bluuebunny/crossref_metadata_2025 huggingface dataset:
A Phase I/II Study Evaluating Escalating Doses of Recombinant Human Albumin-Interferon-α Fusion Protein in Chronic Hepatitis C Patients who have Failed Previous Interferon-α-Based Therapy
Authors: Balan Vijayan , Nelson David R , Sulkowski Mark S , Everson Gregory T , Lambiase Louis R , Wiesner Rusell H , Dickson Rolland C , Post Anthony B , Redfield Robert R , Davis Gary L , Neumann Avidan U , Osborn Blaire L , Freimuth William W , Subramanian G Mani
Published: April 2022

Albumin-interferon-α (IFN-α) is a novel 85.7–kDa recombinant protein consisting of IFN-α that is genetically fused to human serum albumin. In this Phase I/II, multicentre, open-label study, we evaluated the safety and tolerability, pharmacokinetics and pharmacodynamics of albumin-IFN-α in IFN-α-experienced patients with chronic hepatitis C. Albumin-IFN-α was administered in 22 escalating doses (7–900 μg) in a single injection or in two injections 14 days apart. In the 119 patients studied, there were no discontinuations because of adverse events, and albumin-IFN-α had a favourable safety profile at doses up to 900 μg. The most common adverse events were headache (56%), fatigue (52%), injection site erythema (38%), arthralgias (32%) and pyrexia (27%). Reduced clearance resulted in a mean elimination half-life of 159h, which supports dosing at 2- to 4-week intervals. Induction of the IFN-specific gene OAS1 was maintained for ≥28 days following a single injection of albumin-IFN-α at doses of ≥40 μg. Dose-dependent antiviral activity was observed in this IFN-α-experienced study population. Antiviral activity of ≥1.0–log reductions in HCV RNA was observed in 47% (37/78) of patients in the 120- to 900-μg cohorts and in 59% (16/27) in the 400- to 900-μg double-injection cohorts. These results support further clinical studies of albumin-IFN-α for the treatment of patients with chronic hepatitis C.
Comparison of Two Different Regimens of Combined Interferon-α2A and Lamivudine Therapy in Children with Chronic Hepatitis B Infection
Authors: Kansu Aydan , Doğanci Tümay , Akman Sezin A , Artan Reha , Kuyucu Necdet , Kalayci Ayhan Gazi , Dikici Bünyamin , Dalgiç Buket , Selimoğlu Ayşe , Kasirga Erhun , Özkan Tanju B , Kuloğlu Zarife , Aydoğdu Sema , Boşnak Mehmet , Ertekin Vildan , Tanir Gönül , Haspolat Kenan , Girgin Nurten , Yağci Raşit Vural
Published: April 2022

Aim

To evaluate the efficacy of two regimens of combined interferon-α2a (IFN-α2a) and lamivudine (3TC) therapy in childhood chronic hepatitis B.

Methods

A total of 177 patients received IFN-α2a, 9 million units (MU)/m2 for 6 months. In group I (112 patients, 8.7±3.5 years), 3TC (4 mg/kg/day, max 100 mg) was started simultaneously with IFN-α2a, in group II (65 patients, 9.6±3.8 years) 3TC was started 2 months prior to IFN-α2a. 3TC was continued for 6 months after antiHBe seroconversion or stopped at 24 months in non-responders.

Results

Baseline alanine aminotransferase (ALT) was 134.2 ±34.1 and 147.0 ±45.3; histological activity index (HAI) was 7.4 ±2.7 and 7.1 ±2.3; and HBV DNA levels were above 2,000 pg/ml in 76% and 66% of patients in groups I and II, respectively ( P>0.005). Complete response was 55.3% and 27.6% in groups I and II, respectively ( P<0.01). AntiHBe seroconversion was higher and earlier, and HBV DNA clearance was earlier in group I ( P<0.05). HBsAg clearance was 12.5% and 4.6% and antiHBs seroconversion was 9.8% and 6.2% in groups I and II, respectively ( P>0.05). Breakthrough occurred in 17.9% and 24.6%; breakthrough times were 15.9 ±4.6 and 14.1 ±5.1 months; and relapse rates were 6.8% and none in groups I and II, respectively ( P>0.05, P>0.05, P>0.05). Responders had higher HAI (HAI>6) and higher pre-treatment ALT than non-responders.

Conclusion

Simultaneous 3TC+IFN-α2a yields a higher response and earlier antiHBe seroconversion and viral clearance than consecutive combined therapy. Relapse rate is low. Predictors of response are high basal ALT and high HAI scores. 3TC can be administered for 24 months without any side effect and breakthrough rate is comparable with previous studies.
Drug-Specific T Cells in An HIV-Positive Patient with Nevirapine-Induced Hepatitis
Authors: Drummond Nicola S , Vilar F Javier , Naisbitt Dean J , Hanson Anita , Woods Anthony , Park B Kevin , Pirmohamed Munir
Published: April 2022

Background

Nevirapine is associated with idiosyncratic reactions such as skin rash, hepatitis and hypersensitivity syndrome, which have the hallmarks of being immune mediated. However, there is little laboratory evidence to support an immune pathogenesis.

Methods

A HIV-positive individual who developed hepatitis within 6 weeks of starting nevirapine, in the absence of any cutaneous manifestations, is described. Other causes of hepatitis were excluded, and the patients liver function normalized on withdrawal of nevirapine. Lymphocytes from the patient, and six individuals with HIV who were on nevirapine without adverse effects, were exposed to nevirapine and its metabolites, and lymphocyte proliferation assessed by 3H-thymidine incorporation on day 5.

Results

The T cells taken from the nevirapine-hypersensitive patient proliferated in the presence of nevirapine with a stimulation index of greater than 2. There was no proliferation with nevirapine metabolites. T cells taken from HIV-positive control individuals showed no proliferation with either nevirapine or its metabolites.

Conclusion

The results from our patient suggest that T cells may be involved in the pathogenesis of nevirapine-induced hepatitis. Larger numbers of patients need to be studied to fully evaluate the role of T cells in nevirapine-induced hepatitis and nevirapine hypersensitivity syndrome.
Patients’ Preferences regarding the Timing of Highly Active Antiretroviral Therapy Initiation for Chronic Asymptomatic HIV-1 Infection
Authors: Locadia Mirjam , van Grieken Rosa A , Prins Jan M , de Vries Henry JC , Sprangers Mirjam AG , Nieuwkerk Pythia T
Published: April 2022

Objective

In patients with a chronic asymptomatic HIV-1 infection and >200 CD4+ T-cells/μl, the optimal timing of highly active antiretroviral therapy (HAART) initiation is unclear. It involves a trade-off between a potentially reduced risk of mortality, when started earlier in the course of infection, and an earlier exposure to pill burden and potential toxicities. We investigated patients’ preferences for immediate HAART initiation relative to delaying HAART for 1 year.

Methods

Consecutive patients were asked for their preference during an interview. A hypothetical difference in 3-year mortality risk between both options was systematically varied between 0% and 10% to determine the threshold at which preference would switch to HAART initiation.

Results

About 30% of patients preferred HAART initiation even if the mortality risk would be equal for both options. Almost 25% always preferred delaying HAART even if this would result in a 10% greater mortality risk. Most treatment guidelines recommend delaying HAART >350 CD4+ T-cells/μl However, at a risk difference between starting and delaying HAART that corresponds with this CD4+ T-cell count, about 50% would prefer to start HAART immediately. Most guidelines recommend starting HAART below 200 CD4+ T-cells/μl However, at a risk difference between both options corresponding with this CD4+ T-cell count, about 40% preferred delaying HAART.

Conclusions

We found large variation in patients’ preferences. Some patients were more inclined to initiate HAART earlier than the recommended guidelines, whereas others were more inclined to delay HAART. These findings emphasize the need for shared decision-making when deciding on the most optimal timing of HAART initiation in chronic asymptomatic HIV-1 infection.
Rapid Identification of Small Interfering Rna that Can Effectively Inhibit the Replication of Multiple Influenza B Virus Strains
Authors: Gao Yongzhen , Sun Lilian , Dong Jie , Xu Xingye , Shu Yuelong , Chen Meihong , Yin Li , Liang Zicai , Jin Qi
Published: April 2022

Influenza B virus is a cause of substantial morbidity and mortality in humans and current vaccination strategies and antiviral drugs only provide limited protection. Here, we report the evaluation of small interfering RNA (siRNA) for repression of viral replication in cultured cells as well as in chicken embryos. Several siRNAs targeting conserved regions of the virus (in chemically synthesized or plasmid-encoded forms) were found to effectively block the replication of the influenza B virus. The siRNAs were found to offer broad protection over several strains of influenza B virus (B/Beijing/76/98, B/Beijing/37/99 and B/Jiangsu/10/03) that differ substantially in their genetic content. The antiviral effects of 500 ng siRNA-encoding plasmids or 60 nmoles synthetic siRNA were found to be comparable to that of 3.6 μg ribavirin. These results indicated that RNA interference warrants further study for management of influenza B virus infections.
A Novel Mutation in the Ul54 Gene of Human Cytomegalovirus Isolates that Confers Resistance to Foscarnet
Authors: Ducancelle Alexandra , Champier Gaël , Alain Sophie , Petit Françoise , Le Pors Marie-José Sanson , Mazeron Marie-Christine
Published: April 2022

Foscarnet is currently licensed for the treatment of human cytomegalovirus (HCMV) infection. Mutations proven to confer resistance to foscarnet have mostly been mapped to regions II, III and VI of the HCMV UL54-encoded DNA polymerase. We previously showed that sequential foscarnet-resistant HCMV isolates recovered from a patient with lymphoma had change N495K in region delta-C of the DNA polymerase. To evaluate the impact of change N495K on HCMV sensitivity to foscarnet, a recombinant HCMV strain carrying the mutation was produced by homologous recombination. The recombinant virus showed a 3.4-fold increase in foscarnet resistance, and remained sensitive to ganciclovir and cidofovir. In addition, the recombinant strain showed a reduction of infectious virus yield compared with its parent strain. Change N495K should be added to the list of mutations conferring resistance to foscarnet and be taken into account in the genotypic diagnosis of antiviral resistance.
Lopinavir/Ritonavir or Efavirenz plus two Nucleoside Analogues as First-Line Antiretroviral Therapy: A Non-Randomized Comparison
Authors:   on behalf of the I.Co.N.A, UCSC, IMIT-MI and INMI cohorts, Luca Andrea De , Cozzi-Lepri Alessandro , Antinori Andrea , Zaccarelli Mauro , Bongiovanni Marco , Giambenedetto Simona Di , Marconi Patrizia , Cicconi Paola , Resta Francesco , Grisorio Benvenuto , Ciardi Maria , Cauda Roberto , Monforte Antonella d'Arminio
Published: April 2022

Background

Although efavirenz (EFV) and lopinavir/ritonavir (LPV/r) are both recommended antiretroviral agents for combination therapy in drug-naive HIV-infected patients, no randomized comparison of their efficacy and tolerability is available yet. A multi-cohort prospective observational comparative study was performed.

Methods

Efficacy was examined comparing time to virological failure, CD4 recovery and clinical progression. Tolerability was examined comparing time to treatment discontinuation for any reason and for toxicity and time to liver enzymes or lipid alterations. Survival analysis was conducted by an intent-to-treat principle using the Kaplan–Meier method, and standard and weighted Cox regression models.

Results

A total of 674 antiretroviral-naive patients starting a two nucleoside reverse transcriptase inhibitor regimen plus either EFV ( n=481) or LPV/r ( n=193) were examined. At baseline, patients starting LPV/r had higher HIV RNA and lower CD4+ T-cell counts. There was no difference in the adjusted hazards of virological failure (LPV/r versus EFV relative hazard [RH] 1.16, 95% confidence intervals [CI]: 0.58–2.32, P=0.67), CD4 recovery (RH=0.93, 95% CI: 0.66–1.30, P=0.66), clinical progression (RH=1.64, 95% CI: 0.70–3.84, P=0.25), drug discontinuation for toxicity (RH=0.92, 95% CI: 0.51–1.64, P=0.76) and for any reason, and rates of liver enzyme and total/low density lipoprotein (LDL) cholesterol elevation. In contrast, the rate of triglycerides elevations (>1 NCEP Adult Treatment Panel III category increase) was higher in the LPV/r group (RH=1.69, 95% CI: 1.14–2.50; P=0.01). Models weighted for the inverse of conditional probability of receiving either drug applied to the efficacy endpoints yielded similar results. CD4 recovery with both drugs was also similar in the lowest CD4 strata.

Conclusions

Our analysis suggests similar efficacy and tolerability for EFV- or LPV/r-based first-line antiretroviral regimens. LPV/r was associated with higher rates of hypertriglyceridaemia.
Absence of Resistance Mutations in Antiretroviral-Naive Patients Treated with Ritonavir-Boosted Saquinavir
Authors: Ananworanich Jintanat , Hirschel Bernard , Sirivichayakul Sunee , Ubolyam Sasiwimol , Jupimai Thidarat , Prasithsirikul Wisit , Chetchotisakd Ploenchan , Kiertiburanakul Sasisopin , Munsakul Warangkana , Raksakulkarn Phitsanu , Tansuphasawadikul Somboon , Schutz Malte , Snowden Wendy , Ruxrungtham Kiat
Published: April 2022

Background

There are few data on the selection of resistance by ritonavir-boosted saquinavir (SQV/r), particularly in antiretroviral (ARV)-naive patients.

Objective

To assess the incidence of virological failure and evolution of resistance in ARV-naive individuals receiving SQV/r in the induction phase of the Staccato trial.

Methods

ARV-naive subjects ( n=272) received SQV/r 1,600/100 mg once daily with two nucleoside reverse transcriptase inhibitors (NRTIs) for at least 24 weeks. Patients were defined as having virological failure (VF) when there were two consecutive HIV-1 RNA measurements >500 copies/ml after week 12. Viral genotypes (reverse transcriptase [RT] and protease [PRO]) were determined at baseline in all patients and as close as possible to the time of initial failure in patients experiencing VF.

Results

VF was observed in 9/272 patients receiving SQV/r 1,600/100 mg once daily with two NRTIs (3.3%) and occurred 19–48 weeks after treatment initiation. Eight of these patients were evaluable at failure. No major PRO mutations were detected, but 2/8 displayed single new minor PRO substitutions (M36I, L10I) at VF that were known or suspected not to have been present at baseline; both these substitutions exist as natural polymorphisms. A third patient displayed a single new RT mutation (M184I).

Conclusions

SQV/r plus two NRTIs (1,600/100 mg once daily) is an effective initial treatment option for ARV-naive patients, resulting in a low rate of viral rebound (3.3%). Furthermore, no major protease mutations were detected following VF, suggesting that future treatment options are preserved.
Design Issues in Initial HIV-Treatment Trials: Focus on Actg A5095
Authors: Ribaudo Heather J , Kuritzkes Daniel R , Schackman Bruce R , Acosta Edward P , Shikuma Cecilia M , Gulick Roy M
Published: April 2022

ACTG (AIDS Clinical Trials Group) A5095 was a double-blinded Phase III clinical trial designed to compare three simple strategies for the initial treatment of HIV-1 infection: a non-nucleoside reverse transcriptase inhibitor (NNRTI) combined with two nucleosides, a triple-nucleoside regimen, and an NNRTI combined with three nucleosides. The study was designed to provide a rigorous evaluation of the relative effectiveness of the three different treatment strategies in achieving and maintaining durable HIV-1 RNA suppression using both superiority and non-inferiority designs. At the same time, we sought to provide study participants with flexible treatment management options that closely reflected clinical care approaches available outside the setting of a clinical trial in this rapidly changing field of medicine. Fulfilling both of these goals required making decisions about the primary endpoint definition, blinding, treatment changes, and stopping guidelines for the primary efficacy hypotheses. In this paper we describe the study design decisions that were made, in the context of randomized HIV treatment trials in general. We hope that the discussion will inform the design of treatment strategy trials, both for HIV and for other diseases where clinical standards change rapidly. We also hope to inform the field regarding issues in choosing composite versus virological endpoints as well as other key considerations in trial design and monitoring.
Significance of Viral Load, Core Promoter/Precore Mutations and Specific Sequences of Polymerase Gene in Hbv-Infected Patients on 3-Year Lamivudine Treatment
Authors: Yuen Man-Fung , Sablon Erwin , Libbrecht Evelien , Velde Hilde Van De , Wong Danny Ka-Ho , Fung James , Wong Benjamin Chun-Yu , Lai Ching-Lung
Published: April 2022

Background

Comprehensive study on viral factors predicting treatment responsiveness to lamivudine is lacking.

Aims

To define the significance of various viral factors and changes of viral population with lamivudine treatment.

Patients and methods

Hepatitis B virus (HBV) DNA levels at baseline, week 24, 52 and year 3 were measured in 80 patients on continuous lamivudine therapy for 3 years. Genotypes, core promoter/precore mutations, YMDD mutations, polymorphic sequence of polymerase gene (rt91I/L, rt256S/C) were determined at baseline, week 12, 24 and 52. YMDD mutations were also determined at year 3.

Results

High alanine aminotransferase levels and presence of core promoter/ precore mutations at baseline were associated with higher chance of achieving HBV DNA <1,000 copies/ml (good response) and higher rate of hepatitis Be antigen (HBeAg) seroconversion at week 52. Achieving HBV DNA levels <1,000 copies/ml at week 24 as well as baseline core promoter/precore mutations were associated with higher chance of achieving good response, higher rate of HBeAg seroconversion and lower rate of YMDD mutations at year 3. Lamivudine reversed core promoter mutations to wild type in 25% of patients. All 5 patients with rt256C had poor HBV DNA response, persistent HBeAg and YMDD mutations by year 3. There was no difference in treatment response between patients with genotype B and C.

Conclusions

Achieving HBV DNA levels <1,000 copies/ml at 24 week is the best target for short- and long-term treatment efficacy. Core promoter and precore mutations were associated with better treatment outcome, and rt256C polymorphism in the polymerase gene with poor response.
Specific HIV Protease Inhibitors Inhibit the Ability of Hpv16 E6 to Degrade P53 and Selectively Kill E6-Dependent Cervical Carcinoma Cells In Vitro
Authors: Hampson Lynne , Kitchener Henry C , Hampson Ian N
Published: April 2022

Although HIV protease inhibitor (PI) drugs predominantly target HIV proteases 1 and 2, it is also known that part of their efficacy is due to selective inhibition of the proteasome. The pathogenicity of high-risk human papilloma virus (HPV) is dependent on expression of viral E6 proteins which inappropriately activate the 26S proteasome to degrade p53 and other cellular proteins that are detrimental to viral replication. Comparison of the ability of the PIs indinavir, ritonavir, amprenavir, lopinavir, atazanavir, nelfinavir and saquinavir to inhibit E6-mediated proteasomal degradation of mutant p53 in E6-transfected C33A cells showed that 15μM lopinavir, 1 mM indinavir or 125 μM ritonavir treatment for 24 h produced a stable increase in the level of nuclear p53 in these cells with minimal cell death. After 4 h exposure of HPV16+ve SiHa cells to 15 μM lopinavir, a transient increase in wild-type p53 expression was observed associated with a 7% reduction in the chymotryptic activity of the 20S proteasome and apoptosis after 24 h. Comparison of growth rates of PI treated SiHa, CaSki, C33A, C33A-E6 and non-transformed NIH/3T3 cells showed that SiHa were the most sensitive, whereas NIH/3T3 were least affected. In conclusion, these data show that specific HIV PIs such as lopinavir and possibly indinavir, can induce selective toxicity of HPV-transformed cervical carcinoma cells expressing wild-type p53 and may form the basis of a topically applied alternative to surgery for the treatment of HPV-related premalignant lesions of the cervix.
Impact of HIV-1 Reverse Transcriptase Polymorphism at Codons 211 and 228 on Virological Response to Didanosine
Authors: Marcelin Anne-Genevieve , Flandre Philippe , Furco Andre , Wirden Marc , Molina Jean-Michel , Calvez Vincent
Published: April 2022

Objective

To determine the potential impact of reverse transcriptase (RT) mutations, other than those currently known to confer nucleoside reverse transcriptase inhibitors (NRTIs) resistance, on the virological response to didanosine (ddI).

Design and patients

In the placebo-controlled Jaguar trial, 168 patients were randomly assigned to receive ddI ( n=111) or placebo ( n=57) in addition to their currently failing regimen for 4 weeks.

Methods

The virological response was a reduction of HIV-1 RNA from baseline to week 4. In an univariate analysis, we investigated the impact on the virological response to ddI of all the mutations in the RT gene (codons 21–236), except those known to confer NRTI resistance. Using the removing procedure, with a test for trend (Jonckheere's test), a new potential score was calculated incorporating all potential mutations associated to the week 4 virological response.

Results

Two RT polymorphisms were associated with a reduced virological response to ddI, R211A/D/G/K/S and L228H/M/R, and one with a better virological response: F214L. A mutation score (M41L+D67N+T69D-K70R +L74V-M184V/I+T215Y/F+K219Q/E+R211A/D/G/K/S+ L228H/M/R), including two RT polymorphisms not previously described to be associated with ddI resistance (211 and 228) and RT mutations previously described, was associated with a continuum of virological response and increased the predictability of virological response to ddI.

Conclusion

RT polymorphisms should be taken into account to define algorithms able to correctly define resistance to NRTIs and more specifically ddI.
Rare Selection of the K65R Mutation in Antiretroviral-Naive Patients Failing a First-Line Abacavir/Lamivudine-Containing Haart Regimen
Authors: Descamps Diane , Ait-Khaled Mounir , Craig Charles , Delarue Séverine , Damond Florence , Collin Gilles , Brun-Vézinet Françoise
Published: April 2022

Objective

Previous studies have described the presence of the L74V reverse transcriptase (RT) mutation in highly experienced individuals as a risk factor for reduced response to tenofovir and selection of the K65R mutation. This study examined whether, in the context of a first-line abacavir/lamivudine highly active anti-retroviral therapy (HAART) regimen, K65R might occur as a minority population where L74V was detected at virological failure.

Methods

Four previously ART-naive individuals undergoing virological failure were selected, all receiving abacavir and lamivudine with either protease inhibitors or efavirenz and with virus displaying L74V and M184V or M184V alone following transient L74V emergence. Clonal analyses from plasma viral RNA were performed on samples taken at baseline and after virological failure. Clones were screened for the presence of K65R by real time K65R-selective PCR (K65R-sPCR). RT genes from clones displaying K65R were sequenced.

Results

At baseline, all clones were wild type at codon 65 by K65R-sPCR, except in one patient in which one of 720 clones exhibited K65R. At failure with M184V and L74V present by bulk sequencing, this K65R was retained in one of 855 clones assessed. One additional patient (M184V alone by bulk sequencing) displayed K65R in one of 466 failure clones. Virological failure samples from the remaining two patients were wild type at codon 65 in all of 524 and 270 clones, respectively.

Conclusions

Minority species harbouring K65R are uncommon and occur at very low population densities in patients experiencing virological failure on first-line abacavir/lamivudine-containing HAART.
HIV-1 Subtypes and Response to Combination Antiretroviral Therapy in Europe
Authors:   for the EuroSIDA study group, Bannister Wendy P , Ruiz Lidia , Loveday Clive , Vella Stefano , Zilmer Kai , Kjær Jesper , Knysz Brygida , Phillips Andrew N , Mocroft Amanda , Lundgren Jens D
Published: April 2022

Background

Combination antiretroviral therapy (cART) may vary in ability to suppress viral load and increase CD4+ T-cell count in people infected with different HIV-1 subtypes, possibly due to differences in resistance development. Antiretroviral drugs have predominantly been developed in Western Europe/North America on the basis of the most prevalent subtype, B. However, non-B subtypes are increasingly spreading worldwide.

Objective

To compare virological and immunological response to cART between patients infected with B and non-B subtypes across Europe.

Design

EuroSIDA prospective, observational cohort with 11,928 HIV-1-infected patients.

Methods

Response to cART was analysed in patients with subtypes determined pre-cART, via multivariable logistic regression on the first measurements 6–12 months after starting cART. A virological response was defined as a viral load <500 copies/ml and immunological response as a CD4+ T-cell count increase of ≥100 cells/mm3.

Results

Forty-five percent of patients were antiretroviral naive at initiation of cART. Virological suppression was achieved by 58% of 689 subtype-B-infected patients and 66% of 102 non-B-infected patients ( P=0.159). After adjustment for potential confounders, there was no significant difference in odds of achieving virological suppression (non-B compared with B; odds ratio [OR]: 1.05, 95% confidence interval [CI]: 0.58–1.93, P=0.866). An immunological response was achieved by 43% of 753 B-infected patients and 48% of 114 non-B-infected patients ( P=0.334). After adjustment, there was no significant difference in odds of an immunological response (OR: 1.17, 95% CI: 0.73–1.87, P=0.524).

Conclusions

There was no evidence of significant differences in virological or immunological response to cART between patients infected with HIV-1 B and non-B subtypes.
Sustained Virological Response following HCV Therapy is Associated with Non-Progression of Liver Fibrosis in HCV/HIV-Coinfected Patients
Authors: Barreiro Pablo , Labarga Pablo , Martín-Carbonero Luz , Amor Aranzazu , Ruiz-Sancho Andrés , Castellares Carol , González-Lahoz Juan , Soriano Vincent
Published: April 2022

Background

Chronic hepatitis C leads to progressive liver fibrosis, which is accelerated in HIV-coinfected patients. Unfortunately, hepatitis C virus (HCV) therapy provides sustained virological response (SVR) to only 40% of coinfected patients. Little is known about the regression of hepatic fibrosis in treated patients.

Methods

All coinfected patients who had completed a full course of HCV therapy at our institution were identified. Liver fibrosis staging was estimated using non-invasive procedures at the time of initiating HCV therapy and reassessed at the last patient's follow-up using elastometry (FibroScan®).

Results

A total of 103 coinfected patients were identified. HCV genotype distribution was 1 (63%), 3 (29%) and 4 (8%). SVR had been attained by 34 individuals, while the remaining 69 were non-responders and/or relapsers. The mean lag time between the end of HCV therapy and the current assessment of liver fibrosis was 40 months, without differences between groups. Metavir score estimates were comparable before initiating HCV therapy in SVR and non-SVR patients. By contrast, current Metavir scores were lower in SVR than in non-SVR patients; for instance, F3-F4 estimates were 12% versus 54%, respectively ( P<0.001). Moreover, the longer the time elapsed after HCV therapy, the lower the liver fibrosis in SVR patients (ρ=-0.39; P=0.02). Conversely, liver fibrosis staging directly correlated with the lag following HCV therapy in non-SVR patients (ρ=0.25; P=0.03).

Conclusions

SVR after HCV therapy is associated with non-progression of liver fibrosis in HCV/HIV-coinfected patients, although this benefit may not be universal and improvement only been recognizable after several years of follow-up.
A Randomized Controlled Trial of Genotypic HIV Drug Resistance Testing in HIV-1-Infected Children: The Pera (Penta 8) Trial
Authors:   on behalf of the Paediatric European Network for the Treatment of AIDS (PENTA), Green Hannah , Gibb Diana M , Compagnucci Alexandra , Giacomet Vania , de Rossi Anita , Harper Lynda , Saïdi Yacine , Castelli-Gattinara Guido , Pillay Deenan , Babiker Abdel G , Aboulker Jean-Pierre , Lyall Hermione , Bacheler Lee T , Walker A Sarah , Debré Marianne , Rosso Raffaella , Burger David M , Negra Marinella Della , Dunn David T , Giaquinto Carlo
Published: April 2022

Objective

To evaluate the longer-term utility of genotypic resistance testing in HIV-1-infected children with virological failure.

Methods

Children aged 3 months-18 years switching antiretroviral therapy (ART) with HIV-1 RNA >2,000 copies/ml were randomized between genotypic testing (Virtual PhenotypeTM) and no testing at baseline and subsequent virological failures. Children were followed to at least 96 weeks.

Results

One hundred and seventy eligible children, from 24 clinical centres in six countries, were randomized to resistance testing ( n=87) or no testing ( n=83) between June 2000-July 2003. At baseline, mean HIV-1 RNA and CD4+ T-cell percentage were 4.7 log10 copies/ml and 20%, respectively. Children had taken ART for a mean of 5 years; 24% had received all three classes, 53% nucleoside reverse transcriptase inhibitors (NRTIs)+protease inhibitors (PIs), 9% NRTIs+non-nucleoside reverse transcriptase inhibitors (NNRTIs) and 14% NRTIs only. There was no difference between the arms in the drug classes or the individual PIs/NNRTIs prescribed. However, 49% in the resistance test arm (RT) versus 19% in the no-test arm (NT) continued at least one NRTI from their failing regimen; 56% versus 19% were prescribed didanosine+stavudine as their NRTI backbone. Adjusting for baseline HIV-1 RNA, mean reductions in HIV-1 RNA at 48 weeks were 1.51 log10 copies/ml in the RT arm and 1.23 in the NT arm ( P=0.3); the difference between the arms was smaller at week 96 (RT: 1.50, NT: 1.47; P=0.9).

Conclusion

In this first paediatric trial of resistance testing, we observed a substantial difference in NRTI-prescribing behaviour across arms. However statistically significant evidence of a long-term virological or immunological benefit was not observed. This trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN14367816.
Safety and Efficacy of Extended-Release Niacin for the Treatment of Dyslipidaemia in Patients with HIV Infection: Aids Clinical Trials Group Study A5148
Authors:   for the AIDS Clinical Trials Group A5148 Study Team, Meixner Linda , Hoffman Julie , Zwickl Beth , Goldman Mitch , Whitely Kim , Conrad Ann , Fichtenbaum Carl J , Hyc Fran , Spitz Teresa , Shaw Debra Demarco , Norris Jane , Stoudt Sylvia , Castro Jose , Colon Lillian , Cavert Winston P. , Fox Kathy A. , Dubé Michael P , Wu Julia W , Aberg Judith A , Deeg Mark A , Alston-Smith Beverly L , McGovern Mark E , Lee Daniel , Shriver Sharon L , Martinez Ana I , Greenwald Martha , Stein James H
Published: April 2022

Background

Dyslipidaemia is very common in patients with HIV infection, but current therapies are often suboptimal. Since niacin may cause insulin resistance and hepatotoxicity, it has generally been avoided in this setting.

Methods

Non-diabetic male subjects ( n=33) who had well-controlled HIV infection on antiretroviral therapy, fasting triglycerides ≥2.26 mmol/l and non-high density lipoprotein cholesterol (non-HDL-C) ≥4.66 mmol/l received escalating doses of extended-release niacin (ERN) up to 2,000 mg nightly for up to 44 weeks.

Results

Fourteen subjects (42%) had pre-diabetes at entry. Twenty-three subjects (70%) received the maximum dose, eight (24%) received 1,500 mg. Niacin was well-tolerated. Only four subjects (12%) discontinued study treatment. There were small increases in fasting glycaemia and insulin resistance estimated by the homeostasis model assessment, but insulin resistance measures from the 2-h oral glucose tolerance test only transiently worsened. No subject developed persistent fasting hyperglycaemia; one had persistently elevated 2-h glucose >11.1 mmol/l. There were no significant changes in serum transaminases or uric acid. At week 48, the median change in fasting lipid levels in mmol/l (interquartile range) were: total cholesterol -0.21 (-1.35, -0.05), HDL-C +0.013 (-0.03,+0.28), non-HDL-C -0.49 (-1.37, +0.08) and triglycerides -1.73 (-3.68, -0.72). Favourable changes in large HDL and large very low density lipoprotein particle concentration were observed by nuclear magnetic resonance spectroscopy.

Conclusions

ERN in doses up to 2,000 mg daily was safe, well-tolerated and efficacious in HIV-infected subjects with atherogenic dyslipidaemia. Increases in glycaemia and insulin resistance tended to be transient.
Evolution of Resistance Mutations during Low-Level Viral Replication in HIV-1–Infected Patients Treated with Zidovudine/Lamivudine/Abacavir as a First-Line Regimen
Authors: Stürmer Martin , Dauer Brenda , Moesch Manfred , Haberl Annette , Mueller Axel , Locher Leo , Knecht Gaby , Hanke Nora , Doerr Hans W , Staszewski Schlomo
Published: April 2022

Objective

Long-term evaluation of viral evolution in patients who continued first-line therapy with zidovudine/lamivudine/abacavir (Trizivir [TZV]) in the presence of low-level viral replication and assessment of the impact of mutational patterns selected under TZV on viral load (VL), CD4+ T-cell count (CD4) and subsequent therapeutic options.

Design

Analysis of viral evolution based on genotypic resistance tests (GRT) from samples collected during non-suppressive first-line therapy with TZV.

Methods

Patients from the Frankfurt HIV cohort with at least 3 months uninterrupted first-line therapy with TZV in whom VL and CD4 measurements were performed at baseline and at follow up were identified. Criteria for virological failure (VF) were two consecutive VL >400 copies/ml. GRTs were required at baseline, VF and last visit (LV).

Results

Initially, 23/119 patients were classified as VF; 4/23 were lost to follow up. Median time to VF was 48 weeks. Because of the observed virological and immunological benefit, patients continued TZV for a median of 87 weeks despite detectable viraemia. Median CD4 increase and VL reduction at LV were 120 cells/mm3 and 317,100 copies/ml, respectively, compared to baseline. After 54 weeks of treatment with detectable VL, three mutational patterns were observed: Group A ( n=4) characterized by M184V without further regimen-associated mutations, group B ( n=9) by M184V accompanied by one to three thymidine analogue mutations (TAMs), and group C ( n=6) by M184V and four to six TAMs. No virological or CD4 parameters correlated with these patterns. Group A remained unchanged, thus preserving activity of most nucleoside analogues (NA). However, in the majority of patients (groups B and C) accumulation of mutations at different rates was observed, leading to a sequential loss of NA options.

Conclusions

Continuous treatment with TZV in the presence of viral replication is associated with a stepwise accumulation of resistance mutations. M184V was present in all cases, not followed by further selection of TAMs in a small, unpredictable subgroup of patients. However, in the majority of patients selection of M184V was associated with accumulation of TAMs at different rates leading to a substantial loss of active NAs, despite continuous virological and immunological benefit when compared with baseline.
Conservation of First-Line Antiretroviral Treatment Regimen where Therapeutic Options are Limited
Authors: Orrell Catherine , Harling Guy , Lawn Stephen D , Kaplan Richard , McNally Matthew , Bekker Linda-Gail , Wood Robin
Published: April 2022

Objectives

To determine rates and causes of switching from first- to second-line antiretroviral treatment (ART) regimens in a large treatment-naive cohort (a South African community-based ART service) where a targeted adherence intervention was used to manage initial virological breakthrough.

Methods

ART-naive adults ( n=929) commencing first-line non-nucleoside-based ART [according to WHO (2002) guidelines] between September 2002 and August 2005 were studied prospectively. Viral load (VL) and CD4+ T-cell counts were monitored every 4 months. All drug switches were recorded. Counsellor-driven adherence interventions were targeted to patients with a VL >1,000 copies/ml at any visit (virological breakthrough) and the VL measurement was repeated within 8 weeks. Two consecutive VL measurements >1,000 copies/ml was considered virological failure, triggering change to a second-line regimen.

Results

During 760 person-years of observation [median IQR) 189 (85–441) days], 823 (89%) patients were retained on ART, 2% transferred elsewhere, 7% died and 3% were lost to follow-up. A total of 893 (96%) patients remained on first-line therapy and 16 (1.7%) switched to second-line due to hypersensitivity reactions ( n=9) or lactic acidosis ( n=7). A Kaplan-Meier estimate for switching to second-line due to toxicity was 3.0% at 32 months. Virological breakthrough occurred in 67 (7.2%) patients, but, following use of a targeted adherence intervention, virological failure was confirmed in just 20 (2.2%). Kaplan-Meier estimates at 32 months were 20% for virological breakthrough but only 5.6% for confirmed virological failure.

Conclusion

Regimen switches were due to virological failure or toxicity. Although follow-up time was limited, over 95% of individuals remained on first-line ART using a combination of viral monitoring and a targeted adherence intervention.
Adefovir Dipivoxil Monotherapy and Combination Therapy with Lamivudine for the Treatment of Chronic Hepatitis B in an Asian Population
Authors: Fung James , Lai Ching-Lung , Yuen John Chi-Hang , Wong Danny Ka-Ho , Tanaka Yasuhito , Mizokami Masashi , Yuen Man-Fung
Published: April 2022

Aim

To determine differences in Chinese patients treated with adefovir (ADV) monotherapy or ADV in combination with lamivudine (3TC) after development of resistance to 3TC, with respect to biochemical improvement, HBV DNA suppression and development of subsequent ADV resistance.

Methods

All hepatitis B patients with 3TC resistance treated with ADV for 3 months or more at our centre were included, and monitored 3–6 monthly for biochemical and virological response, and development of ADV resistance.

Results

A total of 56 patients were included, 50% switched to ADV monotherapy and 50% received combination 3TC/ADV therapy. Median follow-up was 15.5 months. Normalization of alanine aminotransferase (ALT) occurred in 25 (89%) patients in the ADV group compared with 24 (86%) in the 3TC/ADV group (P=0.686). Virological response (VR) was achieved in seven (35%) patients in the ADV group at 12 months compared with five (28%) in the 3TC/ADV group (P=0.637). By 24 months, seven (64%) patients in the ADV group achieved VR compared with two (40%) in the 3TC/ADV group (P=0.377). Cumulative probability of developing genotypic ADV resistance in the ADV group at 24 months was 18% compared with 7% in the 3TC/ADV group (P=0.94).

Conclusions

There was no obvious improvement in ALT normalization and virological suppression or reduction in the development of ADV-resistant mutations with 3TC/ADV therapy compared with ADV monotherapy. Further studies with longer follow-ups are required to determine whether combination 3TC/ADV therapy will reduce the emergence of ADV resistance compared with ADV monotherapy.
Reversibility of Cirrhosis in HIV/HBV Coinfection
Authors: Mallet Vincent O , Dhalluin-Venier Valérie , Verkarre Virginie , Correas Jean-Michel , Chaix Marie-Laure , Viard Jean-Paul , Pol Stanislas
Published: April 2022

HIV infection worsens the course and the natural history of chronic hepatitis B (HBV) leading to rapid progression to cirrhosis and to end-stage liver disease. Highly active antiretroviral therapy (HAART) regimens including nucleoside and/or nucleotide analogues with activity against both HIV reverse transcriptase and hepatitis B virus polymerase have clearly improved the survival rates of HIV/HBV-coinfected patients. How HAART beneficially affects the natural course of chronic hepatitis B in coinfected patients is not known. We report a biopsy-proven case of reversal of HBV-related cirrhosis in a coinfected patient, parallelling long-term suppression of HBV replication with tenofovir disoproxil fumarate as part of a HAART. Pathological reversibility of cirrhosis was ascertained by normalization of biochemical (platelet count) and morphological (abdominal ultrasonography and gastrointestinal endoscopy) tests as well as non-invasive markers of fibrosis. In conclusion, a HAART regimen including tenofovir disoproxil fumarate in a HBV/HIV-coinfected cirrhotic patient might lead to sustained HBV viral suppression and result in cirrhosis reversal.
Nevirapine Concentrations in HIV-Infected Children treated with Divided Fixed-Dose Combination Antiretroviral Tablets in Malawi and Zambia
Authors: Ellis Jane C , L'homme Rafaëlla FA , Ewings Fiona M , Mulenga Veronica , Bell Frank , Chileshe Regina , Molyneux Elizabeth , Abernethy Julia , Van Oosterhout Joep JG , Chintu Chifumbe , Walker A Sarah , Gibb Diana M , Burger David M
Published: April 2022

Objective

To investigate nevirapine concentrations in African HIV-infected children receiving divided Triomune tablets (stavudine+lamivudine+nevirapine).

Design

Cross-sectional study.

Methods

Steady-state plasma nevirapine concentrations were determined in Malawian and Zambian children aged 8 months to 18 years receiving Triomune in routine outpatient settings. Predictors from height-for-age, body mass index (BMI)-for-age, age, sex, post-dose sampling time and dose/m2/day were investigated using centre-stratified regression with backwards elimination ( P<0.1).

Results

Of the 71 Malawian and 56 Zambian children (median age 8.4 vs 8.5 years, height-for-age -3.15 vs -1.84, respectively), only 1 (3%) of those prescribed ≥300 mg/m2/day nevirapine had subtherapeutic concentrations (<3mg/l) compared with 22 (23%) of those prescribed <300 mg/m2/day; most children with subtherapeutic nevirapine concentrations were taking half or quarter Triomune tablets. Lower nevirapine concentrations were independently associated with lower height-for-age (indicating stunting) (0.37 mg/l per unit higher [95% confidence interval (CI): -0.003, +0.74]; P=0.05), lower prescribed dose/m2 (+0.89 mg/l per 50mg/m2 higher [95% CI: 0.32, 1.46]; P=0.002) and higher BMI-for-age (indicating lack of wasting) (-0.42mg/l per unit higher [95% CI: -0.80, -0.04]; P=0.03).

Conclusions

Currently available adult fixed-dose combination tablets are not well suited to children, particularly at younger ages: Triomune 30 is preferable to Triomune 40 because of the higher dose of nevirapine relative to stavudine. Further research is required to confirm that concentrations are reduced in stunted children but increased in wasted children. Development of appropriate paediatric fixed-dose combination tablets is essential if antiretroviral therapy is to be made widely available to children in resource-limited settings.
Clinical Validation of Saquinavir/Ritonavir Genotypic Resistance Score in Protease-Inhibitor-Experienced Patients
Authors: Marcelin Anne-Genevieve , Flandre Philippe , De Mendoza Carmen , Roquebert Benedicte , Peytavin Gilles , Valer Luisa , Wirden Marc , Abbas Sarah , Katlama Christine , Soriano Vincent , Calvez Vincent
Published: April 2022

Objective

To identify a genotypic score for resistance to saquinavir boosted with ritonavir (SQV/r; 1,000/100 mg twice daily)-based regimens in protease inhibitor (PI)-experienced patients.

Methods

One-hundred and fifty-one PI-experienced patients receiving a SQV/r-containing regimen were enrolled retrospectively. The virological response (VR) was defined as the decrease in HIV RNA at months 3–5. The effect of each mutation in the protease gene on the VR to SQV/r regimen was assessed using non-parametric univariate analyses and then a step-by-step analysis was carried out using a Jonckheere-Tepstra (JT) non-parametric test to retain the group of mutations most strongly associated with VR.

Results

Among the 138 patients with detectable plasma SQV, the median VR was -1.48 [range: -4 to +1.2] log10 copies/ml. Changes at 12 codons were associated with a reduced VR to SQV/r: codons 10, 15, 20, 24, 46, 54, 62, 71, 73, 82, 84 and 90. The JT procedure led to selection of the following genotypic score, 10+15+20+ 24+62+73+82+84+90, as providing the strongest association with VR. In the 35 patients with none of the mutations in this score, the median decrease in HIV RNA was -2.24 log10 copies/ml and it was -1.88 ( n=29), -1.43 ( n=24), -0.52 ( n=30), -0.18 ( n=9), -0.11 ( n=6) and -0.30 ( n=5) log10 copies/ml in those with 1, 2, 3, 4, 5 and 6 mutations, respectively.

Conclusion

With this resistance score to SQV/r, the isolates were classified as having no evidence of resistance (0–2), possible resistance (3) or resistance (≥4) by grouping the number of mutations in samples for which the viral load reduction was similar.
Amantadine-Oseltamivir Combination therapy for H5N1 Influenza Virus Infection in Mice
Authors: Ilyushina Natalia A , Hoffmann Erich , Salomon Rachelle , Webster Robert G , Govorkova Elena A
Published: April 2022

Background

The clinical management of H5N1 influenza virus infection in humans remains unclear. Combination chemotherapy with drugs that target different viral proteins might be more effective than monotherapy.

Methods

BALB/c mice were treated by oral gavage for 5 days with amantadine (1.5, 15 or 30 mg/kg/day) and oseltamivir (1 or 10 mg/kg/day) separately or in combination. Mice were challenged 24 h after initiation of treatment with 10 mouse 50% lethal doses of either amantadine-sensitive (having S31 in the M2 protein) or amantadine-resistant (having N31 in the M2 protein) recombinant A/Vietnam/1203/04 (H5N1) virus.

Results

Combination treatment with amantadine (15 or 30 mg/kg/day) and oseltamivir (10 mg/kg/day) provided greater protection (60% and 90%, respectively) against lethal infection with amantadine-sensitive H5N1 virus than did monotherapy. Moreover, spread of the virus to the brain was prevented by both combination regimens. The efficacy of the drug combinations against amantadine-resistant H5N1 virus was comparable to that of oseltamivir alone. Oseltamivir produced a dose-dependent effect against both recombinant H5N1 viruses ( P<0.05) but did not provide complete protection against lethal infection. Importantly, no mutations in the HA, NA and M2 proteins were detected when the two drugs were used in combination.

Conclusions

Combination chemotherapy provided a survival advantage over single-agent treatment of mice inoculated with neurotropic H5N1 influenza virus. This strategy might be an option for the control of pandemic influenza viruses that are sensitive to amantadine. Combinations that include other drugs should be explored.