Varicella zoster virus (VZV) is less susceptible than herpes simplex virus to acyclovir. The optimal acyclovir regimen during VZV encephalitis remains unknown. We report two cases of acute renal failure after an increase...Varicella zoster virus (VZV) is less susceptible than herpes simplex virus to acyclovir. The optimal acyclovir regimen during VZV encephalitis remains unknown. We report two cases of acute renal failure after an increase in acyclovir dosage from 10 mg to 15 mg/kg/8 h during the treatment of VZV encephalitis according to French guidelines.
BACKGROUND: The long-term trajectory of and factors affecting lean mass in people living with HIV (PLWH) are incompletely described. METHODS: PLWH in the Modena HIV Metabolic Cohort underwent dual-energy X-ray absorptiom...BACKGROUND: The long-term trajectory of and factors affecting lean mass in people living with HIV (PLWH) are incompletely described. METHODS: PLWH in the Modena HIV Metabolic Cohort underwent dual-energy X-ray absorptiometry (DXA) scans every 6-12 months for up to 10 years (median 4.6 scans). Mixed effect regression modelling in combined and sex-stratified models determined annual rates of and clinical factors significantly associated with appendicular lean mass (ALM). RESULTS: A total of 839 women and 1,759 men contributing ≥2 DXA scans had baseline median age 44 years and 14 years since HIV diagnosis; 76% were virologically suppressed on antiretroviral therapy (ART). Baseline median ALM was 16.9 kg for women and 24.8 kg for men. ALM decreased during the study period, with mean yearly ALM loss of -231 g in women and -322 g in men. Less ALM was associated with female sex, age >50 years, detectable HIV-1 RNA, and tenofovir and integrase inhibitor use. Greater ALM was associated with longer ART duration. In sex-stratified models, relationships between ALM and total ART duration and integrase inhibitor use were not significant for women, but the relationship with tenofovir use persisted. For men, AIDS wasting and CD4 T-lymphocyte nadir <200 cells/μl were independently associated with lower ALM. CONCLUSIONS: ALM steadily declined over time in this cohort of PLWH on ART that included a large number of women. HIV- and ART-specific risk factors emerged that varied by sex. The observed associations between tenofovir or integrase inhibitor use and lower ALM particularly warrant further study.
BACKGROUND: In 2001, an international beverage company implemented an HIV workplace programme providing free antiretroviral treatment (ART) for employees and dependents in sub-Saharan Africa, at a time when ART, cost ass...BACKGROUND: In 2001, an international beverage company implemented an HIV workplace programme providing free antiretroviral treatment (ART) for employees and dependents in sub-Saharan Africa, at a time when ART, cost assessments of ART programmes and related public funding was hardly available. This study describes the outcomes of this programme with respect to achieving the UNAIDS 90-90-90 targets in five African countries and analyses trends over the past 15 years. METHODS: Anonymous human resource data were analysed in three cohorts of participants (those enrolling in 2001-2005, 2006-2010 and 2011-2015). RESULTS: Over 15 years, 42,490 unique individuals in five African countries were tested for HIV in this programme and 746 (1.8%) were found to be HIV-infected. Between 2002 and 2015, the proportion of HIV-positive participants on ART increased from 42% to 94% and the proportion of participants on ART who achieved virological suppression increased from 38% to 87%. CONCLUSIONS: This study shows that in one of the earliest HIV treatment programmes in Africa long-term success has been achieved, approaching the current UNAIDS 90-90-90 targets, demonstrating that the treatment of HIV in developing countries is possible with superior results at low costs (45 US dollars/employee). Reasons for this success include continuous access to on-site quality care and ART and the assistance of an independent NGO with experience in HIV treatment. This provides an argument to continue private sector involvement in international efforts to combat HIV/AIDS, particularly in light of increased ART targets, under-capacity in the public sector and stagnating international funding.
BACKGROUND: Nucleoside (or nucleotide) reverse transcriptase inhibitors (NRTIs) cause side effects in some patients, prompting the use of either partly or fully NRTI-sparing regimens. METHODS: We used data from the Swiss...BACKGROUND: Nucleoside (or nucleotide) reverse transcriptase inhibitors (NRTIs) cause side effects in some patients, prompting the use of either partly or fully NRTI-sparing regimens. METHODS: We used data from the Swiss HIV Cohort Study to estimate the effectiveness of two new dolutegravir dual regimens relative to the alternative NRTI-sparing dual regimens that our clinicians used previously. We emulated two trials by propensity score matching case patients on the dolutegravir regimen with control patients on an alternative regimen. We analysed the case control sets using a Bayesian Cox model and estimated effectiveness as the percentage still on their trial regimen without virological failure at 48 weeks. RESULTS: In a comparison of partly NRTI-sparing regimens, 58 cases treated with dolutegravir were matched to 17 controls treated with boosted darunavir (both with lamivudine or emtricitabine). The estimated difference in effectiveness was 15% (95% credible interval [CrI] 2-33) and 12% (95% CrI 0-26) in two sequential analyses 1 year apart. In a comparison of fully NRTI-sparing regimens, 54 cases treated with dolutegravir were matched to 32 controls treated with raltegravir (both with boosted darunavir). The estimated difference in effectiveness was 9% (95% CrI -1-21) and 5% (95% CrI -4-15) in the two sequential analyses. CONCLUSIONS: Estimates of relative effectiveness suggest that both dolutegravir regimens are not inferior to these alternative regimens. All four regimens seem suitable for patients needing an NRTI-sparing regimen: there were few virological failures and few treatment changes due to toxicity.
BACKGROUND: HIV viral load (VL) and resistance testing are limited in sub-Saharan Africa, so individuals may have prolonged time on failing first-line antiretroviral therapy (ART). Our objective was to describe the evolu...BACKGROUND: HIV viral load (VL) and resistance testing are limited in sub-Saharan Africa, so individuals may have prolonged time on failing first-line antiretroviral therapy (ART). Our objective was to describe the evolution of drug resistance mutations among adults failing first-line ART in Zambia. METHODS: We analysed data from a trial of VL monitoring in Lusaka, Zambia. From 2006 to 2011, 12 randomized sites provided either routine VL monitoring (intervention) or discretionary (control) after ART initiation. Samples were collected prospectively following the same schedule in each arm but analysed retrospectively in the control group. For those with virological failure (VF; >400 copies/ml), HIV genotyping was performed retrospectively on baseline (BL) and on all subsequent specimens until censored due to study completion, withdrawal or death. RESULTS: Of 1,973 enrollees, 165 (8.4%) developed VF. 464 genotype results were available including 132 (80%) at BL, 116 (70%) at VF and 125 (76%) had at least one result between VF and censoring. Major nucleoside reverse transcriptase inhibitor (NRTI) or non-nucleoside reverse transcriptase inhibitor (NNRTI) mutations increased from 26% (BL) to 82% (VF) to 89% at last genotype (LG). M184 mutations increased from 2% to 59% to 71%; K65R from 2% to 11% to 13%; 2 or more thymidine analogue mutations from 1% to 3% to 12%. Among those on a failing tenofovir disoproxil fumarate (TDF)-based regimen, TDF resistance increased from 42% to 58%. CONCLUSIONS: We found substantial resistance to NRTIs and NNRTIs at VF with incremental increases after VF while still on a failing first-line ART; this resistance may compromise attainment of the UNAIDS 90-90-90 goals.
Armenia D, Di Carlo D, Cozzi-Lepri A
… +24 more, Calcagno A, Borghi V, Gori C, Bertoli A, Gennari W, Bellagamba R, Castagna A, Latini A, Pinnetti C, Cicalini S, Saracino A, Lapadula G, Rusconi S, Castelli F, Di Giambenedetto S, Andreoni M, Di Perri G, Antinori A, Mussini C, Ceccherini-Silberstein F, Monforte AD, Perno CF, Santoro MM, ICONA Foundation Study Group
BACKGROUND: Pre-cART (combined antiretroviral therapy) plasma viral load >500,000 copies/ml has been associated with a lower probability of achieving virological suppression, while few data about its role on maintenance...BACKGROUND: Pre-cART (combined antiretroviral therapy) plasma viral load >500,000 copies/ml has been associated with a lower probability of achieving virological suppression, while few data about its role on maintenance of virological suppression are available. In this study we aimed to clarify whether high levels of pre-cART viraemia are associated with virological rebound (VR) after virological suppression. METHODS: HIV-infected individuals who achieved virological suppression after first-line cART were included. VR was defined as the first of two consecutive viraemia >50 copies/ml (VR50) or, in an alternative analysis, >200 copies/ml (VR200). The impact of pre-cART viraemia on the risk of VR was evaluated by survival analyses. RESULTS: Among 5,766 patients included, 59.2%, 31.4%, 5.2% and 4.2% had pre-cART viraemia ≤100,000, 100,001-500,000, 500,001-1,000,000 and >1,000,000 copies/ml, respectively. Patients with pre-cART viraemia levels >1,000,000 copies/ml had the highest probability of VR (>1,000,000; 500,000-1,000,000; 100,000-500,000; <100,000 copies/ml; VR50: 28.4%; 24.3%; 17.6%; 13.8%, P<0.0001; VR200: 14.4%; 11.1%; 7.2%; 7.6%; P=0.009). By Cox multivariable analyses, patients with pre-cART viraemia >500,000 and >1,000,000 copies/ml showed a significantly higher risk of VR regardless of the VR end point used. No difference in the risk of VR was found between patients with pre-cART viraemia ranging 500,000-1,000,000 copies/ml and those with pre-cART viraemia >1,000,000 copies/ml, regardless of the VR end point used. CONCLUSIONS: Pre-cART plasma viral load levels >500,000 copies/ml can identify fragile patients with poorer chance of maintaining virological control after an initial response. An effort in defining effective treatment strategies is mandatory for these patients that remain difficult to treat.
BACKGROUND: Protease inhibitors form the main component of second-line antiretroviral treatment in South Africa. Despite their efficacy, mutations arising within the HIV-1 gag and protease coding regions contribute to th...BACKGROUND: Protease inhibitors form the main component of second-line antiretroviral treatment in South Africa. Despite their efficacy, mutations arising within the HIV-1 gag and protease coding regions contribute to the development of resistance against this class of drug. In this paper we investigate a South African HIV-1 subtype C Gag-protease that contains a hinge region mutation and insertion (N37T↑V). METHODS: In vitro single-cycle drug susceptibility and viral replication capacity assays were performed on W1201i, a wild-type reference isolate (MJ4) and a chimeric construct (MJ4GagN37T↑VPR). Additionally, enzyme assays were performed on the N37T↑V protease and a wild-type reference protease. RESULTS: W1201i showed a small (threefold), but significant (P<0.0001) reduction in drug susceptibility to darunavir compared with MJ4. Substitution of W1201i-Gag with MJ4-Gag resulted in an additional small (twofold), but significant (P<0.01) reduction in susceptibility to lopinavir and atazanavir. The W1201i pseudovirus had a significantly (P<0.01) reduced replication capacity (16.4%) compared with the MJ4. However, this was dramatically increased to 164% (P<0.05) when W1201i-Gag was substituted with MJ4-Gag. Furthermore, the N37T↑V protease displayed reduced catalytic processing compared with the SK154 protease. CONCLUSIONS: Collectively, these data suggest that the N37T↑V mutation and insertion increases viral infectivity and decreases drug susceptibility. These variations are classified as secondary mutations, and indirectly impact inhibitor binding, enzyme fitness and enzyme stability. Additionally, polymorphisms arising in Gag can modify the impact of protease with regards to viral replication and susceptibility to protease inhibitors.
Cytomegalovirus (CMV) infections can induce severe complications in immunosuppressed patients. Currently, ganciclovir represents the preferred treatment option; however, in patients with resistance or toxicity related to...Cytomegalovirus (CMV) infections can induce severe complications in immunosuppressed patients. Currently, ganciclovir represents the preferred treatment option; however, in patients with resistance or toxicity related to ganciclovir, the therapeutic options are limited.Cellular immunity plays an important role in the control of viral infections. Adoptive T-cell therapy can contribute to recovering immunological function in immunosuppressed patients. Selective T-cell depletion targeting CD45RA enhances early T-cell recovery and can represent a salvage therapy. In this study, an immunocompromised non-transplanted patient with CMV disease and toxicity to conventional therapy was successfully treated by adoptive transfer of CD45RA-depleted T-cells.
BACKGROUND: Cabotegravir (CAB) is an integrase strand transfer inhibitor in development as a long-acting injectable formulation, with an oral formulation used during a safety lead-in period. Tuberculosis (TB)-HIV coinfec...BACKGROUND: Cabotegravir (CAB) is an integrase strand transfer inhibitor in development as a long-acting injectable formulation, with an oral formulation used during a safety lead-in period. Tuberculosis (TB)-HIV coinfection is common, often requiring simultaneous treatment. Rifabutin (RBT) is an alternative antimycobacterial agent for TB and a moderate inducer of cytochrome P450 and UDP-glucuronosyltransferase isoenzymes. This study evaluated the impact of RBT on the pharmacokinetics (PK) of oral CAB. METHODS: In this Phase I, single-centre, open-label, two-period, fixed-sequence, drug interaction study, subjects received oral CAB 30 mg once daily for 14 days in period 1, and oral CAB plus RBT 300 mg once daily for 14 days in period 2. Serial PK sampling was performed on days 14 and 28. Geometric least squares (GLS) mean ratios with associated 90% CIs were calculated to compare CAB noncompartmental PK parameters following CAB+RBT versus CAB alone. Safety was also assessed. RESULTS: A total of 15 male subjects were enrolled and 12 completed all treatments. Comparing CAB+RBT with CAB alone, the GLS mean ratios (90% CIs) for CAB area under the concentration-time curve from time zero to the end of the dosing interval (AUC), maximum observed plasma concentration (C) and concentration at the end of the dosing interval (C) were 0.79 (0.74, 0.83), 0.83 (0.76, 0.90) and 0.74 (0.70, 0.78), respectively. 11 subjects reported 24 adverse events (AEs); 22 were reported with CAB+RBT (3 drug-related) and 2 with CAB alone (not drug-related). All AEs resolved by study end. CONCLUSIONS: RBT had a modest impact on plasma CAB exposure following oral coadministration, resulting in overall plasma CAB trough exposures above the 10 mg oral dose shown to maintain viral suppression in HIV-1-infected subjects. Oral CAB can be coadministered with RBT without dosage adjustment.
BACKGROUND: A unique chronic hepatitis B patient was followed over 189 months of nucleoside/nucleotide analogue (NA) therapies with the analysis of multiple drug-resistance HBV mutants. METHODS: Clonal sequencing (≥20 cl...BACKGROUND: A unique chronic hepatitis B patient was followed over 189 months of nucleoside/nucleotide analogue (NA) therapies with the analysis of multiple drug-resistance HBV mutants. METHODS: Clonal sequencing (≥20 clones/sample) was performed on sera sampled at 41 time points, and the phenotypic features of eight representative mutants were analysed. RESULTS: Lamivudine (LAM)-, adefovir dipivoxil (ADV)-, entecavir (ETV)- and repeat ADV-resistance mutants emerged upon individual sequential NA monotherapy. The efficacy of NA combination rescue therapies ranked as LAM+ADV < ETV+ADV < ETV+ tenofovir disoproxil fumarate (TDF). Specifically, LAM+ADV and ETV+ADV suppressed viral loads to <100 IU/ml for a long period of time, either with or without late stage HBV DNA fluctuations. Furthermore, ETV+TDF suppressed the viral load to <10 IU/ml. During the LAM+ADV and ETV+ADV combination therapies, ETV-resistance mutants dominated at most time points, and multidrug-resistance (MDR) mutants that harboured LAM-, ETV- and ADV-resistance mutations were intermittently detected. Interestingly, the rtA181T-causative sW172stop to sW172non-stop mutation transition was observed at HBV DNA fluctuations. In a phenotypic analysis, two MDR strains had cross-resistance to LAM, ETV and ADV, and a lower susceptibility to TDF (<10-fold decrease compared with the wild-type strain). In contrast, the natural replication capacity was inversely associated with the number of primary resistant mutations which would limit MDR mutant development. CONCLUSIONS: Taken together, viral drug susceptibility, replication capacity, and perhaps immunological adaptation may play coordinated roles in the fitness of drug-resistance mutants. ETV+TDF therapy is the preferred option for treating chronic hepatitis B patients with multiple drug failure.
BACKGROUND: Currently approved anti-HCV drugs, the direct-acting antivirals (DAAs), are highly effective and target the viral RNA replication stage of the HCV life cycle. Due to high mutation rate of HCV, drug resistant...BACKGROUND: Currently approved anti-HCV drugs, the direct-acting antivirals (DAAs), are highly effective and target the viral RNA replication stage of the HCV life cycle. Due to high mutation rate of HCV, drug resistant variants can arise during DAA monotherapy. Thus, a combination of DAAs is necessary to achieve a high response rate. Novel HCV inhibitors targeting the HCV late stage such as assembly and release may further improve combination therapy with the DAAs. Here we characterize one late stage-targeting candidate compound, 6-(4-chloro-3-methylphenoxy)-pyridin-3-amine (MLS000833705). METHODS: We treated HCV-infected cells with MLS000833705 and other HCV inhibitors and examined HCV RNA and infectious titres. We evaluated the colocalization of HCV core and lipid droplets by confocal microscopy. We performed HCV core-proteinase K digestion assay and several lipid assays to study the mechanism of MLS000833705. RESULTS: We showed that MLS000833705 decreased extracellular HCV RNA levels more than intracellular HCV RNA levels in HCV infectious cell culture. Similarly, MLS000833705 reduced infectious HCV titres substantially more in the culture supernatant than intracellularly. Confocal microscopy showed that MLS000833705 did not affect the colocalization of HCV core protein with cellular lipid droplets where HCV assembles. HCV core-proteinase K digestion assay showed that MLS000833705 inhibited the envelopment of HCV capsid. CONCLUSIONS: Our study demonstrates that MLS000833705 is a late-stage HCV inhibitor targeting HCV morphogenesis and maturation. Therefore, MLS000833705 can be used as a molecular probe to study HCV maturation and secretion and possibly guide development of a new class of HCV antivirals.
Gozlan Y, Bucris E, Shirazi R
… +23 more, Rakovsky A, Ben-Ari Z, Davidov Y, Veizman E, Saadi T, Braun M, Cohen-Naftaly M, Shlomai A, Shibolet O, Zigmond E, Katchman H, Menachem Y, Safadi R, Galun E, Zuckerman E, Nimer A, Hazzan R, Maor Y, Saif AM, Etzion O, Lurie Y, Mendelson E, Mor O
BACKGROUND: Direct-acting antiviral (DAA) therapy has dramatically increased sustained virological response rates in HCV-infected patients. However, resistance-associated substitutions (RAS) interfering with NS3- and NS5...BACKGROUND: Direct-acting antiviral (DAA) therapy has dramatically increased sustained virological response rates in HCV-infected patients. However, resistance-associated substitutions (RAS) interfering with NS3- and NS5A-targeted therapy, still emerge. This real-life study analysed the type and frequency of RAS in rare cases of patients failing DAA regimens in 12 clinical centres in Israel. METHODS: Blood samples and clinical data from 49 patients who failed various DAAs were collected. RAS identified in the NS3 and NS5A regions by population (Sanger) and next-generation sequencing (NGS) were compared by treatment regimen and HCV subtypes. RESULTS: The majority (71.4%, 35/49) of patients were infected with the genotype (GT)1b strain, while 12.2% (6/49) carried GT1a and 14.3% GT3a/b (7), GT4a (1) and GT1b/GT3a. RAS were identified in 85.7% (42/49) of failures, of which 90.5% (38/42) were clinically relevant RAS (known to be associated with a specific GT and DAA in patients failing therapy or those with more than twofold change in in vitro replicon assays). The most abundant RAS were 168A/E/Q/G/N/V (32.6%, 16/49) identified in NS3, and 93H/N (61.2%, 30/49), 31I/M/V (34.7%, 17/49) and 30R/H/K (12.2%, 6/49), identified in NS5A. Significantly more clinically relevant RAS were identified in NS5A (82.2%, 37/45) than in NS3 (35.7%, 10/28; P<0.01). While RAS were identified in all GT1a, GT3b and GT4a failures (100%, 10/10), only 71.8% (28/39) of GT1b or GT3a failures had RAS (P=0.09). In four cases, NGS identified additional clinically relevant RAS and in one patient, NGS deciphered coexistence of GT3a and GT1b infections. CONCLUSIONS: Our findings, together with additional real-life data, will contribute to the optimization of retreatment in DAA failure, when cost-related and suboptimal regimens must be employed.
Younger J, Raboud J, Szadkowski L
… +15 more, Harrigan R, Walmsley S, Bayoumi AM, Klein MB, Cooper C, Burchell AN, Loutfy M, Hull M, Wong A, Thomas R, Hogg R, Montaner J, Tsoukas C, Antoniou T, Canadian Observational Cohort Collaboration
BACKGROUND: The real-world effectiveness of pre-exposure prophylaxis (PrEP) may be influenced by circulating HIV strains resistant to either tenofovir or emtricitabine. Yet, few studies have examined rates of resistance...BACKGROUND: The real-world effectiveness of pre-exposure prophylaxis (PrEP) may be influenced by circulating HIV strains resistant to either tenofovir or emtricitabine. Yet, few studies have examined rates of resistance to these drugs in clinical settings. METHODS: We conducted a retrospective cohort study of antiretroviral-naive participants in the Canadian Observational Cohort collaboration who initiated antiretroviral therapy between 2006 and 2014. In separate analyses, we determined the prevalence of pretherapy resistance and cumulative incidence of follow-up resistance to tenofovir and emtricitabine. We used multivariable proportional hazards models to examine associations between baseline variables and the development of resistance. RESULTS: We studied 6,622 antiretroviral-naive participants initiating therapy, of whom 5,428 (82.0%) had a baseline resistance test. Baseline resistance to tenofovir and emtricitabine was observed in 83 (1.5%) and 21 (0.4%) patients, respectively. Among patients without baseline resistance, the cumulative incidence of resistance to tenofovir and emtricitabine 5 years following treatment initiation was 0.0070 (95% CI 0.0046, 0.0095) and 0.033 (95% CI 0.028, 0.038), respectively. Following multivariable analysis, a baseline viral load ≥100,000 copies/ml was associated with emergence of tenofovir (hazard ratio [HR] 2.88; 95% CI 1.35, 6.15) and emtricitabine (HR 2.27; 95% CI 1.64, 3.15) resistance. Initiating an integrase inhibitor-based regimen and CD4 T-cell count below 200 cells/mm were also associated with resistance to each drug. CONCLUSIONS: We observed a low prevalence of baseline resistance and a low incidence of emergence of resistance to tenofovir and emtricitabine among antiretroviral-naive patients in routine clinical care.
BACKGROUND: Peginterferon alfa-2a (PEG-IFN) treatment stopping rules in chronic hepatitis B (CHB) are clinically desirable. Previous studies exploring this topic contained important limitations resulting in inconsistent...BACKGROUND: Peginterferon alfa-2a (PEG-IFN) treatment stopping rules in chronic hepatitis B (CHB) are clinically desirable. Previous studies exploring this topic contained important limitations resulting in inconsistent recommendations within the current treatment guidelines. We undertook a systematic review and individual patient data meta-analysis to identify the most appropriate PEG-IFN treatment stopping rules. METHODS: Roche's internal database, PubMed and conference abstracts were searched for studies that enrolled >50 treatment-naive patients with CHB who received PEG-IFN treatment for 48 weeks. Stopping rules were identified using receiver-operating characteristic curve analyses and pre-specified biomarker cutoff target performance characteristics (sensitivity >95%, specificity >10%, negative predictive value >90%). Robustness of proposed stopping rules was assessed using internal/external validation analyses. RESULTS: Eight study datasets were included in the meta-analysis (n=1,423; 765 hepatitis B e antigen [HBeAg]-positive, 658 HBeAg-negative patients). In general, performance of hepatitis B surface antigen (HBsAg) and HBV DNA cutoffs at weeks 12 and 24 was similar, and common biomarker cutoffs that met target performance criteria were identified across multiple patient subgroups. For HBeAg-positive genotype B/C and HBeAg-negative genotype D patients the proposed stopping rule is HBsAg >20,000 IU/ml at week 12. Alternatively, HBV DNA level cutoffs of >8 log and >6.5 log IU/ml, respectively, can be used instead. The proposed stopping rules accurately identify up to 26% of non-responders. CONCLUSIONS: The meta-analysis demonstrates that early PEG-IFN discontinuation should be considered in HBeAg-positive genotype B/C and HBeAg-negative genotype D patients at week 12 of treatment based on HBsAg or HBV DNA levels.
Bijker R, Kumarasamy N, Kiertiburanakul S
… +20 more, Pujari S, Lam W, Chaiwarith R, Wong WW, Kamarulzaman A, Kantipong P, Avihingsanon A, Nguyen KV, Tanuma J, Ng OT, Sim BL, Merati TP, Choi JY, Ditangco R, Yunihastuti E, Sun LP, Do CD, Ross J, Law M, TREAT Asia HIV Observational Database (TAHOD) of IeDEA Asia-Pacific
BACKGROUND: We aimed to project the 10-year future incidence of cardiovascular disease (CVD) and model several intervention scenarios based on a multi-site Asian HIV-positive cohort. METHODS: Analyses were based on patie...BACKGROUND: We aimed to project the 10-year future incidence of cardiovascular disease (CVD) and model several intervention scenarios based on a multi-site Asian HIV-positive cohort. METHODS: Analyses were based on patients recruited to the TREAT Asia HIV Observational Database (TAHOD), consisting of 21 sites in 12 countries. Patients on triple antiretroviral therapy (ART) were included if they were alive, without previous CVD, and had data on CVD risk factors. Annual new CVD events for 2019-2028 were estimated with the D:A:D equation, accounting for age- and sex-adjusted mortality. Modelled intervention scenarios were treatment of high total cholesterol, low high-density lipoprotein cholesterol (HDL) or high blood pressure, abacavir or lopinavir substitution, and smoking cessation. RESULTS: Of 3,703 included patients, 69% were male, median age was 46 (IQR 40-53) years and median time since ART initiation was 9.8 years (IQR 7.5-14.1). Cohort incidence rates of CVD were projected to increase from 730 per 100,000 person-years (pys) in 2019 to 1,432 per 100,000 pys in 2028. In the modelled intervention scenarios, most events can be avoided by smoking cessation, abacavir substitution, lopinavir substitution, decreasing total cholesterol, treating high blood pressure and increasing HDL. CONCLUSIONS: Our projections suggest a doubling of CVD incidence rates in Asian HIV-positive adults in our cohort. An increase in CVD can be expected in any ageing population, however, according to our models, this can be close to averted by interventions. Thus, there is an urgent need for risk screening and integration of HIV and CVD programmes to reduce the future CVD burden.
BACKGROUND: There have been increasing reports of HBV reactivation in HBV and HCV coinfected patients with direct-acting antiviral (DAA) treatment. The potential risk of HBV reactivation in patients undergoing haemodialy...BACKGROUND: There have been increasing reports of HBV reactivation in HBV and HCV coinfected patients with direct-acting antiviral (DAA) treatment. The potential risk of HBV reactivation in patients undergoing haemodialysis has also been noted. There is a lack of data pertaining to the reactivation risk during DAA treatment in those coinfected patients with end-stage renal disease who are undergoing haemodialysis. METHODS: HBV-HCV-coinfected patients were screened from 178 persons at two blood purification centres in China and received sofosbuvir (200 mg) combined with daclatasvir (60 mg) daily. The risk and pattern of HBV reactivation during DAA treatment was retrospectively analysed. RESULTS: HBV reactivation occurred in 45.5% (5/11) of the HBV-HCV-coinfected patients undergoing haemodialysis during DAA treatment, which was much higher than the reported rates in the general population of coinfected patients. Five patients with HBV reactivation were all positive for hepatitis B surface antigen (HBsAg) before DAA treatment. Three patients (27.3%) had mild hepatitis flares due to HBV reactivation, but no patients had severe hepatitis or hepatic failure. Compared with the four patients who were HBsAg- at the baseline, the risk of HBV reactivation in HBsAg+ patients was greater (71.4% versus 0; χ=5.238; P=0.061), although the difference was not statistically significant. CONCLUSIONS: A significant proportion of HBV-HCV-coinfected patients undergoing haemodialysis developed HBV reactivation after DAA therapy. The risk of HBV reactivation was greater in HBsAg+ patients than in those patients who were HBsAg- but anti-HBc+ or HBV DNA+.
Pisaturo M, Starace M, Minichini C
… +22 more, De Pascalis S, Macera M, Occhiello L, Messina V, Sangiovanni V, Claar E, Precone D, Stornaiuolo G, Stanzione M, Gentile I, Brancaccio G, Martini S, Masiello A, Megna AS, Coppola C, Federico A, Sagnelli E, Persico M, Lanza AG, Marrone A, Gaeta GB, Coppola N
BACKGROUND: This real-world clinical setting study characterized the virological patterns in genotype-1 patients failing interferon (IFN)-free regimens and evaluated the efficacy of re-treatment. METHODS: A total of 73 c...BACKGROUND: This real-world clinical setting study characterized the virological patterns in genotype-1 patients failing interferon (IFN)-free regimens and evaluated the efficacy of re-treatment. METHODS: A total of 73 consecutive patients failing IFN-free regimens were enrolled (17 genotype-1a and 56 -1b). At failure Sanger sequencing of NS3, NS5A and NS5B regions was performed by home-made protocols. RESULTS: In patients having failed an NS3 inhibitor, the prevalence of NS3-RASs was higher in the 10 with genotype-1a than in the 24 with genotype-1b (80% versus 41.6%). In patients treated with an NS5A inhibitor, the prevalence of NS5A-RASs was very high in the 14 with genotype-1a and the 27 with genotype-1b (78.6% and 92.5%, respectively). In patients having failed sofosbuvir, the prevalence of NS5B-RASs was more frequently identified in the 45 with genotype-1b than in the 10 with genotype-1a (37.7% versus 10%). The prevalence of NS5B-RASs in patients having failed dasabuvir was high in both genotypes, 66.6% in the 6 with genotype-1a and 45.5% in the 11 with genotype-1b. The 6 patients re-treated with genotype-1a less frequently (50%) showed sustained virological response (SVR) than the 18 with genotype-1b (88.8%; P=0.07). SVR was more frequent in the 21 patients with an effective second-line direct-acting antiviral (DAA) regimen than the 3 without (90.4% versus 0%; P<0.005). CONCLUSIONS: The prevalence of RASs was high in our real-world population. NS3, NS5A and NS5B sequencing seems mandatory in the choice of DAA re-treatment.
BACKGROUND: Porcine reproductive and respiratory syndrome virus (PRRSV) is an economically important pathogen and causes significant economic losses to the swine industry worldwide each year. Current vaccination strategi...BACKGROUND: Porcine reproductive and respiratory syndrome virus (PRRSV) is an economically important pathogen and causes significant economic losses to the swine industry worldwide each year. Current vaccination strategies do not effectively prevent and control the virus. Consequently, it is necessary to develop novel antiviral strategies. Carrageenan, extracted from marine red algae, exhibits anti-coagulant, anti-tumour, anti-virus and immunomodulatory activities. METHODS: We investigate the inhibitory effect of iota-carrageenan (CG) on PRRSV strain CH-1a via antiviral assay and viral binding, entry and release assays. RESULTS: We found that CG effectively inhibited CH-1a replication at mRNA and protein levels in both Marc-145 cells and porcine alveolar macrophages (PAMs). The antiviral activity of CG occurred during viral attachment and entry in virus life cycle. In addition, CG suppressed viral release in Marc-145 cells, as well as blocked CH-1a-induced apoptosis during the late period of infection. Furthermore, CG inhibited CH-1a-induced NF-κB activation, thus interfering with cytokine production in Marc-145 cells and PAMs, which contributes to its anti-PRRSV activity. CONCLUSIONS: Taken together, our data imply that CG might be an ideal candidate that is worthwhile developing into a new anti-PRRSV prophylactic and therapeutic drug.