bluuebunny/crossref_metadata_2025 huggingface dataset:
Low Current and Nadir CD4+ T-Cell Counts are Associated with Higher Hepatitis C virus RNA Levels in the Swiss HIV Cohort Study
Authors:   the Swiss HIV Cohort Study,   For The Cost-Effectiveness of Preventing AIDS Complications (CEPAC) Investigators, Rauch Andri , Gaudieri Silvana , Evison John , Nolan David , Cavassini Matthias , Weber Rainer , James Ian , Furrer Hansjakob
Published: April 2022

Background

The aim of this study was to evaluate the effect of CD4+ T-cell counts and other characteristics of HIV-infected individuals on hepatitis C virus (HCV) RNA levels.

Methods

All HIV–HCV-coinfected Swiss HIV Cohort Study participants with available HCV RNA levels and concurrent CD4+ T-cell counts before starting HCV therapy were included. Potential predictors of HCV RNA levels were assessed by multivariate censored linear regression models that adjust for censored values.

Results

The study included 1,031 individuals. Low current and nadir CD4+ T-cell counts were significantly associated with higher HCV RNA levels ( P=0.004 and 0.001, respectively). In individuals with current CD4+ T-cell counts <200/μl, median HCV RNA levels (6.22 log10 IU/ml) were +0.14 and +0.24 log10 IU/ml higher than those with CD4+ T-cell counts of 200-500/μ l and >500/μl. Based on nadir CD4+ T-cell counts, median HCV RNA levels (6.12 log10 IU/ml) in individuals with <200/μl CD4+ T-cells were +0.06 and +0.44 log10 IU/ml higher than those with nadir T-cell counts of 200-500/μ l and >500/μ l. Median HCV RNA levels were also significantly associated with HCV genotype: lower values were associated with genotype 4 and higher values with genotype 2, as compared with genotype 1. Additional significant predictors of lower HCV RNA levels were female gender and HIV transmission through male homosexual contacts. In multivariate analyses, only CD4+ T-cell counts and HCV genotype remained significant predictors of HCV RNA levels.

Conclusions

Higher HCV RNA levels were associated with CD4+ T-cell depletion. This finding is in line with the crucial role of CD4+ T-cells in the control of HCV infection.
Low Response to Pegylated Interferon plus Ribavirin in HIV-Infected Patients with Chronic Hepatitis C Treated with Abacavir
Authors: Vispo Eugenia , Barreiro Pablo , Pineda Juan A , Mira José A , Maida Ivana , Martín-Carbonero Luz , Rodríguez-Nóvoa Sonia , Santos Ignacio , López-Cortes Luis F , Merino Dolores , Rivero Antonio , Soriano Vincent
Published: April 2022

Background

There is little information about the influence of antiretroviral drugs on the antiviral activity of pegylated interferon (PEG-IFN) plus ribavirin (RBV) against hepatitis C virus (HCV).

Methods

All HIV-infected patients with chronic hepatitis C who received first-line PEG-IFN plus RBV were retrospectively analyzed. Only patients in whom virological stopping rules were applied and who did not change their antiretrovirals were chosen. Plasma RBV concentrations were measured at week 4.

Results

A total of 493 patients (78% males, mean age 41 years, 78% on antiretroviral therapy, mean CD4+ T-cell count 561 cells/μl) fit the study inclusion criteria. Mean baseline serum HCV RNA was 5.89 log10 IU/ml, 65% were infected by genotypes 1 or 4 and 40% had advanced liver fibrosis (Metavir F3F4). The overall rate of sustained virological response (SVR) was 38%. Factors associated with lack of SVR in the multivariate analyses (odds ratio [95% confidence interval], P-value) were higher baseline serum HCV RNA (2.42 per log10 IU/ml [1.31–4.46], 0.005), HCV genotypes 1 or 4 (5.95 [2.50–14.29], <0.001) and lower RBV plasma trough concentrations (1.74 per μg/ml [1.15–2.63], 0.009). Interestingly, a trend was noticed for abacavir use (2.22 [0.91–5.40], 0.08), which become significant when only considering the subset of patients with RBV plasma levels <2.3 μg/ml (7.63 [1.39–41.67], 0.02).

Conclusions

The use of abacavir might interfere with the anti-HCV activity of PEG-IFN plus RBV. As both antivirals are guanosine analogues, an inhibitory competition between abacavir and RBV might explain this observation, which is more prominent in patients with lower RBV exposure.
Distinct Signature Type I Interferon Responses are Determined by the Infecting virus and the Target Cell
Authors: Baig Ehtesham , Fish Eleanor N
Published: April 2022

Background

Type I interferons (IFN) include multiple IFN-α subtypes which exhibit considerable amino acid identity and activate the same cell-surface receptor. The promoter regions of the IFN-α genes, however, have different transcription factor binding sites, implying differential transcriptional activation. Evolutionary conservation of multiple subtypes may have resulted from external pressures associated with the crucial nature of an IFN response, namely that different viruses that are tropic for different target tissues determine the nature and extent of an IFN response, specifically the IFN-α subtype profile.

Methods

Studies were undertaken to examine inducible IFN gene expression profiles in response to infection with single-stranded RNA viruses: Sendai virus (SeV), murine hepatitis virus (MHV-1) and coxsackie virus B3 (CVB3).

Results

In vitro, distinct signature profiles of SeV and MHV-1-inducible gene expression for IFN-α2, IFN-α4 and IFN-α5 subtypes in L2 and L929 mouse fibroblast cells, in relation to the extent and kinetics of their induction, were identified. In vivo, whereas A/J mice are highly permissive for both MHV-1 and CVB3 infections and mount a poor IFN response, C57Bl/6 mice are relatively resistant to both virus infections and mount a vigorous IFN response.

Conclusions

These data suggest that the infecting virus and the target cell type dictate the extent and signature of inducible type I IFN gene expression. The extent of IFN response to viral infection influences the subsequent biological outcome: a robust IFN response prescribes a level of resistance, whereas a poor IFN response contributes towards a permissive phenotype for infection.
Specific Inhibition of Orthopoxvirus Replication by a Small Interfering RNA Targeting the D5R Gene
Authors: Vigne Solenne , Germi Raphaële , Duraffour Sophie , Larrat Sylvie , Andrei Graciela , Snoeck Robert , Garin Daniel , Crance Jean-Marc
Published: April 2022

Background

Concerns about the potential use of smallpox in bioterrorism have stimulated interest in the development of novel antiviral treatments. Currently, there are no effective therapies against smallpox and new treatment strategies are greatly needed.

Methods

In this study, specifically designed small interfering RNAs (siRNAs), targeting five proteins essential for orthopoxvirus replication, were investigated for their ability to inhibit vaccinia virus strain Western Reserve (VACVWR) replication.

Results

Among these siRNAs, 100 nM siD5R-2, an siRNA targeting the D5 protein, decreased VACVWR replication up to 90% when used either prophylactically or therapeutically in human lung carcinoma A549 cells. This siRNA induced a striking concentration-dependent inhibition of VACVWR replication and a prolonged prophylactic antiviral effect that lasted for 72 h, at a concentration of 100 nM. Confocal microscopy of Alexa–siD5R-2-treated VACVWR-infected cells confirmed a decrease in viral replication. Furthermore, siD5R-2 was shown to specifically reduce the D5R mRNA and protein expression using real-time reverse tran-scriptase-PCR and western blotting analysis, without inducing interferon-β in A549 cells. We also demonstrated the antiviral potency of siD5R-2 against different pathogenic orthopoxviruses, such as cowpox and monkeypox viruses, which were inhibited up to 70% at the lowest concentration (1 nM) tested. Finally, siD5R-2 showed antiviral effects in VACVWR-infected human keratinocyte and fibroblast cell cultures.

Conclusions

These results suggest that siD5R-2 could be a potential candidate to treat poxvirus infections.
A Decline in Hepatitis B virus Surface Antigen (HBsAg) Predicts Clearance, but does not Correlate with Quantitative HBeAg or HBV DNA Levels
Authors: Wiegand Johannes , Wedemeyer Heiner , Finger Andrea , Heidrich Benjamin , Rosenau Jens , Michel Gerd , Bock C Thomas , Manns Michael P , Tillmann Hans L
Published: April 2022

Background

The elimination of hepatitis B virus surface antigen (HBsAg) is the final goal of hepatitis B treatment, but is rarely achieved. As quantitative assays for HBsAg recently became available, we have investigated whether quantitative HBsAg measurements can substitute for hepatitis B virus (HBV) DNA quantification in treatment monitoring.

Methods

Within this study, 23 liver transplant patients and 18 heart transplant recipients were retrospectively analysed. Patients had been treated with famciclovir and/or lamivudine, in addition some had also received adefovir in cases of lamivudine resistance. Quantitative HBsAg and hepatitis B virus e antigen (HBeAg) levels were determined with the ArchitectTM assay. HBV DNA levels were determined with different assays available at given time points.

Results

We did not find a significant correlation between either HBsAg or HBeAg and HBV DNA levels – both in treated and untreated patients. More importantly, there was no significant concordance between an increase or decrease of HBsAg or HBeAg with HBV DNA. However, the curve and decline of quantitative HBsAg enabled prediction of eventual viral clearance. Eight patients showed a 2 log10 drop of HBsAg levels and eight patients demonstrated a reduction of HBsAg levels below 100 IU/ml; five patients fulfilled both criteria. Three of those five cleared HBsAg and became positive for antibodies against HBsAg.

Conclusions

Quantitative HBsAg and HBeAg cannot substitute for HBV DNA quantification during the assessment of antiviral therapy; however, the decline of HBsAg does predict eventual HBsAg clearance. A 2 log10 drop to below 100 IU/ml is associated with a high likelihood of HBsAg clearance.
Effect of Lopinavir/Ritonavir Monotherapy on Quality of Life and Self-Reported Symptoms among Antiretroviral-Naive Patients: Results of the MONARK Trial
Authors: Spire Bruno , Marcellin Fabienne , Cohen-Codar Isabelle , Flandre Philippe , Boue Francois , Dellamonica Pierre , Raffi François , Norton Michael , Ngo Van Philippe , Delfraissy Jean-François
Published: April 2022

Background

Standard-of-care for HIV-infected patients consists of combining three antiretroviral drugs. However, other therapeutic strategies could be beneficial given long-term toxicity and quality of life (QOL) issues associated with taking multiple antiretroviral drugs for many years. In the prospective, open label, randomized, pilot monotherapy antiretroviral Kaletra® (MONARK) trial among antiretroviral-naive patients, lopinavir/ritonavir (LPV/r) monotherapy was found to be less suppressive for HIV RNA than a standard triple-drug therapy of LPV/r plus zidovudine/lamivudine (on-treatment analysis after 48 weeks). We present data from the MONARK trial concerning QOL and patient-reported symptoms.

Methods

Patient-reported symptoms were collected at baseline and at weeks 4, 12, 24 and 48 using a list of 22 symptoms. QOL was assessed at baseline, week 24 and week 48 using the six-domain World Health Organization QOL short form questionnaire for HIV-infected individuals including an evaluation of global health perception.

Results

Patients treated with the standard triple-drug therapy reported significantly more symptoms over 48 weeks of treatment than patients treated with LPV/r monotherapy (incidence rate ratio [95% confidence interval] 1.3 [1.1, 1.6] P=0.001 and 1.4 [1.2, 1.7] P=0.0004 for the total number of symptoms and the number of symptoms causing discomfort, respectively). No baseline differences and no significant changes were observed in the six QOL scores. The percentage of patients with a positive perception of their global health status increased significantly in the monotherapy arm from 32% at baseline to 67% at week 48 ( P<0.0001).

Conclusions

These results suggest that the number of self-reported symptoms could be used as a treatment-sensitive measure of patients’ well-being in clinical trials.
Long-Term follow-up of Lamivudine Treatment in Patients with Severe Acute Exacerbation of Hepatitis B e Antigen (HBeAg)-Positive Chronic Hepatitis B
Authors: Wong Vincent Wai-Sun , Wong Grace Lai-Hung , Tsang Steven Woon-Choy , Hui Alex Yui , Chim Angel Mei-Ling , Yiu Karen Kar-Lum , Chan Hoi-Yun , Chan Francis Ka-Leung , Sung Joseph Jao-Yiu , Chan Henry Lik-Yuen
Published: April 2022

Background

The long-term efficacy of lamivudine treatment for patients suffering from severe acute exacerbation of hepatitis B e antigen (HBeAg)-positive chronic hepatitis B is unknown.

Methods

Consecutive patients with severe acute exacerbation of HBeAg-positive chronic hepatitis B were prospectively recruited from 1999 to 2004 and treated with lamivudine. All patients had alanine amino-transferase (ALT) and serum bilirubin levels 10x and 3x above the upper limit of normal, respectively. HBeAg-positive patients without severe acute exacerbation served as controls.

Results

Forty-five patients with severe acute exacerbation and 31 controls were treated with lamivudine for a median of 2.8 (range 1.0–7.1) years and 3.8 (range 3.5–8.4) years, respectively. Compared with controls, patients with severe acute exacerbation had higher HBeAg seroconversion rates (78% versus 52%; P=0.02) and lower risk of virological breakthrough. However, 33% of patients with severe acute exacerbation still developed lamivudine resistance and virological breakthrough by year 5. HBV DNA levels at week 4 and prolonged baseline prothrombin time were independent factors associated with virological breakthrough. All patients with week 4 HBV DNA <3 log10 copies/ml had maintained virological response. Among 15 patients who stopped lamivudine after sustained HBeAg seroconversion for ≥6 months, 11 (73%) had virological relapse at a median of 1.4 (0.2-3.9) years. ALT increased beyond 10x the upper limit of normal in six (38%) patients who stopped lamivudine and two (7%) patients on maintained lamivudine treatment ( P=0.02).

Conclusion

Among patients with severe acute exacerbation of HBeAg-positive chronic hepatitis B treated with lamivudine, virological breakthrough and post-treatment relapse are common despite a high rate of HBeAg seroconversion. Severe hepatitis flare is also common particularly among patients developing virological relapse after discontinuation of lamivudine.
The Status of HIV-1 Resistance to Antiretroviral drugs in Sub-Saharan Africa
Authors: Hamers Raph L , Derdelinckx Inge , van Vugt Michèle , Stevens Wendy , Rinke de Wit Tobias F , Schuurman Rob
Published: April 2022

Access to highly active antiretroviral therapy (HAART) for persons infected with HIV in sub-Saharan Africa has greatly improved over the past few years. However, data on long-term clinical outcomes of Africans receiving HAART, patterns of HIV resistance to antiretroviral drugs and implications of HIV type-1 (HIV-1) subtype diversity in Africa for resistance, are limited. In resource-limited settings, concerns have been raised that deficiencies in health systems could create the conditions for accelerated development of resistance. Coordinated surveillance systems are being established to assess the emergence of resistance and the factors associated with resistance development, and to create the possibility for adjusting treatment guidelines as necessary. The purpose of this report is to review the literature on HIV-1 resistance to antiretroviral drugs in sub-Saharan Africa, in relation to the drug regimens used in Africa, HIV-1 subtype diversity and overall prevalence of resistance. The report focuses on resistance associated with treatment, prevention of mother-to-child transmission and transmitted resistance. It also outlines priorities for public health action and research.
Rapid Quantitation of Neuraminidase Inhibitor Drug Resistance in Influenza virus Quasispecies
Authors: Lackenby Angie , Democratis Jane , Siqueira Marilda M , Zambon Maria C
Published: April 2022

Background

Emerging resistance of influenza viruses to neuraminidase inhibitors is a concern, both in surveillance of global circulating strains and in treatment of individual patients. Current methodologies to detect resistance rely on the use of cultured virus, thus taking time to complete or lacking the sensitivity to detect mutations in viral quasispecies. Methodology for rapid detection of clinically meaningful resistance is needed to assist individual patient management and to track the transmission of resistant viruses in the community.

Methods

We have developed a pyrosequencing methodology to detect and quantitate influenza neuraminidase inhibitor resistance mutations in cultured virus and directly in clinical material. Our assays target polymorphisms associated with drug resistance in the neuraminidase genes of human influenza A H1N1 as well as human and avian H5N1 viruses. Quantitation can be achieved using viral RNA extracted directly from respiratory or tissue samples, thus eliminating the need for virus culture and allowing the assay of highly pathogenic viruses such as H5N1 without high containment laboratory facilities.

Results

Antiviral-resistant quasispecies are detected and quantitated accurately when present in the total virus population at levels as low as 10%. Pyrosequencing is a real-time assay; therefore, results can be obtained within a clinically relevant timeframe and provide information capable of informing individual patient or outbreak management.

Conclusions

Pyrosequencing is ideally suited for early identification of emerging antiviral resistance in human and avian influenza infection and is a useful tool for laboratory surveillance and pandemic preparedness.
Population Trends in the Prevalence and Patterns of Protease Resistance Related to Exposure to Unboosted and Boosted Protease Inhibitors
Authors:   The UK Collaborative Group on HIV Drug Resistance and the UK Collaborative HIV Cohort Study, Dunn David , Geretti Anna Maria , Green Hannah , Fearnhill Esther , Pozniak Anton , Churchill Duncan , Pillay Deenan , Sabin Caroline , Phillips Andrew
Published: April 2022

Background

In recent years, several new drugs from the protease inhibitor (PI) class designed to treat HIV infection have become available and the use of ritonavir-boosting has increased in popularity. These changes might be expected to affect the prevalence and patterns of protease resistance in the population of patients who experience treatment failure.

Methods

The UK HIV Drug Resistance Database aims to capture the results of all genotypic resistance tests conducted nationally. Tests on antiretroviral therapy-experienced patients were identified through linkage with the UK Collaborative HIV Cohort Study, from which detailed clinical information on these patients, including a full antiretroviral therapy history, was obtained.

Results

Analyses were on the basis of 8,553 genotypic resistance tests carried out between 1998 and 2005, during which time the overall prevalence of protease resistance halved from 35% to 16%. Substantial declines were observed regardless of whether the patient had been exposed to unboosted PIs and/or boosted PIs. The frequency of protease resistance among patients who had received boosted PIs fell sharply until 2002 with a weaker trend thereafter, falling to 12% in 2005. Individual mutations L33F, M46I/L, V82A/F/T/S/L and I84V became relatively more frequent over the period of study.

Conclusions

The decline in protease resistance was partly due to increasing use of ritonavir-boosting. Nonetheless, the prevalence of resistance was higher than suggested by clinical trials, indicating that prolonged exposure to a boosted PI could ultimately select for major protease mutations.
Mitochondrial DNA Depletion in Oocytes of HIV-Infected Antiretroviral-Treated Infertile Women
Authors: López Sònia , Coll Oriol , Durban Mercè , Hernàndez Sandra , Vidal Ricard , Suy Anna , Morén Constanza , Casademont Jordi , Cardellach Francesc , Mataró Daniel , Miró Òscar , Garrabou Glòria
Published: April 2022

Background

HIV-infected women under highly active antiretroviral therapy (HAART) undergoing in vitro fertilization (IVF) have a lower pregnancy rate than non-infected controls, which depends on oocyte-related factors. We hypothesized that mitochondrial toxicity caused by antiretrovirals could be the underlying mechanism of such disturbance.

Methods

We have studied 16 and 19 frozen-thawed oocytes obtained after oocyte retrieval IVF cycles from 8 and 14 infertile HIV-infected and uninfected women, respectively, matched by age. At inclusion, HIV-positive women had been infected for >13 years and had received HAART for >9 years, including at least one nucleoside reverse transcriptase inhibitor. All of them had undetectable HIV viral load and a good immunological status. Mitochondrial DNA (mtDNA) content was determined by quantitative real-time PCR in each individual oocyte.

Results

HIV-infected infertile women on HAART showed significant oocyte mtDNA depletion when compared with uninfected controls (32% mtDNA decrease, P<0.05). This oocyte mtDNA depletion was even greater on those HIV-infected women who failed to become pregnant when compared with controls (39% mtDNA decrease, P=0.03). No significant correlation was found between mtDNA oocyte content and cumulative doses of antiretrovirals or the immunological status of HIV patients.

Conclusions

Oocytes from infertile HIV-infected HAART-treated women show decreased mtDNA content, and this could explain their poor reproductive outcome.
Effect of Nucleoside and Nucleotide Reverse Transcriptase Inhibitors of HIV on Endogenous Nucleotide Pools
Authors: Vela Jennifer E , Miller Michael D , Rhodes Gerald R , Ray Adrian S
Published: April 2022

Background

Alterations in endogenous nucleotide pools as a result of HIV therapy with nucleoside and nucleotide reverse transcriptase inhibitors (N[t]RTIs) is a proposed mechanism for therapy-related adverse events and drug interactions resulting in treatment failure. In vitro studies were performed in order to understand the effect of N(t)RTIs on endogenous nucleotide pools.

Methods

The T-cell line CEM-CCRF was treated with control antimetabolites or the N(t)RTIs abacavir, didanosine, lamivudine, tenofovir (TFV) and zidovudine (AZT), either alone or in combination. The levels of natural 2′-deoxynucleoside triphosphates (dNTP) and ribonucleoside triphophosphates were determined by liquid chromatography coupled with triple quadrupole mass spectrometry.

Results

Antimetabolites altered nucleotide pools in a manner consistent with their known mechanisms of action. AZT was the only N(t)RTI that significantly altered dNTP pools. Incubation of 10 μM AZT, either alone or in combination with other N(t)RTIs, increased 2′-deoxyadenosine triphosphate, 2′-deoxyguanosine triphosphate and thymidine triphosphate levels by up to 1.44-fold the concentrations observed in untreated cells. At higher than pharmacological concentrations of AZT, evidence for inhibition of 2′-deoxycytidylate deaminase and enzymes involved in the salvage of thymidine was also observed. Phosphorylated metabolites of TFV are known to inhibit purine nucleoside phosphorylase (PNP). However, in contrast to a potent PNP inhibitor, TFV was unable to alter intracellular dNTP pools upon addition of exogenous 2′-deoxyguanosine.

Conclusions

N(t)RTIs have the potential to alter nucleotide pools; however, at the pharmacologically relevant concentrations, tested N(t)RTI or their combinations did not have an effect on nucleotide pools with the notable exception of AZT.
The Maturation Inhibitor Bevirimat (PA-457) can be Active in Patients Carrying HIV type-1 non-B Subtypes and Recombinants
Authors: Yebra Gonzalo , Holguín Africa
Published: April 2022

Background

Bevirimat (PA-457) is the first candidate of a new family of antiretroviral drugs, the maturation inhibitors. Its action is based on disruption of the protease cleavage of the Gag precursor region. Six resistance mutations have been described and analysed in virus from both treatment-naive and protease inhibitor (PI)-experienced patients, but only in the subtype B of HIV type-1 (HIV-1) virus. Thus, genotypic resistance in non-B subtypes still requires analysis.

Methods

HIV-1 sequences of different subtypes (54 B, 81 non-B and recombinants) were analysed for the presence of resistance mutations to bevirimat, located within the capsid (CA) protein and spacer peptide 1 (SP1) cleavage site.

Results

No resistance mutations were found, although polymorphisms appeared in some CA-SP1 residues. The C-terminal CA protein and the N-terminal SP1 presented high conservation, whereas C-terminal SP1 was highly variable in sequence and length, with unknown influence in resistance acquisition.

Conclusions

The results of the present study confirm an absolute conservation of the residues involved in bevirimat in vitro resistance in a large panel of HIV-1 subtypes and recombinants from both treatment-naive and PI- experienced patients. Treatment alone seemed to increase the polymorphisms account in CRF02_AG recombinant sequences; however, the influence of natural polymorphisms needs to be explored.
Virodynamic Predictors of Response to Pegylated Interferon and Lamivudine Combination Treatment of Hepatitis B e Antigen-Positive Chronic Hepatitis B
Authors: Mihm Ulrike , Chan Henry Lik-Yuen , Zeuzem Stefan , Chim Angel Mei-Ling , Hui Alex Yui , Wong Vincent Wai-Sun , Sung Joseph Jao-Yiu , Herrmann Eva
Published: April 2022

Background

Early identification of non-responders to interferon-α and development of stopping rules are needed in patients with chronic hepatitis B to reduce treatment-related costs and morbidity.

Methods

In total, 47 patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B received pegylated interferon-α2b for 8 weeks, lamivudine plus pegylated interferon-α2b combination therapy for 24 weeks and lamivudine monotherapy for 28 weeks. Sustained virological response was defined as HBeAg seroconversion and hepatitis B virus (HBV) DNA<105 copies/ml at the end of treatment and after 52 weeks of follow-up. The early HBV DNA data from the first 12 weeks of therapy were fitted by a viral kinetic model.

Results

Cutoff values for prediction of sustained virological response were defined as a rate of infected cell loss δ≥0.005 per day (negative predictive value [NPV] 100% and positive predictive value [PPV] 33.3%) and log values of the area under the mathematically predicted HBV DNA curve between baseline and week 12 of therapy ≤8.9 log10 copies/ml x days (NPV 100% and PPV 50%). By the latter cutoff, 25/36 (69.4%) patients without sustained virological response could be identified after 12 weeks of therapy.

Conclusions

In the present study, mathematical modelling of viral dynamics allowed prediction of sustained virological response after 12 weeks of therapy. Virodynamic predictors for sustained virological response should be further validated. The area under the mathematically predicted HBV DNA curve seems a promising candidate for potential cutoff values as it summarizes the influence of baseline HBV DNA and treatment effects.
Refining Abacavir Hypersensitivity Diagnoses using a Structured Clinical Assessment and Genetic Testing in the Swiss HIV Cohort Study
Authors: Rauch Andri , Nolan David , Thurnheer Christine , Fux Christoph A , Cavassini Matthias , Chave Jean-Philippe , Opravil Milos , Phillips Elizabeth , Mallal Simon , Furrer Hansjakob ,   the Swiss HIV Cohort Study
Published: April 2022

Background

We aimed to assess the value of a structured clinical assessment and genetic testing for refining the diagnosis of abacavir hypersensitivity reactions (ABC-HSRs) in a routine clinical setting.

Methods

We performed a diagnostic reassessment using a structured patient chart review in individuals who had stopped ABC because of suspected HSR. Two HIV physicians blinded to the human leukocyte antigen (HLA) typing results independently classified these individuals on a scale between 3 (ABC-HSR highly likely) and -3 (ABC-HSR highly unlikely). Scoring was based on symptoms, onset of symptoms and comedication use. Patients were classified as clinically likely (mean score ≥2), uncertain (mean score ≥-1 and ≤1) and unlikely (mean score ≤-2). HLA typing was performed using sequence-based methods.

Results

From 131 reassessed individuals, 27 (21%) were classified as likely, 43 (33%) as unlikely and 61 (47%) as uncertain ABC-HSR. Of the 131 individuals with suspected ABC-HSR, 31% were HLA-B*5701-positive compared with 1% of 140 ABC-tolerant controls ( P<0.001). HLA-B*5701 carriage rate was higher in individuals with likely ABC-HSR compared with those with uncertain or unlikely ABC-HSR (78%, 30% and 5%, respectively, P<0.001). Only six (7%) HLA-B*5701-negative individuals were classified as likely HSR after reassessment.

Conclusions

HLA-B*5701 carriage is highly predictive of clinically diagnosed ABC-HSR. The high proportion of HLA-B*5701-negative individuals with minor symptoms among individuals with suspected HSR indicates overdiagnosis of ABC-HSR in the era preceding genetic screening. A structured clinical assessment and genetic testing could reduce the rate of inappropriate ABC discontinuation and identify individuals at high risk for ABC-HSR.
IP-10 Correlates with Hepatitis C Viral Load, Hepatic Inflammation and Fibrosis and Predicts Hepatitis C Virus Relapse or Non-Response in HIV–HCV Coinfection
Authors: Reiberger Thomas , Aberle Judith H , Kundi Michael , Kohrgruber Norbert , Rieger Armin , Gangl Alfred , Holzmann Heidemarie , Peck-Radosavljevic Markus
Published: April 2022

Background

Interferon (IFN)-γ inducible protein 10 (IP-10) is increased in hepatitis C virus (HCV) monoinfection, correlates with hepatic inflammation and predicts non-response (NR) to antiviral therapy. We aimed to clarify the role of IP-10 in HIV-HCV coinfection.

Methods

Serum IP-10 levels of 30 HIV-HCV- coinfected patients treated with pegylated (PEG)-IFN-α2a (180 μg/week) and ribavirin (800-1,200 mg/day) were measured at baseline and 24 h after first IFN dose. The predictive value of IP-10 was compared with established markers of treatment outcome by applying a multivariate logistic regression model.

Results

Patients with NR (476 ±156 pg/ml) or virological relapse (508 ±298 pg/ml) had significantly higher baseline IP-10 levels compared with patients who had a sustained virological response (SVR; 293 ±97 pg/ml, P=0.001). The IFN-induced increase of IP-10 was significantly stronger in patients with an SVR ( P=0.017). IP-10 levels were associated with HCV viral load, alanine aminotransferase (ALT) levels, hepatic inflammatory activity and fibrosis stage. Advanced fibrosis, high HCV viral load, hepatovenous pressure gradient and pretreatment IP-10>400 pg/ml predicted NR to antiviral therapy. In the multivariate analysis, IP-10 was identified as the strongest baseline predictor of SVR with a specificity and sensitivity of 83.4% and 92.9%, respectively.

Conclusions

Pretreatment IP-10 levels correlated with HCV viral load, ALT levels, hepatic inflammation and fibrosis. An IP-10 cutoff level of 400 pg/ml might serve as a useful predictive marker for anti-HCV therapy in HIV–HCV-coinfected patients because it could discriminate patients with expected NR or HCV relapse after therapy from patients with an SVR before starting antiviral treatment.
Optimizing outcomes in patients with hepatitis C virus genotype 1 or 4
Authors: Lee Samuel S , Ferenci Peter
Published: April 2022

Currently, many decisions for the treatment of hepatitis C virus (HCV) are based on genotype, which is the most significant baseline predictor of response to therapy; however, it has become increasingly apparent that fixed treatment durations might not be appropriate for all patients. The use of on-treatment predictors such as rapid virological response (RVR) at week 4 and early virological response (EVR) at week 12 can be used to predict the likelihood of achieving a sustained virological response (SVR), helping to tailor treatment to the individual. Until now, EVR has been defined as achieving either undetectable HCV RNA (<50 IU/ml) or a >2 log drop in HCV RNA, but still detectable, at week 12. However, rates of SVR in patients achieving an EVR are heterogeneous. It has recently been suggested that by subdividing EVR into RVR (<50 IU/ml at week 4), complete EVR (HCV RNA <50 IU/ml at week 12) or partial EVR (HCV RNA >2 log drop in HCV RNA but still detectable [>50 IU/ml] at week 12), it might be possible to further improve the prediction of patients likely to achieve an SVR and may allow for tailoring of treatment duration. Genotype 1 and 4 patients achieving an RVR have high rates of SVR and may be candidates for shorter treatment duration. Patients with a complete EVR achieve high SVR rates with the current treatment duration of 48 weeks, whereas patients achieving a partial EVR have lower rates of SVR and could benefit from treatment intensification to 72 weeks. Here, we discuss the importance of baseline predictors of response and the emerging concept of response-guided therapy in genotype 1 and 4 patients.
Hepatitis C virus therapy to date
Authors: Foster Graham , Mathurin Philippe
Published: April 2022

Chronic hepatitis C is a major contributor to cirrhosis and hepatocellular cancer worldwide, justifying the considerable research effort aimed at understanding the disease and refining its treatment. As a result, significant therapeutic advances have been made in the last decade, particularly with regard to the development of pegylated interferons and ribavirin. This review will discuss the physical properties, pharmacokinetics, viral kinetics and side-effect profiles of the different treatment options and how they have improved, culminating in the use of pegylated interferon and ribavirin combination therapy as the current standard of care.
The World Health Organization's global strategy for prevention and assessment of HIV drug resistance
Authors: Bennett Diane E , Bertagnolio Silvia , Sutherland Donald , Gilks Charles F
Published: April 2022

Antiretroviral treatment (ART) for HIV is being scaled up rapidly in resource-limited countries. Treatment options are simplified and standardized, generally with one potent first-line regimen and one potent alternate first-line regimen recommended. Widespread HIV drug resistance (HIVDR) was initially feared, but reports from resource-limited countries suggest that initial ART programmes are as effective as in resource-rich countries, which should limit HIV drug resistance if programme effectiveness continues during scale-up. ART interruptions must be minimized to maintain viral suppression on the first-line regimen for as long as possible. Lack of availability of appropriate second-line drugs is a concern, as is the additional accumulation of resistance mutations in the absence of viral load testing to determine failure. The World Health Organization (WHO) recommends a minimum-resource strategy for prevention and assessment of HIVDR in resource-limited countries. The WHO's Global Network HIVResNet provides standardized tools, training, technical assistance, laboratory quality assurance, analysis of results and recommendations for guidelines and public health action. National strategies focus on assessments to guide immediate public health action to improve ART programme effectiveness in minimizing HIVDR and to guide regimen selection. Globally, WHO HIVResNet collects and analyses data to support evidence-based international policies and guidelines. Financial support is provided by major international organizations and technical support from HIVDR experts worldwide. As of December 2007, 25 countries were planning or implementing the strategy; seven countries report results in this supplement.
Antiretroviral drug resistance surveillance among drug-naive HIV-1-infected individuals in Gauteng Province, South Africa in 2002 and 2004
Authors: Pillay Visva , Ledwaba Johanna , Hunt Gillian , Rakgotho Mpho , Singh Beverly , Makubalo Lindiwe , Bennett Diane E , Puren Adrian , Morris Lynn
Published: April 2022

Background

Surveillance for transmitted HIV-1 drug resistance was conducted among drug-naive HIV-1-infected pregnant women in South Africa, where single-dose nevirapine has been in use since 2001 and a national antiretroviral treatment programme started in 2004.

Methods

All subjects were from the Gauteng Province and were part of the 2002 and 2004 annual antenatal HIV seroprevalence survey conducted by the South African National Department of Health. All subjects met the inclusion criteria as set out by the World Health Organisation guidelines for HIV-1 transmitted drug resistance surveillance (women <22 years of age and in first pregnancy). Genotyping was performed on viral RNA by sequencing the protease and reverse transcriptase genes. Samples were also tested for the K103N mutation using a highly sensitive allele-specific realtime PCR assay (AS-PCR).

Results

Of 128 eligible participants from 2002, 65 (51%) samples were successfully amplified. None of them had evidence of resistance mutations by genotyping or by AS-PCR. Of 117 eligible participants from 2004, 48 (41%) samples were successfully amplified. Of these, one had T69D and one had the K70R resistance mutation, to give a total of 2/48 (4.2%) participants with evidence of resistance mutations by genotyping. One sample that was wild-type by genotyping was positive for K103N by AS-PCR. All samples clustered phylogenetically with HIV-1 subtype C, the predominant subtype circulating in South Africa.

Conclusions

Using the threshold survey, resistance prevalence overall and for each drug class in 2002 and 2004 was <5% for the Gauteng province of South Africa. The detection of a low frequency of resistance mutations in the 2004 survey suggests that surveillance should be conducted annually among untreated populations to determine if this increases with time.
Surveillance of transmitted HIV drug resistance in the Manzini-Mbabane corridor, Swaziland, in 2006
Authors: Maphalala Gugu , Okello Velephi , Mndzebele Sibongile , Gwebu Prudence , Mulima Nomsa , Dlamini Sandile , Nhlabatsi Bonisile , Ginindza Themba , Ghebrenegus Yohannes , Ntilivamunda Augustine , Mwanyumba Fabian , Ledwaba Johanna , Pillay Visva , Bennett Diane E
Published: April 2022

Background

In resource-limited settings where anti-retroviral treatment (ART) is being scaled-up, the World Health Organization (WHO) recommends the surveillance of transmitted HIV drug resistance (HIVDR). We used the WHO's HIVDR threshold survey method to assess transmitted HIVDR in three antenatal clinic (ANC) sites along the corridor between the two most populous cities in Swaziland, where ART was introduced in 2003.

Methods

From July–August 2006, remnant sera were aliquoted from HIV serosurvey specimens collected from 70 primagravidas <25 years old attending ANC during the national HIV serosurvey. Genotyping was performed at the National Institute for Communicable Diseases, South Africa. Transmitted resistance was defined by the WHO's surveillance list of mutations. HIVDR prevalence was categorized using the WHO's threshold survey binomial sequential sampling method.

Results

Among the 70 eligible specimens, 61 were sequenced – 60 (98%) were identified as subtype C and one as subtype B. No major nucleoside or non-nucleoside reverse transcriptase inhibitor mutations occurred among the first 34 consecutive specimens, which supported a transmitted resistance categorization to these drug classes as <5%. One protease inhibitor mutation, M46I, was seen among the first 44 specimens, supporting a categorization of PI resistance as <5%.

Conclusion

Our survey indicates that prevalence of transmitted HIVDR among recently infected pregnant women along the Manzini-Mbabane corridor is low (<5%). Surveys will be carried out in this area biannually and may be extended to other areas. Surveys for transmitted resistance make up one element among a spectrum of activities to assess and support minimization of HIVDR.
Perinatal zidovudine prophylaxis in HIV type-1-infected pregnant women with thalassaemia carriage in Thailand
Authors: Briand Nelly , Pornprasert Sakorn , Ngo-Giang-Huong Nicole , Galactéros Fréderic , Pissard Serge , Tatu Thanusak , Sanguansermsri Torpong , Jourdain Gonzague , Lallemant Marc , Le Coeur Sophie
Published: April 2022

Background

To investigate a possible interaction between α-thalassaemia, β-thalassaemia and haemoglobin-E trait and the haematological parameters of HIV type-1 (HIV-1)-infected pregnant women receiving zidovudine prophylaxis for the prevention of mother-to-child HIV-1 transmission in Thailand.

Methods

The study sample was composed of HIV-1-infected pregnant women receiving zidovudine (300 mg twice daily) from 28 weeks of gestational age to delivery as part of the Perinatal HIV Prevention Trial (PHPT-1), a large trial investigating zidovudine use in pregnancy. These women were randomly selected and screened for haemoglobin abnormalities. Haemoglobin levels, haematocrit and erythrocyte, leukocyte, absolute neutrophil and absolute lymphocyte counts were measured at 26, 32 and 35 weeks of gestation and at delivery. PCR genotyping techniques were used to screen for haemoglobin abnormalities, which included α-thalassaemia-1 Southeast Asian type deletion, β-thalassaemia mutation (codons 41/42 [-TCTT], codon 17 [A→T], intervening sequence-I nucleotide 1 [G→T], codons 71/72 [+A]) and haemoglobin-E trait. The evolution of haematological parameters between 26 weeks and delivery was compared according to thalassaemia carriage using linear mixed models adjusted for baseline sociodemographic characteristics, HIV clinical stage, CD4+ T-cell count and viral load.

Results

At baseline, women with thalassaemia or haemoglobin-E trait had significantly lower haemoglobin level and red blood cell counts than women with no haemoglobin abnormalities, whereas absolute neutrophil and leukocyte counts were significantly higher. Exposure to zidovudine until delivery did not increase this difference.

Conclusions

Zidovudine exposure did not appear to have increased haematological toxicity in HIV-1-infected pregnant women with thalassaemia.
Body image is a major determinant of sexual dysfunction in stable HIV-infected women
Authors: Luzi Kety , Guaraldi Giovanni , Murri Rita , De Paola Maria , Orlando Gabriella , Squillace Nicola , Esposito Roberto , Vincenzo Rochira , Zirilli Lucia , Martinez Esteban
Published: April 2022

Background

Prevalence and factors associated with sexual dysfunction in HIV-positive women are poorly known.

Methods

This was a cross-sectional study in a cohort of HIV-infected women. Clinically stable women were invited to participate in a female sexual dysfunction (FSD) evaluation with Female Sexual Function Index (FSFI) exploring desire, arousal, lubrication, orgasm, pain and satisfaction. An FSFI score <23 was used for defining FSD. Variables evaluated included body appearance satisfaction, interference of body changes with habits, social life and attitudinal aspects of body image, health-related quality of life, hormonal assessment, menopause, cumulative exposure to antiretroviral drug classes and immune-virological parameters. Lipodystrophy was defined according to the HIV Outpatient Study definition.

Results

A total of 185 women completed the FSFI. The mean (±sd) age was 42 years (±5), 27% had CDC stage C, the mean (±sd) CD4+ T-cell count was 508 cells/μl (±251) and median HIV RNA was 1.7 log10 copies/ ml (interquartile range 1.7–2.6). Among 161 evaluable patients, 59 (32%) reported FSD. In a multiple linear regression analysis, desire, arousal and satisfaction domains were associated with interference of body changes with habits, social life and attitudinal aspects of body image (β=0.22, 95% confidence interval [CI] 0.06–0.37; β=0.29, 95% CI 0.10–0.48; and β=0.20, 95% CI 0.02–0.38, respectively). Lubrication and orgasm domains were associated with body image satisfaction (β=-0.49, 95% CI -0.88— 0.10 and β=-0.58, 95% CI -1.00—0.16, respectively). No significant associations with sex hormones, CDC stage, CD4+ T-cell count, HIV RNA viral load and cumulative exposure to antiretroviral drug classes were found. In women with FSD, severity of self-perceived abdominal fat accumulation showed a trend towards lower FSFI scores (ANOVA P=0.02).

Conclusions

FSD was highly prevalent in this cohort. Self-perceived body changes was identified as its major determinant.
Mortality and morbidity among HIV type-1-infected patients during the first 5 years of a multicountry HIV workplace programme in Africa
Authors: Van der Borght Stefaan F , Clevenbergh Philippe , Rijckborst Henk , Nsalou Paul , Onyia Ngozi , Lange Joep M , de Wit Tobias F Rinke , van der Loeff Maarten F Schim
Published: April 2022

Background

This study aimed to evaluate the effectiveness of an HIV workplace programme in sub-Saharan Africa.

Methods

The international brewing company, Heineken, introduced an HIV workplace programme in its African subsidiaries in 2001. Beneficiaries from 16 sites in 5 countries were eligible. HIV type-1 (HIV-1)-infected individuals were assessed clinically and immunologically, and started highly active antiretroviral therapy (HAART) if they had AIDS or had a CD4+ T-cell count <300 cells/μl. In this cohort, study patients were followed-up for vital status, new AIDS events, CD4+ T-cell count and haemoglobin.

Results

Over the first 5 years of the programme, 431 adults were found to be HIV-1-infected. The mortality rate among those not yet taking HAART was 2.6 per 100 person-years of observation (pyo). By October 2006, 249 patients had started HAART at a median CD4+ T-cell count of 170 cells/μl; 59 (23.7%) patients were in CDC stage C. Among patients on HAART, 25 died and 7 were lost to follow-up. The mortality rate was 3.7 per 100 pyo overall, 14 per 100 pyo in the first 16 weeks and 2.5 per 100 pyo thereafter ( P<0.0001). At 4 years after start of treatment, 89% of patients were known to be alive. The CD4+ T-cell count increased by a median of 153 and 238 cells/μl after 1 and 4 years of HAART, respectively.

Conclusions

In this HIV workplace programme in sub-Saharan Africa, long-term high survival was achieved.