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1. Pharmacokinetics of tenofovir during pregnancy and postpartum

Author

Best, BM, Burchett, S, Li, H, Stek, A, Hu, C, Wang, J, Hawkins, E, Byroads, M, Watts, DH, Smith, E, Fletcher, CV, Capparelli, EV, Mirochnick, M, Aweeka, F, Chotivanich, N, Cressey, TR, Frenkel, LM, Gupta, A, Jennings, A, Jourdain, G, Kreitchmann, R, Patel, R, Rungruengthanakit, K, Shapiro, D, Sukrakanchana, PO, Kovacs, A, Homans, J, Spencer, LS, Kramer, F, Buschur, S, Hammill, H, Paul, ME, McMullen-Jackson, C, Melvin, A, Venema-Weiss, C, Lane, J, Hitti, J, Knapp, K, Edwin Thorpe, ET, Utech, LJ, Sublette, N, Wara, D, Cohan, D, Tilton, N, Vachon, ME, Baig, MM, Purswani, MU, Gutierrez, J, Luzuriaga, K, Cormier, S, McManus, M, Hull, A, Caffery, M, Norris, K, Spector, SA, Keller, MA, Ballagh, S, Hayes, J, Gonzalez, Y, Barr, E, Kennedy, T, Katai, A, Wallace, J, McAuley, JB, Cejtin, H, McNichols, M, Schmidt, J, Watson, D, Ference, J, Hilyard, C, Crain, M, Simpson, TY, Tita, ATN, Febo, IL, Zorrilla, CD, Tamayo-Agrait, V, and Santos, R

Subjects
Clinical Sciences, Virology
Abstract

Tenofovir disoproxil fumarate (TDF) is increasingly used in the highly active antiretroviral therapy (HAART) regimens of pregnant women, but limited data exist on the pregnancy pharmacokinetics of chronically dosed TDF. This study described tenofovir pharmacokinetics during pregnancy and postpartum. Methods: International Maternal Pediatric and Adolescent AIDS Clinical Trials (IMPAACT) P1026s is a prospective, nonblinded pharmacokinetic study of HIV-infected pregnant women that included a cohort receiving 300mg TDF once daily. Steady-state 24-hour pharmacokinetic profiles were measured at the second and third trimesters, postpartum, and in maternal and umbilical cord samples collected at delivery. Tenofovir was measured by liquid chromatography-mass spectrometry (LC-MS). The target area under the concentration versus time curve from time 0 to 24h post dose (AUC) was ≥1.99μg h/mL (nonpregnant historical control 10th percentile). Results: The median tenofovir AUC was decreased during the second (1.9μg h/mL) and third (2.4μg h/mL; P=0.005) trimesters versus postpartum (3.0μg h/mL). Tenofovir AUC exceeded the target for two of four women (50%) in the second trimester, 27 of 37 women [73%; 95% confidence interval (CI) 56%, 86%] in the third trimester, and 27 of 32 women (84%; 95% CI 67%, 95%) postpartum (P>0.05). Median second/third-trimester troughs were lower (39/54ng/mL) than postpartum (61ng/mL). Median third-trimester weight was greater for subjects below the target AUC versus those above the target (97.9 versus 74.2kg, respectively; P=0.006). The median ratio of cord blood to maternal concentrations was 0.88. No infants were HIV infected. Conclusions: This study found lower tenofovir AUC and troughs during pregnancy. Transplacental passage with chronic TDF use during pregnancy was high. Standard TDF doses appear to be appropriate for most HIV-infected pregnant women but therapeutic drug monitoring with dose adjustment should be considered in pregnant women with high weight (>90kg) or inadequate HIV RNA response.

Published
2015

7. Predictors of faster virological suppression in early treated infants with perinatal HIV from Europe and Thailand

Author

Chan, M. K., Goodall, R., Judd, A., Klein, N., Chiappini, E., Klimkait, T., Ngo-Giang-Huong, Nicole, Palma, P., Rossi, P., Thorne, C., Turkova, A., Zangari, P., Rojo, P., Babiker, A. G. A., Fraaij, P. L., Pajkrt, D., Marques, L., Collins, I. J., Gibb, D. M., Gonzalez-Tome, M. I., Ramos, J. T., Navarro, M. L., Noguera-Julian, A., Warszawski, J., Konigs, C., Spoulou, V., Prata, F., Goetghebuer, T., Galli, L., Naver, L., Giaquinto, C., Marczynska, M., Okhonskaia, L., Malyuta, R., Volokha, A., Ene, L., Gibb, D., Watters, S., Chan, M., McCoy, L., Babiker, A., Marcelin, A. G., Calvez, V., Munoz, M. A., Wahren, B., Foster, C., Cotton, M., Robb, M., Ananworanich, J., Claiden, P., Pillay, D., Persaud, D., De Boer, R. J., Schroter, J., Anelone, A. J. N., Puthanakit, T., Ceci, A., Giannuzzi, V., Luzuriaga, K., Chomont, N., Cameron, M., Cancrini, C., Yates, A., Kuhn, L., Violari, A., Otwombe, K., Pepponi, I., Rocchi, F., Rinaldi, S., Tagarro, A., Lain, M. G., Vaz, P., Lopez, E., Nhampossa, T., EPPICC study group, and EPIICAL study groups

Subjects
early combination antiretroviral therapy, predictors, infants, perinatal HIV, virological suppression
Abstract

Objective: To identify predictors of faster time to virological suppression among infants starting combination antiretroviral therapy (cART) early in infancy. Design: Cohort study of infants from Europe and Thailand included in studies participating in the European Pregnancy and Paediatric HIV Cohort Collaboration. Methods: Infants with perinatal HIV starting cART aged less than 6 months with at least 1 viral load measurement within 15 months of cART initiation were included. Multi-variable interval-censored flexible parametric proportional hazards models were used to assess predictors of faster virological suppression, with timing of suppression assumed to lie in the interval between last viral load at least 400 and first viral load less than 400 copies/ml. Results: Of 420 infants, 59% were female and 56% from Central/Western Europe, 26% United Kingdom/Ireland, 15% Eastern Europe and 3% Thailand; 46 and 54% started a boosted protease inhibitor-based or nonnucleoside reverse transcriptase inhibitor-based regimen, respectively. At cART initiation, the median age, CD4(+) % and viral load were 2.9 [interquartile range (IQR): 1.4-4.1] months, 34 (IQR: 24-45)% and 5.5 (IQR: 4.5-6.0) log(10) copies/ml, respectively. Overall, an estimated 89% (95% confidence interval: 86-92%) achieved virological suppression within 12 months of cART start. In multivariable analysis, younger age [adjusted hazard ratio (aHR): 0.84 per month older; P < 0.001], higher CD4(+) % (aHR: 1.11 per 10% higher; P=0.010) and lower log(10) viral load (aHR: 0.85 per log(10) higher; P < 0.001) at cART initiation independently predicted faster virological suppression. Conclusion: We observed a significant independent effect of age at cART initiation, even within a narrow 6 months window from birth. These findings support the earliest feasible cART initiation in infants and suggest that early therapy influences key virological and immunological parameters that could have important consequences for long-term health.

Published
2019

10. Duration of ruptured membranes and vertical transmission of HIV-1: a meta-analysis from 15 prospective cohort studies

Author

Bulterys, M. B., Fowler, M. G., Hanson, I. C., Lemay, M., Mayaux, M. J., Mofenson, L., Newell, M. -L., Peavy, H., Peckham, C., Read, J. S., Rother, C., Simpson, B. J., Van Dyke, R. B., Harris, D. R., Peavy, H. H., Easley, K., Khammy, A., Nugent, R. P., Mitchell, R., Owen, W., Van Dyke, R., Widmayer, S., Bardeguez, A., Hanson, C., Wiznia, A., Luzuriaga, K., Viscarello, R., Ho, D., Koup, R., Chen, I., Krogstad, P., Mullins, J., Wolinsky, S., Korber, B., Walker, B., Ammann, A., Clapp, S., Mcdonald, D., Lapointe, N., Boucher, M., Fauvel, M., Hankins, C., Samson, J., Newell, M. L., Peckham, C. S., Thorne, C. N., Giaquinto, C., Ruga, E., De Rossi, A., Truscia, D., Grosch-Worner, I., Schafer, A., Mok, J., Johnstone, F., Jiminez, J., de Alba, C., Garcia Rodriguez, M. C., Bates, I., de Josee, I., Hawkins, F., Martinez Zapico, R., Pena, J. M., Gonzalez Garcia, J., Arribas Lopez, J. R., Asensi-Botet, F., Otero, M. C., Peerez-Tamarit, D., Moya, A., Galbis, M. J., Scherpbier, H., Boer, K., Bohlin, A. B., Lindgren, S., Anzen, B., Belfrage, E., Lidin-Jansson, G., Levy, J., Barlow, P., Hainaut, M., Peltier, A., Ferrazin, A., De Maria, A., Gotta, C., Mur, A., Vinolas, M., Paya, A., Loepez-Vilchez, M. A., Coll, O., Fortuny, C., Boguna, J., Casellas Caro, M., Canet, Y., Pardi, G., Ravizza, M., Semprini, E., Castagna, C., Fiore, S., Guerra, B., Lanari, M., Bianchi, S., Bovicelli, L., Prati, E., Zanelli, S., Duse, M., Soresina, A., Scaravelli, G., Stegagno, M., De Santis, M., Muggiasca, M. L., Vigano, A., Spinillo, A., Ravagni Probizer, F., Bucceri, A., Rancilio, L., Taylor, G. P., Lyall, H., Penn, Z., Blott, M., Valerius, N. H., Martinelli, P., Buffolano, W., Tibaldi, C., Ziarati, N., Semprini, A., Della Torre, M., Parazzini, F., Dallacasa, P., Bianchi, U., Pachi, A., Mancuso, S., Villa, P., Conti, M., Principi, N., Muggiasca, M., Marchisio, P., Zara, C., Ravagni, F., Vignali, M., Rossi, G., Selvaggi, L., Greco, P., Vimercati, A., Massi, G., Innocenti, T., Fiscella, A., Sansone, M., Benedetto, C., Tadrist, B., Thevenieau, D., Gondry, J., Paulard, B., Alisy, C., Brault, D., Tordjeman, N., Mamou, J., Rozan, M., Colombani, D., Pincemaille, O., Salvetti, A., Chabanier, C., Hernandorena, X., Leroy, J., Schaal, J., Balde, P., Faucher, P., Lachassinne, E., Benoit, S., Douard, D., Hocke, C., Barjot, P., Brouard, J., Delattre, P., Stien, L., Audibert, F., Labrune, P., Vial, M., Mazy, F., Sitbon, D., Crenn-Hebert, C., Floch-Tudal, C., Akakpo, R., Daveau, C., Leblanc, A., Cesbron, P., Duval-Arnould, M., Huraux-Rendu, C., Lemerle, S., Touboul, C., Guerin, M., Maingueneau, C., Reynaud, I., Rousseau, T., Ercoil, V., Lanza, M., Denavit, M., Garnier, J., Lahsinat, K., Pia, P., Allouche, C., Nardou, M., Grall, F., May, A., Dallot, M., Lhuillier, P., Cecile, W., Mezin, R., Bech, A., Lobut, J., Algava, G., Chalvon Dermesay, A., Busuttil, R., Jacquemot, M., Bader-Meunier, B., Fridman, S., Codaccioni, X., Maxingue, F., Thomas, D., Alain, J., De Lumley, L., Tabaste, J., Bailly Salin, P., Seaume, H., Guichard, A., Kebaill, K., Roussouly, C., Botto, C., De Lanete, A., Wipff, P., Cravello, L., De Boisse, P., Leclaire, M., Michel, G., Crumiere, C., Lefevre, V., Le Lorier, B., Pauly, I., Robichez, B., Seguy, D., Delhinger, M., Rideau, F., Talon, P., Benos, P., Huret, C., Nicolas, J., Heller-Roussin, B., Saint-Leger, S., Delaporte, M., Hubert, C., De Sarcus, B., Karoubi, P., Mechinaud, F., Bertcrottiere, D., Bongain, A., Monpoux, F., De Gennes, C., Devianne, F., Nisand, I., Rousset, M., Mouchnino, G., Muray, J., Munzer, M., Quereux, C., Brossard, V., Clavier, B., Allemon, M., Rotten, D., Stephan, J., Varlet, M., Guyot, B., Narcy, P., Bardinet, F., De Caunes, F., Jeny, R., Robin, M., Raison Boulley, A., Savey, L., Berrebi, A., Tricoire, J., Borderon, J., Fignon, A., Guillot, F., Maria, B., Broyard, A., Chitrit, Y., Firtion, G., Mandelbrot, L., Lafay Pillet, M., Parat, S., Boissinot, C., Garec, N., Levine, M., Ottenwalter, A., Schaller, F., Vilmer, E., Courpotin, C., Brunner, C., Ciraru-Vigneron, N., Hatem-Gantzer, G., Fritel, X., Wallet, A., Bouille, J., Milliez, J., Bensaid Mrejen, D., Dermer, E., Noseda, G., Bardou, D., Cressaty, J., Francoual, C., Carlus Moncomble, C., Cohen, H., Blanche, S., Bastion, H., Benifla, J., Benkhatar, F., Berkane, N., Hervee, F., Ronzier, M., Mayaux, Mj., de Martino, M., Tovo, P. -A., Galli, L., Gabiano, C., Ferraris, G., Garetto, S., Palomba, E., Riva, C., Vierucci, A., de Luca, M., Farina, S., Fundaro, C., Genovese, O., Mereu, G., Forni, G. L., Casadei, A., Zuccotti, G. V., Riva, E., Cellini, M., Baraldi, C., Consolini, R., Palla, G., Ruggeri, M., Ciccimarra, F., Guarino, A., Osimani, P., Benaglia, G., Romano, A., De Mattia, D., Caselli, D., Boni, S., Dell'Erba, G., Bassanetti, F., Sticca, M., Timpano, C., Magnani, C., Salvatore, C., Lipreri, R., Tornaghi, R., Pinzani, R., Cecchi, M. T., Bezzi, T., Battisti, L., Bresciani, E., Castelli Gattinara, G., Nasi, C., Pellegatta, A., Mazza, A., Baldi, F., Altobelli, R., Deiana, M., Colnaghi, C., Tarallo, L., Tondo, U., Anastasio, E., Chiriaco, P. G., Ruggeri, C., Scott, G., Hutto, C., O'Sullivan, M., Malmsberry, A., Willoughby, A., Burns, D., Goedert, J., Landesman, S., Minkoff, H., Mendez, H., Holman, S., Rubinstein, A., Durako, S., Muenz, L., Goodwin, S., Bryson, Y., Dillon, M., Nielsen, K., Boyer, P., Liao, D., Keller, M., Deveikis, A., Nesheim, S., Lindsay, M., Lee, F., Nahmias, A., Sawyer, M., Vink, P., Farley, J., Alger, L., Abrams, E., Bamji, M., Lambert, G., Schoenbaum, E., Thomas, P., Weedon, J., Palumbo, P., Denny, T., Oleske, J., Bulterys, M., Simonds, R., Ethier-Ives, J., Rogers, M., Schluchter, M., Kutner, M., Kaplan, S., Kattan, M., Lipshultz, S., Mellins, R., Shearer, W., Sopko, G., Sloand, E., Wu, M., Kind, C., Nadal, D., Rudin, C., Siegrist, C. -A., Wyler, C. -A., Cheseaux, J. -J., Aebi, C., Gnehm, H., Schubiger, G., Klingler, J., Hunziker, U., Kuchler, H., Gianinazzi, M., Buhlmann, U., Biedermann, K., Lauper, U., Irion, O., Brunelli, A., Spoletini, G., Schreyer, A., Hosli, I., Saurenmann, E., Drack, G., Isenschmid, M., Poorbeik, M., Schupbach, J., Perrin, L., Erb, P., Joller, H., Kovacs, A., Stek, A., Chan, L., Khoury, M., Diaz, C., Pacheco-Acosta, E., Tuomala, R., Cooper, E., Mesthene, D., Pitt, J., Higgins, A., Moroso, G., Rich, K., Turpin, D., Cooper, N., Davenny, K., Thompson, B., Andiman, W., Simpson, J., THE INTERNATIONAL PERINATAL HIV, Group, Martinelli, Pasquale, Bulterys M.B., Fowler M.G., Hanson I.C., Lemay M., Mayaux M.J., Mofenson L., Newell M.-L., Peavy H., Peckham C., Read J.S., Rother C., Simpson B.J., Van Dyke R.B., Harris D.R., Peavy H.H., Easley K., Khammy A., Nugent R.P., Mitchell R., Owen W., Van Dyke R., Widmayer S., Bardeguez A., Hanson C., Wiznia A., Luzuriaga K., Viscarello R., Ho D., Koup R., Chen I., Krogstad P., Mullins J., Wolinsky S., Korber B., Walker B., Ammann A., Clapp S., McDonald D., Lapointe N., Boucher M., Fauvel M., Hankins C., Samson J., Newell M.L., Peckham C.S., Thorne C.N., Giaquinto C., Ruga E., De Rossi A., Truscia D., Grosch-Worner I., Schafer A., Mok J., Johnstone F., Jiminez J., de Alba C., Garcia Rodriguez M.C., Bates I., de Josee I., Hawkins F., Martinez Zapico R., Pena J.M., Gonzalez Garcia J., Arribas Lopez J.R., Asensi-Botet F., Otero M.C., Peerez-Tamarit D., Moya A., Galbis M.J., Scherpbier H., Boer K., Bohlin A.B., Lindgren S., Anzen B., Belfrage E., Lidin-Jansson G., Levy J., Barlow P., Hainaut M., Peltier A., Ferrazin A., De Maria A., Gotta C., Mur A., Vinolas M., Paya A., Loepez-Vilchez M.A., Coll O., Fortuny C., Boguna J., Casellas Caro M., Canet Y., Pardi G., Ravizza M., Semprini E., Castagna C., Fiore S., Guerra B., Lanari M., Bianchi S., Bovicelli L., Prati E., Zanelli S., Duse M., Soresina A., Scaravelli G., Stegagno M., De Santis M., Muggiasca M.L., Vigano A., Spinillo A., Ravagni Probizer F., Bucceri A., Rancilio L., Taylor G.P., Lyall H., Penn Z., Blott M., Valerius N.H., Martinelli P., Buffolano W., Tibaldi C., Ziarati N., Semprini A., Della Torre M., Parazzini F., Dallacasa P., Bianchi U., Pachi A., Mancuso S., Villa P., Conti M., Principi N., Muggiasca M., Marchisio P., Zara C., Ravagni F., Vignali M., Rossi G., Selvaggi L., Greco P., Vimercati A., Massi G., Innocenti T., Fiscella A., Sansone M., Benedetto C., Tadrist B., Thevenieau D., Gondry J., Paulard B., Alisy C., Brault D., Tordjeman N., Mamou J., Rozan M., Colombani D., Pincemaille O., Salvetti A., Chabanier C., Hernandorena X., Leroy J., Schaal J., Balde P., Faucher P., Lachassinne E., Benoit S., Douard D., Hocke C., Barjot P., Brouard J., Delattre P., Stien L., Audibert F., Labrune P., Vial M., Mazy F., Sitbon D., Crenn-Hebert C., Floch-Tudal C., Akakpo R., Daveau C., Leblanc A., Cesbron P., Duval-Arnould M., Huraux-Rendu C., Lemerle S., Touboul C., Guerin M., Maingueneau C., Reynaud I., Rousseau T., Ercoil V., Lanza M., Denavit M., Garnier J., Lahsinat K., Pia P., Allouche C., Nardou M., Grall F., May A., Dallot M., Lhuillier P., Cecile W., Mezin R., Bech A., Lobut J., Algava G., Chalvon Dermesay A., Busuttil R., Jacquemot M., Bader-Meunier B., Fridman S., Codaccioni X., Maxingue F., Thomas D., Alain J., De Lumley L., Tabaste J., Bailly Salin P., Seaume H., Guichard A., Kebaill K., Roussouly C., Botto C., De Lanete A., Wipff P., Cravello L., De Boisse P., Leclaire M., Michel G., Crumiere C., Lefevre V., Le Lorier B., Pauly I., Robichez B., Seguy D., Delhinger M., Rideau F., Talon P., Benos P., Huret C., Nicolas J., Heller-Roussin B., Saint-Leger S., Delaporte M., Hubert C., De Sarcus B., Karoubi P., Mechinaud F., Bertcrottiere D., Bongain A., Monpoux F., De Gennes C., Devianne F., Nisand I., Rousset M., Mouchnino G., Muray J., Munzer M., Quereux C., Brossard V., Clavier B., Allemon M., Rotten D., Stephan J., Varlet M., Guyot B., Narcy P., Bardinet F., De Caunes F., Jeny R., Robin M., Raison Boulley A., Savey L., Berrebi A., Tricoire J., Borderon J., Fignon A., Guillot F., Maria B., Broyard A., Chitrit Y., Firtion G., Mandelbrot L., Lafay Pillet M., Parat S., Boissinot C., Garec N., Levine M., Ottenwalter A., Schaller F., Vilmer E., Courpotin C., Brunner C., Ciraru-Vigneron N., Hatem-Gantzer G., Fritel X., Wallet A., Bouille J., Milliez J., Bensaid Mrejen D., Dermer E., Noseda G., Bardou D., Cressaty J., Francoual C., Carlus Moncomble C., Cohen H., Blanche S., Bastion H., Benifla J., Benkhatar F., Berkane N., Hervee F., Ronzier M., Mayaux MJ., de Martino M., Tovo P.-A., Galli L., Gabiano C., Ferraris G., Garetto S., Palomba E., Riva C., Vierucci A., de Luca M., Farina S., Fundaro C., Genovese O., Mereu G., Forni G.L., Casadei A., Zuccotti G.V., Riva E., Cellini M., Baraldi C., Consolini R., Palla G., Ruggeri M., Ciccimarra F., Guarino A., Osimani P., Benaglia G., Romano A., De Mattia D., Caselli D., Boni S., Dell'Erba G., Bassanetti F., Sticca M., Timpano C., Magnani C., Salvatore C., Lipreri R., Tornaghi R., Pinzani R., Cecchi M.T., Bezzi T., Battisti L., Bresciani E., Castelli Gattinara G., Nasi C., Pellegatta A., Mazza A., Baldi F., Altobelli R., Deiana M., Colnaghi C., Tarallo L., Tondo U., Anastasio E., Chiriaco P.G., Ruggeri C., Scott G., Hutto C., O'Sullivan M., Malmsberry A., Willoughby A., Burns D., Goedert J., Landesman S., Minkoff H., Mendez H., Holman S., Rubinstein A., Durako S., Muenz L., Goodwin S., Bryson Y., Dillon M., Nielsen K., Boyer P., Liao D., Keller M., Deveikis A., Nesheim S., Lindsay M., Lee F., Nahmias A., Sawyer M., Vink P., Farley J., Alger L., Abrams E., Bamji M., Lambert G., Schoenbaum E., Thomas P., Weedon J., Palumbo P., Denny T., Oleske J., Bulterys M., Simonds R., Ethier-Ives J., Rogers M., Schluchter M., Kutner M., Kaplan S., Kattan M., Lipshultz S., Mellins R., Shearer W., Sopko G., Sloand E., Wu M., Kind C., Nadal D., Rudin C., Siegrist C.-A., Wyler C.-A., Cheseaux J.-J., Aebi C., Gnehm H., Schubiger G., Klingler J., Hunziker U., Kuchler H., Gianinazzi M., Buhlmann U., Biedermann K., Lauper U., Irion O., Brunelli A., Spoletini G., Schreyer A., Hosli I., Saurenmann E., Drack G., Isenschmid M., Poorbeik M., Schupbach J., Perrin L., Erb P., Joller H., Kovacs A., Stek A., Chan L., Khoury M., Diaz C., Pacheco-Acosta E., Tuomala R., Cooper E., Mesthene D., Pitt J., Higgins A., Moroso G., Rich K., Turpin D., Cooper N., Davenny K., Thompson B., Andiman W., and Simpson J.

Subjects
Time Factors, Epidemiology, Infectious Disease Transmission, Prevention of perinatal transmission, Extraembryonic Membranes, Human immunodeficiency virus (HIV), HIV Infections, medicine.disease_cause, Cohort Studies, Pregnancy, Risk Factors, INFECTION, Vertical, Immunology and Allergy, HIV Infection, MOTHER-TO-CHILD, Pregnancy Complications, Infectious, Prospective cohort study, prevention of perinatal transmission, vertical transmission, obstetrics/gynaecology, epidemiology, Obstetrics, Transmission (medicine), Infectious, HUMAN-IMMUNODEFICIENCY-VIRUS, MOTHER-TO-CHILD, ZIDOVUDINE PROPHYLAXIS, RISK-FACTORS, TYPE-1, PREGNANCY, INFECTION, TRIAL, PREVENTION, Breast Feeding, Infectious Diseases, Meta-analysis, HUMAN-IMMUNODEFICIENCY-VIRUS, Vertical transmission, Regression Analysis, TRIAL, Female, Delivery, Obstetrics gynaecology, Human, medicine.medical_specialty, Time Factor, Ruptured membranes, Immunology, Regression Analysi, NO, ZIDOVUDINE PROPHYLAXIS, Extraembryonic Membrane, medicine, Humans, TYPE-1, business.industry, Risk Factor, Infant, Newborn, Infant, Obstetric, Delivery, Obstetric, Newborn, PREVENTION, Infectious Disease Transmission, Vertical, Pregnancy Complications, Obstetrics/gynaecology, RISK-FACTORS, Cohort Studie, business
Abstract

Objective: To test the a priori hypothesis that longer duration of ruptured membranes is associated with increased risk of vertical transmission of HIV. Design: The relationship between duration of ruptured membranes and vertical transmission of HIV was evaluated in an individual patient data meta-analysis. Methods: Eligible studies were prospective cohort studies including at least 100 mother-child pairs, from regions where HIV-infected women are counselled not to breastfeed. Analyses were restricted to vaginal deliveries and non-elective Cesarean sections; elective Cesarean section deliveries (those performed before onset of labour and before rupture of membranes) were excluded. Results: The primary analysis included 4721 deliveries with duration of ruptured membranes ≤ 24 h. After adjusting for other factors known to be associated with vertical transmission using logistic regression analysis to assess the strength of the relationship, the risk of vertical HIV transmission increased approximately 2% with an increase of 1 h in the duration of ruptured membranes [adjusted odds ratio, 1.02; 95% confidence interval, 1.01-1.04; for each 1 h increment]. There were no significant interactions of duration of ruptured membranes with study cohort or with any of the covariates, except maternal AIDS. Among women diagnosed with AIDS, the estimated probability of transmission increased from 8% to 31% with duration of ruptured membranes of 2 h and 24 h respectively (P < 0.01). Conclusions: These results support the importance of duration of ruptured membranes as a risk factor for vertical transmission of HIV and suggest that a diagnosis of AIDS in the mother at the time of delivery may potentiate the effect of duration of ruptured membranes. © 2001 Lippincott Williams & Wilkins.

Published
2001
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11. Persistence of Epstein-Barr virus in self-reactive memory B cells

Author

Tracy SI Kakalacheva K Lünemann JD Luzuriaga K Middeldorp J Thorley-Lawson DA.

Abstract

Epstein Barr virus infection has been epidemiologically associated with the development of multiple autoimmune diseases particularly systemic lupus erythematosus and multiple sclerosis. Currently there is no known mechanism that can account for these associations. The germinal center (GC) model of EBV infection and persistence proposes that EBV gains access to the memory B cell compartment via GC reactions by driving infected cells to differentiate using the virus encoded LMP1 and LMP2a proteins which act as functional homologues of CD40 and the B cell receptor respectively. The ability of LMP2a when expressed in mice to allow escape of autoreactive B cells suggests that it could perform a similar role in infected GC B cells permitting the survival of potentially pathogenic autoreactive B cells. To test this hypothesis we cloned and expressed antibodies from EBV(+) and EBV( ) memory B cells present during acute infection and profiled their self and polyreactivity. We find that EBV does persist within self and polyreactive B cells but find no evidence that it favors the survival of pathogenic autoreactive B cells. On the contrary EBV(+) memory B cells express lower levels of self reactive and especially polyreactive antibodies than their uninfected counterparts do. Our work suggests that EBV has only a modest effect on the GC process which allows it to access and persist within a subtly unique niche of the memory compartment characterized by relatively low levels of self and polyreactivity. We suggest that this might reflect an active process where EBV and its human host have coevolved so as to minimize the virus's potential to contribute to autoimmune disease.

Published
2012
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13. The EPIICAL project: an emerging global collaboration to investigate\ud immunotherapeutic strategies in HIV-infected children

Author

Palma, P., Foster, C., Zangari, P., Yates, A., Cotugno, N., Klein, N., Luzuriaga, K., Pahwa, S., Nastouli, E., Gibb, D.M., Borkowsky, W., Bernardi, S., Calvez, V., Manno, E., Mora, Nadia, Compagnucci, A., Wahren, B., Muñoz-Fernández, M.Á., De Rossi, A., Ananworanich, J., Pillay, D., Giaquinto, C., and Rossi, P.

Abstract

The EPIICAL (Early-treated Perinatally HIV-infected Individuals: Improving Children’s Actual Life with Novel Immunotherapeutic Strategies) project arises from the firm belief that perinatally infected children treated with suppressive antiretroviral therapy (ART) from early infancy represent the optimal population model in which to study novel immunotherapeutic strategies aimed at achieving ART-free remission. This is because HIV-infected infants treated within 2–3 months of life have a much reduced viral reservoir size, and rarely show HIV-specific immunity but preserve normal immune development. The goal of EPIICAL is the establishment of an international collaboration to develop a predictive platform using this model to select promising HIV therapeutic vaccine candidates, leading to prioritisation or deprioritisation of novel immunotherapeutic strategies. To establish this platform, the EPIICAL Consortium aims to: develop predictive models of virological and immunological dynamics associated with response to early ART and to treatment interruption using available data from existing cohorts/studies of early-treated perinatally HIV-infected children; optimise methodologies to better characterise immunological, virological and genomic correlates/profiles associated with viral control; test novel immunotherapeutic strategies using in vivo proof-of-concept (PoC) studies with the aim of inducing virological, immunological and transcriptomic correlates/profiles equivalent to those defined by the predictive model. This approach will strengthen the capacity for discovery, development and initial testing of new therapeutic vaccine strategies through the integrated efforts of leading international scientific groups, with the aim of improving the health of HIV-infected individuals.

Published
2015

14. Using CD4 percentage and age to optimize pediatric antiretroviral therapy initiation

Author

Yin, D.E., Warshaw, M.G., Miller, W.C., Castro, H., Fiscus, S.A., Harper, L.M., Harrison, L.J., Klein, N.J., Lewis, J., Melvin, A.J., Tudor Williams, G., Mckinney, R.E., Brouwers, P., Costello, D., Ferguson, E., Fiscus, S., Hodge, J., Hughes, M., Jennings, C., Melvin, A., Mckinney, R., Mofenson, L., Warshaw, M., Smith, M., Spector, S., Stiehm, E., Toye, M., Yogev, R., Babiker, A., Compagnucci, A., De Rossi, A., Giaquinto, C., Darbyshire, J., Debré, M., Gibb, D., Harper, L., Harrison, L., Klein, N., Pillay, D., Saidi, Y., Walker, A., Brody, B., Hill, C., Lepage, P., Modlin, J., Poziak, A., Rein, M., Robb, M., Fleming, T., Vella, S., Kim, K., Bologna, R., Mecikovsky, D., Pineda, N., Sen, L., Mangano, A., Marino, S., Galvez, C., Deluchi, G., Zöhrer, B., Zenz, W., Daghofer, E., Pfurtscheller, K., Pabst, B., Gomez, M., Mcneil, P., Jervis, M., Whyms, I., Kwolfe, D., Scott, S., Mussi Pinhata MM, Issac, M., Cervi, M., Negrini, B., Matsubara, T., de Souza CB, Gabaldi, J., Oliveira, R., Sapia, M., Abreu, T., Evangelista, L., Pala, A., Fernandes, I., Farias, I., Melo M, D.F., Carreira, H., Lira, L., Della Negra, M., Queiroz, W., Lian, Y., Pacola, D., Pinto, J., Ferreira, F., Kakehasi, F., Martins, L., Diniz, A., Lobato, V., Diniz, M., Cleto, S., Costa, S., Romeiro, J., Dollfus, C., Tabone, M., Courcoux, M., Vaudre, G., Dehée, A., Schnuriger, A., Le Gueyades, N., De Bortoli, C., Méchinaud, F., Reliquet, V., Arias, J., Rodallec, A., André, E., Falconi, I., Le Pelletier, A., Monpoux, F., Cottalorda, J., Mellul, S., Lachassinne, E., Galimand, J., Rouzioux, C., Chaix, M., Benabadji, Z., Pourrat, M., Firtion, G., Rivaux, D., Denon, M., Boudjoudi, N., Nganzali, F., Krivine, A., Méritet, J., Delommois, G., Norgeux, C., Guérin, C., Floch, C., Marty, L., Hichou, H., Tournier, V., Faye, A., Le Moal, I., Sellier, M., Dehache, L., Damond, F., Leleu, J., Beniken, D., Alexandre Castor, G., Neubert, J., Niehues, T., Laws, H., Huck, K., Gudowius, S., Siepermann, K., Loeffler, H., Bellert, S., Ortwin, A., Notheis, G., Wintergerst, U., Hoffman, F., Werthmann, A., Seyboldt, S., Schneider, L., Bucholz, B., Feiterna Sperling, C., Peiser, C., Nickel, R., Schmitz, T., Piening, T., Müller, C., Warncke, G., Wigger, M., Neubauer, R., Butler, K., Chong, A., Boulger, T., Menon, A., O'Connell, M., Barrett, L., Rochford, A., Goode, M., Hayes, E., Mcdonagh, S., Walsh, A., Doyle, A., Fanning, J., O'Connor, M., Byrne, M., O'Sullivan, N., Hyland, E., Giacomet, V., Viganò, A., Colombo, I., Trabattoni, D., Berzi, A., Badolato, R., Schumacher, F., Bennato, V., Brusati, M., Sorlini, A., Spinelli, E., Filisetti, M., Bertulli, C., Rampon, O., Zanchetta, M., Mazza, A., Stringari, G., Rossetti, G., Bernardi, S., Martino, A., Castelli Gattinara, G., Palma, P., Pontrelli, G., Tchidjou, H., Furcas, A., Frillici, C., Mazzei, A., Zoccano, A., Concato, C., Duiculescu, D., Oprea, C., Tardei, G., Abaab, F., Mardarescu, M., Draghicenoiu, R., Otelea, D., Alecsandru, L., Matusa, R., Rugina, S., Ilie, M., Netescu, S., Florea, C., Voicu, E., Poalelungi, D., Belmega, C., Vladau, L., Chiriac, A., Ramos Amador JT, Gonzalez Tomé MI, Rojo Conejo, P., Fernandez, M., Delgado Garcia, R., Ferrari, J., Garcia Lopez, M., Mellado Peña MJ, Martin Fontelos, P., Jimenez Nacher, I., Muñoz Fernandez MA, Jimenez, J., García Torre, A., Penin, M., Pineiro Perez, R., Garcia Mellado, I., Finn, A., Lajeunesse, M., Hutchison, E., Usher, J., Ball, L., Dunn, M., Sharland, M., Doerholt, K., Storey, S., Donaghy, S., Chakraborty, R., Wells, C., Buckberry, K., Rice, P., Mcmaster, P., Butler, P., O'Connell C, R., Shenton, J., Haley, H., Orendi, J., Stroobant, J., Navarante, L., Archer, P., Mazhude, C., Scott, D., O'Connell, R., Wong, J., Boddy, G., Shackley, F., Lakshman, R., Hobbs, J., Ball, G., Kudesia, G., Bane, J., Painter, D., Sloper, K., Shah, V., Cheng, A., Aali, A., Ball, C., Hawkins, S., Nayagam, D., Waters, A., Doshi, S., Liebeschuetz, S., Sodiende, B., Shingadia, D., Wong, S., Swan, J., Shah, Z., Collinson, A., Hayes, C., King, J., O'Connor, K., Lyall, H., Fidler, K., Walters, S., Foster, C., Hamadache, D., Newbould, C., Monrose, C., Campbell, S., Yeung, S., Cohen, J., Martinez Allier, N., Melvin, D., Dodge, J., Welch, S., Tatum, G., Gordon, A., Kaye, S., Muir, D., Patel, D., Novelli, V., Moshal, K., Lambert, J., Flynn, J., Farrelly, L., Clapson, M., Spencer, L., Depala, M., Jacobsen, M., Segal, S., Pollard, A., Kelly, D., Yeadon, S., Ohene Kena, B., Peng, Y., Dong, T., Jeffries, K., Snelling, M., Smyth, A., Smith, J., Ward, B., Jungmann, E., Ryan, C., Swaby, K., Buckton, A., Smit, E., Abrams, E., Champion, S., Fernandez, A., Calo, D., Garrovillo, L., Swaminathan, K., Alford, T., Frere, M., Navarra, J., Borkowsky, W., Deygoo, S., Hastings, T., Akleh, S., Ilmet, T., Mohan, K., Bowen, G., Emmanuel, P., Lujan Zimmerman, J., Rodriguez, C., Johnson, S., Marion, A., Graisbery, C., Casey, D., Lewis, G., Guzman Cottrill, J., Croteau, R., Acevedo Flores, M., Gonzalez, M., Angeli, L., Fabregas, L., Valentin, P., Weiner, L., Contello, K., Holz, W., Butler, M., Nachman, S., Kelly, M., Ferraro, D., Rana, S., Reed, C., Yeagley, E., Malheiro, A., Roa, J., Neely, M., Kovacs, A., Homans, J., Rodriguez Lozano, Y., Puga, A., Talero, G., Sellers, R., Lawrence, R., Weinberg, G., Murante, B., Laverty, S., Deveikis, A., Batra, J., Chen, T., Michalik, D., Deville, J., Elkins, K., Marks, S., Jackson Alvarez, J., Palm, J., Fineanganofo, I., Keuth, M., Deveikis, L., Tomosada, W., Van Dyke, R., Alchediak, T., Silio, M., Borne, C., Bradford, S., Eloby Childress, S., Nguyen, K., Rathore, M., Alvarez, A., Mirza, A., Mahmoudi, S., Burke, M., Febo, I., Lugo, L., Santos, R., Church, J., Dunaway, T., Rodier, C., Flynn, P., Patel, N., Discenza, S., Donohoe, M., Luzuriaga, K., Picard, D., Kline, M., Paul, M., Shearer, W., Mcmullen, C., Chadwick, E., Cagwin, E., Kabat, K., Dieudonne, A., Palumbo, P., Johnson, J., Gaur, S., Cerracchio, L., Foca, M., Jurgrau, A., Vasquez Bonilla, S., Silva, G., Gershon, A., Sullivan, J., Bryson, Y., Frenkel, L., Nelson, J., Aboulker, J., Hadjou, G., Léonardo, S., Riault, Y., Saïdi, Y., Buck, L., Forcat, S., Horton, J., Johnson, D., Moore, S., Taylor, C., Collins, D., Buskirk, S., Kamara, P., Nesel, C., Johnson, M., Ferreira, A., Tutko, J., Sprenger, H., Britto, P., Powell, C., Dersimonian, R., Handelsman, E., Ananworanich, J., Belfrage, E., Blanche, S., Bohlin, A., Burger, D., Clayden, P., De Groot, R., Di Biagio, A., Grosch Wörner, I., Hainault, M., Lallemant, M., Levy, J., Marczynska, M., Mellado Pena MJ, Nadal, D., Naver, L., Peckham, C., Popieska, J., Rosado, L., Rosso, R., Rudin, C., Scherpbier, H., Stevanovic, M., Thorne, C., Tovo, P., Valerius, N., Poole, C., Cole, S., and Mcculloh, R.J.

Subjects
CD4-Positive T-Lymphocytes, Male, medicine.medical_treatment, HIV (FISIOLOGIA), lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], Human immunodeficiency virus (HIV), HIV Infections, medicine.disease_cause, Treatment failure, Settore BIO/13 - Biologia Applicata, Antiretroviral Therapy, Highly Active, immunologic, Child, HIV, child, reconstitution, treatment failure, Adolescent, Anti-HIV Agents, CD4 Lymphocyte Count, Child, Preschool, Female, Follow-Up Studies, HIV-1, Humans, Infant, Infant, Newborn, Follow up studies, Immunosuppression, medicine.medical_specialty, Settore MED/17 - Malattie Infettive, Antiretroviral Therapy, World health, Article, Internal medicine, medicine, Highly Active, Preschool, Settore MED/04 - Patologia Generale, business.industry, Disease progression, Settore MED/46 - Scienze Tecniche di Medicina di Laboratorio, Newborn, Antiretroviral therapy, Confidence interval, lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4], Immunologic, Reconstitution, Pediatrics, Perinatology and Child Health, Immunology, business
Abstract

BACKGROUND: Quantifying pediatric immunologic recovery by highly active antiretroviral therapy (HAART) initiation at different CD4 percentage (CD4%) and age thresholds may inform decisions about timing of treatment initiation. METHODS: HIV-1-infected, HAART-naive children in Europe and the Americas were followed from 2002 through 2009 in PENPACT-1. Data from 162 vertically infected children, with at least World Health Organization “mild” immunosuppression and CD4% RESULTS: Seventy-two percent of baseline immunosuppressed children recovered to normal within 4 years. Compared with “severe” immunosuppression, more children with “mild” immunosuppression (difference 36%, 95% confidence interval [CI]: 22% to 49%) or “advanced” immunosuppression (difference 20.8%, 95% CI: 5.8% to 35.9%) recovered a normal CD4%. For each 5-year increase in baseline age, the proportion of children achieving a normal CD4% declined by 19% (95% CI: 11% to 27%). Combining baseline CD4% and age effects resulted in >90% recovery when initiating HAART with “mild” immunosuppression at any age or “advanced” immunosuppression at age CONCLUSIONS: Initiating HAART at higher CD4% and younger ages maximizes potential for immunologic recovery. Guidelines should weigh immunologic benefits against long-term risks.

Published
2014

15. The Mode of Delivery and the Risk of Vertical Transmission of Human Immunodeficiency Virus Type 1 — A Meta-Analysis of 15 Prospective Cohort Studies

Author

Andiman, W., Boucher, M., Burns, D., Bryson, Y., Farley, J., Fowler, H., Gabiano, C., Galli, L., Hutto, C., Kind, C., Korber, B., Kovacs, A., Krogstad, P., Landesman, S., Lapointe, N., Lemay, M., Lew, J., Mandelbrot, L., Mayaux, Mj, Mellins, R., Minkoff, H., Mofenson, L., Nielsen, K., Newell, Ml, Pardi, G., Peavy, H., Peckham, C., Read, J., Rother, C., Rudin, C., Scott, G., Semprini, A., Shearer, W., Simonds, R., Simpson, B., Stek, A., Tovo, Pa, Tuomala, R., Dyke, R., Weedon, J., Martino, M., Lindsay, M., Belair, S., Chan, L., Harris, D., Kalish, L., Muenz, L., Nugent, R., Schluchter, M., Durako, S., Goodwin, S., Mitchell, R., Nourjah, P., Owen, W., Widmayer, S., Bardeguez, A., Hanson, C., Wiznia, A., Luzuriaga, K., Viscarello, R., Ho, D., Koup, R., Chen, I., Mullins, J., Wolinsky, S., Walker, B., Ammann, A., Clapp, S., Mcdonald, D., Fauvel, M., Hankins, C., Samson, J., Bailey, A., Giaquinto, C., Ruga, E., Rossi, A., Truscia, D., Grosch-Worner, I., Schafer, A., Mok, J., Johnstone, F., Jiminez, J., Alba, C., Garcia-Rodriguez, M., Bates, I., Jose, I., Hawkins, F., Zapico, Rm, Asensi-Botet, F., Otero, M., Perez-Tamarit, D., Moya, A., Galbis, M., Scherpbier, H., Boer, K., Bohlin, A., Lindgren, S., Ehrnst, A., Anzen, B., Belfrage, E., Levy, J., Alimenti, A., Barlow, P., Ferrazin, A., Maria, A., Gotta, C., Maritati, V., Mur, A., Rovira, M., Paya, A., Coll, O., Fortuny, C., Boguna, J., Caro, Mc, Canet, Y., Ravizza, M., Castagna, C., Fiore, S., Guerra, B., Lanari, M., Bianchi, S., Bovicelli, L., Prati, E., Duse, M., Soresina, A., Scaravelli, G., Santis, M., Muggiasca, M., Vigano, A., Marchisio, P., Iasci, A., Spinillo, A., Bucceri, A., Grossi, E., Rancilio, L., Della Torre, M., Dallacasa, P., Pachi, A., Principi, N., Zara, C., Vignali, M., Rossi, G., Selvaggi, L., Greco, P., Vimercati, A., Massi, G., Innocenti, T., Fiscella, A., Sansone, M., Benedetto, C., Tibaldi, C., Ziarati, N., Tadrist, B., Thevenicau, D., Gondry, J., Paulard, B., Alisy, C., Brault, D., Tordjeman, P., Mamou, J., Rozan, M., Colombani, D., Pincemaille, O., Salvetti, A., Chabanier, C., Hernandorena, X., Leroy, J., Schaal, J., Balde, P., Faucher, P., Lachassinne, E., Benoit, S., Douard, D., Hocke, C., Barjot, P., Brouard, J., Delattre, P., Stien, L., Audibert, F., Labrune, P., Vial, M., Mazy, F., Sitbon, D., Crenn-Hebert, C., Floch-Tudal, C., Akakpo, R., Daveau, C., Leblanc, A., Cesbron, P., Duval-Arnould, H., Huraux-Rendu, C., Lemerle, S., Touboul, C., Guerin, M., Maingueneau, C., Reynaud, I., Rousseau, T., Ercoil, V., Lanza, M., Denavit, M., Garnier, J., Lahsinat, K., Pia, R., Allouche, C., Nardou, M., Grall, F., May, A., Dallot, M., Lhuillier, P., Cecile, W., Mezin, R., Bech, A., Lobut, J., Algava, G., Dermesay, Ac, Busuttil, R., Jacquemot, M., Bader-Meunier, B., Fridman, S., Codaccioni, X., Maxingue, F., Thomas, D., Alain, J., Lumley, L., Tabaste, J., Salin, Pb, Seaume, H., Guichard, A., Kebaili, K., Roussouly, C., Botto, C., Lanete, A., Wipff, P., Cravello, L., Boisse, P., Leclaire, M., Michel, G., Crumiere, C., Lefevre, V., Le Lorier, B., Pauly, I., Robichez, B., Seguy, D., Dehlinger, M., Rideau, F., Talon, P., Benos, P., Huret, C., Nicolas, J., Heller-Roussin, B., Saint-Leger, S., Delaporte, M., Hubert, C., Sarcus, B., Karoubi, P., Mechinaud, F., Bertcrottiere, D., Bongain, A., Monpoux, F., Gennes, C., Devianne, F., Nisand, I., Rousset, M., Mouchnino, G., Muray, J., Munzer, M., Quereux, C., Brossard, V., Clavier, B., Allemon, M., Rotten, D., Stephan, J., Varlet, M., Guyot, B., Narey, P., Bardinet, F., Caunes, F., Jeny, R., Robin, M., Bouley, Ar, Savey, L., Berrebi, A., Tricoire, J., Borderon, J., Fignon, A., Guillot, F., Maria, B., Broyard, A., Chitrit, Y., Firtion, G., Pillet, Ml, Parat, S., Boissinot, C., Garec, N., Levine, M., Ottenwalter, A., Schaller, F., Vilmer, B., Courpotin, C., Brunner, C., Ciraru-Vigneron, N., Hatem-Gantzer, G., Xavier FRITEL, Wallet, A., Bouille, J., Milliez, J., Mrejen, Db, Dermer, E., Noseda, G., Bardou, D., Cressaty, J., Francoual, C., Moncomble, Cc, Cohen, H., Blanche, S., Bastion, H., Benifla, J., Benkhatar, F., Berkane, N., Herve, F., Ronzier, M., Ferraris, G., Rancillo, L., Tulisso, S., Scolfaro, C., Riva, C., Vierucci, A., Luca, M., Farina, S., Fundaro, C., Genovese, O., Mercu, G., Forni, G., Stegagno, M., Falconieri, P., Zuccotti, G., Riva, E., Cellini, M., Baraldi, C., Consolini, R., Palla, G., Ruggeri, M., Pignata, C., Guarino, A., Osimani, P., Metri, A., Antonellini, A., Benaglia, G., Romano, A., Mattia, D., Caselli, D., Boni, S., Erba, G., Bassanetti, F., Sticca, M., Timpano, C., Magnani, C., Salvatore, C., Gambaretto, G., Lipreri, R., Tornaghi, R., Pinzani, R., Cecchi, M., Bezzi, T., Battisti, L., Bresciani, E., Gattinara, G., Berrino, R., Pellegatta, A., Mazza, A., Baldi, F., Micheletti, E., Altobelli, R., Deiana, M., Colnaghi, C., Tarallo, L., Tondo, U., Anastasio, E., Chiriaco, P., Contardi, I., Ruggeri, C., Ibba, P., O Sullivan, M., Malmsberry, A., Willoughby, A., Goedert, J., Mendez, H., Holman, S., Rubinstein, A., Nesheim, S., Clark, S., Lee, F., Nahmias, A., Sawyer, M., Vink, P., Alger, L., Abrams, E., Bamji, M., Lambert, G., Schoenbaum, E., Thea, D., Thomas, P., Palumbo, P., Denny, T., Oleske, J., Orloff, S., Ethier-Ives, J., Rogers, M., Kutner, M., Kaplan, S., Kattan, M., Lipshultz, S., Sopko, G., Sloand, E., Wu, M., Nadal, D., Siegrist, Ca, Wyler, Ca, Cheseaux, Jj, Aebi, C., Gnehm, H., Schubiger, G., Klingler, J., Hunziker, U., Kuchler, H., Gianinazzi, M., Buhlmann, U., Biedermann, K., Lauper, U., Irion, O., Brunelli, A., Spoletini, G., Schreyer, A., Hosli, I., Saurenmann, E., Drack, G., Isenschmid, M., Poorbeik, M., Schupbach, J., Perrin, L., Erb, P., Joller, H., Dillon, M., Nielsen, R., Boyer, P., Liao, D., Keller, M., Deveikis, A., Khoury, M., Diaz, C., Pacheco-Acosta, E., Cooper, E., Mesthene, D., Pitt, J., Higgins, A., Moroso, G., Rich, K., Turpin, D., Cooper, N., Fowler, M., Smeriglio, V., Mckinlay, S., and Ellis, S.

Subjects
Male, medicine.medical_specialty, Multivariate analysis, Anti-HIV Agents, Birth weight, HIV Infections, Cohort Studies, Pregnancy, Risk Factors, medicine, Birth Weight, Humans, Rupture of membranes, Pregnancy Complications, Infectious, Prospective cohort study, Cesarean Section, Obstetrics, business.industry, Infant, Newborn, General Medicine, Odds ratio, Delivery, Obstetric, medicine.disease, Infectious Disease Transmission, Vertical, Confidence interval, Logistic Models, Multivariate Analysis, Immunology, HIV-1, Female, business, Zidovudine, Cohort study
Abstract

Background To evaluate the relation between elective cesarean section and vertical transmission of human immunodeficiency virus type 1 (HIV-1), we performed a meta-analysis using data on individual patients from 15 prospective cohort studies. Methods North American and European studies of at least 100 mother-child pairs were included in the meta-analysis. Uniform definitions of modes of delivery were used. Elective cesarean sections were defined as those performed before onset of labor and rupture of membranes. Multivariate logistic-regression analysis was used to adjust for other factors known to be associated with vertical transmission. Results The primary analysis included data on 8533 mother-child pairs. After adjustment for receipt of antiretroviral therapy, maternal stage of disease, and infant birth weight, the likelihood of vertical transmission of HIV-1 was decreased by approximately 50 percent with elective cesarean section, as compared with other modes of delivery (adjusted odds ratio, 0.43; 95 percent confidence interval, 0.33 to 0.56). The results were similar when the study population was limited to those with rupture of membranes shortly before delivery. The likelihood of transmission was reduced by approximately 87 percent with both elective cesarean section and receipt of antiretroviral therapy during the prenatal, intrapartum, and neonatal periods, as compared with other modes of delivery and the absence of therapy (adjusted odds ratio, 0.13; 95 percent confidence interval, 0.09 to 0.19). Among mother-child pairs receiving antiretroviral therapy during the prenatal, intrapartum, and neonatal periods, rates of vertical transmission were 2.0 percent among the 196 mothers who underwent elective cesarean section and 7.3 percent among the 1255 mothers with other modes of delivery. Conclusions The results of this meta-analysis suggest that elective cesarean section reduces the risk of transmission of HIV-1 from mother to child independently of the effects of treatment with zidovudine.

Published
1999
Full Text
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16. The mode of delivery and the risk of vertical transmission of human immunodeficiency virus type 1--a meta-analysis of 15 prospective cohort studies. The International Perinatal HIV Group

Author

Andiman W., Boucher M., Burns D., Bryson Y., Farley J., Fowler H., Gabiano C., Galli L., Hutto C., Kind C., Korber B., Kovacs A., Krogstad P., Landesman S., Lapointe N., Lemay M., Lew J., Mandelbrot L., Mayaux M.J., Mellins R., Minkoff H., Mofenson L., Nielsen K., Newell M.L., Pardi G., Peavy H., Peckham C., Read J., Rother C., Rudin C., Scott G., Semprini A., Shearer W., Simonds R., Simpson B., Stek A., Tovo P.A., Tuomala R., Van Dyke R., Weedon J., de Martino M., Lindsay M., Belair S., Chan L., Harris D., Kalish L., Muenz L., Nugent R., Schluchter M., Durako S., Goodwin S., Mitchell R., Nourjah P., Owen W., Widmayer S., Bardeguez A., Hanson C., Wiznia A., Luzuriaga K., Viscarello R., Ho D., Koup R., Chen I., Mullins J., Wolinsky S., Walker B., Ammann A., Clapp S., McDonald D., Fauvel M., Hankins C., Samson J., Bailey A., Giaquinto C., Ruga E., De Rossi A., Truscia D., Grosch Worner I., Schafer A., Mok J., Johnstone F., Jiminez J., de Alba C., Garcia Rodriguez M., Bates I., de Jose I., Hawkins F., Zapico R.M., Asensi Botet F., Otero M., Perez Tamarit D., Moya A., Galbis M., Scherpbier H., Boer K., Bohlin A., Lindgren S., Ehrnst A., Anzen B., Belfrage E., Levy J., Alimenti A., Barlow P., Ferrazin A., De Maria A., Gotta C., Maritati V., Mur A., Rovira M., Paya A., Coll O., Fortuny C., Boguna J., Caro M.C., Canet Y., Ravizza M., Castagna C., Fiore S., Guerra B., Lanari M., Bianchi S., Bovicelli L., Prati E., Duse M., Soresina A., Scaravelli G., De Santis M., Muggiasca M., Vigano A., Marchisio P., Iasci A., Spinillo A., Bucceri A., Grossi E., Rancilio L., Della Torre M., Dallacasa P., Pachi A., Principi N., Zara C., Vignali M., Rossi G., Selvaggi L., Greco P., Vimercati A., Massi G., Innocenti T., Fiscella A., Sansone M., Benedetto C., Tibaldi C., Ziarati N., Tadrist B., Thevenicau D., Gondry J., Paulard B., Alisy C., Brault D., Tordjeman P., Mamou J., Rozan M., Colombani D., Pincemaille O., Salvetti A., Chabanier C., Hernandorena X., Leroy J., Schaal J., Balde P., Faucher P., Lachassinne E., Benoit S., Douard D., Hocke C., Barjot P., Brouard J, Delattre P, Stien L, Audibert F, Labrune P, Vial M, Mazy F, Sitbon D, Crenn Hebert C, Floch Tudal C, Akakpo R, Daveau C, Leblanc A, Cesbron P, Duval Arnould H, Huraux Rendu C, Lemerle S, Touboul C, Guerin M, Maingueneau C, Reynaud I, Rousseau T, Ercoil V, Lanza M, Denavit M, Garnier J, Lahsinat K, Pia R, Allouche C, Nardou M, Grall F, May A, Dallot M, Lhuillier P, Cecile W, Mezin R, Balde P, Bech A, Lobut J, Algava G, Dermesay AC, Busuttil R, Jacquemot M, Bader Meunier B, Fridman S, Codaccioni X, Maxingue F, Thomas D, Alain J, De Lumley L, Tabaste J, Salin PB, Seaume H, Guichard A, Kebaili K, Roussouly C, Botto C, De Lanete A, Wipff P, Cravello L, De Boisse P, Leclaire M, Michel G, Crumiere C, Lefevre V, Le Lorier B, Pauly I, Robichez B, Seguy D, Dehlinger M, Rideau F, Talon P, Benos P, Huret C, Nicolas J, Heller Roussin B, Saint Leger S, Delaporte M, Hubert C, De Sarcus B, Karoubi P, Mechinaud F, Bertcrottiere D, Bongain A, Monpoux F, De Gennes C, Devianne F, Nisand I, Rousset M, Mouchnino G, Muray J, Munzer M, Quereux C, Brossard V, Clavier B, Allemon M, Rotten D, Stephan J, Varlet M, Guyot B, Narey P, Bardinet F, De Caunes F, Jeny R, Robin M, Bouley AR, Savey L, Berrebi A, Tricoire J, Borderon J, Fignon A, Guillot F, Maria B, Broyard A, Chitrit Y, Firtion G, Mandelbrot L, Pillet ML, Parat S, Boissinot C, Garec N, Levine M, Ottenwalter A, Schaller F, Vilmer B, Courpotin C, Brunner C, Ciraru Vigneron N, Hatem Gantzer G, Fritel X, Wallet A, Bouille J, Milliez J, Mrejen DB, Dermer E, Noseda G, Bardou D, Cressaty J, Francoual C, Moncomble CC, Cohen H, Blanche S, Bastion H, Benifla J, Benkhatar F, Berkane N, Herve F, Ronzier M, Mayaux MJ, de Martino M, Tovo PA, Galli L, Gabiano C, Ferraris G, Rancillo L, Bucceri A, Tulisso S, Scolfaro C, Riva C, Vierucci A, de Luca M, Farina S, Fundaro C, Genovese O, Mercu G, Forni G, Stegagno M, Falconieri P, Zuccotti G, Riva E, Cellini M, Baraldi C, Consolini R, Palla G, Ruggeri M, Osimani P, Metri A, Antonellini A, Benaglia G, Romano A, Dallacasa P, De Mattia D, Caselli D, Boni S, Dell'Erba G, Bassanetti F, Sticca M, Timpano C, Magnani C, Salvatore C, Gambaretto G, Lipreri R, Tornaghi R, Pinzani R, Cecchi M, Bezzi T, Battisti L, Bresciani E, Gattinara G, Berrino R, Pellegatta A, Mazza A, Baldi F, Micheletti E, Ruga E, Altobelli R, Deiana M, Colnaghi C, Tarallo L, Tondo U, Anastasio E, Duse M, Chiriaco P, Contardi I, Ruggeri C, Ibba P, Scott G, Hutto C, O'Sullivan M, Malmsberry A, Willoughby A, Burns D, Goedert J, Landesman S, Minkoff H, Mendez H, Holman S, Rubinstein A, Durako S, Muenz L, Goodwin S, Nesheim S, Lindsay M, Clark S, Lee F, Nahmias A, Sawyer M, Vink P, Farley J, Alger L, Abrams E, Bamji M, Lambert G, Schoenbaum E, Thea D, Thomas P, Weedon J, Palumbo P, Bardeguez A, Denny T, Oleske J, Simonds R, Orloff S, Ethier Ives J, Rogers M, Schluchter M, Kutner M, Kaplan S, Kattan M, Lipshultz S, Mellins R, Shearer W, Peavy H, Sopko G, Sloand E, Wu M, Kind C, Nadal D, Rudin C, Siegrist CA, Wyler CA, Cheseaux JJ, Aebi C, Gnehm H, Schubiger G, Klingler J, Hunziker U, Kuchler H, Gianinazzi M, Buhlmann U, Biedermann K, Lauper U, Irion O, Brunelli A, Spoletini G, Schreyer A, Hosli I, Saurenmann E, Drack G, Isenschmid M, Poorbeik M, Schupbach J, Perrin L, Erb P, Joller H, Bryson Y, Dillon M, Nielsen R, Boyer P, Liao D, Keller M, Deveikis A, Kovacs A, Stek A, Chan L, Rother C, Khoury M, Diaz C, Pacheco Acosta E, Tuomala R, Cooper E, Mesthene D, Pitt J, Higgins A, Moroso G, Rich K, Turpin D, Cooper N, Fowler M, Nugent R, Smeriglio V, McKinlay S, Kalish L, Ellis S, Andiman W, PIGNATA, CLAUDIO, GUARINO, ALFREDO, Andiman, W., Boucher, M., Burns, D., Bryson, Y., Farley, J., Fowler, H., Gabiano, C., Galli, L., Hutto, C., Kind, C., Korber, B., Kovacs, A., Krogstad, P., Landesman, S., Lapointe, N., Lemay, M., Lew, J., Mandelbrot, L., Mayaux, M. J., Mellins, R., Minkoff, H., Mofenson, L., Nielsen, K., Newell, M. L., Pardi, G., Peavy, H., Peckham, C., Read, J., Rother, C., Rudin, C., Scott, G., Semprini, A., Shearer, W., Simonds, R., Simpson, B., Stek, A., Tovo, P. A., Tuomala, R., Van Dyke, R., Weedon, J., de Martino, M., Lindsay, M., Belair, S., Chan, L., Harris, D., Kalish, L., Muenz, L., Nugent, R., Schluchter, M., Durako, S., Goodwin, S., Mitchell, R., Nourjah, P., Owen, W., Widmayer, S., Bardeguez, A., Hanson, C., Wiznia, A., Luzuriaga, K., Viscarello, R., Ho, D., Koup, R., Chen, I., Mullins, J., Wolinsky, S., Walker, B., Ammann, A., Clapp, S., Mcdonald, D., Fauvel, M., Hankins, C., Samson, J., Bailey, A., Giaquinto, C., Ruga, E., De Rossi, A., Truscia, D., Grosch Worner, I., Schafer, A., Mok, J., Johnstone, F., Jiminez, J., de Alba, C., Garcia Rodriguez, M., Bates, I., de Jose, I., Hawkins, F., Zapico, R. M., Asensi Botet, F., Otero, M., Perez Tamarit, D., Moya, A., Galbis, M., Scherpbier, H., Boer, K., Bohlin, A., Lindgren, S., Ehrnst, A., Anzen, B., Belfrage, E., Levy, J., Alimenti, A., Barlow, P., Ferrazin, A., De Maria, A., Gotta, C., Maritati, V., Mur, A., Rovira, M., Paya, A., Coll, O., Fortuny, C., Boguna, J., Caro, M. C., Canet, Y., Ravizza, M., Castagna, C., Fiore, S., Guerra, B., Lanari, M., Bianchi, S., Bovicelli, L., Prati, E., Duse, M., Soresina, A., Scaravelli, G., De Santis, M., Muggiasca, M., Vigano, A., Marchisio, P., Iasci, A., Spinillo, A., Bucceri, A., Grossi, E., Rancilio, L., Della Torre, M., Dallacasa, P., Pachi, A., Principi, N., Zara, C., Vignali, M., Rossi, G., Selvaggi, L., Greco, P., Vimercati, A., Massi, G., Innocenti, T., Fiscella, A., Sansone, M., Benedetto, C., Tibaldi, C., Ziarati, N., Tadrist, B., Thevenicau, D., Gondry, J., Paulard, B., Alisy, C., Brault, D., Tordjeman, P., Mamou, J., Rozan, M., Colombani, D., Pincemaille, O., Salvetti, A., Chabanier, C., Hernandorena, X., Leroy, J., Schaal, J., Balde, P., Faucher, P., Lachassinne, E., Benoit, S., Douard, D., Hocke, C., Barjot, P., Brouard, J, Delattre, P, Stien, L, Audibert, F, Labrune, P, Vial, M, Mazy, F, Sitbon, D, Crenn Hebert, C, Floch Tudal, C, Akakpo, R, Daveau, C, Leblanc, A, Cesbron, P, Duval Arnould, H, Huraux Rendu, C, Lemerle, S, Touboul, C, Guerin, M, Maingueneau, C, Reynaud, I, Rousseau, T, Ercoil, V, Lanza, M, Denavit, M, Garnier, J, Lahsinat, K, Pia, R, Allouche, C, Nardou, M, Grall, F, May, A, Dallot, M, Lhuillier, P, Cecile, W, Mezin, R, Balde, P, Bech, A, Lobut, J, Algava, G, Dermesay, Ac, Busuttil, R, Jacquemot, M, Bader Meunier, B, Fridman, S, Codaccioni, X, Maxingue, F, Thomas, D, Alain, J, De Lumley, L, Tabaste, J, Salin, Pb, Seaume, H, Guichard, A, Kebaili, K, Roussouly, C, Botto, C, De Lanete, A, Wipff, P, Cravello, L, De Boisse, P, Leclaire, M, Michel, G, Crumiere, C, Lefevre, V, Le Lorier, B, Pauly, I, Robichez, B, Seguy, D, Dehlinger, M, Rideau, F, Talon, P, Benos, P, Huret, C, Nicolas, J, Heller Roussin, B, Saint Leger, S, Delaporte, M, Hubert, C, De Sarcus, B, Karoubi, P, Mechinaud, F, Bertcrottiere, D, Bongain, A, Monpoux, F, De Gennes, C, Devianne, F, Nisand, I, Rousset, M, Mouchnino, G, Muray, J, Munzer, M, Quereux, C, Brossard, V, Clavier, B, Allemon, M, Rotten, D, Stephan, J, Varlet, M, Guyot, B, Narey, P, Bardinet, F, De Caunes, F, Jeny, R, Robin, M, Bouley, Ar, Savey, L, Berrebi, A, Tricoire, J, Borderon, J, Fignon, A, Guillot, F, Maria, B, Broyard, A, Chitrit, Y, Firtion, G, Mandelbrot, L, Pillet, Ml, Parat, S, Boissinot, C, Garec, N, Levine, M, Ottenwalter, A, Schaller, F, Vilmer, B, Courpotin, C, Brunner, C, Ciraru Vigneron, N, Hatem Gantzer, G, Fritel, X, Wallet, A, Bouille, J, Milliez, J, Mrejen, Db, Dermer, E, Noseda, G, Bardou, D, Cressaty, J, Francoual, C, Moncomble, Cc, Cohen, H, Blanche, S, Bastion, H, Benifla, J, Benkhatar, F, Berkane, N, Herve, F, Ronzier, M, Mayaux, Mj, de Martino, M, Tovo, Pa, Galli, L, Gabiano, C, Ferraris, G, Rancillo, L, Bucceri, A, Tulisso, S, Scolfaro, C, Riva, C, Vierucci, A, de Luca, M, Farina, S, Fundaro, C, Genovese, O, Mercu, G, Forni, G, Stegagno, M, Falconieri, P, Zuccotti, G, Riva, E, Cellini, M, Baraldi, C, Consolini, R, Palla, G, Ruggeri, M, Pignata, Claudio, Guarino, Alfredo, Osimani, P, Metri, A, Antonellini, A, Benaglia, G, Romano, A, Dallacasa, P, De Mattia, D, Caselli, D, Boni, S, Dell'Erba, G, Bassanetti, F, Sticca, M, Timpano, C, Magnani, C, Salvatore, C, Gambaretto, G, Lipreri, R, Tornaghi, R, Pinzani, R, Cecchi, M, Bezzi, T, Battisti, L, Bresciani, E, Gattinara, G, Berrino, R, Pellegatta, A, Mazza, A, Baldi, F, Micheletti, E, Ruga, E, Altobelli, R, Deiana, M, Colnaghi, C, Tarallo, L, Tondo, U, Anastasio, E, Duse, M, Chiriaco, P, Contardi, I, Ruggeri, C, Ibba, P, Scott, G, Hutto, C, O'Sullivan, M, Malmsberry, A, Willoughby, A, Burns, D, Goedert, J, Landesman, S, Minkoff, H, Mendez, H, Holman, S, Rubinstein, A, Durako, S, Muenz, L, Goodwin, S, Nesheim, S, Lindsay, M, Clark, S, Lee, F, Nahmias, A, Sawyer, M, Vink, P, Farley, J, Alger, L, Abrams, E, Bamji, M, Lambert, G, Schoenbaum, E, Thea, D, Thomas, P, Weedon, J, Palumbo, P, Bardeguez, A, Denny, T, Oleske, J, Simonds, R, Orloff, S, Ethier Ives, J, Rogers, M, Schluchter, M, Kutner, M, Kaplan, S, Kattan, M, Lipshultz, S, Mellins, R, Shearer, W, Peavy, H, Sopko, G, Sloand, E, Wu, M, Kind, C, Nadal, D, Rudin, C, Siegrist, Ca, Wyler, Ca, Cheseaux, Jj, Aebi, C, Gnehm, H, Schubiger, G, Klingler, J, Hunziker, U, Kuchler, H, Gianinazzi, M, Buhlmann, U, Biedermann, K, Lauper, U, Irion, O, Brunelli, A, Spoletini, G, Schreyer, A, Hosli, I, Saurenmann, E, Drack, G, Isenschmid, M, Poorbeik, M, Schupbach, J, Perrin, L, Erb, P, Joller, H, Bryson, Y, Dillon, M, Nielsen, R, Boyer, P, Liao, D, Keller, M, Deveikis, A, Kovacs, A, Stek, A, Chan, L, Rother, C, Khoury, M, Diaz, C, Pacheco Acosta, E, Tuomala, R, Cooper, E, Mesthene, D, Pitt, J, Higgins, A, Moroso, G, Rich, K, Turpin, D, Cooper, N, Fowler, M, Nugent, R, Smeriglio, V, Mckinlay, S, Kalish, L, Ellis, S, and Andiman, W

Abstract

To evaluate the relation between elective cesarean section and vertical transmission of human immunodeficiency virus type 1 (HIV-1), we performed a meta-analysis using data on individual patients from 15 prospective cohort studies. North American and European studies of at least 100 mother-child pairs were included in the meta-analysis. Uniform definitions of modes of delivery were used. Elective cesarean sections were defined as those performed before onset of labor and rupture of membranes. Multivariate logistic-regression analysis was used to adjust for other factors known to be associated with vertical transmission. The primary analysis included data on 8533 mother-child pairs. After adjustment for receipt of antiretroviral therapy, maternal stage of disease, and infant birth weight, the likelihood of vertical transmission of HIV-1 was decreased by approximately 50 percent with elective cesarean section, as compared with other modes of delivery (adjusted odds ratio, 0.43; 95 percent confidence interval, 0.33 to 0.56). The results were similar when the study population was limited to those with rupture of membranes shortly before delivery. The likelihood of transmission was reduced by approximately 87 percent with both elective cesarean section and receipt of antiretroviral therapy during the prenatal, intrapartum, and neonatal periods, as compared with other modes of delivery and the absence of therapy (adjusted odds ratio, 0.13; 95 percent confidence interval, 0.09 to 0.19). Among mother-child pairs receiving antiretroviral therapy during the prenatal, intrapartum, and neonatal periods, rates of vertical transmission were 2.0 percent among the 196 mothers who underwent elective cesarean section and 7.3 percent among the 1255 mothers with other modes of delivery. The results of this meta-analysis suggest that elective cesarean section reduces the risk of transmission of HIV-1 from mother to child independently of the effects of treatment with zidovudine.

Published
1999

18. Persistence of episomal HIV-1 infection intermediates in patients on highly active anti-retroviral therapy

Author

Sharkey, M. E., Teo, I., Greenough, T., Sharova, N., Luzuriaga, K., Sullivan, J. L., Bucy, R. P., Kostrikis, Leontios G., Haase, A., Veryard, C., Davaro, R. E., Cheeseman, S. H., Daly, J. S., Bova, C., Ellison III, R. T., Mady, B., Lai, K. K., Moyle, G., Nelson, M., Gazzard, B., Shaunak, S., Stevenson, M., and Kostrikis, Leontios G. [0000-0002-5340-7109]

Subjects
RNA viruses, nevirapine, polymerase chain reaction, Human immunodeficiency virus 1, HIV Infections, Virus Replication, Reference Values, mononuclear cell, Lymphocytes, virus replication, Human immunodeficiency virus, antiretrovirus agent, drug effect, article, General Medicine, Viral Load, zalcitabine, zidovudine, ritonavir, persistent virus infection, priority journal, Reverse Transcriptase Inhibitors, RNA, Viral, Drug Therapy, Combination, lamivudine, HIV Long Terminal Repeat, Viral load, stavudine, Anti-HIV Agents, Biology, Peripheral blood mononuclear cell, General Biochemistry, Genetics and Molecular Biology, Virus, Article, nelfinavir, Pharmacotherapy, virus RNA, Human immunodeficiency virus infection, Complementary DNA, Humans, human, DNA Primers, nonhuman, Base Sequence, abacavir, indinavir, RNA, virus load, Virology, CD4 Lymphocyte Count, Viral replication, Immunology, HIV-1
Abstract

Treatment of HIV-1-infected individuals with a combination of anti- retroviral agents results in sustained suppression of HIV-1 replication, as evidenced by a reduction in plasma viral RNA to levels below the limit of detection of available assays. However, even in patients whose plasma viral RNA levels have been suppressed to below detectable levels for up to 30 months, replication-competent virus can routinely be recovered from patient peripheral blood mononuclear cells and from semen. A reservoir of latently infected cells established early in infection may be involved in the maintenance of viral persistence despite highly active anti-retroviral therapy. However, whether virus replication persists in such patients is unknown. HIV-1 cDNA episomes are labile products of virus infection and indicative of recent infection events. Using episome-specific PCR, we demonstrate here ongoing virus replication in a large percentage of infected individuals on highly active anti-retroviral therapy, despite sustained undetectable levels of plasma viral RNA. The presence of a reservoir of 'covert' virus replication in patients on highly active anti-retroviral therapy has important implications for the clinical management of HIV-1- infected individuals and for the development of virus eradication strategies. 6 76 81 Cited By :342

Published
2000

19. Persistent HIV-1-specific CTL clonal expansion despite high viral burden post in utero HIV-1 infection

Author

Christian Brander, Pj, Goulder, Luzuriaga K, Oo, Yang, Ke, Hartman, Ng, Jones, Bd, Walker, and Sa, Kalams

Subjects
Stem Cells, Epitopes, T-Lymphocyte, Gene Products, gag, Infant, HIV Infections, Viral Load, Cytotoxicity Tests, Immunologic, Virus Replication, Clone Cells, Virus Latency, Pregnancy, Child, Preschool, HIV-1, Humans, Puerperal Infection, Female, Lymphocyte Count, Pregnancy Complications, Infectious, T-Lymphocytes, Cytotoxic
Abstract

To address the issue of clonal exhaustion in humans, we monitored HLA class I-restricted, epitope-specific CTL responses in an in utero HIV-1-infected infant from 3 mo through 5 years of age. Serial functional CTL precursor assays demonstrated persistent, vigorous, and broadly directed HIV-1 specific CTL activity with a dominant response against an epitope in HIV-1 Gag-p17 (SLYNTVATL, aa 77-85). A clonal CTL response directed against the immunodominant, HLA-A*0201-restricted epitope was found to persist over the entire observation period, as shown by TCR analysis of cDNA libraries generated from PBMC. The analysis of autologous viral sequences did not reveal any escape mutations within the targeted epitope, and viral load measurement indicated ongoing viral replication. Furthermore, inhibition of viral replication assays indicated that the epitope was properly processed from autologous viral protein. These data demonstrate that persistent exposure to high levels of viral Ag does not necessarily lead to clonal exhaustion and that epitope-specific clonal CTL responses induced within the first weeks of life can persist for years without inducing detectable viral escape variants.

Published
1999

20. The mode of delivery and the risk of vertical transmission of human immunodeficiency virus type 1--a meta-analysis of 15 prospective cohort studies. The International Perinatal HIV Group

Author

Andiman, W., Boucher, M., Burns, D., Bryson, Y., Farley, J., Fowler, H, Gabiano, C., Gall, L., Hutto, C., Kind, C, Korber, B., Kovacs, A., Krogstad, P., Landesman, S., Lapointe, N., Lemay, M, Lew, J, Mandelbrot, L., Mayaux, Mj, Mellins, R., Minkoff, H., Mofenson, L., Nielsen, K, Newell, Ml, Pardi, G., Peavy, H., Peckham, C., Read, J., Rother, C, Rudin, C., Scott, G., Semprini, A., Shearer, W., Simonds, R., Simpson, A, Stek, A., Tovo, Pa, Tuomala, R., Van Dyke, R., Weedon, J., de Martino, M., Lindsay, M., Belair, S., Chan, L., Harris, D, Kalish, L., Muenz, L., Nugent, R., Schluchter, M., Durako, S., Goodwin, S., Mitchell, R., Nourjah, P., Owen, W., Widmayer, S., Ardeguez, A., Hanson, C., Wiznia, A., Luzuriaga, K., Viscarello, R, Ho, D., Koup, R., Chen, I., Mullins, J., Wolinsky, S., Walker, B, Ammann, A., Clapp, S., Mcdonald, D, Fauvel, M., Hankins, C, Samson, J., Bailey, A., Giaquinto, Carlo, Ruga, E., DE ROSSI, Anita, and Truscia, D.

Subjects
ZIDOVUDINE PROPHYLAXIS, INFANT HIV TRANSMISSION, MOTHER-TO-CHILD, MOTHER-TO-CHILD, INFANT HIV TRANSMISSION, CESAREAN-SECTION, ZIDOVUDINE PROPHYLAXIS, CESAREAN-SECTION
Published
1999

21. A polymorphism in the regulatory region of the CC-chemokine receptor 5 gene influences perinatal transmission of human immunodeficiency virus type 1 to African-American infants

Author

Deutsch, L., Kostrikis, Leontios G., Neumann, A. U., Thomson, B., Korber, B. T., McHardy, P., Karanicolas, R., Huang, Y., Lew, J. F., McIntosh, K., Pollack, H., Borkowsky, W., Spiegel, H. M. L., Palumbo, P., Oleske, J., Bardeguez, A., Luzuriaga, K., Sullivan, J., Wolinsky, S. M., Koup, R. A., Ho, David D., Moore, J. P., and Kostrikis, Leontios G. [0000-0002-5340-7109]

Subjects
Adult, Genotype, Receptors, CCR5, Anti-HIV Agents, regulatory mechanism, European Continental Ancestry Group, HIV Infections, Regulatory Sequences, Nucleic Acid, Linkage Disequilibrium, Cohort Studies, ethnic group, Gene Frequency, chemokine receptor ccr5, newborn, Humans, genetic polymorphism, controlled study, human, gene mutation, Receptors, Cytokine, Alleles, disease transmission, African Americans, Polymorphism, Genetic, Disease Transmission, Vertical, disease course, article, virus diseases, chemokine receptor, major clinical study, infant, Perinatal Care, priority journal, HIV-1, Female, vertical transmission, Receptors, Chemokine, homozygosity, Hispanic Americans, 5' Untranslated Regions, human immunodeficiency virus 1, caucasian, Zidovudine
Abstract

There are natural mutations in the coding and noncoding regions of the human immunodeficiency virus type (HIV-1) CC-chemokine coreceptor 5 (CCR5) and in the related CCR2 protein (the CCR2-64I mutation). Individuals homozygous for the CCRS-Δ32 allele, which prevents CCR5 expression, strongly resist HIV-1 infection. Several genetic polymorphisms have been identified within the CCR5 5' regulatory region, some of which influence the rate of disease progression in adult AIDS study cohorts. We genotyped 1,442 infants (1,235 uninfected and 207 HIV-1 infected) for five CCR5 and CCR2 polymorphisms- CCR5-59353-T/C, CCR5-59356C/T CCR5-59402-A/G, CCRS-Δ32, and CCR2-64I. The clinical significance of each genotype was assessed by measuring whether it influenced the rate of perinatal HIV-1 transmission among 667 AZT-untreated motherinfant pairs (554 uninfected and 113 HIV-1 infected). We found that the mutant CCR5-59356-T allele is relatively common in African-Americans (20.6% allele frequency among 552 infants) and rare in Caucasians and Hispanics (3.4 and 5.6% of 174 and 458 infants, respectively P < 0.001). There were 38 infants homozygous for CCR5-59356-T, of whom 35 were African-Americans. Among the African-American infants in the AZT- untreated group, there was a highly significant increase in HIV-1 transmission to infants with two mutant CCR5-59356-T alleles (47.6% of 21), compared to those with no or one mutant allele (13.4 to 14.1% of 187 and 71, respectively P < 0.001). The increased relative risk was 5.9 (95% confidence interval, 2.3 to 15.3 P < 0.001). The frequency of the CCR5-59356-T mutation varies between population groups in the United States, a low frequency occurring in Caucasians and a higher frequency occurring in African- Americans. Homozygosity for CCR5-59356-T is strongly associated with an increased rate of perinatal HIV-1 transmission. 73 10264 10271 Cited By :109

Published
1999

22. BIRTH-ORDER, DELIVERY ROUTE, AND CONCORDANCE IN THE TRANSMISSION OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 FROM MOTHERS TO TWINS

Author

DULIEGE, AM, AMOS, CI, FELTON, S, BIGGAR, RJ, ZIEGLER, J, CRUIKSHANK, M, LEVY, J, MEATES, MA, GIBB, D, MAYAUX, MJ, TEGLAS, JP, LAURENT, C, BLANCHE, S, ROUZIOUX, C, HELLINGGIESE, G, MATTNER, U, HOEGER, PH, CONLON, T, GRIFFIN, E, DEMARIA, A, BENEDETTO, A, PRINCIPI, N, GIAQUINTO, C, GIANCOMELLI, A, MOK, J, CASABONA, J, FORTUNY, C, URIZ, S, PEREZ, JM, TUSETRUIZ, MC, LEON, P, ELORZA, JFY, CANOSA, C, BRANDLE, B, SEGER, R, NADAL, D, IRION, O, WYLER, CA, DAVIS, P, LALLEMANT, M, LALLEMANTLECOEUR, S, HITIMANA, DG, LEPAGE, P, VANDEPERRE, P, DABIS, F, MARUM, L, NDUGWA, C, TINDYEBWA, D, ACENG, E, MMIRO, F, SUTONGAS, T, OLNESS, K, LAPOINTE, N, RUBINSTEIN, A, BURGE, D, STECHENBERG, BW, COOPER, E, REGAN, AM, SHIPKOWITZ, S, WIZNIA, A, BRUNELL, PA, COURVILLE, T, RUTSTEIN, R, MCINTOSH, K, PETRU, A, OLEARY, M, CHURCH, J, TAYLOR, S, SQUIRES, J, MALLORY, M, YOGEV, R, RAKUSAN, T, PLUMLEY, S, SHELTON, MM, WILFERT, C, LANE, B, ABRAMS, EJ, RANA, S, CHANDAVASU, O, PUVABANDITSIN, S, CHOW, JH, SHAH, K, NACHMAN, S, ONEILL, R, SELWYN, P, SHOENBAUM, E, BARZILAI, A, WARFORD, R, AHERN, L, PAHWA, S, PNUGOTI, N, GARCIATRIAS, DE, BAKSHI, S, LANDESMAN, S, MENDEZ, H, MOROSO, G, MENDEZBAUTISTA, RD, FIKRIG, S, BELMAN, A, KLINE, MW, HANSON, C, EDELSON, P, HINDS, G, VANDYKE, R, CLARK, R, WARA, DW, MANIO, EB, JOHNSON, G, WELLS, L, JOHNSON, JP, ALGER, L, LUZURIAGA, K, MASTRUCCI, T, SUNKUTU, MR, RODRIGUEZ, Z, DOYLE, M, REUBEN, J, BRYSON, Y, DILLON, M, SIMPSON, BJ, ANDIMAN, W, URIBE, P, Klauke, B., and University of Groningen

Subjects
RISK, HIV-1 INFECTION, ANTIBODIES, WOMEN, INFANTS, CHILDREN, POLYMERASE CHAIN-REACTION, DIAGNOSIS, LABOR, SECRETIONS
Abstract

Background: We evaluated data from prospectively identified twins to understand better the mechanisms and covariates of mother-to-infant transmission of human immunodeficiency virus (HIV). Methods: Using data obtained from an international collaboration and multivariate quasilikelihood modeling, we assessed concordance, birth order, route of delivery, and other factors for HIV infection in 115 prospectively studied twin pairs born to HIV-infected women. Actuarial methods were used to evaluate overall survival and survival free of acquired immunodeficiency syndrome for HIV-infected twins. Results: Infection with HIV occurred in 35% of vaginally delivered firstborn (A) twins, 16% of cesarean-delivered A twins, 15% of vaginally delivered second-born (B) twins, and 8% of cesarean-delivered B twins. In a multivariate model, the adjusted odds ratios for HIV infection were 11.8 (confidence interval: 3.1 to 45.3) for concordance of infection with the co-twin, 2.8 (confidence interval: 1.6 to 5.0) for A versus B twins, and 2.7 (confidence interval: 1.1 to 6.6) for vaginally delivered versus cesarean-delivered twins. Among A twins, 52% (lower confidence limit: 6%) of the transmission risk was related to vaginal delivery, Comparing vaginally delivered A twins (infants most exposed to vaginal mucus and blood) to cesarean-delivered B twins (infants least exposed), 76% (lower confidence limit: 48%) of the transmission risk was related to vaginal exposure. Infected B twins had slightly reduced Quetelet indexes and more rapid development of illnesses related to acquired immunodeficiency syndrome. Conclusions: These results indicate that HIV infection of B twins occurs predominantly in utero, whereas infection of A twins (and, by implication, singletons) occurs predominantly intrapartum, We propose that intrapartum transmission is responsible for the majority of pediatric HIV infections and that reducing exposure to HIV in the birth canal may reduce transmission of the virus from mother to infant.

Published
1995

25. Overlapping epitopes in human immunodeficiency virus type 1 gp120 presented by HLA A, B, and C molecules: effects of viral variation on cytotoxic T-lymphocyte recognition

Author

Wilson, C C, primary, Kalams, S A, additional, Wilkes, B M, additional, Ruhl, D J, additional, Gao, F, additional, Hahn, B H, additional, Hanson, I C, additional, Luzuriaga, K, additional, Wolinsky, S, additional, Koup, R, additional, Buchbinder, S P, additional, Johnson, R P, additional, and Walker, B D, additional

Published
1997
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34. Identification and characterization of HIV-1 CD8+ T cell escape variants with impaired fitness.

Author

Sanchez-Merino V, Farrow MA, Brewster F, Somasundaran M, and Luzuriaga K

Abstract

In this study, amino acid sequence variation in human immunodeficiency virus (HIV)-1 Gag CD8(+) T cell epitopes was examined in untreated mother-infant pairs. Several HIV-1 CD8(+) T cell escape variants were identified within maternal plasma viral p17 and p24 sequences that were either not detected or did not persist in the plasma of their non-HLA-matched HIV-1-infected infants. Viruses constructed with each of these mutations demonstrated reduced viral replication in vitro and reduced expression of p17 and p24 proteins compared with wild type. Reduced recognition of the variant sequences compared with wild-type sequence was also demonstrated by enzyme-linked immunospot assays. Nontransmission or reversion after transmission was thus associated with reduced viral fitness cost in vivo. Better understanding of the balance between CD8(+) T cell selective pressures and viral fitness cost may facilitate the identification of optimal viral sequences for inclusion in HIV-1 vaccines. Copyright © 2008 Infectious Diseases Society of America [ABSTRACT FROM AUTHOR]

Published
2008
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35. Cytomegalovirus (CMV) IE1- and pp65-specific CD8+ T cell responses broaden over time after primary CMV infection in infants.

Author

Gibson L, Dooley S, Trzmielina S, Somasundaran M, Fisher D, Revello MG, and Luzuriaga K

Abstract

Cytomegalovirus (CMV) infection remains a significant cause of morbidity and mortality in young children. We have previously shown that CD8(+) T cell responses to CMV pp65 or IE1 protein were readily detectable in children with congenital or postnatal CMV infection. Here, we have further characterized the evolution of the peptide specificity of these responses in 7 infants <6 months of age at the start of the study. Thirteen pp65 and 15 IE1 peptides (median, 5 peptides/infant) were targeted, and most (61%) represented sequences not previously reported. Peptide specificity remained stable or broadened over time despite the clearance of CMV viremia. Loss of peptide recognition was not observed. Responses with the highest functional peptide avidity were not necessarily detected earliest. These data provide additional evidence that young infants can generate diverse CMV-specific CD8(+) T cell responses but show that early responses may exhibit relatively focused peptide specificity and lower peptide avidity. Copyright © 2007 Infectious Diseases Society of America [ABSTRACT FROM AUTHOR]

Published
2007
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38. Combination antiretroviral therapy offers new hope for HIV-infected infants

Author

Luzuriaga, K., Bryson, Y., and Krogstad, P.

Subjects
Zidovudine -- Health aspects -- Research, HIV infection in children -- Drug therapy -- Research -- Health aspects, Antiviral agents -- Research -- Health aspects, Anti-infective agents -- Research -- Health aspects, Didanosine -- Health aspects -- Research, AIDS (Disease) -- Drug therapy -- Research -- Health aspects, HIV infection -- Drug therapy -- Research -- Health aspects, Health, Drug therapy, Research, Health aspects
Abstract

Infants and children who have maternally acquired HIV infection have received limited benefit from therapy with a single antiretroviral agent. However, the results of this study indicate that combination therapy [...]

Published
1997

39. The Ariel Project: a prospective cohort study of maternal-child transmission of human immunodeficiency virus type 1 in the era of maternal antiretroviral therapy [corrected] [published erratum appears in J INFECT DIS 1999 Mar; 179(3): 754].

Author

Van Dyke RB, Korber BT, Popek E, Macken C, Widmayer SM, Bardeguez A, Hanson IC, Wiznia A, Luzuriaga K, Viscarello RR, Wolinsky S, and Ariel Core Investigators

Abstract

In a prospective cohort study, clinical and biologic factors that contribute to maternal-child transmission of human immunodeficiency virus type 1 (HIV-1) were studied. HIV-infected pregnant women and their infants were evaluated prospectively according to a standardized protocol. Of 204 evaluable women, 81% received zidovudine during their pregnancy. The infection rate among the 209 evaluable infants was 9.1%. By univariate analysis, histologic chorioamnionitis, prolonged rupture of membranes, and a history of genital warts were significantly associated with transmission. Additional factors associated with transmission that approached significance included a higher maternal virus load at delivery and the presence of cocaine in the urine. In a logistic regression model, histologic chorioamnionitis was the only independent predictor of transmission. Despite a significantly higher transmission rate at one site, no unique viral genotype was found at any site. Thus, chorioamnionitis was found to be the major risk factor for transmission among women receiving zidovudine. Copyright © 1999 The University of Chicago [ABSTRACT FROM AUTHOR]

Published
1999
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41. Nitrate biosynthesis in man.

Author

Green, L C, Ruiz de Luzuriaga, K, Wagner, D A, Rand, W, Istfan, N, Young, V R, and Tannenbaum, S R

Abstract

Nitrate metabolism was investigated in long-term metabolic studies in healthy young men. Under conditions of constant low ingestion of nitrate (less than 180 mumol/day per subject), the amount of nitrate excreted in urine was an average of 4-fold greater than the amount ingested. Balance studies with 15NO3- showed that the source of the excess nitrate in urine was the endogenous biosynthesis of nitrate, rather than the emptying of a body pool. Nitrate biosynthesis occurred when nitrate ingestion was high as well as low, and the amounts synthesized appeared to be independent of intake and comparable to the amounts ingested from normal diets. Analysis of the 15NO3- data also revealed that half of ingested nitrate was recovered as urinary nitrate. Because nitrate in urine is the net result of (i) intake, (ii) endogenous synthesis, and (iii) metabolic losses, the magnitude of the losses is such that, despite ongoing synthesis, the amount of nitrate in the urine of people consuming most diets will be less than the amount ingested.

Published
1981
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42. Frequent detection of escape from cytotoxic T-lymphocyte recognition in perinatal human immunodeficiency virus (HIV) type 1 transmission: The Ariel project for the prevention of transmission of HIV from mother to infant

Author

Wilson, C. C., Brown, R. C., Bette Korber, Wilkes, B. M., Ruhl, D. J., Sakamoto, D., Kunstman, K., Luzuriaga, K., Hanson, I. C., Widmayer, S. M., Wiznia, A., Clapp, S., Ammann, A. J., Koup, R. A., Wolinsky, S. M., Walker, B. D., Dyke, R. B., Bardeguez, A., Viscarello, R. R., Ho, D., Koup, R., Chen, I., Krogstad, P., and Mullins, J.

43. Antiretroviral therapy and medical management of the human immunodeficiency virus–infected

Author

Connor, E. M., Pizzo, P. A., Frank Balis, Hughes, W., Katz, S., Mc Sherry, G., Oleske, O., Scott, G., W Ara, D., Wilfert, C., Burr, C., Grubman, S., Abrams, E., Ammann, A. J., Bardeguez, A., Balsley, J. F., Broadbent, P. A., Brouwers, P., Bryson, Y. J., Collabelli, N., Connor, J., Cooper, E., Diaz, C., Dipaolo, C., Fischer, G. W., Fowler, M. G., Frenkel, L. M., Grant, R., Goldsmith, J. C., Goosby, E., Gordon, E., Hale, A. R., Hernandez, V., Husson, R., Kovacs, A., Krasinski, K., Luzuriaga, K., Mc Kinney, R., Mc Intosh, K., Mc Pherson, M., Mintz, M., Mofenson, L. M., Moretti, L., Nyman, N., Oxtoby, M., Richartz, K., Santacrose, S., Spector, S. A., Sperling, R., Tudor-Williams, G., Dyke, R., Vendrell, J., Winter, H., Yogev, R., Boland, M., and Murphy, D.

45. Workshop on perinatally acquired human immuno-deficiency virus infection in long-term surviving children: A collaborative study of factors contributing to slow disease progression

Author

Martin, N., Koup, R., Kaslow, R., Ammann, A. A., Ammann, A. J., Asthana, D., Baur, A., Bryson, Y., Clapp, S., DeLaurentis, S., Devine, T., Feinberg, M., Fitzgibbon, J. E., Fowler, M. G., Garratty, E. M., Geffin, R., Gonzaga, A., Gray, M., Hetherington, S., Jansen, J. K., Kaslow, R. A., Keller, A., Klotman, M. E., Korber, B., Louzao, A., Luzuriaga, K., Macken, C., Mathieson, B., McSherry, G., Muldoon, M., Mullins, J. I., Nielsen, K., Oleske, J., Palumbo, P., Petru, A., Plaeger, S., Riviere, Y., Rossi, P., Scott, G., Sullivan, J. L., Vermund, S. H., Wara, D., Winchester, R. J., Winkler, C., Zeegen, S., Martin, N., Koup, R., Kaslow, R., Ammann, A. A., Ammann, A. J., Asthana, D., Baur, A., Bryson, Y., Clapp, S., DeLaurentis, S., Devine, T., Feinberg, M., Fitzgibbon, J. E., Fowler, M. G., Garratty, E. M., Geffin, R., Gonzaga, A., Gray, M., Hetherington, S., Jansen, J. K., Kaslow, R. A., Keller, A., Klotman, M. E., Korber, B., Louzao, A., Luzuriaga, K., Macken, C., Mathieson, B., McSherry, G., Muldoon, M., Mullins, J. I., Nielsen, K., Oleske, J., Palumbo, P., Petru, A., Plaeger, S., Riviere, Y., Rossi, P., Scott, G., Sullivan, J. L., Vermund, S. H., Wara, D., Winchester, R. J., Winkler, C., and Zeegen, S.

46. The Ariel Project: A prospective cohort study of maternal-child transmission of human immunodeficiency virus type 1 in the era of maternal antiretroviral therapy

Author

Van Dyke, R. B., Korber, B. T., Popek, E., Macken, C., Widmayer, S. M., Bardeguez, A., Hanson, I. C., Wiznia, A., Luzuriaga, K., Viscarello, R. R., Wolinsky, S., Ariel Core Investigators, the, Van Dyke, R. B., Korber, B. T., Popek, E., Macken, C., Widmayer, S. M., Bardeguez, A., Hanson, I. C., Wiznia, A., Luzuriaga, K., Viscarello, R. R., Wolinsky, S., and Ariel Core Investigators, the

Abstract

In a prospective cohort study, clinical and biologic factors that contribute to maternal-child transmission of human immunodeficiency virus type 1 (HIV-1) were studied. HIV-infected pregnant women and their infants were evaluated prospectively according to a standardized protocol. Of 204 evaluable women, 81% received zidovudine during their pregnancy. The infection rate among the 209 evaluable infants was 9.1%. By univariate analysis, histologic chorioamnionitis, prolonged rupture of membranes, and a history of genital warts were significantly associated with transmission. Additional factors associated with transmission that approached significance included a higher maternal virus load at delivery and the presence of cocaine in the urine. In a logistic regression model, histologic chorioamnionitis was the only independent predictor of transmission. Despite a significantly higher transmission rate at one site, no unique viral genotype was found at any site. Thus, chorioamnionitis was found to be the major risk factor for transmission among women receiving zidovudine.

49. Combination treatment with Zidovudine, didanosine, and nevirapine in infants with human immunodeficiency virus type 1 infection

Author

Luzuriaga, K., Bryson, Y., Krogstad, P., Robinson, J., Stechenberg, B., Lamson, M., Cort, S., and Sullivan, J.L.

Subjects
HIV infection -- Drug therapy, Drug therapy, Combination -- Usage
Abstract

Luzuriaga, K.; Bryson, Y.; Krogstad, P.; Robinson, J.; Stechenberg, B.; Lam- son, M.; Cort, S.; Sullivan, J.L. "Combination Treatment with Zidovudine, Didanosine, and Nevirapine in Infants with Human Immunodeficiency Virus [...]

Published
1997

50. Early HIV-1 envelope-specific cytotoxic T lymphocyte responses in vertically infected infants

Author

Pikora, C.A., Sullivan, J.L., Panicali, D., and Luzuriaga, K.

Subjects
Disease susceptibility -- Physiological aspects, HIV infection
Abstract

Pikora, C.A.; Sullivan, J.L.; Panicali, D.; Luzuriaga, K. "Early HIV-1 Envelope-Specific Cytotoxic T Lymphocyte Responses in Vertically Infected Infants." Journal of Experimental Medicine, April 7, 1997;185(7):1153-1161. According to the authors' [...]

Published
1997

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