CD4+ and viral load outcomes of antiretroviral therapy switch strategies after virologic failure of combination antiretroviral therapy in perinatally HIV-infected youth in the United States

Lee Fairlie, Brad Karalius, Kunjal Patel, Russell B van Dyke, Rohan Hazra, Miguel A Hernán, George K Siberry, George R Seage 3rd, Allison Agwu, Andrew Wiznia, Pediatric HIV AIDS Cohort Study (PHACS), The International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT), Lee Fairlie, Brad Karalius, Kunjal Patel, Russell B van Dyke, Rohan Hazra, Miguel A Hernán, George K Siberry, George R Seage 3rd, Allison Agwu, Andrew Wiznia, Pediatric HIV AIDS Cohort Study (PHACS), The International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT)

Abstract

Objective: This study compared 12-month CD4 and viral load outcomes in HIV-infected children and adolescents with virological failure, managed with four treatment switch strategies.

Design: This observational study included perinatally HIV-infected (PHIV) children in the Pediatric HIV/AIDS Cohort Study (PHACS) and Pediatric AIDS Clinical Trials (PACTG) Protocol 219C.

Methods: Treatment strategies among children with virologic failure were compared: continue failing combination antiretroviral therapy (cART); switch to new cART; switch to drug-sparing regimen; and discontinue all ART. Mean changes in CD4% and viral load from baseline (time of virologic failure) to 12 months follow-up in each group were evaluated using weighted linear regression models.

Results: Virologic failure occurred in 939 out of 2373 (40%) children. At 12 months, children switching to new cART (16%) had a nonsignificant increase in CD4% from baseline, 0.59 percentage points [95% confidence interval (95% CI) -1.01 to 2.19], not different than those who continued failing cART (71%) (-0.64 percentage points, P = 0.15) or switched to a drug-sparing regimen (5%) (1.40 percentage points, P = 0.64). Children discontinuing all ART (7%) experienced significant CD4% decline -3.18 percentage points (95% CI -5.25 to -1.11) compared with those initiating new cART (P = 0.04). All treatment strategies except discontinuing ART yielded significant mean decreases in log10VL by 12 months, the new cART group having the largest drop (-1.15 log10VL).

Conclusion: In PHIV children with virologic failure, switching to new cART was associated with the best virological response, while stopping all ART resulted in the worst immunologic and virologic outcomes and should be avoided. Drug-sparing regimens and continuing failing regimens may be considered with careful monitoring.

Figures

Fig. 1
Fig. 1
Treatment strategies following virologic failure, by time since failure for those remaining in follow-up.

References

    1. Violari A, Cotton MF, Gibb DM, Babiker AG, Steyn J, Madhi SA, et al. Early antiretroviral therapy and mortality among HIV-infected infants. N Engl J Med 2008; 359:2233.
    1. Meyers T, Dramowsk A, Schneider H, Gardiner N, Kuhn L, Moore D. Changes in pediatric HIV-related hospital admissions and mortality in Soweto, South Africa, 1996-2011: light at the end of the tunnel?. J Acquir Immun Defic Syndr 2012; 60:503–510.
    1. Viani RM, Araneta MRG, Deville JG, Spector SA. Decrease in hospitalization and mortality rates among children with perinatally acquired HIV type 1 infection receiving highly active antiretroviral therapy. Clin Infect Dis 2004; 39:725–731.
    1. Laughton B, Cornell M, Grove D, Kidd M, Springer PE, Dobbels E, et al. Early antiretroviral therapy improves neurodevelopmental outcomes in infants. AIDS Behav 2012; 26:1685–1690.
    1. Patel K, Van Dyke RB, Mittleman MA, Colan SD, Oleske JM, Seage GR, 3rd, et al. The impact of HAART on cardiomyopathy among children and adolescents perinatally infected with HIV-1. AIDS Behav 2012; 26:2027–2037.
    1. Lipshultz SE, Williams PL, Wilkinson JD, Leister E, Van Dyke R, Shearer WT, et al. Cardiac status of HIV-infected children treated with long-term combination antiretroviral therapy: results from the Adolescent Master Protocol of the NIH multicentre Pediatric HIV/AIDS cohort study. JAMA Pediatr 2013; 167:520–527.
    1. World Health Organization. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV Infection recommendations for a public health approach. Geneva, Switzerland: WHO Press; 2013.
    1. Hazra R, Siberry G, Mofenson aL. Growing up with HIV: children, adolescents, and young adults with perinatally aquired HIV infection. Annu Rev Med 2010; 61:169–185.
    1. Williams PL, Storm D, Montepiedra G, Nichols S, Kammerer B, Sirois PA, et al. Predictors of adherence to antiretroviral medications in children and adolescents with HIV infection. Pediatrics 2006; 118:e1745–e1757.
    1. Nachega JB, Hislop M, Nguyen H, Dowdy DW, Chaisson RE, Regensberg L, et al. Antiretroviral therapy adherence, virologic and immunologic outcomes in adolescents compared with adults in Southern Africa. J Acquir Immune Defic Syndr 2009; 51:65–71.
    1. Davies M-A, Keiser O, Technau K, Eley B, Rabie H, Cutsem GV, et al. Virologic failure and second-line antiretroviral therapy in children in South Africa: the IeDEA Southern Africa Collaboration. J Acquir Immune Defic Syndr 2011; 56:270–278.
    1. Musoke PM, Mudiope P, Barlow-Mosha LN, Ajuna P, Bagenda D, Mubiru MM, et al. Growth, immune and viral responses in HIV infected African children receiving highly active antiretroviral therapy: a prospective cohort study. BMC Pediatr 2010; 10:56.
    1. Van Dyke RB, Patel K, Siberry GK, Burchett SK, Spector SA, Chernoff MC, et al. Antiretroviral treatment of U.S. children with perinatally-acquired HIV infection: temporal changes in therapy between 1991 and 2009 and predictors of immunologic and virologic outcomes. J Acquir Immune Defic Syndr 2011; 57:165–173.
    1. Wong FL, Hsu AJ, Pham PA, Siberry GK, Hutton N, Agwu aAL. Antiretroviral treatment strategies in highly treatment experienced perinatally HIV-infected youth. Pediatr Infect Dis J 2012; 31:1279–1283.
    1. Panel on Antiretroviral Therapy and Medical Management of HIV-Infected Children. Guidelines for the use of antiretroviral agents in pediatric HIV infection. Available at [Accessed 15 December 2012]
    1. The PENPACT-1 (PENTA 9 /PACTG 390) Study Team First-line antiretroviral therapy with a protease inhibitor versus non-nucleoside reverse transcriptase inhibitor and switch at higher versus low viral load in HIV-infected children: an open-label, randomised phase 2/3 trial. Lancet Infect Dis 2011; 11:273–283.
    1. Abadi J, Sprecher E, Rosenberg MG, Dobroszycki J, Sansary J, Fennelly G, et al. Partial treatment interruption of protease inhibitor based highly active antiretroviral therapy regimens in HIV-infected children. J Acquir Immune Defic Syndr 2006; 41:289–303.
    1. Siberry GK, Patel K, Dyke RBV, Hazra R, Burchett SK, Spector SA, et al. CD4+ lymphocyte-based immunologic outcomes of perinatally HIV-infected children during antiretroviral therapy interruption. J Acquir Immune Defic Syndr 2011; 57:223–229.
    1. Division of AIDS. Table for grading the severity of adult and pediatric adverse events version 1.0. December 2004; Clarification August 2009. Available at . [Accessed 12 December 2012].
    1. The HIV Causal Collaboration When to initiate combined antiretroviral therapy to reduce mortality and AIDS-defining illness in HIV-infected persons in developed countries: an observational study. Ann Intern Med 2011; 154:509–515.
    1. Centres for Disease Control and Prevention. 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. MMWR 1993. Available at [Accessed 12 December 2012].
    1. Centres for Disease Control and Prevention. 1994 Revised classification system for human immunodeficiency virus infection in children less than 13 years of age. MMWR 1994. Available at [Accessed 12 December 2012].
    1. Gibb DM, Duong T, Leclezio VA, Walker AS, Verweel G, Dunn DT, et al. Immunologic changes during unplanned treatment interruptions of highly active antiretroviral therapy in children with human immunodeficiency virus type 1 infection. Pediatr Infect Dis J 2004; 23:446–450.
    1. Klein N, Sefe D, Mosconi I, Zanchetta M, Castro H, Jacobsen M, et al. The immunological and virological consequences of planned treatment interruptions in children with HIV infection. PLoS One 2013; 8:e76582.
    1. Lee KJ, Lyall EGH, Walker AS, Sharland M, Judd A, Gibb DM, et al. Wide disparity in switch to second-line therapy in HIV infected children in CHIPS. Eighth International Congress on Drug Therapy in HIV infection; 12 November 2006; Glasgow.
    1. Johnston V, Fielding KL, Charalambous S, Churchyard G, Phillips A, Grant AD. Outcomes following virological failure and predictors of switching to second-line antiretroviral therapy in a South African treatment programme. J Acquir Immune Defic Syndr 2012; 61:370–380.
    1. Deeks SG, Barbour JD, Martin JN, Swanson MS, Grant RM. Sustained CD4+ T cell response after virologic failure of protease inhibitor–based regimens in patients with human immunodeficiency virus infection. J Infect Dis 2000; 181:946–953.
    1. Petersen ML, van der Laan MJ, Napravnik S, Eron JJ, Moore RD, Deeks SG. Long term consequences of the delay between virologic failure of highly active antiretroviral therapy and regimen modification. AIDS 2008; 22:2097–2106.
    1. Agwu A, Warshaw M, Siberry G, Melvin A, McFarland E, Wiznia A, et al. 3TC/FTC monotherapy vs. continuing failing cART as a bridging ART strategy in persistently nonadherent HIV-infected youth with M184 V resistance: results of IMPAACT P1094. 6th International Workshop on HIV Pediatrics; 18 July 2014; Melbourne, Australia, oral presentation.
    1. ARROW Trial team Routine versus clinically driven laboratory monitoring and first-line antiretroviral therapy strategies in African children with HIV (ARROW): a 5-year open-label randomised factorial trial. Lancet 2013; 381:1391–1403.
    1. Lazarus EM, Otwombe K, Fairlie L, Untiedt S, Violari A, Laher F, et al. Lamivudine monotherapy as a holding strategy in HIV-infected children in South Africa. J AIDS Clin Res 2013; 4:246–251.
    1. Opravil M, Klimkait T, Louvel S, Wolf E, Battegay M, Fux CA, et al. Prior therapy influences the efficacy of lamivudine monotherapy in patients with lamivudine-resistant HIV-1 infection. J Acquir Immune Defic Syndr 2010; 54:51–58.
    1. Palmer M, Chersich M, Moultrie H, Kuhn L, Fairlie L, Meyers T. Frequency of stavudine substitution due to toxicity in children receiving antiretroviral treatment in Soweto, South Africa. AIDS 2012; 27:781–785.
    1. Giaquinto C, Morelli E, Fregonese F, Rampon O, Penazzato M, de Rossi A, et al. Current and future antiretroviral treatment options in paediatric HIV infection. Clin Drug Invest 2008; 28:375–397.
    1. Scanlon ML, Vreeman RC. Current strategies for improving access and adherence to antiretroviral therapies in resource-limited settings. HIV AIDS 2013; 5:1–17.
    1. Agwu AL, Fairlie L. Antiretroviral treatment, management challenges and outcomes in perinatally HIV-infected adolescents. J Int AIDS Soc 2013; 16:18579.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe