bluuebunny/crossref_metadata_2025_split huggingface dataset:
Antiviral Efficacy of Abacavir in Antiretroviral Therapy-Experienced Adults Harbouring HIV-1 with Specific Patterns of Resistance to Nucleoside Reverse Transcriptase Inhibitors
Authors: Lanier E Randall , Ait-Khaled Mounir , Scott Janna , Stone Chris , Melby Thomas , Sturge Glenn , Clair Marty St , Steel Helen , Hetherington Seth , Pearce Gillian , Spreen William , Lafon Stephen 
Published: April 2022

Objective To evaluate HIV-1 reverse transcriptase genotypic and phenotypic indicators of resistance to abacavir (ABC) as predictors of ABC antiviral efficacy. Design The study was a retrospective, combined analysis of five multicentre trials in which ABC was added as a single agent to background antiretroviral therapy in experienced adults. Methods Baseline HIV-1 genotype and phenotypic susceptibility to ABC were determined and the association of genotype and phenotype with virological response after addition of ABC was analysed. Results Overall, 68% of these therapy-experienced subjects had a virological response (>0.5 log10 or <400 copies/ml; 42% <400 copies/ml) 4 weeks after addition of ABC. Multivariable analyses revealed no significant difference in the response rate between subjects with wild-type virus and those carrying virus with 1–2 nucleoside reverse transcriptase inhibitor (NRTI)-associated mutations. At the 4-week time-point subjects harbouring virus with ≥3 mutations associated with NRTI resistance were significantly less likely to respond to ABC than were subjects harbouring wild-type virus ( P=0.015). However, at the last viral RNA measurement after addition of ABC (12-28 weeks), ≥4 mutations were required to diminish virological response significantly ( P=0.012). Phenotypic resistance was also predictive of antiviral response. Significant breakpoints were identified for virological responses for the PhenoSense™ HIV assay and the Antivirogram™ assay. CD4 responses generally paralleled the antiviral responses with a median increase of 55 cells/μl by weeks 12-28. Conclusions Virological response to ABC may be diminished significantly by multiple NRTI-associated mutations and/or by reductions in phenotypic susceptibility to ABC. However, many subjects with baseline samples showing evidence of resistance to NRTIs respond to ABC.
High Rate of Didanosine-Related Mitochondrial Toxicity in HIV/HCV-Coinfected Patients Receiving Ribavirin
Authors: Moreno Ana , Quereda Carmen , Moreno Leonor , Perez-Elías María J , Muriel Alfonso , Casado Jose L , Antela Antonio , Dronda Fernando , Navas Enrique , Bárcena Rafael , Moreno Santiago 
Published: April 2022

Background Nucleoside analogues may induce mitochondrial toxicity, particularly didanosine. Ribavirin increases didanosine exposure, which might be clinically relevant when coadministered in HIV/HCV-coinfected patients. Objective To evaluate, among 89 patients receiving highly active antiretroviral therapy (HAART) and therapy for chronic hepatitis C, clinically relevant mitochondrial toxicity in those treated with concomitant ribavirin and didanosine ( n=35, 39%). Methods From January 2000 to July 2002 longitudinal analysis of the incidence and clinical course of didanosine-related hyperamylasaemia, pancreatitis, hyperlactataemia/lactic acidosis or neuropathy. Risk factors were evaluated using univariate and multivariate Cox's proportional hazards model. Results Among 35 patients who received concomitant didanosine (400 mg/day in 86%) and ribavirin (≥10 mg/kg/day in 91%), 20 (57%) developed one or more adverse events after a mean of 87 days. Most frequent laboratory abnormalities were hyperamylasaemia (18 patients, 51%) and hyperlactataemia (eight patients, 23%). Acute pancreatitis and symptomatic hyperlactataemia developed in 10 (28%) and six (17%) patients, respectively. Two patients (6%) with pancreatitis and severe lactic acidosis died; the other patients recovered uneventfully despite continuation of anti-HCV therapy in 83% after didanosine withdrawal in 40%. In the Cox's model higher baseline amylase levels (HR: 1.04, 95% CI: 1.02–1.06, P=0.001) and three nucleoside reverse transcriptase inhibitor-based HAART (HR: 5.3, 95% CI: 1.73–16.24, P=0.003) were significantly associated to toxicity. Conclusions The coadministration of didanosine and ribavirin should be avoided in HIV/HCV-coinfected patients, due to a high rate of clinically significant toxicity, particularly in triple nucleoside-based HAART. Amylase levels should be strictly monitored, especially if elevated at baseline.
Enhanced T-Cell Maturation, Differentiation and Function in HIV-1-Infected Individuals after Growth Hormone and Highly Active Antiretroviral Therapy
Authors: Pires Antonio , Pido-Lopez Jeffrey , Moyle Graeme , Gazzard Brian , Gotch Frances , Imami Nesrina 
Published: April 2022

Background Strong virus-specific helper and cytotoxic T-cell responses correlate with non-progression during HIV-1 infection. Administration of antiretroviral therapy (ART) during the chronic phases of HIV-1 infection fails to restore these responses in most patients. Design and methods We assessed the changes in immune function of 12 HIV-1-positive individuals treated with ART for over 4 years, who received 4 mg/day of recombinant human growth hormone (rhGH) for 12 weeks and were then randomized into groups receiving either placebo, twice weekly or alternate day dosing of rhGH. Peripheral blood was drawn for phenotypic analysis and functional assays at time points 0, 12 and 24 weeks. Results At week 12, we observed significant increases in naive CD4 T cells ( P<0.01) and effector CD8 T cells based on CD45RA and CCR7 expression ( P<0.02). In addition, we observed a rise in HIV-1 antigen-specific CD4 ( P<0.005) and CD8 ( P<0.05) T-cell responses. Twelve weeks post-randomization into placebo, alternate day or twice weekly dosing (24 weeks post-baseline), the phenotype and function of the virus-specific effector CD8 T cells seen at week 12 was maintained in most patients regardless of randomization arm and despite the disappearance of HIV-1-specific CD4 T-cell responses. Conclusions Concomitant administration of rhGH at 4 mg/day with highly active ART appears to partially reverse some of the defects exerted on the immune system by HIV-1. This combination may represent a valuable immunotherapeutic intervention aiding in the treatment of chronic HIV-1 infection.
Strategies to Decrease Viral Load Rebound, and Prevent Loss of Cd4 and Onset of Resistance during Structured Treatment Interruptions
Authors: Foli Andrea , Maserati Renato , Barasolo Gabriele , Castelli Francesco , Tomasoni Lina , Migliorino Marco , Maggiolo Franco , Pan Angelo , Paolucci Stefania , Scudeller Luigia , Tinelli Carmine , D'Aquila Richard , Lisziewicz Julianna , Lori Franco 
Published: April 2022

Background Toxicity and other drug adherence-related factors have contributed to decreased compliance to antiretroviral regimens amongst HIV-infected patients. Irregular therapy disruption causes loss of CD4 T cells, onset of drug resistance and rapid rebound of plasma viral load (VL). However, an appropriate choice of drugs and properly scheduled structured treatment interruptions (STIs) may limit VL rebound, maintain CD4 counts and minimize resistance. Methods We conducted a clinical study of STIs, RIGHT 901, involving 60 drug-naive patients with chronic HIV infection (CD4 >300, VL >10000) randomized to receive didanosine-stavudine-indinavir (IDV group) or didanosine-stavudine-hydroxyurea (HU group), for 12 weeks. Subsequently, all patients were randomized again to start STI (short induction) or to continue the therapy for an additional 24 weeks before starting STI (long induction). Both groups underwent four STI cycles and then stopped therapy as long as viraemia remained below 10000 copies/ml before reinitiating another four cycles of STI. Results During continuous therapy VLs were suppressed at similar rates in both the HU and IDV groups, while a blunted CD4 count was documented in the HU group. Following the first stop median VL rebounded close to baseline values in both groups, however, during the following STI median VL rebound decreased in the HU group, while in the IDV group VL continued to rebound to values close to baseline, and the difference between the two groups was statistically significant. Moreover, patients treated with HU had a constant and stable CD4 increase during STI, whereas CD4 counts fluctuated in the IDV group, with sharp falls during treatment interruptions and partial CD4 recovery following treatment restart. Even in the presence of IDV resistance predisposing mutations at baseline, no genotypic change in the protease sequence was observed during STI. A relevant mutation in the reverse transcriptase sequence (K70R) emerged in one patient interrupting treatment after 36 weeks of continuous therapy and in one patient after four STI cycles. Side effects (no major events) were similar among groups. Conclusions An appropriate choice of STI schedule and regimens containing drugs less prone to resistance and/or able to prevent CD4 fluctuation may contribute to optimizing STI for chronically infected patients with respect to limiting viral rebound, improving CD4 counts and maintaining a resistance profile comparable to continuous highly active antiretroviral therapy.
Asymptomatic Hyperlactataemia: Predictive Value, Natural History and Correlates
Authors: McComsey Grace A , Yau Linda 
Published: April 2022

Background The significance of asymptomatic hyperlactataemia is unknown. Methods We measured serial lactate levels in a group of HIV-infected subjects. Objectives were to identify covariates associated with hyperlactataemia, and to explore the natural history of hyperlactataemia. Results Overall, 1487 lactate measurements were performed on 396 subjects; 299 subjects had serial lactate testing, with a median of four performed per patient (range: 2–16). At study entry, lactate was >2.4 mmol/l in 6% of subjects and >3.6 mmol/l in 1%. A multiple logistic regression analysis revealed that cholesterol and current stavudine were the only predictors of hyperlactataemia. Lactate levels were highly reproducible both for short-term (within 3 months) and long-term (>1 year) follow-up. During the study period, 16 subjects were identified with sustained hyperlactataemia; 12/16 remained asymptomatic after a median of 210 days (30–585), and four developed symptoms suggestive of lactic acidosis syndrome. In three of the four, asymptomatic hyperlactataemia had preceded the onset of symptoms by 18–122 days. A longitudinal model showed a rapid rise of lactate levels from 0 to 12 months on nucleoside reverse transcriptase inhibitor (NRTI) and then stabilization. Lactate levels did not correlate with baseline or on-study development of lipoatrophy. Conclusions Even when optimal methods of collection are used, asymptomatic hyperlactataemia does exist and could be sustained in a subset of NRTI-treated subjects for as long as 585 days. A subset of these subjects became symptomatic, after as long as 122 days of asymptomatic hyperlactataemia. Asymptomatic hyperlactataemia is not predictive of lipoatrophy. This work was partly presented at the 9th Conference on Retroviruses & Opportunistic Infections. Seattle, Wash., USA, February 2002.
Influence of Mother and Infant Zidovudine Treatment Duration on the Age at Which HIV Infection Can be Detected by Polymerase Chain Reaction in Infants
Authors: Prasitwattanaseree Sukon , Lallemant Marc , Costagliola Dominique , Jourdain Gonzague , Mary Jean-Yves 
Published: April 2022

Objective To investigate the influence of zidovudine (ZDV) prophylaxis duration in mothers and infants on the age at which infection becomes detectable by DNA polymerase chain reaction (PCR) in non-breastfed infants. Methods Blood samples were collected sequentially from birth to 6 months in a Thailand perinatal HIV prevention trial in which 98 transmissions occurred. The proportions of infections detectable at birth and the Turnbull distributions of age at which infection became detectable after birth were compared according to actual ZDV treatment duration (mothers: no more than 7.5 weeks versus more; infants: 3 days versus at least 4 weeks), provided an adherence greater than 75%. Results Detectable infection at birth was less frequent in children whose mothers received a long treatment as compared to a short treatment (27 vs 50%, P=0.04). When mothers received a long treatment, infant ZDV treatment duration did not influence the distribution of age at which infection became detectable after birth (median 24 days). However, when mothers received a short treatment, this distribution was shifted to the right when infants received a long treatment (median 43 days, P<0.0001), and to the left when infants received a short treatment (median 11 days, P<0.0001). Conclusions When mothers receive a short treatment, the proportion of infections detectable at birth is higher and the time at which infection becomes detectable after birth depends on the infant treatment duration. In the study conditions, a PCR result after 2 months could be used to define infection status.
In Vitro Susceptibility of Lamivudine-Resistant Hepatitis B Virus to Adefovir and Tenofovir
Authors: Lada Olivier , Benhamou Yves , Cahour Annie , Katlama Christine , Poynard Thierry , Thibault Vincent 
Published: April 2022

Emergence of lamivudine-resistant hepatitis B virus (HBV) is a major concern in human immunodeficiency virus (HIV) and HBV coinfected patients. Following selection of resistant mutants, hepatitis flare or rapid progression to cirrhosis may occur. Treatment of patients with new nucleotide analogues such as adefovir dipivoxil (ADV) or tenofovir disoproxil fumarate (TDF) has shown good efficacy in controlling wild-type or lamivudine-resistant HBV replication. The purpose of this study was to assess the in vitro efficacy of new nucleotide analogues on HBV strains isolated from lamivudine-treated patients. After purification of HBV DNA from patient sera, the whole HBV genome was PCR-amplified and cloned. Drug sensitivity was measured after transfection of the isolated full genomes into HepG2 cells and measurement of HBeAg, HBsAg and viral replication in the culture media under increasing drug concentrations. A wild-type strain isolated from an untreated patient served as control. In a clinical study of ADV (Gilead 460i study), seven of the 35 patients carried HBV strains with the triple lamivudine resistance-associated amino-acid changes rtV173L/L180M/M204V at baseline. Although all patients responded to ADV in this clinical study, the serum HBV reduction was lower in the seven patients with the triple mutation (median –3.3 log copies/ml) compared to the patients who had only the rtL180M/M204V mutations (median –4.1 log copies/ml) at week 48 ( P=0.04, Mann-Whitney test). In our in vitro system, lamivudine IC50 on lamivudine-resistant HBV carrying amino-acid substitutions rtL180M and rtM204V within the polymerase encoding region increased by more than 16000-fold (from 6 nM to over 100 μM) when compared to wild-type HBV. For ADV and TDF, comparison of wild-type and lamivudine-resistant HBV IC50 (rtL180M-M204V) showed, respectively, 2.85fold (from 0.07 to 0.2 μM) and 3.3-fold (from 0.06 to 0.2 μM) increases, indicating a mild decrease of both drug activities, in vitro. At the ADV concentration of 0.1 μM, presence of the V173L mutation reduced the inhibition of HBsAg production from 50 to 30% ( P<0.01) and the viral replication from 45 to 32% ( P<0.01, Mann-Whitney). Conversely, tenofovir had similar potency on both HBV mutation profiles with 60% inhibition of HBsAg production and 45% inhibition of viral replication at 0.1 μM. Our study supports the high efficacy of ADV and TDF seen in patients after lamivudine breakthrough. The excellent activity of TDF on lamivudine-resistant virus independently of the resistance mutation profile offers an interesting treatment alternative to HIV–HBV coinfected patients.
Psychosocial Determinants of Adherence to Highly Active Antiretroviral Therapy among Injection Drug Users in Vancouver
Authors: Kerr Thomas , Palepu Anita , Barnes Gordon , Walsh John , Hogg Robert , Montaner Julio , Tyndall Mark , Wood Evan 
Published: April 2022

Background Sub-optimal adherence to highly active antiretroviral therapy (HAART) among injection drug users (IDUs) is a significant concern. As such, there is an urgent need to identify psychosocial determinants of adherence that can be incorporated into interventions designed to promote optimal adherence. Objective To identify psychosocial determinants of adherence to HAART, as well as self-reported reasons for missing doses of HAART among HIV-infected IDUs. Methods We developed an eight-item adherence self-efficacy scale comprised of two sub-scales: adherence efficacy and self-regulatory efficacy. We examined correlates between adherence self-efficacy, outcome expectations, socio-demographic characteristics, drug use and risk behaviours, social support and HAART adherence among 108 HIV-infected participants in the Vancouver Injection Drug Users Study (VIDUS). Pharmacy-based adherence to HAART was obtained through a confidential record linkage to the province of British Columbia's HIV/AIDS Drug Treatment Program. Participants were defined as adherent if they picked-up 95% of their HAART prescriptions. Participants were also asked to indicate reasons for missing doses of HAART. Logistic regression was used to identify the factors independently associated with adherence to HAART. Results Seventy-one (66%) HIV-infected IDUs were less than 95% adherent. Forgetting was the most frequently cited reason (27%) for missing doses of HAART. Factors independently associated with adherence to HAART included adherence efficacy expectations [OR=1.8 (95% CI: 1.0–3.1); P=0.039] and negative outcome expectations [OR=0.8 (95% CI: 0.7–0.9); P=0.027]. Conclusions We found low rates of adherence to HAART among IDUs. Psychological constructs derived from self-efficacy theory are highly germane to the understanding of adherence behaviour, and interventions that address these constructs should be developed and tested among HIV-infected drug users.
HIV Drug Resistance Testing: Is the Evidence Really There?
Authors: Dunn David T , Gibb Diana M , Babiker Abdel G , Green Hannah , Darbyshire Janet H , Weller Ian VD 
Published: April 2022

Objectives To assess the strength of evidence supporting the routine use of HIV drug resistance testing. Design A critical review of all studies relating to the clinical utility of HIV resistance testing, with a focus on randomized trials. Results Two cohort studies found no evidence of a difference in virological response in patients who had resistance testing compared with matched controls. We identified nine published randomized trials that were specifically designed to assess the clinical utility of drug resistance testing. In a meta-analysis of these trials, resistance testing increased the proportion of patients who achieved undetectable viral load by an average of 7% (95% confidence interval: 3–11%). However, this may be an over-estimate of the impact of resistance testing in clinical practice because of the idealized design and analytical approaches used in most of the studies. Conclusions The available evidence does not clearly demonstrate that HIV drug resistance testing is clinically effective. To optimize their value for health decision-making, future trials of HIV resistance testing should be carefully designed to mimic the circumstances of routine clinical practice.
Current Patterns in the Epidemiology of Primary HIV Drug Resistance in North America and Europe
Authors: Pillay Deenan 
Published: April 2022

Despite numerous studies in recent years, it is still difficult to draw general conclusions about the extent to which drug-resistant HIV-1 is transmitted. In addition to the highly stratified nature of primary resistance itself, true epidemiological surveillance has been rare and studies to date have suffered from wide variability in their designs, definitions and datasets. In the absence of consensus standards, this has resulted in a large number of isolated ‘snapshots’ with little scope for data-pooling and comparison. This brief review examines some of the major confounding factors that restrict the utility of individual studies and prevent the combination of studies to increase statistical power. Despite these limitations, data from North America and Europe lead to the tentative conclusion that transmission rates in these areas have generally fallen or remained stable in the past 2–3 years. However, data for the UK seem to indicate an ongoing rise in the transmission of drug resistance mutations, currently present in up to 20% of new infections. Transmission of resistant HIV represents a clinically important phenomenon, although the scale and relevance are being obscured by methodological variations and non-clinical definitions of resistance. Those of us with an interest in the epidemiology of drug resistance, whether in primary transmission or on-treatment, must learn to speak the same language if we are to establish meaningful correlations between survey datasets and the HIV-infected population as a whole.
Comparison of Dual-Energy X-Ray Absorptiometry Machines for Measuring Fat Distribution Changes of HIV-Associated Lipodystrophy
Authors: Yang Yong , Zhu WD Jason , Paton Nicholas I 
Published: April 2022

Background Dual-energy X-ray absorptiometry (DXA) is regarded as a useful objective method for diagnosis of HIV-associated lipodystrophy (LD). Objective To determine whether the use of different DXA machines may affect the diagnosis of LD. Methods Body composition in 24 HIV-infected patients, 12 of whom had clinically diagnosed LD, was measured on two DXA machines (Lunar and Hologic). Results Hologic gave significantly higher values than Lunar DXA for total body fat percent (22.9 vs 20.5%, P<0.001), arm fat percent (27.9 vs 14.5%, P<0.001) and leg fat percent (23.4 vs 17.5%, P<0.001), and significantly lower values than Lunar for trunk fat percent (22.3 vs 24.7%, P<0.001) and trunk-to-limb fat percent ratio (0.89 vs 1.62, P<0.001). When measured by Lunar, patients with LD had significantly lower leg fat percent (13.5 vs 21.6%, P=0.04) and higher trunk-to-limb fat percent ratio (1.85 vs 1.38; P=0.012) than those without LD. When measured by Hologic, patients with LD had values of leg fat percent (20.1 vs 26.8%, P=0.11) and trunk-to-limb fat percent ratio (0.95 vs 0.85, P=0.43) that did not differ significantly from those without LD. There was a significant difference in the contribution to a composite LD score between Lunar and Hologic measurements. Conclusion DXA machines from different manufacturers give major differences in measurements of body fat content and distribution, and this may affect the ability to distinguish patients with LD from those without LD. Further standardization of DXA technology is needed before widespread application in the clinical diagnosis of LD.