BACKGROUND: HBV and HIV infections are highly endemic in sub-Saharan Africa and Nigeria while HBV-HIV coinfection is not uncommon. Antiretroviral (ART)-treatment for HIV can affect HBV whereby antiviral resistance mutati...BACKGROUND: HBV and HIV infections are highly endemic in sub-Saharan Africa and Nigeria while HBV-HIV coinfection is not uncommon. Antiretroviral (ART)-treatment for HIV can affect HBV whereby antiviral resistance mutations in the HBV genome can be selected. Here, we determined the prevalence of resistance mutations among ART-experienced and ART-naive HIV-HBV-coinfected patients in southwestern Nigeria. METHODS: A total of 81 serum samples from HBV-HIV-coinfected patients who were either ART-naive or received lamivudine (3TC)-containing ART-therapy and HBV-monoinfected patients were analysed. Hepatitis B surface antigen (HBsAg) was detected using ELISA. HBV-positive samples were confirmed by PCR amplification of the surface and polymerase regions. Mutations conferring drug resistance to HBV were analysed by direct sequencing. Phylogenetic analysis was performed to identify the HBV genotype. RESULTS: Of the 81 HBsAg-positive samples, 27 had detectable HBV DNA by real-time PCR with mean viral loads of 6.77 log IU/ml. Phylogenetic analyses showed a predominance of HBV genotype E. A high prevalence (22.2%; 6/27) of HBV resistance mutations among ART-experienced HBV-HIV-coinfected patients was detected. However, a relatively high selection rate of resistance mutations in drug-naive HIV-HBV-coinfected (3.7%; 1/27) and in HBV-monoinfected patients, potential drug resistance mutations (7.4%; 2/27) were also observed. HBV polymerase amino acid substitutions found included rtV173L, rtL180M, rtM204V, rtK212R, rtS213T, rtV214A, rtL229V and rtP237A/S. CONCLUSIONS: Drug resistant mutations were detected frequently in ART-experienced HIV-HBV patients. Well-coordinated antiviral therapy for HIV patients coinfected with HBV should include proper HBV diagnosis and resistance testing to minimize the emergence and spread of antiviral drug resistance.
BACKGROUND: This 5-year follow-up of the CCgenos cross-sectional study aimed to observe real-life outcomes in a cohort of 997 Han Chinese patients with chronic HCV infection and to explore the impacts of HCV genotype, pa...BACKGROUND: This 5-year follow-up of the CCgenos cross-sectional study aimed to observe real-life outcomes in a cohort of 997 Han Chinese patients with chronic HCV infection and to explore the impacts of HCV genotype, patient characteristics and treatment status. METHODS: Clinical information and centralized HCV RNA measures were collected every 6/3 months for untreated/treated patients. Overall disease progression was defined as ≥1 of: de novo development of cirrhosis, Child-Turcotte-Pugh score increased by ≥2 points (if cirrhosis at baseline), progression to decompensated cirrhosis, hepatocellular carcinoma (HCC), liver transplant or death. Cox regression assessed risk factors for the time from estimated infection to cirrhosis or HCC. Logistic regression assessed risk factors for incidence rates of cirrhosis and overall disease progression. RESULTS: 281 of 514 patients enrolled across China completed 5 years of follow-up. Overall disease progression occurred in 36/364 (9.9%) treated patients and 35/148 (23.6%) untreated patients (odds ratio = 0.35; 95% CI 0.21, 0.59; P<0.0001). Overall disease progression occurred in 6/231 (2.6%) patients achieving sustained virological response at 24 weeks (SVR24) versus 11/82 (13.4%) who did not (P=0.0002). Cirrhosis development was significantly associated with abnormal aspartate aminotransferase (AST), age ≥40 years, body mass index ≥28 kg/m, HCV GT1, platelet count <100×10/l, and AST to platelet ratio index (APRI) ≥2 (multivariate Cox regression, P<0.05). HCC was significantly associated with HCV GT1 and platelet count <100×10/l (multivariate Cox regression, P<0.05). CONCLUSIONS: Achieving SVR24 significantly reduced the probability of overall disease progression but no significant difference was seen for both cirrhosis and HCC during 5 years of follow-up.
BACKGROUND: The use of dual antiretroviral therapy (ART) regimens for treatment of HIV is increasing. The contemporary combination of boosted darunavir with dolutegravir has not been widely studied. METHODS: This was a r...BACKGROUND: The use of dual antiretroviral therapy (ART) regimens for treatment of HIV is increasing. The contemporary combination of boosted darunavir with dolutegravir has not been widely studied. METHODS: This was a retrospective cohort study that evaluated treatment-experienced individuals within three large urban clinics prescribed boosted darunavir with dolutegravir (study regimen) dual therapy. Follow-up was defined as the number of days from regimen initiation until the last HIV RNA determination on the study regimen. Virological outcomes, HIV RNA ≤50 copies/ml (undetectable), were assessed overall and by baseline HIV RNA status. RESULTS: Of 65 individuals included, 83% were at least 3-class antiretroviral-experienced and median time since starting ART was 19 years (IQR 13-22). Median follow-up was 419 days (IQR 286-744). An undetectable HIV RNA was achieved by 62/65 (95%) individuals at any time point on the study regimen. At the end of follow-up 61/65 (94%) individuals remained undetectable, including 48/49 (98%) with an undetectable HIV RNA at baseline (those changing for optimization) and 13/16 (81%) with viraemia at baseline (those changing therapy during virological failure). At the end of follow-up, 55 (85%) individuals were still taking the study regimen. No individuals stopped therapy due to virological failure or intolerance. CONCLUSIONS: In a highly treatment-experienced cohort, boosted darunavir with dolutegravir dual therapy demonstrated high rates of virological success, even in those with detectable HIV RNA prior to initiating the study regimen. Further study of this potent, simple, high-barrier dual-class regimen is warranted.
BACKGROUND: Bovine herpesvirus type 5 is an important agent of meningoencephalitis in cattle and has been identified in outbreaks of bovine neurological disease in several Brazilian states. In recent years, oxoquinoline...BACKGROUND: Bovine herpesvirus type 5 is an important agent of meningoencephalitis in cattle and has been identified in outbreaks of bovine neurological disease in several Brazilian states. In recent years, oxoquinoline derivatives have become an important focus in antiviral drug research. METHODS: The cytotoxicity and anti BoHV-5RJ42/01 activity of a set of synthetic 4-oxoquinoline derivatives 4a-k were assayed on Madin-Darby Bovine Kidney cell and antiviral activity by plaque reduction assay. RESULTS: The most promising substance (4h) exhibited CC and EC values of 1,239 µM ±5.5 and 6.0 µM ±1.5, respectively, with an SI =206. Two other compounds 4j (CC = 35 µM ±2 and EC = 24 µM ±7.0) and 4k (CC= 55 µM ±2 and EC = 24 µM ±5.1) presented similar inhibitory profile and selectivity indexes of 1.4 and 2.9, respectively. The results of the time-of-addition studies revealed expressive reduction of virus production (≥80%) in different stages of virus replication cycle except for compound 4h that slightly inhibited virus yield in the first 2 h post infection, but it showed expressive virus inhibition after this time. CONCLUSIONS: All three compounds slightly interact with the virus on the virucidal assay and they are not able to block virus attachment and penetration. Antiviral effect of oxoquinoline 4h was more prominent than acyclovir which leads us to suggest compound 4h as a promising molecule for further anti-BoHV-5 drug design.
We report the first two paediatric cases of sofosbuvir treatment during high-intensity myeloablative conditioning and engraftment phases of haematopoietic stem cell transplantation. These reports highlight the safety of...We report the first two paediatric cases of sofosbuvir treatment during high-intensity myeloablative conditioning and engraftment phases of haematopoietic stem cell transplantation. These reports highlight the safety of sofosbuvir during all phases of transplantation and the lack of interaction between sofosbuvir and alkylating or immunosuppressive agents.
BACKGROUND: Pretreatment and acquired drug resistance mutations (DRMs) can limit antiretroviral therapy effectiveness. METHODS: We review prevalence of DRMs with resistance to nucleoside reverse transcriptase inhibitors...BACKGROUND: Pretreatment and acquired drug resistance mutations (DRMs) can limit antiretroviral therapy effectiveness. METHODS: We review prevalence of DRMs with resistance to nucleoside reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs), focusing on lamivudine and rilpivirine, from 127 articles with >100,000 individuals with HIV-1 infection. RESULTS: Estimated global prevalence of pretreatment resistance to any NRTI was 4% and to any NNRTI was 6%. Most prevalent DRMs resistant to lamivudine or rilpivirine were at positions E138 (4%), V179 (1%) and M184 (1%). Estimated acquired DRM prevalence was 58% for any NRTIs and 67% for any NNRTIs, most frequently at positions M184 (58%) and Y181 (21%). CONCLUSIONS: This review suggests low risk of lamivudine- or rilpivirine-resistant mutations in treatment-naive, HIV-1-infected individuals.
BACKGROUND: Doravirine (DOR) is a novel non-nucleoside reverse transcriptase inhibitor available as a single tablet and a three-drug combination with lamivudine (3TC) and tenofovir disoproxil fumarate (TDF) to treat HIV-...BACKGROUND: Doravirine (DOR) is a novel non-nucleoside reverse transcriptase inhibitor available as a single tablet and a three-drug combination with lamivudine (3TC) and tenofovir disoproxil fumarate (TDF) to treat HIV-1 infection. These analyses assessed pharmacokinetic (PK) interactions with coadministration. METHODS: Two trials were conducted. Study 1: two-period, fixed-sequence; eight healthy participants; Period 1, DOR 100 mg followed by ≥7-day washout; Period 2, TDF 300 mg once daily for 18 days, coadministration of DOR 100 mg on day 14. Study 2: three-period, crossover, 15 healthy participants; Treatment A, DOR 100 mg; Treatment B, 3TC 300 mg + TDF 300 mg; Treatment C, DOR 100 mg + 3TC 300 mg + TDF 300 mg; ≥7-day washout between periods. RESULTS: Study 1: geometric mean ratios (GMRs; 90% confidence interval [CI]) of DOR area under the concentration-time curve from time 0 extrapolated to infinity (AUC) and observed plasma concentrations at 24 h post-dose (C; DOR+TDF/DOR) were 0.95 (0.80, 1.12) and 0.94 (0.78, 1.12), respectively. Study 2: GMRs (90% CI) of DOR AUC and C (DOR+3TC+TDF/DOR) were 0.96 (0.87, 1.06) and 0.94 (0.83, 1.06), respectively. GMRs (90% CI) of 3TC and tenofovir AUC (DOR+3TC+TDF/3TC+TDF) were 0.94 (0.88, 1.00) and 1.11 (0.97, 1.28), respectively. Study drugs were generally well tolerated. CONCLUSIONS: Multiple doses of TDF did not have a clinically meaningful effect on DOR PK. The PK of DOR were similar when administered alone or in combination with 3TC and TDF. DOR had no meaningful effect on the PK of 3TC and tenofovir.
BACKGROUND: While acute changes in hepatic fibrosis are recognized shortly after achieving sustained virological response (SVR) using direct-acting antiviral therapies, long-term outcomes for the growing population of su...BACKGROUND: While acute changes in hepatic fibrosis are recognized shortly after achieving sustained virological response (SVR) using direct-acting antiviral therapies, long-term outcomes for the growing population of successfully treated patients with HCV remain uncertain. The aim of this study is to characterize long-term changes in fibrosis following SVR in patients with and without HIV and to identify potential factors associated with progression or regression of fibrosis. METHODS: We completed a prospective longitudinal study of 162 subjects with HCV (34% HIV-coinfected) with pre-treatment fibrosis stage determined by liver biopsy and post-SVR transient elastography. Progression of fibrosis was defined as a two-stage or greater increase in fibrosis, while regression was defined as a two-stage or greater decrease at last follow-up. The median duration of follow-up was 4.1 years. RESULTS: Fibrosis progression occurred in 4% of subjects while regression occurred in 7% and 89% were stable and did not differ by HIV coinfection. Fibrosis progression was associated with increased body mass index (BMI), hepatic steatosis and smoking pack-years. In a multivariable logistic regression, HIV coinfection (P=0.009), lower steatosis score (P<0.05) and lower smoking pack-years (P=0.0007) were associated with a lower fibrosis score at last follow-up. CONCLUSIONS: We identify potentially important relationships between BMI, hepatic steatosis and smoking, and changes in hepatic fibrosis post-SVR in patients with and without HIV coinfection. Attention to modifiable risk factors such as body weight and smoking may reduce the risk of liver disease progression in the growing population of successfully treated chronic HCV patients.
Gatell JM, Morales-Ramirez JO, Hagins DP
… +18 more, Thompson M, Arastéh K, Hoffmann C, Raffi F, Osiyemi O, Dretler R, Harvey C, Xu X, Plettenberg A, Smith DE, Portilla J, Rugina S, Kumar S, Frobose C, Wan H, Rodgers A, Hwang C, Teppler H
BACKGROUND: The safety and efficacy of doravirine were compared with that of efavirenz as initial treatment of adults living with HIV-1 infection (NCT01632345). METHODS: A Phase IIb double-blind trial with participants s...BACKGROUND: The safety and efficacy of doravirine were compared with that of efavirenz as initial treatment of adults living with HIV-1 infection (NCT01632345). METHODS: A Phase IIb double-blind trial with participants stratified by screening HIV-1 RNA (≤ or >100,000 copies/ml) and randomized 1:1:1:1:1 to receive once-daily doravirine (25, 50, 100 or 200 mg) or efavirenz 600 mg (Part I) for up to 96 weeks, with open-label tenofovir disoproxil fumarate 300 mg/emtricitabine 200 mg (TDF/FTC). After dose selection at week 24, doravirine 100 mg was provided to participants receiving the other doses of doravirine and additional participants were randomized 1:1 to receive once-daily doravirine 100 mg or efavirenz 600 mg for 96 weeks with TDF/FTC (Part II). Primary outcomes were the proportion of participants with HIV-1 RNA <40 copies/ml at week 24, and central nervous system (CNS) adverse events (AEs) by weeks 8 and 24 (Parts I+II combined). RESULTS: 210 and 132 participants were randomized in Parts I and II, respectively, and 216 (108 on doravirine 100 mg, 108 on efavirenz) were evaluable for Parts I+II combined. At week 24, the proportion of participants with HIV-1 RNA <40 copies/ml was 72.9% for doravirine 100 mg and 73.1% for efavirenz (difference -0.5 [95% CI -12.3, 11.2]). In addition, CNS AEs were reported by 26.9% and 47.2% of doravirine and efavirenz recipients, respectively (difference -20.4 [95% CI -32.6, -7.5]; P=0.002). CONCLUSIONS: Doravirine 100 mg with TDF/FTC demonstrated similar antiretroviral activity and superior CNS safety compared with efavirenz 600 mg with TDF/FTC.
BACKGROUND: The aims of this study were to describe antiviral drug (AD) utilization and costs in patients with chronic HBV infection. METHODS: We conducted a retrospective study of patients in the hospital and calculated...BACKGROUND: The aims of this study were to describe antiviral drug (AD) utilization and costs in patients with chronic HBV infection. METHODS: We conducted a retrospective study of patients in the hospital and calculated annual proportions of AD utilization and costs among patients. A two-part model was used to estimate adjusted odds ratio (OR) for antiviral therapy and cost ratios for antiviral costs associated with demographics. RESULTS: Of a total of 14,920 records, 143,658 records were involved in the analysis. The annual proportions of AD utilization were 56.99% (45.65%) for inpatients (outpatients) during 2008-2015 and increased annually. Entecavir (ETV), in particular, increased from 11.08% to 70.26% (11.05% to 49.35%) for inpatients (outpatients). The patients with medical insurance were more likely to use AD than patients without insurance, and the adjusted OR was 1.11 (95% CI: 1.03, 1.19) for inpatients and 1.66 (1.59, 1.73) for outpatients. With the disease progressing, the proportion of antiviral costs in total direct medical costs decreased from 13.91% to 4.07% (71.29% to 49.29%) for inpatients (outpatients). CONCLUSIONS: The use of AD for chronic HBV infection was less than expected based on established guidelines, and only half of patients received antiviral treatment. However, the AD utilization, especially ETV, increased annually. Reimbursement policy was the most important factor affecting antiviral treatment. Antiviral therapy was an important part of the direct medical costs, especially in the early stage of disease.
BACKGROUND: Patients with chronic HCV infection are at increased risk of developing B-cell non-Hodgkin lymphoma (B-NHL). Regression of HCV-associated B-NHL (HCV-NHL) can be achieved through HCV eradication using interfer...BACKGROUND: Patients with chronic HCV infection are at increased risk of developing B-cell non-Hodgkin lymphoma (B-NHL). Regression of HCV-associated B-NHL (HCV-NHL) can be achieved through HCV eradication using interferon (IFN). However, only about two-thirds of patients with sustained virological response (SVR) also had a consecutive lymphoma response. miRNA-26b is associated with HCV-NHL response to antiviral therapy. Recent data suggest that IFN-free direct-acting antiviral (DAA) regimens also have anti-lymphoma activity in this patient population. METHODS: We report four patients with HCV-NHL who were treated with different IFN-free DAA regimens as oncological monotherapy in our centre between 2015 and 2016. We analysed the virological and lymphoproliferative disease response. Moreover, we analysed miRNA-26b expression in peripheral blood mononuclear cells at different time points during antiviral therapy for all included patients as well as for a total of 10 controls with (n=5) and without (n=5) chronic HCV infection. RESULTS: All patients had marginal zone lymphoma subtype and received different DAA regimens for 12-24 weeks. All four patients achieved SVR, but only three patients also had lymphoma response (one complete response, two partial responses). One patient showed progression to a high-grade lymphoma subtype after SVR. miRNA-26b expression was generally decreased in patients with HCV-NHL. Moreover, miRNA-26b expression was restored in those HCV-NHL patients with lymphoma response after 6 months (P=0.009). CONCLUSIONS: We have demonstrated that IFN-free DAA treatment of HCV can improve or even cure NHL. miRNA-26b-levels could be a potentially useful biomarker to predict lymphoma response in HCV-NHL patients.
BACKGROUND: Influenza virus infections in lung transplant recipients (LTRs) have an increased risk of unfavourable outcomes. Early initiation of treatment is associated with improved outcomes. In clinical practice, empir...BACKGROUND: Influenza virus infections in lung transplant recipients (LTRs) have an increased risk of unfavourable outcomes. Early initiation of treatment is associated with improved outcomes. In clinical practice, empirical oseltamivir treatment is therefore commonly started prior to diagnostic microbiological confirmation. There is limited data on the patient characteristics, outcomes and safety of this practice. This study investigated outcomes and safety of this pre-emptive treatment strategy using oseltamivir. METHODS: Descriptive analysis of LTRs who received oseltamivir for ≥2 days for suspected influenza infection between July 2011 and June 2012. Analyses were based on data from electronic medical records and our standardized LTR database with prospective documentation of clinical information including medication, laboratory and radiological results, outcomes and adverse events. RESULTS: We included 133 patients with a total of 261 oseltamivir treatment episodes (87.4% as outpatients). Median duration of oseltamivir treatment was 4 days (range 2 to 67) and 98.5% had concomitant antibiotic pharmacotherapy. Indications for oseltamivir included acute respiratory infection (66.7%), non-distinctive inflammatory reaction (51.3%) and influenza-like illness (2.7%). Influenza virus infection was confirmed by PCR in only 7%. Rhinovirus was the most frequent pathogen detected (14.9%). We discovered a wide range of adverse events but none occurred in >5%, and most were mild and of questionable causal relationship to oseltamivir administration. CONCLUSIONS: This non-controlled retrospective analysis suggests that the pre-emptive use of oseltamivir for respiratory tract infections pending microbiological results is safe in LTRs.
BACKGROUND: Dual therapies decrease toxicity, pill-burden and treatment-associated cost. The combination of high genetic barrier drugs such as dolutegravir plus boosted-darunavir may be suitable as simplification regimen...BACKGROUND: Dual therapies decrease toxicity, pill-burden and treatment-associated cost. The combination of high genetic barrier drugs such as dolutegravir plus boosted-darunavir may be suitable as simplification regimen for patients harbouring multidrug-resistant virus. METHODS: Patients switched to a once-daily regimen consisting of dolutegravir plus darunavir, boosted with cobicistat or ritonavir, were included in this cohort study. The primary end point was the proportion of patients with HIV RNA viral load <37 copies/ml at week 48 (NCT02491242). RESULTS: Overall, 51 patients were enrolled. At baseline, all patients had failed to ≥2 antiretroviral classes. Genotypic resistance profiles showed a mean of primary mutations of 1.2 for non-nucleoside reverse transcriptase inhibitors, 2.4 for nucleoside/nucleotide reverse transcriptase inhibitors and 3.5 for protease inhibitors (PIs), but they were virologically suppressed for a median of 33 months (IQR 12-60). Only five patients had reduced sensitivity to darunavir and mean genotypic susceptibility score of dual therapy was 1.95 over 2. At week 48, there were no virological failures, three patients discontinued the regimen due to neuropsychiatric adverse events, two were lost to follow-up, and therefore the efficacy was 90% (95% CI, 82, 99%, intention-to-treat analysis). Mean estimated glomerular filtration rate decreased by 8.8 ml/min/1.73 m, though kidney tubular parameters, high density lipoprotein-cholesterol and triglycerides levels improved after switching to dual therapy. CONCLUSIONS: In highly treatment-experienced patients who were virologically suppressed, switching to the combination of dolutegravir plus boosted-darunavir dual therapy was effective and well tolerated, improving lipid and renal parameters.
BACKGROUND: International liver society guidelines recommended to perform HCV resistance testing at baseline of first-line therapy with certain combination regimens or prior to retreatment in patients previously exposed...BACKGROUND: International liver society guidelines recommended to perform HCV resistance testing at baseline of first-line therapy with certain combination regimens or prior to retreatment in patients previously exposed to a direct-acting antiviral (DAA) containing regimen. Currently, no standardized assays have been developed as purchasable kits for HCV resistance testing. The aim of this study was to evaluate the performance of the Sentosa SQ HCV Genotyping Assay, a novel deep sequencing-based assay, to identify resistance-associated substitutions (RASs) in the NS3 protease, NS5A protein domain I and NS5B polymerase regions for patients infected with HCV genotypes-1a and 1b. METHODS: Serum samples collected from patients with chronic hepatitis C infection who failed to achieve a sustained virological response after receiving a DAA-containing treatment regimen were extracted and sequenced by two methods including population sequencing of the NS3, NS5A and NS5B coding region reference method and the deep sequencing-based Sentosa SQ HCV Genotyping Assay. RESULTS: A high concordance rate with Sanger sequencing, the reference method, was found for the NS3, NS5A and NS5 coding regions, regardless of the genotype-1 subtypes. The deep sequencing-based assay was more sensitive than population sequencing to detect minority variants, representing less than 10% of the viral populations, but also some variants representing up to 30% of the viral quasispecies, as expected. CONCLUSIONS: The Sentosa SQ HCV Genotyping Assay can be confidently used in clinical practice in the indications of HCV resistance testing for these subtypes. Technical improvements are now required to allow for pangenotypic coverage.
BACKGROUND: Infection by herpes simplex type-1 virus (HSV-1) causes several pathological processes, including cutaneous, oral and genital infections, fatal encephalitis and cognitive dysfunction due to grey matter loss....BACKGROUND: Infection by herpes simplex type-1 virus (HSV-1) causes several pathological processes, including cutaneous, oral and genital infections, fatal encephalitis and cognitive dysfunction due to grey matter loss. Acyclovir is the reference compound used as HSV-1 antiviral therapy. However, with the emergence of HSV-resistant strains to current antiviral drugs, development of new antiviral agents with distinct modes of action is urgently needed. METHODS: In this study, we examined the mechanism of action of monoterpenes perillyl alcohol (POH) and perillic acid (PA) upon in vitro replication of HSV-1 KOS wild-type and the syn-mutant 17+ strain on Vero cells by plaque assay. RESULTS: The cytotoxicity of POH and PA was measured by MTT assay and indicated that both compounds had high anti-HSV-1 activities in a concentration range that was not toxic for Vero cells. In addition, PCR analysis showed that POH and PA did not inhibit viral genome replication, but rather the release of infective virion particles from Vero cells. CONCLUSIONS: Such findings suggest that POH and PA exert action upon late stages of HSV-1 maturation, therefore, indicating a promising perspective to its application in clinical investigation as effective anti-HSV-1 therapy preventing intermittent reactivation and progressive grey matter loss.
BACKGROUND: Vitamin D (VitD) and calcium (Ca) supplementation attenuates antiretroviral therapy (ART)-associated bone loss, but it is unclear whether this effect is mediated through immunomodulation. METHODS: In this exp...BACKGROUND: Vitamin D (VitD) and calcium (Ca) supplementation attenuates antiretroviral therapy (ART)-associated bone loss, but it is unclear whether this effect is mediated through immunomodulation. METHODS: In this exploratory analysis of A5280, a 48-week, randomized, double-blind, placebo-controlled study of VitD/Ca supplementation with ART initiation, we characterized lymphocyte phenotypes and receptor activator of nuclear factor kappa-B ligand (RANKL) expression by median fluorescence intensity (MFI) at baseline and 48 weeks. Changes were evaluated within and between treatment groups by Wilcoxon signed rank and rank sum tests, respectively. Spearman correlations estimated relationships between cellular phenotypes and bone mineral density (BMD). RESULTS: Of 165 participants enrolled, 138 had samples for cellular phenotypes (64 VitD/Ca, 74 placebo). Markers of CD4, CD8 activation (CD38HLA-DR) declined (all P<0.001), but did not differ between arms. There was no decline in either %T-cells (CD4 and CD8) expressing RANKL or expression of RANKL by MFI. CD4 and CD8 activation markers were not correlated with BMD at baseline (r<0.15 and P>0.09 for all), but greater declines in CD4 activation correlated with greater declines in hip and spine BMD in both arms (0.25 ≤r ≤0.37, all P<0.05). A greater decline in CD8 activation was correlated with greater declines in both hip and spine BMD in the placebo arm only (hip r=0.31, P=0.009; spine r=0.25, P=0.035). CONCLUSIONS: Reductions in T-cell activation are characteristic of ART initiation, but only correlated modestly with bone loss. VitD/Ca supplementation does not appear to mitigate bone loss through modulation of immune activation or expression of RANKL. TRIAL REGISTRATION NUMBER: NCT01403051.
BACKGROUND: Direct-acting antivirals (DAAs) have revolutionized HCV treatment, but the impact of antiviral resistance at a population level is still not clear. The majority of patients who fail DAA therapy develop resist...BACKGROUND: Direct-acting antivirals (DAAs) have revolutionized HCV treatment, but the impact of antiviral resistance at a population level is still not clear. The majority of patients who fail DAA therapy develop resistance-associated substitutions (RASs), which can impact re-treatment. There is potential for resistance prevalence to rise in the community with treatment scale up, due to transmission of resistant virus. Monitoring for increasing antiviral resistance requires a reliable baseline, yet there are few published data on the prevalence of HCV resistance in Australia. The aim of this study was to determine the prevalence of RASs among untreated Australians with HCV genotype-1a infection, to inform ongoing surveillance. METHODS: A cross-sectional study was performed at a single large university hospital pathology laboratory in Australia. Archived blood samples referred for HCV genotype testing were analysed. All patients were naive to DAAs. The prevalence of RASs in the HCV NS3 and NS5A regions was determined using Sanger based population sequencing. RESULTS: Of 379 samples tested, 34% contained DAA-resistant virus: 24% had resistance to NS3 protease inhibitors, 12% had NS5A inhibitor resistance and 4% of patients had resistance to both drug classes. Clinically relevant RASs conferring resistance against NS5A inhibitors ledipasvir, daclatasvir and elbasvir were detected in 5.8% of samples. CONCLUSIONS: This is the largest study of HCV antiviral drug resistance in Australia, which differs from resistance prevalence in the USA. The results provide valuable data on the baseline prevalence of HCV resistance, which can be used in the future to monitor for increasing antiviral resistance.