195 results on '"Arenas-Pinto A"'
Search Results
152. Neurocognitive Function in HIV Infected Patients on Antiretroviral Therapy
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Andrew De Burgh-Thomas, Martin Fisher, Kazeem Aderogba, Alan Winston, Wolfgang Stöhr, Charles J.N. Lacey, Nicholas I. Paton, David Dunn, Clifford Leen, Chloe Orkin, Nigel O'Farrell, and Alejandro Arenas-Pinto
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Male ,Gerontology ,Multivariate analysis ,Cross-sectional study ,lcsh:Medicine ,HIV Infections ,Neuropsychological Tests ,Social and Behavioral Sciences ,RC0109 ,Cohort Studies ,Cognition ,Risk Factors ,Antiretroviral Therapy, Highly Active ,Neurobiology of Disease and Regeneration ,Pathology ,Psychology ,Medicine ,Hiv infected patients ,lcsh:Science ,Neuropathology ,Medicine(all) ,education.field_of_study ,Multidisciplinary ,Agricultural and Biological Sciences(all) ,Cognitive Neurology ,HIV diagnosis and management ,Middle Aged ,Viral Load ,Antivirals ,Mental Health ,Neurology ,Observational Studies ,Infectious diseases ,Female ,HIV clinical manifestations ,Viral load ,Research Article ,Adult ,medicine.medical_specialty ,Neurovirulence ,Psychometrics ,Clinical Research Design ,Cognitive Neuroscience ,Population ,Retrovirology and HIV immunopathogenesis ,Black People ,Viral diseases ,Microbiology ,White People ,Diagnostic Medicine ,Virology ,Internal medicine ,mental disorders ,Humans ,In patient ,education ,Biology ,Biochemistry, Genetics and Molecular Biology(all) ,business.industry ,lcsh:R ,HIV ,Antiretroviral therapy ,Cross-Sectional Studies ,Anatomical Pathology ,lcsh:Q ,business ,Neurocognitive ,Viral Transmission and Infection ,Neuroscience - Abstract
OBJECTIVE\ud \ud To describe factors associated with neurocognitive (NC) function in HIV-positive patients on stable combination antiretroviral therapy.\ud \ud DESIGN\ud \ud We undertook a cross-sectional analysis assessing NC data obtained at baseline in patients entering the Protease-Inhibitor-Monotherapy-Versus-Ongoing-Triple therapy (PIVOT) trial.\ud \ud MAIN OUTCOME MEASURE\ud \ud NC testing comprised of 5 domains. Raw results were z-transformed using standard and demographically adjusted normative datasets (ND). Global z-scores (NPZ-5) were derived from averaging the 5 domains and percentage of subjects with test scores >1 standard deviation (SD) below population means in at least two domains (abnormal Frascati score) calculated. Patient characteristics associated with NC results were assessed using multivariable linear regression.\ud \ud RESULTS\ud \ud Of the 587 patients in PIVOT, 557 had full NC results and were included. 77% were male, 68% Caucasian and 28% of Black ethnicity. Mean (SD) baseline and nadir CD4+ lymphocyte counts were 553(217) and 177(117) cells/µL, respectively, and HIV RNA was
- Published
- 2013
153. Nucleoside reverse-transcriptase inhibitor cross-resistance and outcomes from second-line antiretroviral therapy in the public health approach: an observational analysis within the randomised, open-label, EARNEST trial
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Paton, Nicholas I, Kityo, Cissy, Thompson, Jennifer, Nankya, Immaculate, Bagenda, Leonard, Hoppe, Anne, Hakim, James, Kambugu, Andrew, van Oosterhout, Joep J, Kiconco, Mary, Bertagnolio, Silvia, Easterbrook, Philippa J, Mugyenyi, Peter, Walker, A Sarah, Agweng, E, Awio, P, Bakeinyaga, G, Isabirye, C, Kabuga, U, Kasuswa, S, Katuramu, M, Kityo, C, Kiweewa, F, Kyomugisha, H, Lutalo, E, Mugyenyi, P, Mulima, D, Musana, H, Musitwa, G, Musiime, V, Ndigendawan, M, Namata, H, Nkalubo, J, Labejja, P Ocitti, Okello, P, Olal, P, Pimundu, G, Segonga, P, Ssali, F, Tamale, Z, Tumukunde, D, Namala, W, Byaruhanga, R, Kayiwa, J, Tukamushaba, J, Abunyang, S, Eram, D, Denis, O, Lwalanda, R, Mugarura, L, Namusanje, J, Nankya, I, Ndashimye, E, Nabulime, E, Mulima, D, Senfuma, O, Bihabwa, G, Buluma, E, Easterbrook, P, Elbireer, A, Kambugu, A, Kamya, D, Katwere, M, Kiggundu, R, Komujuni, C, Laker, E, Lubwama, E, Mambule, I, Matovu, J, Nakajubi, A, Nakku, J, Nalumenya, R, Namuyimbwa, L, Semitala, F, Wandera, B, Wanyama, J, Mugerwa, H, Lugemwa, A, Ninsiima, E, Ssenkindu, T, Mwebe, S, Atwine, L, William, H, Katemba, C, Abunyang, S, Acaku, M, Ssebutinde, P, Kitizo, H, Kukundakwe, J, Naluguza, M, Ssegawa, K, Namayanja, Nsibuka, F, Tuhirirwe, P, Fortunate, M, Acen, J, Achidri, J, Amone, A, Chamai, M, Ditai, J, Kemigisa, M, Kiconco, M, Matama, C, Mbanza, D, Nambaziira, F, Odoi, M Owor, Rweyora, A, Tumwebaze, G, Kalanzi, H, Katabaazi, J, Kiyingi, A, Mbidde, M, Mugenyi, M, Mwebaze, R, Okong, P, Senoga, I, Abwola, M, Baliruno, D, Bwomezi, J, Kasede, A, Mudoola, M, Namisi, R, Ssennono, F, Tuhirwe, S, Abongomera, G, Amone, G, Abach, J, Aciro, I, Arach, B, Kidega, P, Omongin, J, Ocung, E, Odong, W, Philliam, A, Alima, H, Ahimbisibwe, B, Atuhaire, E, Atukunda, F, Bekusike, G, Bulegyeya, A, Kahatano, D, Kamukama, S, Kyoshabire, J, Nassali, A, Mbonye, A, Naturinda, T M, Ndukukire, Nshabohurira, A, Ntawiha, H, Rogers, A, Tibyasa, M, Kiirya, S, Atwongyeire, D, Nankya, A, Draleku, C, Nakiboneka, D, Odoch, D, Lakidi, L, Ruganda, R, Abiriga, R, Mulindwa, M, Balmoi, F, Kafuma, S, Moriku, E, Hakim, J, Reid, A, Chidziva, E, Musoro, G, Warambwa, C, Tinago, G, Mutsai, S, Phiri, M, Mudzingwa, S, Bafana, T, Masore, V, Moyo, C, Nhema, R, Chitongo, S, Heyderman, Robert, Kabanga, Lucky, Kaunda, Symon, Kudzala, Aubrey, Lifa, Linly, Mallewa, Jane, Moore, Mike, Mtali, Chrissie, Musowa, George, Mwimaniwa, Grace, Sikwese, Rosemary, van Oosterhout, Joep, Ziwoya, Milton, Chimbaka, H, Chitete, B, Kamanga, S, Makwakwa, T Kayinga E, Mbiya, R, Mlenga, M, Mphande, T, Mtika, C, Mushani, G, Ndhlovu, O, Ngonga, M, Nkhana, I, Nyirenda, R, Cheruiyot, P, Kwobah, C, Ekiru, W Lokitala, Mokaya, M, Mudogo, A, Nzioka, A, Siika, A, Tanui, M, Wachira, S, Wools-Kaloustian, K, Alipalli, P, Chikatula, E, Kipaila, J, Kunda, I, Lakhi, S, Malama, J, Mufwambi, W, Mulenga, L, Mwaba, P, Mwamba, E, Mweemba, A, Namfukwe, M, Kerukadho, E, Ngwatu, B, Birungi, J, Paton, N, Boles, J, Burke, A, Castle, L, Ghuman, S, Kendall, L, Hoppe, A, Tebbs, S, Thomason, M, Thompson, J, Walker, S, Whittle, J, Wilkes, H, Young, N, Spyer, M, Kapuya, C, Kyomuhendo, F, Kyakundi, D, Mkandawire, N, Mulambo, S, Senyonjo, S, Angus, B, Arenas-Pinto, A, Palfreeman, A, Post, F, Ishola, D, Arribas, J, Colebunders, R, Floridia, M, Giuliano, M, Mallon, P, Walsh, P, De Rosa, M, Rinaldi, E, Weller, I, Gilks, C, Hakim, J, Kangewende, A, Lakhi, S, Luyirika, E, Miiro, F, Mwamba, P, Mugyenyi, P, Ojoo, S, Paton, N, Phiri, S, van Oosterhout, J, Siika, A, Walker, S, Wapakabulo, A, Peto, T, French, N, Matenga, J, Cloherty, G, van Wyk, J, Norton, M, Lehrman, S, Lamba, P, Malik, K, Rooney, J, Snowden, W, and Villacian, J
- Abstract
Cross-resistance after first-line antiretroviral therapy (ART) failure is expected to impair activity of nucleoside reverse-transcriptase inhibitors (NRTIs) in second-line therapy for patients with HIV, but evidence for the effect of cross-resistance on virological outcomes is limited. We aimed to assess the association between the activity, predicted by resistance testing, of the NRTIs used in second-line therapy and treatment outcomes for patients infected with HIV.
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- 2017
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154. Common inherited mitochondrial DNA mutations and nucleoside reverse transcriptase inhibitor-induced severe hyperlactataemia in HIV-infected adults: an exploratory study
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Arenas-Pinto, Alejandro, primary, Weller, Ian, additional, Ekong, Rosemary, additional, Grant, Alison, additional, Karstaedt, Alan, additional, Reiss, Peter, additional, Telisinghe, Lilanganee, additional, Weber, Rainer, additional, Bolhaar, Martine, additional, Bradman, Neil, additional, and Ingram, Catherine, additional
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- 2011
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155. Nevirapine Increases High-Density Lipoprotein Cholesterol Concentration by Stimulation of Apolipoprotein A-I Production
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Franssen, Remco, primary, Sankatsing, Raaj R., additional, Hassink, Elly, additional, Hutten, Barbara, additional, Ackermans, Mariette T., additional, Brinkman, Kees, additional, Oesterholt, René, additional, Arenas-Pinto, Alejandro, additional, Storfer, Stephen P., additional, Kastelein, John J., additional, Sauerwein, Hans P., additional, Reiss, Peter, additional, and Stroes, Erik S., additional
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- 2009
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156. Safety and Efficacy of Didanosine Enteric-Coated Capsule in Patients with HIV-1 Infection
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Arenas-Pinto, Alejandro, primary
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- 2009
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157. Lack of association between mitochondrial DNA polymorphisms and didexoxynucleoside-induced hyperlactataemia in black-African, HIV-1-infected patients
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Ian Weller, Lilanganee Telisinghe, Martine Bolhaar, Alan Karstaedt, Salome Charalambous, Alison D. Grant, Alejandro Arenas-Pinto, Catherine J. E. Ingram, Neil Bradman, and Rosemary Ekong
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medicine.medical_specialty ,Mitochondrial DNA ,business.industry ,Haplogroup H ,Public health ,Public Health, Environmental and Occupational Health ,Single-nucleotide polymorphism ,medicine.disease ,Bioinformatics ,Virology ,Mitochondrial toxicity ,Infectious Diseases ,Pharmacotherapy ,Acquired immunodeficiency syndrome (AIDS) ,Poster Presentation ,medicine ,business ,Lipoatrophy ,health care economics and organizations - Abstract
Background: Recent studies have shown some association between specific mitochondrial DNA (mtDNA) polymorphisms and peripheral neuropathy in both white European and black American populations. An association between mtDNA haplogroup H and peripheral lipoatrophy has been reported in white Europeans. Our group has shown a lack of association between mtDNA polymorphisms and the occurrence of HL in white Europeans exposed to dideoxynucleosides, but there have been no studies in black African people. Supplement: Abstracts of the Tenth International Congress on Drug Therapy in HIV Infection http://www.biomedcentral.com/content/pdf/1758-2652-13-S4-info.pdf Conference: Tenth International Congress on Drug Therapy in HIV Infection 7-11 November 2010 Glasgow, UK (Published: 8 November 2010) doi:10.1186/1758-2652-13-S4-P96 Cite this article as: Arenas-Pinto et al.: Lack of association between mitochondrial DNA polymorphisms and didexoxynucleoside-induced hyperlactataemia in black-African, HIV-1-infected patients. Journal of the International AIDS Society 2010 13(Suppl 4):P96. Full text: PubMed Central: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3113104/
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- 2010
158. The Risk of Developing Peripheral Neuropathy Induced by Nucleoside Reverse Transcriptase Inhibitors Decreases over Time: Evidence from the Delta Trial
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Arenas-Pinto, Alejandro, primary, Bhaskaran, Krishnan, additional, Dunn, David, additional, and Weller, Ian VD, additional
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- 2008
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159. Safety and Efficacy of Didanosine Enteric-Coated Capsule in Patients with HIV-1 Infection
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Alejandro Arenas-Pinto
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Drug ,Cart ,medicine.medical_specialty ,media_common.quotation_subject ,Context (language use) ,Gastroenterology ,immune system diseases ,Abacavir ,Internal medicine ,parasitic diseases ,medicine ,heterocyclic compounds ,Adverse effect ,Didanosine ,media_common ,business.industry ,lcsh:RM1-950 ,virus diseases ,General Medicine ,biochemical phenomena, metabolism, and nutrition ,medicine.disease ,lcsh:Therapeutics. Pharmacology ,Pancreatitis ,Hyperlactatemia ,business ,medicine.drug ,Biomedical engineering - Abstract
Didanosine (ddl) has been used to treat HIV infection, in combination with other anti-retroviral drugs, for over 15 years. However, the use of the original formulation of ddI was limited by serious gastro-intestinal adverse effects, which were mainly attributable to the buffer used to protect ddI from the effect of gastric pH. Didanosine enteric-coated capsule (ddI-EC), a more recently introduced formulation, is less likely to cause gastrointestinal intolerance and its absorption might not be compromised by food intake. In this review we discuss efficacy of ddI-EC-containing anti-retroviral combinations (cART) both in naïve and previously treated patients. Because of its favorable resistance profile, ddI-EC has been shown to be potentially efficacious in rescuing patients in virological failure, even if they have nucleoside reverse transcriptase inhibitors (NRTI)-associated resistance mutations. However, ddI has been shown as a potent inducer of mitochondrial dysfunction. Peripheral neuropathy, severe hyperlactatemia and pancreatitis have all been described in patients exposed to ddI. Close monitoring of patients on ddI-EC-containing cART and low threshold for treatment modifications are required to prevent major complications. In the context of once daily cART, ddI-EC is a valid option, particularly when other agents are not available, or when other medical conditions preclude the use of drugs such as tenofovir or abacavir. The role of ddI-EC in second line cART may be even more important in resource-limited settings where additional options are lacking.
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- 2009
160. PLATELET DYSFUNCTION–EOSINOPHILIA SYNDROME IN PARASITIZED VENEZUELAN CHILDREN
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RUIZ-SÁEZ, ARLETTE, primary, ARENAS-PINTO, ALEJANDRO, additional, POCATERRA, LEONOR, additional, TORRES, OBDULITA, additional, FERRARA, GUISEPPE, additional, GOLDSTEIN, CARLOS, additional, SIFONTES, LUZ NÚÑEZ, additional, GIMÉNEZ, RITA, additional, BOSCH, NORMA, additional, FEIJOO, ROSA, additional, and CERTAD, GABRIELA, additional
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- 2005
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161. CRYPTOSPORIDIOSIS IN HIV-INFECTED VENEZUELAN ADULTS IS STRONGLY ASSOCIATED WITH ACUTE OR CHRONIC DIARRHEA
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CERTAD, GABRIELA, primary, BELLO, ANDREINA, additional, NÚÑEZ, LUZ, additional, FERRARA, GIUSEPPE, additional, CASTRO, JULIO, additional, ARENAS-PINTO, ALEJANDRO, additional, and POCATERRA, LEONOR, additional
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- 2005
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162. ISOSPORIASIS IN VENEZUELAN ADULTS INFECTED WITH HUMAN IMMUNODEFICIENCY VIRUS: CLINICAL CHARACTERIZATION
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CERTAD, GABRIELA, primary, POCATERRA, LEONOR, additional, ARENAS-PINTO, ALEJANDRO, additional, NÚÑEZ, LUZ, additional, BELLO, ANDREINA, additional, CASTRO, JULIO, additional, and FERRARA, GIUSEPPE, additional
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- 2003
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163. Neurocognitive Function in HIV Infected Patients on Antiretroviral Therapy.
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Winston, Alan, Arenas-Pinto, Alejandro, Stöhr, Wolfgang, Fisher, Martin, Orkin, Chloe M., Aderogba, Kazeem, De Burgh-Thomas, Andrew, O'Farrell, Nigel, Lacey, Charles JN., Leen, Clifford, Dunn, David, and Paton, Nicholas I.
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HIV-positive persons , *ANTIRETROVIRAL agents , *HIV infections , *THERAPEUTICS , *CROSS-sectional method , *HEALTH outcome assessment , *COGNITIVE neuroscience , *NEUROLOGICAL disorders , *DATA analysis - Abstract
Objective: To describe factors associated with neurocognitive (NC) function in HIV-positive patients on stable combination antiretroviral therapy. Design: We undertook a cross-sectional analysis assessing NC data obtained at baseline in patients entering the Protease-Inhibitor-Monotherapy-Versus-Ongoing-Triple therapy (PIVOT) trial. Main outcome measure: NC testing comprised of 5 domains. Raw results were z-transformed using standard and demographically adjusted normative datasets (ND). Global z-scores (NPZ-5) were derived from averaging the 5 domains and percentage of subjects with test scores >1 standard deviation (SD) below population means in at least two domains (abnormal Frascati score) calculated. Patient characteristics associated with NC results were assessed using multivariable linear regression. Results: Of the 587 patients in PIVOT, 557 had full NC results and were included. 77% were male, 68% Caucasian and 28% of Black ethnicity. Mean (SD) baseline and nadir CD4+ lymphocyte counts were 553(217) and 177(117) cells/µL, respectively, and HIV RNA was <50 copies/mL in all. Median (IQR) NPZ-5 score was −0.5 (−1.2/−0) overall, and −0.3 (−0.7/0.1) and −1.4 (−2/−0.8) in subjects of Caucasian and Black ethnicity, respectively. Abnormal Frascati scores using the standard-ND were observed in 51%, 38%, and 81%, respectively, of subjects overall, Caucasian and Black ethnicity (p<0.001), but in 62% and 69% of Caucasian and Black subjects using demographically adjusted-ND (p = 0.20). In the multivariate analysis, only Black ethnicity was associated with poorer NPZ-5 scores (P<0.001). Conclusions: In this large group of HIV-infected subjects with viral load suppression, ethnicity but not HIV-disease factors is closely associated with NC results. The prevalence of abnormal results is highly dependent on control datasets utilised. Trial registry: ClinicalTrials.gov, NCT01230580 [ABSTRACT FROM AUTHOR]
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- 2013
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164. Antiretroviral therapy and body weight in the START (Strategic Timing of Antiretroviral Treatment) trial
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Moestrup, K. S., Sharma, S., Baker, J., Collins, S., Carey, D., Maltez, F., Arenas-Pinto, A., Hawkins, K., Neaton, J., Macpherson, C., and Jens Lundgren
165. Systemic inflammation and residual viraemia in HIV-positive adults on protease inhibitor monotherapy: a cross-sectional study
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Arenas-Pinto, Alejandro, Milinkovic, Ana, Peppa, Dimitra, McKendry, Anna, Maini, Mala, and Gilson, Richard
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Infectious Diseases - Full Text
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166. Bone turnover change after randomized switch from tenofovir disoproxil to tenofovir alafenamide fumarate in men with HIV.
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Moore AEB, Burns JE, Sally D, Milinkovic A, Krokos G, John J, Rookyard C, Borca A, Pool ERM, Tostevin A, Harman A, Dulnoan DS, Gilson R, Arenas-Pinto A, Cook GJR, Saunders J, Dunn D, Blake GM, and Pett SL
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- Male, Humans, Middle Aged, Tenofovir adverse effects, Positron Emission Tomography Computed Tomography, Adenine adverse effects, Emtricitabine therapeutic use, Rilpivirine therapeutic use, Anti-HIV Agents adverse effects, HIV Infections drug therapy
- Abstract
Objective: Bone loss in people with HIV (PWH) is poorly understood. Switching tenofovir disoproxil fumarate (TDF) to tenofovir alafenamide (TAF) has yielded bone mineral density (BMD) increases. PETRAM (NCT#:03405012) investigated whether BMD and bone turnover changes correlate., Design: Open-label, randomized controlled trial., Setting: Single-site, outpatient, secondary care., Participants: Nonosteoporotic, virologically suppressed, cis-male PWH taking TDF/emtricitabine (FTC)/rilpivirine (RPV) for more than 24 weeks., Intervention: Continuing TDF/FTC/RPV versus switching to TAF/FTC/RPV (1 : 1 randomization)., Main Outcome Measures: :[ 18 F]NaF-PET/CT for bone turnover (standardized uptake values, SUV mean ) and dual-energy x-ray absorptiometry for lumbar spine and total hip BMD., Results: Thirty-two men, median age 51 years, 76% white, median duration TDF/FTC/RPV 49 months, were randomized between 31 August 2018 and 09 March 2020. Sixteen TAF:11 TDF were analyzed. Baseline-final scan range was 23-103 (median 55) weeks. LS-SUV mean decreased for both groups (TAF -7.9% [95% confidence interval -14.4, -1.5], TDF -5.3% [-12.1,1.5], P = 0.57). TH-SUV mean showed minimal changes (TAF +0.3% [-12.2,12.8], TDF +2.9% [-11.1,16.9], P = 0.77). LS-BMD changes were slightly more favorable with TAF but failed to reach significance (TAF +1.7% [0.3,3.1], TDF -0.3 [-1.8,1.2], P = 0.06). Bone turnover markers decreased more with TAF ([CTX -35.3% [-45.7, -24.9], P1NP -17.6% [-26.2, -8.5]) than TDF (-11.6% [-28.8, +5.6] and -6.9% [-19.2, +5.4] respectively); statistical significance was only observed for CTX ( P = 0.02, P1NP, P = 0.17)., Conclusion: Contrary to our hypothesis, lumbar spine and total hip regional bone formation (SUV mean ) and BMD did not differ postswitch to TAF. However, improved LS-BMD and CTX echo other TAF-switch studies. The lack of difference in SUV mean may be due to inadequate power., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)
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- 2024
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167. Long-term efficacy and safety of a treatment strategy for HIV infection using protease inhibitor monotherapy: 8-year routine clinical care follow-up from a randomised, controlled, open-label pragmatic trial (PIVOT).
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Paton NI, Stöhr W, Arenas-Pinto A, Clarke A, Williams I, Johnson M, Orkin C, Chen F, Lee V, Winston A, Gompels M, Fox J, Sanders K, and Dunn DT
- Abstract
Background: Treatment-simplification strategies are important tools for patient-centred management. We evaluated long-term outcomes from a PI monotherapy switch strategy., Methods: Eligible participants attending 43 UK treatment centres had a viral load (VL) below 50 copies/ml for at least 24 weeks on combination ART. Participants were randomised to maintain ongoing triple therapy (OT) or switch to a strategy of physician-selected PI monotherapy (PI-mono) with prompt return to combination therapy if VL rebounded. The primary outcome, previously reported, was loss of future drug options after 3 years, defined as new intermediate/high level resistance to at least one drug to which the participant's virus was considered sensitive at trial entry. Here we report resistance and disease outcomes after further extended follow-up in routine care. The study was registered as ISRCTN04857074., Findings: We randomised 587 participants to OT (291) or PI-mono (296) between Nov 4, 2008, and July 28, 2010 and followed them for a median of more than 8 years (100 months) until 2018. At the end of this follow-up time, one or more future drug options had been lost in 7 participants in the OT group and 6 in the PI-mono group; estimated cumulative risk by 8 years of 2.7% and 2.1% respectively (difference -0.6%, 95% CI -3.2% to 2.0%). Only one PI-mono participant developed resistance to the protease inhibitor they were taking (atazanavir). Serious clinical events (death, serious AIDS, and serious non-AIDS) were infrequent; reported in a total of 12 (4.1%) participants in the OT group and 23 (7.8%) in the PI-mono group (P = 0.08) over the entire follow-up period., Interpretation: A strategy of PI monotherapy, with regular VL monitoring and prompt reintroduction of combination treatment following rebound, preserved future treatment options. Findings confirm the high genetic barrier to resistance of the PI drug class that makes them well suited for creative, patient-centred, treatment-simplification approaches. The possibility of a small excess risk of serious clinical events with the PI monotherapy strategy cannot be excluded., Funding: The National Institute for Health Research Health Technology Assessment programme., Competing Interests: NP reports grants to institution from Janssen; and honoraria for lectures from Janssen. AA-P reports grants to institution from Janssen, ViiV Healthcare and Gilead Sciences and advisory board fees from ViiV Healthcare. AC reports contracts to run clinical trials with payments to institution from Gilead Sciences, ViiV Healthcare, MSD and GSK; honoraria for lectures from MSD; support for attending meetings from ViiV Healthcare and Gilead Sciences; advisory board fees from Gilead Sciences, ViiV Healthcare and Theratechnologies. CO reports grants to institution from Janssen, Gilead, ViiV Healthcare, MSD and Astrazeneca; honoraria for lectures from Janssen, Gilead, ViiV Healthcare and MSD; and unpaid appointments as President of the Medical Women's Federation and a member of the International AIDS Society governing council. MG reports advisory board fees from Gilead. All other authors declare no competing interests., (© 2024 The Author(s).)
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- 2024
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168. Hepatic steatosis in people older and younger than fifty who are living with HIV and HIV-negative controls: A cross-sectional study nested within the POPPY cohort.
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Arenas-Pinto A, Bakewell N, Milinkovic A, Williams I, Vera J, Post FA, Anderson J, Beynon M, O'Brien A, Doyle N, Gilson R, Pett SL, Winston A, and Sabin CA
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- Humans, Male, Aged, Cross-Sectional Studies, Liver diagnostic imaging, Liver Cirrhosis epidemiology, Liver Cirrhosis complications, Obesity complications, Obesity epidemiology, Papaver, HIV Infections complications, HIV Infections epidemiology, HIV Infections pathology, Fatty Liver epidemiology, Fatty Liver pathology, Elasticity Imaging Techniques adverse effects
- Abstract
Background: Hepatic steatosis is a major cause of chronic liver disease associated with several negative health outcomes. We compared the prevalence of and factors associated with steatosis in people living with and without HIV., Methods: Older (>50 years) and younger (<50 years) people with HIV and older HIV-negative controls (>50 years) underwent liver transient elastography examination with controlled attenuation parameter (steatosis ≥238 dB/m, moderate/severe steatosis ≥280 dB/m, liver fibrosis ≥7.1 kPa). We compared groups using logistic regression/Chi-squared/Fisher's exact/Kruskal-Wallis tests., Results: In total, 317 participants (109 older people with HIV; 101 younger people with HIV; 107 HIV-negative controls) were predominantly white (86%) and male (76%), and 21% were living with obesity (body mass index ≥30 kg/m
2 ). Most (97%) people with HIV had undetectable HIV RNA. The prevalence of fibrosis was 8.4%, 3.0%, and 6.5% in the three groups, respectively (p = 0.26). Fibrosis was predominately (>65%) mild. The prevalence of steatosis was the same in older people with HIV (66.4%) and controls (66.4%) but lower in younger people with HIV (37.4%; p < 0.001). After adjustment, younger people with HIV were less likely to have steatosis (odds ratio [OR] 0.26; 95% confidence interval [CI] 0.14-0.52) than controls, but male sex (OR 2.45; 95% CI 1.20-4.50) and high waist-to-hip ratio (OR 3.04; 95% CI 1.74-5.33) were associated with an increased odds of steatosis. We found no association between steatosis and HIV-related variables., Conclusions: The prevalence of hepatic steatosis and fibrosis was similar between older participants regardless of HIV status. Age, sex, and abdominal obesity, but not HIV-related variables, were associated with steatosis. Interventions for controlling obesity should be integrated into routine HIV care., (© 2023 The Authors. HIV Medicine published by John Wiley & Sons Ltd on behalf of British HIV Association.)- Published
- 2024
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169. Trypanosoma cruzi screening in people living with HIV in the UK.
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Ahmed N, Herbert S, Arenas-Pinto A, Rickman H, Benn P, Edwards SG, Chiodini PL, and Grant AD
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- Humans, Risk Factors, United Kingdom epidemiology, Trypanosoma cruzi physiology, Chagas Disease diagnosis, Chagas Disease epidemiology, HIV Infections complications, HIV Infections diagnosis, HIV Infections epidemiology
- Abstract
People living with HIV (PLWH) are at higher risk of reactivation of Chagas disease, a neglected tropical disease, caused by Trypanosoma cruzi . There are no data from UK HIV clinics on the prevalence of T. cruzi . We implemented T. cruzi screening at our clinic as part of routine care for PLWH with epidemiological risk factors. Among 86 patients screened, none had positive serology: one seropositive patient was identified due to increased clinician awareness. Implementing T. cruzi screening as part of routine clinical care was feasible, though labour intensive and identified at-risk individuals., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
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- 2024
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170. Peripheral Neuropathy in Virologically Suppressed People Living with HIV: Evidence from the PIVOT Trial.
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Schuldt AL, Bern H, Hart M, Gompels M, Winston A, Clarke A, Chen F, Stöhr W, Heslegrave A, Paton NI, Petzold A, and Arenas-Pinto A
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- Adult, Humans, Male, Female, Risk Factors, Protease Inhibitors therapeutic use, HIV Infections complications, HIV Infections drug therapy, Metabolic Syndrome, Peripheral Nervous System Diseases complications
- Abstract
The aim of this study is to identify the factors associated with peripheral neuropathy and to explore neurofilament light chain (NfL) as a biomarker for peripheral neuropathy (PN) in effectively virologically suppressed adults living with HIV. All protease inhibitor monotherapy versus ongoing triple therapy in the long-term management of HIV infection (PIVOT) trial participants with data on PN at baseline were included in the study. NfL plasma levels (pNfL) were measured in a sub-set of participants. Multivariable logistic regression was used to examine the associations of PN with potential risk factors (including age, sex, nadir CD4 cell count, history of dideoxynucleoside (d-drugs) exposure, and blood glucose levels) and NfL levels. Of the 585 participants included, 131 (22.4%) reported PN during the study period (median of 44 months). The participants were predominantly male (76.6%), White (68.2%), and virologically suppressed for a median period of 37 months (range of 20-63) before recruitment. The age at baseline was 44.3 years (standard deviation (SD) of 9.2). PN was independently associated with age (adjusted odds ratio (aOR) = 1.35, 95% CI of 1.20-1.52; additional 5 years), history of d-drugs (aOR 1.88, 95% CI of 1.12-3.16), height (aOR 1.19, 95% CI of 1.05-1.35; additional 5 cm), nadir CD4 cell count (aOR 1.10 CI of 1.00-1.20; 50 cells fewer), and metabolic syndrome (aOR 2.31, 95% CI of 1.27 4.20), but not pNfL. The excess risk for PN associated with d-drug use remains after the exposure has stopped for years, suggesting non-reversible toxicity. In people with HIV, metabolic syndrome is independently associated with PN. There was no additional value for pNfL as a screening test for peripheral neuropathy in effectively virologically suppressed adults living with HIV.
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- 2023
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171. How surgical Trainee Research Collaboratives achieve success: a mixed methods study to develop trainee engagement strategies.
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Clement C, Coulman K, Heywood N, Pinkney T, Blazeby J, Blencowe NS, Cook JA, Bulbulia R, Arenas-Pinto A, Snowdon C, Hilton Z, Magill L, MacLennan G, Glasbey J, Nepogodiev D, Hardy V, and Lane JA
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- Humans, Education, Medical, Graduate, Motivation, Surveys and Questionnaires, Randomized Controlled Trials as Topic, Surgeons education, Specialties, Surgical
- Abstract
Objectives: This study aimed to understand the role of surgical Trainee Research Collaboratives (TRCs) in conducting randomised controlled trials and identify strategies to enhance trainee engagement in trials., Design: This is a mixed methods study. We used observation of TRC meetings, semi-structured interviews and an online survey to explore trainees' motivations for engagement in trials and TRCs, including barriers and facilitators. Interviews were analysed thematically, alongside observation field notes. Survey responses were analysed using descriptive statistics. Strategies to enhance TRCs were developed at a workshop by 13 trial methodologists, surgical trainees, consultants and research nurses., Setting: This study was conducted within a secondary care setting in the UK., Participants: The survey was sent to registered UK surgical trainees. TRC members and linked stakeholders across surgical specialties and UK regions were purposefully sampled for interviews., Results: We observed 5 TRC meetings, conducted 32 semi-structured interviews and analysed 73 survey responses. TRCs can mobilise trainees thus gaining wider access to patients. Trainees engaged with TRCs to improve patient care, surgical evidence and to help progress their careers. Trainees valued the TRC infrastructure, research expertise and mentoring. Challenges for trainees included clinical and other priorities, limited time and confidence, and recognition, especially by authorship. Key TRC strategies were consultant support, initial simple rapid studies, transparency of involvement and recognition for trainees (including authorship policies) and working with Clinical Trials Units and research nurses. A 6 min digital story on YouTube disseminated these strategies., Conclusion: Trainee surgeons are mostly motivated to engage with trials and TRCs. Trainee engagement in TRCs can be enhanced through building relationships with key stakeholders, maximising multi-disciplinary working and offering training and career development opportunities., Competing Interests: Competing interests: NH, TP, JB, NSB, JG, DN have been involved with a TRC; CC, KC, JAC, RB, AA-P, CS, LM, GM, JAL are methodologists who work with a CTU or in trials methodology and ZH and VH are research nurses who work with clinical research networks., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
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- 2023
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172. Intravenous aviptadil and remdesivir for treatment of COVID-19-associated hypoxaemic respiratory failure in the USA (TESICO): a randomised, placebo-controlled trial.
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Brown SM, Barkauskas CE, Grund B, Sharma S, Phillips AN, Leither L, Peltan ID, Lanspa M, Gilstrap DL, Mourad A, Lane K, Beitler JR, Serra AL, Garcia I, Almasri E, Fayed M, Hubel K, Harris ES, Middleton EA, Barrios MAG, Mathews KS, Goel NN, Acquah S, Mosier J, Hypes C, Salvagio Campbell E, Khan A, Hough CL, Wilson JG, Levitt JE, Duggal A, Dugar S, Goodwin AJ, Terry C, Chen P, Torbati S, Iyer N, Sandkovsky US, Johnson NJ, Robinson BRH, Matthay MA, Aggarwal NR, Douglas IS, Casey JD, Hache-Marliere M, Georges Youssef J, Nkemdirim W, Leshnower B, Awan O, Pannu S, O'Mahony DS, Manian P, Awori Hayanga JW, Wortmann GW, Tomazini BM, Miller RF, Jensen JU, Murray DD, Bickell NA, Zatakia J, Burris S, Higgs ES, Natarajan V, Dewar RL, Schechner A, Kang N, Arenas-Pinto A, Hudson F, Ginde AA, Self WH, Rogers AJ, Oldmixon CF, Morin H, Sanchez A, Weintrob AC, Cavalcanti AB, Davis-Karim A, Engen N, Denning E, Taylor Thompson B, Gelijns AC, Kan V, Davey VJ, Lundgren JD, Babiker AG, Neaton JD, and Lane HC
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- Adult, Humans, Female, Middle Aged, Male, SARS-CoV-2, Treatment Outcome, COVID-19 Drug Treatment, Oxygen, COVID-19 complications, Respiratory Insufficiency drug therapy, Respiratory Insufficiency etiology
- Abstract
Background: There is a clinical need for therapeutics for COVID-19 patients with acute hypoxemic respiratory failure whose 60-day mortality remains at 30-50%. Aviptadil, a lung-protective neuropeptide, and remdesivir, a nucleotide prodrug of an adenosine analog, were compared with placebo among patients with COVID-19 acute hypoxaemic respiratory failure., Methods: TESICO was a randomised trial of aviptadil and remdesivir versus placebo at 28 sites in the USA. Hospitalised adult patients were eligible for the study if they had acute hypoxaemic respiratory failure due to confirmed SARS-CoV-2 infection and were within 4 days of the onset of respiratory failure. Participants could be randomly assigned to both study treatments in a 2 × 2 factorial design or to just one of the agents. Participants were randomly assigned with a web-based application. For each site, randomisation was stratified by disease severity (high-flow nasal oxygen or non-invasive ventilation vs invasive mechanical ventilation or extracorporeal membrane oxygenation [ECMO]), and four strata were defined by remdesivir and aviptadil eligibility, as follows: (1) eligible for randomisation to aviptadil and remdesivir in the 2 × 2 factorial design; participants were equally randomly assigned (1:1:1:1) to intravenous aviptadil plus remdesivir, aviptadil plus remdesivir matched placebo, aviptadil matched placebo plus remdesvir, or aviptadil placebo plus remdesivir placebo; (2) eligible for randomisation to aviptadil only because remdesivir was started before randomisation; (3) eligible for randomisation to aviptadil only because remdesivir was contraindicated; and (4) eligible for randomisation to remdesivir only because aviptadil was contraindicated. For participants in strata 2-4, randomisation was 1:1 to the active agent or matched placebo. Aviptadil was administered as a daily 12-h infusion for 3 days, targeting 600 pmol/kg on infusion day 1, 1200 pmol/kg on day 2, and 1800 pmol/kg on day 3. Remdesivir was administered as a 200 mg loading dose, followed by 100 mg daily maintenance doses for up to a 10-day total course. For participants assigned to placebo for either agent, matched saline placebo was administered in identical volumes. For both treatment comparisons, the primary outcome, assessed at day 90, was a six-category ordinal outcome: (1) at home (defined as the type of residence before hospitalisation) and off oxygen (recovered) for at least 77 days, (2) at home and off oxygen for 49-76 days, (3) at home and off oxygen for 1-48 days, (4) not hospitalised but either on supplemental oxygen or not at home, (5) hospitalised or in hospice care, or (6) dead. Mortality up to day 90 was a key secondary outcome. The independent data and safety monitoring board recommended stopping the aviptadil trial on May 25, 2022, for futility. On June 9, 2022, the sponsor stopped the trial of remdesivir due to slow enrolment. The trial is registered with ClinicalTrials.gov, NCT04843761., Findings: Between April 21, 2021, and May 24, 2022, we enrolled 473 participants in the study. For the aviptadil comparison, 471 participants were randomly assigned to aviptadil or matched placebo. The modified intention-to-treat population comprised 461 participants who received at least a partial infusion of aviptadil (231 participants) or aviptadil matched placebo (230 participants). For the remdesivir comparison, 87 participants were randomly assigned to remdesivir or matched placebo and all received some infusion of remdesivir (44 participants) or remdesivir matched placebo (43 participants). 85 participants were included in the modified intention-to-treat analyses for both agents (ie, those enrolled in the 2 x 2 factorial). For the aviptadil versus placebo comparison, the median age was 57 years (IQR 46-66), 178 (39%) of 461 participants were female, and 246 (53%) were Black, Hispanic, Asian or other (vs 215 [47%] White participants). 431 (94%) of 461 participants were in an intensive care unit at baseline, with 271 (59%) receiving high-flow nasal oxygen or non-invasive ventiliation, 185 (40%) receiving invasive mechanical ventilation, and five (1%) receiving ECMO. The odds ratio (OR) for being in a better category of the primary efficacy endpoint for aviptadil versus placebo at day 90, from a model stratified by baseline disease severity, was 1·11 (95% CI 0·80-1·55; p=0·54). Up to day 90, 86 participants in the aviptadil group and 83 in the placebo group died. The cumulative percentage who died up to day 90 was 38% in the aviptadil group and 36% in the placebo group (hazard ratio 1·04, 95% CI 0·77-1·41; p=0·78). The primary safety outcome of death, serious adverse events, organ failure, serious infection, or grade 3 or 4 adverse events up to day 5 occurred in 146 (63%) of 231 patients in the aviptadil group compared with 129 (56%) of 230 participants in the placebo group (OR 1·40, 95% CI 0·94-2·08; p=0·10)., Interpretation: Among patients with COVID-19-associated acute hypoxaemic respiratory failure, aviptadil did not significantly improve clinical outcomes up to day 90 when compared with placebo. The smaller than planned sample size for the remdesivir trial did not permit definitive conclusions regarding safety or efficacy., Funding: National Institutes of Health., Competing Interests: Declaration of interests SMB reports funding from the National Institutes of Health during the conduct of the study and chairing a Data and Safety Monitoring Board (DSMB) for Hamilton Ventilators, outside of the study. CEB reports funding from the National Institutes of Health (NIH) for the Aviptadil study, during the conduct of the study. BG reports grants from the NIH, during the conduct of the study. SS reports a grant from the NIH, during the conduct of the study. ANP reports grants from the Wellcome Trust, the National Institute for Health and Care Research, UK Research and Innovation (UKRI), and the Bill & Melinda Gates Foundation, and consulting fees from the Bill & Melinda Gates Foundation, outside of the submitted work. IDP reports funding from NIH and the National Institute of General Medical Sciences, during the conduct of the study, a grant from Janssen for a study of influenza patient reported outcomes, and a contract with Regeneron for a COVID-19 therapy trial, outside of the submitted work. JRB reports a grant from the NIH, during the conduct of the study, grants from the NIH, Quantum Leap Healthcare Collaborative, and Sedana Medical, consulting fees from Sedana Medical, Biomarck, and Global Blood Therapeutics, and compensation from Hamilton Medical for participation as a medical monitor, outside of the submitted work. ESHa reports study materials from NeuroRx and Gilead through a National Heart, Lung, and Blood Institute (NHLBI) subcontract, during the conduct of the study, subcontracts with Bristol Meyers Squibb (BMS), Allergan, Gilead, and Janssen for the Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV-1) clinical trial, subcontracts with AstraZeneca, Brii Biosciences, Vir Biotechnology, and Eli Lilly for the Therapeutics for Inpatients with COVID-19 (TICO) clinical trial, and additional subcontracts with Rigel, APEIRON Biologics, and Trevena for the Novel Experimental COVID-19 Therapies Affecting Host Response (NECTAR) clinical trial, outside of the submitted work. EAM reports study materials from NeuroRx and Gilead through an NHLBI subcontract, during the conduct of the study, subcontracts with BMS, Allergan, Gilead, and Janssen for the ACTIV-1 clinical trial, subcontracts with AstraZeneca, Brii Biosciences, Vir Biotechnology, and Eli Lilly for the TICO clinical trial, and additional subcontracts with Rigel, APEIRON Biologics, and Trevena for the NECTAR clinical trial, outside of the submitted work. MAGB reports study materials from NeuroRx and Gilead through an NHLBI subcontract, during the conduct of the study, subcontracts with BMS, Allergan, Gilead, and Janssen for the ACTIV-1 clinical trial, subcontracts with AstraZeneca, Brii Biosciences, Vir Biotechnology, and Eli Lilly for the TICO clinical trial, and subcontracts with Rigel, APEIRON Biologics, and Trevena for the NECTAR clinical trial, outside of the submitted work. KSM reports grants and contracts from NIH, NHLBI, and the Society for Critical Care Medicine, participation as a steering committee member for Roivant-Kinevant Sciences, and employment as a clinical research physician at Chiesi USA, outside of submitted work. JM reports receiving study materials and funding from the Albert Einstein College of Medicine for the study protocol, during the conduct of the study. CH reports funding from the National Institute of Allergy and Infectious Diseases (NIAID) in the form of per-patient payments for A Multicenter, Adaptive, Randomized, Blinded Controlled Trial of the Safety and Efficacy of Investigational Therapeutics for Hospitalized Patients with Acute Respiratory Distress Syndrome Associated with COVID-19, during the conduct of the study. AK reports grants from Eli Lilly, AstraZeneca, 4D Medical, United Therapeutics, Regeneron Pharmaceuticals, and Dompe Pharmaceuticals and consulting fees from Dompe Pharmaceuticals for clinical trial design, outside of the submitted work. AD reports grants from NHLBI Prevention and Early Treatment of Acute Lung Injury network and the US Centers for Disease Control and Prevention (CDC) and data safety monitoring board (DSMB) or advisory board participation for Alung Technologies, outside of the submitted work. SD reports a grant from Chest Sonosite Ultrasound to study the incidence of deep vein thrombosis in patients with COVID-19, during the conduct of the study. AJG reports payment from Sound Pharmaceuticals for participation as a medical monitor for a COVID therapeutic trial, outside of the submitted work. USS reports consulting fees from Shionogi, Paratek, and ViiV Healthcare for participation on advisory boards and speaking fees from Shionogi and Paratek, outside of the submitted work. NJJ reports grants from the CDC, the US Department of Defense (DOD), and NIH and participation on a DSMB for the Legacy Health System, outside of the submitted work. MAM reports grants from NIH and NIAID, during the conduct of the study. NRA reports funding from NIH, during the conduct of the study. JDC reports grants from NIH and DOD, outside of the submitted work. DDM reports funding from the Danish National Research Foundation (DNRF126), during the conduct of study. AAG reports funding from NIH, during the conduct of the study, grants or contracts from NIH, DOD, CDC, Faron Pharmaceuticals, and Abbvie, and participation on a DSMB or advisory board for NIH, outside of the submitted work. WHS reports funding from NIH and NIAID, during the conduct of the study. CFO reports contracts with NIH and NHLBI, outside of the submitted work. BTT reports a grant from NHLBI, consulting fees from Bayer, Genetec, and Novartis, and participation on a DSMB or advisory board for Aperion, outside of the submitted work. During a portion of this research, BTT had a financial interest in Direct Biologics, a developer and manufacturer of regenerative biologic products, including an investigational treatment of COVID-19-associated ARDS. BTT's interests were reviewed and are managed by Massachusetts General Hospital and Mass General Brigham in accordance with their conflict of interest policies, and had no relationship to the agents studied. VK reports subcontracts with University of Minnesota, NIAID, and NIH for the TICO and Therapeutics for Severely Ill Inpatients with COVID-19 platform trials, outside of the submitted work. AGB reports a grant from University of Minnesota, during the conduct of the study, grants from the Medical Reserve Corps and UKRI, payment from NIAID for participation on a COVID-19 Vaccines DSMB, and participation on the WHO Trial Data and Safety Monitoring Committee, outside of the submitted work. JDN reports grants from NIAID, NIH, and Leidos Biomedical, outside of the submitted work. HCL reports employment from NIAID, during the conduct of the study. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)
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- 2023
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173. Derivation of a Protein Risk Score for Cardiovascular Disease Among a Multiracial and Multiethnic HIV+ Cohort.
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Safo SE, Haine L, Baker J, Reilly C, Duprez D, Neaton JD, Jain MK, Arenas-Pinto A, Polizzotto M, and Staub T
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- Humans, Case-Control Studies, Risk Factors, Biomarkers, Cardiovascular Diseases diagnosis, Cardiovascular Diseases epidemiology, Cardiovascular Diseases complications, HIV Infections diagnosis, HIV Infections epidemiology, HIV Infections complications
- Abstract
Background Cardiovascular disease risk prediction models underestimate CVD risk in people living with HIV (PLWH). Our goal is to derive a risk score based on protein biomarkers that could be used to predict CVD in PLWH. Methods and Results In a matched case-control study, we analyzed normalized protein expression data for participants enrolled in 1 of 4 trials conducted by INSIGHT (International Network for Strategic Initiatives in Global HIV Trials). We used dimension reduction, variable selection and resampling methods, and multivariable conditional logistic regression models to determine candidate protein biomarkers and to generate a protein score for predicting CVD in PLWH. We internally validated our findings using bootstrap. A protein score that was derived from 8 proteins (including HGF [hepatocyte growth factor] and interleukin-6) was found to be associated with an increased risk of CVD after adjustment for CVD and HIV factors (odds ratio: 2.17 [95% CI: 1.58-2.99]). The protein score improved CVD prediction when compared with predicting CVD risk using the individual proteins that comprised the protein score. Individuals with a protein score above the median score were 3.10 (95% CI, 1.83-5.41) times more likely to develop CVD than those with a protein score below the median score. Conclusions A panel of blood biomarkers may help identify PLWH at a high risk for developing CVD. If validated, such a score could be used in conjunction with established factors to identify CVD at-risk individuals who might benefit from aggressive risk reduction, ultimately shedding light on CVD pathogenesis in PLWH.
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- 2023
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174. Long-Term Benefits from Early Antiretroviral Therapy Initiation in HIV Infection.
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Lundgren JD, Babiker AG, Sharma S, Grund B, Phillips AN, Matthews G, Kan VL, Aagaard B, Abo I, Alston B, Arenas-Pinto A, Avihingsanon A, Badal-Faesen S, Brites C, Carey C, Casseb J, Clarke A, Collins S, Corbelli GM, Dao S, Denning ET, Emery S, Eriobu N, Florence E, Furrer H, Fätkenheuer G, Gerstoft J, Gisslén M, Goodall K, Henry K, Horban A, Hoy J, Hudson F, Azwa RISR, Kedem E, Kelleher A, Kityo C, Klingman K, Rosa A, Leturque N, Lifson AR, Losso M, Lutaakome J, Madero JS, Mallon P, Mansinho K, Filali KME, Molina JM, Murray DD, Nagalingeswaran K, Nozza S, Ormaasen V, Paredes R, Peireira LC, Pillay S, Polizzotto MN, Raben D, Rieger A, Sanchez A, Schechter M, Sedlacek D, Staub T, Touloumi G, Turner M, Madruga JV, Vjecha M, Wolff M, Wood R, Zilmer K, Lane HC, and Neaton JD
- Abstract
Background: For people with HIV and CD4
+ counts >500 cells/mm3 , early initiation of antiretroviral therapy (ART) reduces serious AIDS and serious non-AIDS (SNA) risk compared with deferral of treatment until CD4+ counts are <350 cells/mm3 . Whether excess risk of AIDS and SNA persists once ART is initiated for those who defer treatment is uncertain., Methods: The Strategic Timing of AntiRetroviral Treatment (START) trial, as previously reported, randomly assigned 4684 ART-naive HIV-positive adults with CD4+ counts .500 cells/mm3 to immediate treatment initiation after random assignment (n = 2325) or deferred treatment (n= 2359). In 2015, a 57% lower risk of the primary end point (AIDS, SNA, or death) for the immediate group was reported, and the deferred group was offered ART. This article reports the follow-up that continued to December 31, 2021. Cox proportional-hazards models were used to compare hazard ratios for the primary end point from randomization through December 31, 2015, versus January 1, 2016, through December 31, 2021., Results: Through December 31, 2015, approximately 7 months after the cutoff date from the previous report, the median CD4+ count was 648 and 460 cells/mm3 in the immediate and deferred groups, respectively, at treatment initiation. The percentage of follow-up time spent taking ART was 95% and 36% for the immediate and deferred groups, respectively, and the time-averaged CD4+ difference was 199 cells/mm3 . After January 1, 2016, the percentage of follow-up time on treatment was 97.2% and 94.1% for the immediate and deferred groups, respectively, and the CD4+ count difference was 155 cells/mm3 . After January 1, 2016, a total of 89 immediate and 113 deferred group participants experienced a primary end point (hazard ratio of 0.79 [95% confidence interval, 0.60 to 1.04] versus hazard ratio of 0.47 [95% confidence interval, 0.34 to 0.65; P<0.001]) before 2016 (P=0.02 for hazard ratio difference)., Conclusions: Among adults with CD4+ counts >500 cells/mm3 , excess risk of AIDS and SNA associated with delaying treatment initiation was diminished after ART initiation, but persistent excess risk remained. (Funded by the National Institute of Allergy and Infectious Diseases and others.).- Published
- 2023
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175. Learning and memory function in young people with and without perinatal HIV in England.
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Arenas-Pinto A, Judd A, Melvin D, Le Prevost M, Foster C, Sturgeon K, Winston A, Thompson LC, Gibb DM, and Castro H
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- Adolescent, Adult, Executive Function, Female, Humans, Infectious Disease Transmission, Vertical, Learning, Male, Pregnancy, Young Adult, Acquired Immunodeficiency Syndrome, HIV Infections complications, HIV Infections epidemiology, HIV Infections psychology
- Abstract
Learning and memory are important for successful education and career progression. We assess these functions in young people (YP) with perinatal HIV (PHIV) (with or without a previous AIDS-defining illness) and a comparable group of HIV-negative YP. 234 PHIV and 68 HIV-negative YP completed 9 tests; 5 National Institutes of Health (NIH) Toolbox tests (2 executive function, 1 speed of information processing, 2 memory); 2 Hopkins Verbal Learning Test Revised (HVLT-R) (learning (L), delayed recall (R)), and 2 verbal application measures. Z-scores for each test were calculated using normative data and averaged by domain where appropriate. The effect of predictors on test scores in the three domains with the lowest z-scores were analysed using linear regression. 139(59%) and 48(71%) PHIV and HIV-negative YP were female, 202(86%) and 52(76%) Black, and median age was 19 [17, 21] and 18 [16, 21] years respectively. 55(24%) PHIV had a previous Center for Disease Control and Prevention (CDC) class C AIDS-defining diagnosis (PHIV/C). For HVLT-R, there was a trend towards PHIV/C YP having the lowest mean z-scores (L -1.5 (95% CI -1.8,-1.2), R -1.7 (-2.0,-1.4)) followed by PHIV without a CDC C diagnosis (L -1.3 (-1.4,-1.1), R -1.4 (-1.5,-1.2)) and then the HIV-negative group (L -1.0 (-1.3,-0.7), R -1.1 (-1.3,-0.8)); all were greater than 1 SD below the reference mean. The same trend was seen for verbal application measures; however, z-scores were within 1 SD below the reference mean. NIH Toolbox tests were similar for all groups. In multivariable analyses PHIV/C and Black ethnicity predicted lower HVLT-R scores. Black ethnicity also predicted lower executive function scores, however each year increase in age predicted higher scores. In conclusion, cognitive performance in verbal learning and recall fell below population normative scores, and was more pronounced in PHIV/C, supporting wider findings that earlier antiretroviral therapy initiation, before the occurrence of AIDS-defining conditions, may protect aspects of cognitive development., Competing Interests: The authors have declared that no competing interests exist.
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- 2022
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176. Human Immunotypes Impose Selection on Viral Genotypes Through Viral Epitope Specificity.
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Gabrielaite M, Bennedbæk M, Zucco AG, Ekenberg C, Murray DD, Kan VL, Touloumi G, Vandekerckhove L, Turner D, Neaton J, Lane HC, Safo S, Arenas-Pinto A, Polizzotto MN, Günthard HF, Lundgren JD, and Marvig RL
- Subjects
- Adult, Epitopes genetics, Female, Genome, Human, Genome-Wide Association Study, Genotype, HIV Infections immunology, HIV Infections virology, HIV-1 immunology, Humans, Male, Middle Aged, Viral Load immunology, Genome, Viral, HIV Infections genetics, HIV-1 genetics, Polymorphism, Single Nucleotide, Viral Load genetics
- Abstract
Background: Understanding the genetic interplay between human hosts and infectious pathogens is crucial for how we interpret virulence factors. Here, we tested for associations between HIV and host genetics, and interactive genetic effects on viral load (VL) in HIV-positive antiretroviral treatment-naive clinical trial participants., Methods: HIV genomes were sequenced and the encoded amino acid (AA) variants were associated with VL, human single nucleotide polymorphisms (SNPs), and imputed HLA alleles using generalized linear models with Bonferroni correction., Results: Human (388 501 SNPs) and HIV (3010 variants) genetic data were available for 2122 persons. Four HIV variants were associated with VL (P < 1.66 × 10-5). Twelve HIV variants were associated with a range of 1-512 human SNPs (P < 4.28 × 10-11). We found 46 associations between HLA alleles and HIV variants (P < 1.29 × 10-7). HIV variants and immunotypes when analyzed separately were associated with lower VL, whereas the opposite was true when analyzed in concert. Epitope binding predictions supported our observations., Conclusions: Our results show the importance of immunotype specificity on viral antigenic determinants, and the identified genetic interplay emphasizes that viral and human genetics should be studied in the context of each other.Clinical Trials Registration: NCT00867048., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)
- Published
- 2021
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177. SARS-CoV-2 inhibition using a mucoadhesive, amphiphilic chitosan that may serve as an anti-viral nasal spray.
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Pyrć K, Milewska A, Duran EB, Botwina P, Dabrowska A, Jedrysik M, Benedyk M, Lopes R, Arenas-Pinto A, Badr M, Mellor R, Kalber TL, Fernandez-Reyes D, Schätzlein AG, and Uchegbu IF
- Subjects
- A549 Cells, Animals, Antiviral Agents administration & dosage, Chlorocebus aethiops, Humans, Male, Methylation, Mice, Inbred BALB C, Mice, Transgenic, SARS-CoV-2 physiology, Surface-Active Agents administration & dosage, Surface-Active Agents therapeutic use, Vero Cells, Viral Load drug effects, Mice, Antiviral Agents therapeutic use, Nasal Sprays, SARS-CoV-2 drug effects, COVID-19 Drug Treatment
- Abstract
There are currently no cures for coronavirus infections, making the prevention of infections the only course open at the present time. The COVID-19 pandemic has been difficult to prevent, as the infection is spread by respiratory droplets and thus effective, scalable and safe preventive interventions are urgently needed. We hypothesise that preventing viral entry into mammalian nasal epithelial cells may be one way to limit the spread of COVID-19. Here we show that N-palmitoyl-N-monomethyl-N,N-dimethyl-N,N,N-trimethyl-6-O-glycolchitosan (GCPQ), a positively charged polymer that has been through an extensive Good Laboratory Practice toxicology screen, is able to reduce the infectivity of SARS-COV-2 in A549
ACE2+ and Vero E6 cells with a log removal value of - 3 to - 4 at a concentration of 10-100 μg/ mL (p < 0.05 compared to untreated controls) and to limit infectivity in human airway epithelial cells at a concentration of 500 μg/ mL (p < 0.05 compared to untreated controls). In vivo studies using transgenic mice expressing the ACE-2 receptor, dosed nasally with SARS-COV-2 (426,000 TCID50 /mL) showed a trend for nasal GCPQ (20 mg/kg) to inhibit viral load in the respiratory tract and brain, although the study was not powered to detect statistical significance. GCPQ's electrostatic binding to the virus, preventing viral entry into the host cells, is the most likely mechanism of viral inhibition. Radiolabelled GCPQ studies in mice show that at a dose of 10 mg/kg, GCPQ has a long residence time in mouse nares, with 13.1% of the injected dose identified from SPECT/CT in the nares, 24 h after nasal dosing. With a no observed adverse effect level of 18 mg/kg in rats, following a 28-day repeat dose study, clinical testing of this polymer, as a COVID-19 prophylactic is warranted., (© 2021. The Author(s).)- Published
- 2021
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178. Network meta-analysis of post-exposure prophylaxis randomized clinical trials.
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Fernández I, de Lazzari E, Inciarte A, Diaz-Brito V, Milinkovic A, Arenas-Pinto A, Etcheverrry F, García F, and Leal L
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- Homosexuality, Male, Humans, Male, Network Meta-Analysis, Post-Exposure Prophylaxis, Randomized Controlled Trials as Topic, Anti-HIV Agents therapeutic use, HIV Infections drug therapy, HIV Infections prevention & control, Sexual and Gender Minorities
- Abstract
Objectives: We performed a network meta-analysis of PEP randomized clinical trials to evaluate the best regimen., Methods: After MEDLINE/Pubmed search, studies were included if: (1) were randomized, (2) comparing at least 2 PEP three-drug regimens and, (3) reported completion rates or discontinuation at 28 days. Five studies with 1105 PEP initiations were included and compared ritonavir-boosted lopinavir (LPV/r) vs. atazanavir (ATV) (one study), cobicistat-boosted elvitegravir (EVG/c) (one study), raltegravir (RAL) (one study) or maraviroc (MVC) (two studies). We estimated the probability of each treatment of being the best based on the evaluation of five outcomes: PEP non-completion at day 28, PEP discontinuation due to adverse events, PEP switching due to any cause, lost to follow-up and adverse events., Results: Participants were mostly men who have sex with men (n = 832, 75%) with non-occupational exposure to HIV (89.86%). Four-hundred fifty-four (41%) participants failed to complete their PEP course for any reason. The Odds Ratio (OR) for PEP non-completion at day 28 in each antiretroviral compared to LPV/r was: ATV 0.95 (95% CI 0.58-1.56; EVG/c: OR 0.65 95% CI 0.30-1.37; RAL: OR 0.68 95% CI 0.41-1.13; and MVC: OR 0.69 95% CI 0.47-1.01. In addition, the rankogram showed that EVG/c had the highest probability of being the best treatment for the lowest rates in PEP non-completion at day 28, switching, lost to follow-up or adverse events and MVC for PEP discontinuations due to adverse events., Conclusions: Our study shows the advantages of integrase inhibitors when used as PEP, particularly EVG as a Single-Tablet Regimen., (© 2020 British HIV Association.)
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- 2021
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179. Factors Associated With Nonadherence to Antiretroviral Therapy Among Young People Living With Perinatally Acquired HIV in England.
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Judd A, Melvin D, Thompson LC, Foster C, Le Prevost M, Evangeli M, Winston A, Arenas-Pinto A, Sturgeon K, Rowson K, Gibb DM, and Castro H
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- Adolescent, Cohort Studies, England epidemiology, Female, HIV Infections epidemiology, Humans, Male, Medication Adherence psychology, Prevalence, Prospective Studies, Surveys and Questionnaires, Viral Load, Anti-HIV Agents therapeutic use, Antiretroviral Therapy, Highly Active statistics & numerical data, HIV Infections drug therapy, HIV Infections virology, HIV Long-Term Survivors psychology, Medication Adherence statistics & numerical data, Quality of Life psychology
- Abstract
Young people living with perinatally acquired HIV may be at risk of poor adherence to antiretroviral therapy; identification of predictors, using a conceptual framework approach proposed previously by others, is important to identify those at higher risk. In 261 young people with perinatally acquired HIV in England, 70 (27%) reported 3-day nonadherence, 82 (31%) last month nonadherence, and 106 (41%) nonadherence on either measure. Of those reporting nonadherence on both measures, 52% (23/44) had viral load of <50 copies/ml, compared with 88% (127/145) of those reported being fully adherent. In multivariable analysis, young person and medication theme factors were associated with nonadherence. The main predictors of 3-day nonadherence were antiretroviral therapy containing a boosted protease inhibitor and poorer quality of life. Predictors of last month nonadherence were having told more people about one's HIV status, worse self-perception about having HIV, and boosted protease inhibitor-based regimens. The consistency of individual young person and medication factors in predicting nonadherence gives insight into where interventions may best be targeted to improve adherence.
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- 2020
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180. Risky Alcohol Consumption and Associated Health Behaviour Among HIV-Positive and HIV-Negative Patients in a UK Sexual Health and HIV Clinic: A Cross-Sectional Questionnaire Study.
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Suonpera E, Matthews R, Milinkovic A, and Arenas-Pinto A
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- Adult, Alcohol Drinking psychology, Alcohol-Related Disorders psychology, Antiretroviral Therapy, Highly Active, Cross-Sectional Studies, Depression epidemiology, Depression psychology, Female, HIV Infections drug therapy, HIV Infections psychology, HIV Seropositivity, Humans, Male, Medication Adherence statistics & numerical data, Middle Aged, Prevalence, Sexual Behavior statistics & numerical data, Sexual Health, Socioeconomic Factors, Substance-Related Disorders epidemiology, Substance-Related Disorders psychology, Surveys and Questionnaires, United Kingdom epidemiology, Unsafe Sex, Alcohol Drinking epidemiology, Alcohol-Related Disorders diagnosis, Alcohol-Related Disorders epidemiology, HIV Infections epidemiology, Health Behavior, Medication Adherence psychology, Sexual Behavior psychology
- Abstract
Alcohol misuse has been associated with negative consequences among HIV-positive patients. Data on real prevalence of risky alcohol consumption among the HIV-positive population in the UK are lacking. A cross-sectional questionnaire study using standardised validated instruments among HIV-positive (n = 227) and HIV-negative (n = 69) patients was performed. The prevalence of risky alcohol consumption (AUDIT) and associations with depressive symptoms (PHQ-9), problematic drug use (DUDIT), adherence to ART (CASE Adherence Index), sexual behaviour and demographic characteristics were assessed among both patient groups independently. A quarter (25.1%) of HIV-positive patients and 36.1% of HIV-negative patients reported risky alcohol consumption (AUDIT-score ≥ 8). In the multivariable analysis among HIV-positive patients depressive symptoms (p = 0.03) and problematic drug use (p = 0.007) were associated with risky alcohol consumption. Among HIV-negative patients these associations were not present. Risky alcohol consumption among HIV-positive patients is prevalent, and together with depressive symptoms and problematic drug use, may influence HIV-disease progression and patients' wellbeing.
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- 2020
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181. Reversible effect on lipids by switching from tenofovir disoproxil fumarate to tenofovir alafenamide and back.
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Milinkovic A, Berger F, Arenas-Pinto A, and Mauss S
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- Adenine therapeutic use, Adult, Alanine, Female, Germany, HIV Infections blood, HIV-1, Humans, Logistic Models, Male, Middle Aged, RNA, Viral blood, Retrospective Studies, Treatment Outcome, Viral Load, Adenine analogs & derivatives, Anti-HIV Agents therapeutic use, Cholesterol blood, Drug Substitution, HIV Infections drug therapy, Tenofovir therapeutic use
- Abstract
Objective: The aim of the current study is to assess the effect of tenofovir alafenamide (TAF) and tenofovir disoproxil fumarate (TDF) on lipids in patients switching from TDF to TAF and back., Methods: Retrospective data collection on patients who were initially switched from TDF to TAF and switched back to TDF after generics of TDF became available., Results: In total, 385 patients were included. Median duration of TDF exposure before switch was 317 weeks (interquartile range 172-494). After switching from TDF to TAF, mean total cholesterol (TC) increased from 186 ± 37 mg/dl at baseline to 206 ± 43 and 204 ± 43 mg/dl at weeks 12 and 24 (P < 0.001). The increase in TC was mainly due to an increase in LDL cholesterol. However, ratio of TC/HDL remained unchanged, indicating a simultaneous rise of LDL and HDL cholesterol. Baseline triglycerides increased from mean 153 ± 96 to 176 ± 120 and 176 ± 124 mg/dl at weeks, 12 and 24 (P < 0.001). From 385 patients 168 were switched back from TAF to TDF after median duration on TAF of 96 weeks (interquartile range 89-104). At switching back from TAF to TDF, mean TC was 202 ± 40 mg/dl and decreased at weeks 12 and 24 to 183 ± 41 and 185 ± 35 mg/dl (P < 0.001). Mean triglycerides were 163 ± 119 mg/dl and decreased to 145 ± 108 and 157 ± 112 mg/dl, respectively (P < 0.05). Patients with higher increases in TC after switching from TDF to TAF also showed more pronounced decreases after switching back., Conclusion: The results demonstrate a reversible effect on lipids by switching from TDF to TAF and back.
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- 2019
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182. Anxiety and depression symptoms in young people with perinatally acquired HIV and HIV affected young people in England.
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Le Prevost M, Arenas-Pinto A, Melvin D, Parrott F, Foster C, Ford D, Evangeli M, Winston A, Sturgeon K, Rowson K, Gibb DM, and Judd A
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- Adolescent, Adult, Caregivers, Child, Cohort Studies, England, Female, Humans, Male, Pregnancy, Self Concept, Young Adult, Anxiety psychology, Depression psychology, HIV Infections psychology
- Abstract
Adolescents with perinatal HIV (PHIV) may be at higher risk of anxiety and depression than HIV negative young people. We investigated prevalence of anxiety and depression symptoms in 283 PHIV and 96 HIV-affected (HIV-negative) young people in England recruited into the Adolescents and Adults Living with Perinatal HIV (AALPHI) cohort. We used Hospital Anxiety and Depression Scale (HADS) scores and linear regression investigated predictors of higher (worse) scores.115 (41%) and 29 (30%) PHIV and HIV-affected young people were male, median age was 16 [interquartile range 15,18] and 16 [14,18] years and 241 (85%) and 71 (74%) were black African, respectively. There were no differences in anxiety and depression scores between PHIV and HIV-affected participants. Predictors of higher anxiety scores were a higher number of carers in childhood, speaking a language other than English at home, lower self-esteem, ever thinking life was not worth living and lower social functioning. Predictors of higher depression scores were male sex, death of one/both parents, school exclusion, lower self-esteem and lower social functioning. In conclusion, HIV status was not associated with anxiety or depression scores, but findings highlight the need to identify and support young people at higher risk of anxiety and depression.
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- 2018
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183. No neurocognitive advantage for immediate antiretroviral treatment in adults with greater than 500 CD4+ T-cell counts.
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Wright EJ, Grund B, Robertson KR, Cysique L, Brew BJ, Collins GL, Poehlman-Roediger M, Vjecha MJ, Penalva de Oliveira AC, Standridge B, Carey C, Avihingsanon A, Florence E, Lundgren JD, Arenas-Pinto A, Mueller NJ, Winston A, Nsubuga MS, Lal L, and Price RW
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- AIDS Dementia Complex pathology, Adult, CD4 Lymphocyte Count, Female, Humans, Longitudinal Studies, Male, Treatment Outcome, AIDS Dementia Complex prevention & control, Anti-Retroviral Agents therapeutic use, HIV Infections drug therapy, Secondary Prevention
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Objective: To compare the effect of immediate versus deferred antiretroviral treatment (ART) on neuropsychological test performance in treatment-naive HIV-positive adults with more than 500 CD4 cells/μl., Design: Randomized trial., Methods: The START parent study randomized participants to commence immediate versus deferred ART until CD4 less than 350 cells/μl. The START Neurology substudy used eight neuropsychological tests, at baseline, months 4, 8, 12 and annually, to compare groups for changes in test performance. Test results were internally standardized to z-scores. The primary outcome was the average of the eight test z-scores (QNPZ-8). Mean changes in QNPZ-8 from baseline were compared by intent-to-treat using longitudinal mixed models. Changes from baseline to specific time points were compared using ANCOVA models., Results: The 592 participants had a median age of 34 years; median baseline CD4 count was 629 cells/μl; the mean follow-up was 3.4 years. ART was used for 94 and 32% of accrued person-years in the immediate and deferred groups, respectively. There was no difference between the immediate and deferred ART groups in QNPZ-8 change through follow-up [-0.018 (95% CI -0.062 to 0.027, P = 0.44)], or at any visit. However, QNPZ-8 scores increased in both arms during the first year, by 0.22 and 0.24, respectively (P < 0.001 for increase from baseline)., Conclusion: We observed substantial improvement in neurocognitive test performance during the first year in both study arms, underlining the importance of using a control group in studies assessing neurocognitive performance over time. Immediate ART neither benefitted nor harmed neurocognitive performance in individuals with CD4 cell counts above 500 cells/μl.
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- 2018
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184. Factors associated with virological rebound in HIV-infected patients receiving protease inhibitor monotherapy.
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Stöhr W, Dunn DT, Arenas-Pinto A, Orkin C, Clarke A, Williams I, Johnson M, Beeching NJ, Wilkins E, Sanders K, and Paton NI
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- Adult, Female, Humans, Male, Middle Aged, Protease Inhibitors, Risk Factors, Treatment Failure, HIV Infections drug therapy, HIV Infections virology, HIV Protease Inhibitors therapeutic use, HIV-1 isolation & purification, Viral Load
- Abstract
Objective: The Protease Inhibitor Monotherapy Versus Ongoing Triple Therapy (PIVOT) trial found that protease inhibitor monotherapy as a simplification strategy is well tolerated in terms of drug resistance but less effective than combination therapy in suppressing HIV viral load. We sought to identify factors associated with the risk of viral load rebound in this trial., Methods: PIVOT was a randomized controlled trial in HIV-positive adults with suppressed viral load for at least 24 weeks on combination therapy comparing a strategy of physician-selected ritonavir-boosted protease inhibitor monotherapy versus ongoing triple therapy. In participants receiving monotherapy, we analysed time to confirmed viral load rebound and its predictors using flexible parametric survival models., Results: Of 290 participants initiating protease inhibitor monotherapy (80% darunavir, 14% lopinavir, and 6% other), 93 developed viral load rebound on monotherapy. The risk of viral load rebound peaked at 9 months after starting monotherapy and then declined to approximately 5 per 100 person-years from 18 months onwards. Independent predictors of viral load rebound were duration of viral load suppression before starting monotherapy (hazard ratio 0.81 per additional year <50 copies/ml; P < 0.001), CD4 cell count (hazard ratio 0.73 per additional 100 cells/μl for CD4 nadir; P = 0.008); ethnicity (hazard ratio 1.87 for nonwhite versus white, P = 0.025) but not the protease inhibitor agent used (P = 0.27). Patients whose viral load was analysed with the Roche TaqMan-2 assay had a 1.87-fold risk for viral load rebound compared with Abbott RealTime assay (P = 0.012)., Conclusion: A number of factors can identify patients at low risk of rebound with protease inhibitor monotherapy, and this may help to better target those who may benefit from this management strategy.
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- 2016
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185. Cost Effectiveness of Protease Inhibitor Monotherapy Versus Standard Triple Therapy in the Long-Term Management of HIV Patients: Analysis Using Evidence from the PIVOT Trial.
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Oddershede L, Walker S, Stöhr W, Dunn DT, Arenas-Pinto A, Paton NI, and Sculpher M
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- Adult, Anti-HIV Agents administration & dosage, Anti-HIV Agents economics, Cost Savings, Cost-Benefit Analysis, Drug Therapy, Combination, Female, HIV Infections economics, HIV Protease Inhibitors economics, Humans, Male, Randomized Controlled Trials as Topic, Treatment Outcome, United Kingdom, Viral Load, HIV Infections drug therapy, HIV Protease Inhibitors administration & dosage, Models, Economic, Quality-Adjusted Life Years
- Abstract
Background: Protease inhibitor (PI) monotherapy can maintain virological suppression in the majority of patients once it has been established on triple therapy and may also have the potential for substantial cost savings arising from the use of fewer drugs. However, the cost effectiveness of PI monotherapy has yet to be demonstrated., Objectives: In this study we examine the cost effectiveness of PI monotherapy with prompt return to combination therapy in the event of viral load rebound compared with ongoing triple therapy (OT) in patients with suppressed viral load on combination antiretroviral therapy (ART) in the UK., Methods: The analysis used data from the PIVOT trial in which HIV-positive adults with suppressed viral load for ≥24 weeks on combination ART were randomised to maintain OT or to a strategy of PI monotherapy with prompt return to combination therapy if viral load rebounded. A cost-effectiveness analysis including long-term modelling was conducted. Main outcomes included UK National Health Service (NHS) costs and quality-adjusted life-years (QALYs) with comparative results presented as incremental cost-effectiveness ratios., Results: PI monotherapy was cost saving as a result of large savings in ART drug costs while being no less effective in terms of QALYs in the within-trial analysis and marginally less effective with lifetime modelling. In the base-case analysis over 3 years, the incremental total cost per patient was -£6424.11 (95 % confidence interval -7418.84 to -5429.38) and incremental QALYs were 0.0051 (95 % CI -0.0479 to 0.0582), resulting in PI monotherapy 'dominating' OT. Multiple scenario analyses found that PI monotherapy was cost saving with no marked differences in QALYs. Modelling of lifetime costs and QALYs showed that PI monotherapy was associated with significant cost savings and was marginally less effective; PI monotherapy was cost effective at accepted cost-effectiveness thresholds in all but one scenario analysis., Conclusions: Under most assumptions, PI monotherapy appears to be a cost-effective treatment strategy compared with OT for HIV-infected patients who have achieved sustained virological suppression.
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- 2016
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186. Host and disease factors are associated with cognitive function in European HIV-infected adults prior to initiation of antiretroviral therapy.
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Winston A, Stöhr W, Antinori A, Arenas-Pinto A, Llibre JM, Amieva H, Cabié A, Williams I, Di Perri G, Tellez MJ, Rockstroh J, Babiker A, Pozniak A, Raffi F, and Richert L
- Subjects
- Adult, Anti-Retroviral Agents administration & dosage, Europe, Female, HIV Infections drug therapy, Humans, Male, Middle Aged, Psychological Tests, Cognitive Dysfunction etiology, Cognitive Dysfunction pathology, HIV Infections complications, HIV Infections pathology
- Abstract
Objectives: Deficits in cognitive function remain prevalent in HIV-infected individuals. The aim of this European multicentre study was to assess factors associated with cognitive function in antiretroviral therapy (ART)-naïve HIV-infected subjects at the time of enrolment in the NEAT 001/Agence Nationale de Recherche sur le SIDA (ANRS) 143 study., Methods: Prior to starting ART, seven cognitive tests exploring domains including episodic memory, verbal fluency, executive function and psychomotor speed were administered with scores standardized to z-score using the study population sample mean and standard deviation. The primary measure was overall z-score average (NPZ). We assessed associations between baseline factors and test results using multivariable regression models., Results: Of 283 subjects with baseline cognitive assessments, 90% were male and 12% of black ethnicity. Median (interquartile range) age, years of education, years of known HIV infection, baseline CD4 count and baseline HIV RNA were 39 (31, 47) years, 13 (11, 17) years, 1 (0, 4) years, 344 (279, 410) cells/μL and 4.74 (4.28, 5.14) log10 HIV-1 RNA copies/mL, respectively. Forty per cent were current smokers. Factors significantly associated with poorer overall cognitive performance in multivariable models included older age, shorter duration of education, black ethnicity, lower height, and lower plasma HIV RNA., Conclusions: In this large, European-wide, ART-naïve population with relatively preserved immunity and early HIV infection, cognitive function scores at the time of ART initiation were associated with demographic and HIV-disease factors., (© 2015 British HIV Association.)
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- 2016
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187. Neurocognitive Function at the First-Line Failure and on the Second-Line Antiretroviral Therapy in Africa: Analyses From the EARNEST Trial.
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Kambugu A, Thompson J, Hakim J, Tumukunde D, van Oosterhout JJ, Mwebaze R, Hoppe A, Abach J, Kwobah C, Arenas-Pinto A, Walker SA, and Paton NI
- Subjects
- Adult, Africa South of the Sahara, CD4 Lymphocyte Count, Drug Therapy, Combination, Female, HIV Infections complications, HIV Infections virology, Humans, Lopinavir therapeutic use, Male, Middle Aged, Neurocognitive Disorders drug therapy, Raltegravir Potassium therapeutic use, Ritonavir therapeutic use, Viral Load drug effects, Anti-HIV Agents therapeutic use, Cognition drug effects, HIV Infections drug therapy, HIV Protease Inhibitors therapeutic use, HIV-1 drug effects, Neurocognitive Disorders etiology, Reverse Transcriptase Inhibitors therapeutic use
- Abstract
Objective: To assess neurocognitive function at the first-line antiretroviral therapy failure and change on the second-line therapy., Design: Randomized controlled trial was conducted in 5 sub-Saharan African countries., Methods: Patients failing the first-line therapy according to WHO criteria after >12 months on non-nucleoside reverse transcriptase inhibitors-based regimens were randomized to the second-line therapy (open-label) with lopinavir/ritonavir (400 mg/100 mg twice daily) plus either 2-3 clinician-selected nucleoside reverse transcriptase inhibitors, raltegravir, or as monotherapy after 12-week induction with raltegravir. Neurocognitive function was tested at baseline, weeks 48 and 96 using color trails tests 1 and 2, and the Grooved Pegboard test. Test results were converted to an average of the 3 individual test z-scores., Results: A total of 1036 patients (90% of those >18 years enrolled at 13 evaluable sites) had valid baseline tests (58% women, median: 38 years, viral load: 65,000 copies per milliliter, CD4 count: 73 cells per cubic millimeter). Mean (SD) baseline z-score was -2.96 (1.74); lower baseline z-scores were independently associated with older age, lower body weight, higher viral load, lower hemoglobin, less education, fewer weekly working hours, previous central nervous system disease, and taking fluconazole (P < 0.05 in multivariable model). Z-score was increased by mean (SE) of +1.23 (0.04) after 96 weeks on the second-line therapy (P < 0.001; n = 915 evaluable), with no evidence of difference between the treatment arms (P = 0.35)., Conclusions: Patients in sub-Saharan Africa failing the first-line therapy had low neurocognitive function test scores, but performance improved on the second-line therapy. Regimens with more central nervous system-penetrating drugs did not enhance neurocognitive recovery indicating this need not be a primary consideration in choosing a second-line regimen.
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- 2016
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188. The Protease Inhibitor Monotherapy Versus Ongoing Triple Therapy (PIVOT) trial: a randomised controlled trial of a protease inhibitor monotherapy strategy for long-term management of human immunodeficiency virus infection.
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Paton NI, Stöhr W, Oddershede L, Arenas-Pinto A, Walker S, Sculpher M, and Dunn DT
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- Adult, Anti-Retroviral Agents adverse effects, CD4 Lymphocyte Count, Drug Resistance, Viral, Drug Therapy, Combination, HIV drug effects, HIV isolation & purification, HIV Infections virology, HIV Protease Inhibitors adverse effects, Humans, Male, Middle Aged, Quality of Life, Ritonavir adverse effects, Treatment Outcome, United Kingdom, Viral Load, Anti-Retroviral Agents therapeutic use, HIV Infections drug therapy, HIV Protease Inhibitors therapeutic use, Ritonavir therapeutic use
- Abstract
Background: Standard-of-care antiretroviral therapy (ART) for human immunodeficiency virus (HIV) infection uses a combination of drugs, until now considered essential to minimise treatment failure and development of drug resistance. Protease inhibitors (PIs) are potent with a high genetic barrier to resistance and have the potential for use as monotherapy after viral load (VL) suppression achieved on combination therapy. However, longer-term resistance and toxicity risks are uncertain., Objective: To compare the effectiveness, toxicity profile and cost-effectiveness of PI monotherapy with those of standard-of-care triple therapy in a pragmatic long-term clinical trial., Design: Open-label, parallel-group, randomised controlled trial., Setting: Forty-three HIV clinical centres in the UK NHS., Participants: HIV-positive adults taking standard combination ART with a suppressed VL for ≥ 6 months., Interventions: Patients were randomised to maintain ongoing triple therapy (OT) or switch to a strategy of physician-selected ritonavir-boosted PI monotherapy (PI-mono), with prompt return to combination therapy in the event of VL rebound., Main Outcome Measures: The primary outcome was reduction of future drug options, defined as new intermediate-/high-level resistance to one or more drugs to which the patient's virus was considered to be sensitive at trial entry (non-inferiority comparison, 10% margin). Secondary outcomes included confirmed virological rebound, serious drug- or disease-related complications, total grade 3 or 4 adverse events (AEs), neurocognitive function change, cluster of differentiation 4 (CD4) cell count change, change in health-related quality of life, cardiovascular risk change, health-care costs and health economic analysis., Results: In total, 587 participants were randomised (77% male, 68% white) to OT (n = 291) or PI-mono (n = 296) and followed for a median of 44 months, of whom 2.7% withdrew/were lost to follow-up. One or more episodes of confirmed VL rebound were observed in eight patients (Kaplan-Meier estimate 3.2%) in the OT group and 95 patients (35.0%) in the PI-mono group [absolute risk difference 31.8%, 95% confidence interval (CI) 24.6% to 39.0%; p < 0.001]. PI-mono patients who changed to ART after VL rebound all resuppressed (median 3.5 weeks). The proportions with loss of a future drug option at 3 years were 0.7% in the OT group and 2.1% in the PI-mono group (difference 1.4%, (95% CI -0.4% to 3.4%); non-inferiority demonstrated). There were no significant differences in serious disease complications between groups or in the frequency of grade 3 or 4 clinical AEs (16.8% OT group vs. 22% PI-mono group; absolute risk difference 5.1%, 95% CI -1.3% to 11.5%; p = 0.12). Overall, the PI-mono strategy was shown to be cost-effective compared with OT under most scenarios explored. PI-mono was cost saving because of the large savings in ART drug costs while being no less effective in terms of quality-adjusted life-years in the within-trial analysis and only marginally less effective when extrapolated to lifetime outcomes., Conclusions: PI monotherapy, with prompt reintroduction of combination therapy for VL rebound, was non-inferior to combination therapy in preserving future treatment options and is an acceptable and cost-effective alternative for long-term management of HIV infection., Trial Registration: Current Controlled Trials ISRCTN04857074., Funding: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 21. See the NIHR Journals Library website for further project information.
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- 2016
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189. Peripheral neuropathy in HIV patients in sub-Saharan Africa failing first-line therapy and the response to second-line ART in the EARNEST trial.
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Arenas-Pinto A, Thompson J, Musoro G, Musana H, Lugemwa A, Kambugu A, Mweemba A, Atwongyeire D, Thomason MJ, Walker AS, and Paton NI
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- Adult, Africa South of the Sahara, Alcohol Abstinence, Antiretroviral Therapy, Highly Active, Antitubercular Agents therapeutic use, CD4 Lymphocyte Count, CD4-Positive T-Lymphocytes drug effects, CD4-Positive T-Lymphocytes pathology, CD4-Positive T-Lymphocytes virology, Drug Combinations, Female, HIV Infections complications, HIV Infections physiopathology, HIV Infections virology, HIV-1 drug effects, HIV-1 growth & development, Humans, Isoniazid therapeutic use, Logistic Models, Male, Middle Aged, Peripheral Nervous System Diseases complications, Peripheral Nervous System Diseases physiopathology, Peripheral Nervous System Diseases virology, RNA, Viral antagonists & inhibitors, Smoking physiopathology, Tuberculosis, Pulmonary drug therapy, Viral Load drug effects, Anti-HIV Agents therapeutic use, HIV Infections drug therapy, Lopinavir therapeutic use, Peripheral Nervous System Diseases drug therapy, RNA, Viral blood, Raltegravir Potassium therapeutic use, Ritonavir therapeutic use
- Abstract
Sensory peripheral neuropathy (PN) remains a common complication in HIV-positive patients despite effective combination anti-retroviral therapy (ART). Data on PN on second-line ART is scarce. We assessed PN using a standard tool in patients failing first-line ART and for 96 weeks following a switch to PI-based second-line ART in a large Randomised Clinical Trial in Sub-Saharan Africa. Factors associated with PN were investigated using logistic regression. Symptomatic PN (SPN) prevalence was 22% at entry (N = 1,251) and was associated (p < 0.05) with older age (OR = 1.04 per year), female gender (OR = 1.64), Tuberculosis (TB; OR = 1.86), smoking (OR = 1.60), higher plasma creatinine (OR = 1.09 per 0.1 mg/dl increase), CD4 count (OR = 0.83 per doubling) and not consuming alcohol (OR = 0.55). SPN prevalence decreased to 17% by week 96 (p = 0.0002) following similar trends in all study groups (p = 0.30). Asymptomatic PN (APN) increased over the same period from 21 to 29% (p = 0.0002). Signs suggestive of PN (regardless of symptoms) returned to baseline levels by week 96. At weeks 48 and 96, after adjusting for time-updated associations above and baseline CD4 count and viral load, SPN was strongly associated with TB (p < 0.0001). In summary, SPN prevalence was significantly reduced with PI-based second-line therapy across all treatment groups, but we did not find any advantage to the NRTI-free regimens. The increase of APN and stability of PN-signs regardless of symptoms suggest an underlying trend of neuropathy progression that may be masked by reduction of symptoms accompanying general health improvement induced by second-line ART. SPN was strongly associated with isoniazid given for TB treatment.
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- 2016
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190. Protease inhibitor monotherapy for long-term management of HIV infection: a randomised, controlled, open-label, non-inferiority trial.
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Paton NI, Stöhr W, Arenas-Pinto A, Fisher M, Williams I, Johnson M, Orkin C, Chen F, Lee V, Winston A, Gompels M, Fox J, Scott K, and Dunn DT
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- Adult, Aged, CD4 Lymphocyte Count, Drug Resistance, Viral, Female, HIV drug effects, HIV isolation & purification, HIV Infections virology, Humans, Male, Middle Aged, Treatment Outcome, United Kingdom, Viral Load, Young Adult, HIV Infections drug therapy, HIV Protease Inhibitors therapeutic use, Maintenance Chemotherapy methods
- Abstract
Background: Standard-of-care antiretroviral therapy (ART) uses a combination of drugs deemed essential to minimise treatment failure and drug resistance. Protease inhibitors are potent, with a high genetic barrier to resistance, and have potential use as monotherapy after viral load suppression is achieved with combination treatment. We aimed to assess clinical risks and benefits of protease inhibitor monotherapy in long-term clinical use: in particular, the effect on drug resistance and future treatment options., Methods: In this pragmatic, parallel-group, randomised, controlled, open-label, non-inferiority trial, we enrolled adults (≥18 years of age) positive for HIV attending 43 public sector treatment centres in the UK who had suppressed viral load (<50 copies per mL) for at least 24 weeks on combination ART with no change in the previous 12 weeks and a CD4 count of more than 100 cells per μL. Participants were randomly allocated (1:1) to maintain ongoing triple therapy (OT) or to switch to a strategy of physician-selected ritonavir-boosted protease inhibitor monotherapy (PI-mono); we recommended ritonavir (100 mg)-boosted darunavir (800 mg) once daily or ritonavir (100 mg)-boosted lopinavir (400 mg) twice daily, with prompt return to combination treatment if viral load rebounded. All treatments were oral. Randomisation was with permuted blocks of varying size and stratified by centre and baseline ART; we used a computer-generated, sequentially numbered randomisation list. The primary outcome was loss of future drug options, defined as new intermediate-level or high-level resistance to one or more drugs to which the patient's virus was deemed sensitive at trial entry (assessed at 3 years; non-inferiority margin of 10%). We estimated probability of rebound and resistance with Kaplan-Meier analysis. Analyses were by intention to treat. This trial is registered with the International Standard Randomised Controlled Trial Number registry, number ISRCTN04857074., Findings: Between Nov 4, 2008, and July 28, 2010, we randomly allocated 587 participants to OT (291) or PI-mono (296). At 3 years, one or more future drug options had been lost in two participants (Kaplan-Meier estimate 0·7%) in the OT group and six (2·1%) in the PI-mono group: difference 1·4% (-0·4 to 3·4); non-inferiority shown. 49 (16·8%) participants in the OT group and 65 (22·0%) in the PI-mono group had grade 3 or 4 clinical adverse events (difference 5·1% [95% CI -1·3 to 11·5]; p=0·12); 45 (six treatment related) and 56 (three treatment related) had serious adverse events., Interpretation: Protease inhibitor monotherapy, with regular viral load monitoring and prompt reintroduction of combination treatment for rebound, preserved future treatment options and did not change overall clinical outcomes or frequency of toxic effects. Protease inhibitor monotherapy is an acceptable alternative for long-term clinical management of HIV infection., Funding: National Institute for Health Research., (Copyright © 2015 Paton et al. Open Access article published under the terms of CC BY. Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2015
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191. Week 48 efficacy and central nervous system analysis of darunavir/ritonavir monotherapy versus darunavir/ritonavir with two nucleoside analogues.
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Antinori A, Clarke A, Svedhem-Johansson V, Arribas JR, Arenas-Pinto A, Fehr J, Gerstoft J, Horban A, Clotet B, Ripamonti D, Girard PM, Hill AM, and Moecklinghoff C
- Subjects
- Adult, Anti-HIV Agents adverse effects, Antiretroviral Therapy, Highly Active adverse effects, Female, Humans, Male, Middle Aged, Treatment Outcome, Anti-HIV Agents administration & dosage, Antiretroviral Therapy, Highly Active methods, Brain Diseases chemically induced, Brain Diseases epidemiology, Central Nervous System pathology, HIV Infections drug therapy
- Abstract
Background: In previous studies in virologically suppressed patients, protease inhibitor monotherapy has shown trends for more low-level elevations in HIV-1 RNA compared with triple therapy, but no increase in the risk of drug resistance., Methods: A total of 273 patients with HIV-1 RNA less than 50 copies/ml on first-line antiretrovirals switched to darunavir/ritonavir (DRV/r) 800/100 mg once daily, either as monotherapy (n = 137) or as triple therapy with two nucleoside analogues (n = 136). Treatment failure was defined as HIV-1 RNA levels 50 copies/ml or above, or discontinuation of study treatment by week 48 (FDA Snapshot algorithm)., Results: Patients were 83% male and 88% white, with mean age 42 years. In the primary efficacy analysis, HIV-1 RNA less than 50 copies/ml by week 48 [intention-to-treat (ITT)] was 118 of 137 (86%) in the DRV/r monotherapy arm versus 129 of 136 (95%) in the triple therapy arm (difference = -8.7%, 95% confidence interval -15.50, -1.80). In a post-hoc analysis, for patients with nadir CD4 cell count 200 cells/μl or above, rates of HIV-1 RNA suppression were 91 of 96 (95%) in the DRV/r monotherapy arm and 100 of 106 (94%) in the triple therapy arm. There was no difference in neurocognitive function or the risk of neuropsychiatric adverse events between DRV/r monotherapy and triple therapy. Two patients in the monotherapy arm with CD4 nadir less than 200 cells/μl developed viraemia in both cerebrospinal fluid (CSF) and plasma, with one symptomatic case., Conclusions: In this study for patients with HIV-1 RNA less than 50 copies/ml at baseline, switching to DRV/r monotherapy showed lower efficacy versus triple therapy at week 48 in the primary ITT switch equals failure analysis, with two cases of viraemia in the CSF in the protease inhibitor monotherapy arm.
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- 2015
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192. Baseline prevalence and predictors of liver fibrosis among HIV-positive individuals: a substudy of the INSIGHT Strategic Timing of AntiRetroviral Treatment (START) trial.
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Matthews GV, Neuhaus J, Bhagani S, Mehta SH, Vlahakis E, Doroana M, Naggie S, Arenas-Pinto A, Peters L, and Rockstroh JK
- Subjects
- Adult, Biomarkers blood, CD4 Lymphocyte Count, Cross-Sectional Studies, Elasticity Imaging Techniques, Female, HIV Infections immunology, Humans, Male, Prevalence, HIV Infections complications, HIV Infections pathology, Liver Cirrhosis diagnosis, Liver Cirrhosis epidemiology
- Abstract
Objectives: Liver disease is increasingly recognized in HIV-positive individuals, even among those without viral hepatitis, partly as a result of the recent availability of noninvasive methods of liver fibrosis assessment. The objective of this substudy is to compare the effects of early versus deferred antiretroviral therapy (ART) on liver fibrosis progression., Methods: Sites in the Strategic Timing of AntiRetroviral Treatment (START) study with access to FibroScan® were invited to participate in the Liver Fibrosis Progression Substudy. All substudy participants underwent FibroScan® at baseline, and two noninvasive serum algorithms, APRI and FIB-4, were calculated. Demographic and liver-related information was collected for all START participants at baseline., Results: A total of 230 participants were enrolled in the substudy (11.5% with hepatitis B or C virus coinfection), of whom 221 had a valid transient elastography (TE) result. The median TE score was 4.9 kPa [interquartile range (IQR) 4.3-6.0 kPa]. Seventeen patients (7.8%) [95% confidence interval (CI) 5.1-12.1%] had a TE score of > 7.2 kPa, indicating significant liver fibrosis. Baseline factors associated with higher TE scores in multivariate analysis were higher alanine aminotransferase (ALT) per 10 U/L (P = 0.045), higher log10 HIV RNA (P < 0.001) and Hispanic/Latino ethnicity (P = 0.01). TE correlated weakly with noninvasive markers., Conclusions: At baseline, significant liver fibrosis was observed in approximately 8% of participants, with higher ALT and HIV RNA the only clinical factors associated with increasing TE score. TE will be used annually to monitor fibrosis and evaluate the role of ART in further fibrosis progression., (© 2015 British HIV Association.)
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- 2015
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193. Short- and long-term mortality and causes of death in HIV/tuberculosis patients in Europe.
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Podlekareva DN, Panteleev AM, Grint D, Post FA, Miro JM, Bruyand M, Furrer H, Obel N, Girardi E, Vasilenko A, Losso MH, Arenas-Pinto A, Caylá J, Rakhmanova A, Zeltina I, Werlinrud AM, Lundgren JD, Mocroft A, and Kirk O
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- Adult, Anti-HIV Agents therapeutic use, Antitubercular Agents therapeutic use, Argentina, Cause of Death, Cohort Studies, Europe, Female, HIV Infections complications, HIV Infections drug therapy, Humans, Male, Multivariate Analysis, Tuberculosis complications, Tuberculosis drug therapy, Coinfection mortality, HIV Infections mortality, Tuberculosis mortality
- Abstract
Mortality of HIV/tuberculosis (TB) patients in Eastern Europe is high. Little is known about their causes of death. This study aimed to assess and compare mortality rates and cause of death in HIV/TB patients across Eastern Europe and Western Europe and Argentina (WEA) in an international cohort study. Mortality rates and causes of death were analysed by time from TB diagnosis (<3 months, 3-12 months or >12 months) in 1078 consecutive HIV/TB patients. Factors associated with TB-related death were examined in multivariate Poisson regression analysis. 347 patients died during 2625 person-years of follow-up. Mortality in Eastern Europe was three- to ninefold higher than in WEA. TB was the main cause of death in Eastern Europe in 80%, 66% and 61% of patients who died <3 months, 3-12 months or >12 months after TB diagnosis, compared to 50%, 0% and 15% in the same time periods in WEA (p<0.0001). In multivariate analysis, follow-up in WEA (incidence rate ratio (IRR) 0.12, 95% CI 0.04-0.35), standard TB-treatment (IRR 0.45, 95% CI 0.20-0.99) and antiretroviral therapy (IRR 0.32, 95% CI 0.14-0.77) were associated with reduced risk of TB-related death. Persistently higher mortality rates were observed in HIV/TB patients in Eastern Europe, and TB was the dominant cause of death at any time during follow-up. This has important implications for HIV/TB programmes aiming to optimise the management of HIV/TB patients and limit TB-associated mortality in this region.
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- 2014
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194. Common inherited mitochondrial DNA mutations and nucleoside reverse transcriptase inhibitor-induced severe hyperlactataemia in HIV-infected adults: an exploratory study.
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Arenas-Pinto A, Weller I, Ekong R, Grant A, Karstaedt A, Reiss P, Telisinghe L, Weber R, Bolhaar M, Bradman N, and Ingram C
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- Adult, Anti-HIV Agents adverse effects, Anti-HIV Agents therapeutic use, Black People genetics, Case-Control Studies, Didanosine therapeutic use, Female, Humans, Leukocytes, Mononuclear cytology, Male, Middle Aged, Mitochondria genetics, Mitochondria metabolism, Mutation, Polymorphism, Single Nucleotide, Sequence Deletion, Stavudine therapeutic use, White People genetics, Zidovudine therapeutic use, Acidosis, Lactic genetics, DNA, Mitochondrial genetics, HIV Infections genetics, Reverse Transcriptase Inhibitors adverse effects
- Abstract
Background: Genetic predisposition to dideoxynucleoside-induced mitochondrial dysfunction might be related to mitochondrial DNA (mtDNA) polymorphisms. Severe hyperlactataemia is probably the best model to assess such a predisposition., Methods: For this exploratory study in White European and Black African HIV-infected adults, hypervariable region 1 of mtDNA samples from peripheral blood mononuclear cells or buccal smears of patients who have developed confirmed severe hyperlactataemia was sequenced. Additionally, 21 single nucleotide polymorphisms and a 9 bp deletion were genotyped to assign mtDNA haplogroups. Finally, entire mtDNA sequencing was performed in a subset of European samples. Samples were obtained from Black African cases and controls recruited from a single centre in Johannesburg, South Africa and from white European cases from Amsterdam, London and Zurich., Results: A total of 40 cases and 38 controls from Johannesburg were included. All of the cases and 33 controls were receiving stavudine-based therapy at the time of the index date (P=0.024). The distribution of mtDNA haplotypes was not different between cases and controls (P=0.137), and neither were the predicted haplogroups (P=0.751). In total, 11 of the 12 European cases were on stavudine and/or didanosine at the time of the event. No hypervariable region 1 haplotype was consistently found in the European cases. Sequencing of the entire mtDNA from three of these cases supported the absence of any shared mutations other than major alleles frequently seen in the mtDNA database., Conclusions: We did not find an association between homoplasmic inherited mtDNA polymorphisms and severe hyperlactataemia. Our data do not support the existence of non-synonymous mtDNA mutations that explain an increased predisposition to dideoxynucleoside-induced mitochondrial dysfunction.
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- 2012
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195. Risk factors for fatality in HIV-infected patients with dideoxynucleoside-induced severe hyperlactataemia or lactic acidosis.
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Arenas-Pinto A, Grant A, Bhaskaran K, Copas A, Carr A, Worm SW, Martinez E, Reiss P, Dunn D, Weber R, Hoy J, and Weller I
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- Acidosis, Lactic blood, Adult, Female, HIV Infections complications, HIV Infections drug therapy, HIV-1, Humans, Male, Middle Aged, Risk Factors, Severity of Illness Index, Acidosis, Lactic chemically induced, Acidosis, Lactic mortality, Anti-HIV Agents adverse effects, Dideoxynucleosides adverse effects, HIV Infections mortality, Lactic Acid adverse effects, Lactic Acid blood
- Abstract
Background: Lactic acidosis (LA) and severe hyperlactataemia (HL) are infrequent but serious complications of antiretroviral therapy that have been associated with a high fatality rate., Methods: In a multinational retrospective cohort study, LA was defined as arterial blood pH<7.35, bicarbonate <20 mmol/l and lactate above normal, and HL as confirmed blood lactate >5 mmol/l. Logistic regression was used to identify factors associated with fatality. Sensitivity and specificity of different case definitions as predictors of death were compared., Results: The overall case-fatality rate was 19/110 (17.3%), but among acidotic patients it was 33% (16/49 cases). There were 10 asymptomatic patients and none of them died as a consequence of the event. The median lactate for fatal, non-fatal and all patients was 8.3 mmol/l (IQR 7.2-13.1), 6.4 mmol/l (IQR 5.4-7.8) and 6.7 mmol/l (IQR 5.5-8.1), respectively. After adjusting for age and current CD4(+) T-cell count, lactate >7 mmol/l (OR 6.27, 95% CI 1.13-34.93), blood bicarbonate <12 mmol/l (OR 10.02 relative to >18 mmol/l, 95% CI 1.33-75.65) and concurrent opportunistic infections (OR 8.69, 95% CI 1.45-52.22) were independently associated with case fatality. Blood lactate >7 mmol/l showed a sensitivity of 84% for fatality with a specificity of 60%, whereas bicarbonate <12 mmol/l showed a better specificity (85%) but a poorer sensitivity (42%). Bicarbonate <18 mmol/l appears to be as good as lactate <7 mmol/l at predicting death (sensitivity 90% and specificity 54%)., Conclusions: Our data suggest that blood lactate >7 mmol/l and blood bicarbonate <18 mmol/l appear to predict death and might help clinicians in selecting patients who may benefit from more intense monitoring.
- Published
- 2011
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