Novel Dosing Strategies Increase Exposures of the Potent Antituberculosis Drug Rifapentine but Are Poorly Tolerated in Healthy Volunteers

ABSTRACT Rifapentine is a potent antituberculosis drug currently in phase III trials. Bioavailability decreases with increasing dose, yet high daily exposures are likely needed to improve efficacy and shorten the tuberculosis treatment duration. Further, the limits of tolerability are poorly defined. The phase I multicenter trial in healthy adults described here investigated two strategies to increase rifapentine exposures: dividing the dose or giving the drug with a high-fat meal. In arm 1, rifapentine was administered at 10 mg/kg of body weight twice daily and 20 mg/kg once daily, each for 14 days, separated by a 28-day washout; the dosing sequence was randomized. In arm 2, 15 mg/kg rifapentine once daily was given with a high-fat versus a low-fat breakfast. Sampling for pharmacokinetic analysis was performed on days 1 and 14. Population pharmacokinetic analyses were performed. This trial was stopped early for poor tolerability and because of safety concerns. Of 44 subjects, 20 discontinued prematurely; 11 of these discontinued for protocol-defined toxicity (a grade 3 or higher adverse event or grade 2 or higher rifamycin hypersensitivity). Taking rifapentine with a high-fat meal increased the median steady-state area under the concentration-time curve from time zero to 24 h (AUC 0–24ss ) by 31% (relative standard error, 6%) compared to that obtained when the drug was taken with a low-fat breakfast. Dividing the dose increased exposures substantially (e.g., 38% with 1,500 mg/day). AUC 0–24ss was uniformly higher in our study than in recent tuberculosis treatment trials, in which toxicity was rare. In conclusion, two strategies to increase rifapentine exposures, dividing the dose or giving it with a high-fat breakfast, successfully increased exposures, but toxicity was common in healthy adults. The limits of tolerability in patients with tuberculosis remain to be defined. (AIDS Clinical Trials Group study A5311 has been registered at ClinicalTrials.gov under registration no. NCT01574638.

Diverse Human Immunodeficiency Virus-1 Drug Resistance Profiles at Screening for ACTG A5288: A Study of People Experiencing Virologic Failure on Second-line Antiretroviral Therapy in Resource-limited Settings

CITATION: Wallis, C. L. et al. Diverse Human Immunodeficiency Virus–1 drug resistance profiles at screening for ACTG A5288 : a study of people experiencing virologic failure on second-line antiretroviral therapy in resource-limited settings. Clinical Infectious Diseases, 71(7): e170–e177. doi:10.1093/cid/ciz1116The original publication is available at https://academic.oup.com/cid/Background: Human immunodeficiency virus (HIV) drug resistance profiles are needed to optimize individual patient management and to develop treatment guidelines. Resistance profiles are not well defined among individuals on failing second-line antiretroviral therapy (ART) in low- and middle-income countries (LMIC). Methods: Resistance genotypes were performed during screening for enrollment into a trial of third-line ART (AIDS Clinical Trials Group protocol 5288). Prior exposure to both nucleoside reverse transcriptase inhibitors (NRTIs) and non-NRTIs and confirmed virologic failure on a protease inhibitor-containing regimen were required. Associations of drug resistance with sex, age, treatment history, plasma HIV RNA, nadir CD4+T-cell count, HIV subtype, and country were investigated. Results: Plasma HIV genotypes were analyzed for 653 screened candidates; most had resistance (508 of 653; 78%) to 1 or more drugs. Genotypes from 133 (20%) showed resistance to at least 1 drug in a drug class, from 206 (32%) showed resistance to at least 1 drug in 2 drug classes, and from 169 (26%) showed resistance to at least 1 drug in all 3 commonly available drug classes. Susceptibility to at least 1 second-line regimen was preserved in 59%, as were susceptibility to etravirine (78%) and darunavir/ritonavir (97%). Susceptibility to a second-line regimen was significantly higher among women, younger individuals, those with higher nadir CD4+ T-cell counts, and those who had received lopinavir/ritonavir, but was lower among prior nevirapine recipients. Conclusions: Highly divergent HIV drug resistance profiles were observed among candidates screened for third-line ART in LMIC, ranging from no resistance to resistance to 3 drug classes. These findings underscore the need for access to resistance testing and newer antiretrovirals for the optimal management of third-line ART in LMIC.https://academic.oup.com/cid/article/71/7/e170/5625392?login=truePublishers versio

The “structurally minimal” isoform KChIP2d modulates recovery of Kv4.3 N-terminal deletion mutant Δ2-39

Mechanisms underlying Kv4 (Shal type) potassium channel macroscopic (open state) inactivation and recovery are unknown, as are mechanisms by which KChIP2 isoforms modulate these two processes. In a recent study (Xenopus oocytes, 2 microelectrode voltage clamp) we demonstrated that: i) Partial deletion of the Kv4.3 proximal N-terminal domain (Δ2-39; deletes N-terminal amino acids 2–39) not only slowed macroscopic inactivation, but also slowed the net rate of recovery; and ii) Co-expression of KChIP2b significantly accelerated the rate Δ2-39 recovery from inactivation. The latter effect demonstrated that an intact N-terminal domain was not obligatorily required for KChiP2b-mediated modulation of Kv4.3 recovery. To extend these prior observations, we have employed identical protocols to determine effects of KChiP2d on Δ2-39 macroscopic recovery. KChiP2d is a “structurally minimal” isoform (consisting of only the last 70 amino acids of the common C-terminal domain of larger KChIP2 isoforms) that exerts functional modulatory effects on native Kv4.3 channels. We demonstrate that KChiP2d also accelerates Δ2-39 recovery from macroscopic inactivation. Consistent with our prior Δ2-39 + KChIP2b study, these Δ2-39 + KChIP2d results: i) Further indicate that KChIP2 isoform-mediated acceleration of Kv4.3 macroscopic recovery is not obligatorily dependent upon an intact proximal N-terminal; and ii) Suggest that the last 70 amino acids of the common C-terminal of KChiP2 isoforms may contain the domain(s) responsible for modulation of recovery

A pilot metabolomics study of tuberculosis immune reconstitution inflammatory syndrome.

BackgroundDiagnosis of paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) is challenging and new tools are needed for early diagnosis as well as to understand the biochemical events that underlie the pathology in TB-IRIS.MethodsPlasma samples were obtained from participants from a randomized HIV/TB treatment strategy study (AIDS Clinical Trials Group [ACTG] A5221) with (n = 26) and without TB-IRIS (n = 22) for an untargeted metabolomics pilot study by liquid-chromatography mass spectrometry. The metabolic profile of these participants was compared at the study entry and as close to the diagnosis of TB-IRIS as possible (TB-IRIS window). Molecular features with p < 0.05 and log2 fold change ≥0.58 were submitted for pathway analysis through MetaboAnalyst. We also elucidated potential metabolic signatures for TB-IRIS using a LASSO regression model.ResultsAt the study entry, we showed that the arachidonic acid and glycerophospholipid metabolism were altered in the TB-IRIS group. Sphingolipid and linoleic acid metabolism were the most affected pathways during the TB-IRIS window. LASSO modeling selected a set of 8 and 7 molecular features with the potential to predict TB-IRIS at study entry and during the TB-IRIS window, respectively.ConclusionThis study suggests that the use of plasma metabolites may distinguish HIV-TB patients with and without TB-IRIS

Viral hepatitis B and C in HIV-exposed South African infants

CITATION: Tchuem, C. T., et al. 2020. Viral hepatitis B and C in HIV-exposed South African infants, BMC Pediatrics, 20:563, doi:10.1186/s12887-020-02479-x.The original publication is available at https://bmcpediatr.biomedcentral.comPublication of this article was funded by the Stellenbosch University Open Access FundBackground: Whilst much attention is given to eliminating HIV mother-to-child transmission (MTCT), little has been done to ensure the same for hepatitis B virus (HBV) transmission. The introduction of HBV immunization at six weeks of age has reduced HBV horizontal transmission in South Africa. However, in order to eliminate HBV MTCT, further interventions are needed. The risk of hepatitis C virus (HCV) MTCT in HIV-infected (HIV+) African women is not yet well described. This study aimed to determine the rate of HBV and HCV vertical transmission in HIV-exposed infants in South Africa. Methods: Serum samples from infants enrolled in an isoniazid prevention study (P1041) were screened for HBV and HCV serology markers; screening was performed on samples collected at approximately 60 weeks of age of the infants. HBV DNA was quantified in HBsAg positive samples and HBV strains characterized through gene sequencing. All HCV antibody samples with inconclusive results underwent molecular testing. Results: Three of 821 infants were positive for both HBsAg and HBV DNA. All HBV strains belonged to HBV subgenotype A1. The rtM204I mutation associated with lamivudine resistance was identified in one infant, a second infant harboured the double A1762T/G1764A BCP mutation. Phylogenetic analysis showed clustering between mother and infant viral genomic sequences. Twenty-one of 821 HIV-exposed infants tested had inconclusive HCV antibody results, none were HCV PCR positive. Conclusions: This study suggests that HBV vertical transmission is likely to be occurring in HIV-exposed infants in South Africa.. A more robust strategy of HBV prevention, including birth dose vaccination, is required to eradicate HBV MTCT. HCV infection was not detected.https://bmcpediatr.biomedcentral.com/articles/10.1186/s12887-020-02479-xPublisher's versio

KV4.3 N-terminal deletion mutant Δ2–39: Effects on inactivation and recovery characteristics in both the absence and presence of KChIP2b

Gating transitions in the KV4.3 N-terminal deletion mutant Δ2–39 were characterized in the absence and presence of KChIP2b. We particularly focused on gating characteristics of macroscopic (open state) versus closed state inactivation (CSI) and recovery. In the absence of KChIP2b Δ2–39 did not significantly alter the steady-state activation “a4” relationship or general CSI characteristics, but it did slow the kinetics of deactivation, macroscopic inactivation and macroscopic recovery. Recovery kinetics (for both WT KV4.3 and Δ2–39) were complicated and displayed sigmoidicity, a process which was enhanced by Δ2–39. Deletion of the proximal N-terminal domain therefore appeared to specifically slow mechanisms involved in regulating gating transitions occurring after the channel open state(s) had been reached. In the presence of KChIP2b Δ2–39 recovery kinetics (from both macroscopic and CSI) were accelerated, with an apparent reduction in initial sigmoidicity. Hyperpolarizing shifts in both “a4” and isochronal inactivation “i” were also produced. KChIP2b-mediated remodeling of KV4.3 gating transitions was therefore not obligatorily dependent upon an intact N-terminus. To account for these effects we propose that KChIP2 regulatory domains exist in KV4.3 α subunit regions outside of the proximal N-terminal. In addition to regulating macroscopic inactivation, we also propose that the KV4.3 N-terminus may act as a novel regulator of deactivation-recovery coupling

Brief Report: HIV Drug Resistance in Adults Failing Early Antiretroviral Treatment: Results From the HIV Prevention Trials Network 052 Trial

Submitted by Sandra Infurna ([email protected]) on 2017-12-21T12:34:31Z No. of bitstreams: 1 mariza_morgado_etal_IOC_2016.pdf: 137842 bytes, checksum: 9c34307109b7b6cd29edde12809a3008 (MD5)Approved for entry into archive by Sandra Infurna ([email protected]) on 2017-12-21T13:02:47Z (GMT) No. of bitstreams: 1 mariza_morgado_etal_IOC_2016.pdf: 137842 bytes, checksum: 9c34307109b7b6cd29edde12809a3008 (MD5)Made available in DSpace on 2017-12-21T13:02:47Z (GMT). No. of bitstreams: 1 mariza_morgado_etal_IOC_2016.pdf: 137842 bytes, checksum: 9c34307109b7b6cd29edde12809a3008 (MD5) Previous issue date: 2016Johns Hopkins Univ. School of Medicine. Dept. of Pathology. Baltimore, Maryland, USA.Johns Hopkins Univ. School of Medicine. Dept. of Pathology. Baltimore, Maryland, USA.Fred Hutchinson Cancer Research Center. Vaccine and Infectious Disease Division. Seattle, VA, USA.Frontier Science & Technology Research Foundation. Amherst, NY, USA.Lancet Laboratories and BARC-SA. Specialty Molecular Division. Johannesburg, South Africa.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de AIDS e Imunologia Molecular. Rio de Janeiro, RJ. Brasil.Y. R. Gaitonade Centre for AIDS Research and Education. Chennai, India.National JALMA Institute for Leprosy and Other Mycobacterial Diseases. Agra, India.Frontier Science & Technology Research Foundation. Amherst, NY, USA.Johns Hopkins Univ. School of Medicine. Dept. of Pathology. Baltimore, MD, USA.Johns Hopkins Univ. School of Medicine. Dept. of Pathology. Baltimore, MD, USA.Science Facilitation Department. FHI 360. Washington, DC, USA.Science Facilitation Department. FHI 360, Durham, NC, USA.Fred Hutchinson Cancer Research Center. Vaccine and Infectious Disease Division. Seattle, WA, USA.Univ. of North Carolina at Chapel Hill. Dept. of Medicine. Chapel Hill, NC, USA.Southwest CARE Center. Santa Fe, NM, USA.College of Medicine. Johns Hopkins Project. Blantyre, Malawi.Botswana Harvard AIDS Institute. Gaborone, Botswana.YRGCARE Medical Centre.VHS. Chennai, India.Chiang Mai University. Research Institute for Health Sciences. Chiang Mai, Thailand.University of Zimbabwe. Dept. of Medicine. Harare, Zimbabwe.Univ. of Witwatersrand. Johannesburg, South Africa.Kenya Medical Research Institute. Kisumu, Kenya. / Center for Disease Control. Kisumu, Kenya.Univ. of North Carolina at Chapel Hill. Division of Infectious Diseases. Chapel Hill, NC, USA / UNC Project-Malawi. Institute for Global Health and Infectious Diseases. Lilongwe, Malawi.Hospital Nossa Senhora da Conceição. Serviço de Infectologia. Porto Alegre, RS, Brasil.National AIDS Research Institute (ICMR). Pune, India.Hospital Geral de Nova Iguacu. Nova Iguaçu, RJ, Brasil / Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de AIDS e Imunologia Molecular. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Nacional de Infectologia Evandro Chagas. Rio de Janeiro, RJ, Brasil.University of the Witwatersrand. Perinatal HIV Research Unit. Soweto, South Africa.The Fenway Institute. Fenway Health and Infectious Disease Division. Boston, MA, USA / Harvard Medical School. Beth Israel Deaconess Medical Center/Dept. of Medicine. Boston, MA, USA.Fred Hutchinson Cancer Research Center. Vaccine and Infectious Disease Division and Public Health Sciences Division. Seattle, VA, USA.Univ. of North Carolina at Chapel Hill. Department of Medicine. Chapel Hill, NC, USA.Univ. of North Carolina at Chapel Hill. Dept. of Pathology. Baltimore, MD, USA.Early initiation of antiretroviral treatment (ART) reduces HIV transmission and has health benefits. HIV drug resistance can limit treatment options and compromise use of ART for HIV prevention. We evaluated drug resistance in 85 participants in the HIV Prevention Trials Network 052 trial who started ART at CD4 counts of 350-550 cells per cubic millimeter and failed ART by May 2011; 8.2% had baseline resistance and 35.3% had resistance at ART failure. High baseline viral load and less education were associated with emergence of resistance at ART failure. Resistance at ART failure was observed in 7 of 8 (87.5%) participants who started ART at lower CD4 cell counts

Brief Report: HIV Drug Resistance in Adults Failing Early Antiretroviral Treatment: Results From the HIV Prevention Trials Network 052 Trial

Early initiation of antiretroviral therapy (ART) reduces HIV transmission and has health benefits. HIV drug resistance can limit treatment options and compromise use of ART for HIV prevention. We evaluated drug resistance in 85 participants in the HPTN 052 trial who started ART at CD4 counts of 350–550 cells/mm(3) and failed ART by May 2011; 8.2% had baseline resistance and 35.3% had resistance at ART failure. High baseline viral load and less education were associated with emergence of resistance at ART failure. Resistance at ART failure was observed in 7/8 (87.5%) participants who started ART at lower CD4 cell counts