bluuebunny/crossref_metadata_2025 huggingface dataset:
Altered Adipokine Response in Murine 3T3-F442A Adipocytes Treated with Protease Inhibitors and Nucleoside Reverse Transcriptase Inhibitors
Authors: Jones Simon P , Janneh Omar , Back David J , Pirmohamed Munir
Published: April 2022

Background

Abnormal levels of tumour necrosis factor (TNF)-α, interleukin (IL)-6 and adiponectin have been observed in HIV patients with lipodystrophy. However, because these patients have long drug and disease histories, it is unclear which drugs are responsible for these abnormalities. We have therefore investigated the effects of individual antiretrovirals on adipokine expression and adipogenesis using a murine cell line in vitro.

Methods

Differentiating murine 3T3-F442A adipocytes were incubated with 20 μM nucleoside reverse transcriptase inhibitors (NRTIs) zidovudine or stavudine, or protease inhibitors (PIs) indinavir, ritonavir, saquinavir or nelfinavir, in the presence and absence of rosiglitazone (10 μM). Adipogenesis was assessed using glycerol-3-phosphate dehydrogenase activity, while expression of TNF-α, IL-6 and adiponectin at protein and mRNA levels was assessed by ELISA and quantitative real-time PCR, respectively.

Results

Nelfinavir, ritonavir and saquinavir inhibited adipogenesis and up-regulated the expression of TNF-α and IL-6, but this effect was not seen with indinavir, zidovudine and stavudine. Adiponectin expression was significantly reduced in both NRTI- and PI-treated cells, although the most profound reductions were found with ritonavir and saquinavir. Co-incubation with rosiglitazone led to a partial attenuation of the change in TNF-α, IL-6 and adiponectin secretion.

Conclusions

Our data suggest that the PIs nelfinavir, ritonavir and saquinavir have potent effects in inhibiting adipocyte differentiation whilst up-regulating TNF-α and IL-6 mRNA levels and decreasing adiponectin levels. These changes were partially attenuated by rosiglitazone. Taken together, the data show that antiretrovirals have complex effects on adipocyte function, which may be mediated by an altered adipokine response.
In Vitro Susceptibility of Adenovirus to Antiviral Drugs is Species-Dependent
Authors: Morfin Florence , Dupuis-Girod Sophie , Mundweiler Stéphanie , Falcon Delphine , Carrington David , Sedlacek Petr , Bierings Marc , Cetkovsky Petr , Kroes Aloys CM , van Tol Maarten JD , Thouvenot Danielle
Published: April 2022

Adenovirus infections are a frequent and serious complication following allogeneic haematopoietic stem cell transplantation (HSCT). The antiviral drugs cidofovir and ribavirin have been used as first-line therapy for disseminated infections with variable results. In the present study, in vitro susceptibility to these two drugs was evaluated on HEp-2 cells in adenovirus reference strains representing serotypes of each of the six species and in clinical isolates. Susceptibility to cidofovir was comparable between species with inhibition of replication of all tested serotypes in a narrow dose range (IC50= 17–81 μM). However, susceptibility to ribavirin was highly dependent on the species. Serotypes from species A, B, D, E and F were all resistant to ribavirin (IC50=396 to >500 μM). Only replication of serotypes from species C was inhibited by ribavirin (IC50=48–108 μM). This species-dependent susceptibility of adenovirus to ribavirin was confirmed in clinical isolates. When tested on other cell lines (PLC, A549 and 293), all species were revealed to be resistant to ribavirin. If our in vitro findings are predictive of virological responses in vivo, these results suggest that ribavirin would not be effective for management of non-C species adenovirus infections after HSCT.
Field Assessment of Generic Antiretroviral Drugs: A Prospective Cohort Study in Cameroon
Authors: Bourgeois Anke , Laurent Christian , Mougnutou Rose , Nkoué Nathalie , Lactuock Bernadette , Ciaffi Laura , Liégeois Florian , Andrieux-Meyer Isabelle , Zekeng Léopold , Calmy Alexandra , Mpoudi-Ngolé Eitel , Delaporte Eric
Published: April 2022

Objective

To assess the effectiveness of generic anti-retroviral drugs in terms of survival and virological and immunological responses, as well as their tolerability and the emergence of viral resistance.

Methods

A total of 109 HIV-1-infected patients were enrolled in a prospective cohort study in Yaoundé, Cameroon. Available generic drugs were a fixed-dose combination (FDC) of zidovudine (ZDV) and lamivudine (3TC), an FDC of 3TC, stavudine (d4T) and nevirapine (NVP), and individual formulations of ZDV, 3TC and NVP.

Results

At baseline, the median CD4 cell count was 150/mm3 [interquartile range (IQR) 61–223] and median viral load was 5.4 log10 copies/ml (IQR 4.8–5.6); 78% of patients received ZDV/3TC/NVP and 22% received 3TC/d4T/NVP. Median follow-up was 16 months (IQR 11–23). The survival probability was high (0.92 at 12 months); plasma viral load declined by a median of 3.3 log10 copies/ml and 86.9% of the intention-to-treat population had viral load <400 copies/ml at 12 months; CD4 count had increased by a median of 106 cells/mm3 at 12 months; drug resistance rarely emerged (incidence rate 3.2 per 100 person-years); and the treatments were reasonably well-tolerated (incidence rate of severe adverse effects 7.8 per 100 person-years).

Conclusion

Together with previous pharmacological and clinical studies, this prospective study suggests that these generic antiretroviral drugs can be used in developing countries.
Therapeutic Vaccination of HIV-1-Infected Patients on Haart with a Recombinant HIV-1 Nef-Expressing Mva: Safety, Immunogenicity and Influence on Viral Load during Treatment Interruption
Authors: Harrer Ellen , Bäuerle Michael , Ferstl Barbara , Chaplin Paul , Petzold Barbara , Mateo Luis , Handley Amanda , Tzatzaris Maria , Vollmar Jens , Bergmann Silke , Rittmaier Marion , Eismann Kathrin , Müller Sandra , Kalden Joachim R , Spriewald Bernd , Willbold Dieter , Harrer Thomas
Published: April 2022

The safety and immunogenicity of an HIV-1 nef-expressing modified vaccinia virus Ankara (MVA) was investigated in 14 HIV-1-positive patients (CD4 >400/μl) on highly active antiretroviral therapy (HAART). Patients were vaccinated at weeks 0, 4 and 16, followed by interruption of HAART at week 18. MVA- nef was well-tolerated except for local reactions, with only mild systemic side effects reported in a few patients. Vaccination with MVA- nef was associated with recognition of new HIV-1 T-cell epitopes (cytotoxic T-lymphocyte epitopes in 9/14 patients, CD4 epitope/recombinant Nef protein in 2/14) and an increase in CD4+ and CD8+ T cells. All patients had been vaccinated against smallpox and a strong T-cell and antibody response to MVA was induced in all patients. After interruption of HAART, viral load rebounded in all patients, but after a median time of 36 (4–76) weeks in 9/14 patients, viraemia remained below the pre-HAART viral load and CD4 counts stayed above the pre-HAART levels. While six patients have remained off therapy for a median time of 64 (57–76) weeks, HAART was resumed in 8/14 patients after a median treatment interruption time of 15 (4–38) weeks. This study has demonstrated that MVA- nef is safe and immunogenic in HIV-1-infected subjects and has provided encouraging data on the potential of therapeutic vaccinations.
Lamivudine Treatment in Hbeag-Negative Chronic Hepatitis B Patients with Low Level Viraemia
Authors: Bozkaya Hakan , Yurdaydin Cihan , Idilman Ramazan , Tüzün Ali , Cinar Kubilay , Erkan Özlem , Bozdayi A Mithat , Erden Esra , Uzun Yusuf , Cetinkaya Hülya , Uzunalimoglu Özden
Published: April 2022

Background

Our aim was to determine the short-term natural course of viraemia and the response to lamivudine treatment in HBeAg-negative chronic hepatitis B patients with a persistently low hepatitis B virus (HBV)-DNA level.

Methods

A total of 55 patients were included. Group 1 consisted of 37 patients with low-level viraemia and high serum alanine aminotransferase (ALT) levels and further randomized to two groups: group 1a ( n=19) patients received 1 year of lamivudine therapy and group 1b ( n=18) patients were untreated controls. Group 2 consisted of 18 inactive carriers who were followed as controls of untreated low viraemic chronic hepatitis B patients. HBV DNA was longitudinally determined by real-time polymerase chain reaction assay.

Results

A female predominance in group 2 was observed while males were predominant in group 1. Mean age and baseline HBV-DNA levels did not differ between group 1 and 2 patients while group 1 patients had a higher histological score ( P<0.01). Of group 1a patients, 44% had complete ALT normalization at end of treatment, whereas 21% untreated group 1b patients had normal ALT at the end of the follow-up. No change in histological activity was observed in group 1a patients at the end of treatment. HBV-DNA levels did not significantly change from baseline to end-of-treatment/observation period in patient groups. The viraemia course was not different across the groups.

Conclusions

Low viraemic HBeAg-negative patients with high ALT present with minimal/mild histological activity. Inactive carriers cannot be differentiated from low viraemic patients with high ALT based on HBV DNA determination. Although lamivudine treatment can be effective in some cases, observation rather than a prompt treatment attempt seems to be more logical because of mild histological changes and low response rate to treatment in these patients.
Open, Randomized, Multicentre Italian Trial on Peg-Ifn plus Ribavirin versus Peg-Ifn Monotherapy for Chronic Hepatitis C in HIV-Coinfected Patients on Haart
Authors:   the Italian Co-infection Study (ICOS) Group, Cargnel Antonietta , Angeli Elena , Mainini Annalisa , Gubertini Guido , Giorgi Riccardo , Schiavini Monica , Duca Piergiorgio , Scalise G , Cesare S Di , Chiodo F , Verucchi G , Farci P , Serra G , Sagnelli E , Nacca C , Ferraro T , Scerbo A , Santoro D , Pusterla L , Viganò P , Magnani C , Ghinelli F , Sighinolfi L , Vigevani G , Pastecchia C , Moroni M , Milazzo L , Esposito R , Borghi V , Piccinino F , Filippini P , Cadrobbi P , Sattin A , Ferrari C , Antoni A Degli , Stagni G , Francisci D , Petrelli E , Alberici F , Sacchini D , Zauli T , Donà D De , Arlotti M , Mori F , Marranconi F , Caramello P , Lipani F , Soranzo ML , Macor A , Vaglia A , Rossi MC , Grossi P , Tambini R , De Lalla F , Tositti G
Published: April 2022

Background

Chronic hepatitis C is common and aggressive in HIV-positive patients, so the development of a well-tolerated HCV therapy is a priority. We evaluated the efficacy and safety of pegylated interferon α2b (PEG-IFN) plus ribavirin (RBV) versus PEG-IFN monotherapy in HIV/HCV-coinfected patients undergoing highly active antiretroviral therapy (HAART), and analysed the predictive factors of response.

Methods

An Italian, multicentre, open-label trial including 135 coinfected patients, randomized to PEG-IFN 1.5 μg/kg/week plus RBV 400 mg twice daily ( n=69, arm A) or PEG-IFN 1.5 μg/kg/week ( n=66, arm B) for 48 weeks. We assessed the predictive values of early virological response (EVR) at week 8 (HCV-RNA drop >2 log10 compared with baseline or undetectable levels) on sustained virological response (SVR).

Results

Fifty-five patients (28 from arm A and 27 from arm B) completed 48 weeks of therapy. At the end of treatment, 20/28 patients in arm A and 11/27 in arm B had HCV-RNA <50 IU/ml. In a per-protocol analysis, SVR was reached by 54% of patients in arm A (genotype 2–3, 11/16; genotype 1–4, 4/12) and 22% in arm B (genotype 2–3, 3/15; genotype 1–4, 3/12). In an intention-to-treat analysis, the SVR was 22% in arm A (genotype 2–3, 11/32; genotype 1–4, 4/37) versus 9% in arm B (genotype 2–3, 3/32; genotype 1–4, 3/34). The best predictors of SVR were the use of combination therapy, infection with HCV genotype 3 versus genotype 1, and EVR at week 8. Thirty patients (15 from arm A and 15 from arm B) dropped out of the trial prematurely due to side effects. The positive predictive value of EVR at week 8 was 65%, the negative predictive value was 86%.

Conclusions

PEG-IFN plus RBV can be considered a solid option for the treatment of HIV/HCV-coinfected patients. The key to successfully improving efficacy is strong compliance through strict overall patient monitoring, in order to best manage drug toxicity. EVR assessment at week 8 may become a useful stategy in the management of therapy.
In Vitro Combination Studies of Tenofovir and Other Nucleoside Analogues with Ribavirin against HIV-1
Authors: Margot Nicolas A , Miller Michael D
Published: April 2022

In patients coinfected and treated for both HIV-1 and hepatitis C virus (HCV), administration of ribavirin (RBV) may result in altered intracellular drug levels of nucleoside reverse transcriptase inhibitors through inhibition of inosine 5′-monophosphate dehydrogenase. Drug interactions between tenofovir and RBV were studied in vitro in order to provide insights into the safety of co-administration of tenofovir disoproxil fumarate (DF) and RBV in HCV/HIV-1-coinfected patients. In accordance with previous in vitro studies, strongly increased anti-HIV activity was observed when RBV was combined with didanosine (ddI). In contrast, low-level anti-HIV antagonism was observed when RBV was combined with either tenofovir or abacavir. Significantly stronger anti-HIV antagonism was observed when RBV was combined with either zidovudine, stavudine, emtricitabine or lamivudine. Thus, although tenofovir and ddI are both adenosine analogues, their in vitro interactions with RBV are markedly different. These results suggest a low potential for increased toxicity upon co-administration of teno-fovir DF with RBV in patients.
Rare One and Two Amino Acid Inserts Adjacent to Codon 103 of the HIV-1 Reverse Transcriptase (Rt) Affect Susceptibility to Non-Nucleoside Rt Inhibitors
Authors: Winters Mark A , Kagan Ron M , Kovari Ladislau , Heseltine Peter NR , Merigan Thomas C
Published: April 2022

HIV-1 strains that possess a one or two amino acid insert between codons 102 and 103 of the reverse transcriptase (RT) gene were identified in three HIV-1-infected individuals. Each strain also had one or more known mutations associated with nucleoside RT inhibitors (NRTIs) and non-nucleoside RT inhibitors (NNRTIs). Recombinant viruses from these strains had reduced susceptibility to efavirenz and nevirapine, and homology modelling predicted a loss of binding contacts with efavirenz. Mutagenesis studies indicated that replication of insert-containing strains was dependent on RT gene mutations and polymorphisms that co-evolved with the insert. These results suggest that inserts in the NNRTI-binding pocket contribute to NNRTI resistance, but are tolerated only under specific genetic conditions.
Synthetic Peptides outside the Spike Protein Heptad Repeat Regions as Potent Inhibitors of Sars-Associated Coronavirus
Authors: Zheng Bo-Jian , Guan Yi , He Ming-Liang , Sun Hongzhe , Du Lanying , Zheng Ying , Wong Kin-Ling , Chen Honglin , Chen Ying , Lu Linyu , Tanner Julian A , Watt Rory M , Niccolai Neri , Bernini Andrea , Spiga Ottavia , Woo Patrick CY , Kung Hsiang-fu , Yuen Kwok-Yung , Huang Jian-Dong
Published: April 2022

A novel severe acute respiratory syndrome (SARS)-associated coronavirus (SARS-CoV) has been identified as the aetiological agent of SARS. We previously isolated and characterized SARS-CoV and SARS-CoV-like viruses from human and animals, respectively, suggesting that SARS could be transmitted from wild/farmed animals to humans. Comparison of the viral genomes indicated that sequence variation between animal and human isolates existed mainly in the spike (S) gene. We hypothesized that these variations may underlie a change of binding specificity of the S protein to the host cells, permitting viral transmission from animals to humans. Here we report that four 20-mer synthetic peptides (S protein fragments), designed to span these sequence variation otspots, exhibited significant antiviral activities in a cell line. SARS-CoV infectivity was reduced over 10 000-fold through pre-incubation with two of these peptides, while it was completely inhibited in the presence of three peptides. Molecular modelling of the SARS-CoV peplomer suggests that three of these antiviral peptides map to the interfaces between the three monomers of the trimeric peplomer rather than the heptad repeat region from which short peptides are known to inhibit viral entry. Our results revealed novel regions in the spike protein that can be targeted to inhibit viral infection. The peptides identified in this study could be further developed into antiviral drugs.
HBV-DNA Suppression and Disease Course in HBV Cirrhosis Patients on Long-Term Lamivudine Therapy
Authors: Di Marco Vito , Stefano Rosa Di , Ferraro Donatella , Almasio Piero Luigi , Bonura Celestino , Giglio Maria , Parisi Pietro , Cappello Maria , Alaimo Giuseppe , Craxì Antonio
Published: April 2022

In hepatitis B virus (HBV) cirrhosis patients on long-term lamivudine (LAM), the relationships between HBV suppression, development of viral resistance and disease outcome are unclear. We analysed the dynamic of serum HBV-DNA and its relationship with the clinical course of 59 patients (52 males, mean age 51.4 ±8.4 years, 12 HBeAg positive and 47 HBeAg negative, and 57 genotype D and two genotype A) with cirrhosis (45 in Child-Turcotte-Pugh class A) and high levels of serum HBV-DNA (median 14.7x107 genomes/ml) treated with LAM [median (range): 44 (15–78) months]. A total of 50 patients (84.7%) achieved a virological response (serum HBV-DNA negative by PCR) during the first 6 months of therapy, and nine (13.3%) achieved a reduction in viral load of >3 log10. Mutations in the YMDD motif of HBV polymerase were documented in 26 patients [median (range) 18: (7–42) months]. At the time of the emergence of mutants, 22 patients had HBV-DNA <105 genomes/ml and normal alanine aminotransferase (ALT) levels. The appearance of virological resistance was followed by an increase of HBV-DNA to ≥105 genomes/ml and of ALT values in 19 out of 26 patients [median (range): 8 (3–19) months]. Event-free survival was significantly longer ( P=0.001) in patients who maintained virological suppression than in those who did not have a complete virological response or suffered a breakthrough. Patients with advanced cirrhosis were more likely to develop liver failure after the emergence of YMDD mutants. The risk of development of hepatocellular carcinoma in patients with compensated cirrhosis and YMDD mutations was maintained, regardless of HBV-DNA serum levels.

Profound and maintained HBV-DNA suppression correlates with a better outcome. Early identification of LAM resistance mutations allows switching to other antivirals before liver decompensation or hepatocellular carcinoma development.
Current Status and Future Prospects of Therapeutic Drug Monitoring and Applied Clinical Pharmacology in Antiretroviral Therapy
Authors: Boffito Marta , Acosta Edward , Burger David , Fletcher Courtney V , Flexner Charles , Garaffo Rodolphe , Gatti Giorgio , Kurowski Michael , Perno Carlo Federico , Peytavin Gilles , Regazzi Mario , Back David
Published: April 2022

The consensus of current international guidelines for the treatment of HIV infection is that data on therapeutic drug monitoring (TDM) of non-nucleoside reverse transcriptase inhibitors and protease inhibitors provide a framework for the implementation of TDM in certain defined scenarios in clinical practice. However, the utility of TDM is considered to be on an individual basis until more data are obtained from large clinical trials showing the benefit of TDM.

In April 2004, a panel of experts met in Rome, Italy. This followed an inaugural meeting in Perugia, Italy, in October 2000, which resulted in the article published in AIDS 2002, 16(Suppl 1):S5–S37. The objectives of this second meeting were to review the questions surrounding TDM of antiretroviral drugs and discuss the clinical utility, current concerns and future prospects of drug concentration monitoring in the care of HIV-1-infected individuals.

This report, which has been updated to include material published or presented at international conferences up to the end of September 2004, reviews pharmacokinetic and pharmacodynamic data and reports the issues discussed by the panel, offering advice to clinical care providers who may be currently, or are considering incorporating TDM into the routine care of their patients. In addition, the panel formulated a series of position statements that are relevant to the interpretation of current data and can aid the design of future clinical trials.

Part 2 of this Special article, Therapeutic drug monitoring and drug–drug interactions involving antiretroviral drugs, will be published in Antiviral Therapy 10(4).
Lack of a Metabolic and Antiviral Drug Interaction between Tenofovir, Abacavir and Lamivudine
Authors: Ray Adrian S , Myrick Florence , Vela Jennifer E , Olson Loren Y , Eisenberg Eugene J , Borroto-Esoda Katyna , Miller Michael D , Fridland Arnold
Published: April 2022

Objective

An anti-HIV regimen composed of the nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) tenofovir (TFV) disoproxil fumarate (TDF), abacavir (ABC) and lamivudine (3TC) has performed poorly in patients. This study evaluated the combination of TFV, ABC and 3TC for metabolic or antiviral antagonism in vitro. Design: Procedures were developed to evaluate the in vitro metabolism and antiviral activity of drug combinations of TFV, ABC and 3TC in cell types relevant for HIV infection.

Methods

Anabolism of combinations of TFV and ABC were studied over a 24 h period in the human T leukaemic CEM lymphoblast cell line and human primary peripheral blood mononuclear cells (PBMCs) stimulated with human interleukin-2 and phytohaemagglutinin. The anti-HIV activity of combinations of TFV and ABC in the presence or absence of 3TC was studied in stimulated PBMCs infected with the HXB2 strain of HIV-1.

Results

Levels of the active metabolites produced from TFV and ABC after incubation with CEM or PBMCs showed no significant change upon introduction of the other NRTI. Moreover, the pool sizes for the natural substrates of 2′-deoxyadenosine triphosphate and 2′-deoxyguanosine triphosphate were also unchanged. In anti-HIV assays in PBMCs, the combination of TFV and ABC was found to be additive with respect to inhibition of HIV replication. Addition of 3TC to the combination did not result in synergistic or antagonistic effects.

Conclusions

The poor efficacy of the triple NRTI regimen of TDF, ABC and 3TC is probably not due to a metabolic drug interaction resulting in antagonism of antiviral activity.
Chronic Hepatitis B and Viral Genotype: The Clinical Significance of Determining HBV Genotypes
Authors: Guettouche Toumy , Hnatyszyn H James
Published: April 2022

The global health challenge posed by the hepatitis B virus (HBV) centres around the widespread distribution and the serious complications as a result of persistent infection with the virus. As with other chronic diseases mediated by pathogens such as human immunodeficiency virus (HIV) and hepatitis C virus (HCV), clinicians are searching for epidemiological, pathological and viral characteristics of HBV infection that may lead to more effective management of patients with chronic infection. Unlike HCV, the role of HBV genotype in disease progression, severity, response to therapy and drug resistance is still under investigation and just beginning to be clarified. This review examines the potential role of HBV genotype determination in the clinic with emphasis on how this genetic information may used to provide effective management for the treatment of patients with chronic hepatitis B.
A Randomized, Double-Blind, Placebo-Controlled Dose-Escalation Trial of Merimepodib (VX-497) and Interferon-α in Previously Untreated Patients with Chronic Hepatitis C
Authors: McHutchison John G , Shiffman Mitchell L , Cheung Ramsey C , Gordon Stuart C , Wright Teresa L , Pottage John C , McNair Lindsay , Ette Ene , Moseley Scott , Alam John
Published: April 2022

Inhibition of inosine monophosphate dehydrogenase (IMPDH) is one of several proposed mechanisms of action for ribavirin (RBV), a critical component of the current treatment for chronic hepatitis C (CHC).

This study was a double-blind, placebo-controlled dose-escalation study of a novel, selective, orally active small molecule inhibitor of IMPDH, merimepodib (VX-497 or MMPD) in combination with standard interferon-alpha (IFN-α). Fifty-four treatment-naive patients with genotype-1 CHC were randomized to receive IFN-α 3 MIU subcutaneously three times a week, alone or in combination with 100 mg or 300 mg (every 8 h) of MMPD for 4 weeks. At the end of 4 weeks, all patients were offered 48 weeks of treatment with IFN-α/RBV. The objectives of the study were to evaluate the tolerability of the IFN-α/MMPD combination and to evaluate whether MMPD had an on-treatment effect on HCV-RNA, similar to RBV when added to IFN-α.

The drug combination was generally well tolerated; one patient at the higher dose discontinued because of elevated alanine aminotransferase levels. No pharmacokinetic interactions were evident between the two drugs. Analysis of covariance that adjusted for a baseline imbalance in HCV-RNA in the intent-to-treat population did not show any significant differences between the treatment groups, or between MMPD plus IFN-α compared with IFN-α alone. However, the per-protocol primary efficacy analysis based on treatment-compliant patients demonstrated a greater reduction in mean HCV-RNA in the combination of 100 mg MMPD plus IFN-α compared with IFN-α alone (-1.78 log vs -0.86 log, P=0.037).

In conclusion, the addition of a selective IMPDH inhibitor to IFN-α was well tolerated. In a low-dose range, the addition of MMPD may have the potential to add to the antiviral efficacy of IFN-α. Larger, longer duration trials incorporating pegylated IFN would be required to determine whether this combination, alone or with RBV, would increase either early or sustained virological response rates.
Feline Immunodeficiency Virus Plasma Load Reduction by a Retroinverso Octapeptide Reproducing the Trp-Rich Motif of the Transmembrane Glycoprotein
Authors: Giannecchini Simone , Alcaro Maria Claudia , Isola Patrizia , Sichi Olimpia , Pistello Mauro , Papini Anna Maria , Rovero Paolo , Bendinelli Mauro
Published: April 2022

The Trp-rich motif (TrpM) of the transmembrane glycoprotein (TM) of lentiviruses is an attractive domain on which to design new potential cell entry peptide inhibitors. We recently demonstrated that an octapeptide reproducing the TrpM of feline immunodeficiency virus (FIV), designated C8, broadly inhibited this virus in vitro and that the retroinverso analogue of this peptide (riC8) was almost as inhibitory and exhibited features suggestive of a much increased stability. Here, we demonstrated that riC8 is indeed highly stable, maintaining its concentration unchanged for at least 24 h in cat serum in vitro. Furthermore, once inoculated into cats, riC8 produced no major acute toxic effects and exhibited satisfactory pharmacokinetic properties. Finally, we report the results of a short-term monotherapy experiment in chronically FIV-infected cats showing that riC8 is well tolerated and also has substantial antiviral activity in vivo. In particular, the mean viral load of riC8-treated animals declined progressively with increasing time of treatment, whereas that of control animals given C8 or solvent alone did not. These results provide the first evidence that clinically useful inhibition of virus replication with a small peptide derived from a functional domain of the TM of a lentivirus can be achieved in vivo.
Cross-Resistance Testing of Next-Generation Nucleoside and Nucleotide Analogues against Lamivudine-Resistant HBV
Authors: Yang Huiling , Qi Xiaoping , Sabogal Alex , Miller Michael , Xiong Shelly , Delaney William E
Published: April 2022

Several next-generation nucleoside and nucleotide analogues are currently in clinical development for the treatment of chronic hepatitis B. However, the efficacy of newer agents against lamivudine-resistant hepatitis B virus (HBV) has not been fully explored. To investigate this in vitro, we generated novel stable cell lines expressing HBV encoding the four major patterns of lamivudine resistance mutations (rtL180M+rtM204V, rtV173L+rtL180M+rtM204V, rtM204I and rtL180M+ rtM204I). Using these cell lines, we assessed the susceptibility of all four strains of lamivudine-resistant HBV to eleven nucleoside analogues in various stages of clinical development. Our studies indicate that lamivudine-resistant HBV remain sensitive to acyclic phosphonate nucleotides (adefovir, tenofovir, and alamifovir), have reduced susceptibility to entecavir, and have high-level cross-resistance to all L-nucleosides tested including emtricitabine, telbivudine, clevudine, and torcitabine.
Low Density Lipoprotein Apolipoprotein B Metabolism in Treatment-Naive HIV Patients and Patients on Antiretroviral Therapy
Authors: Umpleby A Margot , Das Satyajit , Stolinski Michael , Shojaee-Moradie Fariba , Jackson Nicola C , Jefferson William , Crabtree Nicky , Nightingale Peter , Shahmanesh Mohsen
Published: April 2022

Background

Dyslipidaemia and lipodystrophy have been described in treated HIV patients and in a small percentage of untreated HIV patients. Lipodystrophy in these patients has been shown to be associated with a lower expression of low density lipoprotein (LDL) receptors.

Methods

We have investigated the effect of antiretroviral treatment with either a protease inhibitor (PI) or a non-nucleoside reverse transcriptase inhibitor (NNRTI) on body fat distribution and LDL apolipoprotein B (apoB) kinetics in 12 HIV-negative controls and 52 HIV-infected patients, including antiretroviral treatment-naive (TN) patients ( n=13) and patients taking two nucleoside analogues plus either a PI ( n=15) or an NNRTI ( n=24).

Results

LDL cholesterol was not different between groups. Compared with the controls, LDL apoB absolute synthetic rate (ASR) and fractional catabolic rate (FCR) were lower and residence time (RT) was higher in the PI and NNRTI groups ( P<0.05). In the TN patients, LDL ASR was lower ( P<0.05) and there was a trend for a lower FCR and higher RT compared with the controls ( P=0.07). LDL apoB pool size was greater in the PI group compared with the controls ( P<0.05). In the PI group, patients on ritonavir (RTV)-containing regimens had a lower LDL apoB ASR ( P=0.009) and a trend to a lower LDL apoB FCR and increased RT compared with non-RTV-containing PI regimens ( P=0.05). There was a positive correlation between LDL apoB FCR and limb fat/lean body mass ( P=0.004) in all subjects.

Conclusions

Decreased LDL FCR, despite unchanged LDL cholesterol, was demonstrated in both treated and untreated HIV patients. It was more marked with RTV-containing regimens and was associated with reduced limb fat. The increased LDL RT may lead to an increased risk of atherogenesis thus contributing to the risk for cardiovascular disease in these patients.
Impact of Ribavirin Exposure on Early Virological Response to Hepatitis C Therapy in HIV-Infected Patients with Chronic Hepatitis C
Authors: Núnez Marina , Camino Nuria , Ramos Belén , Berdún Miguel Angel , Barreiro Pablo , Losada Elena , Santos Ignacio , Echevarría Santiago , Ocampo Antonio , Miralles Celia , Arazo Piedad , Martín-Carbonero Luz , Romero Miriam , García-Samaniego Javier , Soriano Vincent
Published: April 2022

Background

The use of pegylated interferon (PEG-IFN) plus ribavirin (RBV) is currently the recommended treatment for chronic hepatitis C virus (HCV) infection. Coinfection with HIV is a negative predictor of response, for reasons not well understood.

Methods

We examined the virological response at weeks 4 and 12 in 198 HCV/HIV-coinfected patients enrolled in a prospective trial in which PEG-IFN alpha 2a (180 μg per week) and RBV (1000-1200 mg daily) were provided.

Results

In an on-treatment analysis, 52.8% of patients achieved undetectable HCV-RNA (<600 IU/ml) at week 4, while 63% and 77.2% of patients had a decline of at least 2 and 1 log10, respectively. At week 12, 73.1% of patients reached undetectable HCV-RNA, and 83.5% and 89% achieved at least a 2- and 1-log10 drop, respectively. More than 85% of HCV genotypes 2/3 cleared HCV-RNA at week 4, a proportion significantly higher when compared with genotypes 1 (33.8%) and 4 (28.6%). Multivariate logistic regression analysis identified genotype 3 and RBV exposure (mg/kg of body weight) as independent predictors of virological response at week 12 of therapy.

Conclusion

Early virological response rates to PEG-IFN plus RBV in HCV/HIV-coinfected patients seem to be similar to those reported for HCV-monoinfected subjects. The use of suboptimal doses of RBV in most earlier trials might account for the low response rates seen in coinfected patients. To our knowledge, this is the first report demonstrating that RBV exerts a significant independent effect on early virological response. Therefore, strategies aimed at optimizing doses and adherence to RBV might help to improve responses to HCV therapy in coinfected patients.
Zidovudine Administration during Pregnancy and Mitochondrial Disease in the offspring
Authors: Tovo Pier-Angelo , Chiapello Nadia , Gabiano Clara , Zeviani Massimo , Spada Marco
Published: April 2022

Prophylactic administration of zidovudine (ZDV) to mother–child pairs reduces HIV transmission. ZDV can impair mitochondrial (mt) DNA polymerase γ, leading to mtDNA depletion. Signs of mitochondrial dysfunction have been observed in a few children with prenatal exposure to nucleoside analogues, although no mtDNA depletion was demonstrated. Other studies failed to confirm mitochondrial disorders in children who were exposed to antiretroviral agents in utero. A child, whose HIV-infected mother received ZDV from the fourth month of pregnancy, developed neonatal encephalomyopathy, anaemia and hyperlactataemia. At 2 weeks of age, a muscle biopsy exhibited red-ragged-like fibres, proliferation of abnormal mitochondria and a 90% depletion of mtDNA without qualitative abnormalities. At 6 months, the depletion was less profound (about 50% of normal values). Severe psychomotor delay and visual disturbances persisted at 30 months, but they were greatly reduced at 5-year follow-up. These laboratory and clinical findings clearly demonstrated that mtDNA alteration was acquired and not consequent to an inherited disorder. Fetal exposure to ZDV may have caused the mtDNA depletion, which, although temporary, led to irreversible but not progressive brain damage.
Two-Year Interferon Therapy with Or without Ribavirin in Chronic Delta Hepatitis
Authors: Gunsar Fulya , Akarca Ulus Salih , Ersoz Galip , Kobak Arzu Celebi , Karasu Zeki , Yuce Gul , Ilter Tankut , Batur Yucel
Published: April 2022

The only beneficial agent for the treatment of chronic delta hepatitis (CDH) is interferon (IFN). However, there is no consensus on the best dosage or duration of IFN therapy. As ribavirin (RBV) increases the sustained response when added to IFN in chronic hepatitis C, probably because of its immunomodulatory effect, we aimed to investigate the efficacy of 2-year IFN treatment and whether RBV had any additive effect to IFN in CDH.

Methods

Patients ( n=31) with CDH were randomized with a 1:2 ratio as 10 patients (3 females/7 males, age 39 ±9) receiving IFN monotherapy (9 MU IFN-α2a three times weekly) and 21 patients (8 females/13 males, age 38 ±11) receiving IFN plus RBV for 2 years (IFN at the same dosage and RBV at 1000–1200 mg/day). Alanine transferase normalization and hepatitis delta virus (HDV) RNA negativity at the end of treatment and at the end of the follow-up period (at least 6 months following 2-year treatment) were primary endpoints of the study. In addition, virological response and biochemical response were determined separately.

Results

Eight of 31 patients (25%) had cirrhosis in liver biopsies. Six patients from the IFN monotherapy group and 12 patients from the combination group had biochemical response. Five patients from the IFN monotherapy group and 11 patients from the combination group had virological response at the end of therapy. Two patients from the IFN group and five patients from the combination group had sustained biochemical response at the end of the follow-up period. Hepatitis B virus (HBV) activations with HBV DNA positivity were observed in two patients (one from the IFN monotherapy group, one from the combination group). Two patients (20%) in the IFN group and five patients (23.5%) in IFN plus RBV group remained as virological responders at the end of the follow-up period ( P>0.05). None of the patients with liver cirrhosis were responsive at the end of the follow-up period.

Conclusion

Almost 20% of the patients with CDH were responsive to 2-year IFN treatment at the end of the follow-up period and no additional effect of RBV was observed. Patients with advanced liver disease failed to respond to treatment.
Cerebrospinal Fluid HIV-1 Infection Usually Responds Well to Antiretroviral Treatment
Authors: Mellgren Åsa , Antinori Andrea , Cinque Paola , Price Richard W , Eggers Christian , Hagberg Lars , Gisslén Magnus
Published: April 2022

The primary objective of this retrospective study was to determine how many patients in routine practice who were treated with combination antiretroviral treatment reached HIV-1 RNA levels below 50–400 copies/ml in cerebrospinal fluid (CSF). Seventy-four antiretroviral-naive HIV-1-infected patients from five different centres in Germany, Italy, Sweden and the USA were included. Thirty-nine percent of the patients had a HIV-1-associated neurological disease and 53% of the patients had AIDS. HIV-1 RNA in CSF and plasma were quantified before and after approximately 3 months of treatment. At baseline, the median value of HIV-1 RNA in CSF was 4.12 log copies/ml (interquartile range (IQR): 3.28–4.85) and it decreased to <1.70 log copies/ml (IQR: <1.70–2.48; P<0.001) after in median 3 months of treatment. Seventy-six percent of the patients had HIV-1 RNA levels below the limits of detection in CSF at follow-up, and 85% reached below 400 copies/ml. In plasma, 45% of the patients had levels of HIV-1 RNA below the limits of detection at follow-up and 80% reached below 400 copies/ml. The group of patients with a neurological disease had a significantly higher CSF viral load both at baseline and at follow-up compared with the neurologically asymptomatic patients. We conclude that the central nervous system (CNS) is usually not a ‘sanctuary site’, difficult to reach with combination anti-retroviral treatment.
A Randomized Trial to Evaluate Lopinavir/Ritonavir versus Saquinavir/Ritonavir in HIV-1-Infected Patients: The Maxcmin2 Trial
Authors:   for the MaxCmin2 trial group, Belloso W , Ivalo S , Benetucci J , Pugliese D , Garone D , Cahn P , Krolewiecki A , Casiro A , Cassetti I , Bologna R , Duran A , Toibaro J , Rieger A , Vago B , Clumeck N , Kabeya K , Cooper C , Dufresne S , Lalonde R , Walmsley S , Gerstoft J , Mathiesen L , Nielsen H , Obel N , Pedersen C , Lazzarin A , Castagna A , Bruun J N , Gatell J M , Arnaiz J , Blaxhult A , Flamholc L , Gisslén M , Vernazza P , Bingham J , Peters B , Gazzard B , Nelson M , Johnson M , Youle M , Weber J , Scullard G , Brar I , Bouzi V , Brutus A , Jayaweera D T , Mogyoros M , Rodwick B M , Stein D , Wiznia A , Schwartz R , Vandenberg-Wolf M G , Tedaldi E , Dragsted Ulrik B , Gerstoft Jan , Youle Mike , Fox Zoe , Losso Marcello , Benetucci Jorge , Jayaweera Dushyantha T , Rieger Armin , Bruun Johan N , Castagna Antonella , Gazzard Brian , Walmsley Sharon , Hill Andrew , Lundgren Jens D.
Published: April 2022

Objective

To assess the rate of protocol-defined treatment failure and safety of lopinavir/ritonavir (LPV/r) and saquinavir/ritonavir (SAQ/r).

Design

Open-label, prospective, randomized (1:1), international multi-centre trial.

Methods

Adult HIV-1-infected patients were assigned LPV/r 400/100 mg twice daily or SAQ/r 1000/100 mg twice daily with two or more nucleoside reverse transcriptase inhibitors (NRTIs)/non-NRTIs. All patients, whether on or off the assigned treatment, were followed for 48 weeks.

Results

Of 339 randomized patients, 324 initiated assigned treatment (intention-to-treat/exposed [ITT/e] population). At 48 weeks, treatment failure occurred in 29/163 (18%) and 53/161 (33%) of patients in the LPV/r and SAQ/r arms, respectively (ITT/e, P=0.002, log rank test). In an analysis that also considered those patients who discontinued treatment as having failed treatment (ITT/e/discontinuation=failure), 40/161 (25%) LPV/r-treated individuals versus 63/161 (39%) SAQ/R-treated individuals failed treatment ( P=0.005, log rank test). Discontinuation of the assigned treatment occurred in 23/163 (14%) patients in the LPV/r-treated group, compared with 48/161 (30%) in the SAQ/r-treated group (ITT/e; P=0.001). The primary reasons for premature discontinuation were non-fatal adverse events (LPV/r: 12/163; SAQ/r: 21/161) and patients’ choice (LPV/r: 7/163; SAQ/r: 8/161). In the on-treatment analysis of time to treatment failure, no difference was observed between the two arms ( P=0.27, log rank test).

Conclusion

LPV/r had better antiretroviral effects compared with SAQ/r at the doses and in the formulations studied. This may have been a result of patients’ preferences and ability to adhere to assigned therapy, rather than a result of differences in the intrinsic potency of the study protease inhibitors.
Resistance to New Anti-HIV Agents: Problems in the Pathway of Drug Registration
Authors: Dalmau David , Klimkait Thomas , Telenti Amalio
Published: April 2022

Resistance data are now requested by the regulatory agencies as an integral part of the approval process of new antiretroviral drugs. We examined the means by which resistance data was gathered during pre-clinical and clinical Phases I, II and III of drug development, and how the public and academic experts access these proprietary data. The analysis identified various opportunities for improvement of the current process, in particular the need for standards in generating and reporting resistance data on new antiretroviral drugs, and the need to enforce warnings in the product labelling on the drug combinations that can potentially lead to resistance and treatment failure.
Antiretroviral Drug Resistance among Drug-Naive HIV-1-Infected Individuals in Djibouti (Horn of Africa)
Authors: Maslin Jérôme , Rogier Christophe , Caron Melanie , Grandadam Marc , Koeck Jean-Louis , Nicand Elisabeth
Published: April 2022

Objective

To survey the frequency of genotypic anti-retroviral resistance in drug-naive HIV-1-infected Djiboutians.

Methods

A national study was conducted in the general population of Djibouti in March 2002 to determine HIV-1 seroprevalence. Blood samples were collected anonymously and plasma samples scoring positive for HIV-1 antibodies were tested for viral load. Genotypic studies were performed with viral RNA from plasma using the consensus technique of the Agence Nationale de Recherche sur le SIDA ( www.hivfrenchresistance.org ). Mutations were identified using the International AIDS Society-USA resistance panel and resistant virus was defined according to the ANRS algorithm.

Results

A panel of 2423 individuals representing the general population of Djibouti was included. Antibodies were detected in 53 of 2423 samples tested. The HIV-1 seroprevalence in the general population was 2.2%. Genotype C was the most prevalent, and the other isolates were CRF_02 AG, or subtype A or D. Forty-seven of the 53 samples were tested for genotypic resistance, and mutations concerning all three classes of antiretrovirals were found. The most frequent were secondary mutations associated with protease inhibitors (PIs): M36I, R41K and K20I/R. A few strains displayed primary mutations (the non-nucleoside reverse transcriptase inhibitor [NNRTI]-associated mutations K101E, K103T, L100I and G190V; the PI-associated mutation N88D; and the NRTI-associated mutation K65R). The presence of these mutations may be due to the transmission of strains from treated patients.

Conclusion

Substantial polymorphism and a few primary mutations are found in HIV-1 non-B subtype isolates from Djiboutian antiretroviral-drug-naive individuals. This needs to be taken into account to adapt antiretroviral regimens and prophylactic schedules locally.
Association of the CCR5Δ32 Mutation with Clinical Response and >5-year Survival following Initiation of First Triple Antiretroviral Regimen
Authors: Brumme Zabrina L , Henrick Bethany M , Brumme Chanson J , Hogg Robert S , Montaner Julio SG , Harrigan P Richard
Published: April 2022

Objective

The CCR5Δ32 mutation is associated with slower HIV disease progression in untreated infection. However, it remains controversial as to whether CCR5Δ32 is a relevant prognostic marker in the context of highly active antiretroviral therapy (HAART). Here we investigate associations between CCR5Δ32 and HAART outcomes in a large, population-based cohort of >1000 antiretroviral-naive individuals initiating triple therapy over a median >5 year follow-up.

Methods

CCR5Δ32 genotypes were determined using PCR and DNA sequencing in a cohort of 1188 antiretroviral-naive individuals initiating triple therapy in British Columbia. Associations between CCR5Δ32 and baseline (pre-therapy) sociodemographic and clinical parameters were investigated in a cross-sectional analysis. Cox proportional hazards regression was used to investigate the effect of CCR5Δ32 on clinical outcomes following therapy initiation. The endpoints that were evaluated included time to plasma viral load (pVL) suppression <400 copies HIV RNA/ml, subsequent time to pVL rebound ≥400 copies/ml, time to CD4+ cell decline below baseline, and time to non-accidental death over a median >5 year follow-up.

Results

CCR5Δ32 genotypes were available for 1174 of 1188 individuals (98.8%): 171 (14.6%) CCR5wt/Δ32 and 1003 (85.4%) CCR5wt/wt. At baseline, CCR5wt/Δ32 individuals had higher CD4+ cell counts ( P=0.04), lower plasma viral loads ( P=0.06) and were slightly older than CCR5wt/wt individuals ( P=0.04). In multivariate analyses controlling for baseline parameters and adherence estimates, we observed a significant association between CCR5wt/Δ32 and a shorter time to initial pVL suppression <400 copies/ml (multivariate hazard ratio [HR]: 1.20; 95% confidence interval [CI]: 1.01-1.44). No associations were observed between CCR5Δ32 and other clinical outcomes including subsequent time to pVL rebound or time to CD4+ cell decline below baseline. In univariate analyses, we observed a significant association between CCR5wt/Δ32 genotype and improved survival over the median >5 year period following initiation of HAART ( P=0.03). However, this association did not remain significant in multivariate analyses after adjusting for baseline factors including adherence (multivariate HR: 0.64; 95% CI: 0.38-1.07; P=0.09)

Conclusion

Results indicate that, after controlling for adherence, the CCR5Δ32 mutation is likely not a clinically significant predictor of longer-term clinical responses or survival in the context of HAART.
The Liver in HIV in Africa
Authors: Feld Jordan J , Ocama Ponsiano , Ronald Allan
Published: April 2022

As access to antiretroviral therapy improves across the African continent, liver disease is emerging as an important cause of morbidity and mortality among HIV-infected individuals. Although coinfection with hepatitis B virus (HBV) and hepatitis C virus (HCV), along with highly active antiretroviral therapy (HAART)-induced hepatotoxicity appear to be the major causes of liver disease in this population, other diseases endemic to Africa with hepatic manifestations are influenced by HIV infection as well. In this review we present the available data on liver disease in HIV-infected populations in Africa and discuss relevant data from the rest of the world. In addition, we highlight important areas for further study.