bluuebunny/crossref_metadata_2025 huggingface dataset:
Very Early Viral Kinetics on Interferon Treatment in Chronic Hepatitis C virus Genotype 4 Infection
Authors: Jessner Wolfgang , Gschwantler Michael , Formann Elisabeth , Gurguta Calin , Watkins-Riedel Thomas , Wrba Friedrich , Ferenci Peter
Published: April 2022

Background

Interferon (IFN)-resistant hepatitis C virus strains limit efficacy of antiviral combination therapy in patients infected with genotypes 1 and 4. A single test dose of IFN was useful to identify non-responders to IFN-α2b/ribavirin (RBV) or likely non-responders to pegylated (PEG)-IFN-α2a/RBV therapy in genotype 1 patients. Our aim was to investigate this approach in genotype 4 patients.

Methods

Viral load was measured in 46 patients before and 24 h after 10 megaunits (MU) IFN-α2b, and before and during 2 weeks of daily 5 MU IFN-α2b administration. Thereafter, patients received 48 weeks combination therapy with either 180 μg PEG-IFN-α2a/week ( n=33), 1.5 μg/kg PEG-IFN-α2b/week ( n=7) or 5 MU IFN-α2b/2 days ( n=6), along with 1–1.2g RBV/day. For prediction analysis the largest group (PEG-IFN-α2a) was evaluated only.

Results

Median 24 h log10 change after 10 MU IFN-α2b was 1.15 (range 0.08–2.48) and after 5 MU IFN-α2b was 0.81 (-0.12–2.22; P<0.0001). Log10 changes after 2 weeks on 5 MU IFN-α2b daily and 24 h after 10 MU were the best predictors of early virological response (defined by negativity of a standard qualitative PCR) to PEG-IFN-α2a/RBV combination therapy (area under curve [AUC]=0.97; P<0.001, receiver operating characteristics), 24 h log10 change after 10 MU was the best predictor of sustained virological response (SVR; AUC=0.91, P=0.001).

Conclusion

As in genotype 1 patients, there is large variation in IFN responsiveness, including the presence of resistant strains, in genotype 4 patients. A 24 h log10 change after 10 MU IFN-α2b is an excellent predictor of SVR on PEG-IFNα2a/RBV combination therapy. This test may be useful to obtain homogeneous groups for clinical studies and could help in clinical decision making.
Prevalence and Risk Factors for Etravirine Resistance among Patients Failing on Non-Nucleoside Reverse Transcriptase Inhibitors
Authors: Lapadula Giuseppe , Calabresi Alessandra , Castelnuovo Filippo , Costarelli Silvia , Quiros-Roldan Eugenia , Paraninfo Giuseppe , Ceresoli Francesca , Gargiulo Franco , Manca Nino , Carosi Giampiero , Torti Carlo
Published: April 2022

Background

Prevalence and factors associated with etravirine (ETV) resistance mutations among patients failing on first-generation non-nucleoside reverse transcriptase inhibitors (NNRTI) merit investigation.

Methods

The study comprised an analysis of all sequential patients attending the Institute of Infectious Diseases (Brescia, northern Italy) who performed a genotypic resistance testing (GRT) after ≥3 months of a stable NNRTI-based regimen between 2001 and 2006. Multivariable ordinal logistic regression analysis was performed to assess predictors of ETV resistance mutations.

Results

Out of 248 strains, 153 (61.7%) harboured ≥1 ETV resistance mutations. In particular, 88 (35.5%), 53 (21.4%) and 12 (4.8%) harboured one, two and three mutations, respectively. The most frequent mutations were G190A (23%), Y181C (23%) and K101E (14.1%). Use of nevirapine (odds ratio [OR] 2.73; 95% confidence level [CI] 1.62–4.62; P<0.001) and a longer time frame between first HIV RNA >500 copies/ml and GRT (per month, OR 1.05; 95% CI 1.01–1.09; P=0.012) were associated with a greater number of ETV resistance mutations. Conversely, higher CD4+ T-cell counts at nadir (per 100 cells/mm3, OR 0.81; 95% CI 0.67–0.98; P=0.029) and use of lamivudine/emtricitabine (OR 0.57; 95% CI 0.37–0.87; P=0.009) were protective. Accumulation of ETV resistance-associated mutations was demonstrated by sequential GRT in 4/35 patients (all treated with nevirapine).

Conclusions

Mutations associated with ETV resistance were common among patients failing on NNRTI, but prevalence of viral strains harbouring three mutations was low. Use of efavirenz and co-administration of lamivudine reduced the risk of ETV resistance. The continued use of the current NNRTI in a failing regimen may select for additional resistant variants.
Mapping Natural Polymorphisms of Hepatitis C virus NS3/4A Protease and Antiviral Resistance to Inhibitors in Worldwide Isolates
Authors: López-Labrador F Xavier , Moya Andrés , Gonzàlez-Candelas Fernando
Published: April 2022

Background

Several inhibitors for the hepatitis C virus (HCV) NS3/4A protease are under development. Although previous studies identified viral resistance mutations, there is little information on the natural variability of proteases from the different viral subtypes. Here, we aimed to determine both the natural variability and presence of resistance or compensatory mutations to new protease inhibitors (PI) in NS3/4A proteases from worldwide HCV isolates.

Methods

A comprehensive analysis was performed in 380 HCV NS3 sequences (275 genotype 1; 105 other genotypes) from public HCV databases (EuHCVdb and Los Alamos). Amino acid polymorphism and signature patterns were deduced in the protease domain, including all sites associated with resistance to the PIs BILN-2061, Telaprevir (VX-950), Boceprevir (SCH-503034), SCH-6 and ITMN-191.

Results

Few of the residues in the catalytic triad or in substrate/metal-binding sites were polymorphic, and were identified in only 4/380 isolates. However, a relevant polymorphism was found in sites associated either with resistance to PI (V36, I170 and D168) or with compensatory mutations (I71, T72, Q86 and I153). Furthermore, some unique genotype-specific signature patterns associated with resistance to PI were also identified.

Conclusions

We describe for the first time the relevant natural polymorphisms of the HCV NS3/4A protease in worldwide isolates. Although the prevalence of major resistance mutations is very low, many compensatory sites are naturally polymorphic among proteases from several HCV subtypes. These data will help to determine whether HCV resistance is likely to be selected with new PIs and will aid the design of genotypic resistance testing.
Pharmacokinetic Interaction between Ethinyl Estradiol, Norethindrone and Darunavir with Low-Dose Ritonavir in Healthy Women
Authors: Sekar Vanitha J , Lefebvre Eric , Guzman Sabrina Spinosa , Felicione Elise , De Pauw Martine , Vangeneugden Tony , Hoetelmans Richard MW
Published: April 2022

Background

An open-label, randomized, crossover study was performed to investigate the effect of multiple doses of darunavir co-administered with low-dose ritonavir (DRV/r) on the steady-state pharmacokinetics of the oral contraceptives ethinyl estradiol (EE) and norethindrone (NE) (commercial name of the combined drug Ortho-Novum 1/35) in 19 HIV-negative healthy women.

Methods

In session 1, participants received 35 μg EE and 1.0 mg NE from days 1 to 21. In session 2, participants received the same oral contraceptive treatment as in session 1 on days 1 to 21 plus DRV/r (600 mg/100 mg twice daily) on days 1 to 14. Pharmacokinetic assessments were performed on day 14 for each session.

Results

Steady-state systemic exposure to EE and NE decreased when DRV/r was co-administered, based on the ratio of least square means of the minimum plasma concentration (Cmin), the maximum plasma concentration (Cmax), and the area under the curve (AUC24h) of EE (which decreased by 62%, 32% and 44%, respectively) and NE (which decreased by 30%, 10% and 14%, respectively) compared with administration of EE and NE alone. Five participants discontinued the study due to grade 2 cutaneous events, as required per protocol, during treatment with EE and NE in combination with DRV/r. There were no clinically relevant findings for laboratory and cardiovascular parameters.

Conclusions

The pharmacokinetic interaction observed here is considered to be clinically relevant as EE concentrations are considerably reduced when DRV/r is co-administered with EE and NE. Alternative or additional contraceptive measures should be used when oestrogen-based contraceptives are co-administered with DRV/r.
Genetic Variability of Hepatitis B virus and Response to Antiviral Therapy
Authors: Liu Chun-Jen , Kao Jia-Horng
Published: April 2022

Hepatitis B virus (HBV) infection is a global health issue. Effective and individualized treatment of chronic hepatitis B to prevent progression to end-stage liver diseases and hepatocellular carcinoma is needed. HBV can be classified into eight genotypes (A–H) on the basis of genome sequence divergence. In addition, several naturally occurring HBV mutants have also been identified. The epidemiology of HBV genotypes and their implications for response to antiviral therapy have become increasingly recognized. Recent studies suggested that responses to standard interferon treatment in patients with genotype A or B are better than those with genotype C or D; however, conflicting results exist regarding the response to pegylated interferon. The influence of dose and duration on interferon-based therapy remains to be clarified. In addition to genotype, naturally occurring mutations such as precore and core promoter mutations have also attracted much attention, because they have been shown to affect the disease progression of HBV-related chronic liver disease and possibly the response to antiviral therapy. Here, we review the differences in antiviral theraputic response among HBV genotypes and discuss the role of precore or core promoter mutations in response to antiviral therapy.
Putative Functional Domains of Human Cytomegalovirus pUL56 Involved in Dimerization and Benzimidazole D-Ribonucleoside Activity
Authors: Champier Gaël , Couvreux Anthony , Hantz Sébastien , Rametti Armelle , Mazeron Marie-Christine , Bouaziz Serge , Denis François , Alain Sophie
Published: April 2022

Background

Benzimidazole d-ribonucleosides inhibit DNA packaging during human cytomegalovirus (HCMV) replication. Although they have been shown to target pUL56 and pUL89 (the large and small subunits of the HCMV terminase, respectively) their mechanism of action is not yet fully understood. We aimed here to better understand HCMV DNA maturation and the mechanism of action of benzimidazole derivatives.

Methods

The HCMV pUL56 protein was studied by sequence analysis of the HCMV UL56 gene and herpesvirus counterparts combined with primary structure analysis of the corresponding amino acid sequences.

Results

The UL56 sequence analysis of 45 HCMV strains and counterparts among herpesviruses allowed the identification of 12 conserved regions. Moreover, comparison with the product of gene 49 (gp49) of bacteriophage T4 suggested that the pUL56 zinc finger is localized close to the dimerization site of pUL56, providing a spatial organization of the catalytic site that allows recognition and cleavage of DNA.

Conclusions

This study provides a basis to investigate the mechanism of concatemeric DNA cleavage and a biochemical basis for DNA packaging inhibition by benzimidazole derivatives.
Safety, tolerability and pharmacokinetics of enfuvirtide administered by a needle-free injection system compared with subcutaneous injection
Authors: Gottlieb Michael , Thommes James A ,   the WAND Study Team
Published: April 2022

Background

Injection site reactions (ISRs) can present a challenge to patients when using enfuvirtide (ENF). This study compared ISRs associated with use of a needle-free injection device (NFID) with those associated with a standard 27-gauge half-inch needle/syringe (NS).

Methods

In this single-blind, crossover study, 58 ENF-naive participants were randomized to self-administer ENF with the NFID for 4 weeks (followed by 4 weeks using NS) or with the NS for 4 weeks (followed by 4 weeks using the NFID). A primary composite endpoint of painful ISR was defined as the combination of grade 1–3 ongoing pain plus either associated grade 3–4 (≥25 mm) induration or grade 2–4 nodules/cysts (>20 mm). An ISR summary score described ISR frequency/severity. Self-reported device preference was also evaluated at baseline and at study completion.

Results

Fewer participants using NFID experienced the primary composite endpoint of painful ISRs (10/28; 35.7%) compared with NS (20/28; 71.4%) ( P=0.004). There was a trend towards a reduced incidence/severity of ISR signs and symptoms with NFID, with significant reductions seen in pain/discomfort and pruritus ( P<0.05 and P<0.01, respectively). At the end of the study, most participants (22/25; 88%) expressed a preference for NFID. Haematoma was the sole NFID-related serious adverse event, but this did not lead to discontinuation.

Conclusions

Compared with a standard NS, use of an NFID to administer ENF was associated with a substantially lower incidence of painful ISRs, was generally safe and well-tolerated, and was preferred by most participants in the study.
Is transmission of HIV-1 in non-viraemic serodiscordant couples possible?
Authors: Stμrmer Martin , Doerr Hans W , Berger Annemarie , Gute Peter
Published: April 2022

Several studies have shown that HIV-1 transmission in serodiscordant couples is significantly reduced when the plasma viral load (pVL) in the infected partner is low or undetectable. However, residual infectivity in the seminal compartment despite undetectable pVL has also been shown. Here we report HIV-1 transmission in a serodiscordant couple despite successful antiretroviral therapy of the HIV-infected partner. The newly infected partner had a negative HIV-1 screening ELISA when his HIV-1- positive partner was already on antiretroviral treatment with undetectable pVL, which remained undetectable beyond the time of seroconversion in the initially negative partner. Frozen blood samples were analyzed phylogenetically from the HIV-1-positive patient and the newly infected partner before treatment and shortly after seroconversion, respectively; they showed a true relationship. On the basis of these data, the present report suggests that transmission of HIV-1 can occur despite undetectable pVL. This should be added to the discussion of prevention strategies, which should not advise the abandonment of safer-sex practices without referring to the relatively low but not impossible risk of HIV-1 transmission in this context.
A Pharmacokinetic and Pharmacogenetic Study of Efavirenz in Children: Dosing Guidelines can Result in Subtherapeutic Concentrations
Authors: Heine Robter , Scherpbier Henriette J , Crommentuyn Kristel ML , Bekker Vincent , Beijnen Jos H , Kuijpers Taco W , Huitema Alwin DR
Published: April 2022

Background

Our main objectives were to study the population pharmacokinetics of efavirenz and to explore the adequacy of dosing guidelines.

Methods

A total of 33 HIV-1-infected patients were recruited from the Emma Children's Hospital (Amsterdam, the Netherlands). Gender, age, drug formulation, the presence of the c.516G>T polymorphism in the CYP2B6 gene and the quantitation of liver enzymes alanine aminotransferase and aspartate aminotransferase at baseline were collected. A non-linear mixed effect pharmacokinetic model was developed.

Results

CYP2B6 genotype and drug formulation significantly influenced efavirenz pharmacokinetics. Clearance was 29.7% lower in children carrying the CYP2B6-516-G/T genotype compared with children carrying the G/G genotype. Relative bioavailiability of the oral liquid compared with tablets or capsules was 46.6%. Children carrying the CYP2B6-516-G/G genotype had a 50–70% probability of developing a subtherapeutic trough level of efavirenz and only 1–3% probability of developing a trough level >4 mg/l. To reduce the probability of developing a subtherapeutic trough concentration, we propose to give an adult efavirenz dose to children weighing ≥25 kg and to allometrically scale doses for other weight levels a priori. The dose of the oral solution should be twice the dose of capsules.

Conclusions

Population pharmacokinetics of efavirenz in children were adequately described. Current dosing guidelines can result in subtherapeutic concentrations in children carrying the CYP2B6-516-G/G genotype and with the liquid formulation. A priori dose adaptations in the paediatric population seem feasible and need prospective validation.
Inhibition of Human Metapneumovirus Replication by Small Interfering RNA
Authors: Deffrasnes Céline , Cavanagh Marie-Hélène , Goyette Nathalie , Cui Kunyuan , Ge Qing , Seth Shaguna , Templin Michael V , Quay Steven C , Johnson Paul H , Boivin Guy
Published: April 2022

Background

Human metapneumovirus (hMPV) is a major respiratory viral pathogen in young children, elderly individuals and immunocompromised patients. Despite its major effects related to bronchiolitis, pneumonia and its potential role in recurrent wheezing episodes, there is still no commercial treatment or vaccine available against this paramyxovirus.

Methods

We tested a therapeutic strategy for hMPV that was based on RNA interference.

Results

An hMPV genome-wide search for small interfering RNAs (siRNAs) by computational analysis revealed 200 potentially effective 21-mer siRNAs. Initial screening with a luciferase assay identified 57 siRNAs of interest. Further evaluation of their inhibitory potential against the four hMPV subgroups by quantitative real-time reverse transcriptase PCR and plaque immunoassay identified two highly potent siRNAs with 50% inhibitory concentration (IC50) values in the subnanomolar range. siRNA45 targets the nucleoprotein messenger RNA (mRNA) and had IC50 values <0.078 nM against representative strains from the four hMPV subgroups, whereas siRNA60, which targets the phosphoprotein mRNA, had IC50 values between 0.090– <0.078 nM against the same panel of hMPV strains. Longer 25/27-mer siRNAs known as Dicer substrates designed from the top two siRNA candidates were also evaluated and were at least as effective as their corresponding 21-mer siRNAs. Interestingly, the presence of one or two nucleotide mismatches in the target mRNA sequence of some hMPV subgroups did not always affect hMPV inhibition in vitro.

Conclusions

We successfully identified two highly efficient siRNAs against hMPV targeting essential components of the hMPV replication complex.
Highly Active Antiretroviral Therapy versus Zidovudine/Nevirapine Effects on Early Breast Milk HIV Type-1 RNA: A Phase II Randomized Clinical Trial
Authors: Chung Michael H , Kiarie James N , Richardson Barbra A , Lehman Dara A , Overbaugh Julie , Kinuthia John , Njiri Francis , John-Stewart Grace C
Published: April 2022

Background

Defining the effect of antiretroviral regimens on breast milk HIV type-1 (HIV-1) levels is useful to inform the rational design of strategies to decrease perinatal HIV-1 transmission.

Methods

Pregnant HIV-1 seropositive women (CD4+ T-cell count >250 and <500 cells/mm3) electing to breastfeed in Nairobi, Kenya were randomized to highly active anti-retroviral therapy (HAART; zidovudine [ZDV], lamivudine and nevirapine [NVP]) during pregnancy and 6 months post-partum or to short-course ZDV plus single-dose NVP (ZDV/NVP). Breast milk samples were collected two to three times per week in the first month post-partum.

Results

Between November 2003 and April 2006, 444 breast milk samples were collected from 58 randomized women during the first month after delivery. Between 3 and 14 days post-partum, women in the HAART and ZDV/NVP arms had a similar prevalence of undetectable breast milk HIV-1 RNA. From 15 to 28 days post-partum, women in the HAART arm had significantly lower levels of breast milk HIV-1 RNA than women randomized to ZDV/NVP (1.7 log10 copies/ml [limit of detection] versus >2.10 log10 copies/ml, P<0.001). In contrast to breast milk HIV-1 RNA, suppression of plasma HIV-1 RNA during the neonatal period was consistently several log10 greater in the HAART arm compared with the ZDV/NVP arm.

Conclusions

HAART resulted in lower breast milk HIV-1 RNA than ZDV/NVP; however, ZDV/NVP yielded comparable breast milk HIV-1 RNA levels in the first 2 weeks post-partum. Breast milk HIV-1 RNA remained suppressed in the ZDV/NVP arm despite increased plasma HIV-1 levels, which might reflect local drug effects or compartmentalization.
Successful Rescue Therapy with a Darunavir/Ritonavir and Etravirine Antiretroviral Regimen in a Child with Vertically Acquired Multidrug-Resistant HIV-1
Authors: Viganò Alessandra , Meroni Luca , Marchetti Giulia , Vanzulli Angelo , Giacomet Vania , Fasan Silvia , Pradella Andrea , Cerini Chiara , Zuccotti Gian V
Published: April 2022

An increasing prevalence of antiretroviral therapy (ART) resistance in ART-experienced and ART-naive pregnant women has been reported. Some studies suggest that antiretroviral drug-resistant viruses might have decreased replication capacity and transmissibility. However, cases of perinatal transmission of multidrug-resistant HIV type-1 (HIV-1) have been described. Here, we report the case of one child with vertically-acquired multidrug-resistant HIV-1 and the outcome of a rescue therapy with a darunavir/ritonavir- and etravirine-containing antiretroviral regimen. During the 15 months of therapy, the child showed clinical improvement, including no side effects, persistent suppression of viral replication and a great increase in CD4+ T-cell count. Paediatric HIV specialists should be prepared to manage a small, but increasing, number of babies with a ‘nightmare’ multid-rug-resistant virus with no available treatment options. The use of experimental agents might become a compelling issue in vertically HIV-infected children born in the era of highly active ART.
Pharmacokinetics of Atazanavir/Ritonavir Once Daily and Lopinavir/Ritonavir Twice and once Daily over 72 h following drug Cessation
Authors: Boffito Marta , Else Laura , Back David , Taylor Jessica , Khoo Saye , Sousa Marta , Pozniak Anton , Gazzard Brian , Moyle Graeme
Published: April 2022

Background

We investigated the pharmacokinetics of atazanavir/ritonavir once daily and lopinavir/ritonavir twice and once daily over 72 h following drug intake cessation.

Methods

This was an open-label, three-session, pharmacokinetic trial. Healthy volunteers received atazanavir/ritonavir 300/100 mg once daily and lopinavir/ ritonavir 400/100 mg twice daily and 800/200 mg once daily separately for 10 days. Pharmacokinetic profiles were assessed for each phase on day 10 over 72 h. Pharmacokinetic parameters were determined over 12 or 24 h and to the last measurable concentration by non-compartmental methods.

Results

Sixteen participants completed the study. Geometric mean terminal elimination half-life to 72 h of atazanavir was 8.35 h and not different from the 0–24 h half-life (9.91 h). Terminal elimination half-life of lopinavir was 2.33 h (twice daily) and 2.44 h (once daily). These values were lower compared with the half-life over the respective dosing intervals (7.15 and 4.88 h for 0–12 and 0–24 h, respectively). No participant on atazanavir had concentrations below the minimum effective concentration (MEC) of 150 ng/ml at 24 h. In total, 44% of the participants on lopinavir once daily had concentrations below the MEC of 1,000 ng/ml at 24 h. At 16 h and 20 h, 13% and 63% of participants were below target for twice daily lopinavir, respectively. At 36 h, all participants on lopinavir and 31% on atazanavir were below target. Ritonavir area under the plasma concentration–time curve was 30% lower and 26% higher when dosed at 100 mg or 200 mg with lopinavir versus atazanavir.

Conclusions

This study investigated the pharmacokinetic forgiveness of two boosted protease inhibitors. Whereas the decline in lopinavir concentrations occured rapidly as the boosting effect of ritonavir diminished, the rate of decline of atazanavir remained constant to 72 h.
Antiviral Potency Analysis and Functional Comparison of Consensus Interferon, Interferon-α2a and Pegylated Interferon-α2b against Hepatitis C virus Infection
Authors: Erickson Andrea K , Seiwert Scott , Gale Michael
Published: April 2022

Background

Current treatments for chronic hepatitis C virus (HCV) employing pegylated interferon (PEG-IFN) plus ribavirin are successful in approximately 50% of patients. Consensus IFN (CIFN) is a recombinant type I IFN that has demonstrated efficacy where conventional therapy has failed. We evaluated the host cell antiviral response and anti-HCV actions induced by IFN-α2a, PEG-IFN-α2b or CIFN on cultured immortalized human hepatocytes, Huh7 human hepatoma cells and Huh7 cells that harboured genetically distinct HCV RNA replicons or were infected with HCV 2a.

Methods

Cultured cells were treated with each IFN at relevant dosing based upon the pharmacological attainable in vivo serum maximum IFN concentrations. Gene expression and antiviral properties were measured using protein, RNA and virus quantification assays.

Results

CIFN treatment maximally triggered Janus kinase signal transducer and activator of transcription signalling in association with enhanced IFN-stimulated gene (ISG) expression. Increased antiviral potency of CIFN was associated with enhancement of IFN-induced blockade upon viral protein synthesis, protection of the cellular IFN promoter stimulator-1 (IPS-1) protein from HCV proteolysis and reduced replication of an IFN-resistant HCV replicon variant. Microarray analyses revealed that CIFN treatment induced a distinct pattern of ISG expression in cultured hepatocytes compared with other IFNs.

Conclusions

CIFN exhibits increased anti-HCV potency over IFN-α2a and PEG-IFN through maximal and distinct induction of ISG expression and enhanced intracellular innate antiviral response, while protecting IPS-1 from HCV proteolysis. CIFN might offer a treatment regimen imparting translational control programmes and restoration of the retinoic acid-inducible gene-1/IPS-1 pathway and could be considered for previous treatment failures.
Abacavir does not Influence the Rate of Virological Response in HIV–HCV-Coinfected Patients Treated with Pegylated Interferon and Weight-Adjusted Ribavirin
Authors: Laufer Natalia , Laguno Montserrat , Perez Iñaki , Cifuentes Carmen , Murillas Javier , Vidal Francesc , Bonet Lucia , Veloso Sergio , Gatell José María , Mallolas Josep
Published: April 2022

Background

The combination of pegylated interferon (PEG-IFN) plus ribavirin (RBV) is the standard of care for hepatitis C virus (HCV) treatment in HIV-coinfected individuals. In 2007, abacavir (ABC)-based antiretroviral therapy was, for the first time, reported to be associated with early virological failure during HCV treatment. The aim of our study was to evaluate the effect of ABC on the response rate to HCV therapy.

Methods

A retrospective analysis of HIV–HCV- coinfected patients treated with PEG-IFN and weight-adjusted RBV in four hospitals in Spain was performed. An analysis of baseline descriptive variables was conducted. Logistic regression models were used to test possible associations between non-response and pretreatment characteristics, including antiretroviral drugs.

Results

A total of 244 HIV–HCV-coinfected patients treated with PEG-IFN and RBV were included. Overall, 85% of patients were on highly active antiretroviral therapy; of these patients, 24% received ABC-based regimens. The most frequent genotypes were 1 and 3. RBV dosing was ≥13.2 mg/kg/day in 97% of the patients. In the global intent-to-treat analyses, 46.3% of patients reached a sustained virological response (SVR; 46.2% in ABC group versus 46.7% in non-ABC group, P=1). The only two factors in the multivariate analysis that were statistically associated with an increased risk of failure to achieve SVR were HCV genotypes 1 or 4 and older age. The use of ABC was not associated with failure to achieve SVR at any of the other time points evaluated.

Conclusions

Our data suggest that the use of ABC-based regimens in the context of HCV therapy does not negatively affect the outcome of this treatment.
Raltegravir Susceptibility and Fitness Progression of HIV Type-1 Integrase in Patients on Long-Term Antiretroviral Therapy
Authors: Buzón Maria José , Marfil Silvia , Puertas Maria C , Garcia Elisabet , Clotet Bonaventura , Ruiz Lidia , Blanco Julià , Martinez-Picado Javier , Cabrera Cecilia
Published: April 2022

Background

HIV type-1 (HIV-1) protease (PR), reverse transcriptase (RT) and integrase (IN) share the same precursor polyprotein and there is much evidence to suggest functional interactions between IN and RT. We aimed to elucidate whether long-term highly active antiretroviral therapy (HAART) targeting PR and RT could influence raltegravir susceptibility and the fitness of IN.

Methods

HIV-1 IN sequences from 45 heavily antiretroviral-experienced patients with longitudinal samples separated by a median of 10 years were obtained to estimate the rate of nucleotide substitution. IN recombinant viruses were generated from five selected patients. Phenotypic susceptibility to raltegravir was tested in vitro. Changes in viral replication capacity were assayed by growth kinetics and competition of intrapatient IN recombinant viruses.

Results

The amino acid substitution rate within IN was 0.06% per year during long-term antiretroviral treatment. Some substitutions had previously been associated with resistance to different IN inhibitors. Despite this, neither the early- nor late-derived IN recombinant viruses showed an increase in phenotypic susceptibility to raltegravir. Moreover, IN recombinant viruses corresponding to IN samples after 10 years of HAART had a replication capacity that was similar to or better than IN recombinant viruses from baseline samples.

Conclusions

HIV-1 IN from longitudinal samples taken from patients treated with IN inhibitor-sparing regimens showed no evidence of genotypic or phenotypic resistance to raltegravir. Additionally, long-term pressure with PR and RT inhibitors did not impair the fitness of HIV-1 IN. These data suggest that current antiretroviral regimens do not diminish the fitness of IN or influence raltegravir efficacy.
A Hepatitis C Viral Kinetic Model that Allows for Time-Varying Drug Effectiveness
Authors: Shudo Emi , Ribeiro Ruy M , Talal Andrew H , Perelson Alan S
Published: April 2022

Background

The standard model of hepatitis C virus (HCV) dynamics under high-dose daily interferon (IFN) therapy assumed that the drug effectiveness remains constant. However, for treatment with pegylated (PEG)-IFN-α2b dosed weekly, drug levels fall substantially and viral load rebounds have been observed toward the end of the weekly dosing interval, implying non-constant drug efficacy.

Methods

In this paper, we developed the decreasing effectiveness (DE) model, a new mathematical model that allows the drug effectiveness to change with time.

Results

The DE model can describe viral load rebounds as well as other viral kinetic patterns observed in clinical practice, such as biphasic viral declines. We applied the DE model to the HCV RNA kinetic data under PEG-IFN-α2b therapy. The average drug effectiveness during the first week of therapy estimated in the DE model agreed with the one estimated from HCV RNA kinetic data plus pharmacokinetic data.

Conclusions

We illustrated the usefulness of the DE model by analysing HCV RNA data from patients who received PEG-IFN-α2b once weekly plus daily ribavirin.
Severe Hyperlactataemia Complicating Stavudine First-Line Antiretroviral Therapy in South Africa
Authors: Stead David , Osler Meg , Boulle Andrew , Rebe Kevin , Meintjes Graeme
Published: April 2022

Background

In the public sector antiretroviral therapy (ART) programme in South Africa the standardized first-line regimen includes stavudine (d4T). Severe symptomatic hyperlactataemia (SHL) is a potentially life- threatening complication of d4T.

Methods

GF Jooste Hospital is a referral centre for six ART clinics. We retrospectively reviewed cases referred with lactate levels ≥5 mmol/l that were attributed to nucleoside reverse transcriptase inhibitors from August 2003 to November 2005. We calculated cumulative ART exposure in patients attending these clinics to derive a referral rate.

Results

In total, 75 patients were referred with severe SHL (71 female). All had been on d4T and on ART for a median of 10 months. The referral rate for severe SHL was 17.5 cases per 1,000 patient-years. In 53 patients (71%), lactic acidosis (standard bicarbonate [SHCO3]<20 mmol/l) was confirmed, resulting in a referral rate of 12.3 cases per 1,000 patient-years. Twelve patients (16%) died during acute admission (≤30 days). SHCO3<15 mmol/l and pH<7.2 were the only factors associated with acute mortality (odds ratio [OR] 22.5, 95% confidence interval [CI] 2.8–1,045.7 and OR 13.9, 95% CI 2.7–86.9, respectively). A total of 30 less severe cases were rechallenged with zidovudine without recurrence of SHL.

Conclusions

This study confirms a high incidence of severe SHL in Africa, which has been shown in previous studies. Rechallenge with zidovudine in less severe cases was found to be safe.
Tenofovir use is Associated with an Increase in Serum Alkaline Phosphatase in the Swiss HIV Cohort Study
Authors: Fux Christoph A , Rauch Andri , Simcock Mathew , Bucher Heiner C , Hirschel Bernard , Opravil Milos , Vernazza Pietro , Cavassini Matthias , Bernasconi Enos , Elzi Luigia , Furrer Hansjakob ,   the Swiss HIV Cohort Study
Published: April 2022

Background

Tenofovir (TDF) use has been associated with proximal renal tubulopathy, reduced calculated glomerular filtration rates (cGFR) and losses in bone mineral density. Bone resorption could result in a compensatory osteoblast activation indicated by an increase in serum alkaline phosphatase (sAP). A few small studies have reported a positive correlation between renal phosphate losses, increased bone turnover and sAP.

Methods

We analysed sAP dynamics in patients initiating ( n=657), reinitiating ( n=361) and discontinuing ( n=73) combined antiretroviral therapy with and without TDF and assessed correlations with clinical and epidemiological parameters.

Results

TDF use was associated with a significant increase of sAP from a median of 74 U/l (interquartile range 60–98) to a plateau of 99 U/l (82–123) after 6 months ( P<0.0001), with a prompt return to baseline upon TDF discontinuation. No change occurred in TDF-sparing regimes. Univariable and multivariable linear regression analyses revealed a positive correlation between sAP and TDF use ( P≤0.003), but no correlation with baseline cGFR, TDF-related cGFR reduction, changes in serum alanine aminotransferase (sALT) or active hepatitis C.

Conclusions

We document a highly significant association between TDF use and increased sAP in a large observational cohort. The lack of correlation between TDF use and sALT suggests that the increase in sAP is because of the bone isoenzyme and indicates stimulated bone turnover. This finding, together with published data on TDF-related renal phosphate losses, this finding raises concerns that TDF use could result in osteomalacia with a loss in bone mineral density at least in a subset of patients. This potentially severe long-term toxicity should be addressed in future studies.
Cystatin C as a Marker of Renal Function is Affected by HIV Replication Leading to an Underestimation of Kidney Function in HIV Patients
Authors: Mauss Stefan , Berger Florian , Kuschak Dieter , Henke Julia , Hegener Petra , Wolf Eva , Schauseil Stephan , Schmutz Guenther
Published: April 2022

Background

Broad use of tenofovir and an ageing HIV-infected population have created an interest in renal function in HIV patients. Serum cystatin C is a newer marker of renal function and might be more sensitive than creatinine.

Methods

Patients were enrolled consecutively in an observational study. HIV-seropositive patients naive to antiretroviral therapy ( n=261) were compared with healthy volunteers undergoing check-up procedures ( n=193). Estimated glomerular filtration rate (eGFR) was derived using creatinine-based Modification of Diet in Renal Disease (MDRD) and Cockcroft–Gault formulas or cystatin C-based calculations. HIV-seropositive patients starting antiretroviral therapy ( n=92) were followed prospectively after enrolment.

Results

MDRD showed a higher median eGFR in antiretroviral- naive HIV-seropositive patients compared with controls (104 versus 93 ml/min; P<0.001). Cockcroft–Gault gave similar results (118 versus 106 ml/min; P<0.001). By contrast, cystatin C levels in HIV-seropositive individuals were higher, resulting in a lower median eGFR compared with controls (99 versus 120 ml/min; P<0.001). Cystatin C was positively correlated with HIV RNA ( r=0.33, P<0.01) and inversely correlated with CD4+ T-cell count ( r=-0.29, P<0.01). Initiating antiretroviral therapy ( n=92) decreased cystatin C levels and led to an increased cystatin C-based eGFR from median 84 to 103 ml/min at week 24 ( P<0.001). Serum creatinine was not substantially altered.

Conclusions

Correlation of cystatin C with HIV RNA and CD4+ T–cell count, plus decrease of cystatin C after suppression of HIV replication, suggest an increase of cystatin C levels by active HIV infection. This might result in overestimation of renal impairment, particularly in treatment-naive patients. Therefore, use of cystatin C to calculate GFR in HIV-seropositive individuals should not be recommended without further validation.
Broad Advances in Understanding HIV Resistance to Antiretrovirals: Report on the XVII International HIV Drug Resistance Workshop
Authors: Mascolini Mark , Larder Brendan A , Boucher Charles AB , Richman Douglas D , Mellors John W
Published: April 2022

The 2008 International HIV Drug Resistance Workshop explored six topics on viral resistance: new antiretrovirals; clinical implications; epidemiology; new technologies and interpretations; HIV pathogenesis, fitness, and resistance; and mechanisms of resistance. The last of these topics provided a forum for new work on resistance of hepatitis B and C viruses, which were also explored in two poster sessions. Much work focused on resistance to the two most recent antiretroviral classes (integrase inhibitors and CCR5 antagonists), a new set of entry inhibitor candidates and one new class represented by the maturation inhibitor bevirimat. Other research explored two novel non-nucleoside reverse transcriptase inhibitors, etravirine and IDX899. Epidemiological work analysed rates of transmitted resistant virus, multiclass resistance in antiretroviral-experienced patients and a heightened resistance risk in injecting drug users regardless of adherence. New research on resistance technologies involved an enhanced assay for HIV-1 coreceptor determination and improved gene-based tools for predicting coreceptor use. In the pathogenesis arena, a small study of intensification shed light on the likely source of residual viraemia in patients on successful antiretro-viral therapy. A large study in Mozambique correlated the timing of infant infection with selection, transmission and persistence of nevirapine resistance mutations. Mechanistic research explored resistance to the integrase inhibitor raltegravir, K65R-mediated resistance to tenofovir and the role of connection domain mutations in resistance to zidovudine.
Adefovir for Chronic Hepatitis B Treatment: Identification of Virological Markers Linked to Therapy Response
Authors: Rodriguez-Frias Francisco , Jardi Rosendo , Schaper Melanie , Buti Maria , Ferrer-Costa Carles , Tabernero David , Homs Maria , Esteban Rafael
Published: April 2022

Background

HBV variants rtA181V/T, rtN236T and rtI233V, which confer resistance to adefovir dipivoxil (ADV), are not detected in many non-responding patients. Virological characteristics useful for predicting response have not been clearly elucidated. We determined pre-treatment virological markers to predict non-response and possible emergence of new variants during therapy.

Methods

This longitudinal study included 41 patients with chronic hepatitis B virus (HBV) infection receiving ADV monotherapy or ADV plus lamivudine (3TC). A fragment of HBV polymerase including catalytic domains was analysed for ADV-resistant variants.

Results

Complete virological response (CVR; HBV DNA<2.5 log10 copies/ml) was observed in 15 (36.6%) patients and partial virological response (PVR; HBV DNA<4 log10 copies/ml) in 23 (56.1%) patients. On multivariate analyses, hepatitis B e antigen (HBeAg) status was independently associated with CVR (hazard ratio [HR]=0.27, P=0.002) and PVR (HR=0.21, P<0.001) and viral genotype with CVR (HR=0.13, P=0.01). Predictive values for HBeAg were 88% for PVR in HBeAg-negative and 79% for non-CVR in HBeAg-positive patients. Predictive values for viral genotype were 93% for non-CVR and 72% for non-PVR for genotype A. On sequencing, variant rt217R (associated with subgenotype A2) was predictive of non-CVR (100%) and non-PVR (72.7%); the rtS219A variant emerged during therapy in three non-PVR patients. Both positions are located in a region likely to be related to the substrate union site, as predicted by our structural model of the HBV polymerase.

Conclusions

Virological pretreatment characteristics (HBeAg, viral genotype and rtL217R polymorphism) are potentially associated with ADV response. HBV polymerase structural modelling has provided a hypothesis to explain the molecular mechanism for ADV resistance associated with rtR217.
Future directions in therapy for chronic hepatitis C
Authors: Jensen Donald M , Ascione Antonio
Published: April 2022

The development of new antiviral therapies in the treatment of hepatitis C virus (HCV) is reviewed, including a discussion of the potential advances that this treatment will bring. Data from new molecules in Phase I and II clinical trials, specifically polymerase and protease inhibitors, will be discussed. The potential for resistance has been reported when these have been used as monotherapy. However, their use in combination with pegylated interferon, particularly in the presence of ribavirin, has resulted in significant improvements in antiviral activity. Preliminary studies have confirmed that the new molecules are well tolerated and further clinical studies are underway to evaluate their efficacy. Nevertheless, because of its critical role at all stages of therapy, pegylated interferon is likely to remain the cornerstone of HCV therapy.
Recommendations for surveillance of transmitted HIV drug resistance in countries scaling up antiretroviral treatment
Authors: Bennett Diane E , Myatt Mark , Bertagnolio Silvia , Sutherland Donald , Gilks Charles F
Published: April 2022

Background

The World Health Organization (WHO) HIV drug resistance (HIVDR) threshold survey method was developed for surveillance of transmitted HIVDR in resource-limited countries. The method is being implemented with minimal resources as a routine public health activity to produce comparable results in multiple countries and areas within countries. Transmitted drug resistant HIV strains will be seen first in cities or health districts where antiretroviral treatment (ART) has been widely available for years. WHO recommends countries begin surveillance in these areas.

Methods

Each survey requires ≤47 specimens from individuals consecutively diagnosed with HIV to categorize resistance to each relevant drug class as <5%, 5–15% or >15%. Use of routinely collected information and remnant specimens is recommended to minimize costs. Site and individual eligibility criteria are designed to minimize inclusion of ARV-experienced individuals and individuals infected before ART was available.

Results

Surveys have been implemented in 21 countries. In this supplement, seven countries report results of <5% transmitted HIVDR in areas where ART has been available for the longest time period. The main challenges in implementation are acquiring sufficient numbers of eligible specimens and optimizing specimen handling.

Conclusion

The WHO HIVDR threshold survey method is feasible in resource-limited countries and produces information relevant to ART and drug resistance prevention planning.
World Health Organization surveys to monitor HIV drug resistance prevention and associated factors in sentinel antiretroviral treatment sites
Authors: Jordan Michael R , Bennett Diane E , Bertagnolio Silvia , Gilks Charles F , Sutherland Donald
Published: April 2022

The World Health Organization (WHO) estimates that >2 million people will have started antiretroviral therapy (ART) by the end of 2006. As the development of some HIV drug resistance (HIVDR) is inevitable in populations taking ART, the emergence of HIVDR must be balanced against the benefits of providing ART, including improved health outcomes and decreased HIV/AIDS-associated morbidity and mortality. ART programmes should operate to minimize the emergence of HIVDR in populations receiving therapy and HIVDR itself must be monitored to ensure ongoing regimen efficacy. ART regimens in resource-limited settings are usually selected at the national level following a public health approach: generally only one first-line regimen with alternate regimen(s) incorporating within-class drug substitutions are available in the public sector. The WHO has developed a population-based HIVDR assessment and prevention strategy, which includes standardized HIVDR monitoring surveys in populations receiving first-line ART at sentinel sites. The WHO surveys monitor HIVDR prevention in sentinel sites by utilizing a standardized, minimum-resource prospective survey methodology to assess the success of adult and paediatric ART sites in preventing HIVDR emergence during the first year of ART. The surveys also identify associated factors that can be addressed at the level of the ART site or programme. WHO HIVDR monitoring surveys are designed to be integrated easily into a country's ongoing, routine HIV-related evaluation activities. Performed regularly at representative sites, the data generated will inform evidence-based decision making regarding national and global ART regimen selection and minimize the emergence of HIVDR at a population level.
HIV drug resistance threshold survey using specimens from voluntary counselling and testing sites in Hanoi, Vietnam
Authors: Nguyen Hien Tran , Duc Nguyen Bui , Shrivastava Ritu , Tran Tram Hong , Nguyen Tuan Anh , Thang Pham Hong , McNicholl Janet M , Leelawiwat Wanna , Chonwattana Wannee , Sidibe Kassim , Fujita Masami , Luu Chau Minh T , Kakkar Reshma , Bennett Diane E , Kaplan Jonathan , Cosimi Lisa , Wolfe Mitchell I
Published: April 2022

Background

In countries where antiretroviral therapy has been available or is being rapidly expanded, the World Health Organization (WHO) recommends surveillance for transmitted HIV drug resistance (HIVDR) by threshold surveillance methods using specimens from antenatal clinics or voluntary counselling and testing (VCT) sites. The aim of this study was to implement the HIVDR threshold survey in VCT sites in Vietnam, where HIV prevalence is high. Estimating transmitted resistance in the infected population will enable the appropriateness of current antiretroviral drug regimens to be assessed and will inform plans for future HIVDR surveillance.

Methods

Consecutive blood specimens were collected from 70 newly diagnosed HIV-positive clients 18–24 years of age at two sites in Hanoi, Vietnam. Informed consent and serum specimens were obtained from each eligible client, with serum frozen at -70°C until shipping to Thailand for resistance testing using the TruGene system.

Results

From February until August 2006, 559 clients were eligible to participate in this survey. Of the 535 clients (95.7%) who agreed to participate, 70 (13%) were HIV-positive and were included in the survey. Of the 70 specimens sent for genotyping, 52 consecutive samples were amplified, 49 of which could be genotyped. Only 1 of 49 genotyped specimens had mutations associated with drug resistance (L74V and Y181C) in the reverse transcriptase gene, indicating that the prevalence of transmitted HIVDR to all drugs and drug classes evaluated was <5%.

Conclusion

The prevalence of transmitted HIVDR was low in Hanoi as determined using threshold surveillance methods. The Ministry of Health plans to repeat this survey methodology in one more province and to confirm these findings by expanded HIVDR surveillance.