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SAMJ: South African Medical Journal

On-line version ISSN 2078-5135
Print version ISSN 0256-9574

SAMJ, S. Afr. med. j. vol.105 n.5 Pretoria May. 2015

http://dx.doi.org/10.7196/SAMJ.9211 

CORRESPONDENCE

 

Outcomes in treatment with darunavir/ritonavir in ART-experienced paediatric patients

 

 

To the Editor: Increasing development of resistant mutations to first- and second-line antiretroviral (ART) regimens among children is a matter of concern, as limited third-line paediatric ART preparations are available in the public sector.[1,2] There are various explanations for this increase,[3] including drug interactions leading to reduced bioavailability as seen in tuberculosis (TB) co-infection.[4,5]

In children <3 years of age, a first-line ART regimen consisting of two nucleoside reverse transcriptase inhibitors (NRTIs) with the protease inhibitor (PI) lopinavir, boosted with ritonavir (LPV/r), is recommended.[6,7] Many children may have resistance mutations to the non-nucleoside reverse transcriptase inhibitors (NNRTIs) because of prior exposure to nevirapine during prophylaxis for prevention of mother-to-child transmission.[8,9]

In a review of children failing first-line ART in resource-poor countries, at least 54% had major PI mutations.[2] It is therefore imperative for paediatric formulations of new antiretrovirals to be developed and be accessible for these children.[10,11]

Darunavir, a PI, boosted with ritonavir (DRV/r), has been shown to be effective in viral suppression in PI-experienced patients and has a low side-effect profile.[12] The drug has been tested clinically in South Africa (SA) and found to be safe and effective in PI-experienced paediatric participants.[13,14] DRV has since been registered for paediatric use in SA in children aged >3 years,[14] but is available only in the private sector and at the discretion of the paediatric third-line committee in the public sector.

We conducted a retrospective chart analysis of the outcomes of patients receiving DRV/r at Harriet Shezi Clinic (HSC), a paediatric ART clinic based at Chris Hani Baragwanath Hospital, Johannesburg, SA. Five of the 1 128 children currently on follow-up at HSC received DRV/r as part of their antiretroviral regimen from September 2010 to March 2014. DRV was obtained for these children from the manufacturer through a compassionate use programme with the permission of the SA Medicines Control Council (MCC). Permission to study the children was obtained from the bioethics committee of the University of the Witwatersrand (M130760) in 2013. Informed consent was obtained from the caregivers for use of DRV, as it was not registered in the country at the time.

Sociodemographic, laboratory, anthropometric and clinical information for the five patients was extracted from the clinic database. Standard-of-care viral loads and CD4 counts conducted by the National Health Laboratory Service were assessed. Genotype resistance testing was done by the Division of Virology, Stellenbosch University, using the Stanford University HIV Drug Resistance Database for interpretation of the resistance tests.

The median age of initiating first-line PI-based ART in the five children was 3.8 months (range 1.4 - 57.7), and all had World Health Organization stage 3 HIV infection or higher. The median time to virological failure after first-line ART initiation was 30.4 months (range 15.4 - 50.6). All had at least three major PI mutations, V82A, M46L and I54V, which reduced susceptibility to LPV/r. Notably, four of the five patients were on concomitant TB treatment and therefore received double-dose LPV/r; the fifth child was on suboptimal ART for socioeconomic reasons.

The median age at DRV/r initiation was 50.3 months (range 38.5 -106.7). The baseline median weight-for-age z-score (WAZ) was -0.79 (range -0.65 - -0.94), and the median height-for-age z-score (HAZ) was -0.88 (range -0.82 - -0.97). WAZ and HAZ scores remained constant over 24 months.

Median time to virological suppression on DRV/r was 6 months (range 3 - 12). There were viral rebounds in three of the five patients, but all remained suppressed at 24 months. CD4 counts remained constant. There was no hospitalisation or any significant morbidity on DRV/r.

We found that it was feasible to use DRV/r in a public healthcare setting and achieve virological suppression by 24 weeks. Despite viral rebounds the children managed to resuppress and maintain suppression at 24 months of follow-up, with adequate adherence counselling. These findings are similar to the ARIEL study, which included children with a similar drug resistance profile;[13] virological suppression was observed in 56% of the ARIEL participants at 24 weeks and in 81% by week 48.[14]

While lipid profiles were not monitored, which is one of our limitations, there were no major safety concerns. We recommend that paediatric preparations of DRV be readily available at tertiary paediatric healthcare facilities so that children failing an LPV/r-based regimen can be treated at the discretion of the treating physician and without resort to a third-line committee. We would like to highlight the importance of adequate super-boosting of LPV/r in children co-treated for TB to ensure that virological suppression is maintained during co-treatment.

Acknowledgements. We thank the children, their caregivers and the staff of HSC. We also thank Hermien Gous and Angela Oosthuizen for organising the darunavir and for adherence counselling, Gert van Zyl and his laboratory at Stellenbosch University for genotyping, Shobna Sawry for Therapy Edge access, and Merleesa Govender for the MCC applications.

Disclosure statement. The authors declare no conflicts of interest. Darunavir was obtained from Janssen from their compassionate use programme.

Gurpreet Kindra
Wits Reproductive Health and HIV Institute, University of the Witwatersrand, Johannesburg, South Africa gurpreetkindra@gmail.com

Nosisa Sipambo
Wits Reproductive Health and HIV Institute, University of the Witwatersrand, Johannesburg, South Africa, and Chris Hani Baragwanath Hospital, Johannesburg

Harry Moultrie
Wits Reproductive Health and HIV Institute, University of the Witwatersrand, Johannesburg, South Africa

Lee Fairlie
Wits Reproductive Health and HIV Institute, University of the Witwatersrand, Johannesburg, South Africa, and Chris Hani Baragwanath Hospital, Johannesburg

 

References

1. Taylor BS, Hunt G, Abrams EJ, et al. Rapid development of antiretroviral drug resistance mutations in HIV-infected children less than two years of age initiating protease inhibitor-based therapy in South Africa. AIDS Res Hum Retroviruses 2011;27(9):945-956. [http://dx.doi.org/10.1089/AID.2010.0205]        [ Links ]

2. Sigaloff KC, Calis JC, Geelen SP, van Vugt M, de Wit TF. HIV-1-resistance-associated mutations after failure of first-line antiretroviral treatment among children in resource-poor regions: A systematic review. Lancet Infect Dis 2011;11(10):769-779. [http://dx.doi.org/10.1016/S1473-3099(11)70141-4]        [ Links ]

3. Arage G, Tessema GA, Kassa H. Adherence to antiretroviral therapy and its associated factors among children at South Wollo Zone hospitals, Northeast Ethiopia: A cross-sectional study. BMC Public Health 2014;14(1):365. [http://dx.doi.org/10.1186/1471-2458-14-365.         [ Links ]

4. McIlleron H, Ren Y, Nuttall J, et al. Lopinavir exposure is insufficient in children given double doses of lopinavir/ritonavir during rifampicin-based treatment for tuberculosis. Antivir Ther 2011;16(3):417-421. [http://dx.doi.org/10.3851/IMP1757]        [ Links ]

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6. World Health Organization. Antiretroviral therapy for HIV infection in infants and children: Recommendations for a public health approach: 2010 revision. http://www.who.int/hiv/pub/paediatric/infants2010/en/ (accessed 28 May 2014).         [ Links ]

7. Department of Health, South Africa. The South African Antiretroviral Treatment Guidelines 2013. http://www.sahivsoc.org/upload/documents/2013%20ART%20Treatment% 20Guidelines%20Final%2025%20March%202013%20corrected.pdf (accessed 28 May 2014).         [ Links ]

8. Palumbo P, Lindsey JC, Hughes MD, et al. Antiretroviral treatment for children with peripartum nevirapine exposure. N Engl J Med 2010;363(16):1510-1520. [http://dx.doi.org/10.1056/NEJMoa1000931]        [ Links ]

9. Hunt GM, Coovadia A, Abrams EJ, et al. HIV-1 drug resistance at antiretroviral treatment initiation in children previously exposed to single-dose nevirapine. AIDS 2011;25(12):1461-1469. [http://dx.doi.org/10.1097/QAD.0b013e3283492180].         [ Links ]

10. Eley BS, Meyers T. Antiretroviral therapy for children in resource-limited settings: Current regimens and the role of newer agents. Paediatr Drugs 2011;13(5):303-316. [http://dx.doi.org/10.2165/11593330-000000000-00000]        [ Links ]

11. Boyd MA, Hill AM. Clinical management of treatment-experienced, HIV/AIDS patients in the combination antiretroviral therapy era. Pharmacoeconomics 2010;28(Suppl 1):17-34. [http://dx.doi.org/10.2165/11587420-000000000-00000]        [ Links ]

12. McKeage K, Scott LJ. Darunavir: in treatment-experienced pediatric patients with HIV-1 infection. Paediatr Drugs 2010;12(2):123-131. [http://dx.doi.org/10.2165/11204530-000000000-00000]        [ Links ]

13. Violari A, Bologna R, Kimutai R, et al. ARIEL: 24-week safety and efficacy of darunavir/ritonavir in treatment-experienced pediatric patients aged 3 to <6 years. http://www.hivandhepatitis.com/2011_conference/croi2011/posters/ARIEL.pdf (accessed 28 May 2014).         [ Links ]

14. Violari A, Bologna R, Kumarasamy N, et al. Safety and efficacy of darunavir/ritonavir in treatment-experienced pediatric patients aged 3 to <6 years: Week 48 analysis of the ARIEL trial. Presented at the 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention, Kuala Lumpur, Malaysia, 30 June - 3 July 2013. Abstract MOAB0102. http://pag.ias2013.org/abstracts.aspx?aid=1116 (accessed 28 May 2014).         [ Links ]

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