bluuebunny/crossref_metadata_2025 huggingface dataset:
Response to Interferon-Based Therapies in HIV-Infected Patients with Chronic Hepatitis C Due to Genotype 4
Authors: Soriano Vincent , Núñez Marina , Sánchez-Conde Matilde , Barreiro Pablo , García-Samaniego Javier , Martín-Carbonero Luz , Romero Miriam , González-Lahoz Juan
Published: April 2022

Background

The hepatitis C virus (HCV) genotype is the main predictor of response to interferon (IFN)-based therapies. HCV genotype 4 is spreading among European intravenous drug users, who are frequently coinfected with HIV. Information about treatment response in this subset of patients is scarce and conflicting results have been reported.

Methods

All HIV-infected patients treated for chronic hepatitis C at our institution with a minimum follow-up of 6 months after discontinuing therapy were retrospectively analysed. They had received one of three HCV treatment modalities: IFN monotherapy, IFN plus ribavirin (RBV) or pegylated interferon (PEG-IFN) plus RBV. Treatment responses were stratified according to HCV genotype.

Results

A total of 390 patients were analysed. Sustained virological response (SVR) to HCV therapy had been reached by 90 (23.1%): 22/119 (18.5%) with IFN monotherapy; 17/106 (16%) with IFN plus RBV; and 51/165 (30.9%) with PEG-IFN plus RBV. SVR was significantly higher among those with HCV genotypes 2 or 3 (40.4%; 61/151) than in patients with either HCV genotype 1 (11.2%; 22/197) or HCV genotype 4 (16.7%; 7/42) ( P<0.0001). In contrast, there were no significant differences in the response rate comparing HCV genotypes 1 and 4 ( P=0.53).

Conclusions

Response to IFN-based therapies in HIV-positive patients with hepatitis C due to HCV genotype 4 is poor, similar to that obtained for HCV genotype 1 and much lower than for HCV genotypes 2 and 3. Therefore, HIV-infected patients with hepatitis C due to genotype 4 should be considered as a particular subset of difficult-to-treat patients. New treatment strategies and drugs for these patients are eagerly awaited.
Pharmacokinetics of Reduced-Dose Indinavir/Ritonavir 400/100 Mg Twice Daily in HIV-1-Infected Thai Patients
Authors: Boyd Mark , Mootsikapun Piroon , Burger David , Chuenyam Theshinee , Ubolyam Sasiwimol , Mahanontharit Apicha , Sangkote Jongkol , Bunyaprawit Parichart , Horsakulchai Manasinee , Lange Joep , Cooper David , Phanuphak Praphan , Ruxrungtham Kiat
Published: April 2022

Objective

To study the pharmacokinetics of indinavir/ ritonavir 400/100 mg twice daily in antiretroviral-naive patients at Srinagarind Hospital in Khon Kaen, Thailand.

Methods

This was a steady-state, open-label pharmacokinetic study of 19 patients. A 12 h pharmacokinetic curve was recorded after an overnight fast. Plasma levels of indinavir and ritonavir were determined by a validated HPLC method. Virological failure was defined according to the most recent US Department of Health and Human Services guidelines as a viral load above 400 copies/ml at week 24.

Results

Median baseline values for CD4 and viral load were 13 cells/mm3 and 167000 copies/ml, respectively. The median (interquartile ranges) for indinavir AUC, Cmax and Cmin were 18.1 (15.3–23.8) mg/l•h, 4.1 (3.6–4.8) mg/l and 0.17 (0.12–0.30) mg/l, respectively. These values represent 37%, 39% and 24% of the AUC, Cmax and Cmin values found, respectively, for the indinavir/ritonavir 800/100 mg dose in HIV-1-infected Thai patients. Short-term virological response was satisfactory. There were three subjects with an indinavir Cmin below the target value of 0.10 mg/l, of whom one had virological failure (33%). Among the other 16 subjects with an indinavir Cmin above 0.10 mg/l, there was also one virological failure (6%) ( P=0.30).

Conclusions

Indinavir exposure in this reduced-dose regimen of 400 mg with 100 mg ritonavir twice daily was more than dose-proportionally lower than previously observed with the indinavir/ritonavir 800/100 mg twice daily regimen. Therapeutic Cmin levels of indinavir were achieved in >80% of the subjects and short-term virological response was satisfactory in this cohort of patients starting highly active antiretroviral therapy at an advanced disease stage with high baseline viral loads.
Muscle and Liver Lactate Metabolism in Haart-Treated and Naive HIV-Infected Patients: The Mitovir Study
Authors: Ghosn Jade , Guiguet Marguerite , Jardel Claude , Benyaou Rabah , Zeller Valérie , Simon Anne , Valantin Marc-Antoine , Amellal Bahia , Assoumo Lambert , Hogrel Jean-Yves , Costagliola Dominique , Katlama Christine , Lombès Anne
Published: April 2022

Objective

To assess the impact of nucleoside analogue reverse transcriptase inhibitor (NRTI) combination therapy on muscle and liver lactate metabolism in HIV-infected patients.

Methods

This cross-sectional study involved HIV-infected patients who were either antiretroviral-naive (Group 1) or were receiving either a stable triple-drug combination including at least one d-drug (zidovudine, zalcitabine, stavudine, didanosine; Group 2) or a backbone of abacavir and lamivudine (Group 3). Lactataemia was measured at rest. Muscle lactate metabolism was assessed during a standardized exercise test and liver lactate metabolism during intravenous lactate infusion. Mitochondrial DNA was quantified in peripheral blood mononuclear cells.

Results

A total of 65 patients were enrolled (16, 31 and 18 patients in Group 1, Group 2 and Group 3, respectively). None of the patients had symptoms of hyperlactataemia. Patients in Group 3 had received d-drugs for a median of seven years before switching to abacavir and lamivudine. Median baseline lactataemia, although within the normal range, was significantly higher in both treatment groups than in the naive patients (Group 2: 1.4, Group 3: 1.5, and Group 1: 1.0 mmol/l, P=0.005). Muscle lactate clearance was significantly lower in both treatment groups than in naive patients (Group 2: 1.6, Group 3: 1.8, and Group 1: 2.1, P=0.01). Lactate liver metabolism and mitochondrial DNA levels did not differ among the three groups.

Conclusions

In HIV-infected patients without symptomatic hyperlactataemia, all NRTI-containing HAART regimens appear to cause muscle mitochondrial damage but to spare the liver. Absence of difference between Group 2 and Group 3 raises questions about the potential reversibility of muscle mitochondrial dysfunction, and/or the ability of abacavir and lamivudine to induce such mitochondrial damage.
Efficacy and Safety of Once-Daily Combination Therapy with Didanosine, Lamivudine and Nevirapine in Antiretroviral-Naive HIV-Infected Patients
Authors: Ribera Esteban , Rodríguez-Pardo Dolors , Rubio Manuel , Soler Anna , Pedrol Enric , Blanco José L , González Alicia , Crespo Manel , Falcó Vicenç , Ocaña Imma , Deig Elisabeth , Miró Jose M , Pahissa Albert
Published: April 2022

Background

Simplified antiretroviral regimens are needed to improve patient adherence and quality of life. The purpose of this study was to evaluate the efficacy and safety of a once-daily regimen consisting of didanosine (ddI), lamivudine (3TC) and nevirapine (NVP) for adult antiretroviral-naive patients with HIV-1 infection.

Methods

This was a prospective, one-arm, multicentre pilot study. Daily drug dosage was 250 or 400 mg didanosine, 300 mg lamivudine and 400 mg nevirapine. The primary outcome measure was the percentage of patients with a plasma HIV-RNA level <50 copies/ml at 12 months on an intention-to-treat (ITT) basis.

Results

Seventy patients were enrolled in the study. At baseline, mean plasma HIV-1 RNA was 5.10 log10 copies/ml, and mean CD4 cell count was 262 cells/μl. At month 12, 67% (95% CI: 56–78) of patients maintained a viral load of <50 copies/ml in the ITT analysis and CD4 counts increased a median of 201 cells/μl. The treatment was more effective in patients with baseline CD4 counts >100 cells/μl than in those with a poorer immunological status at baseline, although the number of patients with CD4 counts <100 was low. Four patients died during the study period. Therapy was discontinued in 18 patients due to virological failure in 11, adverse events in seven, loss to follow-up or withdrawal of consent in four and death in one. Eight out of nine patients with available genotype after virological failure showed resistance mutations to NVP (Y181C and others) and 3TC (M184V/I), and four of them also had ddI resistance (L74V). The lipid profile was favourable, with a decrease in the ratio of total-to-high density lipoprotein cholesterol.

Conclusion

A once-daily combination of ddI, 3TC and NVP seems to be an effective, safe and easy-to-take regimen in antiretroviral-naive patients, at least in those who do not have severe immunodepression at baseline.
Lipid Profiles for Antiretroviral-Naive Patients Starting Pi- and Nnrti-Based Therapy in the Swiss HIV Cohort Study
Authors:   the Swiss HIV Cohort Study, Young Jim , Weber Rainer , Rickenbach Martin , Furrer Hansjakob , Bernasconi Enos , Hirschel Bernard , Tarr Philip E , Vernazza Pietro , Battegay Manuel , Bucher Heiner C , Battegay M , Bernasconi E , Böni J , Bucher H , Bürgisser Ph , Cattacin S , Cavassini M , Dubs R , Egger M , Elzi L , Erb P , Fantelli K , Fischer M , Flepp M , Fontana A , Francioli P , Furrer H , Gorgievski M , Günthard H , Hirschel B , Kaiser L , Kind C , Klimkait Th , Lauper U , Ledergerber B , Opravil M , Paccaud F , Pantaleo G , Perrin L , Piffaretti J-C , Rudin C , Schmid P , Schüpbach J , Speck R , Telenti A , Trkola A , Vernazza P , Weber R , Yerly S
Published: April 2022

Background

Blood lipid abnormalities in patients on highly active antiretroviral therapy (HAART) have been associated with exposure to protease inhibitors (PIs), particularly ritonavir. First therapy with a non-nucleoside reverse transcriptase inhibitor (NNRTI) leads to relatively favourable lipid profiles. We report on medium-term lipid profiles (up to 5 years) for antiretroviral-naive patients starting NNRTI- and PI-based HAART in the Swiss HIV Cohort Study.

Methods

Since April 2000, blood samples taken at visits scheduled every 6 months have been analysed for cholesterol and triglyceride concentrations. For 1065 antiretroviral-naive patients starting HAART after April 2000, we estimated changes in concentration over time using multivariate linear regression with adjustment for baseline covariates, use of lipid-lowering drugs and whether the sample was taken in a fasting state.

Results

Non-high density lipoprotein (HDL) cholesterol levels increase with increasing exposure to either PI- or NNRTI-based therapy, HDL cholesterol levels increase and triglyceride levels decrease with increasing exposure to NNRTI-based therapy, whereas triglyceride levels increase with increasing exposure to PI-based therapy. Between NNRTI-based therapies, there is a slight difference in triglyceride levels, which tend to increase with increasing exposure to efavirenz and to decrease with increasing exposure to nevirapine. Of the three common PI-based therapies, nelfinavir appears to have a relatively favourable lipid profile, with little change with increasing exposure. Of the other two PI therapies, lopinavir with ritonavir has a more favourable profile than indinavir with ritonavir, with smaller increases in both non-HDL cholesterol and triglycerides and an increase in HDL cholesterol. Increasing exposure to abacavir is associated with a decrease in the level of triglycerides.

Conclusion

In general, NNRTI-based therapy is associated with a more favourable lipid profile than PI-based therapy, but different PI-based therapies are associated with very different lipid profiles. Nelfinavir appears to have a relatively favourable lipid profile. Of the two boosted PI therapies, lopinavir appears to have a more favourable lipid profile than indinavir.
Prostratin and Bortezomib are Novel Inducers of Latent Kaposi'S Sarcoma-Associated Herpesvirus
Authors: Brown Helen J , McBride William H , Zack Jerome A , Sun Ren
Published: April 2022

Kaposi's sarcoma-associated herpesvirus (KSHV) establishes latent infections in lymphocytes and endothelial cells, and latent infection is closely linked to tumorigenesis. As few viral markers are expressed during latency, compounds that can safely and efficiently increase lytic gene expression in vivo have been sought. We have found that the non-tumour-promoting phorbol ester prostratin and the proteasome inhibitor bortezomib induce immediate-early, early and late KSHV gene expression from two lymphoma cell lines in vitro. Their ability to induce lytic gene expression supports a role for phorbol-ester and proteasome-regulated signalling pathways in KSHV reactivation and prompts further investigation of prostratin and bortezomib as therapeutic agents for KSHV-associated malignancies.
The Prevalence, Clinical Features and Response to Antiviral Therapy of Patients with Chronic Hepatitis C who are Seropositive for Liver–Kidney Microsome Type 1 Antibodies
Authors: Monti Valentina , Aghemo Alessio , Rumi Maria Grazia , Donato Maria Francesca , Ninno Ersilio Del , Colombo Massimo
Published: April 2022

Background

Antibodies to liver–kidney microsome type 1 (anti-LKM-1), which are a marker of autoimmune hepatitis, are found in a minority of patients with chronic hepatitis C virus (HCV) infection. Whether interferon/ribavirin therapy is safe and effective in these patients is unclear.

Aim

To describe the prevalence, clinical features and response to interferon/ribavirin therapy of anti-LKM-1 seropositive patients with chronic hepatitis C.

Patients and methods

All anti-LKM-1 seropositive patients with chronic hepatitis C who between 1997 and 2002 underwent a diagnostic liver biopsy at the Liver Center Maggiore Hospital, Milan, were studied. Serum HCV RNA was tested by in-house PCR with a limit sensitivity of 50 IU/ml. Tissue antibodies were assessed by indirect immunofluorescence on cryostat sections from rat liver, kidney and stomach. Liver biopsies were graded and staged by the Ishak score. Autoimmune hepatitis was defined according to the International Autoimmune Hepatitis Grading (IAHG) score.

Results

Forty-eight (1.8%) of 2675 HCV patients circulated anti-LKM-1 (30 females, 55 years of age). Twenty-eight had genotype 2, 18 genotype 1, and two genotype 3. Aminotransferase levels had been high for 23 ± 12 years, on average. Using IAHG, autoimmune hepatitis was excluded in 44 patients (92%) and found to be probable in 4 patients (8%). Chronic hepatitis was histologically mild in 34 patients (70%), moderate to severe in 7 patients (15%) and with cirrhosis in 7 patients (15%). A sustained virological response (SVR) was achieved in 20 of the 27 patients who received interferon/ribavirin (13 genotype 2c with 87% SVR, and 7 genotype 1b with 58% SVR). None of the patients had serum aminotransferases, immunoglobulins or anti-LKM-1 levels flaring following therapy.

Conclusions

LKM-1 antibodies rarely occur in patients with chronic hepatitis C and do not predict autoimmune hepatitis, interferon/ribavirin hyporesponsiveness or immune-related reactions to therapy.
Saquinavir 500 mg Film-Coated Tablets Demonstrate Bioequivalence to Saquinavir 200 mg Hard Capsules When Boosted with Twice-Daily Ritonavir in Healthy Volunteers
Authors: Bittner Beate , Riek Myriam , Holmes Beverly , Grange Susan
Published: April 2022

Objective

To establish the bioequivalence of a 500 mg film-coated tablet of saquinavir mesylate (FCT SQV) to the 200 mg hard-capsule saquinavir mesylate (HC SQV), both boosted with ritonavir and administered under fed conditions.

Methods

We carried out a multi-centre, open-label, randomized, two-sequence, four-period, two-treatment, replicated crossover study in 93 healthy men and 7 healthy women. Individuals were randomly assigned to receive sequential single doses of saquinavir in one of two treatment sequences: ABAB or BABA. Individuals received 100mg ritonavir twice daily for 24 days. On days 14, 17, 20 and 23, study participants took 1000mg of HC SQV (five 200 mg capsules, treatment A) or FCT SQV (two 500 mg tablets, treatment B) with a high-fat, high-calorie breakfast, and pharmacokinetic analyses were carried out over the next 24 hours. Area under the saquinavir concentration–time curve (AUC0–∞), maximum saquinavir plasma concentration (Cmax), time to Cmax and terminal half-life were calculated. The relative bioavailability of FCT SQV versus HC SQV was calculated as the ratio of the respective estimated mean saquinavir AUC0-∞ and Cmax. The calculation was based on an ANOVA including the factors site, sex, sequence, period, treatment and study participant to the log-transformed parameters log(AUC0-∞) and log(Cmax); the relative bioavailability and the 90% confidence intervals (CIs) were estimated using the treatment contrasts of the ANOVA. Bioequivalence was concluded as for both parameters, AUC0-∞ and Cmax, the 90% CIs for the relative bioavailability were entirely included in the reference region [0.80–1.25].

Results

Saquinavir plasma concentration–time profiles for the two formulations were similar. Geometric mean AUC0-∞ and Cmax values were clearly increased for FCT SQV (26 826 versus 24 430 h*ng/ml; and 3644 versus 3064 ng/ml, respectively); ratios of mean exposures were estimated to be 1.10 for AUC0-∞ and 1.19 for Cmax of saquinavir. However, the corresponding two-sided 90% CIs (1.04–1.16 and 1.14–1.25, respectively) all fell within the limits set for equivalence (0.80, 1.25). The adverse event profile for FCT SQV was similar to that for HC SQV.

Conclusion

The new 500 mg FCT SQV formulation is bioequivalent to the 200 mg HC SQV formulation, at the dose of 1000 mg, in combination with 100 mg ritonavir under fed conditions. The 500 mg FCT SQV formulation reduces pill count for boosted saquinavir (SQV/r) from six capsules to three tablets twice daily. This may increase patient acceptability of SQV/r, particularly in less treatment-experienced patients.
Predictors of Hypertension and Changes of Blood Pressure in HIV-Infected Patients
Authors: Thiébaut Rodolphe , El-Sadr Wafaa M , Friis-Møller Nina , Rickenbach Martin , Reiss Peter , Monforte Antonella D'Arminio , Morfeldt Linda , Fontas Eric , Kirk Ole , Wit Stephane De , Calvo Gonzalo , Law Matthew G , Dabis François , Sabin Caroline A , Lundgren Jens D ,   for the “Data Collection of Adverse events of anti-HIV Drugs” (D:A:D) Study Group, El-Sadr W , Calvo G , Dabis F , Kirk O , Law M , Monforte A d'Arminio , Morfeldt L , Pradier C , Reiss P , Weber R , Wit S De , Zaheri S , Gras L , Thiébaut R , Balestre E , Petoumenos K , Mateu S , Torres F , Sommereijns B , Poll B , Bartsch G , Thompsen G , Kjær J , Pezzotti P , Fontas E , Caissotti C , Sundström A , Thulin G , Rickenbach M , Keiser O , Sabin CA , Phillips AN , Collins S , Friis-Møller N , Worm S W , Sawitz A , Lundgren JD , Mertenskoetter T , Loeliger E , Tressler R , Weller I
Published: April 2022

Objective

We assessed predictors of changes in systolic (SBP) and diastolic (DBP) blood pressure during follow-up and of the development of hypertension in HIV-infected individuals.

Methods

International cohort collaborative study (D:A:D) of established prospective cohorts of HIV-1-infected patients. Longitudinal analysis of changes in blood pressure (BP) was performed using mixed effects models in 17170 patients. Predictors of development of hypertension during follow-up (systolic BP ≥140 and/or diastolic BP ≥90 mmHg or initiation of antihypertensive treatment) were assessed using Cox models in 8 984 patients with a normal BP level at baseline.

Results

73548 BP measurements with a median of 4 per patient (interquartile range [IQR]: 2–6) were recorded over a median follow-up of 2.3 years (IQR: 1.5–2.6). Risk factors significantly associated with a development of higher systolic BP and diastolic BP (differences ≥5 mmHg and P-values <0.001) during follow-up were: older age, male sex, higher body mass index (BMI) and use of BP-lowering drugs. In patients with normal BP at baseline, 1186 developed hypertension for an incidence of 72.1 per 1000 person-years (95% confidence interval: 68.2–76.0). Factors associated with development of hypertension were: male sex, higher BMI, older age, higher BP at baseline, high total cholesterol and clinical lipodystrophy. Cumulative duration of exposure to nucleoside reverse transcriptase inhibitors ( P=0.75), protease inhibitors ( P=0.92) as well as type of antiretroviral treatment at baseline ( P=0.18) were not associated with a higher risk of hypertension. Cumulative duration of exposure to non-nucleoside reverse transcriptase inhibitors (NNRTIs) was significantly associated with lower risk of hypertension (hazard ratio=0.78 and 0.67 for those treated ≤10 months and >10 months compared with no exposure; P=0.005).

Conclusions

Increased blood pressure in HIV-infected individuals is associated with established risk factors for hypertension. There was no evidence for an independent deleterious effect of any class of antiretroviral drugs on BP, although the use of NNRTIs was associated with a lower risk of development of hypertension.
Baseline Factors associated with Haematological Toxicity that Leads to a Dosage Reduction of Pegylated Interferon-α2a and Ribavirin in HIV- and HCV-Coinfected Patients on HCV Antiviral Therapy
Authors: Fuster Daniel , Huertas Jaime A , Gómez Guadalupe , Solà Ricard , García Juan González , Vilaró Josep , Pedrol Enric , Force Lluís , Tor Jordi , Sirera Guillem , Videla Sebastiá , Planas Ramon , Clotet Bonaventura , Tural Cristina ,   for the PEG-TOX Research Group, Fuster Daniel , Tor Jordi , Sirera Guillem , Videla Sebastiá , Planas Ramon , Clotet Bonaventura , Tural Cristina , Huertas Jaime A , Gómez Guadalupe , Solà Ricard , García Juan González , Vilaró Josep , Pedrol Enric , Force Lluís , Cervantes Manel , García Isabel , Roget Mercè
Published: April 2022

Objective

To assess the baseline factors associated with haematological toxicity that lead to ribavirin or pegylated interferon (peginterferon) dosage reductions in hepatitis C and human immunodeficiency virus (HCV/HIV)-coinfected patients.

Design

Multicentre, prospective, observational study.

Setting

Eleven hospitals in Spain during the period 2002–2003.

Subjects and methods

One-hundred and forty-two HIV/HCV-coinfected patients received peginterferon-α2a plus ribavirin. Baseline characteristics and haematological parameters were recorded at baseline, week 4, 8, 12, 24 and 48. Cox's regression model was used to study the factors associated with the appearance of a haemoglobin level below 10g/dl (haemoglobin-endpoint), a neutrophil count below 750/mm3 (neutrophil-endpoint) and a platelet count below 50,000/mm3 (platelet-endpoint).

Results

Nineteen patients (13.4%) reached the haemoglobin-endpoint, 22.5% the neutrophil-endpoint and 7% the platelet-endpoint. Mean time of follow-up was 8 months (±3.5). A baseline haemoglobin level below 14g/dl [hazard ratio (HR): 3.65; 95% confidence interval (CI): 1.46–9.06] and treatment with zidovudine (HR: 3.25; 95% CI: 1.31–8.11) were the independent factors associated with the appearance of the haemoglobin-endpoint. A baseline neutrophil below 2050/mm3 (HR: 3.59; 95% CI: 1.77–7.28) and baseline weight <60 kg (HR: 2.21; 95% CI: 1.04–4.56) were independently associated with the appearance of the neutrophil-endpoint. Baseline platelet count (x1000/mm3 decrease) (HR: 1.074; 95% CI: 1.04-1.11) was independently associated with the appearance of the platelet-endpoint.

Conclusions

Baseline factors allow the identification of a subset of HIV/HCV-coinfected patients who are prone to experience haematological toxicity during HCV antiviral therapy.
Improvement in Dyslipidaemia after Switching Stavudine to Tenofovir and Replacing Protease Inhibitors with Efavirenz in HIV-Infected Children
Authors: Viganò Alessandra , Aldrovandi Grace M , Giacomet Vania , Merlo Marzia , Martelli Laura , Beretta Silvia , Luraschi Paola , Rombolà Giuseppe , Mora Stefano
Published: April 2022

Objective

To assess the impact on immunological, virological and metabolic parameters of replacing protease inhibitors (PIs) with efavirenz and replacing stavudine with tenofovir in HIV-infected children.

Methods

A 48-week prospective evaluation of 28 HIV-infected children, with stable undetectable HIV-1 loads, who were taking highly active antiretroviral therapy (HAART) containing lamivudine, stavudine and a PI. Individuals were randomized to switch PI to efavirenz and stavudine to tenofovir at baseline (Group 1) or at week 24 (Group 2). Patient assessment included: clinical evaluation, viral load, CD4+ T-cell count, fasting blood levels and urine samples.

Results

All individuals maintained HIV RNA <50 copies/ml and unchanged CD4+ T-cell count through week 48. In Group 1 individuals, a significant decrease in cholesterol ( P<0.05), cholesterol:high-density lipoprotein (HDL) ratio ( P<0.01) and triglycerides ( P<0.05) was observed 24 and 48 weeks after the switch of HAART. The percentage of Group 1 children with increased cholesterol and triglycerides markedly decreased over the study period (from 43% to 0% and from 36% to 7%, respectively). In Group 2 individuals, unchanged lipids in the 24 weeks prior to the switch of HAART and a significant improvement on cholesterol ( P<0.05), cholesterol:HDL ratio ( P<0.01) and triglycerides ( P<0.05) were observed 24 weeks after the switch of HAART. The percentage of Group 2 children with increased cholesterol and triglycerides markedly decreased 24 weeks after the switch of HAART (from 46% to 7% and from 54% to 0%, respectively). Proteinuria and glucosuria were not detected in any individual. The mean values of serum creatinine, serum phosphorus, serum bicarbonate, estimated glomerular filtration rate, urinary microalbumin/creati-nine, α-1-microglobulin/creatinine ratio and maximal tubular phosphate reabsorption remained unchanged in both groups.

Conclusions

In HIV-infected children, switching PI to efavirenz and stavudine to tenofovir is virologically and immunologically safe, is not associated with renal impairment and provides a significant improvement in lipid profile.
Neuraminidase Inhibitor Susceptibility Network Position Statement: Antiviral Resistance in Influenza A/H5N1 Viruses
Authors: Hayden Frederick , Klimov Alexander , Tashiro Masato , Hay Alan , Monto Arnold , McKimm-Breschkin Jennifer , Macken Catherine , Hampson Alan , Webster Robert G , Amyard Michèle , Zambon Maria
Published: April 2022

The emerging epidemic of H5N1 avian influenza virus with spillover into the human population in Asia has provoked intense concern globally about the potential of these particularly pathogenic viruses to evolve with the capacity for human-to-human transmission with a consequent pandemic. The availability of antiviral drugs with activity against influenza A viruses and the recognition of drug-resistant variants to these drugs prompted the following report by a select group of the global experts – members of the Neuraminidase Inhibitor Susceptibility Network – on the best use of the available drugs, both for prophylaxis and treatment. The editors of Antiviral Therapyare pleased to be able to provide this document in an expeditious manner.
The Role of Hepatitis C Virus (HCV) in Mitochondrial Dna Damage in HIV/HCV-Coinfected Individuals
Authors: de Mendoza Carmen , Soriano Vincent
Published: April 2022

Oxidative stress accompanying hepatitis C virus (HCV) infection seems to result in mitochondrial (mt) dysfunction. In HIV/HCV-coinfected individuals, HCV-related mt damage could be further enhanced and clinical manifestations of mt damage may appear, particularly following exposure to some antiretroviral drugs. Furthermore, when HCV medications are used together with certain antiretrovirals, the risk of developing mt adverse events may be particularly frequent, such as development of pancreatitis when ribavirin and didanosine are coadministered. The management of HIV/HCV-coinfected individuals needs to consider the high risk of mitochondria-associated toxicities in this population, which may significantly influence treatment decisions and therapeutic modalities.
When to Initiate Highly Active Antiretroviral Therapy in Sub-Saharan Africa? A South African Cost-Effectiveness Study
Authors: Badri Motasim , Cleary Susan , Maartens Gary , Pitt Jennifer , Bekker Linda-Gail , Orrell Catherine , Wood Robin
Published: April 2022

Background

Large-scale programmes increasing access to highly active antiretroviral therapy (HAART) are being implemented in sub-Saharan Africa. However, cost-effectiveness of initiating treatment at different CD4 count thresholds has not been explored in resource-poor settings.

Methods

A cost-effectiveness analysis was conducted from a public health perspective using primary treatment outcomes, healthcare utilisation and cost data (Jan 2004 local prices; US$1=7.6 Rands) derived from the Cape Town AIDS Cohort. A Markov state-transition model was developed to estimate life-expectancy, lifetime costs, quality-adjusted life-years (QALYs), cost per life-year and QALY gained for initiating HAART at three CD4 cell count thresholds (<200/μl, 200–350/μl and >350/μl), including the no antiretroviral therapy (No-ART) alternative. Each treatment option was compared with the next most effective undominated option.

Results

Mean life-expectancy was 6.2, 18.8, 21.0 and 23.3 years; discounted (8%) QALYs were 3.1, 6.2, 6.7 and 7.4; and discounted lifetime costs were US$5,250, US$5,434, US$5,740, US$6,588 for No-ART, and therapy initiation at <200/μl, 200–350/μl and >350/μl scenarios respectively. Clinical benefits increased significantly with early therapy initiation. Initiating therapy at <200/μl had an incremental cost-effectiveness ratio (ICER) of US$54 per QALY versus No-ART, 200–350/μl had an ICER of US$616 versus therapy initiation at <200/μl, and >350/μl had an ICER of US$1,137 versus therapy initiation at 200–350/μl ICERs were sensitive to HAART cost.

Conclusions

HAART is reasonably cost-effective for HIV-infected patients in South Africa, and most effective if initiated when CD4 count >200/μl. Deferring treatment to <200/μl would reduce the aggregate cost of treatment, but this should be balanced against the significant clinical benefits associated with early therapy.
An Open-Label, Randomized Comparative Pilot Study of a Single-Class Quadruple Therapy Regimen versus a 2–Class Triple Therapy Regimen for Individuals Initiating Antiretroviral Therapy
Authors: Moyle Graeme , Higgs Christopher , Teague Alastair , Mandalia Sundhiya , Nelson Mark , Johnson Margaret , Fisher Martin , Gazzard Brian
Published: April 2022

Objective

To examine the antiviral potency and tolerability profile of a single-class four drug (quadruple) nucleoside reverse transcriptase inhibitor (NRTI) regimen compared with a 2-class standard-of-care regimen.

Methodology

A three-centre, randomized, open-label comparative pilot study of zidovudine/lamivudine/efavirenz (triple) versus abacavir/lamivudine/zidovudine/tenofovir (quadruple) therapy in HIV-1-infected, treatment-naive individuals. Both regimens were taken without regard to food and consisted of a twice-daily regimen and 3 pills/day. The study power was based on time-weighted average changes in HIV-1 RNA load.

Results

A total of 114 individuals (56 triple, 57 quadruple) received at least one dose of medication. Patients were well matched at baseline for viral load (mean 5.26 log10 versus 5.13 log10, respectively) and CD4 cell count (median 193 versus 153 cells/mm3, respectively). The two regimens performed similarly with regards to all endpoints. At week 48, by intention-to-treat, missing=failure analysis, 68% of triple- and 67% of quadruple-drug treated patients had an HIV-1 RNA <50 copies/ml ( P>0.05). On-treatment analysis showed 40/40 (100%) of triple- and 39/40 (97.5%) of quadruple-drug treated patients ( P=0.996) had responded to <50 copies/ml. No unexpected adverse events were reported. Changes in total cholesterol and triglycerides were modest but significantly favoured the quadruple therapy regimen at multiple time points.

Conclusion

This pilot study suggests a quadruple NRTI-based regimen provides similar antiviral potency, tolerability and administrative characteristics to a 2-class triple therapy regimen. These findings should be confirmed in a more fully powered study. Potent quadruple NRTI-based regimens may have advantages for some individuals with regards to salvageability, tolerability and drug interactions.
Hepatic Interferon Receptor Mrna Expression: Clinical Relevance and Its Relationship with Effectiveness of Interferon plus Ribavirin Therapy in Patients with Genotype 1B Hepatitis C Virus Infection
Authors: Lee Chuan-Mo , Kee Kwong-Ming , Hung Chao-Hung , Eng Hock-Liew , Chang Chien-Hwa , Huang Chao-Min , Wang Jing-Houng , Hu Tsung-Hui , Lu Sheng-Nan , Changchien Chi-Sin , Chen Wei-Jen
Published: April 2022

Background/aims

Hepatic expression of interferon (IFN) receptor mRNA has been shown to correlate with the effectiveness of IFN monotherapy in patients with chronic hepatitis C virus (HCV) infection. We investigated the expression of hepatic IFN receptor alpha/beta (IFNAR2c) mRNA and its association with the effectiveness of IFN plus ribavirin (RBV) therapy and with the clinical features in patients with HCV genotype 1b (HCV-1b) infection.

Methods

A total of 42 naive patients who had chronic HCV-1b infection were treated with IFN alpha-2b 3 MU or 5 MU three times weekly plus RBV for 24 weeks. Hepatic IFNAR2c mRNA was quantified by real-time RT-PCR.

Results

There was no significant difference in the mean expression level of IFNAR2c mRNA between patients with sustained virological response (SVR) and non-SVR (0.069 ±0.042 versus 0.053 ±0.033, P=0.182). Multiple linear regression analysis showed that lower fibrosis scores ( P=0.006) and younger age ( P=0.03) were associated with hepatic IFNAR2c mRNA expression with r2=0.34.

Conclusions

Hepatic IFNAR2c mRNA expression may not be useful for predicting the response to IFN plus RBV therapy in patients with HCV-1b infection, but appeared to correlate inversely with the fibrosis stage and age.
Exploring Mitochondrial Nephrotoxicity as a Potential Mechanism of Kidney Dysfunction among HIV-Infected Patients on Highly Active Antiretroviral Therapy
Authors: Côté Hélène CF , Magil Alex B , Harris Marianne , Scarth Brian J , Gadawski Izabelle , Wang Nancy , Yu Eugenia , Yip Benita , Zalunardo Nadia , Werb Ron , Hogg Robert , Harrigan P Richard , Montaner Julio S
Published: April 2022

Background

Tenofovir (TDF) exposure has been associated with renal dysfunction. Mitochondrial nephrotoxicity was investigated as an underlying mechanism. Given the interaction between TDF and didanosine (ddI), their concurrent use was also investigated.

Design

Relative kidney biopsy mitochondrial DNA (mtDNA) to nuclear DNA ratios were measured retrospectively. HIV+ individuals on TDF within 6 months preceeding the biopsy (HIV+/TDF+, n=21) were compared to HIV+ individuals who never received TDF (HIV+/TDF-, n=10) and to HIV uninfected controls (HIV–, n=22). Twelve of the HIV+/TDF+ individuals received concurrent ddI, 10 of those once at unadjusted ddI dosage. Tubular mitochondria morphology was also examined by electron microscopy. Statistical analyses were done on log-transformed mtDNA/nDNA, using non-parametric tests.

Results

Kidney mtDNA levels were different among the three groups ( P=0.046). mtDNA ratios were lower in HIV+/TDF+ subjects (7.5 [2.0–12.1]) than in HIV- ones (14.3 [6.0–16.5], P=0.014), but not lower than HIV+/TDF-controls (6.4 [2.8–11.9], P=0.82). Among HIV+ subjects, there was a difference between TDF-, TDF+/ddI- and TDF+/ddI+ ( P=0.005), with concurrent TDF/ddI use associated with lower mtDNA (2.1 [1.9–5.5], n=12) than TDF+/ddI- (13.8 [7.5–16.4], n=9, P=0.003). No TDF–/ddI+ biopsies were available. In regression analyses, only HIV infection ( P=0.03), and TDF/ddI use ( P=0.003) were associated with lower mtDNA. At the ultrastructural level, abnormal tubular mitochondria was more prevalent in HIV+/TDF+ biopsies than HIV+/TDF- and HIV- ones together ( P<0.001) but not more so in TDF+/ddI+ biopsies than TDF+/ddI- ones ( P=0.67).

Conclusions

Renal dysfunction in this population may be mediated through mitochondrial nephrotoxicity that involves more than one drug and/or pathogenesis. Kidney mtDNA depletion was associated with HIV infection and concurrent TDF/ddI therapy but not TDF use alone, while kidney ultrastructural mitochondrial abnormalities were seen with TDF use. The interaction between TDF and ddI may be relevant in the kidney where both drugs are cleared. The clinical relevance of our findings needs to be evaluated given the current recommendation for reduced doses of ddI when used in conjunction with TDF.
Risks of Non-Accidental Mortality by Baseline CD4+ T-Cell Strata in Hepatitis-C-Positive and -Negative Individuals Initiating Highly Active Antiretroviral Therapy
Authors: Moore David M , Hogg Robert S , Braitstein Paula , Wood Evan , Yip Benita , Montaner Julio SG
Published: April 2022

Background

Patients coinfected with hepatitis C virus (HCV) and HIV experience higher mortality rates than patients infected with HIV alone. We designed a study to determine whether risks for later mortality are similar for HCV-positive and HCV-negative individuals when subjects are stratified on the basis of baseline CD4+ T-cell counts.

Methods

Antiretroviral-naive individuals, who initiated highly active antiretroviral therapy (HAART) between 1996 and 2002 were included in the study. HCV-positive and HCV-negative individuals were stratified separately by baseline CD4+ T-cell counts of 50 cell/μl increments. Cox-proportional hazards regression was used to model the effect of these strata with other variables on survival.

Results

CD4+ T-cell strata below 200 cells/μl, but not above, imparted an increased relative hazard (RH) of mortality for both HCV-positive and HCV-negative individuals. Among HCV-positive individuals, after adjustment for baseline age, HIV RNA levels, history of injection drug use and adherence to therapy, only CD4+ T-cell strata of <50 cells/μl (RH=4.60; 95% confidence interval [CI] 2.72–7.76) and 50–199 cells/μl (RH=2.49; 95% CI 1.63–3.81) were significantly associated with increased mortality when compared with those initiating therapy at cell counts >500 cells/μl. The same baseline CD4+ T-cell strata were found for HCV-negative individuals.

Conclusion

In a within-groups analysis, the baseline CD4+ T-cell strata that are associated with increased RHs for mortality are the same for HCV-positive and HCV-negative individuals initiating HAART. However, a between-groups analysis reveals a higher absolute mortality risk for HCV-positive individuals.
In Combination, Nucleoside Reverse Transcriptase Inhibitors Have Significant Effects on 3T3–L1 Adipocyte Lipid Accumulation and Survival
Authors: Kosmiski Lisa A , Miller Heidi L , Klemm Dwight J
Published: April 2022

The use of nucleoside reverse transcriptase inhibitors (NRTIs) for the treatment of HIV infection is clearly linked to the development of subcutaneous fat atrophy. Until recently, however, in vitro studies of adipocytes have shown no or only modest and inconsistent effects of these agents on adipocyte biology. This is in contrast to the protease inhibitors (PIs), which are also linked to the development of HIV lipodystrophy. These agents have relatively consistent inhibitory effects on the differentiation of cultured adipocytes, and have occasionally been found to have other effects on adipocyte biology as well. We aimed to explore more thoroughly the effects of NRTIs and combinations of antiretroviral agents commonly used in clinical practice on multiple aspects of adipocyte biology using the 3T3-L1 adipocyte cell line. We found that when used individually, NRTIs decrease cell survival but only lamivudine significantly alters lipid accumulation. However, NRTI and dual NRTI-PI combinations do significantly decrease lipid accumulation in 3T3-L1 adipocytes, have a much greater detrimental impact on cell survival and decrease adipocyte differentiation.
Evolution of Transmitted HIV-1 with Drug-Resistance Mutations in the Absence of Therapy: Effects on Cd4+ T-Cell Count and HIV-1 Rna Load
Authors: Bezemer Daniela , de Ronde Anthony , Prins Maria , Porter Kholoud , Gifford Robert , Pillay Deenan , Masquelier Bernard , Fleury Hervé , Dabis Francois , Back Nicole , Jurriaans Suzanne , van der Hoek Lia ,   the CASCADE collaboration, Babiker Abdel , Bhaskaran Krishnan , Darbyshire Janet , Porter Kholoud , Walker A Sarah , Gifford Rob , Pillay Deenan , Balestre Eric , Capdepont Sophie , Chê Genevneiève , Dabis Francois , Hervé Fleury , Masquelier Bernard , Thiébaut Rodolphe , Hamouda Osamah , Kücherer Claudia , Poggensee Gabriele , Balotta Claudia , Longo Benedetta , Rezza Giovanni , Deho Lorenzo , Rodriguez Carmen , Soriano Vicente , García-Saiz Alfredo , del Romero Jorge , Ortiz Marta , de Mendoza Carmen , Back Nicole , Coutinho Roel , Prins Maria , van der Hoek Lia , Jørgensen Louise Bruun , Nielsen Claus , Pedersen Court , Babiker Abdel , Darbyshire Janet H , Gill Noël , Johnson Anne M , Phillips Andrew N , Porter Kholoud , Gill M John , Gingues Sonia
Published: April 2022

Sequence analysis of HIV-1 from 440 therapy-naive individuals included within the CASCADE study, who seroconverted within 18 months of the last negative test, identified 65 persons infected with a strain carrying resistance-associated mutations. Population-based sequencing was performed for 20 of these individuals during the therapy-free follow-up period. The median time of follow-up was 15 months (interquartile range from 10 to 23 months). Of these individuals, 12 showed subsequent evolution at the resistance positions, whereas the virus of 8 people was stable during this period. In the reverse transcriptase (RT) gene, the drug-resistant 215Y or 215F codons evolved to alternative codons in all six cases, 70R reverted to the wild-type 70K in 3 of the 4 individuals, 67N evolved only in 1 of 4 patients to a wild-type 67D, 215S evolved to wild-type 215T in 1 of 3 patients, 219N evolved to 219K in 1 of 2 patients, and one patient with 184V reversed to the wild-type 184M. The 181C variant evolved to the wild-type 181Y in 1 of 2 individuals. These codon changes were caused by single nucleotide mutations. No evolution was observed for other RT mutations: 41L, 69D, 69N, 190S, 210W, 215L, 215C, 215E and 219Q. In the protease gene, resistance mutations 84V and 90M were stable in 2 individuals. Comparing the CD4+ T-cell count of the 12 evolving versus the 8 stable cases revealed no statistically significant difference at the date of the first sequence following seroconversion. Interestingly, a lower CD4+ T-cell count was observed in the group without evolution at the second sequence time point ( P=0.043). No difference in HIV-1 RNA load was observed. These results, together with the apparent pressure to mutate at the resistance-associated positions exemplify the decreased fitness of viruses carrying 215Y/F, 70R or 184V
Antiviral Efficacy and Genotypic Resistance Patterns of Combination Therapy with Stavudine/Tenofovir in Highly Active Antiretroviral Therapy Experienced Patients
Authors: Antinori Andrea , Trotta Maria Paola , Nasta Paola , Bini Teresa , Bonora Stefano , Castagna Antonella , Zaccarelli Mauro , Quirino Tiziana , Landonio Simona , Merli Stefania , Tozzi Valerio , Perri Giovanni Di , Andreoni Massimo , Perno Carlo Federico , Carosi Giampiero
Published: April 2022

Objectives

To evaluate antiviral efficacy of stavudine/tenofovir (d4T/TDF) backbone combination in late-line antiretroviral therapy, and to assess clinical and virological determinants of treatment success.

Design

Multicentric retrospective analysis on patients starting d4T/TDF after highly active antiretroviral therapy (HAART) failure.

Methods

The primary endpoint was the change in plasma HIV-1 RNA from the baseline (time of d4T/TDF initiation) to 6 months of therapy; secondary endpoint was the risk of virological failure.

Results

Among 172 patients included, a mean change in HIV-1 RNA of -1.69 (+1.23) and -1.53 (+1.43) log10 cp/ml was observed respectively at weeks 24 and 48 after starting d4T/TDF combination. Any single type-1 thymidine analogue mutation (TAM; M41L, L210W, T215Y) had a negative effort on the change in HIV RNA at 6 months, whereas among type-2 TAMs (D67N, K70R, K219Q), only D67N showed a trend for a negative effect. Presence of M184V mutation was related with a greater reduction in HIV RNA during d4T/TDF exposure. The risk of virological failure at 6 months after d4T/TDF starting was 22%. Type-1 TAMs were associated with a greater risk of failure (adjusted hazard ratio [HR]=1.65; 95% confidence interval [CI] 1.19–2.29). Conversely, M184V showed a protective effect. In 17 genotypic tests available at failure, no K65R mutation was detected, whereas a trend for an increasing prevalence of d4T-associated mutations was found.

Conclusions

Combining TDF with a thymidine analogue as d4T may be effective as component of antiretroviral rescue regimens in HIV-infected patients with previous exposure to nucleoside analogue reverse transcriptase inhibitor. Previous selection of type-1 TAMs induces a detrimental effect over virological response.
Low Genetic Barrier to Large Increases in HIV-1 Cross-Resistance to Protease Inhibitors during Salvage Therapy
Authors: Morand-Joubert Laurence , Charpentier Charlotte , Poizat Gwendoline , Chêne Geneviève , Dam Elisabeth , Raguin Gilles , Taburet Anne-Marie , Girard Pierre-Marie , Hance Allan J , Clavel François
Published: April 2022

HIV-1 resistance to protease inhibitors (PIs) is characterized by extensive cross-resistance within this drug class. Some PIs, however, appear less affected by cross-resistance and are often prescribed in salvage therapy regimens for patients who have failed previous PI treatment. To examine the capacity of HIV-1 to adapt to these treatment changes, we have followed the evolution of HIV-1 protease genotypes and phenotypes in 21 protease-inhibitor-experienced patients in whom 26 weeks of an aggressive salvage regimen associating lopinavir, amprenavir and ritonavir failed to suppress viral replication. Baseline genotypes exhibited a median of seven resistance mutations in the protease. After 26 weeks of treatment, changes in protease genotypes were seen in 13/21 patients. The evolution of these protease genotypes was rapid, with more than one-third of the changes occurring during the first 6 weeks. Although the mean number of additional mutations was small (2.15 new mutations at week 26) these mutations were sufficient to promote remarkable changes in resistance phenotype. In several patients, some of the new mutations were found to exist before salvage treatment as part of minority quasi-species. Thus, in the face of the strong pharmacological pressure exerted by combinations of PIs to which it has never been exposed, and in spite of limited cross-resistance to these drugs before salvage therapy, HIV-1 can rapidly adapt its resistance genotype and phenotype at a minimal evolutionary cost.
Oligonucleotide-Based Therapeutic Options against Hepatitis C Virus Infection
Authors: Trepanier Janie B , Tanner Jerome E , Alfieri Caroline
Published: April 2022

The hepatitis C virus (HCV) is the cause of a silent pandemic that, due to the chronic nature of the disease and the absence of curative therapy, continues to claim an ever-increasing number of lives. Current antiviral regimens have proven largely unsatisfactory for patients with HCV drug-resistant genotypes. It is therefore important to explore alternative therapeutic stratagems whose mode of action allows them to bypass viral resistance. Antisense oligonucleotides, ribozymes, small interfering RNAs, aptamers and deoxyribozymes constitute classes of oligonucleotide-based compounds designed to target highly conserved or functionally crucial regions contained within the HCV genome. The therapeutic expectation for such compounds is the elimination of HCV from infected individuals. Progress in oligonucleotide-based HCV antivirals towards clinical application depends on development of nucleotide designs that bolster efficacy while minimizing toxicity, improvement in liver-targeting delivery systems, and refinement of small-animal models for preclinical testing.