Metabolic effects of switching to Biktarvy (B/F/TAF) in patients with HIV-1 treated with antiretroviral regimens that do not include tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide (TAF): The Metabic study.

BACKGROUND: Studies on switching to tenofovir alafenamide (TAF)-based regimens raise concerns about a worse metabolic profile in people with HIV, even though most received tenofovir disoproxil fumarate (TDF) in their previous regimen. This study aims to evaluate changes in lipid fractions, glucose, and serum markers for hepatic steatosis (HS) after switching from a TDF- or TAF-sparing regimen to bictegravir/emtricitabine/TAF (B/F/TAF). METHODS: We performed a retrospective cohort study of people with HIV who switched to B/F/TAF from TDF- or TAF-sparing regimens between January 2019 and May 2022 with at least 6 months of follow-up. The primary endpoint was the absolute change in lipid fractions at 6 months. Secondary outcomes were changes in lipid fractions at 12 months and changes in other metabolic parameters (glucose, creatinine, and HS based on the triglyceride-to-glucose [TyG] ratio at 6 and 12 months). Changes were analysed using mixed linear regression models with random intercept and time as a fixed effect. RESULTS: The study included 259 people with HIV (median age 55 [interquartile range (IQR) 47-60] years; 80% male; 88% Caucasian; CD4+ T-cell count 675 [IQR 450-880] cells/mm3; 84.3% HIV-RNA <50 copies/mL). In total, 63 patients (30%) had hypertension, 93 (44%) dyslipidaemia, 30 (14%) diabetes, and 45% obesity/overweight. Most (60%) switched from integrase inhibitor-based regimens, and 21% switched from a boosted regimen. At 6 months, significant reductions were observed in total cholesterol (-7.64 mg/dL [95% confidence interval (CI) -13.52 to -1.76; p = 0.002]), triglycerides (-23.4 [95% CI -42.07 to -4.65]; p = 0.003), and TyG ratio (-0.14 [95% CI -0.23 to -0.05]; p < 0.001). CONCLUSION: In our real-life cohort, the effect of switching TDF-/TAF-sparing regimens to triple therapy with B/F/TAF improved total cholesterol, triglycerides, and serum markers of HS at 6 months and was neutral for the remaining metabolic parameters at 12 months.

Description of Saccocoelioides miguelmontesi n. sp. (Digenea: Haploporidae) from characid fishes in the Iguazu River Basin based on morphological and molecular evidence.

Here we describe a new species of the genus Saccocoelioides found parasitizing Astyanax dissimilis Garavello & Sampaio, Psalidodon bifasciatus (Garavello and Sampaio) and Bryconamericus ikaa Casciotta, Almirón & Azpelicueta from the Iguazu National Park, Misiones province, Argentina. Saccocoelioides miguelmontesi n. sp. was studied based on morphological and molecular (28S rDNA and COI mtDNA sequences) data. The COI mtDNA tree indicated that the specimens collected from the three fish hosts are conspecific, with an intragroup p-distance of 0%. The new species shows an intermediate morphological configuration between the diminutive and robust forms described for Saccocoelioides by Curran (2018). Although, in the 28S rDNA tree, it is placed in a well-supported clade with the two robust species analysed (S. elongatus and S. magnus; p-distance of 1 and 2%, respectively), it differs from the robust group by the range of body size, mature egg size, oral and ventral sucker size, sucker ratio, oral sucker to pharynx ratio, and post-cecal or post-testis/body length percentage. Our results led us to redefine the robust group as having eggs shorter or equal in length to the pharynx. Saccocoelioides miguelmontesi n. sp. the 10th species reported from Argentina and the 7th species within the robust group.

Three-year efficacy of switching to dolutegravir plus lamivudine: A real-world study.

BACKGROUND: Dolutegravir (DTG) plus lamivudine (3TC) has proven highly efficacious as a switching strategy in virologically suppressed people with HIV (PWH). As this strategy was introduced relatively recently, real-world, long-term durability studies are lacking. METHODS: We performed a retrospective review of treatment-experienced patients who started DTG + 3TC in a cohort of PWH. HIV-RNA <50 copies/mL was analysed at 144 weeks in an intention-to-treat (ITT) analysis (missing = failure) and a per-protocol (PP) analysis (patients with missing data or changes for reasons other than virological failure were excluded). RESULTS: The study population comprised 358 PWH (19% women). Median age and time with HIV infection were 51.7 and 13.4 years, respectively. The median number of previous antiretroviral combinations was three. Previous virological failure was reported in 27.1% of patients, and the M184V resistance mutation was detected in 17 patients. At 144 weeks, the percentage of individuals with HIV-RNA <50 copies/mL was 77.4% (277/358) in the ITT analysis and 95.5% (277/290) in the PP analysis. A total of 68 participants were excluded from the PP analysis (data missing, 25, discontinuation due to toxicity, 19; other, 16; death, 8). Two people with virological failure selected resistance-associated mutations (M184V and M184V + R263K). HIV-RNA remained undetectable in 17 patients with a previous history of the M184V mutation. CONCLUSION: Our results confirm the real-world, long-term efficacy, tolerability and high genetic barrier of DTG + 3TC in treatment-experienced PWH. Although scarce, mutations causing resistance to nucleosides and integrase can emerge.

Efficacy and safety of dolutegravir/rilpivirine in real-world clinical practice. GeSIDA study 1119.

INTRODUCTION: Dolutegravir/rilpivirine (DTG/RPV) is an effective antiretroviral (ART) regimen endorsed by clinical trials as a switch therapy. The aim of our study was to analyse the efficacy and safety of DTG/RPV in real-world clinical practice. METHODS: Observational, multicentre study of patients who started DTG/RPV. Efficacy, adverse events and metabolic changes at 48 weeks were analysed. RESULTS: A total of 348 patients were included; median time of HIV infection was 21.1 years, 33.7% were AIDS cases; median nadir CD4 was 160 cells/µL; 90.5% had received ≥3 lines of ART and 179 (53.8%) had prior virological failure. Convenience (43.5%), toxicity/intolerance (28.4%) and interactions (17.0%) were the main reasons for starting DTG/RPV. Previous regimens were protease inhibitors (PI) (31.6%), non-nucleoside reverse transcriptase inhibitors (NNRTI) (20.4%) and integrase strand transfer inhibitors (INSTI) (14.9%). Efficacy (HIV-RNA <50 copies/mL) at 48 weeks was 89.7% (95% CI 86.1-92.6) by intention-to-treat (ITT) and 94.2% (95% CI 91.3-96.4) by on treatment (OT); 10 patients (3.1%) were not suppressed (3 had abandoned ART). There was a mean decrease in triglycerides, total cholesterol, low-density lipoprotein-cholesterol, glutamic-pyruvic transaminase (GPT), gamma-glutamyl transferase (GGT) and alkaline phosphatase; creatinine increased with a decrease in glomerular filtration rate. CONCLUSIONS: This study confirms the effectiveness, tolerability and safety of DTG/RPV in real-world clinical practice in a different population from clinical trials, with many years of infection, low CD4 nadir, several previous treatment lines, more than half with virological failures, and one-third diagnosed with AIDS. The switch to DTG/RPV was safe with few discontinuations due to adverse effects. Modifications of the lipid and liver profiles were favourable. There were no relevant changes in kidney function.

Proctitis in patients with monkeypox infection: a single-center analysis of 42 consecutive cases from a multidisciplinary observational study on monkeypox proctitis.

BACKGROUND: The current monkeypox (MP) virus outbreak was declared an international emergency in July 2022. The aim of this report is to describe our initial experience with patients with MP, focusing on proctitis. METHODS: We conducted an observational study between 20 May and 31 July 2022, on patients with MP at a reference tertiary center in Madrid, Spain. A descriptive analysis on MP was performed, focusing on its characteristics, symptoms, diagnosis, and outcomes. RESULTS: A total of 143 positive MP cases were diagnosed in our center; 42 of them [all male, median age 39 years (range: 22-57 years)] had proctitis (29.37%), and 3 patients (2.09%/MP total cases and 7.14%/MP proctitis) required surgical drainage of a perianal abscess. CONCLUSIONS: General and digestive surgeons must be aware of the presence of proctological impairment and complications due to MP virus.

Phylogenetic position of the Neotropical Family Zonocotylidae (Paramphistomoidea) using partial 28S rDNA sequences.

Six families belonging to the Paramphistomoidea superfamily have been reported in South America, with only Zonocotylidae and Balanorchiidae being endemic. The Zonocotylidae was initially classified as Aspidogastrea and then as a paramphistomoid. This family comprises a single genus, Zononocotyle, with two species. It is primarily characterized by having an attachment organ with transverse ridges and a single testis. The placement of Zonocotylidae within Paramphistomoidea is controversial, as some researchers speculate that this genus is the most primitive member of the superfamily, while others consider it an aberrant form. The main objectives of our study were to provide the first sequences of Zonocotylidae and elucidate its phylogenetic position. We amplified the 28S gene from two parasites from Cyphocharax sp. from Punta Lara, Buenos Aires. Newly generated sequences were used to infer the phylogenetic relationships with other Paramphistomoidea species using a Bayesian approach. Zonocotylidae were clustered with Dadayiinae and Kalitrematinae (Cladorchiidae) species found in freshwater fishes from South America. Genetic analyses revealed that they formed a well-supported clade with cladorchiids in freshwater hosts from South America. However, the occurrence of genera of Cladorchiidae in North America, Middle America, Asia, and Australia suggested its polyphyletic nature and may indicate the need for the erection of new families. Other Paramphistomoidea families may also require further revision. The addition of new sequences to phylogenetic analyses along with a comprehensive and more detailed description of the genera will help resolve the relationships within this group.

Integrative analysis of new Clinostomum metacercariae (Digenea, Clinostomidae) using COI mtDNA and morphology rises the number of lineages found in South American freshwater fishes.

Clinostomidae is a diverse family of digenean parasitizing fish-eating birds as adults and fishes as metacercariae. The species composition, within the genus Clinostomum has been steadily increasing in recent years. In Argentina, four named species of Clinostomum have been documented, accompanied by four metacercariae representing distinct genetic lineages whose adults have not been identified. This study focused on examining clinostomids in three fish species - Australoheros scitulus (ASI), Cichlasoma dimerus (CDIM), and Pimelodella laticeps (PLA) - at various localities in Argentina. We conducted both morphological and molecular characterizations of the Clinostomum metacercariae collected from these fish species. Molecular phylogenetic analyses using COI mtDNA were performed to determine the placement of these metacercariae within the clinostomid phylogenetic tree. Clinostomum ASC represents a distinct lineage, morphologically distinguishable from other sequenced metacercariae due to its body shape (widest anteriorly and becoming slender towards the posterior end); this lineage was found to be closely related to C. caffarae. While Clinostomum CDIM and Clinostomum PLA exhibited morphological differences, they clustered together genetically with metacercariae reported in previous studies as Clinostomum L3 and Clinostomum CVI. This outcome, coupled with a low genetic distance (0 to 3%), suggests that they are conspecific with metacercariae found in fish across Mexico, Costa Rica, and Argentina. In light of the extensive diversity of fish species in Argentine freshwater ecosystems (over 500 species), and considering the relatively constrained extent of prior investigations, the anticipation of unearthing additional Clinostomum species or lineages is plausible.

First Direct Detection Constraints on Planck-Scale Mass Dark Matter with Multiple-Scatter Signatures Using the DEAP-3600 Detector.

Dark matter with Planck-scale mass (≃10^{19} GeV/c^{2}) arises in well-motivated theories and could be produced by several cosmological mechanisms. A search for multiscatter signals from supermassive dark matter was performed with a blind analysis of data collected over a 813 d live time with DEAP-3600, a 3.3 t single-phase liquid argon-based detector at SNOLAB. No candidate signals were observed, leading to the first direct detection constraints on Planck-scale mass dark matter. Leading limits constrain dark matter masses between 8.3×10^{6} and 1.2×10^{19} GeV/c^{2}, and ^{40}Ar-scattering cross sections between 1.0×10^{-23} and 2.4×10^{-18} cm^{2}. These results are interpreted as constraints on composite dark matter models with two different nucleon-to-nuclear cross section scalings.

Saccocoelioides kirchneri n. sp. (Digenea: Haploporidae) from the killifish Cnesterodon decemmaculatus (Cyprinodontiformes: Poeciliidae) from Argentina, morphological and molecular description.

This paper presents a new haploporid digenean that expands the number of species of Saccoccoelioides to 27. The new species, Saccocoelioides kirchneri n. sp. was collected from the intestine of Cnesterodon decemmaculatus (Poeciliidae: Cyprinodontiformes) from Lago del Bosque, La Plata, Argentina. The new species possesses the diagnostic features for Saccocoelioides: a sac like ceca; the vitellarium confined in two irregular groups of follicles distributed between the ventral sucker and the anterior margin of the testis; and a uterus confined largely in the hind-body, but encroaching into the range of the ventral sucker. The new species is differentiated from the 26 congeners by the body size, pharynx size, ventral sucker size, posterior extent of ceca, posterior extent of uterus and egg size. S. kirchneri n. sp. also is supported by the molecular analysis.

Description of Diegoglossidium maradonai n. g. and n. sp. (Digenea: Alloglossidiidae) through an integrative taxonomy approach, with an amended diagnosis of the family.

This paper describes Diegloglossidium maradonai n. g., n. sp. a parasite of the intestine of Hoplosternum littorale (Hancock) from La Plata River basin. The new genus is morphologically similar to members of Alloglossidiidae and Macroderoidiidae although they also share some traits observed in both families. Those families can be differentiated from each other by the combination of morphological features, including the density and distribution of the tegumental spines, the distribution of the vitelline follicles and the extent of the post-testicular space. The molecular analyses based on the large subunit of the ribosomal RNA gene, and the internal transcribed spacer (ITS) regions including ITS1, 5.8S and ITS2 unequivocally place the new genus in the family Alloglossidiidae which is amended based on new observed features. Diegoglossidium n. g. is characterized by a combination of characteristics, being most notably the presence of a deeply lobed ovary. Lastly, the geographical distribution and host associations of the two closely related Neotropical genera of Alloglossidiidae: Magnivitellinum and Diegoglossidium are discussed, and the host and distribution range of Magnivitellinum saltaensis is expanded into Argentina.

Metacercariae in the brain of Erythrinus cf. erythrinus (Characiformes: Erythrinidae) from Iguazú National Park (Argentina): do they belong to Dolichorchis lacombeensis (Digenea, Diplostomidae)?

In Argentina, the family Diplostomidae is composed of eight genera: Austrodiplostomum Szidat & Nani; Diplostomum von Nordmann; Dolichorchis Dubois; Hysteromorpha Lutz; Neodiplostomum Railliet; Posthodiplostomum Dubois; Sphincterodiplostomum Dubois; and Tylodelphys Diesing. During a parasitological survey of fishes from the Iguazú National Park we detected diplostomid metacercariae in the brain of Erythrinus cf. erythrinus. Fish were caught using crab traps, transported alive to the field laboratory, cold-anaesthetized and euthanized by cervical dissection. Some metacercariae were heat-killed in water and fixed in 10% formalin and others were preserved in alcohol 96% for DNA extraction. They were sequenced for the partial segment of the 28S rDNA, internal transcribed spacer (ITS) rDNA and cytochrome c oxidase subunit I (COI) mtDNA genes. Phylogenetic reconstruction was carried out using Bayesian inference and the proportion (p) of absolute nucleotide sites (p-distance) was obtained. In the 28S rDNA tree, the metacercaria sequenced grouped as Dolichorchis sp. The COI mtDNA p-distance between the metacercariae with Dolichorchis lacombeensis was 0.01. There is a small number of ITS sequences for the Diplostomidae family deposited in the GenBank. The oral sucker, ventral sucker, holdfast organ and the distance between oral and ventral suckers are larger in the adult compared with the metacercariae. Additionally, hind-body length and width are larger in the adult due to the development of the genital complex. Further studies using an integrative approach will help confirm the affiliation of other species to the genus Dolichorchis.

Environmental Impact of UV Filters. / Impacto de los filtros ultravioleta en el entorno natural.

UV filters are used daily by millions of people. Not all of these filters, however, are 100% biodegradable, and many wastewater treatments plants are ill-equipped to filter them properly. As a result, UV filters are increasingly reaching the environment. Various types have been detected in soil, continental water, oceans, and numerous organisms, including algae, corals, fish, mammals, and even land birds. In addition, some filters, benzophenone-3 and octocrylene in particular, are toxic to these organisms. Toxic effects include coral bleaching and interference with metabolic, enzymatic, and reproductive activities in practically all organisms. Preliminary data suggest that UV filters may be bioaccumulating in humans, as they have been detected in urine and breast milk. It should be noted, however, that research into the environmental impact of UV filters holds challenges and limitations.

Description of a new species of Auriculostoma (Digenea: Allocreadiidae) from Characidium heirmostigmata (Characiformes: Crenuchidae) from Argentina, using morphological and molecular data.

During a parasitological survey of fishes at Iguazu National Park, Argentina, specimens belonging to the allocreadiid genus Auriculostoma were collected from the intestine of Characidium heirmostigmata. The erection of the new species is based on a unique combination of morphological traits as well as on phylogenetic analysis. Auriculostoma guacurarii n. sp. resembles four congeneric species - Auriculostoma diagonale, Auriculostoma platense, Auriculostoma tica and Auriculostoma totonacapanensis - in having smooth and oblique testes, but can be distinguished by a combination of several morphological features, hosts association and geographic distribution. Morphologically, the new species can be distinguished from both A. diagonale and A. platense by the egg size (bigger in the first and smaller in the last); from A. tica by a shorter body length, the genital pore position and the extension of the caeca; and from A. totonacapanensis by the size of the oral and ventral sucker and the post-testicular space. Additionally, one specimen of Auriculostoma cf. stenopteri from the characid Charax stenopterus (Characiformes) from La Plata River, Argentina, was sampled and the partial 28S rRNA gene was sequenced. The phylogenetic analysis revealed that A. guacurarii n. sp. clustered with A. tica and these two as sister taxa to A. cf. stenopteri. The new species described herein is the tenth species in the genus and the first one parasitizing a member of the family Crenuchidae.

Pathology associated with three new Clinostomum metacercariae from Argentina with morphological and DNA barcode identification.

In the Laboratory of Parasites of Fishes, Crustaceans and Mollusks (CEPAVE), we undertook a parasitological study on three species of fish from the Espinal and Esteros del Iberá ecoregions of Argentina. Clinostomid metacercariae were found parasitizing Characidium rachovii, Crenicichla vittata and Gymnogeophagus balzanii. In this study, we analysed the damage that these parasites inflict on their hosts through the evaluation of histological sections. In addition, Clinostomum metacercariae were identified using morphological characters and DNA barcoding. In the pathological analysis, we observed that muscle tissue was the most affected. The inflammatory response showed vascular congestion areas and infiltration of numerous inflammatory cells, mainly lymphocytes. The molecular and morphological approach supports the presence of three new lineages of clinostomid metacercariae in Argentina. This could lead to the discovery of a high number of lineages or species of Clinostomum from South America.

Prosthenhystera gattii n. sp. (Digenea: Callodistomidae), a gallbladder parasite of Bryconamericus ikaa from the lower Iguazú River, described based on combined molecular and morphological evidence.

Adult forms of members of the Callodistomidae always parasitize the gallbladder of freshwater fishes and occur in Africa and America. This study provides a description of a new South American species belonging in Prosthenhystera from the gallbladder of a characid fish (Bryconamericus ikaa), and ribosomal gene sequences (28S rDNA and ITS1-5.8S-ITS2) are used to demonstrate molecular differences between the new species and congeners as well as explore interrelationships among congeners. Additionally, the first cytological analysis is conducted for a member of the family to determine chromosome number and arrangement. Prosthenhystera gattii n. sp. most closely resembles Prosthenhystera caballeroi in morphology, but the vitellarium is more extensive reaching anterior to the caecal bifurcation in the new species and the uterus is confined to the hindbody in P. gattii n. sp., whereas it extends to the level of the pharynx in P. caballeroi. Also, the testes, cirrus sac, seminal receptacle and the ratio of body length to width are larger in P. gattii n. sp. Independent Bayesian inference analyses of 28S rDNA and ITS1-5.8S-ITS2 sequence fragments produced phylograms that showed P. gattii n. sp. is more similar to Prosthenhystera obesa + Prosthenhystera oonastica than P. caballeroi + two unidentified species of Prosthenhystera, but with poor posterior probability support for the node in the ITS1-5.8S-ITS2-based phylogram. Further, the genetic distance between P. oonastica and P. gattii n. sp. are the largest among Prosthenhystera spp. Cytological analysis revealed ten metacentric chromosomes, which is fewer than the 12-18 chromosomes present in species from the closely related Gorgoderidae.

Zoonotic approach to Shiga toxin-producing Escherichia coli: integrated analysis of virulence and antimicrobial resistance in ruminants and humans.

In 2014-2016, we conducted a cross-sectional survey in 115 sheep, 104 beef and 82 dairy cattle herds to estimate Shiga toxin-producing Escherichia coli (STEC) prevalence, and collected data on human clinical cases of infection. Isolates were characterised (stx1, stx2, eae, ehxA) and serogroups O157 and O111 identified by PCR, and their antimicrobial resistance (AMR) profiles were determined by broth microdilution. STEC were more frequently isolated from beef cattle herds (63.5%) and sheep flocks (56.5%) than from dairy cattle herds (30.5%) (P < 0.001). A similar but non-significant trend was observed for O157:H7 STEC. In humans, mean annual incidence rate was 1.7 cases/100 000 inhabitants for O157 STEC and 4.7 for non-O157 STEC, but cases concentrated among younger patients. Distribution of virulence genes in STEC strains from ruminants differed from those from human clinical cases. Thus, stx2 was significantly associated with animal STEC isolates (O157 and non-O157), ehxA to ruminant O157 STEC (P = 0.004) and eae to human non-O157 STEC isolates (P < 0.001). Resistance was detected in 21.9% of human and 5.2% of animal O157 STEC isolates, whereas all non-O157 isolates were fully susceptible. In conclusion, STEC were widespread in ruminants, but only some carried virulence genes associated with severe disease in humans; AMR in ruminants was low but profiles were similar to those found in human isolates.

Analyses of the genetic diversity and population structures of Histoplasma capsulatum clinical isolates from Mexico, Guatemala, Colombia and Argentina, using a randomly amplified polymorphic DNA-PCR assay.

We studied the genetic diversity and the population structure of human isolates of Histoplasma capsulatum, the causative agent of histoplasmosis, using a randomly amplified polymorphic DNA-polymerase chain reaction (RAPD-PCR) assay to identify associations with the geographic distribution of isolates from Mexico, Guatemala, Colombia and Argentina. The RAPD-PCR pattern analyses revealed the genetic diversity by estimating the percentage of polymorphic loci, effective number of alleles, Shannon's index and heterozygosity. Population structure was identified by the index of association (IA) test. Thirty-seven isolates were studied and clustered into three groups by the unweighted pair-group method with arithmetic mean (UPGMA). Group I contained five subgroups based on geographic origin. The consistency of the UPGMA dendrogram was estimated by the cophenetic correlation coefficient (CCCr = 0.94, P = 0.001). Isolates from Mexico and Colombia presented higher genetic diversity than isolates from Argentina. Isolates from Guatemala grouped together with the reference strains from the United States of America and Panama. The IA values suggest the presence of a clonal population structure in the Argentinian H. capsulatum isolates and also validate the presence of recombining populations in the Colombian and Mexican isolates. These data contribute to the knowledge on the molecular epidemiology of histoplasmosis in Latin America.

Comparing two commercial domestic dog (Canis familiaris) STR genotyping kits for forensic identity calculations in a mixed-breed dog population sample.

Almost half of all US households own a dog (Canis familiaris). Though these household pets can attack humans and other animals, they are also frequently victims of cruelty, neglect and theft. In human-oriented investigations, the tendency of domestic dogs to leave behind physical traces (such as hair) can serve as valuable links between crime scenes and suspects/victims. This demonstrated utility of canine biological evidence has created demand for genotyping marker sets for canine forensic genetic testing. Through research and casework, short tandem repeat (STR) panels have been shown to be very efficient for identity and parentage testing in dogs. However, there is an absence of comparative studies between different canine forensic identification kits. The Thermo Fisher Scientific Canine Genotypes ™ Panel 1.1 and 2.1 Kits were originally designed and developed for routine and forensic use respectively, although both kits can be used for either purpose. In this study, we evaluated both STR panels to determine how critical forensic genetic metrics are affected by panel-to-panel variation in marker composition and design. Our results show that although STR panel composition can influence estimates such as inbreeding, combined power of discrimination and combined probability of exclusion, greater average allele number values exhibited across all markers in Panel 2.1 facilitated significantly more precise estimates of random match probability (RMP) and combined probability of identity. Furthermore, we demonstrate that a theta (θ) correction of 0.09 can be used to conservatively adjust RMPs generated from a small reference database of fewer than 50 samples, confirming that Panel 2.1 is a more robust forensic genotyping system than is Panel 1.1. for domestic dogs. We also demonstrate that opportunistic local sampling of fewer than 50 mixed-breed dogs can produce sufficient discriminatory and exclusionary power with either genotyping kit.

Coformulated bictegravir, emtricitabine, and tenofovir alafenamide versus dolutegravir with emtricitabine and tenofovir alafenamide, for initial treatment of HIV-1 infection (GS-US-380-1490): a randomised, double-blind, multicentre, phase 3, non-inferiority trial.

BACKGROUND: Integrase strand transfer inhibitors (INSTIs) coadministered with two nucleoside or nucleotide reverse transcriptase inhibitors (NRTIs) are recommended as first-line treatment for HIV, and coformulated fixed-dose combinations are preferred to facilitate adherence. We report 48-week results from a study comparing initial HIV-1 treatment with bictegravir-a novel INSTI with a high in-vitro barrier to resistance and low potential as a perpetrator or victim of clinically relevant drug interactions-coformulated with the NRTI combination emtricitabine and tenofovir alafenamide as a fixed-dose combination to dolutegravir administered with coformulated emtricitabine and tenofovir alafenamide. METHODS: In this randomised, double-blind, multicentre, placebo-controlled, non-inferiority trial, HIV-infected adults were screened and enrolled at 126 outpatient centres in 10 countries in Australia, Europe, Latin America, and North America. Participants were previously untreated adults (HIV-1 RNA ≥500 copies per mL) with estimated glomerular filtration rate of at least 30 mL/min. Chronic hepatitis B virus or hepatitis C co-infection was allowed. We randomly assigned participants (1:1) to receive oral fixed-dose combination bictegravir 50 mg, emtricitabine 200 mg, and tenofovir alafenamide 25 mg or dolutegravir 50 mg with coformulated emtricitabine 200 mg and tenofovir alafenamide 25 mg, with matching placebo, once a day for 144 weeks. Investigators, participants, study staff, and those assessing outcomes were masked to treatment group. All participants who received at least one dose of study drug were included in primary efficacy and safety analyses. The primary endpoint was the proportion of participants with plasma HIV-1 RNA of less than 50 copies per mL at week 48 (US Food and Drug Administration snapshot algorithm), with a prespecified non-inferiority margin of -12%. This study is registered with ClinicalTrials.gov, number NCT02607956. FINDINGS: Between Nov 11, 2015, and July 15, 2016, 742 participants were screened for eligibility, of whom 657 were randomly assigned to treatment (327 with bictegravir, emtricitabine, and tenofovir alafenamide fixed-dose combination [bictegravir group] and 330 with dolutegravir plus emtricitabine and tenofovir alafenamide [dolutegravir group]). 320 participants who received the bictegravir regimen and 325 participants who received the dolutegravir regimen were included in the primary efficacy analyses. At week 48, HIV-1 RNA <50 copies per mL was achieved in 286 (89%) of 320 participants in the bictegravir group and 302 (93%) of 325 in the dolutegravir group (difference -3·5%, 95·002% CI -7·9 to 1·0, p=0·12), showing non-inferiority of the bictegravir regimen to the dolutegravir regimen. No treatment-emergent resistance to any study drug was observed. Incidence and severity of adverse events were similar between groups, and few participants discontinued treatment due to adverse events (5 [2%] of 320 in the bictegravir group and 1 [<1%] 325 in the dolutegravir group). Study drug-related adverse events were less common in the bictegravir group than in the dolutegravir group (57 [18%] of 320 vs 83 [26%] of 325, p=0·022). INTERPRETATION: At 48 weeks, virological suppression with the bictegravir regimen was achieved and was non-inferior to the dolutegravir regimen in previously untreated adults. There was no emergent resistance to either regimen. The fixed-dose combination of bictegravir, emtricitabine, and tenofovir alafenamide was safe and well tolerated compared with the dolutegravir regimen. FUNDING: Gilead Sciences Inc.