bluuebunny/crossref_metadata_2025 huggingface dataset:
Temporary HBV Resolution in an HIV-Coinfected Patient during Hbv-Directed Combination Therapy Followed by Relapse of HBV
Authors: Wursthorn Karsten , Buggisch Peter , Lutgehetmann Marc , Zollner Bernhard , Petersen Jorg
Published: April 2022

Coinfection of hepatitis B virus (HBV) and HIV is common due to overlapping routes of transmission accompanied by an increased risk for liver-related mortality. We report the case of a chronically infected hepatitis Be antigen positive patient, coinfected with HIV (CD4+ T-cell count >500 cells/μl), with histological evidence of advanced liver disease. The patient developed anti-HBs (antibody to hepatitis B surface antigen [HBsAg]) seroconversion, a strong reduction of intrahepatic covalently closed circular DNA and a marked improvement of liver histology after 24 weeks of HBV-targeted combination therapy with adefovir dipivoxil and pegylated interferon-α2b followed by another 12 weeks of adefovir dipivoxil monotherapy. Antiviral therapy was stopped after the development of stable anti-HBs titres, and anti-HBs titres remained stable for additional 9 months post-treatment. A continuous decline of anti-HBs was observed during the next 6 months until anti-HBs disappeared despite a stable HIV infection. A triple course of therapeutic vaccination failed to re-establish anti-HBs antibodies, but reappearance of HBV DNA and HBsAg was detected. By enzyme-linked immunosorbent spot analyses, HBV-directed T-cell responses clearly increased during antiviral combination therapy followed by a reduction to pre-treatment levels in association with disappearance of anti-HBs antibodies despite therapeutic vaccination. The presented case highlights the volatile nature of chronic HBV infection even after a prolonged disease-free period in the setting of an underlying HIV coinfection in a patient with a stable and relatively high CD4+ T-cell count but nevertheless impaired immune system and calls for further investigation of probably temporary immunomodulatory effects of interferon-α and/or nucleoside analogues in immunocompromised patients.
Metabolic and Mitochondrial Effects of Switching Antiretroviral-Experienced Patients to Enfuvirtide, Tenofovir and Saquinavir/Ritonavir
Authors: Miró Òscar , Garrabou Glòria , López Sònia , Deig Elisabeth , Vidal Immaculada , Infante Anna B , Cardellach Francesc , Casademont Jordi , Pedrol Enric
Published: April 2022

Objective

Investigate the metabolic and mitochondrial effects of switching a highly active antiretroviral therapy (HAART) regimen with a high mitochondrial toxicity profile to a HAART with a theoretically low mitochondrial toxicity.

Patients and Methods

Six consecutive HAART-experienced patients receiving at least one dideoxy-nucleoside reverse transcriptase inhibitor (NRTI) switched to enfuvirtide plus tenofovir plus saquinavir/ritonavir (T20+TDF+SQV/r). Blood samples were collected at baseline, 12 and 24 weeks after the switch, and viral load (VL) and lymphocyte CD4+ T-cell count were determined. Metabolic parameters consisted of fasting serum triglycerides, cholesterol (total and fractions), glucose, insulin, C-peptide and lactate. Mitochondrial assessment consisted on mitochondrial DNA (mtDNA) quantification, COX-II mitochondrial protein expression rate, mitochondrial respiratory chain complex III and IV activities, and oxygen consumption in peripheral blood mononuclear cells. For baseline mitochondrial comparisons, we included six HIV-infected patients naive for ART.

Results

Switched patients exhibited a mean increase of 26 CD4+ T-cells/mm3 and a mean decrease of 1.1 log in VL ( P=NS for both). Lactate, lipids and glycaemia remained stable during the study; only insulin levels increased significantly ( P<0.05). Switched patients exhibited, at baseline, low mitochondrial measurements, being significant only for complex III and IV activities with respect to naive patients ( P<0.05 for both). MtDNA content did not rise significantly during the study. However, we observed increases in COX-II mitochondrial protein synthesis (124%, P<0.05), complex III activity (127%, P<0.05), complex IV activity (86%, P=0.37) and oxygen consumption (194%, P<0.05).

Conclusion

Switching a HAART-containing dideoxy-NRTI to T20+TDF+SQV/r minimally alters metabolic parameters and exerts beneficial effects on mitochondrial function at 24 weeks. Mitochondrial improvement should be considered as an additional advantage of this rescue therapy.
The Xivth International HIV Drug Resistance Workshop, Quebec City, Canada, June 2005
Authors: Boucher Charles , Larder Brendan , Mellors John , Richman Douglas
Published: April 2022

This report summarizes research advances that further our understanding of the evolution, mechanisms and clinical impact of HIV drug resistance presented at the XIVth International HIV Drug Resistance Workshop held in Quebec City, Canada from June 7–11, 2005. The topics that were discussed included the clinical implications of resistance in mother-to-child transmission, breakthroughs in technologies for studying resistance, resistance to new antiretroviral agents, mechanisms of HIV drug resistance, epidemiological trends, and HIV fitness and pathogenesis.
3′-Azido-2′,3′-Dideoxythymidine (Zidovudine) Uptake Mechanisms in T Lymphocytes
Authors: Purcet Sergi , Minuesa Gerard , Molina-Arcas Míriam , Erkizia Itziar , Casado F Javier , Clotet Bonaventura , Martínez-Picado Javier , Pastor-Anglada Marçal
Published: April 2022

The nucleoside reverse transcriptase inhibitors (NRTIs) make up a family of antiretroviral drugs widely used in the treatment of HIV-1 infection. Human concentrative nucleoside transporters and equilibrative nucleoside transporters, encoded by SLC28 and SLC29 gene families, respectively, are known to be involved in the uptake of a variety of nucleoside analogues used in anticancer treatment. We therefore examined whether SLC28- and SLC29-encoded proteins contribute to the entry of these NRTIs into the human leukaemic T-cell line Molt-4. Cis-inhibition experiments demonstrated that nucleoside transporters have a negligible role in antiviral drug uptake. Moreover, the previously identified 3′-azido-2′,3′-dideoxythymidine (zidovudine; AZT) carriers, organic anion transporters (organic anion transporter [hOATs], members of the SLC22 gene family) have not been detected in T cells, either functionally or at the mRNA level, thus ruling out a role for hOATs in antiviral drug uptake in these cells. Nevertheless, the data provided here argue against the hypothesis of simple diffusion across the plasma membrane as the unique mechanism of AZT uptake. Actually, this pyrimidine derivative seems to have a temperature-sensitive route of entrance, a finding that, along with the evidence that, AZT inhibits its own uptake and its transport into phytohaemagglutinin-stimulated peripheral blood mononuclear cells is upregulated, strongly support the idea that AZT uptake into T-cells is associated with a mediated and regulated, transport mechanism.
Virological Response and Incidence of Adefovir Resistance in Lamivudine-Resistant Patients Treated with Adefovir Dipivoxil
Authors: Chen Chien-Hung , Wang Jing-Houng , Lee Chuan-Mo , Hung Chao-Hung , Hu Tsung-Hui , Wang Jyh-Chwan , Lu Sheng-Nan , Changchien Chi-Sin
Published: April 2022

Background and aims

The incidence of adefovir dipivoxil (ADV) resistance in patients with lamivudine (3TC)-resistant mutants who received ADV therapy remains unclear. The aims of this study were to determine the virological response to ADV, the incidence and the risk factors of ADV resistance, and the associated factors of initial virological response (IVR) in lamivudine-resistant patients.

Patients and methods

Forty-six consecutive lamivudine-resistant chronic hepatitis B patients treated with ADV for more than 12 months with or without 3TC overlapping were prospectively examined for virological response and adefovir resistance.

Results

IVR was documented in 24 (52.2%) of patients. Of the 46 patients, 11 had ADV resistance (5 rtN236T, 5 rtA181T, 1 rtA181T and rtN236T). The cumulative incidence of ADV resistance at month 6, 12, 18 and 24 was 0%, 6.5%, 24.6% and 38.3% respectively. Compared with those without ADV resistance, patients with ADV resistance had a significantly higher rate of liver cirrhosis. Based on Cox regression analysis, the significant risk factor of ADV resistance was younger age (OR=0.92, 95% CI=0.86–0.99, P=0.023) and liver cirrhosis (OR=5.3, 95% CI=1.12–25.09, P=0.036). In addition, patients with ADV resistance were associated with higher HBV DNA levels and lower HBV DNA reduction in first 6 months of ADV treatment than those without ADV resistance.

Conclusion

Only half of our patients achieved IVR on ADV treatment. The incidence of ADV resistance was high in 3TC-resistant patients treated with ADV.
Hepatitis B Virus Replication and Liver Disease Progression: The Impact of Antiviral Therapy
Authors: Liaw Yun-Fan
Published: April 2022

Chronic hepatitis B virus (HBV) infection is a serious health issue worldwide. The presence of HBV replication markers — hepatitis B e antigen (HBeAg) or HBV DNA — is associated with continuing hepatitis activity or intermittent hepatitis flares and subsequent disease progression, including hepatic decompensation and development of liver cirrhosis or hepatocellular carcinoma (HCC). Long-term (>10 years) prospective studies in patients ≥30 years of age have shown that HBeAg seropositivity is associated with increased risk of disease progression, and the risk of cirrhosis and HCC begins to increase at an HBV DNA level of 104 copies/ml. Therefore, elimination of HBV, or at least sustained or maintained suppression of HBV, is the key to reducing hepatitis and thereby halting or preventing disease progression. Therapy with interferon-α or a direct antiviral agent has been shown to reduce the risk of cirrhosis and prevent further disease worsening. In both the woodchuck hepatitis model and in HBV patients, maintained suppression of HBV replication by a direct antiviral agent may reduce the progression to HCC. However, the efficacy of current antiviral therapy is still far from satisfactory. The ability to achieve a high rate of sustained or maintained HBV suppression with a low risk of drug resistance would be the ultimate goal in the treatment of chronic HBV infection.
A Virosomal Immunization Strategy against Cervical Cancer and Pre-Malignant Cervical Disease
Authors: Bungener Laura , de Mare Arjan , de Vries-Idema Jacqueline , Sehr Peter , van der Zee Ate , Wilschut Jan , Daemen Toos
Published: April 2022

In this study, we demonstrate that fusion-active virosomes, containing recombinant human papillomavirus type 16 (HPV16) E7 protein antigen, are capable of inducing a robust class I MHC-restricted cytotoxic T-lymphocyte (CTL) response against HPV-transformed tumour cells in a murine model system. Virosomes are reconstituted viral envelopes, which do not contain the genetic material of the native virus. During the reconstitution process, protein antigens can be encapsulated within the virosomes. In the present study, we used virosomes derived from influenza virus. These virosomes retain the cell binding and membrane fusion characteristics of native influenza virus, and have the capacity to deliver encapsulated antigens to the cytosol of antigen-presenting cells through fusion from within acidic endosomes. After immunization of mice with virosomes containing encapsulated HPV16 E7 protein, the animals developed a strong E7–specific CTL response as assessed by 51Cr release measurements and MHC tetramer staining of spleen cells. Immunization with E7–containing virosomes also resulted in E7-specific antibody responses.

In tumour challenge experiments, immunization of mice with E7-containing virosomes prevented tumour outgrowth in >70% of the animals. Thus, influenza-derived virosomes with encapsulated HPV E7 protein antigen act as an excellent vaccine delivery system for induction of cellular immunity against HPV-transformed cells and represent a promising immunotherapeutic vaccine for the treatment of (precursor lesions of) cervical cancer.
One-Year Entecavir or Lamivudine Therapy Results in Reduction of Hepatitis B Virus Intrahepatic Covalently Closed Circular DNA Levels
Authors: Ka-Ho Wong Danny , Yuen Man-Fung , Ngai Vincent Wing-Shun , Fung James , Lai Ching-Lung
Published: April 2022

Entecavir and lamivudine are potent nucleoside analogues that can suppress hepatitis B virus (HBV) replication. However, the effects of these two antiviral agents on intrahepatic total HBV DNA and covalently closed circular DNA (cccDNA) are not known. In this study, we aimed to assess the effect of 48 weeks of entecavir/lamivudine therapy on intrahepatic total HBV DNA and cccDNA levels. Forty chronic hepatitis B patients, participating in two Phase III entecavir trials at our centre, were randomized to receive 48 weeks of either 0.5 mg once daily of entecavir ( n=21) or 100 mg once daily of lamivudine ( n=19). Their serological, virological and biochemical responses, as well as intrahepatic HBV DNA levels were monitored. There was no significant difference between entecavir and lamivudine therapy in terms of post-treatment serological, virological and biochemical responses. Both nucleoside analogues reduced serum viral load, intrahepatic total HBV DNA, and cccDNA by about 4.8 logs, 2 logs, and 1 log respectively. An increase in the proportion of intrahepatic HBV DNA in the form of cccDNA was seen after 48 weeks of therapy. In conclusion, both entecavir and lamivudine can successfully reduce intrahepatic HBV DNA and cccDNA. CccDNA becomes the dominant form of HBV DNA during viral suppression and is possibly responsible for viral rebound after short-term antiviral therapy.
Cerebrospinal Fluid Viral Loads Reach Less than 2 Copies/ML in HIV-1-Infected Patients with Effective Antiretroviral Therapy
Authors: Yilmaz Aylin , Svennerholm Bo , Hagberg Lars , Gisslén Magnus
Published: April 2022

Background

A low-grade persisting viraemia despite long-term treatment with highly active antiretroviral therapy (HAART) has previously been demonstrated in HIV-1-infected patients. Whether ongoing viral replication also could be detected in cerebrospinal fluid (CSF) in those circumstances has not been studied before.

Methods

Paired CSF and blood samples from 13 neurologically asymptomatic HIV-1-infected patients on stable HAART were analysed regarding HIV-1 RNA, by using a PCR assay with a detection limit of 2 copies/ml.

Results

All 13 patients had HIV-1 RNA <2 copies/ml in CSF, compared with 8/13 in plasma.

Conclusion

We could not demonstrate any persistent viral replication in the CSF of neurologically asymptomatic HIV-1-infected patients on effective HAART, rendering it unlikely that CSF acts as a viral reservoir in this category of patients.
Compensatory Mutations at the HIV Cleavage Sites P7/P1 and P1/P6-Gag in Therapy-Naive and Therapy-Experienced Patients
Authors: Verheyen Jens , Litau Elena , Sing Tobias , Däumer Martin , Balduin Melanie , Oette Mark , Fätkenheuer Gerd , Rockstroh Jürgen K , Schuldenzucker Ulrike , Hoffmann Daniel , Pfister Herbert , Kaiser Rolf
Published: April 2022

Background

Mutations in the genome of HIV conferring drug resistance are a major reason for the failure of antiretroviral therapy, but they often compromise viral fitness. Protease (PR) cleavage site (CS) mutations could compensate for impaired replication capacity of drug-resistant viruses.

Patients and methods

We analysed the cleavage sites p1/p7 and p1/p6-gag of 500 HIV-1 subtype B infected patients. The collective consists of 275 therapy-naive and 225 therapy-experienced patients with at least one primary PR mutation, from whom eight underwent therapy-interruption in different clinical settings.

Results

Multiple mutations within the CS p7/p1 and p1/p6-gag accumulated in therapy-experienced isolates (p7/p1: A431V-K436R-I437V and p1/p6-gag: L449F/V-P452S-P453L/A). Further rare CS mutations were totally absent in therapy-naive viruses. Sixty percent of all therapy-experienced viruses exhibited at least one therapy-associated CS mutation, but so did 10% of therapy-naive viruses. The analysis of CS and PR mutations in therapy-experienced viruses revealed several positive correlations - A431V with L24I-M46I/L-I54V-V82A; I437V with I54V-V82F/T/S; L449V with I54M/L/S/T/A; and L449F/R452S/P453L: with D30N-I84V - whereas P453L and V82A were negatively correlated. Mutagenetic trees constructed form this cross-sectional data showed an ordered accumulation of the most prominent CS mutations along two pathways - L90M-I84V- P453L and I54-V82– A431V followed by either M46L or L24I. Furthermore, eight viruses with at least one therapy-associated mutation at each CS displayed an outstanding maintenance of major PR mutations during therapy interruption.

Conclusions

These findings emphasize the relevance of CS mutations in the evolution of HIV resistance to PR inhibitors. Therefore, therapy-associated CS mutations should be considered in HIV resistance tests to estimate viral fitness in different clinical settings.
A Prospective Clinical and Pathological Examination of Injection Site Reactions with the HIV-1 Fusion Inhibitor Enfuvirtide
Authors: Myers Sarah A , Selim Angelica A , McDaniel Margaret A , Hall Russell , Zhang Ying , Bartlett John A , True Andrea L
Published: April 2022

Objective

Antiretroviral regimens containing the fusion inhibitor enfuvirtide (ENF) are associated with sustained viral suppression and immunological benefit. However, local injection site reactions (ISR) occur in the majority of patients. The aim of this study was to determine the pathogenesis of ISRs.

Methods

Injection sites were evaluated prospectively from 30 min up to 15–30 days post-injection in ENF-experienced (Cohort I) and ENF-naive patients (Cohort II) during the first 2 weeks of therapy. Four to five injections were given in rotating abdominal sites by a nurse using a standardized technique and were rigorously evaluated.

Results

Reactions were observed in 80–100% of patients; the majority of the reactions were mild to moderate, generally appeared within 24–48 h post-injection, and pain, induration and erythema were the most common clinical signs. Whereas most patients experienced ISRs, the overall prevalence in Cohort II was low (35% maximum). Punch biopsies of injection sites in Cohort I consisted primarily of mixed lymphocytic infiltrates with eosinophils and neutrophils. Injection vehicle (ENF buffer minus ENF) and reduced volume (2x0.5 ml ENF [45 mg] versus 1.0 ml [90 mg] ENF) were investigated in Cohort II. Fewer reactions appeared with vehicle and pain was absent with the smaller injection volume. Pathology was indistinguishable between ENF, vehicle and normal tissue in Cohort II patients.

Conclusion

These results suggest that injection technique, injection volume and peptide may influence ISR to ENF.
Short-Term Lamivudine Therapy in Hbeag-Negative Chronic Active Hepatitis B in Taiwan
Authors: Chien Rong-Nan , Liaw Yun-Fan
Published: April 2022

Lamivudine treatment in hepatitis B e antigen (HBeAg)-negative and hepatitis B virus (HBV) DNA-positive chronic hepatitis B (CHB) patients is associated with poor sustained response. A previous study has shown that short-term lamivudine therapy in HBeAg-positive patients with alanine aminotransferase (ALT) >5x upper limit of normal (ULN) could achieve a high HBeAg response rate and low lamivudine resistance rate. We, therefore, prospectively treated 85 HBeAg-negative CHB patients with ALT >5x ULN by lamivudine for 6–12 months. The mean pretreatment levels were as follows: ALT (normal <36 U/l) 533 U/l (range: 180–2,418 U/l); total bilirubin (normal<1.3 mg/dl) 2.0mg/dl (range: 0.2–29.6 mg/dl), HBV DNA (normal, undetectable) 1.6x108 copies/ml (range: 1.4x105-1.7x109 copies/ml). After a mean of 7.4 months (6–12 months) treatment, 69 (81%) patients achieved complete response. In a follow-up, 12 months after stopping lamivudine therapy, 33 (39%) patients showed sustained complete response. Patients with sustained response were younger than the relapsed patients (39.7 ±11.9 years versus 47.0 ±10.3 years; P=0.005). The emergence of lamivudine-resistant variant HBV was documented in two patients (2%). It is concluded that in HBeAg-negative chronic hepatitis B patients with ALT levels above 5x ULN, a 6–12 month course of lamivudine therapy may achieve sustained an off-treatment response in approximately one-third of patients.
Unusual Selection of Rta181V Hbv Mutants Cross-Resistant to Adefovir following Prolonged Lamivudine Monotherapy: Report of Two Cases
Authors: Gerolami Rene , Bourliere Marc , Colson Philippe , Halfon Philippe , Borentain Patrick , Henry Mireille , Botta Daniele , Thibault Vincent , Khiri Hacene , Tamalet Catherine
Published: April 2022

Development of hepatitis B virus (HBV)-resistant strains following nucleos(t)ide analogue treatment is a major concern. The A181V mutation within the reverse transcriptase (RT) of HBV has been shown to be associated with HBV resistance to adefovir dipivoxil (ADV), and its level of sensitivity to other nucleos(t)ide analogues is an important issue. This article reports two cases of chronically HBV infected patients who developed rtA181V HBV mutants following lamivudine (LAM) monotherapy. This was subsequently associated with virological breakthrough under LAM monotherapy or LAM/ADV bi-therapy, which were rescued by tenofovir disoproxil fumarate treatment. These observations suggest that rtA181V mutation may unusually emerge under LAM monotherapy, and may be associated with cross resistance to LAM and ADV, but remains sensitive to tenofovir disoproxil fumarate. Moreover, they highlight that HBV sequence analysis is an essential tool to optimize therapeutic management of HBV chronic infection in clinical practice in order to choose the appropriate nucleos(t)ide analogues.
Indomethacin Has a Potent Antiviral Activity against Sars Coronavirus
Authors: Amici Carla , Caro Antonino Di , Ciucci Alessandra , Chiappa Lucia , Castilletti Concetta , Martella Vito , Decaro Nicola , Buonavoglia Canio , Capobianchi Maria R , Santoro M Gabriella
Published: April 2022

Severe acute respiratory syndrome (SARS) is a newly emerging, highly transmissible and fatal disease caused by a previously unknown coronavirus (SARS-CoV). Existing in non-identified animal reservoirs, SARS-CoV continues to represent a threat to humans because there is no effective specific antiviral therapy for coronavirus infections.

Objectives

Starting from the observation that cyclopentenone cyclooxygenase (COX) metabolites are active against several RNA viruses, we investigated the effect of the COX inhibitor indomethacin on coronavirus replication.

Methods

Work involving infectious SARS-CoV was performed in biosafety level 3 facilities. SARS-CoV was grown in monkey VERO cells and human lung epithelial A549 cells, while canine coronavirus (CCoV) was grown in A72 canine cells. Antiviral activity was analysed by determining infective virus titres by TCID50, viral RNA synthesis by Northern blot analysis and real-time RT-PCR, and viral protein synthesis by SDS-PAGE analysis after 35S-methio-nine-labelling. Antiviral efficacy in vivo was determined by evaluating virus titres in CCoV-infected dogs treated orally with 1 mg/kg body weight indomethacin (INDO).

Results

Unexpectedly, we found that INDO has a potent direct antiviral activity against the coronaviruses SARS-CoV and CCoV. INDO does not affect coronavirus binding or entry into host cells, but acts by blocking viral RNA synthesis at cytoprotective doses. This effect is independent of cyclooxygenase inhibition. INDO's potent antiviral activity (>1,000-fold reduction in virus yield) was confirmed in vivo in CCoV-infected dogs.

Conclusions

The results identify INDO as a potent inhibitor of coronavirus replication and suggest that, having both anti-inflammatory and antiviral activity, INDO could be beneficial in SARS therapy.
Impact of Neuraminidase Mutations Conferring Influenza Resistance to Neuraminidase Inhibitors in the N1 and N2 Genetic Backgrounds
Authors: Abed Yacine , Baz Mariana , Boivin Guy
Published: April 2022

Subtype-specific neuraminidase (NA) mutations conferring resistance to NA inhibitors (NAIs) have been reported during in vitro passages and in clinic. In this study, we evaluated the impact of various NA mutations (E119A/G/V, H274Y, R292K and N294S) on the susceptibility profiles to different NAIs (oseltamivir, zanamivir and peramivir) using recombinant NA proteins of influenza A/WSN/33 (H1N1) and A/Sydney/5/97-like (H3N2) viruses. In the N1 subtype, the E119V mutation conferred cross-resistance to oseltamivir, zanamivir and peramivir [1,727–2,144 and 5,050-fold increase in IC50 values compared with wild-type (WT)] whereas only oseltamivir-resistance (1,028-fold increase in IC50) was conferred by the same mutation in the N2 subtype. The N294S mutation conferred resistance to oseltamivir in both the N1 and N2 subtypes (197- and 1,879-fold increase in IC50 values, respectively) whereas the H274Y mutation conferred resistance to oseltamivir (754-fold increase) and peramivir (260-fold increase) in the N1 subtype only. The virulence of reverse genetics-rescued A/WSN/33 viruses harbouring H274Y and N294S NA mutations was investigated in Balb/c mice. The WT and H274Y recombinants had identical LD50 values (103 PFUs) and generated similar viral lung titres, whereas a higher LD50 (104 PFUs) and a 1-log decrease in viral lung titres were obtained with the N294S mutant. This study shows that some NA mutations at framework residues may confer resistance to one or three NAIs depending on the viral subtype. It suggests that certain drug-resistant NA mutants may still be virulent although additional studies using clinical isolates are needed to confirm our results.
A Randomized Placebo-Controlled, Dose-Finding Study of Oral Lb80380 in Hbeag-Positive Patients with Chronic Hepatitis B
Authors: Yuen Man-Fung , Kim John , Kim Chung Ryeol , Ngai Vincent , Yuen John Chi-Hang , Min Changhee , Kang Hyang Mi , Shin Beom Soo , Yoo Sun Dong , Lai Ching-Lung
Published: April 2022

Background

LB80380 is potent antiviral agent against hepatitis B virus (HBV) in vitro and in the woodchuck model. It has an excellent preclinical safety profile including lower potential for renal toxicity than adefovir. It is effective against both wild-type and YMDD mutant HBV. LB80380 is converted to its parent drug, LB80331, after oral absorption, and further metabolized to its active form, LB80317.

Aims/Methods

This randomized placebo-controlled Phase I/II clinical study of LB80380 was conducted to assess the safety, antiviral activity and pharmacokinetics of its parent drug LB80331 and its active form LB80317 in 29 Asian adults with chronic hepatitis B positive for hepatitis B e antigen in four escalating dose groups (30, 60, 120 and 240 mg once per day) for 4 weeks with a 12-week follow-up period.

Results

The mean maximum HBV DNA reduction was 3.05, 4.20, 3.67 and 3.68 log10 copies/ml for 30, 60, 120 and 240 mg per day, respectively. Viral dynamic analysis suggested a high degree of inhibition of HBV replication at doses of 60 mg or higher per day. LB80380 was well tolerated at all dose groups, and no dose-related clinical or laboratory adverse event was reported.

Conclusion

LB80380 is shown to be a potent and safe antiviral agent for HBV. Marked HBV DNA suppression was observed in all dose groups. The HBV DNA suppression was approximately constant at doses of 60 mg and higher over the 28-day dosing period. The dose response of LB80380 will be evaluated further in large clinical studies.
Early Antiviral Treatment of Hepatitis C Virus Recurrence after Liver Transplantation in HIV-Infected Patients
Authors: Castells LLuís , Esteban Juan I , Bilbao Itxarone , Vargas Víctor , Allende Helena , Ribera Esteban , Piron Maria , Sauleda Silvia , Len Oscar , Pahissa Albert , Esteban Rafael , Guardia Jaime , Margarit Carlos
Published: April 2022

Objective

To investigate the efficacy of early antiviral treatment for hepatitis C virus (HCV) recurrence in HIV/HCV-coinfected patients undergoing liver transplantation for end-stage liver disease.

Methods

Open prospective trial of early treatment of HCV recurrence in consecutive HIV/HCV-coinfected patients transplanted at a tertiary hospital in Barcelona between 2002 and 2004. All patients had indication for liver transplantation, no previous CDC class C HIV-associated opportunistic events, a CD4+ T-cell count >100 cells/fxl, and undetectable plasma HIV RNA on highly active antiretroviral therapy. Treatment with pegylated interferon-a2b (1.5 μg/kg/week) and ribavirin (800–1000 mg/day) was given for 24 to 48 weeks, as soon as HCV recurrence was histologically documented.

Results

Of six patients who underwent transplant, five patients surviving the early post-transplantation period developed HCV recurrence, presenting as severe cholestatic hepatitis in three, and were started on antiviral treatment a median of 12 weeks (range: 5–31) after transplantation. After a median follow-up of 24 months all treated patients were alive. Biochemical response was achieved in all patients, although only one achieved a sustained virological response. Mild rejection before HCV recurrence occurred in two cases. Treatment was well tolerated with no episodes of rejection or mitochondrial toxicity. No patient required modification of the antiretroviral regimen. Liver biopsies performed in patients without virological response, 12–34 months after transplantation, showed cirrhosis in two and moderate chronic active hepatitis in the remainder.

Conclusions

Despite early antiviral treatment, severe HCV recurrence after liver transplantation may compromise long-term survival in HIV-infected patients. Improved treatment strategies for these patients are urgently required.
Quantitative Subtyping of Hepatitis B Virus Reveals Complex Dynamics of Ymdd Motif Mutants Development during Long-Term Lamivudine Therapy
Authors: Ding Chunming , Wong Vincent WS , Chow Katherine CK , Chan Hoi-Yun , Hui Alex Y , Wong Grace LH , Lo YM Dennis , Sung Joseph JY , Chan Henry LY
Published: April 2022

Background/aims

Treatment of chronic hepatitis B (CHB) with lamivudine (3TC) is limited by development of drug-resistant mutants at the YMDD motif. We aimed to validate the use of mass spectrometry to detect YMDD mutants and quantify viral subpopulations.

Methods

A total of 21 Chinese patients with severe acute exacerbation of CHB treated with 3TC were studied. Serial serum samples were tested for wild-type and YMDD mutants using matrix assisted laser desorption/ionization time-of-flight mass spectrometry. INNO-LiPA assay was performed for comparison.

Results

At a median follow-up of 192 weeks, 11 patients developed YMDD mutants (six had YIDD, four had YVDD and one had YV/IDD). Mass spectrometry was concordant with INNO-LiPA in all but one patient, in which INNO-LiPA detected coexistence of YIDD and YVDD but mass spectrometry and direct sequencing detected YVDD only. Mass spectrometry was able to reliably detect a minor hepatitis B virus (HBV) subtype at 5% or above. By serial quantitative measurement, several patterns of viral dynamics were observed. In some cases, YMDD mutants dominated the whole viral population. In other cases, the proportion of YMDD mutants fluctuated with time. When more than one mutant was present (that is, YIDD and YVDD), the different mutants might dominate during different time periods.

Conclusions

Mass spectrometry is an accurate and cheap method for the detection of YMDD mutants, even in the presence of overwhelming wild-type HBV. We observed some intriguing mutant viral dynamics during 3TC treatment. Further studies are needed to clarify whether they have any clinical significance.
Nelfinavir Induces Adipocyte Insulin Resistance through the Induction of Oxidative Stress: Differential Protective Effect of Antioxidant Agents
Authors: Ben-Romano Ronit , Rudich Assaf , Etzion Sharon , Potashnik Ruth , Kagan Ella , Greenbaum Uri , Bashan Nava
Published: April 2022

Background

Antiretroviral therapy is frequently associated with adverse metabolic effects and lipodystrophy, but the role of HIV protease inhibitors and the mechanisms involved are poorly understood. The HIV protease inhibitor nelfinavir (NFV) impairs insulin signal propagation by inducing similar signalling defects to those induced by exposure to oxidative stress.

Aim

We set out to determine if oxidative stress is involved in NFV-induced insulin resistance in 3T3-L1 adipocytes, and whether antioxidant agents with unique modes of action can prevent this effect.

Results

Cells exposed to NFV exhibited the following markers of increased oxidative stress: a decrease in both total and low molecular weight reduced thiols, a 20-fold increase in haem oxygenase 1 (HO-1) mRNA, an increase in intracellular reactive oxygen species production (determined by 2′,7′-dichlorofluorescein fluorescence), and increased markers of apoptosis. Enhancing cellular thiols with N-acetylcystein prevented the NFV-induced drop in reduced thiols and partially protected against the induction in HO-1, but failed to prevent insulin resistance or cleavage of poly ADP ribose polymerase (PARP), a process indicative of activation of pro-apoptotic caspases. Conversely, the superoxide dismutase-mimetic antioxidant MnTBAP had no effect on cellular thiols in response to NFV, but protected against HO-1 induction and against the impairment in insulin-stimulated Akt/protein kinase B activation and PARP cleavage.

Conclusions

Induction of oxidative stress plays a role in adipocyte insulin resistance and apoptosis induced by NFV through a radical-dependent but thiol-independent mechanism(s). The results may suggest a new mechanism for the adverse effects of NFV on fat cells, and offer potential new intervention approaches.
Macroenzyme Creatine Kinase (Ck) Type 2 in HIV-Infected Patients is Significantly Associated with Tdf and Consists of Ubiquitous Mitochondrial Ck
Authors: Schmid Holger , Mühlbayer Dieter , Röling Jörg , Sternfeld Thomas , Jülg Boris , Schlattner Uwe , Nelson Peter J , Bogner Johannes R , Wallimann Theo , Goebel Frank D
Published: April 2022

Objective

To evaluate the prevalence and origin of macroenzyme creatine kinase type 2 (Macro CK2) in HIV-1-infected patients on antiretroviral treatment.

Design

CK, CK-MB activity and protein weight, electrophoretic behaviour, glomerular filtration rate (GFR), aspartate aminotransferase (AST), alanine aminotransferase (ALT), bone alkaline phosphatase (AP), (2-microglobulin serum levels and proteinuria were analysed in 468 HIV-infected outpatients. Sera with detectable Macro CK2 were further analysed using immunoblotting.

Results

CK-MB isoenzyme activity and mass concentration revealed the presence of Macro CK2 in 32/408 (7.8%) outpatients. Tenofovir DF (TDF) treatment was a prominent common feature in these patients. Prospective examination of sera from 41 patients collected prior to and during TDF exposure showed Macro CK2 in 20/41 (48%) TDF-treated patients and in 0/19 control sera from patients with TDF-free regimens. Macro CK2 was not present prior to TDF exposure. Patients with Macro CK2 showed a significant elevation of serum (2-microglobulin levels. GFR, AST/ALT ratio, bone AP and proteinuria remained unchanged. Electrophoresis and immunoblotting demonstrated that the Macro CK2 in TDF-treated patients consisted of the ubiquitous (uMtCK) and not the sarcomeric type (sMtCK) of mitochondrial CK (MtCK).

Conclusions

Macro CK2 consisting of uMtCK is associated with the use of TDF-containing regimens. Whether the appearance of uMtCK in these patients reflects mitochondrial damage remains to be clarified.
Outcome of Chronic Hepatitis C Patients who Required Early Termination of Pegylated Interferon-α plus Ribavirin Combination Therapy
Authors: Yu Ming-Lung , Dai Chia-Yen , Lee Li-Po , Hsieh Ming-Yen , Hou Nai-Jen , Huang Jee-Fu , Lin Zu-Yau , Chen Shinn-Cherng , Hsieh Ming-Yuh , Wang Liang-Yen , Chang Wen-Yu , Chuang Wan-Long
Published: April 2022

Background

Pegylated interferon/ribavirin (peg-IFN/RBV) combination therapy is effective for chronic hepatitis C (CHC) but frequently causes adverse events, leading to early termination. Little is known about the outcome of CHC patients who required early termination.

Methods

Of 617 treatment-naive CHC patients prescribed a 24-week protocol of peg-IFN/RBV, 29 (4.7%) patients who terminated treatment early at <20 weeks were recruited to evaluate the rate of and the factors associated with sustained virological response (SVR), defined as seronegativity of hepatitis C virus (HCV) RNA throughout the 24-week off-treatment follow-up period.

Results

The reasons for early termination were flu-like symptoms/signs ( n=9, 31.0%), irritability ( n=1, 3.4%), severe urticaria ( n=1, 3.4%), insomnia ( n=2, 6.9%), pulmonary tuberculosis ( n=1, 3.4%), suicide idea ( n=2, 6.9%), poor response ( n=2, 6.9%), depression ( n=2, 6.9%), unwilling to continue ( n=1, 3.4%), mortality ( n=1, 3.4%), gastrointestinal upset ( n=1, 3.4%), pancytopenia complicated with cellulitis ( n=1, 3.4%), anaemia ( n=3, 10.3%), overseas work ( n=1, 3.4%) and an unknown cause ( n=1, 3.4%). Five (17.2%) patients achieved an SVR, comprising none of 16 HCV genotype-1 and five of the 13 (38.5%) genotype-2 patients ( P=0.001). All sustained responders were HCV RNA seronegative at week 4 of treatment. The SVR rate among HCV-2 patients was 0% (0/1), 0% (0/2), 25% (1/4), 33% (1/3) and 100% (3/3) in those who received peg-IFN/RBV for 1–3, 4–7, 8–11, 12–15 and 16–19 weeks, respectively ( P=0.019, χ2 with linear trend).

Conclusions

Based on this limited study, we observed that an SVR might be achieved in patients who required early termination of a 24-week regimen of peg-IFN/RBV, especially for HCV-2 patients with HCV RNA seronegativity at week 4.
Optimizing Treatment Outcomes in Chronic Hepatitis C: Management of Non-Response
Authors: Pol Stanislas , Bourlière Marc
Published: April 2022

The overarching goal in treating chronic hepatitis C (CHC) is the prevention of serious hepatic complications such as cirrhosis, end-stage liver disease and hepatocellular carcinoma. Successful eradication of the hepatitis C virus has been shown to prevent liver disease progression and even promote regression of fibrosis. The treatment of CHC has improved significantly over the past decade with the introduction of interferons (IFNs), and more recently, pegylated IFNs. Up to two-thirds of all patients treated with a pegylated IFN combined with ribavirin can now achieve viral eradication if treated according to current guidelines. Despite this success rate, limited treatment options currently exist for the growing number of patients who do not respond to this combination, and those who have previously failed treatment with conventional IFN-based regimens. There are numerous host-and viral-related factors that can contribute to these outcomes. In addition, treatment insufficiency, whether due to treatment type, side effects or non-compliance, can result in inadequate antiviral pressure and a reduced likelihood of response. This review explores putative management strategies for patients who have previously failed to achieve a response to IFN-based therapy, and summarises retreatment options that have been, and are currently being evaluated.
Prediction of Treatment-Related HBsAg Loss in HBeAg-Negative Chronic Hepatitis B: A Clue from Serum HBsAg Levels
Authors: Manesis Emanuel K , Hadziyannis Emilia S , Angelopoulou Olga P , Hadziyannis Stephanos J
Published: April 2022

Background

Quantification of HBsAg in serum may be of clinical importance in predicting HBsAg seroconversion and complete response to treatment.

Methods

Serum HBsAg was quantified by ADVIA Centaur® in 63 patients with HBeAg-negative chronic hepatitis B (CHBe-). A total of 42 had received interferon-α2b (IFN-α2b) (median 12.1 months; 19 sustained responders including 12 HBsAg-seroconvertors; 23 non-sustained responders) and 21 were on lamivudine (LAM) (median 33.0 months). Measurements were done at baseline, during and at the end of treatment, and during and at the end of follow-up.

Results

Baseline median [interquartile range (IQR)] HBsAg levels in all patients were 3,286 (1,602–7,458) IU/ml, not different between IFN- and LAM-treated ( P=0.139). IFN significantly depressed HBsAg in all patients except IFN non-responders, but HBsAg decline persisted only in sustained responders. Low pretreatment HBsAg level was the only significant prognostic variable of HBsAg seroconversion by multivariate analysis. LAM treatment also suppressed HBsAg levels but at a significantly slower rate compared with IFN ( P=0.022). The median (IQR) estimated time to HBsAg undetectability (ETU-HBsAg), derived from best curve fitting, was 127 (87.6–263.5) months for LAM virological responders and 65.3 (36.3–95.0) months for IFN sustained responders ( P=0.002). In 12 HBsAg seroconvertors, ETU-HBsAg was similar to the real time of HBsAg loss ( P=0.525) and seroconversion (0.056).

Conclusions

In CHBe-, IFN induces a sharper decrease in serum HBsAg compared with LAM and low pretreatment levels are significantly associated with HBsAg seroconversion. Serial HBsAg measurements may be useful for prediction of HBsAg loss and our data suggest that to achieve this, 5.4 years of sustained response to IFN or 10.6 years of effective LAM therapy are probably needed.
Evaluation of Cytomegalovirus DNAaemia versus pp65-Antigenaemia Cutoff for Guiding Preemptive therapy in Transplant Recipients: A Randomized Study
Authors: Gerna Giuseppe , Baldanti Fausto , Torsellini Maria , Minoli Lorenzo , Viganò Mario , Oggionni Tiberio , Rampino Teresa , Castiglioni Barbara , Goglio Antonio , Colledan Michele , Mammana Carmelo , Nozza Francesca , Lilleri Daniele
Published: April 2022

Methods

A bicentre, randomized, prospective open-label study aimed at defining a DNAaemia versus antigenaemia cutoff for guiding preemptive therapy of human cytomegalovirus (HCMV) infections in solid organ transplant recipients (SOTR) was completed. Overall, 99 patients were enrolled in the DNAaemia arm and 101 patients in the antigenaemia arm. Patients were randomized to be monitored for HCMV infection in the blood by either assay. Antiviral treatment was started in both seropositive and seronegative patients when levels greater than 300,000 DNA copies/ml blood or 100 pp65-positive leukocytes in the relevant arm were reached.

Results

HCMV infection was detected in 81/99 (81.8%) patients in the DNAaemia arm and in 87/101 (86.1%) patients in the antigenaemia arm ( P=ns). Antiviral treatment was given to 23/99 (23.0%) patients in the DNAaemia arm and 42/101 (41.0%) patients in the antigenaemia arm ( P=0.01). In the DNAaemia arm, antiviral therapy was significantly delayed and duration of the first course of treatment was significantly greater than in the antigenaemia arm. However, total duration of treatment was comparable in the two arms. No case of HCMV disease occurred in patients treated after reaching the relevant cutoff. However, four patients (three in the antigenaemia arm, and one in the DNAaemia arm) suffered from HCMV disease prior to reaching the relevant cutoff.

Conclusions

Compared with antigenaemia, a single DNAaemia cutoff: (i) significantly reduces the number of patients requiring treatment; (ii) may be safely adopted to guide preemptive therapy of both primary and reactivated HCMV infections in SOTR; and (iii) does not significantly modify the overall duration of treatment.
Renal Function in Antiretroviral-Experienced Patients treated with Tenofovir Disoproxil Fumarate associated with Atazanavir/ritonavir
Authors: Gérard Laurence , Chazallon Corine , Taburet Anne-Marie , Girard Pierre-Marie , Aboulker Jean-Pierre , Piketty Christophe
Published: April 2022

Objective

To determine the evolution of renal function in highly treatment-experienced patients with normal renal function at baseline receiving tenofovir disoproxil fumarate (TDF) as part of a fixed combined antiretroviral regimen and to identify prognostic factors of change in renal function, including tenofovir concentrations.

Methods

A prospective 48-week open-label trial was carried out, evaluating the safety of TDF, associated with atazanavir/ritonavir, and optimized nucleoside reverse transcriptase inhibitors, in patients with documented failure in previous treatments. Statistical analysis was performed on an intent-to-treat basis.

Results

Fifty-three patients were included, with a median CD4+ T-cell count of 206x106/l and a median HIV RNA level of 5 log10 copies/ml. All patients had normal serum creatinine levels and creatinine clearances (CLCr) at baseline, which were stable within the 2 months preceding inclusion. Two patients discontinued TDF as a result of severe renal impairment. Two patients never started TDF. A total of 49 patients without clinical nephrotoxicity were analysed. The median creatinine level increased significantly from baseline to week 48 (+0.04 mg/dl [+5.8%]; P=0.008), and the median CLCr decreased significantly (-7.8 ml/min [-7.6%]; P=0.005). Trough tenofovir concentration was not associated with change in CLCr ( P=0.79). No risk factors, including tenofovir plasma trough levels, were significantly associated with change in CLCr at week 24.

Conclusions

This study confirms that TDF-related severe nephrotoxicity is an uncommon event. In patients without clinical nephrotoxicity, the use of TDF during a 1-year period was associated with a slight but significant alteration of renal function, which was not associated with increased trough concentration.
Genetic Diversity and Drug Resistance Mutations in HIV type 1 from Untreated Patients in Bamako, Mali
Authors: Derache Anne , Traore Ousmane , Koita Victoria , Sylla Aliou , Tubiana Roland , Simon Anne , Canestri Ana , Carcelain Guislaine , Katlama Christine , Calvez Vincent , Cisse Mamadou , Marcelin Anne-Geneviève
Published: April 2022

Objective

To determine the genetic diversity of HIV-1 reverse transcriptase (RT) and protease sequences and the presence of mutations linked to antiretroviral (ARV) resistance in treatment-naive, HIV-1-infected individuals living in Mali.

Methods

Ninety-eight samples from ARV drug-naive, HIV-1-infected patients were collected in one clinical centre in Bamako, Mali in 2005. RT and protease genes were sequenced in order to perform phylogenetic and resistance analyses.

Results

The most prevalent subtype was CRF02-AG (75% of cases), followed by the CRF06-cpx subtype (20%). Intersubtype recombinants between CRF02-AG, CRF01-AE and CRF06-cpx were also described in 5% of cases. After 4 years of ARV use in Mali, two previously untreated individuals (2%; 95% CI: 0.00–4.77%) were found to have resistant viruses, one with a single nucleoside mutation and one with K103N non-nucleoside reverse transcriptase inhibitor resistance mutation. No evidence of transmitted protease inhibitor resistance mutations was found.

Conclusion

These data provide direct evidence for the circulation of HIV-1 isolates containing resistance mutations in treatment-naive patients in Mali. Since ARV use in Mali began, more than 5,000 patients have started treatment, mostly with Triomune (stavudine/lamivu-dine/nevirapine). The resistance-associated mutations detected in the present study are consistent with this treatment regimen. Continued surveillance will be required to monitor the emergence of ARV resistance in this country.