bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of Steatosis on Long-Term Histological Outcome in Chronic Hepatitis C after Antiviral Therapy
Authors: Hung Chao-Hung , Kuo Fang-Ying , Wang Jing-Houng , Lu Sheng-Nan , Hu Tsung-Hui , Chen Chien-Hung , Lee Chuan-Mo , Eng Hock-Liew
Published: April 2022

Background/Aims

Steatosis is recognized as a cofactor influencing the presence and progression of fibrosis in chronic hepatitis C. It has been reported that antiviral therapy may reduce the progression of fibrosis and leads to regression in chronic hepatitis C patients achieving a sustained virological response (SVR). Whether steatosis might affect the long-term histological outcome of antiviral therapy remains unclear.

Methods

One-hundred and sixty-one consecutive patients (genotype 1, n=76; genotype 2, n=73) receiving interferon-α2b and ribavirin were analysed. Ninety patients had paired biopsies with a mean interval of 29.1 ±7.1 months.

Results

Variables associated with baseline steatosis were higher body mass index (≥25, P=0.002) and higher fibrosis stage (≥2, P=0.019). Neither the presence nor the severity of steatosis was associated with SVR. Evaluation of paired biopsies showed no different distribution of steatosis evolution between patients with and without SVR ( P=0.374). Among patients achieving a SVR, there was a significant difference in fibrosis changes between those with grade 0 or 1 steatosis and with grade 2 or 3 steatosis at post-treatment biopsy (-0.6 ±1.2 vs 0.3 ±1.3, P=0.041), whereas changes in histological activity index did not differ (-3.7 ±2.6 vs -4.0 ±2.9, P=0.740). Stepwise logistic regression analysis showed that SVR (odds ratio [OR]: 16.33, P=0.004) and grade 0 or 1 post-treatment steatosis (OR: 12.82, P=0.018) were independently associated with fibrosis regression.

Conclusions

In patients with chronic hepatitis C, steatosis not only correlates with advanced fibrosis at baseline but also affects fibrosis regression after antiviral therapy.
Vascular Ophthalmological Side Effects Associated with Antiviral Therapy for Chronic Hepatitis C are Related to Vascular Endothelial Growth Factor Levels
Authors: Andrade Raúl J , González F Jesús , Vázquez Luis , Cilvetti Angel , Camargo Raquel , García-Cortés Miren , Martos-VanDussen Juan V , Rosón Pedro , Lucena M Isabel , Clavijo Encarnaciòn
Published: April 2022

We have screened for the incidence of vascular ophthalmological side effects (VOSE) in chronic hepatitis C (CHC) patients undergoing pegylated interferon (peg-IFN) plus ribavirin (RBV) therapy and sought evidence for angiogenesis activation. Thirty-four CHC patients were prospectively evaluated (18 patients with 180 μg/week of peg-IFN-α2a plus 800 mg/day of RBV and 16 with 1.5μg/kg/week of peg-IFN-α2b plus 800–1,200 mg/day of RBV). Complete ophthalmological evaluation and serum vascular endothelial growth factor (VEGF) levels were assessed before and at the end of therapy. Thirteen patients (38.2%) developed VOSE, eight (23.5%) featured subconjunctival haemorrhage, and five (14.7%) had evidence of retinopathy – all were unrelated to age, sex, genotype, the type of antiviral schedule used and response to therapy. At the end of treatment, the VOSE group had significantly higher serum VEGF levels than the group of patients without detectable side effects (median 281 [range 106–386] vs 117 [83–225] pg/ml, P=0.05). These differences increased when VEGF values were corrected by platelet count. In the VOSE group, baseline VEGF and VEGF/platelet values were also significantly higher (164 [55–260] vs 64 [21–172] pg/ml, P=0.046; and 0.920 [0.217–1.543] vs 0.320 [0.100–0.661] pg/106 platelets, P=0.024, respectively]. In a multivariate model VEGF/platelet values at end of treatment and hepatic fibrosis stage were the only predictors of VOSE development. In 3 out of 13 patients visual acuity was affected and 2 had residual lesions in the follow-up. In this exploratory study, antiviral therapy of CHC frequently induces VOSE, apparently through an activation of angiogenesis.
Enfuvirtide in HIV-1-Infected Individuals Changing Therapy to A Nucleoside Reverse Transcriptase Inhibitor Sparing Regimen: The Alliance Study
Authors: Dwyer Dominic E , Workman Cassy , Hales Gillian , Amin Janaki , Cooper David , Miller John , Emery Sean
Published: April 2022

The role of the fusion inhibitor enfuvirtide in nucleoside reverse transcriptase inhibitor (NRTI)-sparing regimens was assessed in an open-label study of fifty-nine highly antiretroviral drug exposed HIV-1-infected individuals. There was a reduction in plasma HIV-1 RNA of 1.43 (95% confidence interval [CI]: -2.06, -1.22) log10 copies/ml plasma over 96 weeks, and 44% (95% CI: 31, 58) of individuals had a viral load less than 400 copies/ml. A viral load below detection at 96 weeks was predicted by a baseline genotypic sensitivity score greater than 1. There was an average increase of 67 cells/μl (95% CI: 15, 120) from baseline CD4+ T-cell count to week 96, and the percentage of patients with CD4+ T-cell counts above 100 and 200 cells/μl increased over the trial. Injection site reactions (ISRs) were less common in people with CD4+ T-cell counts >250 cells/μl at any time during follow-up, and were more severe in patients with lower baseline peripheral fat. Adherence over 48 weeks to enfuvirtide injections ranged from 96.3-99.5%. During the 96 week trial there were two discontinuations due to ISRs and two discontinuations following hypersensitivity reactions. Over the 96 weeks of study lean body mass increased by an average 2.7 kg (95% CI; 1.7, 3.6 kg). Mean peripheral fat increased by 0.2 kg (95% CI; -0.2, 0.6 kg). Baseline NRTI-associated toxicities resolved in 17% of participants during follow-up. Enfuvirtide is an important component of antiretroviral therapy in highly treatment-experienced individuals where NRTI sparing may be desirable.
Pharmacokinetics of a Once-Daily Regimen of Lopinavir/Ritonavir in HIV-1-Infected Children
Authors: van der Lee Manon , Verweel Gwenda , de Groot Ronald , Burger David
Published: April 2022

Introduction

Lopinavir is an HIV protease inhibitor that is co-formulated with ritonavir. The approved paediatric dose is 230/57.5 mg/m2 twice daily. Once-daily dosing may offer an advantage to adherence. We studied the pharmacokinetics of lopinavir/ritonavir in a once-daily regimen in HIV-1-infected children.

Methods

HIV-1-infected children on stable antiretroviral therapy with a viral load <50 copies/ml for at least 6 months received lopinavir/ritonavir 460/115 mg/m2 once daily with zidovudine and lamivudine. Blood samples were collected at 0, 2, 4, 6, 8, 12, 18 and 24 h after observed intake during steady state. Target level for lopinavir Cmin was 1.0 mg/l, based on in vitro IC50 data.

Results

Nineteen HIV-1-infected children with a median (range) age of 4.5 (1.4–12.9) years were enrolled. The median (interquartile range) dose of lopinavir was 456 (444–477) mg/m2. The mean (standard deviation) AUC0–24, Cmax and Cmin of lopinavir were 149.8 ±58.8 h*mg/l, 10.77 ±2.90 mg/l and 2.88 ±3.74 mg/l respectively. These values are comparable to data observed in adults using lopinavir/ritonavir 800/200 mg once daily. In 10/19 (53%) children Cmin was considered to be too low (<1.0 mg/l). Younger children more often experienced subtherapeutic trough levels.

Conclusion

Our findings indicate that 460/115 mg/m2 lopinavir/ritonavir once daily leads to mean pharmacokinetic parameters comparable to data of 800/200 mg lopinavir/ritonavir once daily in adults, although the variability observed in the trough levels is much higher in children. Further research, especially in young children, is necessary to determine whether a higher dosage of lopinavir/ritonavir once daily must be given to reach the target level for Cmin.
Future Therapies for Hepatitis C
Authors: Pawlotsky Jean-Michel , Gish Robert G
Published: April 2022

Although pegylated interferon-α plus ribavirin has become the standard for treating chronic hepatitis C virus infection, a substantial number of patients do not tolerate therapy and require dose reduction or discontinuation, or do not respond to this combination therapy. Thus, new therapeutic options are needed. An increased knowledge of the hepatitis C virus and an understanding of its replication cycle, as well as advances in biotechnology, have stimulated the development of numerous new antiviral treatments for patients with hepatitis C virus infection. This review focuses on four classes of new agents: new interferons, ribavirin-like molecules, specific small-molecule hepatitis C virus inhibitors and new immune therapies, with particular emphasis on medications in the later stages of development.
Drug-Class-Wide Resistance to Antiretrovirals in HIV-Infected Patients Failing Therapy: Prevalence, Risk Factors and Virological Outcome
Authors: Tozzi Valerio , Zaccarelli Mauro , Bonfigli Sandro , Lorenzini Patrizia , Liuzzi Giuseppina , Trotta Maria Paola , Forbici Federica , Gori Caterina , Bertoli Ada , Bellagamba Rita , Narciso Pasquale , Perno Carlo Federico , Antinori Andrea
Published: April 2022

Background

Drug-class-wide resistance (DCWR) to anti-retrovirals substantially reduces treatment options.

Methods

A database of 602 patients failing highly active antiretroviral therapy (HAART) undergoing genotypic resistance test (GRT) was analysed. DCWR was defined according to the International AIDS Society consensus. A multiple logistic regression model was built to define factors significantly associated with DCWR and to assess virological response to salvage regimens.

Results

NRTI DCWR was observed in 28.5% of 592 NRTI-exposed patients, NNRTI DCWR in 57.7% of 284 NNRTI exposed patients, PI DCWR in 19.9% of 412 PI exposed patients, and three-class resistance in 21.4% of 112 three-class-exposed patients. The prevalence of NRTI and PI DCWR increased significantly by year of exposure to the same class from 8.9% (<1 year) to 35.3% (>4 years) and from 1.2% (<1 year) to 34.8% (>4 years), respectively ( P<0.001, for trend). The risk of developing NRTI and PI DCWR increased by 25% (95% confidence interval [CI]: 1.6%–51.3%) and by 53% (20.5%–94.3%) for each year of treatment, and by 17% (95% CI: 5.6%–29.3%) and by 32% (17.7%–50.3%) for each previous failing NRTI- and PI-containing regimen, respectively. NRTI DCWR due to at least four nucleoside analogues mutations (NAMs) increased by year of NRTI exposure from 8.9% (<1 year) to 32.6% (>4 years; P<0.001, for trend). After adjustment for confounding factors, the probability of achieving plasma viral load <500 copies/ml was significantly reduced in patients with NRTI (OR: 0.750; 95% CI: 0.574–0.979), NNRTI (OR: 0.746; 95% CI: 0.572–0.975), PI (OR: 0.655; 95% CI: 0.456–0.941), three-class (OR: 0.220; 95% CI: 0.082–0.593) resistance.

Conclusions

The probability of developing NRTI and PI DCWR increased with length of class exposure and with the number of previously failing regimens. By contrast, high levels of NNRTI DCWR were observed within 1 year in NNRTI-failing patients, with a steady prevalence over time. The increase in prevalence with time of NRTI DCWR was due to the accumulation of NAMs. DCWR to NRTIs, NNRTIs, PIs or all the three together was associated with an increased probability of virological failure to subsequent HAART regimens.
Mitochondrial (Mt)Dna Changes in Tissue May Not be Reflected by Depletion of Mtdna in Peripheral Blood Mononuclear Cells in HIV-Infected Patients
Authors: Maagaard Anne , Holberg-Petersen Mona , Kollberg Gittan , Oldfors Anders , Sandvik Leiv , Bruun Johan N
Published: April 2022

Objectives

Most data on mitochondrial toxicity have been derived from peripheral blood mononuclear cells (PBMCs). However, whether mitochondrial DNA (mtDNA) content in PBMCs reflects the mitochondrial state in tissues remains elusive. We report herein on mitochondrial toxicity in skeletal muscle in HIV-infected patients naive to antiretroviral treatment (ART [HIV+ART-naive]; n=10) patients exposed to nucleoside reverse transcriptase inhibitors (NRTIs [HIV+NRTI+]; n=24) and healthy controls ( n=11), and compare these tissue data with mtDNA in PBMCs.

Methods

Muscle biopsies were examined for (i) mtDNA and nuclear DNA (nDNA) content using TaqMan realtime PCR system, (ii) mtDNA deletions using long expand PCR with subsequent gel electrophoresis, and (iii) mitochondrial myopathy expressed as cytochrome c oxidase (COX)-deficient muscle fibres.

Results

The mt/n DNA ratio in muscle from HIV+NRTI+patients was reduced compared with HIV-negative controls ( P=0.028). Moreover, mtDNA deletions were more frequent in HIV+NRTI+ patients than in both HIV-negative controls ( P=0.009) and HIV+ART-naive patients ( P=0.005). HIV+NRTI+ also tended to have more COX-deficient fibres than HIV-negative controls ( P=0.076). COX-deficient fibres were positively correlated with mtDNA deletions in HIV+NRTI+ patients (r=0.83, P<0.001). Patients with current use of didanosine (ddI) had more frequent mtDNA deletions and COX-deficient fibres than HIV+NRTI+ not on current treatment with ddI. It should be noted that mitochondrial alterations were not correlated with mtDNA/cell in PBMCs in any group.

Conclusions

In skeletal muscle, HIV+NRTI+ had a reduced mt/n DNA ratio, more frequent mtDNA deletions and possibly more COX-deficient muscle fibres than HIV-negative controls. However, the mtDNA/cell in peripheral blood was decreased in both HIV+NRTI+ and HIV+ART-naive patients. Thus, mtDNA in peripheral blood may not be a relevant marker of mitochondrial toxicity in organ-specific tissue.
Genomics of Hepatitis B and C Infections: Diagnostic and Therapeutic Applications of Microarray Profiling
Authors: Berzsenyi Mark D , Roberts Stuart K , Beard Michael R
Published: April 2022

Microarray profiling offers many potential advances in diagnostic and therapeutic intervention in human disease because of its unparalleled ability to conduct high-throughput analysis of gene expression. However, limitations of this technique relate in part to issues regarding the various methodologies and experimental designs as well as difficulties in the interpretation of results. Despite this, microarray profiling has led to a better understanding of the molecular pathogenesis of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection. Key events in clearance and the development of chronicity of HCV have been identified that may prove to have a role in the development of future treatments. In addition, pharmacogenomic studies of interferon-based treatment for chronic HCV and HBV have provided mechanistic insights into the therapeutic action of interferons. These advances have implications with respect to the development of improved therapeutic agents. New biomarkers for cancer screening and gene profiles with prognostic value for survival have also been developed for hepatocellular carcinoma, which frequently complicates chronic viral hepatitis. Thus, microarray profiling offers enormous potential for improvements in antiviral therapy and our understanding of blood-borne viral hepatitis.
A Smoking Cessation Programme in HIV-Infected Individuals: A Pilot Study
Authors:   the Swiss HIV Cohort Study, Battegay M , Bernasconi E , Böni J , Bucher H , Bürgisser P , Cattacin S , Cavassini M , Dubs R , Egger M , Elzi L , Erb P , Fischer M , Flepp M , Fontana A , Francioli P , Furrer H , Gorgievski M , Günthard H , Hirschel B , Hösli I , Kahlert Ch , Kaiser L , Karrer U , Keiser O , Kind C , Klimkait T , Ledergerber B , Martinez B , Müller N , Nadal D , Opravil M , Paccaud F , Pantaleo G , Perrin L , Bijker J-C , Rickenbach M , Rudin C , Schmid P , Schultze D , Schüpbach J , Speck R , Taffé P , Tarr P , Telenti A , Trkola A , Vernazza P , Weber R , Yerly S , Elzi Luigia , Spoerl David , Voggensperger Jacqueline , Nicca Dunja , Simcock Mathew , Bucher Heiner C , Spirig Rebecca , Battegay Manuel
Published: April 2022

Background

Antiretroviral therapy (ART) is a risk factor for cardiovascular disease (CVD) and smoking the most important modifiable cardiovascular risk factor.

Methods

We prospectively evaluated a smoking cessation programme (SCP) in HIV-infected individuals (intervention: counselling and nicotine replacement therapy). Primary endpoint was the smoking cessation rate at 12 months; secondary endpoints were CVD morbidity and mortality. Controls were a not randomized control group of smokers not participating in the SCP.

Results

Four-hundred and seventeen of 680 (61%) patients were smokers, and 34 of these participated in the SCP. Of these 34 individuals, 82% were male, the median age was 43 years, prior AIDS was recorded in 29%, and depressive disorder was recorded in 18%. Twenty-five (74%) patients were receiving ART. Additional risk factors were dyslipidaemia (68%), a prior cardiovascular event (24%), hypertension (15%), and a family history of CVD in 2/34 (6%) individuals. According to the Framingham equation, the 10-year risk of CVD was higher in SCP participants than in controls (11.2% versus 8.5%, P=0.06). At termination of the SCP, 17/34 (50%) individuals had stopped smoking compared with 57/383 (15%) controls. Self-reported smoking abstinence for ≥12 months was 13/34 (38%) in the intervention group and 27/383 (7%) in the control group (odds ration 6.2, 95% confidence interval 2.8–14.3). During the follow-up, two SCP participants and 4 controls experienced a myocardial infarction. One patient in the control group died of CVD.

Conclusions

SCP in HIV-infected individuals is feasible and should be encouraged. The long-term impact of smoking cessation on CVD morbidity and mortality should be evaluated in comparative trials.
Antiretroviral Therapy Based on Protease Inhibitors as a Protective Factor against Liver Fibrosis Progression in Patients with Chronic Hepatitis C
Authors: Macías Juan , Mira José A , López-Cortés Luis F , Santos Ignacio , Girón-González José A , González-Serrano Mercedes , Merino Dolores , Hernández-Quero José , Rivero Antonio , Merchante Nicolás , Trastoy Mónica , Carrillo-Gómez Raquel , Arizcorreta-Yarza Ana , Gómez-Mateos Jesús , Pineda Juan A
Published: April 2022

Cohort studies have shown that highly active antiretroviral therapy (HAART) can improve liver-related mortality in HIV/hepatitis C virus (HCV)-coinfected patients. A reduction in the accelerated liver fibrosis progression observed in HIV infection induced by HAART could explain these findings. A few studies have assessed the impact of HAART on liver fibrosis, but with contradictory results. Therefore, we evaluated the associations between the use of different antiretroviral drug classes and HAART combinations, and liver fibrosis in HIV-infected patients with chronic hepatitis C. Six hundred and eighty-three HIV/HCV-coinfected patients, who underwent a liver biopsy and who had not received anti-HCV treatment were included. Age at HCV infection <23 years (adjusted odds ratio [AOR]=0.7, 95% confidence interval [95% CI]=0.3-0.9, P=0.05) and protease inhibitor (PI)-based HAART versus no use of HAART (AOR=0.5, 95% CI=0.3-0.9, P=0.01) were negatively associated with advanced fibrosis (≥F3). PI-based HAART versus no use of HAART (AOR=0.4, 95% CI=0.2-0.7, P=0.001) was negatively associated with fibrosis progression rate ≥0.2 units/year and independently of age at HCV infection and CD4+ T-cell counts. Fifteen (17%) patients treated only with PIs and zidovudine plus lamivudine showed ≥F3, compared with 65 (37%) patients without HAART ( P=0.001). Forty (31%) patients on PI and stavudine plus lamivudine showed ≥F3 ( P=0.3, when compared with patients with no HAART). The use of PI-based HAART in HIV/HCV-coinfected patients is associated with less severe fibrosis and slower progression of fibrosis. The nucleoside analogue backbone in a HAART regimen may influence this association.
A Sustained Virological Response to Interferon or Interferon/Ribavirin Reduces Hepatocellular Carcinoma and Improves Survival in Chronic Hepatitis C: A Nationwide, Multicentre Study in Taiwan
Authors: Yu Ming-Lung , Lin Shi-Ming , Chuang Wan-Long , Dai Chia-Yen , Wang Jing-Houng , Lu Sheng-Nan , Sheen I-Shyan , Chang Wen-Yu , Lee Chuan-Mo , Liaw Yun-Fan
Published: April 2022

Background

The long-term benefit for chronic hepatitis C (CHC) patients treated with interferon (IFN)/ribavirin (RBV) combination therapy remains unclear. We aimed to evaluate the long-term effects of IFN monotherapy and IFN/RBV combination therapy on reducing hepatocellular carcinoma (HCC) and mortality in patients with chronic hepatitis C virus (HCV) infection, adjusting for risk factors.

Methods

A total of 1,619 patients with biopsy-proven CHC, including 1,057 receiving IFN-based therapy (760 on IFN/RBV combination therapy) and 562 untreated controls from three medical centres and one regional core hospital in Taiwan were enrolled in this retrospective-prospective cohort study.

Results

The incidence of HCC and survival during a follow-up period of 1.0–15.3 (mean 5.18) and 1–16 (mean 5.15) years in treated and untreated patients, respectively, was analysed using Cox proportional hazards regression. The cumulative incidence of HCC was 35.2% and 12.2% for untreated and treated groups, respectively ( P=0.0013). The cumulative survival rate was 93.1% and 96.2% for untreated and treated groups, respectively ( P=0.3928). Significantly lower incidences of HCC and mortality were observed in sustained virological responders (both for IFN monotherapy and IFN/RBV combination) but not in non-responders when compared with untreated patients. HCV genotype 1 patients had significantly higher incidences of HCC than genotype non-1 patients. In multivariate analysis, pre-existing cirrhosis, non-response, HCV geno-type-1 and age were associated with HCC; pre-existing cirrhosis and non-response correlated to mortality.

Conclusion

A sustained virological response secondary to IFN monotherapy or IFN/RBV combination therapy could reduce the risk for HCC and improve survival of CHC patients.
Pegylated Interferon-α for the Treatment of Sexually Transmitted Acute Hepatitis C in HIV-Infected Individuals
Authors: Vogel Martin , Nattermann Jacob , Baumgarten Axel , Klausen Gerd , Bieniek Bernhard , Schewe Knud , Jessen Heiko , Boesecke Christoph , Rausch Michael , Lutz Thomas , Fenske Stefan , Schranz Dietmar , Kümmerle Tim , Schuler Christoph , Theisen Albert , Mayr Christoph , Seidel Thomas , Rockstroh Jürgen K
Published: April 2022

Background

Sexually transmitted acute hepatitis C among HIV-positive homosexual men has been noted as an emerging epidemic.

Methods

Forty-seven patients with mainly sexually acquired, acute hepatitis C were enrolled in this prospective, multicentre trial, and 36 of these patients were treated within the acute phase of hepatitis C infection with pegylated interferon (peg-IFN) therapy.

Results

Early treatment resulted in sustained virological response in 61% of patients. Peg-IFN alone showed similar treatment response rates and lower incidence of anaemia compared with peg-IFN+ribavirin combination therapy. Higher treatment response rates were observed in patients treated over 48 weeks compared with 24 weeks.

Conclusions

Treatment of hepatitis C in HIV-positive individuals in the acute phase of infection leads to high rates of sustained virological response. Optimal time and mode of therapy have yet to be defined.
A Virological Benefit from an Induction/Maintenance Strategy: The Forte Trial
Authors: Asboe David , Williams Ian G , Goodall Ruth L , Darbyshire Janet H , Hooker Malcolm H , Babiker Abdel G
Published: April 2022

Objective

To evaluate whether the addition of a fourth drug for up to 32 weeks to a standard three-drug anti-retroviral combination decreases the risk of virological failure without increasing toxicity in treatment-naive patients.

Design

Induction/maintenance (IM) therapy [two nucleoside reverse transcriptase inhibitors (NRTIs) + one non-NRTI (NNRTI) + one protease inhibitor for 24–32 weeks until plasma HIV RNA viral load (VL) ≤50 copies/ml then two NRTIs + NNRTI] was compared with standard therapy (ST) (two NRTIs + NNRTI). The primary endpoint was virological failure: VL >50 copies/ml at 32 (and 24) weeks or subsequent rebound to >400 copies/ml.

Results

122 (62 IM, 60 ST) participants were randomized and followed for a median of 81 weeks (IQR 64–145). 52% were asymptomatic; median CD4+ T-cell count was 160x106/l (IQR 92-260) and median VL 98,830 copies/ml (IQR 37,500–241,290). In an intent-to-treat analysis, the proportion of participants with virological failure at or after 32 weeks was higher in the ST arm [26 (43%) versus 11 (18%), P=0.002]. The mean decrease in VL at 48 weeks was 0.84 95% confidence interval (CI) (0.15, 1.53) log10 copies/ml greater in the IM arm ( P=0.02). There were no significant differences between the two arms in the change in CD4+ T-cell count from baseline to 48 weeks, the number of participants with adverse events or the frequency of progression to AIDS/death. Drug resistance at failure was detected less frequently in the IM arm.

Conclusions

Starting antiretroviral therapy with an IM strategy improved virological outcomes compared with a three-drug regimen, without significantly increasing toxicity.
A Computer-Based System to aid in the Interpretation of Plasma Concentrations of Antiretrovirals for Therapeutic Drug Monitoring
Authors: Goicoechea Miguel , Vidal Andrea , Capparelli Edmund , Rigby Andrew , Kemper Carol , Diamond Catherine , Witt Mallory D , Haubrich Richard
Published: April 2022

Objectives

To develop a computer-based system for modelling and interpreting plasma antiretroviral concentrations for therapeutic drug monitoring (TDM).

Methods

Data were extracted from a prospective TDM study of 199 HIV-infected patients (CCTG 578). Lopinavir (LPV) and efavirenz (EFV) pharmacokinetic (PK) parameters were modelled using a Bayesian method and interpreted by an expert committee of HIV specialists and pharmacologists who made TDM recommendations. These PK models and recommendations formed the knowledge base to develop an artificial intelligence (AI) system that could estimate drug exposure, interpret PK data and generate TDM recommendations. The modelled PK exposures and expert committee TDM recommendations were considered optimum and used to validate results obtained by the AI system.

Results

A group of patients, 67 on LPV, 46 on EFV and three on both drugs, were included in this analysis. Correlations were high for LPV and EFV estimated trough and 4 h post-dose concentrations between the AI estimates and modelled values (r>0.79 for all comparisons; P<0.0001). Although trough concentrations were similar, significant differences were seen for mean predicted 4 h concentrations for EFV (4.16 μg/ml versus 3.89 μg/ml; P=0.02) and LPV (7.99 μg/ml versus 8.79 μg/ml; P<0.001). The AI and expert committee TDM recommendations agreed in 53 out of 69 LPV cases [kappa (κ)=0.53; P<0.001] and 47 out of 49 EFV cases (κ=0.91; P<0.001).

Conclusions

The AI system successfully estimated LPV and EFV trough concentrations and achieved good agreement with expert committee TDM recommendations for EFV- and LPV-treated patients.
Frequency, determinants and consequences of delayed access to care for HIV infection in France
Authors: Lanoy Emilie , Mary-Krause Murielle , Tattevin Pierre , Perbost Isabelle , Poizot-Martin Isabelle , Dupont Caroline , Costagliola Dominique ,   on behalf of the ANRS CO04 French Hospital Database on HIV Clinical Epidemiological Group
Published: April 2022

Background and objectives

We analysed the frequency and predictors of delayed access to care (DAC) for HIV infection, and its influence on survival.

Methods

We studied predictors of DAC among 18,721 patients enrolled between 1997 and 2002 in the French Hospital Database on HIV (FHDH), DAC being defined by a CD4+ T-cell count below 200 copies/mm3 and/or AIDS at FHDH enrolment. The association of DAC with the initiation of combined antiretroviral therapy (cART) and of DAC with survival were analysed with Cox multivariable models.

Results

The overall prevalence of DAC was 35.7%. Compared with patients under 30 years of age, patients over 60 were 3.5 times more likely to have DAC (P<10-4). Compared with non-migrant women, odds ratios (OR) of DAC were higher among migrant women (1.5), non-migrant men (1.6) and migrant men (1.9; all P<10-4). Compared with men who have sex with men, other transmission groups had an estimated OR for DAC of 1.6 (P<10-4). DAC was more frequent among patients with a recent diagnosis of HIV infection [OR=1.3, 95% confidence intervals (CI)=(1.2;1.4)]. Patients with DAC received cART earlier than other patients [hazard ratio (HR)=2.2, 95% CI=(2.1;2.3)]. The DAC/mortality HR was 13.9 in the first 6 months after enrolment in the FHDH, and remained significantly higher than 1 during the subsequent 4 years.

Conclusion

DAC is common in France and was associated with a higher mortality, despite early initiation of cART. Earlier access to care and specific clinical management of patients with DAC should be considered.
Uridine Supplementation for the treatment of Antiretroviral Therapy-Associated Lipoatrophy: A Randomized, Double-Blind, Placebo-Controlled Trial
Authors: Sutinen Jussi , Walker Ulrich A , Sevastianova Ksenia , Klinker Hartwig , Häkkinen Anna-Maija , Ristola Matti , Yki-Järvinen Hannele
Published: April 2022

Background

Highly active antiretroviral therapy (HAART) is associated with loss of subcutaneous fat (lipoatrophy) presumably due to mitochondrial toxicity of nucleoside reverse transcriptase inhibitors. In vitro, uridine abrogates thymidine analogue-induced toxicity in adipocytes.

Methods

A total of 20 patients with HAART-associated lipoatrophy were randomized to receive either a dietary uridine supplement (36 g three times a day for 10 consecutive days/month) or placebo, for 3 months. Body composition was measured using dual energy X-ray absorptiometry, magnetic resonance imaging and proton spectroscopy. Data are mean ± standard error of mean.

Results

The mean increases in limb fat (880 ±140 versus 230 ±270 g; P<0.05), intra-abdominal fat (210 ±80 versus -80 ±70 cm3; P<0.05) and total body fat (1,920 ±240 versus 240 ±520 g; P<0.01) were significantly greater in the uridine than in the placebo group. Within the uridine group, the changes from baseline to 3 months were statistically significant in total limb fat ( P<0.001), intra-abdominal fat ( P<0.05) and total body fat ( P<0.001). The proportion of limb fat to total fat increased from 18% to 25% ( P<0.05) in the uridine group. Liver fat content and lean body mass remained unchanged in both groups. High-density lipoprotein-cholesterol concentrations decreased in the uridine and increased in the placebo group, whereas fasting serum insulin concentrations did not change. Uridine supplementation was well tolerated and the virological effect of HAART was not affected.

Conclusion

Uridine supplementation significantly and predominantly increased subcutaneous fat mass in lipoatrophic HIV-infected patients during unchanged HAART.
Does Tenofovir Influence Efavirenz Pharmacokinetics?
Authors: Rotger Margalida , Colombo Sara , Furrer Hansjakob , Décosterd Laurent , Buclin Thierry , Telenti Amalio ,   the Swiss HIV Cohort Study
Published: April 2022

Introduction

A recent report described a possible interaction between tenofovir (TFV) and efavirenz (EFV). Patients developed neuropsychiatric manifestations upon introduction of TFV on a stable EFV-containing regimen. We evaluated the possibility of a pharmacokinetic interaction between TFV and EFV by assessing cross-sectional and longitudinal data in 169 individuals receiving EFV.

Results

EFV plasma area-under-the-curve (AUC) levels were comparable among individuals receiving ( n=18) or not receiving TFV ( n=151); 57,962 versus 52,293 ng*h/ml. However, under conditions of limited EFV metabolism, that is, the group of 23 individuals carrying two copies of CYP2B6 loss/diminished-function alleles, plasma AUC values were highest among individuals receiving TFV ( n=5, 353,031 ng*h/ml), compared with those not receiving TFV ( n=18, 180,689 ng*h/ml). Statistical analysis identified both a global, sixfold effect of CYP2B6 loss/diminished function ( P<0.0001) and a significant interaction between the number of loss/diminished-function alleles and the co-medication with TFV ( P=0.009).

Conclusion

Although there is no clear evidence for a pharmacokinetic interaction between TFV and EFV, we cannot rule out an interaction between these drugs restricted to individuals who are slow EFV metabolizers.
Key Reports from the XV International HIV Drug Resistance Workshop 2006
Authors: Mascolini Mark , Boucher Charles , Larder Brendan , Mellors John , Richman Douglas
Published: April 2022

The XV International HIV Drug Resistance Workshop recorded advances in basic and clinical science of HIV resistance to antiretrovirals as well as new findings on resistance by hepatitis B virus (HBV) and hepatitis C virus (HCV). In the clinical arena, attendees learned of four cases of resistance to lopinavir/ritonavir monotherapy, correlation between low-frequency pretreatment mutations and failure of a first antiretroviral regimen, emergence of non-nucleoside-related mutations in 20% of patients interrupting a suppressive nonnucleoside regimen, and evolution of mutations conferring resistance to an HIV entry inhibitor that is being studied as a vaginal microbicide. New data reported from the POWER 1, 2 and 3 salvage trials suggested that there is a close correlation between darunavir (TMC114) phenotypic susceptibility, the number of baseline protease inhibitor-related resistance mutations and virological response. Scientists exploring the mechanisms of resistance reported of mutations in the carboxy-terminal domain of reverse transcriptase that may further resistance to zidovudine, novel mutations that may contribute to resistance of both nucleoside and non-nucleoside reverse transcriptase inhibitors, and a mechanism that HCV and HIV may share to resist antiviral therapy.
Normalization of Fat Accrual in Lipoatrophic, HIV-Infected Children Switched from Stavudine to Tenofovir and from Protease Inhibitor to Efavirenz
Authors: Viganò Alessandra , Brambilla Paolo , Cafarelli Laura , Giacomet Vania , Borgonovo Simona , Zamproni Ilaria , Zuccotti Gianvincenzo , Mora Stefano
Published: April 2022

Objective

An antiretroviral regimen based on lamivudine +stavudine+protease inhibitor impairs peripheral fat accrual in HIV-infected children and adolescents. We assess the effect on body composition parameters of replacing stavudine with tenofovir and protease inhibitor with efavirenz in paediatric patients.

Methods

A 96-week prospective study on 24 patients, (age range: 5.0–17.9 years) with stable undetectable HIV-1 loads, who were switched from stavudine to tenofovir and from protease inhibitor to efavirenz. Patient assessment included: body composition parameters measured by dual-energy X-ray absorptiometry (DXA), viral load and CD4+ T-count and percentage. As a control group for DXA data, we studied 143 healthy controls (HCs; age range: 4.9–20.0 years).

Results

Virological suppression and unchanged CD4+T-cell count and percentage were maintained in all patients. At baseline, patients showed decreased total, arm and leg fat masses ( P<0.01) but a similar trunk fat mass to HCs. From baseline to week 96, patient fat mass increases were comparable to those for HCs (total fat: 1.3 vs 1.2 kg; fat in arms: 0.09 vs 0.08 kg; fat in legs: 0.5 vs 0.5 kg; trunk fat: 0.6 vs 0.6 kg). However, at week 96, total and leg fat mass in patients were still significantly lower than those in HCs ( P<0.02). At baseline and at week 96, lean mass in patients was similar to that expected in HCs.

Conclusions

Replacing stavudine with tenofovir and protease inhibitor with efavirenz for 96 weeks in lipoatrophic paediatrics patients led to a restoration of physiological fat accrual. Lipoatrophy did not progress but was still present, indicating the need for additional strategies.
Low-level HCV Viraemia after Initial Response during Antiviral Therapy: Transcription-Mediated Amplification Predicts Treatment Failure
Authors: Gelderblom Huub C , Reesink Henk W , Beld Marcel GHM , Weegink Christine J , Jansen Peter LM , Dijkgraaf Marcel GW , Zaaijer Hans L
Published: April 2022

Background

In chronic hepatitis C patients with an initial virological response (IVR) during antiviral therapy (that is, HCV RNA becomes negative before week 16 of treatment) the significance of reappearing viraemia below the detection limit of PCR is not known. We studied this phenomenon in subsets of patients.

Methods

We assessed HCV RNA at weeks 16 and 20 of therapy by PCR and by more sensitive transcription-mediated amplification (TMA) in 23 patients with breakthrough or relapse and in 34 patients with sustained virological response (SVR). All patients participated in a high-dose-interferon induction study for difficult-to-treat patients. Therapy consisted of amantadine hydrochloride and ribavirin, combined with interferon-α2b induction during the first 6 weeks and thereafter combined with weekly pegylated interferon-α2b.

Results

Among the 57 IVR patients, we detected transient or persistent reappearance of low levels of HCV RNA in 10 of the 23 (43%) patients with eventual breakthrough or relapse; but in none of the 34 SVR patients. In 5 of 10 patients reappearing HCV RNA was only detectable by TMA.

Conclusion

Reappearance of low levels of HCV RNA in patients with IVR predicts treatment failure.
Quantitative Analysis of Hepatitis D Virus RNA and Hepatitis B Surface Antigen Serum Levels in Chronic Delta Hepatitis Improves Treatment Monitoring
Authors: Manesis Emanuel K , Schina Maria , Le Gal Frédéric , Agelopoulou Olga , Papaioannou Christos , Kalligeros Constantine , Arseniou Vaios , Manolakopoulos Spilios , Hadziyannis Emilia S , Gault Elyanne , Koskinas John , Papatheodoridis George , Archimandritis Athanasios J
Published: April 2022

Background/aims

Treatment of chronic delta hepatitis is long and difficult and better monitoring is needed.

Methods

In this study, hepatitis delta virus (HDV) RNA, hepatitis B surface antigen (HBsAg) and hepatitis B virus (HBV) DNA were retrospectively quantified in 53 patients with hepatitis B e antigen (HBeAg)-negative chronic hepatitis delta. Twenty-one had received 28 courses of 3–5 MU interferon-α2b (IFN-α2b) thrice weekly for a median of 12.6 months (interquartile range [IQR]: 7.3–31.6), five had received eight courses of 100 mg lamivudine (LAM) daily for 23.6 months (IQR: 8.4–61.5) and 27 were untreated. The controls were 54 untreated, randomly selected, HBeAg-negative chronic hepatitis B patients without delta infection. Quantification of serum HDV RNA, HBsAg and HBV DNA were performed at baseline, during and at the end of treatment and end of follow up.

Results

Untreated patients had significantly higher median HBsAg levels than controls (5,872 vs 3,501 IU/ml; P=0.046), but lower median HBV DNA levels (2.933 vs 6.459 log10 copies/ml; P<0.001). Median baseline HDV RNA (6.374 log10 copies/ml) was similar in IFN-α2b-treated, LAM-treated and untreated patients. At the end of treatment, IFN-α2b significantly suppressed in paired measurements HDV RNA ( P=0.012) and HBsAg ( P=0.043), but LAM was inefficient. In IFN-α2b-treated patients, HDV RNA became undetectable in five patients within a median of 30 months (IQR: 8–90), followed by a slower decrease in HBsAg.

Conclusions

In untreated chronic delta hepatitis, suppressed HBV replication is associated with significantly increased HBsAg serum levels. IFN-α2b significantly suppresses both HDV RNA and HBsAg, but LAM has no effect. Long-term IFN-α2b treatment (IQR: 1.5–5.0 years) appears necessary for undetectable serum HDV RNA and further treatment is required for HBsAg loss. Monitoring of HDV RNA and HBsAg serum levels in patients with chronic delta hepatitis provides insight during treatment.
Synergistic Inhibition of Protease-Inhibitor-Resistant HIV type 1 by Saquinavir in Combination with Atazanavir or Lopinavir
Authors: Dam Elisabeth , Lebel-Binay Sophie , Rochas Séverine , Thibaut Laurent , Faudon Jean-Louis , Thomas Claire-Marie , Essioux Laurent , Hill Andrew , Schutz Malte , Clavel François
Published: April 2022

Background

Double-boosted protease inhibitors (PIs) are under investigation for the treatment of patients who are unable to take nucleoside reverse transcriptase inhibitors because of cross-resistance and/or intolerance. Evidence of synergistic inhibition of wild-type HIV has been reported for saquinavir with atazanavir or lopinavir.

Methods

We investigated the activity of these two combinations against a panel of six site-directed mutant HIV-1 strains and 14 clinically derived recombinant HIV-1 strains presenting a range of PI-resistance profiles.

Results

No evidence of synergy was observed against wild-type virus for either combination. The combination of saquinavir and lopinavir showed evidence of synergy against four viruses displaying high-level resistance to lopinavir and low-level resistance to saquinavir. Similarly, evidence of synergy between saquinavir and atazanavir was only observed in two viruses which were more susceptible to saquinavir than to atazanavir.

Conclusions

We hypothesize that differences between the PIs in intracellular protein-binding behaviour or inhibition of drug transporters (P glycoprotein, MDR1 and MDR2) could result in intracellular levels of saquinavir being increased by co-administration with lopinavir or atazanavir. The effect of this increase would be masked in cases involving viruses that were susceptible to atazanavir or lopinavir. In virus resistant to lopinavir or atazanavir but susceptible to saquinavir, the majority of the antiviral effect is due to saquinavir; thus even small increases in intracellular concentration could significantly increase virus inhibition. These results confirm that in vitro synergy can be observed between PIs and suggest that the degree of synergy observed might depend on the resistance profile of the virus.
Evolution of T-cell Responses to Hepatitis C Virus (HCV) during Pegylated Interferon plus Ribavirin treatment in HCV-Monoinfected and in HCV/HIV-Coinfected Patients
Authors: Capa Laura , Soriano Vincent , García-Samaniego Javier , Nuñez Marina , Romero Miriam , De Mendoza Carmen , Cascajero Almudena , Muñoz Fernando , González-Lahoz Juan , Benito José M
Published: April 2022

Background

The role of T-cell immunity in chronic hepatitis C virus (HCV) infection remains controversial. As in HIV infection, virus replication could drive or be contained by T-cell immunity. We have examined the effect of HIV coinfection and of suppression of HCV replication with therapy on HCV-specific T-cell responses.

Patients and Methods

Thirty-five patients with chronic hepatitis C (17 coinfected with HIV) initiating anti-HCV therapy were analysed. HCV-specific responses were assessed at different time points using intracellular interferon-γ staining in response to a panel of overlapping peptides comprising E2, NS3, NS5a and NS5b HCV proteins.

Results

At baseline, HCV-specific responses were significantly lower in HIV-coinfected patients. At week 12 of therapy, CD8+ T-cell responses against all HCV proteins significantly decreased in HCV-monoinfected patients and this was maintained throughout the follow-up period. Although the same trend occurred in the HIV-coinfected group, differences were not significant. CD4+ T-cell responses against NS3 significantly diminished in the HCV-monoinfected group, whereas in coinfected patients CD4+ T-cell responses were low at baseline and did not experience any significant variation.

Conclusions

HCV-specific T-cell responses are lower in HIV-coinfected patients and vanish following complete suppression of HCV replication under successful HCV therapy, suggesting that they are dependent on continuous antigenic stimulation.
Immunizations with Chimeric Hepatitis B Virus-Like Particles to Induce Potential Anti-Hepatitis C Virus Neutralizing Antibodies
Authors: Vietheer Patricia TK , Boo Irene , Drummer Heidi E , Netter Hans-Jürgen
Published: April 2022

Background

Virus-like particles (VLPs) are highly immunogenic and proven to induce protective immunity. The small surface antigen (HBsAg-S) of hepatitis B virus (HBV) self-assembles into VLPs and its use as a vaccine results in protective antiviral immunity against HBV infections. Chimeric HBsAg-S proteins carrying foreign epitopes allow particle formation and have the ability to induce anti-foreign humoral and cellular immune responses.

Methods/results

The insertion of the hypervariable region 1 (HVR1) sequence derived from the envelope protein 2 (E2) of hepatitis C virus (HCV) into the major antigenic site of HBsAg-S (‘a’-determinant) resulted in the formation of highly immunogenic VLPs that retained the antigenicity of the inserted HVR1 sequence. BALB/c mice were immunized with chimeric VLPs, which resulted in antisera with anti-HCV activity. The antisera were able to immunoprecipitate native HCV envelope complexes (E1E2) containing homologous or heterologous HVR1 sequences. HCV E1E2 pseudotyped HIV-1 particles (HCVpp) were used to measure entry into HuH-7 target cells in the presence or absence of antisera that were raised against chimeric VLPs. Anti-HVR1 VLP sera interfered with entry of entry-competent HCVpps containing either homologous or heterologous HVR1 sequences. Also, immunizations with chimeric VLPs induced anti-surface antigen (HBsAg) antibodies, indicating that HBV-specific antigenicity and immunogenicity of the ‘a’-determinant region is retained.

Conclusions

A multivalent vaccine against different pathogens based on the HBsAg delivery platform should be possible. We hypothesize that custom design of VLPs with an appropriate set of HCV-neutralizing epitopes will induce antibodies that would serve to decrease the viral load at the initial infecting inoculum.
Recent Advances in the Search for Antiviral Agents against Human Papillomaviruses
Authors: Fradet-Turcotte Amélie , Archambault Jacques
Published: April 2022

Infection by human papillomavirus (HPV) is extremely common and associated with the development of benign warts or malignant lesions of the skin and mucosa. Infection by a high-risk (oncogenic) anogenital HPV type, most often through sexual contacts, is the starting point of virtually all cases of cervical cancers and the majority of anal cancers. The same viral types are also increasingly being linked with a subset of head-and-neck and non-melanoma skin cancers. Although prophylactic vaccines are now available to protect against the four types most commonly found in cervical and anal cancers (HPV16 and HPV18) and anogenital warts (HPV6 and HPV11), these neither protect against all genital HPVs nor are of therapeutic utility for already infected patients. Thus, the need for antiviral agents to treat HPV-associated diseases remains great, but none currently exist. This article reviews the recent progress made towards the development of antiviral agents to treat HPV infections, from target identification and validation to the discovery of lead compounds with therapeutic potential. Emphasis has been placed on novel low-molecular-weight compounds that antagonize HPV proteins or, alternatively, inhibit cellular proteins which have been usurped by papillomaviruses and are mediating their pathogenic effects.