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1. Dolutegravir plus lamivudine versus dolutegravir plus tenofovir disoproxil fumarate and emtricitabine in antiretroviral-naive adults with HIV-1 infection (GEMINI-1 and GEMINI-2): week 48 results from two multicentre, double-blind, randomised, non-inferiority, phase 3 trials

Author

Cahn, P, Madero, J, Arribas, J, Antinori, A, Ortiz, R, Clarke, A, Hung, C, Rockstroh, J, Girard, P, Sievers, J, Man, C, Currie, A, Underwood, M, Tenorio, A, Pappa, K, Wynne, B, Fettiplace, A, Gartland, M, Aboud, M, Smith, K, Cassetti, L, David, D, Figueras, L, Losso, M, Lopardo, G, Lupo, S, Porteiro, N, Sanchez, M, Bloch, M, Cooper, D, Finlayson, R, Kelleher, A, Koh, K, Lewis, D, Mcmahon, J, Moore, R, Roth, N, Shields, M, De Wit, S, Florence, E, Goffard, J, Demeester, R, Lacor, P, Vandercam, B, Vandekerckhove, L, Angel, J, Baril, J, Conway, B, De Pokomandy, A, Szabo, J, Walmsley, S, Bouchaud, O, Chidiac, C, Delobel, P, Goujard, C, Katlama, C, Molina, J, Pialoux, G, Philibert, P, Bogner, J, Esser, S, Krznaric, I, Lehmann, C, Spinner, C, Stellbrink, H, Stephan, C, Stoehr, A, Barchi, E, Caramello, P, Castelli, F, Cattelan, A, D'Arminio Monforte, A, Di Biagio, A, Di Perri, G, Gori, A, Maggiolo, F, Menzaghi, B, Migliorino, G, Mussini, C, Penco, G, Puoti, M, Rizzardini, G, Gulminetti, R, Lazzarin, A, Quirino, T, Sighinolfi, L, Viale, P, Amaya Tapia, G, Andrade Villanueva, J, Granados Reyes, E, Perez Rios, A, Santoscoy Gomez, M, Den Hollander, J, Rijnders, B, Hidalgo, J, Hercilla Vasquez, L, Illescas, L, Olczak, A, Mansinho, K, Correia Pacheco, P, Teofilo, E, Saraiva da Cunha, J, Sarmento e Castro, R, Serrao, R, Arbune, M, Jianu, C, Oprea, A, Preotescu, L, Prisacariu, L, Belonosova, E, Borodkina, O, Chernova, O, Gankina, N, Kizhlo, S, Kulagin, V, Kurina, N, Nagimova, F, Pokrovsky, V, Ryamova, E, Voronin, E, Yakovlev, A, Kaplan, R, Lee, S, Kim, S, Kim, W, Antela Lopez, A, Casado Osorio, J, Castano Carracedo, M, De Los Santos Gil, I, Estrada Perez, V, Falco Ferrer, V, Force, L, Galinda Puerto, M, Garcia Deltoro, M, Gatell, J, Goenaga Sanchez, M, Gonzalez Cordon, A, Knobel, H, Lopez Bernaldo de Quiros, J, Losa Garcia, J, Masia, M, Montero-Alsonso, M, Ocampo Hermida, A, Pasquau Liano, J, Portilla Sogorb, J, Pulido Ortega, F, Rivera Roman, A, Santos Fernandez, J, Torres Perea, R, Troya Garcia, J, Viciana Fernandez, P, Calmy, A, Hauser, C, Fehr, J, Cheng, S, Ko, W, Lin, H, Lu, P, Tseng, Y, Wang, N, Wong, W, Yang, C, Arduino, R, Benson, P, Berhe, M, Bredeek, F, Brinson, C, Campbell, T, Crofoot, G, Cunningham, D, Dejesus, E, Dretler, R, Eron, J, Fife, K, Fichtenbaum, C, Flamm, J, Goldstein, D, Gupta, S, Hagins, D, Hoffman-Terry, M, Jayaweera, D, Kinder, C, Klein, D, Mcdonald, C, Mills, A, Nahass, R, Osiyemi, O, Overton, E, Parks, D, Prelutsky, D, Ramgopal, M, Schrader, S, Sha, B, Simon, G, Sims, J, Skiest, D, Slim, J, Tashima, K, Thedinger, B, Gazzard, B, Fox, J, Johnson, M, Kegg, S, Khoo, S, Mazhude, C, Orkin, C, Schembri, G, Ustianowski, A, Cahn P., Madero J. S., Arribas J. R., Antinori A., Ortiz R., Clarke A. E., Hung C. -C., Rockstroh J. K., Girard P. -M., Sievers J., Man C., Currie A., Underwood M., Tenorio A. R., Pappa K., Wynne B., Fettiplace A., Gartland M., Aboud M., Smith K., Cassetti L., David D., Figueras L., Losso M., Lopardo G., Lupo S., Porteiro N., Sanchez M., Bloch M., Cooper D., Finlayson R., Kelleher A., Koh K., Lewis D., McMahon J., Moore R., Roth N., Shields M., De Wit S., Florence E., Goffard J. -C., Demeester R., Lacor P., Vandercam B., Vandekerckhove L., Angel J., Baril J. -G., Conway B., De Pokomandy A., Szabo J., Walmsley S., Bouchaud O., Chidiac C., Delobel P., Goujard C., Katlama C., Molina J. -M., Pialoux G., Philibert P., Bogner J., Esser S., Krznaric I., Lehmann C., Spinner C., Stellbrink H. -J., Stephan C., Stoehr A., Barchi E., Caramello P., Castelli F., Cattelan A. M., D'Arminio Monforte A., Di Biagio A., Di Perri G., Gori A., Maggiolo F., Menzaghi B., Migliorino G., Mussini C., Penco G., Puoti M., Rizzardini G., Gulminetti R., Lazzarin A., Quirino T., Sighinolfi L., Viale P., Amaya Tapia G., Andrade Villanueva J., Granados Reyes E. R., Perez Rios A., Santoscoy Gomez M., Den Hollander J., Rijnders B., Hidalgo J. A., Hercilla Vasquez L., Illescas L., Olczak A., Mansinho K., Correia Pacheco P. P., Teofilo E., Saraiva da Cunha J., Sarmento e Castro R., Serrao R., Arbune M., Jianu C., Oprea A., Preotescu L., Prisacariu L. -J., Belonosova E., Borodkina O., Chernova O., Gankina N., Kizhlo S., Kulagin V., Kurina N., Nagimova F., Pokrovsky V., Ryamova E., Voronin E., Yakovlev A., Kaplan R., Lee S. H., Kim S. -W., Kim S. -I., Kim W. J., Antela Lopez A., Casado Osorio J. L., Castano Carracedo M. A., De Los Santos Gil I., Estrada Perez V., Falco Ferrer V., Force L., Galinda Puerto M. J., Garcia Deltoro M., Gatell J. M., Goenaga Sanchez M. A., Gonzalez Cordon A., Knobel H., Lopez Bernaldo de Quiros J. C., Losa Garcia J. E., Masia M., Montero-Alsonso M., Ocampo Hermida A., Pasquau Liano J., Portilla Sogorb J., Pulido Ortega F., Rivera Roman A., Santos Fernandez J. R., Torres Perea R., Troya Garcia J., Viciana Fernandez P., Calmy A., Hauser C., Fehr J., Cheng S. -H., Ko W. -C., Lin H. -H., Lu P. -L., Tseng Y. -T., Wang N. -C., Wong W. -W., Yang C. -J., Arduino R., Benson P., Berhe M., Bredeek F., Brinson C., Campbell T., Crofoot G., Cunningham D., DeJesus E., Dretler R., Eron J., Fife K., Fichtenbaum C., Flamm J., Goldstein D., Gupta S., Hagins D., Hoffman-Terry M., Jayaweera D., Kinder C., Klein D., McDonald C., Mills A., Nahass R., Osiyemi O., Overton E., Parks D., Prelutsky D., Ramgopal M., Schrader S., Sha B., Simon G., Sims J., Skiest D., Slim J., Tashima K., Thedinger B., Gazzard B., Fox J., Johnson M., Kegg S., Khoo S., Mazhude C., Orkin C., Schembri G., Ustianowski A., Cahn, P, Madero, J, Arribas, J, Antinori, A, Ortiz, R, Clarke, A, Hung, C, Rockstroh, J, Girard, P, Sievers, J, Man, C, Currie, A, Underwood, M, Tenorio, A, Pappa, K, Wynne, B, Fettiplace, A, Gartland, M, Aboud, M, Smith, K, Cassetti, L, David, D, Figueras, L, Losso, M, Lopardo, G, Lupo, S, Porteiro, N, Sanchez, M, Bloch, M, Cooper, D, Finlayson, R, Kelleher, A, Koh, K, Lewis, D, Mcmahon, J, Moore, R, Roth, N, Shields, M, De Wit, S, Florence, E, Goffard, J, Demeester, R, Lacor, P, Vandercam, B, Vandekerckhove, L, Angel, J, Baril, J, Conway, B, De Pokomandy, A, Szabo, J, Walmsley, S, Bouchaud, O, Chidiac, C, Delobel, P, Goujard, C, Katlama, C, Molina, J, Pialoux, G, Philibert, P, Bogner, J, Esser, S, Krznaric, I, Lehmann, C, Spinner, C, Stellbrink, H, Stephan, C, Stoehr, A, Barchi, E, Caramello, P, Castelli, F, Cattelan, A, D'Arminio Monforte, A, Di Biagio, A, Di Perri, G, Gori, A, Maggiolo, F, Menzaghi, B, Migliorino, G, Mussini, C, Penco, G, Puoti, M, Rizzardini, G, Gulminetti, R, Lazzarin, A, Quirino, T, Sighinolfi, L, Viale, P, Amaya Tapia, G, Andrade Villanueva, J, Granados Reyes, E, Perez Rios, A, Santoscoy Gomez, M, Den Hollander, J, Rijnders, B, Hidalgo, J, Hercilla Vasquez, L, Illescas, L, Olczak, A, Mansinho, K, Correia Pacheco, P, Teofilo, E, Saraiva da Cunha, J, Sarmento e Castro, R, Serrao, R, Arbune, M, Jianu, C, Oprea, A, Preotescu, L, Prisacariu, L, Belonosova, E, Borodkina, O, Chernova, O, Gankina, N, Kizhlo, S, Kulagin, V, Kurina, N, Nagimova, F, Pokrovsky, V, Ryamova, E, Voronin, E, Yakovlev, A, Kaplan, R, Lee, S, Kim, S, Kim, W, Antela Lopez, A, Casado Osorio, J, Castano Carracedo, M, De Los Santos Gil, I, Estrada Perez, V, Falco Ferrer, V, Force, L, Galinda Puerto, M, Garcia Deltoro, M, Gatell, J, Goenaga Sanchez, M, Gonzalez Cordon, A, Knobel, H, Lopez Bernaldo de Quiros, J, Losa Garcia, J, Masia, M, Montero-Alsonso, M, Ocampo Hermida, A, Pasquau Liano, J, Portilla Sogorb, J, Pulido Ortega, F, Rivera Roman, A, Santos Fernandez, J, Torres Perea, R, Troya Garcia, J, Viciana Fernandez, P, Calmy, A, Hauser, C, Fehr, J, Cheng, S, Ko, W, Lin, H, Lu, P, Tseng, Y, Wang, N, Wong, W, Yang, C, Arduino, R, Benson, P, Berhe, M, Bredeek, F, Brinson, C, Campbell, T, Crofoot, G, Cunningham, D, Dejesus, E, Dretler, R, Eron, J, Fife, K, Fichtenbaum, C, Flamm, J, Goldstein, D, Gupta, S, Hagins, D, Hoffman-Terry, M, Jayaweera, D, Kinder, C, Klein, D, Mcdonald, C, Mills, A, Nahass, R, Osiyemi, O, Overton, E, Parks, D, Prelutsky, D, Ramgopal, M, Schrader, S, Sha, B, Simon, G, Sims, J, Skiest, D, Slim, J, Tashima, K, Thedinger, B, Gazzard, B, Fox, J, Johnson, M, Kegg, S, Khoo, S, Mazhude, C, Orkin, C, Schembri, G, Ustianowski, A, Cahn P., Madero J. S., Arribas J. R., Antinori A., Ortiz R., Clarke A. E., Hung C. -C., Rockstroh J. K., Girard P. -M., Sievers J., Man C., Currie A., Underwood M., Tenorio A. R., Pappa K., Wynne B., Fettiplace A., Gartland M., Aboud M., Smith K., Cassetti L., David D., Figueras L., Losso M., Lopardo G., Lupo S., Porteiro N., Sanchez M., Bloch M., Cooper D., Finlayson R., Kelleher A., Koh K., Lewis D., McMahon J., Moore R., Roth N., Shields M., De Wit S., Florence E., Goffard J. -C., Demeester R., Lacor P., Vandercam B., Vandekerckhove L., Angel J., Baril J. -G., Conway B., De Pokomandy A., Szabo J., Walmsley S., Bouchaud O., Chidiac C., Delobel P., Goujard C., Katlama C., Molina J. -M., Pialoux G., Philibert P., Bogner J., Esser S., Krznaric I., Lehmann C., Spinner C., Stellbrink H. -J., Stephan C., Stoehr A., Barchi E., Caramello P., Castelli F., Cattelan A. M., D'Arminio Monforte A., Di Biagio A., Di Perri G., Gori A., Maggiolo F., Menzaghi B., Migliorino G., Mussini C., Penco G., Puoti M., Rizzardini G., Gulminetti R., Lazzarin A., Quirino T., Sighinolfi L., Viale P., Amaya Tapia G., Andrade Villanueva J., Granados Reyes E. R., Perez Rios A., Santoscoy Gomez M., Den Hollander J., Rijnders B., Hidalgo J. A., Hercilla Vasquez L., Illescas L., Olczak A., Mansinho K., Correia Pacheco P. P., Teofilo E., Saraiva da Cunha J., Sarmento e Castro R., Serrao R., Arbune M., Jianu C., Oprea A., Preotescu L., Prisacariu L. -J., Belonosova E., Borodkina O., Chernova O., Gankina N., Kizhlo S., Kulagin V., Kurina N., Nagimova F., Pokrovsky V., Ryamova E., Voronin E., Yakovlev A., Kaplan R., Lee S. H., Kim S. -W., Kim S. -I., Kim W. J., Antela Lopez A., Casado Osorio J. L., Castano Carracedo M. A., De Los Santos Gil I., Estrada Perez V., Falco Ferrer V., Force L., Galinda Puerto M. J., Garcia Deltoro M., Gatell J. M., Goenaga Sanchez M. A., Gonzalez Cordon A., Knobel H., Lopez Bernaldo de Quiros J. C., Losa Garcia J. E., Masia M., Montero-Alsonso M., Ocampo Hermida A., Pasquau Liano J., Portilla Sogorb J., Pulido Ortega F., Rivera Roman A., Santos Fernandez J. R., Torres Perea R., Troya Garcia J., Viciana Fernandez P., Calmy A., Hauser C., Fehr J., Cheng S. -H., Ko W. -C., Lin H. -H., Lu P. -L., Tseng Y. -T., Wang N. -C., Wong W. -W., Yang C. -J., Arduino R., Benson P., Berhe M., Bredeek F., Brinson C., Campbell T., Crofoot G., Cunningham D., DeJesus E., Dretler R., Eron J., Fife K., Fichtenbaum C., Flamm J., Goldstein D., Gupta S., Hagins D., Hoffman-Terry M., Jayaweera D., Kinder C., Klein D., McDonald C., Mills A., Nahass R., Osiyemi O., Overton E., Parks D., Prelutsky D., Ramgopal M., Schrader S., Sha B., Simon G., Sims J., Skiest D., Slim J., Tashima K., Thedinger B., Gazzard B., Fox J., Johnson M., Kegg S., Khoo S., Mazhude C., Orkin C., Schembri G., and Ustianowski A.

Abstract

Background: Effective two-drug regimens could decrease long-term drug exposure and toxicity with HIV-1 antiretroviral therapy (ART). We therefore aimed to evaluate the efficacy and safety of a two-drug regimen compared with a three-drug regimen for the treatment of HIV-1 infection in ART-naive adults. Methods: We conducted two identically designed, multicentre, double-blind, randomised, non-inferiority, phase 3 trials: GEMINI-1 and GEMINI-2. Both studies were done at 192 centres in 21 countries. We included participants (≥18 years) with HIV-1 infection and a screening HIV-1 RNA of 500 000 copies per mL or less, and who were naive to ART. We randomly assigned participants (1:1) to receive a once-daily two-drug regimen of dolutegravir (50 mg) plus lamivudine (300 mg) or a once-daily three-drug regimen of dolutegravir (50 mg) plus tenofovir disoproxil fumarate (300 mg) and emtricitabine (200 mg). Both drug regimens were administered orally. We masked participants and investigators to treatment assignment: dolutegravir was administered as single-entity tablets (similar to its commercial formulation, except with a different film colour), and lamivudine tablets and tenofovir disoproxil fumarate and emtricitabine tablets were over-encapsulated to visually match each other. Primary endpoint was the proportion of participants with HIV-1 RNA of less than 50 copies per mL at week 48 in the intention-to-treat-exposed population, using the Snapshot algorithm and a non-inferiority margin of −10%. Safety analyses were done on the safety population. GEMINI-1 and GEMINI-2 are registered with ClinicalTrials.gov, numbers NCT02831673 and NCT02831764, respectively. Findings: Between July 18, 2016, and March 31, 2017, 1441 participants across both studies were randomly assigned to receive either the two-drug regimen (n=719) or three-drug regimen (n=722). At week 48 in the GEMINI-1 intention-to-treat-exposed population, 320 (90%) of 356 participants receiving the two-drug regimen and 332

Published
2019

2. Week 48 Resistance Analyses of the Once-Daily, Single-Tablet Regimen Darunavir/Cobicistat/Emtricitabine/Tenofovir Alafenamide (D/C/F/TAF) in Adults Living with HIV-1 from the Phase III Randomized AMBER and EMERALD Trials

Author

Lathouwers E, Wong E, Brown K, Baugh B, Ghys A, Jezorwski J, Mohsine E, Van Landuyt E, Opsomer M, De Meyer S, De Wit S, Florence E, Vandekerckhove L, Vandercam B, Brunetta J, Klein M, Murphy D, Rachlis A, Walmsley S, Ajana F, Cotte L, Girard P, Katlama C, Molina J, Poizot-Martin I, Raffi F, Rey D, Reynes J, Teicher E, Yazdanpanah Y, Arasteh K, Bickel M, Bogner J, Esser S, Faetkenheuer G, Jessen H, Kern W, Rockstroh J, Spinner C, Stellbrink H, Stoehr A, Antinori A, Castelli F, Chirianni A, De Luca A, Di Biagio A, Galli M, Lazzarin A, Maggiolo F, Maserati R, Mussini C, Garlicki A, Gasiorowski J, Halota W, Horban A, Parczewski M, Piekarska A, Belonosova E, Chernova O, Dushkina N, Kulagin V, Ryamova E, Shuldyakov A, Sizova N, Tsybakova O, Voronin E, Yakovlev A, Antela A, Arribas J, Berenguer J, Casado J, Estrada V, Galindo M, Del Toro M, Gatell J, Gorgolas M, Gutierrez F, Gutierrez M, Negredo E, Pineda J, Podzamczer D, Sogorb J, Rivero A, Rubio R, Viciana P, De Los Santos I, Clarke A, Gazzard B, Johnson M, Orkin C, Reeves I, Waters L, Benson P, Bhatti L, Bredeek F, Crofoot G, Cunningham D, DeJesus E, Eron J, Felizarta F, Franco R, Gallant J, Hagins D, Henry K, Jayaweera D, Lucasti C, Martorell C, McDonald C, McGowan J, Mills A, Morales-Ramirez J, Prelutsky D, Ramgopal M, Rashbaum B, Ruane P, Slim J, Wilkin A, deVente J, Moutschen M, Van Wijngaerden E, Vekerckhove L, Vercam B, Conway B, Shafran S, AMBER Study Grp, and EMERALD Study Grp

Subjects
resistance, deep sequencing, TAF, efficacy, virus diseases, darunavir, cobicistat, archived RAMs, emtricitabine, single-tablet regimen
Abstract

Darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10 mg is being investigated in two Phase III trials, AMBER (NCT02431247; treatment-naive adults) and EMERALD (NCT02269917; treatment-experienced, virologically suppressed adults). Week 48 AMBER and EMERALD resistance analyses are presented. Postbaseline samples for genotyping/phenotyping were analyzed from protocol-defined virologic failures (PDVFs) with viral load (VL) >= 400 copies/mL at failure/later time points. Post hoc analyses were deep sequencing in AMBER, and HIV-1 proviral DNA from baseline samples (VL = 3 thymidine analog-associated mutations (24% not fully susceptible to tenofovir) detected at screening. All achieved VL

Published
2020

3. Week 48 Resistance Analyses of the Once-Daily, Single-Tablet Regimen Darunavir/Cobicistat/Emtricitabine/Tenofovir Alafenamide (D/C/F/TAF) in Adults Living with HIV-1 from the Phase III Randomized AMBER and EMERALD Trials

Author

Lathouwers, Erkki, Wong, Eric Y, Brown, Kimberley, Baugh, Bryan, Ghys, Anne, Jezorwski, John, Mohsine, El Ghazi, Van Landuyt, Erika, Opsomer, Magda, De Meyer, Sandra, De Wit, S, Florence, E, Vandekerckhove, L, Vandercam, B, Brunetta, J, Klein, M, Murphy, D, Rachlis, A, Walmsley, S, Ajana, F, Cotte, L, Girard, P-M, Katlama, C, Molina, J-M, Poizot-Martin, I, Raffi, F, Rey, D, Reynes, J, Teicher, E, Yazdanpanah, Y, Arasteh, K, Bickel, M, Bogner, J, Esser, S, Faetkenheuer, G, Jessen, H, Kern, W, Rockstroh, J, Spinner, C, Stellbrink, H-J, Stoehr, A, Antinori, A, Castelli, F, Chirianni, A, De Luca, A, Di Biagio, A, Galli, M, Lazzarin, A, Maggiolo, F, Maserati, R, Mussini, C, Garlicki, A, Gasiorowski, J, Halota, W, Horban, A, Parczewski, M, Piekarska, A, Belonosova, E, Chernova, O, Dushkina, N, Kulagin, V, Ryamova, E, Shuldyakov, A, Sizova, N, Tsybakova, O, Voronin, E, Yakovlev, A, Antela, A, Arribas, JR, Berenguer, J, Casado, J, Estrada, V, Galindo, MJ, Garcia Del Toro, M, Gatell, JM, Gorgolas, M, Gutierrez, F, Gutierrez, MDM, Negredo, E, Pineda, JA, Podzamczer, D, Portilla Sogorb, J, Rivero, A, Rubio, R, Viciana, P, De Los Santos, I, Clarke, A, Gazzard, BG, Johnson, MA, Orkin, C, Reeves, I, Waters, L, Benson, P, Bhatti, L, Bredeek, F, Crofoot, G, Cunningham, D, DeJesus, E, Eron, J, Felizarta, F, Franco, R, Gallant, J, Hagins, D, Henry, K, Jayaweera, D, Lucasti, C, Martorell, C, McDonald, C, McGowan, J, Mills, A, Morales-Ramirez, J, Prelutsky, D, Ramgopal, M, Rashbaum, B, Ruane, P, Slim, J, Wilkin, A, deVente, J, Moutschen, M, Van Wijngaerden, E, Vekerckhove, L, Vercam, B, Conway, B, Shafran, S, Janssen Pharmaceutica [Beerse], Janssen Pharmaceutical Research and Development Titusville, AMBER and EMERALD Study Groups: S De Wit, E Florence, L Vandekerckhove, B Vandercam, J Brunetta, M Klein, D Murphy, A Rachlis, S Walmsley, F Ajana, L Cotte, P-M Girard, C Katlama, J-M Molina, I Poizot-Martin, F Raffi, D Rey, J Reynes, E Teicher, Y Yazdanpanah, K Arastéh, M Bickel, J Bogner, S Esser, G Faetkenheuer, H Jessen, W Kern, J Rockstroh, C Spinner, H-J Stellbrink, A Stoehr, A Antinori, F Castelli, A Chirianni, A De Luca, A Di Biagio, M Galli, A Lazzarin, F Maggiolo, R Maserati, C Mussini, A Garlicki, J Gasiorowski, W Halota, A Horban, M Parczewski, A Piekarska, E Belonosova, O Chernova, N Dushkina, V Kulagin, E Ryamova, A Shuldyakov, N Sizova, O Tsybakova, E Voronin, A Yakovlev, A Antela, J R Arribas, J Berenguer, J Casado, V Estrada, M J Galindo, M Garcia Del Toro, J M Gatell, M Gorgolas, F Gutierrez, Mdm Gutierrez, E Negredo, J A Pineda, D Podzamczer, J Portilla Sogorb, A Rivero, R Rubio, P Viciana, I De Los Santos, A Clarke, B G Gazzard, M A Johnson, C Orkin, I Reeves, L Waters, P Benson, L Bhatti, F Bredeek, G Crofoot, D Cunningham, E DeJesus, J Eron, F Felizarta, R Franco, J Gallant, D Hagins, K Henry, D Jayaweera, C Lucasti, C Martorell, C McDonald, J McGowan, A Mills, J Morales-Ramirez, D Prelutsky, M Ramgopal, B Rashbaum, P Ruane, J Slim, A Wilkin, J deVente, S De Wit, E Florence, M Moutschen, E Van Wijngaerden, L Vandekerckhove, B Vandercam, J Brunetta, B Conway, M Klein, D Murphy, A Rachlis, S Shafran, S Walmsley, F Ajana, L Cotte, P-M Girard, C Katlama, J-M Molina, I Poizot-Martin, F Raffi, D Rey, J Reynes, E Teicher, Y Yazdanpanah, J Gasiorowski, W Halota, A Horban, A Piekarska, A Witor, J R Arribas, I Perez-Valero, J Berenguer, J Casado, J M Gatell, F Gutierrez, M J Galindo, Mdm Gutierrez, J A Iribarren, H Knobel, E Negredo, J A Pineda, D Podzamczer, J Portilla Sogorb, F Pulido, C Ricart, A Rivero, I Santos Gil, A Blaxhult, L Flamholc, M Gisslèn, A Thalme, J Fehr, A Rauch, M Stoeckle, A Clarke, B G Gazzard, M A Johnson, C Orkin, F Post, A Ustianowski, L Waters, J Bailey, P Benson, L Bhatti, I Brar, U F Bredeek, C Brinson, G Crofoot, D Cunningham, E DeJesus, C Dietz, R Dretler, J Eron, F Felizarta, C Fichtenbaum, J Gallant, J Gathe, D Hagins, S Henn, K W Henry, G Huhn, M Jain, C Lucasti, C Martorell, C McDonald, A Mills, J Morales-Ramirez, K Mounzer, R Nahass, H Olivet, O Osiyemi, D Prelutsky, M Ramgopal, B Rashbaum, G Richmond, P Ruane, A Scarsella, A Scribner, P Shalit, D Shamblaw, J Slim, K Tashima, G Voskuhl, D Ward, A Wilkin, J de Vente, and Malbec, Odile

Subjects
0301 basic medicine, [SDV]Life Sciences [q-bio], efficacy, Human immunodeficiency virus (HIV), HIV Infections, darunavir, medicine.disease_cause, VIRALLY SUPPRESSED ADULTS, PLUS LAMIVUDINE, DOUBLE-BLIND, 0302 clinical medicine, INFECTION, Medicine and Health Sciences, Emtricitabine, 030212 general & internal medicine, Darunavir, Emtricitabine tenofovir alafenamide, Alanine, Cobicistat, Single tablet regimen, virus diseases, Viral Load, OPEN-LABEL, 3. Good health, [SDV] Life Sciences [q-bio], Drug Combinations, Infectious Diseases, NON-INFERIORITY, INITIAL TREATMENT, Reverse Transcriptase Inhibitors, Life Sciences & Biomedicine, Tablets, medicine.drug, Adult, TENOFOVIR DISOPROXIL FUMARATE, Anti-HIV Agents, Darunavir/Cobicistat, Immunology, archived RAMs, Tenofovir alafenamide, Drug Administration Schedule, single-tablet regimen, resistance, 03 medical and health sciences, deep sequencing, Virology, Drug Resistance, Viral, medicine, darunavir/cobicistat/emtricitabine/TAF, Humans, Clinical Trials/Clinical Studies, Tenofovir, emtricitabine, DRUG-RESISTANCE, Science & Technology, TREATMENT-NAIVE PATIENTS, business.industry, Adenine, cobicistat, 030104 developmental biology, TAF, HIV-1, business
Abstract

Darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10 mg is being investigated in two Phase III trials, AMBER (NCT02431247; treatment-naive adults) and EMERALD (NCT02269917; treatment-experienced, virologically suppressed adults). Week 48 AMBER and EMERALD resistance analyses are presented. Postbaseline samples for genotyping/phenotyping were analyzed from protocol-defined virologic failures (PDVFs) with viral load (VL) ≥400 copies/mL at failure/later time points. Post hoc analyses were deep sequencing in AMBER, and HIV-1 proviral DNA from baseline samples (VL

Published
2019

5. Long-Acting Cabotegravir and Rilpivirine for Maintenance of HIV-1 Suppression.

Author

Swindells, S., Andrade-Villanueva, J.-F., Richmond, G. J., Rizzardini, G., Baumgarten, A., Masiá, M., Latiff, G., Pokrovsky, V., Bredeek, F., Smith, G., Cahn, P., Kim, Y.-S., Ford, S. L., Talarico, C. L., Patel, P., Chounta, V., Crauwels, H., Parys, W., Vanveggel, S., and Mrus, J.

Subjects
*HIV infections, *PYRIDINE, *ANTI-HIV agents, *RESEARCH, *COMBINATION drug therapy, *GENETIC mutation, *ORAL drug administration, *VIRAL load, *RESEARCH methodology, *RNA, *ANTIRETROVIRAL agents, *EVALUATION research, *MEDICAL cooperation, *INTRAMUSCULAR injections, *COMPARATIVE studies, *PSYCHOLOGICAL tests, *RANDOMIZED controlled trials, *CD4 lymphocyte count, *DRUG therapy, *DRUG resistance in microorganisms, *STATISTICAL sampling, *HIV
Abstract

Background: Simplified regimens for the treatment of human immunodeficiency virus type 1 (HIV-1) infection may increase patient satisfaction and facilitate adherence.Methods: In this phase 3, open-label, multicenter, noninferiority trial involving patients who had had plasma HIV-1 RNA levels of less than 50 copies per milliliter for at least 6 months while taking standard oral antiretroviral therapy, we randomly assigned participants (1:1) to either continue their oral therapy or switch to monthly intramuscular injections of long-acting cabotegravir, an HIV-1 integrase strand-transfer inhibitor, and long-acting rilpivirine, a nonnucleoside reverse-transcriptase inhibitor. The primary end point was the percentage of participants with an HIV-1 RNA level of 50 copies per milliliter or higher at week 48, determined with the use of the Food and Drug Administration snapshot algorithm.Results: Treatment was initiated in 308 participants per group. At week 48, HIV-1 RNA levels of 50 copies per milliliter or higher were found in 5 participants (1.6%) receiving long-acting therapy and in 3 (1.0%) receiving oral therapy (adjusted difference, 0.6 percentage points; 95% confidence interval [CI], -1.2 to 2.5), a result that met the criterion for noninferiority for the primary end point (noninferiority margin, 6 percentage points). An HIV-1 RNA level of less than 50 copies per milliliter at week 48 was found in 92.5% of participants receiving long-acting therapy and in 95.5% of those receiving oral therapy (adjusted difference, -3.0 percentage points; 95% CI, -6.7 to 0.7), a result that met the criterion for noninferiority for this end point (noninferiority margin, -10 percentage points). Virologic failure was confirmed in 3 participants who received long-acting therapy and 4 participants who received oral therapy. Adverse events were more common in the long-acting-therapy group and included injection-site pain, which occurred in 231 recipients (75%) of long-acting therapy and was mild or moderate in most cases; 1% withdrew because of this event. Serious adverse events were reported in no more than 5% of participants in each group.Conclusions: Monthly injections of long-acting cabotegravir and rilpivirine were noninferior to standard oral therapy for maintaining HIV-1 suppression. Injection-related adverse events were common but only infrequently led to medication withdrawal. (Funded by ViiV Healthcare and Janssen; ATLAS ClinicalTrials.gov number, NCT02951052.). [ABSTRACT FROM AUTHOR]

Published
2020
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6. Dolutegravir plus lamivudine versus dolutegravir plus tenofovir disoproxil fumarate and emtricitabine in antiretroviral-naive adults with HIV-1 infection (GEMINI-1 and GEMINI-2): week 48 results from two multicentre, double-blind, randomised, non-inferiority, phase 3 trials

Author

Pedro Cahn, Juan Sierra Madero, José Ramón Arribas, Andrea Antinori, Roberto Ortiz, Amanda E Clarke, Chien-Ching Hung, Jürgen K Rockstroh, Pierre-Marie Girard, Jörg Sievers, Choy Man, Alexander Currie, Mark Underwood, Allan R Tenorio, Keith Pappa, Brian Wynne, Anna Fettiplace, Martin Gartland, Michael Aboud, Kimberly Smith, Lidia Cassetti, Daniel David, Laura Figueras, Marcelo Losso, Gustavo Lopardo, Sergio Lupo, Norma Porteiro, Marisa Sánchez, Mark Bloch, David Cooper, Robert Finlayson, Anthony Kelleher, Kenneth Koh, David Lewis, James McMahon, Richard Moore, Norman Roth, Matthew Shields, Stephane De Wit, Eric Florence, Jean-Christophe Goffard, Remy Demeester, Patrick Lacor, Bernard Vandercam, Linos Vandekerckhove, Jonathan Angel, Jean-Guy Baril, Brian Conway, Alexandra De Pokomandy, Jason Szabo, Sharon Walmsley, Olivier Bouchaud, Christian Chidiac, Pierre Delobel, Cecile Goujard, Christine Katlama, Jean-Michel Molina, Gilles Pialoux, Patrick Philibert, Johannes Bogner, Stefan Esser, Ivanka Krznaric, Clara Lehmann, Christoph Spinner, Hans-Jurgen Stellbrink, Christoph Stephan, Albrecht Stoehr, Enrico Barchi, Pietro Caramello, Francesco Castelli, Anna Maria Cattelan, Antonella D'Arminio Monforte, Antonio Di Biagio, Giovanni Di Perri, Andrea Gori, Franco Maggiolo, Barbara Menzaghi, Guglielmo Migliorino, Cristina Mussini, Giovanni Penco, Massimo Puoti, Giuliano Rizzardini, Roberto Gulminetti, Adriano Lazzarin, Tiziano Quirino, Laura Sighinolfi, Pierluigi Viale, Gerardo Amaya Tapia, Jaime Andrade Villanueva, Enrique R Granados Reyes, Alma Perez Rios, Mario Santoscoy Gomez, Jan Den Hollander, Bart Rijnders, José A Hidalgo, Luis Hercilla Vasquez, Luis Illescas, Anita Olczak, Kamal Mansinho, Patricia Paula Correia Pacheco, Eugénio Teófilo, Jose Saraiva da Cunha, Rui Sarmento e Castro, Rosário Serrão, Manuela Arbune, Cristian Jianu, Anca Oprea, Liliana Preotescu, Liviu-Jany Prisacariu, Elena Belonosova, Olga Borodkina, Oxana Chernova, Natalia Gankina, Svetlana Kizhlo, Valeriy Kulagin, Nadezhda Kurina, Firaya Nagimova, Vadim Pokrovsky, Elena Ryamova, Evgeny Voronin, Alexey Yakovlev, Richard Kaplan, Sun Hee Lee, Shin-Woo Kim, Sang-Il Kim, Woo Joo Kim, Antonio Antela Lopez, Jose L Casado Osorio, Manuel A Castaño Carracedo, Ignacio De Los Santos Gil, Vicente Estrada Perez, Vicenç Falco Ferrer, Luis Force, Maria Jose Galinda Puerto, Miguel Garcia Deltoro, Josep M Gatell, Miguel A Goenaga Sanchez, Ana González Cordón, Hernando Knobel, Juan Carlos Lopez Bernaldo de Quiros, Juan E Losa Garcia, Mar Masia, Marta Montero-Alsonso, Antonio Ocampo Hermida, Juan Pasquau Liaño, Joaquin Portilla Sogorb, Federico Pulido Ortega, Antonio Rivera Roman, Jose Ramon Santos Fernandez, Rafael Torres Perea, Jesus Troya Garcia, Pompeyo Viciana Fernandez, Alexandra Calmy, Christoph Hauser, Jan Fehr, Shu-Hsing Cheng, Wen-Chien Ko, Hsi-Hsun Lin, Po-Liang Lu, Yu-Ting Tseng, Ning-Chi Wang, Wing-Wai Wong, Chia-Jui Yang, Roberto Arduino, Paul Benson, Mezgebe Berhe, Fritz Bredeek, Cynthia Brinson, Thomas Campbell, Gordon Crofoot, Douglas Cunningham, Edwin DeJesus, Robin Dretler, Joseph Eron, Kenneth Fife, Carl Fichtenbaum, Jason Flamm, Deborah Goldstein, Samir Gupta, Debbie Hagins, Margaret Hoffman-Terry, Dushyantha Jayaweera, Clifford Kinder, Daniel Klein, Cheryl McDonald, Anthony Mills, Ronald Nahass, Olayemi Osiyemi, Edgar Overton, David Parks, David Prelutsky, Moti Ramgopal, Shannon Schrader, Beverly Sha, Gary Simon, James Sims, Daniel Skiest, Jihad Slim, Karen Tashima, Blair Thedinger, Brian Gazzard, Julie Fox, Margaret Johnson, Stephen Kegg, Saye Khoo, Charles Mazhude, Chloe Orkin, Gabriel Schembri, Andrew Ustianowski, Clinical sciences, Microbiology and Infection Control, Internal Medicine, Cahn, P, Madero, J, Arribas, J, Antinori, A, Ortiz, R, Clarke, A, Hung, C, Rockstroh, J, Girard, P, Sievers, J, Man, C, Currie, A, Underwood, M, Tenorio, A, Pappa, K, Wynne, B, Fettiplace, A, Gartland, M, Aboud, M, Smith, K, Cassetti, L, David, D, Figueras, L, Losso, M, Lopardo, G, Lupo, S, Porteiro, N, Sanchez, M, Bloch, M, Cooper, D, Finlayson, R, Kelleher, A, Koh, K, Lewis, D, Mcmahon, J, Moore, R, Roth, N, Shields, M, De Wit, S, Florence, E, Goffard, J, Demeester, R, Lacor, P, Vandercam, B, Vandekerckhove, L, Angel, J, Baril, J, Conway, B, De Pokomandy, A, Szabo, J, Walmsley, S, Bouchaud, O, Chidiac, C, Delobel, P, Goujard, C, Katlama, C, Molina, J, Pialoux, G, Philibert, P, Bogner, J, Esser, S, Krznaric, I, Lehmann, C, Spinner, C, Stellbrink, H, Stephan, C, Stoehr, A, Barchi, E, Caramello, P, Castelli, F, Cattelan, A, D'Arminio Monforte, A, Di Biagio, A, Di Perri, G, Gori, A, Maggiolo, F, Menzaghi, B, Migliorino, G, Mussini, C, Penco, G, Puoti, M, Rizzardini, G, Gulminetti, R, Lazzarin, A, Quirino, T, Sighinolfi, L, Viale, P, Amaya Tapia, G, Andrade Villanueva, J, Granados Reyes, E, Perez Rios, A, Santoscoy Gomez, M, Den Hollander, J, Rijnders, B, Hidalgo, J, Hercilla Vasquez, L, Illescas, L, Olczak, A, Mansinho, K, Correia Pacheco, P, Teofilo, E, Saraiva da Cunha, J, Sarmento e Castro, R, Serrao, R, Arbune, M, Jianu, C, Oprea, A, Preotescu, L, Prisacariu, L, Belonosova, E, Borodkina, O, Chernova, O, Gankina, N, Kizhlo, S, Kulagin, V, Kurina, N, Nagimova, F, Pokrovsky, V, Ryamova, E, Voronin, E, Yakovlev, A, Kaplan, R, Lee, S, Kim, S, Kim, W, Antela Lopez, A, Casado Osorio, J, Castano Carracedo, M, De Los Santos Gil, I, Estrada Perez, V, Falco Ferrer, V, Force, L, Galinda Puerto, M, Garcia Deltoro, M, Gatell, J, Goenaga Sanchez, M, Gonzalez Cordon, A, Knobel, H, Lopez Bernaldo de Quiros, J, Losa Garcia, J, Masia, M, Montero-Alsonso, M, Ocampo Hermida, A, Pasquau Liano, J, Portilla Sogorb, J, Pulido Ortega, F, Rivera Roman, A, Santos Fernandez, J, Torres Perea, R, Troya Garcia, J, Viciana Fernandez, P, Calmy, A, Hauser, C, Fehr, J, Cheng, S, Ko, W, Lin, H, Lu, P, Tseng, Y, Wang, N, Wong, W, Yang, C, Arduino, R, Benson, P, Berhe, M, Bredeek, F, Brinson, C, Campbell, T, Crofoot, G, Cunningham, D, Dejesus, E, Dretler, R, Eron, J, Fife, K, Fichtenbaum, C, Flamm, J, Goldstein, D, Gupta, S, Hagins, D, Hoffman-Terry, M, Jayaweera, D, Kinder, C, Klein, D, Mcdonald, C, Mills, A, Nahass, R, Osiyemi, O, Overton, E, Parks, D, Prelutsky, D, Ramgopal, M, Schrader, S, Sha, B, Simon, G, Sims, J, Skiest, D, Slim, J, Tashima, K, Thedinger, B, Gazzard, B, Fox, J, Johnson, M, Kegg, S, Khoo, S, Mazhude, C, Orkin, C, Schembri, G, and Ustianowski, A

Subjects
Male, HIV Dolutegravir, HIV Infections, 030204 cardiovascular system & hematology, Piperazines, chemistry.chemical_compound, 0302 clinical medicine, Abacavir, Heterocyclic Compounds, Emtricitabine, 030212 general & internal medicine, Viral, Tenofovir/adverse effects, Lamivudine/adverse effects, Medicine(all), education.field_of_study, Adult, Anti-HIV Agents, Anti-Retroviral Agents, Double-Blind Method, Drug Therapy, Combination, Female, HIV-1, Heterocyclic Compounds, 3-Ring, Humans, Lamivudine, Middle Aged, RNA, Viral, Tenofovir, Viral Load, Heterocyclic Compounds, 3-Ring/adverse effects, General Medicine, Emtricitabine/adverse effects, Tolerability, Dolutegravir, Combination, medicine.drug, medicine.medical_specialty, Pyridones, Population, HIV Infections/drug therapy, Anti-Retroviral Agents/adverse effects, 3-Ring, 03 medical and health sciences, Drug Therapy, SDG 3 - Good Health and Well-being, Internal medicine, Oxazines, medicine, HIV-1/isolation & purification, RNA, Viral/blood, education, business.industry, Viral Load/drug effects, Regimen, chemistry, RNA, Anti-HIV Agents/adverse effects, Ritonavir, business
Abstract

Summary Background Effective two-drug regimens could decrease long-term drug exposure and toxicity with HIV-1 antiretroviral therapy (ART). We therefore aimed to evaluate the efficacy and safety of a two-drug regimen compared with a three-drug regimen for the treatment of HIV-1 infection in ART-naive adults. Methods We conducted two identically designed, multicentre, double-blind, randomised, non-inferiority, phase 3 trials: GEMINI-1 and GEMINI-2. Both studies were done at 192 centres in 21 countries. We included participants (≥18 years) with HIV-1 infection and a screening HIV-1 RNA of 500 000 copies per mL or less, and who were naive to ART. We randomly assigned participants (1:1) to receive a once-daily two-drug regimen of dolutegravir (50 mg) plus lamivudine (300 mg) or a once-daily three-drug regimen of dolutegravir (50 mg) plus tenofovir disoproxil fumarate (300 mg) and emtricitabine (200 mg). Both drug regimens were administered orally. We masked participants and investigators to treatment assignment: dolutegravir was administered as single-entity tablets (similar to its commercial formulation, except with a different film colour), and lamivudine tablets and tenofovir disoproxil fumarate and emtricitabine tablets were over-encapsulated to visually match each other. Primary endpoint was the proportion of participants with HIV-1 RNA of less than 50 copies per mL at week 48 in the intention-to-treat-exposed population, using the Snapshot algorithm and a non-inferiority margin of −10%. Safety analyses were done on the safety population. GEMINI-1 and GEMINI-2 are registered with ClinicalTrials.gov, numbers NCT02831673 and NCT02831764, respectively. Findings Between July 18, 2016, and March 31, 2017, 1441 participants across both studies were randomly assigned to receive either the two-drug regimen (n=719) or three-drug regimen (n=722). At week 48 in the GEMINI-1 intention-to-treat-exposed population, 320 (90%) of 356 participants receiving the two-drug regimen and 332 (93%) of 358 receiving the three-drug regimen achieved plasma HIV-1 RNA of less than 50 copies per mL (adjusted treatment difference −2·6%, 95% CI −6·7 to 1·5); in GEMINI-2, 335 (93%) of 360 in the two-drug regimen and 337 (94%) of 359 in the three-drug regimen achieved HIV-1 RNA of less than 50 copies per mL (adjusted treatment difference −0·7%, 95% CI −4·3 to 2·9), showing non-inferiority at a −10% margin in both studies (pooled analysis: 655 [91%] of 716 in the two-drug regimen vs 669 [93%] of 717 in the three-drug regimen; adjusted treatment difference −1·7%, 95% CI −4·4 to 1·1). Numerically, more drug-related adverse events occurred with the three-drug regimen than with the two-drug regimen (169 [24%] of 717 vs 126 [18%] of 716); few participants discontinued because of adverse events (16 [2%] in the three-drug regimen and 15 [2%] in the two-drug regimen). Two deaths were reported in the two-drug regimen group of GEMINI-2, but neither was considered to be related to the study medication. Interpretation The non-inferior efficacy and similar tolerability profile of dolutegravir plus lamivudine to a guideline-recommended three-drug regimen at 48 weeks in ART-naive adults supports its use as initial therapy for patients with HIV-1 infection. Funding ViiV Healthcare.

Published
2019

7. Long-acting cabotegravir and rilpivirine dosed every 2 months in adults with HIV-1 infection (ATLAS-2M), 48-week results: a randomised, multicentre, open-label, phase 3b, non-inferiority study.

Author

Overton ET, Richmond G, Rizzardini G, Jaeger H, Orrell C, Nagimova F, Bredeek F, García Deltoro M, Swindells S, Andrade-Villanueva JF, Wong A, Khuong-Josses MA, Van Solingen-Ristea R, van Eygen V, Crauwels H, Ford S, Talarico C, Benn P, Wang Y, Hudson KJ, Chounta V, Cutrell A, Patel P, Shaefer M, Margolis DA, Smith KY, Vanveggel S, and Spreen W

Subjects
Adult, Alanine Transaminase blood, Anti-HIV Agents adverse effects, Anti-HIV Agents blood, Delayed-Action Preparations, Drug Administration Schedule, Drug Therapy, Combination, Female, Humans, Injections, Intramuscular, Male, Middle Aged, Pyridones adverse effects, Pyridones blood, RNA, Viral blood, Rilpivirine adverse effects, Rilpivirine blood, Viral Load, Anti-HIV Agents administration & dosage, HIV Infections drug therapy, HIV-1, Pyridones administration & dosage, Rilpivirine administration & dosage
Abstract

Background: Phase 3 clinical studies showed non-inferiority of long-acting intramuscular cabotegravir and rilpivirine dosed every 4 weeks to oral antiretroviral therapy. Important phase 2 results of every 8 weeks dosing, and supportive modelling, underpin further evaluation of every 8 weeks dosing in this trial, which has the potential to offer greater convenience. Our objective was to compare the week 48 antiviral efficacy of cabotegravir plus rilpivirine long-acting dosed every 8 weeks with that of every 4 weeks dosing., Methods: ATLAS-2M is an ongoing, randomised, multicentre (13 countries; Australia, Argentina, Canada, France, Germany, Italy, Mexico, Russia, South Africa, South Korea, Spain, Sweden, and the USA), open-label, phase 3b, non-inferiority study of cabotegravir plus rilpivirine long-acting maintenance therapy administered intramuscularly every 8 weeks (cabotegravir 600 mg plus rilpivirine 900 mg) or every 4 weeks (cabotegravir 400 mg plus rilpivirine 600 mg) to treatment-experienced adults living with HIV-1. Eligible newly recruited individuals must have received an uninterrupted first or second oral standard-of-care regimen for at least 6 months without virological failure and be aged 18 years or older. Eligible participants from the ATLAS trial, from both the oral standard-of-care and long-acting groups, must have completed the 52-week comparative phase with an ATLAS-2M screening plasma HIV-1 RNA less than 50 copies per mL. Participants were randomly assigned 1:1 to receive cabotegravir plus rilpivirine long-acting every 8 weeks or every 4 weeks. The randomisation schedule was generated by means of the GlaxoSmithKline validated randomisation software RANDALL NG. The primary endpoint at week 48 was HIV-1 RNA ≥50 copies per mL (Snapshot, intention-to-treat exposed), with a non-inferiority margin of 4%. The trial is registered at ClinicalTrials.gov, NCT03299049 and is ongoing., Findings: Screening occurred between Oct 27, 2017, and May 31, 2018. Of 1149 individuals screened, 1045 participants were randomised to the every 8 weeks (n=522) or every 4 weeks (n=523) groups; 37% (n=391) transitioned from every 4 weeks cabotegravir plus rilpivirine long-acting in ATLAS. Median participant age was 42 years (IQR 34-50); 27% (n=280) female at birth; 73% (n=763) white race. Cabotegravir plus rilpivirine long-acting every 8 weeks was non-inferior to dosing every 4 weeks (HIV-1 RNA ≥50 copies per mL; 2% vs 1%) with an adjusted treatment difference of 0·8 (95% CI -0·6-2·2). There were eight (2%, every 8 weeks group) and two (<1%, every 4 weeks group) confirmed virological failures (two sequential measures ≥200 copies per mL). For the every 8 weeks group, five (63%) of eight had archived non-nucleoside reverse transcriptase inhibitor resistance-associated mutations to rilpivirine at baseline. The safety profile was similar between dosing groups, with 844 (81%) of 1045 participants having adverse events (excluding injection site reactions); no treatment-related deaths occurred., Interpretation: The efficacy and safety profiles of dosing every 8 weeks and dosing every 4 weeks were similar. These results support the use of cabotegravir plus rilpivirine long-acting administered every 2 months as a therapeutic option for people living with HIV-1., Funding: ViiV Healthcare and Janssen., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Published
2021
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8. Ombitasvir, paritaprevir co-dosed with ritonavir, dasabuvir, and ribavirin for hepatitis C in patients co-infected with HIV-1: a randomized trial.

Author

Sulkowski MS, Eron JJ, Wyles D, Trinh R, Lalezari J, Wang C, Slim J, Bhatti L, Gathe J, Ruane PJ, Elion R, Bredeek F, Brennan R, Blick G, Khatri A, Gibbons K, Hu YB, Fredrick L, Schnell G, Pilot-Matias T, Tripathi R, Da Silva-Tillmann B, McGovern B, Campbell AL, and Podsadecki T

Subjects
2-Naphthylamine, Adult, Anilides adverse effects, Carbamates adverse effects, Coinfection, Cyclopropanes, Drug Therapy, Combination, Female, HIV Infections complications, HIV-1, Hepacivirus genetics, Hepatitis C complications, Humans, Lactams, Macrocyclic, Macrocyclic Compounds adverse effects, Male, Middle Aged, Pilot Projects, Proline analogs & derivatives, Ribavirin adverse effects, Ritonavir adverse effects, Sulfonamides adverse effects, Treatment Outcome, Uracil administration & dosage, Uracil adverse effects, Valine, Anilides administration & dosage, Antiviral Agents administration & dosage, Carbamates administration & dosage, HIV Infections drug therapy, Hepatitis C drug therapy, Macrocyclic Compounds administration & dosage, Ribavirin administration & dosage, Ritonavir administration & dosage, Sulfonamides administration & dosage, Uracil analogs & derivatives
Abstract

Importance: Patients co-infected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) are at high risk for liver disease progression. However, interferon-based treatments for HCV infection have significant toxicities, limiting treatment uptake., Objective: To assess the all-oral 3 direct-acting antiviral (3D) regimen of ombitasvir, paritaprevir (co-dosed with ritonavir [paritaprevir/r]), dasabuvir, and ribavirin in HCV genotype 1-infected adults with HIV-1 co-infection, including patients with cirrhosis., Design, Setting, and Participants: TURQUOISE-I is a randomized, open-label study. Part 1a of this pilot study was conducted at 17 sites in the United States and Puerto Rico between September 2013 and August 2014 and included 63 patients with HCV genotype 1 and HIV-1 co-infection who were HCV treatment-naive or had history of prior treatment failure with peginterferon plus ribavirin therapy. The study allowed enrollment of patients, including those with cirrhosis, with a CD4+ count of 200/mm3 or greater or CD4+ percentage of 14% or more and plasma HIV-1 RNA suppressed while taking a stable atazanavir- or raltegravir-inclusive antiretroviral regimen., Interventions: Ombitasvir/paritaprevir/r, dasabuvir, and ribavirin for 12 or 24 weeks of treatment as randomized., Main Outcomes and Measures: The primary assessment was the proportion of patients with sustained virologic response (HCV RNA <25 IU/mL) at posttreatment week 12 (SVR12)., Results: Among patients receiving 12 or 24 weeks of 3D and ribavirin, SVR12 was achieved by 29 of 31 (94%; 95% CI, 79%-98%) and 29 of 32 patients (91%; 95% CI, 76%-97%), respectively. Of the 5 patients who did not achieve SVR, 1 withdrew consent, 2 had confirmed virologic relapse or breakthrough, and 2 patients had clinical history and phylogenetic evidence consistent with HCV reinfection. The most common treatment-emergent adverse events were fatigue (48%), insomnia (19%), nausea (18%), and headache (16%). Adverse events were generally mild, with none reported as serious or leading to discontinuation. No patient had a confirmed HIV-1 breakthrough of 200 copies/mL or greater during treatment., Conclusions and Relevance: In this open-label, randomized uncontrolled study, treatment with the all-oral, interferon-free 3D-plus-ribavirin regimen resulted in high SVR rates among patients co-infected with HCV genotype 1 and HIV-1 whether treated for 12 or 24 weeks. Further phase 3 studies of this regimen are warranted in patients with co-infection., Trial Registration: clinicaltrials.gov Identifier: NCT01939197.

Published
2015
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9. Switch to Stribild versus continuation of NVP or RPV with FTC and TDF in virologically suppressed HIV adults: a STRATEGY-NNRTI subgroup analysis.

Author

Stellbrink HJ, Antinori A, Pozniak A, Flamm J, Bredeek F, Patel K, Garner W, and Piontkowsky D

Abstract

Introduction: Switch to Stribild (STB) was non-inferior to continuation of a non-nucleoside reverse transcriptase inhibitor (NNRTI) with emtricitabine and tenofovir DF (FTC/TDF) at week 48 in virologically suppressed HIV adults (1). We report the Week 48 efficacy and safety of STB versus nevirapine (NVP) or rilpivirine (RPV) with FTC/TDF in suppressed subjects., Materials and Methods: Virologically suppressed subjects on an NNRTI with FTC/TDF regimens for ≥6 months were randomized (2:1) to switch to STB versus continue their NNRTI regimen. Eligibility criteria included no documented resistance to FTC and TDF, no history of virologic failure and eGFR ≥70 mL/min. The primary endpoint was the proportion of subjects in the modified ITT population who maintained HIV-1 RNA <50 copies(c)/mL at Week 48 by FDA snapshot algorithm (12% non-inferiority margin). Subgroup analysis by non-EFV NNRTI use (NVP [74]; RPV [19]; etravirine [3]) at screening was pre-specified., Results: The mITT population included 433 subjects who were randomized and treated. In the non-EFV NNRTI subgroup, 59 switched to STB; 37 continued a non-EFV NNRTI (27 NVP, 10 RPV) with FTC/TDF. At week 48, 97% STB versus 95% non-EFV NNRTI maintained HIV-1 RNA <50 c/mL. No emergent resistance was detected in either group. No difference in median increases from baseline in CD4 count at week 48 (cells/µL): 25 STB versus 55 non-EFV NNRTI (p=0.78). No discontinuation due to adverse events; no cases of proximal renal tubulopathy. As expected, there were no significant changes in the frequency of neuropsychiatric symptoms (i.e. anxiety, insomnia, dizziness, vivid dreams, weird/intense dreams, and nightmares) reported on the HIV Symptom Index at week 48 compared to baseline after switching to STB. There was a greater but non-progressive decrease from baseline in eGFR in the STB versus non-EFV NNRTI group; median changes (mL/min) at week 48: -9.1 versus -1.4. Switch to STB was associated with a higher treatment ease (convenience, flexibility, demand, lifestyle, understanding) score (range: -15 to 15) at week 4 (median: 14 vs 11; p=0.047) and week 24 (median: 14 vs 12.5; p=0.038)., Conclusions: In this small group of virologically suppressed subjects, switch to STB vs continuation of NVP or RPV with FTC/TDF was safe, well-tolerated, and associated with a high rate of virologic suppression at week 48. There was more treatment ease with STB use.

Published
2014
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10. Role of GB virus C in HIV-1-infected and hepatitis C virus-infected hemophiliac children and adolescents.

Author

Tenckhoff S, Kaiser T, Bredeek F, Donfield S, Menius E, Lail A, Mössner J, Daar ES, and Tillmann HL

Subjects
Adolescent, Child, Cohort Studies, Female, HIV Infections pathology, Hepatitis, Viral, Human virology, Humans, Male, Prevalence, RNA, Viral blood, Real-Time Polymerase Chain Reaction, Young Adult, GB virus C isolation & purification, HIV Infections complications, Hemophilia A complications, Hepatitis C, Chronic complications, Hepatitis, Viral, Human epidemiology
Abstract

Background: GB Virus C (GBV-C) has been associated with a better prognosis of HIV-1 disease in adults. Little is known about prevalence and interaction between GBV-C, HIV-1, and/or hepatitis C virus (HCV) in hemophiliac children and adolescents., Methods: A well-characterized cohort of HIV-1-infected and HIV-1-uninfected hemophiliac children and adolescents followed in the Hemophilia Growth and Development Study (HGDS) were evaluated using quantitative reverse transcription polymerase chain reaction to detect GBV-C RNA in samples from baseline and last follow-up visit., Results: HIV-1-infected (n = 202) and HIV-1-uninfected (n = 119) patients had a low prevalence of GBV-C infection at baseline (0.9 and 0%), which increased at time of last follow-up visit to 25.2% and 26.3%, respectively. In addition, at the time of the follow-up GBV-C measurement, those GBV-C infected had been followed longer and had higher CD4(+) cell counts and lower HIV-1 viral loads than those GBV-C uninfected. These beneficial effects of GBV-C were no longer significant after controlling for CD4(+) cell count and HIV-1 RNA at baseline. HCV RNA clearance was more common amongst those who were not GBV-C infected than those who became GBV-C viremic., Conclusions: This study confirms a positive association of GBV-C with milder course of HIV-1 infection. GBV-C infection was associated with a higher likelihood of persistent HCV infection.

Published
2012
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