bluuebunny/crossref_metadata_2025 huggingface dataset:
Single- and multiple-dose pharmacokinetics of etravirine administered as two different formulations in HIV-1-infected patients
Authors: Kakuda Thomas N , Schöller-Gyμre Monika , Workman Cassy , Arasteh Keikawus , Pozniak Anton L , Smedt Goedele De , Beets Greet , Peeters Monika , Vandermeulen Kati , Woodfall Brian J , Hoetelmans Richard MW
Published: April 2022

Background

An open-label, randomized, crossover study to evaluate the pharmacokinetics of two different formulations of etravirine after single and multiple dosing.

Methods

Treatment-experienced HIV-1-infected patients with viral load <50 copies/ml continued their current antiretroviral regimen and added etravirine twice daily for 7 days with a morning intake on day 8. Etravirine was administered following food as either 800 mg twice daily of the Phase II formulation or 100 mg or 200 mg twice daily of the Phase III formulation. A 12 h pharmacokinetic assessment was performed on days 1 and 8.

Results

After single- and multiple-dose administration, the exposure to etravirine was lower with 100 mg twice daily and higher with 200 mg twice daily compared with 800 mg twice daily. On day 8, the mean (±sd) area under the plasma concentration-time curve over 12 h (AUC0–12 h) was 1,284 (±958) ng•h/ml when etravirine was administered as 100 mg twice daily ( n=33), 3,713 (±2,069) ng•h/ml when administered as 200 mg twice daily ( n=27) and 2,607 (±2,135) ng•h/ml when administered as 800 mg twice daily ( n=32). Both formulations and all doses of etravirine tested were generally safe and well tolerated.

Conclusions

The range of exposure to etravirine was comparable between 200 mg twice daily dose and 800 mg twice daily. The Phase III formulation of etravirine significantly improves the bioavailability of etravirine over the Phase II formulation with reduced interpatient variability in etravirine pharmacokinetics.
Adherence to antiretroviral therapy in patients enrolled in a comprehensive care program in Cambodia: A 24-month follow-up assessment
Authors: Spire Bruno , Carrieri Patrizia , Sopha Pal , Protopopescu Camelia , Prak Narom , Quillet Catherine , Ngeth Chanchhaya , Ferradini Laurent , Delfraissy Jean-François , Laureillard Didier
Published: April 2022

Background

The long-term maintenance of antiretroviral therapy (ART) remains an important issue, especially in limited-resource settings where additional barriers exist. A cross-sectional study was performed 24 months after ART initiation for patients treated in Cambodia in order to estimate the prevalence and identify determinants of non-adherence.

Methods

Adults receiving ART for 24 ±2 months were considered eligible for the study. Self-reported non-adherence was defined according to an algorithm based on six items. The questionnaire also assessed ART-related side effects and HIV disclosure. HIV-1 RNA plasma viral load was measured using real-time PCR. Multivariate rare events logistic regression analysis was used to identify independent factors associated with non-adherence.

Results

A total of 346 patients participated in the study. At 24 months, 95% of patients were adherent, 80% had HIV RNA <40 copies/ml and 75% had CD4+ T-cell counts >200 cells/mm3. Virological success was significantly higher in adherent patients than in non-adherent patients (81% versus 56%, P=0.021). Living in a rural area, limited HIV disclosure and perceived lipodystrophy were independently associated with non-adherence.

Conclusions

At 24 months, adherence to ART was high and explained positive virological outcomes. In order to maintain adherence and long-term virological benefits, special attention should be given to patients living in rural areas, those with lipodystrophy-related symptoms and others who express difficulties disclosing their condition to close family members.
Dynamic Evolution of Therapy for Chronic Hepatitis C: How will Novel Agents be Incorporated into the Standard of Care?
Authors: Zeuzem Stefan , Nelson David R , Marcellin Patrick
Published: April 2022

There is a need for improved treatment strategies and new therapeutic agents to increase cure rates in chronic hepatitis C virus (HCV) infection. Ongoing trials are aimed at optimizing sustained virological response rates with pegylated interferon (PEG-IFN) plus ribavirin. For a new agent to supplant the standard of care it must augment the strengths or compensate for the weaknesses of PEG-IFN plus ribavirin. To improve cure rates on its own, a new agent must not only suppress replication of the virus, but also clear infected hepatocytes. It is now clear that new anti-HCV agents will be used, at least initially, against a backbone of PEG-IFN plus ribavirin. A broad spectrum of agents is under investigation and it is hoped that these drugs will ultimately increase cure rates, reduce the required duration of therapy, improve tolerability and possibly simplify therapy. Reductions in serum HCV RNA ranging from 2 to 5 log10 IU/ml have been obtained in human trials with NS3/4A protease inhibitors and polymerase inhibitors. A minimum of additive reductions in serum HCV RNA levels have been observed when agents in these classes have been administered with PEG-IFN plus ribavirin in treatment-naive patients. Preliminary results in non-responders to IFN are less promising. Combinations of small molecules will be needed in order to produce sustained suppression of HCV replication in the absence of the standard of care, and such large clinical trials are several years away. The treatment paradigm for chronic hepatitis C continues to evolve and will eventually incorporate new drugs as they are approved.
The Oncogenic Potential of Hepatitis B virus rtA181T/ Surface Truncation Mutant
Authors: Lai Ming-Wei , Yeh Chau-Ting
Published: April 2022

Background

Previously, a less prevalent lamivudine-resistant mutant (rtA181T) was discovered in Taiwanese patients, in which a stop codon in the surface gene concomitantly occurred, leading to impaired secretion of hepatitis B virus (HBV) surface antigen. The rtA181T mutant also conferred drug resistance to adefovir. We discovered a 39-year-old patient with advanced hepatocellular carcionoma, who was seropositive for HBV e antigen but seronegative for HBV surface antigen. Nucleotide sequence analysis revealed the presence of polymerase rtA181T/surface truncation mutant in both the serum and hepatoma samples. Surprisingly, this patient has never received lamivudine or adefovir antiviral therapy. Here, we aimed to evaluate the oncogenic potential of HBV rtA181T/surface truncation mutant.

Methods

Site-directed mutagenesis experiments followed by transactivation assays were performed in HepG2 cells to evaluate the transactivation activities of the corresponding pre-S/S truncation mutant for c-Myc, c-Fos and Simian virus 40 promoters. NIH3T3 cells stably expressing the mutant were used to assess the tumourigenicity in nude mice.

Results

Transactivation experiments revealed that the corresponding pre-S/S truncation mutant was capable of transactivating the Simian virus 40 and human c-Myc promoters but not the c-Fos promoter. NIH3T3 cells stably expressing this mutant were tumourigenic in four of the five nude mice tested.

Conclusion

Our data indicate that an HBV polymerase rtA181T/surface truncation mutant could emerge spontaneously without previous antiviral treatment. The presence of this mutant in a patient with advanced hepatocellular carcinoma as well as its oncogenic potential warrants careful re-evaluation of the current strategy of prolonged antiviral therapy.
Using Biomarkers to Stage Disease Progression in a Lethal Mousepox Model Treated with CMX001
Authors: Parker Scott , Schriewer Jill , Oberle Christina , Robertson Alice , Lanier Randall , Painter George , Buller R Mark
Published: April 2022

Background

The emergence of human monkeypox and the potential use of recombinant variola and monkey-pox viruses as biological terrorist agents have necessitated the development of therapeutic and prophylactic therapies. The primary, or index, cases of smallpox and/ or human monkeypox will likely be identified by a characteristic rash. Effective biomarkers will be required to monitor disease progression, guide the choice of therapeutic intervention strategies and evaluate their efficacies. To address this we have evaluated several biomarkers of disease in a lethal mousepox model.

Methods

The efficacy of a single dose of a hexadecyloxypropyl ester of cidofovir (CMX001) at 20, 25 and 30 mg/ kg doses administered on days 4, 5, 6 and 7 post-infection was evaluated in A/Ncr mice intranasally infected with low doses of ectromelia virus (<20 plaque-forming units). Mice were monitored for weight loss, blood interferon-γlevels, alanine aminotransferase (ALT), aspartate amino-transferase, viral DNA copies and neutrophilia levels to stage disease progression.

Results

We have used these biomarkers to establish the optimal dosing regimen for treatment and reveal that a single dose of 25 mg/kg of CMX001 can be efficacious at treating lethal mousepox when administered on days 4 or 5 post-infection. This dose significantly reduces ALT, interferon-γand DNA copies found in the blood of infected animals.

Conclusions

A single dose regimen of CMX001 is efficacious at treating mousepox. Disease progression and antiviral efficacy can be monitored using several biomarkers that could readily be used in the case of a human monkeypox or smallpox outbreak.
Antiviral Activity of Lauryl Gallate against Animal Viruses
Authors: Hurtado Carolina , Bustos Maria Jose , Sabina Prado , Nogal Maria Luisa , Granja Aitor G , González Maria Eugenia , Gónzalez-Porqué Pedro , Revilla Yolanda , Carrascosa Angel L
Published: April 2022

Background

Antiviral compounds are needed in the control of many animal and human diseases.

Methods

We analysed the effect of the antitumoural drug lauryl gallate on the infectivity of the African swine fever virus among other DNA (herpes simplex and vaccinia) and RNA (influenza, porcine transmissible gastroenteritis and Sindbis) viruses, paying attention to its effect on the viability of the corresponding host cells.

Results

Viral production was strongly inhibited in different cell lines at non-toxic concentrations of the drug (1–10 μM), reducing the titres 3–>5 log units depending on the multiplicity of infection. In our model system (African swine fever virus in Vero cells), the addition of the drug 1 h before virus adsorption completely abolished virus productivity in a one-step growth virus cycle. Interestingly, no inhibitory effect was observed when lauryl gallate was added after 5–8 h post-infection. Both cellular and viral DNA synthesis and late viral transcription were inhibited by the drug; however, the early viral protein synthesis and the virus-mediated increase of p53 remained unaffected. Activation of the apoptotic effector caspase-3 was not detected after lauryl gallate treatment of Vero cells. Furthermore, the presence of the drug abrogated the activation of this protease induced by the virus infection.

Conclusions

Lauryl gallate is a powerful antiviral agent against several pathogens of clinical and veterinary importance. The overall results indicate that a cellular factor or function might be the target of the antiviral action of alkyl gallates.
NICE Guidelines and a Treatment Algorithm for the Management of Chronic Hepatitis B: A Review of 12 Years Experience in West London
Authors: Kennedy Patrick TF , Lee Heather C , Jeyalingam Lukshmy , Malik Raza , Karayiannis Peter , Muir David , Main Janice , Thursz Mark , Goldin Robert , Smith Belinda , Brown Ashley , Thomas Howard C
Published: April 2022

Background

Treatment strategies in chronic hepatitis B (CHB) are evolving as more potent oral antivirals become available. However, drug resistance remains a major challenge and policy guidelines on management are limited by the evidence base. This study aims to review the implications of the National Institute for Health and Clinical Excellence (NICE) guidelines in a cohort of unselected CHB patients in the United Kingdom and to evolve a management algorithm for their treatment.

Methods

In total, 783 unselected hepatitis B surface antigen-positive patients, were assessed of whom 212 (27%) underwent liver biopsy. Age, alanine aminotransferase, hepatitis B virus DNA and necroinflammatory score were analysed to determine their value as predictors of fibrosis. Patients with biopsy evidence of fibrosis were offered treatment and followed longitudinally. Six-month on-treatment virologic response was evaluated to determine the validity of this strategy in predicting the early emergence of resistance.

Results

Age, gender and necroinflammatory score were predictors of fibrosis in CHB patients, whereas age >40 years was a predictor of cirrhosis in both hepatitis B e antigen (HBeAg)-positive ( P<0.03) and HBeAg-negative patients ( P<0.003). A total of 81% of HBeAg-positive and 65% of HBeAg-negative CHB patients who required adefovir add-on therapy were identifiable after 6 months of lamivudine monotherapy, by continuing HBV DNA positivity ( P<0.002 and P<0.0001, respectively).

Conclusions

Advanced liver disease was present in patients falling outside current treatment guidelines, highlighting the importance of liver histology in identifying fibrosis and the need for antiviral therapy. While 6 month on-treatment virologic response as a trigger for instituting add-on therapy may be an improvement on the current recommendations, such a strategy should be integrated into any new treatment algorithm, likely to consist of entecavir and tenofovir.
Key Data from the 10th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV, 6–8 November 2008, London, UK
Authors: Tadayyon Moh , Cameron Stephen
Published: April 2022

Although the list of clinical complications associated with HIV therapy continues to grow, the underlying mechanisms remain incompletely understood. Metabolic abnormalities, such as dyslipidaemia, insulin resistance and cardiovascular disease continue to top the list, but there is an increasing appreciation of the effect of HIV and anti-retroviral therapy on body composition, bone metabolism, muscle function and autonomic nervous system control of lipid and glucose metabolism. The 10th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV brought together physicians and researchers in the area of HIV management with world experts involved in adipose tissue metabolism and lipid regulation, bone and muscle metabolism and renin- angiotensin and blood pressure control to review and discuss recent findings in these areas. The data presented at the meeting highlight that studies of adipose tissue remain a major focus of attempts to unravel the pathophysiology that accompany lipodystrophy associated with HIV infection and/ or its therapy. There is also a growing appreciation and understanding of the direct role of HIV in the development of various comorbidities, including bone disease, cardiac dysfunction and neuropathologies, including peripheral neuropathy. Two key emerging themes were those of mitochondrial dysfunction and a heightened basal inflammatory state, exemplified by increased levels of proinflammatory cytokines, chemokines and markers such as C-reactive protein. These might prove to be the common denominators that link HIV-associated pathologies with diverse organ systems.
Specific Targeting of the F13L Protein by St-246 Affects Orthopoxvirus Production Differently
Authors: Duraffour Sophie , Vigne Solenne , Vermeire Kurt , Garcel Aude , Vanstreels Els , Daelemans Dirk , Yang Guang , Jordan Robert , Hruby Dennis E , Crance Jean-Marc , Garin Daniel , Andrei Graciela , Snoeck Robert
Published: April 2022

Background

ST-246 is a potent anti-orthopoxviral molecule targeting the F13L protein of vaccinia virus, which is involved in the wrapping of viruses. The discrepancy in sensitivities of several orthopoxviruses to ST-246 has raised questions about potential differences in their replicative cycles and/or the presence of another drug target.

Methods

Density gradients were used to evaluate the differences between the viral cycles of vaccinia, cow-pox and camelpox viruses. Also, to investigate if ST-246 inhibits a single target, we compared its activity to that of small interfering RNAs designed to silence the F13L gene (siF13Ls).

Results

We showed that the spread of vaccinia virus involved both intracellular and extracellular enveloped viruses, whereas both cowpox and camelpox viruses seemed to propagate via non-enveloped intracellular forms and cell-associated viral particles. Although ST-246 exerted a clear antiviral activity by interfering with the egress of the virus from infected cells, we observed that cowpox and camelpox viruses, in contrast to vaccinia virus, could be directed towards a lytic cycle under ST-246 treatment. We specifically knocked down the F13L transcripts of vaccinia and camelpox viruses by >85%, reduced virus progeny by 90% and showed that siF13Ls affect camelpox and vaccinia virus propagation differently. Flow cytometry data validated that ST-246 interfered with the activity of the F13L protein, whereas siF13Ls silenced the F13L gene.

Conclusions

Our observations support that vaccinia, cow-pox and camelpox viruses exhibit different levels of sensitivity to ST-246 because of dissimilarities between their ways of propagation, and provide a better understanding of the mode of action of ST-246.
Ribavirin considerations in treatment optimization
Authors: Dusheiko Geoffrey , Nelson David , Reddy K Rajender
Published: April 2022

Ribavirin is a guanosine analogue that has little antiviral activity when used alone, but considerably enhances the efficacy of conventional and pegylated interferon in the treatment of hepatitis C virus (HCV). The precise mode of action of ribavirin is not fully understood; however, it is crucial for the achievement of high sustained virological response (SVR) rates by enhancing virological response and reducing relapse rates. Data from several studies have confirmed that higher initial doses of ribavirin lead to higher SVR rates. Furthermore, intensified ribavirin dosing might also improve SVR rates in ‘difficult-to-cure’ patients. It is also important to minimize ribavirin dose reductions to promote high SVR rates and to maintain ribavirin levels throughout treatment to prevent viral breakthrough and relapse. The pharmacokinetic profile of ribavirin reveals a long elimination half-life due to accumulation in the blood, such that its side-effect profile includes haemolytic anaemia. Therefore, finding the optimal ribavirin dose requires a balance between efficacy and its associated side effects to ensure improved patient outcomes. Here, we discuss how optimizing the ribavirin component of combined therapy for HCV is an essential part of treatment optimization.
Threshold survey evaluating transmitted HIV drug resistance among public antenatal clinic clients in Addis Ababa, Ethiopia
Authors: Abegaz Woldaregay Erku , Grossman Zehava , Wolday Dawit , Ram Daniela , Kaplan Jonathan , Sibide Kassim , Wuhib Tadesse , Ismael Shabbir , Nkengasong John , Mekonen Teferi , Berhanu Hiwot , Messele Tsehaynesh , Lulseged Sileshi , Maayan Shlomo , Mengistu Yohannes
Published: April 2022

Background

Expanded access to HIV therapy in the developing world raises serious concerns regarding the potential emergence and transmission of drug-resistant HIV strains. Although HIV drug resistance surveillance is recommended to track transmitted HIV drug resistance among newly infected individuals, the financial constraints in resource-limited countries prohibit such surveillance on a regular basis. The World Health Organization (WHO) recently introduced guidelines to address this issue.

Methods

A survey was conducted in Ethiopia following the WHO guidelines to assess transmitted HIV drug resistance among recently HIV-infected individuals in Addis Ababa. Antiretroviral drug usage started 3 years earlier than commencement of the current expanded access to antiretroviral therapy in Ethiopia.

Results

Of 75 eligible samples, 39 (52%) were successfully sequenced and genotyped in the protease and reverse transcriptase region, using both the ViroSeq® and TrueGene® genotyping systems, and analysed for drug resistance mutations using an algorithm from the Stanford HIV Reverse Transcriptase and Protease Database. The analysis revealed that transmitted HIV drug resistance in Addis Ababa is below the 5% threshold level for all three classes of antiretrovirals.

Conclusions

The current first-line antiretroviral therapy strategy can be used with confidence in Ethiopia at this time; however, Ethiopia should conduct similar periodic surveys that include the capitals of Ethiopia's larger regional states to ensure early detection of any changes in the country's HIV drug resistance trend.
Surveillance of transmitted HIV drug resistance with the World Health Organization threshold survey method in Lilongwe, Malawi
Authors:   the Malawi HIV Drug Resistance Task Force, Kamoto Kelita , Aberle-Grasse John
Published: April 2022

Background

Malawi started rapid scale-up of antiretroviral therapy (ART) in 2004 and by December 2006 had initiated 81,821 patients on treatment in the public sector. Owing to capacity constraints, standard patient care, treatment initiation and follow up are based on World Health Organization (WHO) clinical staging and do not provide laboratory monitoring to assess treatment failure.

Methods

To monitor possible transmission of HIV drug resistance (HIVDR) an HIVDR threshold surveillance based on the WHO guidelines was implemented in Malawi. Anonymous dried blood specimens were collected from routine blood samples of HIV-positive women attending primagravida antenatal care and aged <25 years.

Results

Of 59 samples tested, 54 were successfully amplified indicating good specimen quality and processing. The WHO protocol algorithm to classify the prevalence of transmitted drug resistance in the site sample only required the genotyping of 34 of the samples. None of the major drug resistance mutations on the WHO surveillance list were found in these 34 specimens.

Conclusions

Malawi HIVDR transmission can be classified as <5% for all relevant drugs and drug classes in this population. On the basis of the very positive experience of this survey, an expanded HIVDR surveillance system will be implemented to inform the ART program as it continues to scale-up.
Surveillance of transmitted HIV drug resistance among women attending antenatal clinics in Dar es Salaam, Tanzania
Authors: Somi Geofrey R , Kibuka Tabitha , Diallo Karidja , Tuhuma Tulli , Bennett Diane E , Yang Chunfu , Kagoma Charles , Lyamuya Eligius F , Swai Roland O , Kassim Sidibe
Published: April 2022

Background

In resource-limited settings where antiretroviral treatment (ART) access is being scaled-up, the World Health Organization (WHO) recommends surveillance of transmitted HIV drug resistance (HIVDR). We used the WHO HIVDR threshold survey method to assess transmitted HIVDR in Dar es Salaam where ART was introduced in 1995 and where ∼11,000 people are currently on ART.

Methods

From November 2005 to February 2006, dried blood spot (DBS) specimens were made from remnant specimens collected during the national HIV serosurvey from 60 primagravidas <25 years old attending six antenatal clinics for routine syphilis testing. Genotyping was performed at the Centers for Disease Control and Prevention, Atlanta, Georgia, USA. Protease and reverse transcriptase drug resistance mutations were identified using the Stanford University HIV drug resistance database. We used the National Institutes of Health genotyping tool for HIV-1 subtyping. HIVDR prevalence categorization was based on the WHO threshold survey binomial sequential sampling method.

Results

Among the 60 eligible specimens collected, 50 DBS were successfully amplified using RT-PCR. Sequencing was performed on the first 39 specimens: 13 (33.3%) were subtype A1, 13 (33.3%) subtype C, and 4 (10.3%) subtype D, the remainder differed in the closest subtype based on protease versus reverse transcriptase. No resistance mutations were seen; HIVDR to all drug classes was categorized as <5%.

Conclusions

Our survey indicates that prevalence of transmitted HIVDR among recently infected pregnant women in Dar es Salaam is low (<5%). The survey should be repeated during the next HIV sentinel survey in Dar es Salaam and extended to other regions where ART is being scaled up.
Factors affecting early viral load decline of Asian chronic hepatitis C patients receiving pegylated interferon plus ribavirin therapy
Authors: Hsu Ching-Sheng , Liu Chen-Hua , Liu Chun-Jen , Chen Chi-Ling , Lai Ming-Yang , Chen Pei-Jer , Chen Ding-Shinn , Kao Jia-Horng
Published: April 2022

Background

Early viral load decline following pegylated interferon-α2a and ribavirin therapy is an important predictor of the treatment responses in chronic hepatitis C (CHC) patients, thus, it is essential to evaluate the influence of host and viral factors on early viral load decline.

Methods

Clinical and serial virological data were collected from 145 consecutive Asian CHC patients with pegylated interferon-α2a plus ribavirin therapy. A dose of pegylated interferon-α2a was administered at week 1 and then weekly with daily oral ribavirin for 24 or 48 weeks. Genotyping and quantification of hepatitis C virus (HCV) RNA were done using molecular methods.

Results

A total of 81 patients were infected with HCV genotype 1, 61 with genotype 2 and 3 with both genotypes 1 and 2. At the end of follow-up, 110 patients attained sustained virological response (SVR). In multivariate analyses, body mass index (BMI) and genotype were related to viral load decline at day 2, baseline viral load and high-density lipoprotein (HDL) cholesterol levels were correlated with viral load decline between days 2 and 28. Genotype, baseline viral load, alanine aminotransferase (ALT) levels and BMI independently predicted rapid virological response, whereas only genotype 2, lower baseline viral load and more substantial viral load decline at day 28 predicted a higher SVR.

Conclusions

HCV genotype, baseline viral load, pretreatment BMI, HDL and ALT levels have a significant effect on early viral load decline of Asian CHC patients with interferon-based therapy. Only HCV genotype, baseline viral load and viral load decline at day 28 can independently predict SVR.
Effects of dietary supplementation with conjugated linoleic acid on experimental human rhinovirus infection and illness
Authors: Peterson Kristine M , O'Shea Marianne , Stam Wiro , Mohede Inge CM , Patrie James T , Hayden Frederick G
Published: April 2022

Background

Because studies suggest that the dietary supplement conjugated linoleic acid (CLA) has immunomodulatory activities that might benefit common colds, we performed two studies of CLA effects in experimental human rhinovirus (HRV) infection.

Methods

The first study explored whether CLA supplementation (Safforin™; Loders Croklaan, BV, Wormerveer, the Netherlands) altered the virological or clinical course of experimental HRV infection, and the second explored whether CLA affected the frequency and severity of HRV cold-associated sore throat and cough. The trials were randomized, double-blinded and placebo-controlled. In total, 50 healthy volunteers aged 18–45 years and susceptible to HRV type-39 (serum neutralizing antibody titre ≤1:2) participated in study 1 and 80 similar volunteers susceptible to Hank's HRV participated in study 2. Participants ingested CLA 2 g/day or placebo for 4 weeks before and 4 days following intranasal HRV inoculation. The primary endpoint for study 1 was the frequency of colds and for study 2 was the symptom severity scores for sore throat and cough.

Results

In study 1, 10/24 (42%) placebo compared with 7/21 (33%) CLA participants developed colds ( P=0.53). CLA was associated with significant reductions in mean scores for cough (0 CLA versus 0.9 placebo) and sore throat (0.8 CLA versus 2.9 placebo). In study 2, clinical colds developed in 19/33 (58%) placebo and 27/43 (63%) CLA participants. Symptom scores for cough (0.9 CLA versus 1.0 placebo) and sore throat (2.6 CLA versus 3.2 placebo) were not significantly different. Similarly no differences in nasal viral titres or serological responses were found.

Conclusions

CLA dietary supplementation had no consistent effects on the virological or clinical course of experimental HRV colds. A larger study would be required to detect more subtle effects of CLA on HRV cold-associated symptoms.
Inhibitory effect of the combination of CpG-induced cytokines with lamivudine against hepatitis B virus replication in vitro
Authors: Vincent Isabelle E , Lucifora Julie , Durantel David , Hantz Olivier , Chemin Isabelle , Zoulim Fabien , Trepo Christian
Published: April 2022

Background

Currently approved antiviral monotherapies against chronic hepatitis B fail to eradicate hepatitis B virus (HBV), to overcome the defects in HBV-specific immune responses and to prevent HBV relapse after cessation of therapy. CpG oligodesoxynucleotides (CpG ODN) are synthetic agonists of Toll-like receptor 9 and potent inducers of innate and acquired immunity. Our aim was to establish the proof of concept of the antiviral benefit of combining a nucleoside analogue with CpG-induced cytokines on HBV replication in vitro.

Methods

Peripheral blood mononuclear cells from HBV-negative individuals were stimulated with CpG ODN to generate CpG-induced cytokine supernatants. Proliferating HepaRG and HepG2 cells were transduced with recombinant HBV baculovirus and differentiated HepaRG cells were inoculated with HBV virions. Antiviral effects of CpG-induced cytokine with or without lamivudine were evaluated by analysing HBV DNA, HBV RNA and antigen secretion (hepatitis B surface antigen [HBsAg] and hepatitis B e antigen [HBeAg]).

Results

Following transduction or HBV inoculation, CpG-induced cytokines strongly inhibited HBV viral intermediates of replication, as well as HBsAg and HBeAg secretion from infected cells. Strikingly, in transduced HepaRG cells, the combination of CpG-induced cytokines with lamivudine reduced the 50% effective concentration of lamivudine by 100-fold. Importantly, the treatment of CpG-induced cytokines prior to HBV inoculation conferred a partial protection against infection to hepatocytes.

Conclusions

CpG-induced cytokines associated with polymerase inhibitors represent a promising combination to suppress HBV replication. Such an immunotherapeutic strategy should be evaluated in vivo to assess restoration and duration of anti-HBV-specific immune responses.
Prolonged exposure to tenofovir monotherapy 1 month after treatment discontinuation because of tenofovir-related renal failure
Authors: ter Heine Rob , Huitema Alwin DR , Jansen Robert S , Smits Paul HM , van Gorp Eric CM , Wagenaar Jiri FP , Beijnen Jos H , Mulder Jan W
Published: April 2022

In this study, we present a case of renal failure in a patient who was on a tenofovir- containing regimen, resulting in extremely high tenofovir exposure and prolonged tenofovir monotherapy. We considered this case report important because exposure to tenofovir monotherapy might have consequences for future discontinuation strategies in cases of renal failure.
A new era of antiretroviral drug toxicity
Authors: Calmy Alexandra , Hirschel Bernard , Cooper David A , Carr Andrew
Published: April 2022

The spectrum of drugs used in HIV-infected patients has dramatically changed since triple antiretroviral combinations were introduced, albeit at the expense of some severe adverse events, in 1996. Abandonment of stavudine in countries that can afford it, new drugs from new classes with a wide therapeutic window and the impressive scale-up of drug access in resource-limited settings are several of the key new events. Drug safety is likely to be the most important factor to distinguish one antiretroviral regimen from another. We review life-threatening adverse events, adverse events of new investigational or recently marketed drugs, adverse events with a genetic component and tissue-specific adverse events of fat, heart, bone, kidney and liver.
Association of baseline viral factors with response to lamivudine therapy in chronic hepatitis B patients with high serum alanine aminotransferase levels
Authors: Tseng Tai-Chung , Liu Chun-Jen , Wang Chia-Chi , Chen Pei-Jer , Lai Ming-Yang , Chen Ding-Shinn , Kao Jia-Horng
Published: April 2022

Background

With the exception of alanine aminotransferase (ALT) level, baseline factors predictive of therapeutic response to lamivudine in patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) remain unknown. We thus studied the influence of pre-therapy viral factors on end-of-treatment responses to lamivudine.

Methods

A total of 116 treatment-naive HBeAg-positive CHB patients who had pre-therapy ALT level >5x the upper limit of normal (ULN) and received lamivudine for 12–18 months were enrolled. HBeAg seroclearance and combined HBeAg seroclearance, ALT normalization and undetectable hepatitis B virus DNA at the end of therapy were defined as primary and secondary endpoints, respectively. Pre-therapy viral factors including viral load, genotype, precore (PC) stop codon status, basal core promoter status and pre-S deletion were determined to correlate with therapeutic endpoints.

Results

The frequency of patients with detectable PC stop codon mutation (G1896A), basal core promoter mutation (A1762T/G1764A) and pre-S deletion at baseline was 22.4%, 21.6% and 12.1%, respectively. After the end of 12–18 months of lamivudine therapy, the overall HBeAg seroclearance rate was 56.0%. Patients with HBeAg seroclearance had a higher prevalence of baseline PC stop codon mutation than those without (30.8% versus 11.8%; P=0.015). By using multivariate analyses, the odds ratio of patients with the PC stop codon mutation to develop HBeAg seroclearance was 3.33 ( P=0.024). The presence of the PC stop codon mutation also correlated with the combined response.

Conclusions

For lamivudine-treated HBeAg-positive CHB patients with pre-therapy ALT levels >5xULN, the PC stop codon mutation could predict a higher HBeAg seroclearance rate at the end of 12–18 months of therapy.
Risk factors for loss of virological suppression in patients receiving lopinavir/ritonavir monotherapy for maintenance of HIV suppression
Authors: Pulido Federico , Pérez-Valero Ignacio , Delgado Rafael , Arranz Alberto , Pasquau Juan , Portilla Joaquín , Rubio Rafael , González-García Juan , Miralles Pilar , Pérez-Elías Maria J , Ocampo Antonio , Hernando Asunción , Estrada Vicente , Clotet Bonaventura , Podzamczer Daniel , Arribas José R
Published: April 2022

Background

Risk factors for loss of virological response in patients receiving lopinavir/ritonavir (LPV/r) monotherapy as maintenance treatment have not been determined.

Methods

In 121 patients enrolled in the OK and OK04 clinical trials assigned to receive monotherapy with LPV/r, we attempted to identify factors associated with loss of virological suppression at 48 weeks, defined as confirmed serum HIV type-1 RNA>50 copies/ml, with missing data or changes caused by toxicity censored. Univariate and multivariate Cox proportional hazard models were used to calculate hazard ratios for the risk of loss of virological suppression.

Results

At week 48, 15 patients experienced loss of virological suppression. Probability of loss of virological suppression was 12.7%. Less than 9 months of maintenance of virological suppression prior to monotherapy, a lower baseline haemoglobin and low adherence measured by self-reported total missed doses in the week prior to study visit were associated with loss of virological suppression in the univariate analyses. Independent factors associated with loss of virological suppression by multivariate analyses were ≥2 visits with self-reported missed doses in the week prior to the study visit, a lower baseline haemoglobin and a nadir CD4+ T-cell count <100 cells/μl

Conclusions

Suboptimal adherence, lower baseline haemoglobin and a nadir CD4+ T-cell count <100 cells/μl were the main risk factors for losing virological suppression in patients randomized to monotherapy with LPV/r.
Constraints on the dominant mechanism for HIV viral dynamics in patients on raltegravir
Authors: Sedaghat Ahmad R , Siliciano Robert F , Wilke Claus O
Published: April 2022

Background

Raltegravir is the first publicly released HIV integrase inhibitor. In clinical trials, patients on a raltegravir-based highly active antiretroviral therapy (HAART) regimen were observed to have 70% less viraemia in the second-phase decay of viraemia than patients on an efavirenz- based HAART regimen. Because of this accelerated decay of viraemia, raltegravir has been speculated to have greater antiretroviral activity than efavirenz. Alternative explanations for this phenomenon are also possible. For example, the stage in the viral life cycle at which raltegravir acts might explain the distinct viral dynamics produced by this drug.

Methods

In this report, we use a mathematical model of HIV viral dynamics to explore several hypotheses for why raltegravir causes different viral dynamics than efavirenz. Using the experimentally observed viral dynamics of raltegravir, we calculated constraints on the mechanisms possibly responsible for the unique viral dynamics produced by raltegravir.

Results

We predicted that the dominant mechanism for the 70% reduction in the second-phase viraemia is not antiviral efficacy but the stage of the HIV viral life cycle at which raltegravir acts. Furthermore, we found that the kinetic constraints placed on the identity of the virus-producing cells of the second phase were most consistent with monocytes/macrophages.

Conclusions

Our model predictions have important implications for the motivation behind the use of raltegravir and our understanding of the virus-producing cells of the second-phase viraemia. Our results also highlight that the viral dynamics produced by different antiretroviral drugs should not be directly compared with each other.
Historical resistance profile helps to predict salvage failure
Authors:   for the Collaborative Group for Clinical Use of HIV Genotype Resistance Test, Zaccarelli Mauro , Lorenzini Patrizia , Ceccherini-Silberstein Francesca , Tozzi Valerio , Forbici Federica , Gori Caterina , Trotta Maria P , Boumis Evangelo , Narciso Pasquale , Perno Carlo F , Antinori Andrea
Published: April 2022

Background

This study compared the predictive value for treatment failure of extended resistance detected in the current genotype resistance test (GRT) versus those from GRT history in patients with multiple combination anti-retroviral therapy (cART) failures.

Methods

Patients who underwent three GRT between 1999 and 2007 were included. Extended resistance at genotypic sensitivity score (GSS) using the Rega 7.1 interpretation system compared with a non-standard definition (defined as class-wide resistance [CWR] on the basis of International AIDS Society–USA mutations) was assessed both for current and historical GRTs (a combination of mutations was detected in all three tests). The predictive role of extended resistance for treatment failure was evaluated with an adjusted Cox proportional hazard model.

Results

Overall, 177 patients were included. The historical GRT increased the number of patients with extended resistance to all three major drug classes by 25% in comparison with the current GRT. Using the GSS method, the absence of detection of any active drug in any drug class was predictive of failure with both the current and historical GRTs. Similarly, the number of active drugs in the cART regimen after the third resistance test, used as continuous variable, was also predictive of failure. Using both GSS approaches, current genotype had a higher effect than historical genotype on risk of treatment failure. Using the non-standard definition (CWR), historical resistance predicted failure better than current resistance.

Conclusions

Our results provide an epidemiological demonstration that analysis of a combined latest and historical GRT, which also considers archived mutations, might better identify of the more virologically impaired patients in order to assess the best salvage treatment.
Evolution and predictors of HIV type-1 drug resistance in patients failing combination antiretroviral therapy in Italy
Authors: Di Giambenedetto Simona , Zazzi Maurizio , Corsi Paola , Gonnelli Angela , Di Pietro Massimo , Giacometti Andrea , Almi Paolo , Trezzi Michele , Boeri Enzo , Gianotti Nicola , Menzo Stefano , Gobbo Romana Del , Francisci Daniela , Nerli Alessandro , Galli Luisa , Luca Andrea De
Published: April 2022

Background

This study aimed to examine the evolution of genotypic drug resistance prevalence in treatment-failing patients in the multicentre, Italian, Antiretroviral Resistance Cohort Analysis (ARCA).

Methods

Patients with a drug resistance genotype test performed between 1999 and 2006 at failure of a combination antiretroviral therapy and with complete treatment history were selected. The prevalence of resistance was measured overall, per calendar year, per drug class and per treatment line at failure.

Results

The overall resistance prevalence was 81%. Resistance to nucleoside reverse transcriptase inhibitors (NRTIs) declined after 2002 (68% in 2006; χ2 for trend P=0.004); resistance to non-NRTIs (NNRTIs) stabilized after 2004; and resistance to protease inhibitors (PIs) declined after 2001 (43% in 2006; P=0.004). In first-line failures, NRTI resistance decreased after 2002 ( P=0.006), NNRTI resistance decreased after 2003 ( P=0.001) and PI resistance decreased after 2001 ( P<0.001). Independent predictors of resistance to any class were HIV type-1 transmission by heterosexual contacts as compared with injecting drug use, a higher number of experienced regimens, prior history of suboptimal therapy, higher viral load and CD4+ T-cell counts, more recent calendar year and viral subtype B carriage, whereas the use of PI-based versus NNRTI-based regimens at failure was associated with a reduced risk of resistance. There was an increase of type-1 thymidine analogue and of protease mutations L33F, I47A/V, I50V and I54L/M, whereas L90M decreased over calendar years.

Conclusions

During more recent years, emerging drug resistance has decreased, particularly in first-line failures. The prevalence continues to be high in multiregimen-failing patients.
Investigation of expert rule bases, logistic regression, and non-linear machine learning techniques for predicting response to antiretroviral treatment
Authors: Prosperi Mattia CF , Altmann Andre , Rosen-Zvi Michal , Aharoni Ehud , Borgulya Gabor , Bazso Fulop , Sönnerborg Anders , Schülter Eugen , Struck Daniel , Ulivi Giovanni , Vandamme Anne-Mieke , Vercauteren Jurgen , Zazzi Maurizio
Published: April 2022

Background

The extreme flexibility of the HIV type-1 (HIV-1) genome makes it challenging to build the ideal antiretroviral treatment regimen. Interpretation of HIV-1 genotypic drug resistance is evolving from rule-based systems guided by expert opinion to data-driven engines developed through machine learning methods.

Methods

The aim of the study was to investigate linear and non-linear statistical learning models for classifying short-term virological outcome of antiretroviral treatment. To optimize the model, different feature selection methods were considered. Robust extra-sample error estimation and different loss functions were used to assess model performance. The results were compared with widely used rule-based genotypic interpretation systems (Stanford HIVdb, Rega and ANRS).

Results

A set of 3,143 treatment change episodes were extracted from the EuResist database. The dataset included patient demographics, treatment history and viral genotypes. A logistic regression model using high order interaction variables performed better than rule-based genotypic interpretation systems (accuracy 75.63% versus 71.74–73.89%, area under the receiver operating characteristic curve [AUC] 0.76 versus 0.68–0.70) and was equivalent to a random forest model (accuracy 76.16%, AUC 0.77). However, when rule-based genotypic interpretation systems were coupled with additional patient attributes, and the combination was provided as input to the logistic regression model, the performance increased significantly, becoming comparable to the fully data-driven methods.

Conclusions

Patient-derived supplementary features significantly improved the accuracy of the prediction of response to treatment, both with rule-based and data-driven interpretation systems. Fully data-driven models derived from large-scale data sources show promise as antiretroviral treatment decision support tools.
Rapid decrease of wild-type hepatitis C virus on telaprevir treatment
Authors: Adiwijaya Bambang S , Hare Brian , Caron Paul R , Randle John CR , Neumann Avidan U , Reesink Hendrik W , Zeuzem Stefan , Herrmann Eva
Published: April 2022

Background

Telaprevir (TVR) is a hepatitis C virus (HCV) NS3.4A protease inhibitor that has exhibited antiviral activity in patients with HCV genotype 1 infection. The viral dynamics in patients dosed with TVR were compared with those reported for patients treated with interferon (IFN).

Methods

The dynamics of wild-type HCV genotype 1 in patients dosed with TVR monotherapy ( n=36) and TVR plus pegylated interferon (PEG-IFN)-α2a ( n=8) were quantified using a biphasic viral dynamic model.

Results

Patients dosed with either TVR monotherapy or TVR plus PEG-IFN-α2a had median first and second phase decreases of 12 per day and 1.1 per day, respectively. The second phase decrease was approximately 10-fold higher than reported values for IFN-based treatments ( P<0.0001). Patients dosed with TVR plus PEG-IFN-α2a had a median remaining viral production after blockage (1-ε) of -2.37 log10. In patients dosed with TVR mono-therapy, increased TVR dosage of the same schedule was related to better blockage.

Conclusions

These results suggested that TVR-based regimens for chronic HCV infection will lead to an early and more rapid viral decrease that could potentially result in higher sustained viral response rates as well as offer the potential for a reduced duration of treatment.
Incidence rate and risk factors for loss to follow-up in HIV-infected patients from five French clinical centres in Northern France – January 1997 to December 2006
Authors: Ndiaye Bakhao , Ould-Kaci Karim , Salleron Julia , Bataille Pierre , Bonnevie Frederique , Choisy Philippe , Cochonat Karine , Fontier Clotilde , Guerroumi Habib , Ajana Faiza , Chaud Pascal , Yazdanpanah Yazdan
Published: April 2022

Background

Our goal was to determine the incidence rate and risk factors for loss to follow-up (LTFU) of HIV-infected patients in Northern France.

Methods

We estimated the incidence rate of LTFU in 1,007 HIV-infected patients under care from January 1997 to December 2006. We then investigated potential risk factors for LTFU at inclusion and during follow-up.

Results

The incidence of LTFU was estimated to be 3.5 per 100 person-years. Risk factors for LTFU at enrolment in a multivariate Cox model were age <30 years (hazard ratio [HR] 1.66 versus >40 years, 95% confidence interval [CI] 1.04–2.64), transmission by injection drug use (HR 5.26 versus men who have sex with men, 95% CI 2.90– 9.52), no phone number provided (HR 5.4, 95% CI 3.6–8.2), no primary care physician (HR 2.10, 95% CI 1.25–3.52) and sub-Saharan African origin (HR 2.09, 95% CI 1.36–3.22). Patients with CD4+ T-cell counts <200 cells/mm3 (HR 0.49 versus ≥350 cells/mm3, 95% CI 0.32– 0.76) and 200– 349 cells/mm3 at baseline (HR 0.63 versus ≥350 cells/mm3, 95% CI 0.41–0.98) had a decreased risk of LTFU. During follow-up, the risk of LTFU increased when the most recent CD4+ T-cell count was <200 cells/ mm3 (HR 2.06, 95% CI 1.16–3.66), the patient was not on highly active antiretroviral therapy (HAART; HR 4.20, 95% CI 2.66–6.61) and the patient was on HAART but had a detectable viral load (HR 1.92, 95% CI 1.19–3.01).

Conclusions

Our findings will help clinicians recognize patients who require additional support for retention in care, including younger patients, injection drug users, people of sub-Saharan African origin, patients who are healthier at enrolment and patients who do not adhere to HAART during follow-up.