Antiretroviral therapy outcomes in HIV-infected children after adjusting protease inhibitor dosing during tuberculosis treatment

Cordula Frohoff, Magendhree Moodley, Lee Fairlie, Ashraf Coovadia, Harry Moultrie, Louise Kuhn, Tammy Meyers, Cordula Frohoff, Magendhree Moodley, Lee Fairlie, Ashraf Coovadia, Harry Moultrie, Louise Kuhn, Tammy Meyers

Abstract

Background: Modification of ritonavir-boosted lopinavir (LPV/r)-based antiretroviral therapy is required for HIV-infected children co-treated for tuberculosis (TB). We aimed to determine virologic and toxicity outcomes among TB/HIV co-treated children with the following modifications to their antiretroviral therapy (ART): (1) super-boosted LPV/r, (2) double-dose LPV/r or (3) ritonavir.

Methods and findings: A medical record review was conducted at two clinical sites in Johannesburg, South Africa. The records of children 6-24 months of age initiating LPV/r-based therapy were reviewed. Children co-treated for TB were categorized based on the modifications made to their ART regimen and were compared to children of the same age at each site not treated for TB. Included are 526 children, 294 (56%) co-treated for TB. All co-treated children had more severe HIV disease, including lower CD4 percents and worse growth indicators, than comparisons. Children in the super-boosted group (n = 156) were as likely to be virally suppressed (<400 copies/ml) at 6 months as comparisons (69.2% vs. 74.8%, p = 0.36). Children in the double-dose (n = 47) and ritonavir groups (n = 91) were significantly less likely to be virally suppressed at 6 months (53.1% and 49.3%) than comparisons (74.8% and 82.1%; p = 0.02 and p<0.0001, respectively). At 12 months only children in the ritonavir group still had lower rates of virological suppression relative to comparisons (63.9% vs 83.3% p<0.05). Grade 1 or greater ALT elevations were more common in the super-boosted (75%) than double-dose (54.6%) or ritonavir (33.9%) groups (p = 0.09 and p<0.0001) but grade 3/4 elevations were observed in 3 (13.6%) of the super-boosted, 7 (15.9%) of the double-dose and 5 (8.9%) of the ritonavir group (p = 0.81 and p = 0.29).

Conclusion: Good short-term virologic outcomes were achieved in children co-treated for TB and HIV who received super-boosted LPV/r. Treatment limiting toxicity was rare. Strategies for increased dosing of LPV/r with TB treatment warrant further investigation.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1. Flow diagram of study participants.
Figure 1. Flow diagram of study participants.

References

    1. Dye C, Fengzeng Z, Scheele S, Williams B. Evaluating the impact of tuberculosis control: number of deaths prevented by short-course chemotherapy in China. Int J Epidemiol. 2000;29:558–564.
    1. World Health Organization W, editor. World Health Organization W. Global Tuberculosis Control, a short update to the 2009 report. 2009.
    1. Nelson LJ, Wells CD. Global epidemiology of childhood tuberculosis. Int J Tuberc Lung Dis. 2004;8:636–647.
    1. Elenga N, Kouakoussui KA, Bonard D, Fassinou P, Anaky MF, et al. Diagnosed tuberculosis during the follow-up of a cohort of human immunodeficiency virus-infected children in Abidjan, Côte d'Ivoire. Pediatr Infect Dis J. 2005;24:1077–1082.
    1. Palme IB, Gudetta B, Bruchfeld J, Muhe L, Giesecke J. Impact of human immunodeficiency virus 1 infection on clinical presentation, treatment outcome and survival in a cohort of Ethiopian children with tuberculosis. Pediatr Infect Dis J. 2002;21:1053–1061.
    1. Vishnuvardhan D, Moltke LL, Richert C, Greenblatt DJ. Lopinavir: acute exposure inhibits P-glycoprotein; extended exposure induces P-glycoprotein. AIDS. 2003;17:1092–1094.
    1. Sham HL, Kempf DJ, Molla A, Marsh KC, Kumar GN, et al. ABT-378, a highly potent inhibitor of the human immunodeficiency virus protease. Antimicrob Agents Chemother. 1998;42:3218–3224.
    1. Burger DM, Agarwala S, Child M, Been-Tiktak A, Wang Y, et al. Effect of rifampin on steady-state pharmacokinetics of atazanavir with ritonavir in healthy volunteers. Antimicrob Agents Chemother. 2006;50:3336–3342.
    1. Burton ME, Shaw LM, Schentag JJ, Evans WE. Applied pharmacokinetics and pharmakodynamics, Principles of therapeutic drug monitoring: Lippincott Williams and Wilkins. 2005.
    1. La Porte CJ, Colbers EP, Bertz R, Voncken DS, Wikstrom K, et al. Pharmacokinetics of adjusted-dose lopinavir-ritonavir combined with rifampin in healthy volunteers. Antimicrob Agents Chemother. 2004;48:1553–1560.
    1. McIlleron H, Ren Y, Nuttall J, Riddick A, Kleynhans L, et al. Double-dose lopinavir/ritonavir provides insufficient lopinavir exposure in children receiving rifampicin-based anti-TB treatment; 2009 Feb 8-11; Montreal.
    1. Kumar GN, Rodrigues AD, Buko AM, Denissen JF. Cytochrome P450-mediated metabolism of the HIV-1 protease inhibitor ritonavir (ABT-538) in human liver microsomes. J Pharmacol Exp Ther. 1996;277:423–431.
    1. Government SA, editor. South African Government. South African Guidelines, Factsheet Section 10, Antiretroviral. 2007. pp. 76–95. South African Government.
    1. World Health Organization. WHO press; 2008. Revised treatment recommendations for infants.
    1. Llibre JM, Bonjoch A, Iribarren J, Galindo MJ, Negredo E, et al. Targeting only reverse transcriptase with zidovudine/lamivudine/abacavir plus tenofovir in HIV-1-infected patients with multidrug-resistant virus: a multicentre pilot study. HIV Med. 2008;9:508–513.
    1. Nijland HM, L'Homme RF, Rongen GA, van Uden P, van Crevel R, et al. High incidence of adverse events in healthy volunteers receiving rifampicin and adjusted doses of lopinavir/ritonavir tablets. Aids. 2008;22:931–935.
    1. Health Do. Guidelines for the Management of HIV infected Children in South Africa. 2005.
    1. World Health Organization W. WHO press; 2006. Guidance for national tuberculosis programmes on the management of tuberculosis in children.
    1. Regulatory compliance center. 2009. Table for Grading the Severity of Adult and Pediatric Adverse Events Version 1.0 - December 2004 (Clarification dated August 2009) Regulatory compliance center.
    1. World Health Organization W. World Health Organization (WHO); 2005. WHO Anthro (version 2) and macros. 2005 ed.
    1. van Zyl GU, van der Merwe L, Claassen M, Cotton MF, Rabie H, et al. Protease inhibitor resistance in South African children with virologic failure. Pediatr Infect Dis J. 2009;28:1125–1127.
    1. Hsu A, Granneman GR, Bertz RJ. Ritonavir. Clinical pharmacokinetics and interactions with other anti-HIV agents. Clin Pharmacokinet. 1998;35:275–291.
    1. Reitz C, Coovadia A, Ko S, Meyers T, Strehlau R, et al. Initial Response to Protease-Inhibitor-Based Antiretroviral Therapy among Children Less than 2 Years of Age in South Africa: Effect of Cotreatment for Tuberculosis. J Infect Dis. 2010;201:1121–1131.
    1. Ren Y, Nuttall JJ, Egbers C, Eley BS, Meyers TM, et al. Effect of rifampicin on lopinavir pharmacokinetics in HIV-infected children with tuberculosis. J Acquir Immune Defic Syndr. 2008;47:566–569.
    1. Centers for Disease Control and Prevention (CDC) Atlanta (GA): Centers for Disease Control and Prevention (CDC); 2009. Managing drug interactions in the treatment of HIV-related tuberculosis.
    1. Harries AD, Hargreaves NJ, Kemp J, Jindani A, Enarson DA, et al. Deaths from tuberculosis in sub-Saharan African countries with a high prevalence of HIV-1. Lancet. 2001;357:1519–1523.
    1. Pozniak AL, Miller R, Ormerod LP. The treatment of tuberculosis in HIV-infected persons. Aids. 1999;13:435–445.
    1. Ren Y, Nuttall JJ, Eley BS, Meyers TM, Smith PJ, et al. Effect of rifampicin on efavirenz pharmacokinetics in HIV-infected children with tuberculosis. J Acquir Immune Defic Syndr. 2009;50:439–443.
    1. World Health Organization. WHO Press; 2010. Antiretroviral therapy for HIV infection in infants and children: Towards universal access.
    1. Munderi P, Walker AS, Kityo C, Babiker AG, Ssali F, et al. Nevirapine/zidovudine/lamivudine has superior immunological and virological responses not reflected in clinical outcomes in a 48-week randomized comparison with abacavir/zidovudine/lamivudine in HIV-infected Ugandan adults with low CD4 cell counts. HIV Med. 2010;11:334–344.
    1. Arribas JR. The rise and fall of triple nucleoside reverse transcriptase inhibitor (NRTI) regimens. J Antimicrob Chemother. 2004;54:587–592.
    1. Barlow-Mosha L, Musoke P, Parsons T, Ajuna P, Lutajjumwa M, et al. 2009. Nevirapine Concentrations in HIV-infected Ugandan Children on Adult Fixed-dose Combination Tablet ART, with and without Rifampicin-based Treatment for Active M. tuberculosis Infection. 16th Conference on Retroviruses and Opportunistic Infections; Montreal.
    1. Elsherbiny D, Cohen K, Jansson B, Smith P, McIlleron H, et al. Population pharmacokinetics of nevirapine in combination with rifampicin-based short course chemotherapy in HIV- and tuberculosis-infected South African patients. Eur J Clin Pharmacol. 2009;65:71–80.
    1. Palumbo P, Violari A, Lindsey J, Hughes M, Jean-Philippe P, et al. 2009. Nevirapine vs. lopinavir-ritonavir- based antiretroviral therapy (ART) in single dose nevirapine (sdNVP)-exposed HIV infected infants: preliminary results from the IMPAACT P1060 trial. HIV Pediatrics; Cape Town, South Africa.
    1. Zhang C, Denti P, van der Walk J-S, Simonsson USH, Maartens G, et al. Population Pharmacokinetics of Lopinavir and Ritonavir in Combination with Rifampicin-based Antitubercular Treatment in HIV-infected Children. 2010. 19 Population Approach Group in Europe; Berlin, Germany.

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