Virological failure of first-line antiretroviral therapy in children living with HIV in Indonesia and associated factors

Nia Kurniati; Zakiudin Munasir; Pramita Gayatri; Evy Yunihastuti; Budiman Bela; Anggraini Alam

doi:10.14238/pi62.5.2022.295-303

Nia Kurniati Department of Child Health, University of Indonesia, Medical School/Dr. Cipto Mangunkusumo Hospital, Jakarta http://orcid.org/0000-0002-6380-6672
Zakiudin Munasir Department of Child Health, Universitas Indonesia/Cipto Mangunkusumo Hospital, Jakarta http://orcid.org/0000-0002-7929-9011
Pramita Gayatri Department of Child Health, Universitas Indonesia/Cipto Mangunkusumo Hospital, Jakarta http://orcid.org/0000-0002-2792-5586
Evy Yunihastuti Department of Internal Medicine, Universitas Indonesia/Cipto Mangunkusumo Hospital, Jakarta http://orcid.org/0000-0001-6650-0559
Budiman Bela Department of Microbiology, Universitas Indonesia/Cipto Mangunkusumo Hospital, Jakarta http://orcid.org/0000-0002-9010-2427
Anggraini Alam Universitas Padjadjaran Medical School/Dr. Hasan Sadikin Hospital, Bandung, West Java http://orcid.org/0000-0001-6740-2002

DOI: https://doi.org/10.14238/pi62.5.2022.295-303

Keywords: HIV, virological failure, severe immunosuppression

Abstract

Background The World Health Organization (WHO) recommends viral load (VL) monitoring for HIV patients on antiretroviral therapy (ART). However, availability of VL monitoring in low-income countries remains limited.

Objective To investigate factors associated with virological failure in HIV-infected children treated without routine VL monitoring.

Methods This cohort study was done in children living with HIV (CLHIV) registered at Cipto Mangunkusumo General Hospital from 2004 to 2021. Viral load monitoring was not routinely done. Subjects with at least one VL result after 6 months on ART were included in the study. Virological failure was defined as a VL of >1,000 copies. Subjects’ data were obtained from medical records, laboratory reports, and dispensing pharmacies. Statistical analysis was done following survival analysis with hazard ratio.

Results There were 384 children who had at least 1 VL result after ART was initiated. Median age at diagnosis was 30 months. Length of follow-up ranged from 6 to 216 months, with a mean frequency of VL monitoring of 0.7 times/person/year. Most subjects were already in clinical stages 3 and 4 (77.8%); 75% met severe immunodeficiency criteria. Virological failure was found in 45.8% of subjects after a median of 33 months on first-line ART, yielding an incidence of 3.3 per 1,000 person months. Independent associated factors were age at diagnosis of <60 months (HR 1.714; 95%CI 1.13 to 2.6), severe immunodeficiency (HR 1.71; 95%CI 1.15 to 2.54), referral cases (HR 1.70; 95%CI 1.23 to 2.36), and WHO clinical staging 3 (HR 1.987; 95%CI 0.995 to 3.969) and 4 (HR 2.084; 95%CI 1.034 to 4.201). Subjects with virological failure had lower weight-for-age z-scores [median 1.92; interquartile range (IQR) -3.003 to -0.81] and height-for-age z-scores [median -2.05; IQR -2.902 to -1.04] at the time of failure.

Conclusions In HIV-infected children treated without routine VL monitoring, age at diagnosis <60 months, severe immunodeficiency, WHO clinical stage 3 and 4, and referral from other centers were associated with virological failure.

References

1. Joint United Nations Programme on HIV/AIDS. UNAIDS data 2021. Geneva: Joint United Nations Programme on HIV/AIDS; 2021.
2. Joint United Nations Programme on HIV/AIDS. Seizing the moment: tackling entrenched inequalities to end epidemics. Geneva: Joint United Nations Programme on HIV/AIDS; 2020.
3. Nash D, Yotebieng M, Sohn AH. Treating all people living with HIV in sub-Saharan Africa: a new era calling for new approaches. J Virus Erad. 2018;4:1–4. PMID: 30515307.
4. Gelaw B, Mulatu G, Tesfa G, Marew C, Chekole B, Alebel A. Magnitude and associated factors of virological failure among children on ART in Bahir Dar Town public health facilities, Northwest Ethiopia: a facility based cross- sectional study. Ital J Pediatr. 2021;47:84. DOI: https://doi.org/10.1186/s13052-021-01030-7.
5. Shumetie A, Moges NA, Teshome M, Gedif G. Determinants of virological failure among HIV-infected children on first-line antiretroviral therapy in West Gojjam Zone, Amhara Region, Ethiopia. HIV AIDS. 2021;13:1035–44. DOI: https://doi.org/10.2147/HIV.S334067
6. World Health Organization. Consolidated guidelines on HIV prevention, testing, service delivery and monitoring: recommendation for a public health approach. Geneva: World Health Organization; 2021. Licence: CC BY-NC-SA 3.0 IGO
7. Shoko C, Chikobvu D. A superiority of viral load over CD4 cell count when predicting mortality in HIV patients on therapy. BMC Infect Dis. 2019;19:169. DOI: https://doi.org/ 10.1186/s12879-019-3781-1.
8. Ngo-Malabo ET, Ngoupo T PA, Zekeng M, Ngono V, Ngono L, Sadeuh-Mba SA, et al. A cheap and open HIV viral load technique applicable in routine analysis in a resource limited setting with a wide HIV genetic diversity. Virol J. 2017;14:224. DOI: https://doi.org/10.1186/s12985-017-0893-3.
9. Chandrasekaran P, Shet A, Srinivasan R, Sanjeeva G, Subramanyan S, Sunderesan S, et al. Long-term virological outcome in children receiving first-line antiretroviral therapy. AIDS Res Ther. 2018;15:23. DOI: https://doi.org/10.1186/s12981-018-0208-9.

10. Sovershaeva E, Shamu T, Wilsgaard T, Bandason T, Flægstad T, Katzenstein D, et al. Patterns of detecable viraemia among children and adults with HIV infection taking antiretroviral therapy in Zimbabwe. Int J Infect Dis. 2019;78:65–71.DOI: https://doi.org/10.1016/j.ijid.2018.10.01.
11. Bayleyegn B, Kifle ZD, Geremew D. Virological failure and associated factors among children receiving anti-retroviral therapy, Northwest Ethiopia. PLoS One. 2021;16:e0257204. DOI: https://doi.org/10.1371/journal.pone.0257204.
12. Kityo C, Boerma RS, Sigaloff KC, Kaudha E, Calis JC, Musiime V, et al. Pretreatment HIV drug resistance results in virological failure and accumulation of additional resistance mutations in Ugandan children. J Antimicrob Chemother. 2017;72:2587–95. DOI: https://doi.org/10.1093/jac/dkx188
13. Kadima J, Patterson E, Mburu M, Blat C, Nyanduko M, Bukusi EA, et al. Adoption of routine virologic testing and predictors of virologic failure among HIV- infected children on antiretroviral treatment in western Kenya. PLoS One. 2018;13:e0200242. DOI: https://doi.org/10.1371/journal.pone.0200242
14. Huibers M, Moons P, Cornelissen M, Zorgdrager F, Maseko N, Gushu M, et al. High prevalence of virological failure and HIV drug mutations in a first-line cohort of Malawian children. J Antimicrob Chemother. 2018;73:3471–5. DOI: https://doi.org/10.1093/jac/dky348
15. Makatini Z, Blackard JT, Mda S, Miles P, Towobola O. High virological failure rates in HIV-1 perinatally infected children in South Africa: a retrospective cohort study. S Afr Med J. 2021;111:255–9. DOI: https://doi.org/10.7196/SAMJ.2021.v111i3.15221
16. Makadzange A, Higgins-Biddle M, Chimukangara B, Birri R, Gordon M, Mahlanza T, et al. Clinical, virologic, immunologic outcomes and emerging HIV drugs resistance patterns in children and adolescents in Public ART Care in Zimbabwe. PLoS One. 2015;10:e0144057. DOI: https://doi.org/10.1371/journal.pone.0144057
17. Zenebe E, Washo A, Gesese AA. Time to first-line antiretroviral treatment failure and its predictors among HIV-positive children in Shashemene Town Health Facilities, Oromia Region, Ethiopia, 2019. Scientific World J. 2021;2021:8868479. DOI: https://doi.org/10.1155/2021/8868479
18. Afrane AK, Goka BQ, Renner L, Yawson AE, Alhassan Y, Owiafe SN, et al. HIV virological non-suppression and its associated factors in children on antiretroviral therapy at a major treatment centre in Southern Ghana: a cross-sectional study. BMC Infect Dis. 2021;21:731. DOI: https://doi.org/10.1186/s12879-021-06459-z
19. Barlow-Mosha L, Angelidou K, Lindsey J, Archary M, Cotton M, Dittmer S, et al. Nevirapine- versus Lopinavir/Ritonavir-based antiretroviral therapy in HIV-infected infants and young children: long-term follow-up of the IMPAACT P1060 randomized trial. Clin Infect Dis. 2016;63:1113–21. DOI: https://doi.org/10.1093/cid/ciw488.
20. Osman FT, Yizengaw MA. Virological failure and associated risk factors among HIV/AIDS pediatric patients at the ART Clinic of Jimma University Medical Center, Southwest Ethiopia. Open AIDS J. 2020;14:61–7. DOI: https://doi.org/10.2174/1874613602014010061.
21. Getaneh T, Negesse A, Dessie G, Desta M, Assemie MA, Tigabu A, et al. Treatment failure and its associated factors among children receiving highly active antiretroviral therapy in Ethiopia: a systematic review and meta-analysis. SAGE Open Med. 2022;10:1–11. DOI: https://doi.org/107.711/2707/5203510321212120108811335.
22. Palumbo PE, Raskino C, Fiscus S, Palwa S, Fowler MG, Spector SA, et al. Predictive value of quantitative plasma HIV RNA and CD4+ lymphocyte count in HIV-infected infants and children. JAMA 1998;279:756-61. DOI: https://doi.org/10.1001/jama.279.10.756
23. World Health Organization. Guideline: Updates on the management of severe acute malnutrition in infants and children. Geneva: World Health Organization; 2013.
24. Newman LP, Pagkas-Bather J, Njoroge A, Wamalwa D, Nduati R, Overbaugh J, et al. Virological failure in children living with HIV on antiretroviral therapy: correlates and predictive value of clinical measurements and CD4 cell count. Int J STD AIDS. 2019;30:1207–13. DOI: https://doi.org/10.1177/0956462419871422.
25. Shroufi A, Van Cutsem G, Cambiano V, Bansi-Matharu L, Duncan K, Murphy RA, et al. Simplifying switch to second-line antiretroviral therapy in sub Saharan Africa: predicted effect of using a single viral load to define efavirenz-based first-line failure. AIDS. 2019;33:1635–44. DOI: https://doi.org/10.1097/QAD.0000000000002234.
26. Turkova A, White E, Mujuru HA, Kekitiinwa AR, Kityo CM, Violari A, et al. Dolutegravir as first- or second-line treatment for HIV-1 infection in children. N Engl J Med. 2021;385:2531–43. DOI: https://doi.org/10.1056/NEJMoa2108793.