Performance of clinical and histological prognostic scores for kidney survival in ANCA-associated vasculitis.

OBJECTIVES: Integrating clinical and histological parameters into prognostic scores may enhance the prediction of progression to kidney failure in anti-neutrophil cytoplasm antibodies-associated vasculitis (AAV). This study aimed to evaluate the prognostic performance of histological classifications and scoring systems for kidney survival in AAV. METHODS: This retrospective cohort study included 101 AAV patients with kidney involvement diagnosed by biopsy and followed for ≥12 months. The main outcome was the time to kidney failure. The prognostic performance of each histological and prognostic score was evaluated using Harrell's C statistic and Akaike's Information Criteria. RESULTS: Among the 101 patients, 37 progressed to kidney failure over a median follow-up of 75 months (IQR 39-123). The Harrell's C statistic was 0.702 (0.620-0.784), 0.606 (0.473-0.738), 0.801 (0.736-0.867), 0.782 (0.706-0.858), and 0.817 (0.749-0.885) for the EUVAS/Berden classification, Mayo Clinic Chronicity Score, Percentage of ANCA Crescentic Score (PACS), ANCA renal risk score (ARRS), and the improved ANCA kidney risk score (AKRiS), respectively. The AKRiS best discriminated the risk of kidney failure progression among subgroups. The AKRiS performance decreased with longer follow-up intervals. Adding the peak estimated glomerular filtration rate attained post-therapy improved the AKRiS performance at all follow-up intervals. Kidney relapses precipitated kidney failure in 71% of cases that progressed after the first year of follow-up. CONCLUSION: The novel AKRiS enhances the prediction of kidney failure in AAV with kidney involvement. As the prognostic yield of AKRiS decreases over time, a second calculation of AKRiS, including post-therapy kidney function, may improve its long-term performance.

Treatment of Iron-Induced Cutaneous Hyperpigmentation With Energy-Based Devices.

OBJECTIVES: Iatrogenic cutaneous siderosis is a well-recognized dermatologic complication after parenteral iron infusion. The condition manifests as discrete, hyperpigmented patches near the site of injection. Most cases do not resolve spontaneously, leading to significant aesthetic and psychological distress to patients. A recent case of iatrogenic cutaneous siderosis at our institution prompted a systematic review of the efficacy of energy-based devices previously reported in the treatment of this condition. METHODS: PubMed and Cochrane databases were searched for all peer-reviewed articles published using the following search terms: "iron OR heme OR hemosiderosis OR siderosis" and "hyperpigmentation OR staining OR tattoo." Articles reporting on energy-based devices in the treatment of iron-induced hyperpigmentation were included. RESULTS: A total of seven articles and 54 total patients were included in this review. All patients, including the patient treated at our institution, were female, with an average age of 44 years. Hyperpigmentation was most commonly associated with intravenous iron infusion (48/54, 89%), on the arm or forearm (44/54, 81%), and used for the treatment of underlying iron deficiency anemia (54/54, 100%). The application of six different nanosecond or picosecond quality-switched laser systems was reported in the treatment of cutaneous siderosis, with wavelengths ranging from 532 to 1064 nm. Spot sizes varied between 2 and 7 mm, with energy fluences spanning 0.5-40 J/cm2 depending on both the device and spot size. Outcomes were measured after an average of 5.4 laser treatments and 10.4 months, with over half of all reported patients experiencing complete clearance (27/50, 54%). Our patient received treatment in three test areas with picosecond alexandrite 785 nm, nanosecond Nd:YAG 532 nm, and picosecond Nd:YAG 532 nm devices. The nanosecond Nd:YAG 532 nm treated area demonstrated the greatest improvement, and the entire arm was subsequently treated with this device. CONCLUSIONS: Despite the often intractable nature of iatrogenic cutaneous siderosis, laser surgery is a reasonable and safe treatment modality for patients seeking cosmetic improvement of this dyschromia. Dermatologists should be aware of this entity and the efficacy of the energy-based devices currently in our armamentarium. A combination approach may need to be utilized with different wavelengths and pulsed widths to target iron pigment in both dermal and subcutaneous layers.

Effect of antimalarials on clinical outcomes in lupus nephritis.

OBJECTIVES: To evaluate the effect of antimalarial drugs in response to therapy, incidence of LN flares, and progression of kidney disease in a large LN cohort. METHODS: We retrospectively studied 424 biopsy-proven LN patients followed for >3 years. We obtained demographic, clinical, laboratory, histopathological, and treatment variables. Antimalarial use was approached as 1) users versus no users, 2) according to prevalent vs incident use regarding the LN flare, and 3) according to the type of antimalarial. All outcomes were evaluated by time-to-event analyses. Adjusted hazard ratios were obtained by Cox regression. RESULTS: The cohort included 424 patients, median age of 29 years (IQR 23-37), 96% female, with a median eGFR of 81 ml/min/1.73m2 (IQR 48-118) and proteinuria of 3.4 g/g (IQR 1.9-5.5). Antimalarial use was associated with higher complete response (aHR 1.57, 1.08-2.27), lower incidence of kidney flares (aHR 0.63, 0.43-0.92), and lower progression to kidney failure (aHR 0.37, 0.23-0.53). The effect on these outcomes was modified by the presentation eGFR, histological class, and/or concomitant initial immunosuppressor. These protective effects were observed in patients with prevalent or incident use regarding the LN flare and patients using hydroxychloroquine. The incidence of toxic retinopathy was 1.7%, 5.7%, and 8.8% by 3-, 5-, and 7 years of continued antimalarial use. CONCLUSION: The use of antimalarial drugs is associated with increased response to therapy, lower incidence of kidney flares, and lower progression to kidney failure in LN patients. Conversely, this population is at high risk of toxic maculopathy, and yearly ophthalmologic examination is recommended.

Dengue virus 3 genotype I (GI) lineage 1 (L1) isolates elicit differential cytopathic effect with syncytium formation in human glioblastoma cells (U251).

BACKGROUND: Dengue virus (DENV) is a Flaviviridae member classified into four antigenically distinct serotypes (DENV 1, 2, 3, and 4) and further subdivided genotypes. DENV3 is subdivided into four or five genotypes, depending on the classification adopted. Despite their high genetic proximity, as revealed by phylogenetic complete polyprotein analysis, DENV3 MG-20 and DENV3 PV_BR showed different neurovirulence in mice models. Our group identified six amino acid mutations in protein E, including the E62K and E123Q, which may affect interactions of hydrophobic clusters on domain II, thus leading to the observed differences in the studied viruses. METHODS: Human glioblastoma cells (U251) derived from a malignant glioblastoma tumor by explant technique were infected by the DENV3 GIL1 isolates DENV3 MG-20 and DENV3 PV_BR and analyzed by plaque assays and titration, optical, immunofluorescence, and transmission electronic microscopy. RESULTS: The two isolates showed different cytopathic effects (CPE) and fusogenic patterns, further confirmed by indirect immunofluorescence. Transmission electron microscopy revealed intense cytopathic effects in DENV3 MG-20 infected U251 cells, displaying endoplasmic reticulum hypertrophy and turgid vesicles with proteins and multiple viruses, distinct from DENV3 PV_BR infected cells. It is hypothesized that the different amino acids in the DENV3 MG-20 isolate are related to an increased membrane fusion ability in viral infection, thus facilitating immune system evasion and increased chances of central nervous system cell infection. CONCLUSION: These results emphasize the biological differences between the isolates, which could be a critical factor in host-virus interaction and severe dengue development. Our study presents comparative results of highly similar isolates with the potential to generate more subsidies for a deeper understanding of the DENV pathogenesis. The neurotropism of the isolate DENV3 MG-20 (belonging to the DENV3 GI L1 genotype) showing infection of nervous system cells (U251) could contribute to understanding neurological dengue disease.

iPLA2ß-Null Mice Show HCC Protection by an Induction of Cell-Cycle Arrest after Diethylnitrosamine Treatment.

Group VIA phospholipase A2 (iPLA2ß) play diverse biological functions in epithelial cells and macrophages. Global deletion in iPLA2ß-null (KO) mice leads to protection against hepatic steatosis in non-alcoholic fatty liver disease, in part, due to the replenishment of the loss of hepatocellular phospholipids. As the loss of phospholipids also occurs in hepatocellular carcinoma (HCC), we hypothesized that global deletion in KO mice may lead to protection against HCC. Here, HCC induced by diethylnitrosamine (DEN) was chosen because DEN causes direct injury to the hepatocytes. Male wild-type (WT) and KO mice at 3-5 weeks of age (12-13 mice/group) were subjected to a single intraperitoneal treatment with 10 mg/kg DEN, and mice were killed 12 months later. Analyses of histology, plasma cytokines, and gene expression were performed. Due to the low-dose DEN used, we observed a liver nodule in 3 of 13 WT and 2 of 12 KO mice. Only one DEN-treated WT mouse was confirmed to have HCC. DEN-treated KO mice did not show any HCC but showed suppressed hepatic expression of cell-cycle cyclinD2 and BCL2 as well as inflammatory markers IL-1ß, IL-10, and VCAM-1. Notably, DEN-treated KO mice showed increased hepatic necrosis and elevated levels of plasma lactate dehydrogenase suggesting an exacerbation of liver injury. Thus, global iPLA2ß deficiency in DEN-treated mice rendered HCC protection by an induction of cell-cycle arrest. Our results suggest the role of iPLA2ß inhibition in HCC treatment.

Baseline Neurocognitive Impairment (NCI) Is Associated With Incident Frailty but Baseline Frailty Does Not Predict Incident NCI in Older Persons With Human Immunodeficiency Virus (HIV).

BACKGROUND: Neurocognitive impairment (NCI) and frailty are more prevalent among persons with human immunodeficiency virus (HIV, PWH) compared to those without HIV. Frailty and NCI often overlap with one another. Whether frailty precedes declines in neurocognitive function among PWH or vice versa has not been well established. METHODS: AIDS Clinical Trials Group (ACTG) A5322 is an observational cohort study of older PWH. Participants undergo annual assessments for NCI and frailty. ACTG A5322 participants who developed NCI as indexed by tests of impaired executive functioning and processing speed during the first 3 years were compared to persons who maintained normal cognitive function; those who demonstrated resolution of NCI were compared to those who had persistent NCI. Participants were similarly compared by frailty trajectory. We fit multinomial logistic regression models to assess associations between baseline covariates (including NCI) and frailty, and associations between baseline covariates (including frailty) and NCI. RESULTS: In total, 929 participants were included with a median age of 51 years (interquartile range [IQR] 46-56). At study entry, 16% had NCI, and 6% were frail. Over 3 years, 6% of participants developed NCI; 5% developed frailty. NCI was associated with development of frailty (odds ratio [OR] = 2.06; 95% confidence interval [CI] = .94, 4.48; P = .07). Further adjustment for confounding strengthened this association (OR = 2.79; 95% CI = 1.21, 6.43; P = .02). Baseline frailty however was not associated with NCI development. CONCLUSIONS: NCI was associated with increased risk of frailty, but frailty was not associated with development of NCI. These findings suggest that the presence of NCI in PWH should prompt monitoring for the development of frailty and interventions to prevent frailty in this population.

Dengue virus 3 genotype I shows natural changes in heparan sulphate binding sites, cell interactions, and neurovirulence in a mouse model.

Dengue virus (DENV) is the most prevalent pathogen of the Flaviviridae family. Due to the considerable increase in DENV incidence and spread, symptoms such as CNS involvement have increased. Heparan sulphate (HS) was the first molecule identified as an adhesion factor for DENV in mammalian cells. Viral phenotypes with different HS interactions are associated with various clinical symptoms, including neurological alterations. Here, using in silico analyses, in vitro studies, and the in vivo mouse model, we characterized two natural circulating DENV3 genotype I (GI) lineage 1 (L1) in Brazil-DENV3 MG-20 (from Minas Gerais) and DENV3 PV_BR (from Rondônia) that present divergent neurovirulent profiles and sensitivity to sulphated molecules. We identified substitutions at the viral envelope (E) in positions 62 and 123 as likely responsible for the differences in neurovirulence. The E62K and E123Q substitutions in DENV3 MG-20 and DENV3 PV_BR, respectively, greatly influenced in silico electrostatic density and heparin docking results. In vivo, mice inoculated with DENV3 MG-20 died, but not those infected with DENV3 PV_BR. The clinical symptoms, such as paralysis of the lower limbs and meningoencephalitis, and histopathology, also differed between the inoculated groups. In vitro heparin and heparinases assays further demonstrated the biological impact of these substitutions. Other characteristics that have been previously associated with alterations in cell tropism and neurovirulence, such as changes in the size of lysis plaques and differences in cytopathic effects in glioblastoma cells, were also observed.

P052 National Registration of Patients With Inflammatory Bowel Disease in Brazil on Behalf of GEDIIB.

BACKGROUND: The IBD National Patient Registry is an initiative of the GEDIIB (Brazilian Study Group of Inflammatory Bowel Disease) who aims to survey the epidemiological profile of IBD patients through the creation of a centralized registry with data on patients monitored in public and private health services which will allow the planning of actions by the GEDIIB to facilitate the diagnosis and access to treatment of IBD, enabling the implementation of actions of the GEDIIB and the partnership with government agencies to improve care and, consequently, the quality of life of patients with IBD. This study aims to show the results of the IBD National Patient Registry. METHODS: A cohort study was performed. Data were collected from July 2020 to August 2021. Data were obtained from medical records and/or from patients during the regular follow-up visit and stored in pre-established records for further analysis. Only patients with an established diagnosis of CD and UC were included. The study was approved by the local ethical committees and all patients signed the consent form. RESULTS: In total, 797 patients were included, 60% with UC and 40% with CD; 52.9% from University Hospitals. The mean age was 44.75 ± 16.11 (12 - 92y), 59.9% female, 59.3% married, 76.4% Caucasian, 85.1% non-smokers, 30.5% completed higher education, 14.9% presented familial history of IBD. The age of onset of symptoms ranged from 3 - 79 years (32.94 ± 14.22) and 33.2% presented diarrhea as an initial manifestation. The age of diagnosis ranged from 4 - 81 years (35.07 ± 14.60) and the time from symptoms to diagnosis ranged from 1 to 2 years. The Montreal classification of CD patients were A1: 6.3%, A2: 59.9%, A3: 33.8%; L1: 38%, L2: 16.7%, L3: 43.9%, B1: 51.5%, B2: 27.8%, B3: 7.8%; perianal 12.8%. In UC, 47.8% presented pancolitis, 30.3% left-sided and 21.8% distal colitis. EIMs were present in 45.7% of patients, the most frequent being rheumatological 21.8%. Comorbidities were present in 72%, the most frequent were high blood pressure (15.3%) and diabetes (6.3%); 50% were with BMI > 25 Kg/m2. Most of the patients were in use of medical therapy (95.5%), of which 81.3% salicylate, 70.3% biological therapy, 49% immunosuppressor, 25.6% corticosteroid and 1.2% tofacitinib. Regarding biological therapy, the following medications were used: infliximab 47.6%, adalimumab 28.4%, vedolizumab 9.5%, ustekinumab 7.5%, certolizumab 2.2% and golimumab 1.3%. Eleven women used the medication during pregnancy. IBD surgery-related was performed in 69.7%, 77.2% abdominal and 22.8% perianal. Almost 30% performed more than one surgery. In 62% of patients, at least one complication was reported; most of them were infective disorders, demanding prolonged hospitalizations. CONCLUSION: To date, there is no IBD epidemiologic study covering the entire Brazilian territory. The results found with the registry will be fundamental to show the epidemiology of a country with continental dimensions such as Brazil. The greater the number of researchers included and from different regions of the country, the greater the representativeness of the data and may even help direct government actions on behalf of IBD patients.

Long-term Outcomes in a Large Randomized Trial of HIV-1 Salvage Therapy: 96-Week Results of AIDS Clinical Trials Group A5241 (OPTIONS).

BACKGROUND: Short-term (48-week) results of the OPTIONS trial showed that nucleoside reverse transcriptase inhibitors (NRTIs) can be safely omitted from salvage therapy as long as the regimen has a cumulative activity of >2 active antiretroviral medications. The long-term durability of this approach and outcomes in persons who have more-extensive HIV-1 drug resistance are uncertain. METHODS: Participants with virologic failure and anticipated antiretroviral susceptibility received an optimized regimen and were randomized to omit or add NRTIs. A separate group with more resistance (cumulative activity ≤2 active agents) received an optimized regimen including NRTIs. RESULTS: At week 96, among 360 participants randomized to omit or add NRTIs, 70% and 65% had HIV-1 RNA <200 copies/mL, respectively. Virologic failure was uncommon after week 48. Younger age and starting fewer new antiretroviral medications were associated with higher odds of virologic failure. In the highly resistant group, 53% had HIV-1 RNA <200 copies/mL at week 96. CONCLUSIONS: HIV-1 salvage therapy can safely omit NRTIs without compromising efficacy or durability of response as long as the new regimen has a cumulative activity of >2 active drugs. Younger people and those receiving fewer new antiretrovirals require careful monitoring. Even among individuals with more-extensive resistance, most achieve virologic suppression. CLINICAL TRIALS REGISTRATION: NCT00537394.

Treatment with integrase inhibitor suggests a new interpretation of HIV RNA decay curves that reveals a subset of cells with slow integration.

The kinetics of HIV-1 decay under treatment depends on the class of antiretrovirals used. Mathematical models are useful to interpret the different profiles, providing quantitative information about the kinetics of virus replication and the cell populations contributing to viral decay. We modeled proviral integration in short- and long-lived infected cells to compare viral kinetics under treatment with and without the integrase inhibitor raltegravir (RAL). We fitted the model to data obtained from participants treated with RAL-containing regimes or with a four-drug regimen of protease and reverse transcriptase inhibitors. Our model explains the existence and quantifies the three phases of HIV-1 RNA decay in RAL-based regimens vs. the two phases observed in therapies without RAL. Our findings indicate that HIV-1 infection is mostly sustained by short-lived infected cells with fast integration and a short viral production period, and by long-lived infected cells with slow integration but an equally short viral production period. We propose that these cells represent activated and resting infected CD4+ T-cells, respectively, and estimate that infection of resting cells represent ~4% of productive reverse transcription events in chronic infection. RAL reveals the kinetics of proviral integration, showing that in short-lived cells the pre-integration population has a half-life of ~7 hours, whereas in long-lived cells this half-life is ~6 weeks. We also show that the efficacy of RAL can be estimated by the difference in viral load at the start of the second phase in protocols with and without RAL. Overall, we provide a mechanistic model of viral infection that parsimoniously explains the kinetics of viral load decline under multiple classes of antiretrovirals.

Central and peripheral nervous system involvement in Zika virus infection in a child.

A 7-year-old boy that presented an encephalomyeloradiculitis and no classic symptoms of arboviruses. Zika virus (ZIKV) was confirmed by molecular analyses of cerebrospinal fluid and 1 year later by plaque reduction neutralization test. This case demonstrates that ZIKV can be associated with diffuse nervous system infection in children.

Safety and Tolerability of Maraviroc-Containing Regimens to Prevent HIV Infection in Women: A Phase 2 Randomized Trial.

BACKGROUND: Maraviroc (MVC) is a candidate drug for HIV preexposure prophylaxis (PrEP). OBJECTIVE: To assess the safety and tolerability of MVC-containing PrEP over 48 weeks in U.S. women at risk for HIV infection. DESIGN: Phase 2 randomized, controlled, double-blinded study of 4 antiretroviral regimens used as PrEP. (ClinicalTrials.gov: NCT01505114). SETTING: 12 clinical research sites of the HIV Prevention Trials Network and AIDS Clinical Trials Group. PARTICIPANTS: HIV-uninfected women reporting condomless vaginal or anal intercourse with at least 1 man with HIV infection or unknown serostatus within 90 days. INTERVENTION: MVC only, MVC-emtricitabine (FTC), MVC-tenofovir disoproxil fumarate (TDF), and TDF-FTC (control). MEASUREMENTS: At each visit, clinical and laboratory (including HIV) assessments were done. Primary outcomes were grade 3 and 4 adverse events and time to permanent discontinuation of the study regimen. All randomly assigned participants were analyzed according to their original assignment. RESULTS: Among 188 participants, 85% completed follow-up, 11% withdrew early, and 4% were lost to follow-up; 19% discontinued their regimen prematurely. The number discontinuing and the time to discontinuation did not differ among regimens. Grade 3 or 4 adverse events occurred in 5 (MVC), 13 (MVC-FTC), 9 (MVC-TDF), and 8 (TDF-FTC) participants; rates did not differ among regimens. One death (by suicide) occurred in the MVC-TDF group but was judged not to be related to study drugs. Of available plasma samples at week 48 (n = 126), 60% showed detectable drug concentrations. No new HIV infections occurred. LIMITATIONS: Participants were not necessarily at high risk for HIV infection. The regimen comprised 3 pills taken daily. The study was not powered for efficacy. CONCLUSION: Maraviroc-containing PrEP regimens were safe and well-tolerated compared with TDF-FTC in U.S. women. No new HIV infections occurred, although whether this was due to study drugs or low risk in the population is uncertain. Maraviroc-containing PrEP for women may warrant further study. PRIMARY FUNDING SOURCE: National Institutes of Health.

Phase 2 Study of the Safety and Tolerability of Maraviroc-Containing Regimens to Prevent HIV Infection in Men Who Have Sex With Men (HPTN 069/ACTG A5305).

BACKGROUND: Maraviroc (MVC) is a candidate for human immunodeficiency virus (HIV) pre-exposure prophylaxis. METHODS: Phase 2 48-week safety/tolerability study was conducted, comparing 4 regimens: MVC alone, MVC plus emtricitabine (FTC), MVC plus tenofovir disoproxil fumarate (TDF), and TDF plus FTC. Eligible participants were HIV-uninfected men and transgender women reporting condomless anal intercourse with ≥1 HIV-infected or unknown-serostatus man within 90 days. At each visit, assessments, laboratory testing, and counseling were done. Analyses were intention to treat. RESULTS: Among 406 participants, 84% completed follow-up, 7% stopped early, and 9% were lost to follow-up; 9% discontinued their regimen early. The number discontinuing and the time to discontinuation did not differ among study regimens (P = .60). Rates of grade 3-4 adverse events did not differ among regimens (P = .37). In a randomly selected subset, 77% demonstrated detectable drug concentrations at week 48. Five participants acquired HIV infection (4 MVC alone, 1 MVC + TDF; overall annualized incidence, 1.4% [95% confidence interval, .5%-3.3%], without differences by regimen; P = .32); 2 had undetectable drug concentrations at every visit, 2 had low concentrations at the seroconversion visit, and 1 had variable concentrations. CONCLUSIONS: MVC-containing regimens were safe and well tolerated compared with TDF + FTC; this study was not powered for efficacy. Among those acquiring HIV infection, drug concentrations were absent, low, or variable. MVC-containing regimens may warrant further study for pre-exposure prophylaxis. CLINICAL TRIALS REGISTRATION: NCT01505114.

Plasma and intracellular ribavirin concentrations are not significantly altered by abacavir in hepatitis C virus-infected patients.

OBJECTIVES: The objective of this study was to evaluate the effects of abacavir on intracellular ribavirin triphosphate and plasma ribavirin trough concentrations. METHODS: Hepatitis C virus-infected subjects who had been cured or failed prior treatment were randomized to 8 weeks of ribavirin alone (N = 14; weight-based dosing) or weight-based ribavirin + abacavir (N = 14; 300 mg orally every 12 h). Ribavirin trough concentrations were measured on days 14, 28, 42 and 56; PBMCs for ribavirin triphosphate determination were sampled on days 28 and 56, pre-dose and at 6 and 12 h post-dose. ClinicalTrials.gov: NCT01052701. RESULTS: Twenty-six subjects completed the study (24 males, 17 Caucasians, median age 52 years); 2 were excluded for missed pharmacokinetic visits. Fourteen subjects received ribavirin + abacavir and 12 received ribavirin alone. Mean ±â€ŠSD plasma ribavirin trough concentrations (µg/mL) on days 14, 28, 42 and 56, respectively, were not significantly different with coadministration of abacavir (1.54 ±â€Š0.60, 1.93 ±â€Š0.54, 2.14 ±â€Š0.73 and 2.54 ±â€Š1.05) compared with ribavirin alone (1.48 ±â€Š0.32, 2.08 ±â€Š0.41, 2.32 ±â€Š0.47 and 2.60 ±â€Š0.62) (P > 0.40). Mean ribavirin triphosphate intracellular concentrations (pmol/10(6) cells) on days 28 and 56, respectively, did not differ statistically between abacavir users (11.98 ±â€Š9.86 and 15.87 ±â€Š12.52) and non-users (15.91 ±â€Š15.58 and 15.93 ±â€Š12.69) (P > 0.4). Adverse events were mild or moderate, except for three grade 3 occurrences of transaminitis, cholecystitis and low absolute neutrophil count that resolved and were judged not attributable to study medications. CONCLUSIONS: Abacavir did not significantly alter ribavirin or ribavirin triphosphate concentrations.

Pharmacogenetics of unboosted atazanavir in HIV-infected individuals in resource-limited settings: a sub-study of the AIDS Clinical Trials Group (ACTG) PEARLS study (NWCS 342).

OBJECTIVES: The multinational PEARLS (ACTG A5175) study, conducted mainly in resource-limited settings, identified an increased treatment failure rate among HIV-infected individuals randomized to once-daily unboosted atazanavir, didanosine-EC, and emtricitabine compared with efavirenz-based regimens. We evaluated associations between selected human genetic polymorphisms and atazanavir pharmacokinetics in PEARLS. METHODS: Polymorphisms in CYP3A5, ABCB1, SLCO1B1 and NR1I2 were genotyped in PEARLS participants randomized to atazanavir plus didanosine-EC plus emtricitabine in Peru, South Africa and the USA, who also consented to genetic analysis. Non-linear mixed-effects population pharmacokinetic modelling was used to predict atazanavir oral clearance (CL/F) and concentration at 24 h (C24). Atazanavir mono-oxidation metabolites M1 and M2 were quantified from the same single-point plasma sample used to quantify the parent drug. Data were log10 transformed for statistical analysis using unpaired t-tests and one-way ANOVA and are presented as geometric mean (95% CI). RESULTS: Eighty-four HIV-infected participants were genotyped, including 44 Black Africans or African Americans and 28 women. Median age was 34 years. We identified 56 CYP3A5 expressers and 28 non-expressers. Atazanavir CL/F and C24 did not differ between CYP3A5 expressers and non-expressers: 13.2 (12.1-14.4) versus 12.7 L/h (11.7-13.9), P = 0.61, and 75.3 (46.1-123.0) versus 130.9 ng/mL (86.9-197.2), P = 0.14, respectively. M1/atazanavir and M2/atazanavir ratios were higher in expressers than in non-expressers: 0.0083 (0.0074-0.0094) versus 0.0063 (0.0053-0.0075), P = 0.008, and 0.0065 (0.0057-0.0073) versus 0.0050 (0.0042-0.0061), P = 0.02, respectively. CONCLUSIONS: Expression of CYP3A5 appears to be associated with increased M1 and M2 atazanavir metabolite formation, without significantly affecting parent compound pharmacokinetics.

The effectiveness of acupuncture as a treatment for tinnitus: a randomized controlled trial using (99m)Tc-ECD SPECT.

OBJECTIVE: Investigate the effect of acupuncture on brain perfusion using ethyl cysteinate dimer single-photon emission computed tomography ((99m)Tc-ECD SPECT) in patients with tinnitus. METHODS: This randomized, single-blind, sham-control study examined patients (18-60 years old) with normal hearing and chronic, idiopathic, continuous tinnitus. Fifty-seven subjects were randomly assigned to true (n = 30) or sham (n = 27) acupuncture (ACP); (99m)Tc-ECD SPECT examinations were performed before and after 12 twice-weekly ACP sessions. Secondary outcomes included changes in the Tinnitus Handicap Inventory (THI), Visual Analog Scale (VAS), Hamilton Anxiety Scale (HAS) and Beck Depression Inventory (BDI). Imaging data were analysed using Statistical Parametric Mapping (SPM8) software. Regression models were used to examine secondary outcomes via two paradigms: intention-to-treat (ITT; where multiple imputations were conducted because of study attrition) and complete cases. RESULTS: No between-group brain perfusion differences were observed. However, a significant improvement in THI scores was observed at the end of true ACP treatment for all domains (all p values < 0.01) except the catastrophic scale. CONCLUSIONS: ACP might reduce the effects of tinnitus on daily life; however, additional studies should be conducted to verify the effects of ACP on the neural architecture and brain function of tinnitus patients. KEY POINTS: • Efficacy of acupuncture on brain perfusion and symptoms of tinnitus patients. • Acupuncture improved the Tinnitus Handicap Inventory scores in tinnitus patients. • No significant changes in brain perfusion were observed after 12 twice-weekly sessions. • Perfusion changes would reflect changes in neuronal function.

HIV Salvage Therapy Does Not Require Nucleoside Reverse Transcriptase Inhibitors: A Randomized, Controlled Trial.

BACKGROUND: Nucleoside reverse transcriptase inhibitors (NRTIs) are often included in antiretroviral regimens in treatment-experienced patients in the absence of data from randomized trials. OBJECTIVE: To compare treatment success between participants who omit versus those who add NRTIs to an optimized antiretroviral regimen of 3 or more agents. DESIGN: Multicenter, randomized, controlled trial. (ClinicalTrials.gov: NCT00537394). SETTING: Outpatient HIV clinics. PARTICIPANTS: Treatment-experienced patients with HIV infection and viral resistance. INTERVENTION: Open-label optimized regimens (not including NRTIs) were selected on the basis of treatment history and susceptibility testing. Participants were randomly assigned to omit or add NRTIs. MEASUREMENTS: The primary efficacy outcome was regimen failure through 48 weeks using a noninferiority margin of 15%. The primary safety outcome was time to initial episode of a severe sign, symptom, or laboratory abnormality before discontinuation of NRTI assignment. RESULTS: 360 participants were randomly assigned, and 93% completed a 48-week visit. The cumulative probability of regimen failure was 29.8% in the omit-NRTIs group versus 25.9% in the add-NRTIs group (difference, 3.2 percentage points [95% CI, -6.1 to 12.5 percentage points]). No significant between-group differences were found in the primary safety end points or the proportion of participants with HIV RNA level less than 50 copies/mL. No deaths occurred in the omit-NRTIs group compared with 7 deaths in the add-NRTIs group. LIMITATION: Unblinded study design, and the study may not be applicable to resource-poor settings. CONCLUSION: Treatment-experienced patients with HIV infection starting a new optimized regimen can safely omit NRTIs without compromising virologic efficacy. Omitting NRTIs will reduce pill burden, cost, and toxicity in this patient population. PRIMARY FUNDING SOURCES: National Institute of Allergy and Infectious Diseases, Boehringer Ingelheim, Janssen, Merck, ViiV Healthcare, Roche, and Monogram Biosciences (LabCorp).

Regimen selection in the OPTIONS trial of HIV salvage therapy: drug resistance, prior therapy, and race-ethnicity determine the degree of regimen complexity.

BACKGROUND: Regimen selection for highly treatment-experienced patients is complicated. METHODS: Using a web-based utility, study team members reviewed antiretroviral (ARV) history and resistance data and recommended individual ARV regimens and nucleoside reverse transcriptase inhibitor (NRTI) options for treatment-experienced participants consisting of 3-4 of the following agents: raltegravir (RAL), darunavir (DRV)/ritonavir, tipranavir (TPV)/ritonavir, etravirine (ETR), maraviroc (MVC), and enfuvirtide (ENF). We evaluated team recommendations and site selection of regimen and NRTIs. Associations between baseline factors and the selection of a complex regimen (defined as including four ARV agents or ENF) were explored with logistic regression. RESULTS: A total of 413 participants entered the study. Participants initiated the first or second recommended regimen 86% of the time and 21% of participants started a complex regimen. In a multivariable model, ARV resistance to NRTI (odds ratio [OR] = 2.2), non-nucleoside reverse transcriptase inhibitor (NNRTI, OR = 6.2) or boosted protease inhibitor (PI, OR = 6.6), prior use of integrase strand transfer inhibitor (INSTI, OR = 25), and race-ethnicity (all P ≤ 0.01) were associated with selection of a complex regimen. Black non-Hispanic (OR = 0.5) and Hispanic participants from the continental US (OR = 0.2) were less likely to start a complex regimen, compared to white non-Hispanics. CONCLUSIONS: In this multi-center trial, we developed a web-based utility that facilitated treatment recommendations for highly treatment-experienced patients. Drug resistance, prior INSTI use, and race-ethnicity were key factors in decisions to select a more complex regimen.

25-Hydroxyvitamin D insufficiency and deficiency is associated with HIV disease progression and virological failure post-antiretroviral therapy initiation in diverse multinational settings.

BACKGROUND: Low 25-hydroxyvitamin D (25(OH)D) has been associated with increased HIV mortality, but prospective studies assessing treatment outcomes after combination antiretroviral therapy (cART) initiation in resource-limited settings are lacking. METHODS: A case-cohort study (N = 411) was nested within a randomized cART trial of 1571 cART-naive adults in 8 resource-limited settings and the United States. The primary outcome (WHO stage 3/4 disease or death within 96 weeks of cART initiation) was met by 192 cases, and 152 and 29 cases met secondary outcomes of virologic and immunologic failure. We studied prevalence and risk factors for baseline low 25(OH)D (<32 ng/mL) and examined associated outcomes using proportional hazard models. RESULTS: Low 25(OH)D prevalence was 49% and ranged from 27% in Brazil to 78% in Thailand. Low 25(OH)D was associated with high body mass index (BMI), winter/spring season, country-race group, and lower viral load. Baseline low 25(OH)D was associated with increased risk of human immunodeficiency virus (HIV) progression and death (adjusted hazard ratio (aHR) 2.13; 95% confidence interval [CI], 1.09-4.18) and virologic failure (aHR 2.42; 95% CI, 1.33-4.41). CONCLUSIONS: Low 25(OH)D is common in diverse HIV-infected populations and is an independent risk factor for clinical and virologic failure. Studies examining the potential benefit of vitamin D supplementation among HIV patients initiating cART are warranted.

A pilot study assessing the safety and latency-reversing activity of disulfiram in HIV-1-infected adults on antiretroviral therapy.

BACKGROUND: Transcriptionally silent human immunodeficiency virus type 1 (HIV-1) DNA persists in resting memory CD4(+) T cells despite antiretroviral therapy. In a primary cell model, the antialcoholism drug disulfiram has been shown to induce HIV-1 transcription in latently infected resting memory CD4(+) T cells at concentrations achieved in vivo. METHODS: We conducted a single-arm pilot study to evaluate whether 500 mg of disulfiram administered daily for 14 days to HIV-1-infected individuals on stable suppressive antiretroviral therapy would result in reversal of HIV-1 latency with a concomitant transient increase in residual viremia or depletion of the latent reservoir in resting memory CD4(+) T cells. RESULTS: Disulfiram was safe and well tolerated. There was a high level of subject-to-subject variability in plasma disulfiram levels. The latent reservoir did not change significantly (1.16-fold change; 95% confidence interval [CI], .70- to 1.92-fold; P = .56). During disulfiram administration, residual viremia did not change significantly compared to baseline (1.53-fold; 95% CI, .88- to 2.69-fold; P = .13), although residual viremia was estimated to increase by 1.88-fold compared to baseline during the postdosing period (95% CI, 1.03- to 3.43-fold; P = .04). In a post hoc analysis, a rapid and transient increase in viremia was noted in a subset of individuals (n = 6) with immediate postdose sampling (HIV-1 RNA increase, 2.96-fold; 95% CI, 1.29- to 6.81-fold; P = .01). CONCLUSIONS: Administration of disulfiram to patients on antiretroviral therapy does not reduce the size of the latent reservoir. A possible dose-related effect on residual viremia supports future studies assessing the impact of higher doses on HIV-1 production. Disulfiram affects relevant signaling pathways and can be safely administered, supporting future studies of this drug.