022

Objective

Information about the virological response to sequential highly active antiretroviral therapy (HAART) for HIV infection is limited. The virological response to four consecutive therapies was evaluated in the Swiss HIV Cohort.

Design

Retrospective analysis in an observational cohort.

Methods

1140 individuals receiving uninterrupted HAART for 4.8 ±0.6 years were included. The virological response was classified as success (<400 copies/ml), low-level (LF: 400–5000 copies/ml) or high-level failure (HF: >5000 copies/ml). Potential determinants of the virological response, including patient demographics, treatment history and virological response to previous HAART regimens were analysed using survival and logistic regression analyses.

Results

40.1% failed virologically on the first (22.0% LF; 18.1% HF), 35.1% on the second (14.2% LF; 20.9% HF), 34.2% on the third (9.9% LF; 24.3% HF) and 32.7% on the fourth HAART regimen (9% LF; 23.7% HF). Nucleoside pre-treatment (OR: 2.34; 95% CI: 1.67–3.29) and low baseline CD4 T-cell count (OR: 0.79/100 cells rise; 95% CI: 0.72–0.88) increased the risk of HF on the first HAART. Virological failure on HAART with HIV-1 RNA levels exceeding 1000 copies/ml predicted a poor virological response to subsequent HAART regimens. A switch from a protease inhibitor- to a non-nucleoside reverse transcriptase inhibitor-containing regimen significantly reduced the risk of HF. Multiple switches of HAART did not affect the recovery of CD4 T lymphocytes.

Conclusion

Multiple sequential HAART regimens do not per se reduce the likelihood of long-term virological suppression and immunological recovery. However, early virological failure increases significantly the risk of subsequent unfavourable virological responses. The choice of a potent initial antiretroviral drug regimen is therefore critical. This study has been presented in part at the 10th Conference on Retroviruses & Opportunistic Infections. Boston, Mass., USA, 2003. Abstract #571.
Skin Reactions in Patients with Influenza Treated with Oseltamivir: A Retrospective Cohort Study
Authors: Nordstrom Beth L , Oh Kelly , Sacks Susan T , L'Italien Gilbert J
Published: April 2022

Oseltamivir phosphate is an FDA-approved treatment for influenza that has been available for prescription use in the USA since 1999. The present report describes findings from a post-marketing safety study of skin reactions associated with oseltamivir use. All patients in the claims-derived Ingenix Research Database with a physician diagnosis of influenza and/or a dispensing of oseltamivir between 1 December 1999 and 31 March 2002 were identified. Cohort eligibility criteria included minimum baseline enrolment duration of 3 months, age of at least 1 year and no influenza vaccination on the date of influenza diagnosis or oseltamivir dispensing. Patients were classified into two primary cohorts, influenza diagnosis and oseltamivir dispensing on the same day, and influenza diagnosis but no oseltamivir at any time, and a cohort included for secondary analyses comprising patients who received an oseltamivir dispensing without an influenza diagnosis on the same day. Outcomes included general skin reactions and several specific skin reactions. Events occurring during the 30 days following the date of influenza diagnosis or oseltamivir dispensing were examined using Cox proportional hazards models. Model covariates included age, use of another influenza drug, month and year of index date, and use of antitussives. Adjusted rate ratios for the general class of skin reactions among the primary cohort of oseltamivir users versus non-users were 1.05 (95% CI: 0.88–1.24) for incident cases and 0.98 (95% CI: 0.77–1.24) among patients with a history of a skin reaction. Similar results were seen for the other skin reaction categories, and secondary analyses investigating the oseltamivir users without influenza revealed no elevation in risk. It is concluded that oseltamivir use does not appear to be associated with an increased risk of skin reactions.
Adherence to Antiretroviral Therapy and Cd4 T-Cell Count Responses among HIV-Infected Injection Drug Users
Authors: Wood Evan , Montaner Julio SG , Yip Benita , Tyndall Mark W , Schechter Martin T , O'Shaughnessy Michael V , Hogg Robert S
Published: April 2022

Objective

To evaluate the time to CD4 cell count response (≥50 cells/mm3) among patients initiating highly active antiretroviral therapy (HAART) with and without a history of injection drug use, and to examine the potential role of non-adherence to HAART on differential CD4 responses.

Methods

Population-based analysis of treatment-naive patients initiating HAART during the period 1 August 1996 to 31 July 2000 and who were followed until 31 March 2002. Patients were stratified based on 95% adherence and history of injection drug use, and Kaplan-Meier methods and Cox regression were used to evaluate CD4 response rates and factors associated with CD4 responses.

Results

Overall, the CD4 cell count response rate was slower among injection drug users in Kaplan-Meier analyses (log-rank: P<0.05). However, no differences existed when the analyses were restricted to adherent patients (log-rank: P=0.349). Similarly, the differences in the time to CD4 cell count response observed in univariate Cox regression analyses for patients with a history of injection drug use [relative hazard: 0.85 (95% CI: 0.75–0.97)] diminished after adjustment for adherence [adjusted relative hazard: 1.02 (95% CI: 0.89–1.16)].

Conclusion

These data demonstrate the importance of adherence on CD4 cell count responses and highlight the need for interventions to improve antiretroviral adherence among injection drug user.
Il-7/Il-7 Receptor System Regulation following Il-2 Immunotherapy in HIV-Infected Patients
Authors: Marchetti Giulia , Meroni Luca , Molteni Chiara , Taskaris Greta , Gazzola Lidia , Galli Massimo , Clerici Mario , Moroni Mauro , Franzetti Fabio , Gori Andrea
Published: April 2022

Interleukin-2 (IL-2) and IL-7 are the most intriguing molecules in immune-based HIV infection treatment. An in vitro IL-2/IL-7 cross-talk due to IL-2-driven IL-7 receptor-α-chain (IL-7Rα) down-modulation, potentially blocking IL-7 signalling has been described. We investigated the in vivo IL-2 effect on IL-7/IL-7R system, measuring free IL-7, and IL-7Rα CD4 and CD8 in 12 HIV-positive patients enrolled in a randomized IL-2 trial.

Compared to HAART alone, IL-2 induced a parallel expansion in total and naive CD4, TRECs and IL-7 plasma levels, with no IL-7Rα CD4 and IL-7Rα CD8 changes ( P>0.05), suggesting that in vivo IL-2 boosts IL-7 production without down-modulating IL-7Rα, preserving IL-7-mediated T-lymphocyte homeostatic regulation. Our data confirm the pivotal role of IL-2 and IL-7 in the regulation of T-lymphocyte homeostasis in HIV infection.
Pharmacokinetics of Once-Daily Saquinavir/Ritonavir in HIV-Infected Subjects: Comparison with the Standard Twice-Daily Regimen
Authors: Boffito Marta , Dickinson Laura , Hill Andrew , Back David , Moyle Graeme , Nelson Mark , Higgs Chris , Fletcher Carl , Mandalia Sundhiya , Gazzard Brian , Pozniak Anton
Published: April 2022

Objective

To evaluate the steady-state pharmacokinetics and safety of two once-daily saquinavir/ritonavir (SQV/RTV) regimens, 1600/100 and 2000/100 mg, in HIV-positive patients.

Methods

Eighteen HIV-infected adults treated with the standard twice-daily SQV/RTV 1000/100 mg regimen were enrolled in this open-label, two-phase, crossover pharmacokinetic study. The steady-state pharmacokinetics of SQV administered with 100 mg RTV were investigated following once-daily doses of 1600 mg or 2000 mg or a twice-daily dose of 1000 mg. Plasma drug concentrations were determined by high performance liquid chromatography–tandem mass spectrometry and pharmacokinetic parameters were calculated using a non-compartmental model.

Results

Compared with SQV 1000 mg twice daily, the Cmax of SQV following a 1600 mg and 2000 mg dose increased in a dose-proportional manner [geometric mean (95% CI) 1915 (1656–2850) ng/ml for 1000 mg, 2782 (2249–4330) ng/ml for 1600 mg and 4179 (3429–6105) ng/ml for 2000 mg doses, respectively]. SQV Ctrough values were 539 (453–1011), 106 (76–223) and 231 (75–822) ng/ml, respectively. A SQV Ctrough value greater than 100 ng/ml was achieved in all subjects on the twice-daily regimen, in 9/18 (50%) subjects on the 1600/100 mg once-daily regimen, and in 14/17 (82%) subjects on the 2000/100 mg once-daily regimen. The once-daily regimens were well tolerated, with mild-to-moderate gastrointestinal symptoms being the only events reported by a small number of patients.

Conclusion

This is the first study to evaluate the pharmacokinetics of once-daily SQV/RTV 2000/100 mg in HIV-infected subjects. Our findings suggest that this regimen may be an alternative to twice-daily 1000/100 mg doses and should be further evaluated in efficacy studies. The data indicate that most patients (14/17) on once-daily 2000/100 mg achieve trough concentrations above target values (determined for HIV wild-type) for efficacy of SQV with the use of just 100 mg RTV/day and with good tolerability.
A Reverse Genetics Study of Resistance to Neuraminidase Inhibitors in An Influenza A/H1N1 Virus
Authors: Abed Yacine , Goyette Nathalie , Boivin Guy
Published: April 2022

A system of reverse genetics was used to generate influenza A/H1N1 viruses harbouring neuraminidase (NA) mutations previously associated with resistance to NA inhibitors in various viral subtypes. The His274Tyr and Glu119Gln mutants were rescued whereas the Arg292Lys and Glu119→Gly, Val, Ala or Asp mutants could not be generated. In NA inhibition assays, the His274Tyr mutant was resistant to oseltamivir (430-fold over wild-type) and BCX-1812 (50-fold) but was sensitive to zanamivir. A similar trend was seen when the mutant was evaluated by plaque reduction assay (PRA). The Glu119Gln mutant expressed a low level of resistance to oseltamivir (ninefold) and zanamivir (fourfold) in NA inhibition assay but was only marginally resistant to oseltamivir (fourfold) in PRA. The replication capacity of both mutants, in particular that of the His274Tyr virus, was impaired when compared with the wild-type virus in vitro.
Viral Dynamics and Pharmacokinetics of Peginterferon Alpha-2A and Peginterferon Alpha-2B in Naive Patients with Chronic Hepatitis C: A Randomized, Controlled Study
Authors: Bruno Raffaele , Sacchi Paolo , Ciappina Valentina , Zochetti Cristina , Patruno Savino , Maiocchi Laura , Filice Gaetano
Published: April 2022

The two available pegylated interferon formulations, peginterferon alpha-2a and peginterferon alpha-2b, have different pharmacokinetic profiles; as a result they may have differing abilities to suppress the hepatitis C virus. A recently reported study by Formann and colleagues assessing early viral kinetics among 20 patients receiving peginterferon alpha-2b either once or twice weekly suggests that once-weekly administration of peginterferon alpha-2b is not sufficient for continuous exposure to interferon over 160 h. Twice-weekly administration is recommended to avoid increases in viral load as interferon levels decline prior to the end of the one-week dosing period. The objective of this study was to compare viral dynamics and pharmacokinetics between peginterferon alpha-2a and peginterferon alpha-2b in interferon-naive chronic hepatitis C patients. Patients were randomized to receive peginterferon alpha-2a 180 μg ( n=10) or peginterferon alpha-2b 1.0 μg/kg ( n=12) once weekly. Serum peginterferon concentrations were measured at baseline, 24, 48, 120 and 168 h. Hepatitis C virus (HCV) RNA was measured at baseline, 24, 48, 120 and 168 h during week 1 and then at 4 and 12 weeks. Peginterferon alpha-2b achieved maximal serum levels at 24 h, and then decreased rapidly. Of the 12 patients who received peginterferon alpha-2b, no drug was detectable in seven (58%) patients at 120 h and in 11 (92%) at 168 h. In contrast, peginterferon alpha-2a concentrations increased continuously over time, reaching maximal serum levels from 48 to 168 h. Drug was detectable in all 10 patients at 168 h. At weeks 1 and 4 no significant difference was observed in mean HCV RNA between the groups. However, at week 12, mean HCV RNA was significantly lower in the peginterferon alpha-2a group versus the peginterferon alpha-2b group (2.8126 vs 3.8726; P<0.01). The differences in mean HCV RNA values at 12 weeks may be related to the different absorption and distribution profiles of the two drugs. In conclusion, once-weekly administration of peginterferon alpha-2b (1.0 μg/kg/wk) may be insufficient for continuous interferon exposure; twice-weekly administration may help avoid increases in viral replication as interferon levels decline. Larger-scale studies assessing both viral kinetics and sustained virological responses are needed to confirm these observations.
Salvage Therapy with Amprenavir, Lopinavir and Ritonavir 200 Mg/D or 400 Mg/D in HIV-Infected Patients in Virological Failure
Authors:   the Puzzle 1 Study Group, Raguin Gilles , Chêne Geneviève , Morand-Joubert Laurence , Taburet Anne-Marie , Droz Cécile , Le Tiec Clotilde , Clavel François , Girard Pierre-Marie , Rozenbaum W , Naït-Ighil L , Nguyen TH , Slama L , Girard PM , Molina JM , Sereni D , Colin de Verdière N , Lascoux-Combes C , Pintado C , Ponscarme D , Prevoteau de Clary F , Tourneur M , Bentata M , Guillevin L , Launay O , Mansouri R , Rouges F , Kazatchkine M , Aouba A , Azizi M , Fiessinger JN , Le Houssine P , Sicard D , Bernasconi C , Salmon D , Silbermann B , Cassuto JP , Ceppi C , Poiree Dr , Raguin G , Merad M , Delfraissy JF , Goujard C , Quertainmont Y , Perronne C , de Truchis P , Dupont B , Bresson JL , Calatroni I , Raffi F , Esnault JL , Leautez S
Published: April 2022

Objectives

To compare the antiviral efficacy of a salvage therapy combining lopinavir and amprenavir with 200 mg/d or 400 mg/d ritonavir, together with nucleoside reverse transcriptase inhibitors, over a 26-week period in HIV-infected patients in whom multiple anti-retroviral regimens had failed.

Design

Phase IIb, randomized, open-label, multicentre trial. Patients were eligible if they had <500 CD4+ cells/mm3 and >4 log10 copies/ml HIV-RNA after treatment with at least two protease inhibitors (PIs) and one non-nucleoside reverse transcriptase inhibitor.

Results

At baseline ( n=37), the median CD4+ cell count was 207/mm3 and the median plasma HIV-1 RNA level was 4.7 log10 copies/ml; the median number of PI mutations was seven and the median decrease in phenotypic susceptibility to lopinavir and amprenavir was 9.7 and 2.6, respectively. The mean number of antiretrovirals received prior to randomization was 7.7. The fall in the median HIV-1 RNA level at week 26 was -1.4 log10 copies/ml in the 200 mg/d ritonavir group and -2.5 log10 copies/ml in the 400 mg/d group ( P=0.02). Viral load fell below 50 copies/ml in 32% and 61% of patients, respectively ( P=0.07). After adjustment for the ritonavir dose, a smaller number of PI mutations was the only baseline characteristic associated with a better virological response at week 26. Amprenavir concentrations were significantly lower in presence of lopinavir. The lopinavir inhibitory quotient at week 6 correlated weakly with the change in the HIV-RNA level at week 26.

Conclusion

Combination of amprenavir, lopinavir and 400 mg/d ritonavir shows significant virological efficacy without increased toxicity in HIV-infected patients in whom multiple antiretroviral regimens have failed.