Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection

Management of Children Receiving Antiretroviral Therapy

Antiretroviral Treatment Interruption in Children with HIV

Unplanned Treatment Interruptions

Temporary discontinuation of antiretroviral therapy (ART) may be unavoidable in some situations—such as in cases of serious treatment-related toxicity, acute illnesses, or planned surgeries—that preclude oral intake. Lack of available medication also may result in temporary ART discontinuation. In resource-limited settings, children might experience interruptions due to drugs being out of stock locally. Children with HIV who are immigrating to the United States also may experience gaps in medication availability. Prolonged interruptions of ART also can result from disengagement from care or other social or psychological issues that affect adherence. Some patients, particularly adolescents and young adults, might attempt to conceal long periods of treatment interruption by restarting treatment in the few weeks ahead of clinic visits and viral load testing.

Observational studies of children and youth with unplanned or nonprescribed treatment interruptions suggest that interruptions are common and that prolonged interruptions can lead to immunologic decline.^1-4 In a retrospective study of 483 children in a French pediatric cohort from the National Agency for Research on AIDS and Viral Hepatitis (ANRS), 42% of participants had treatment interruptions of ≥3 months (with a median of 12.1 months). Interruption was associated with lower CD4+ T lymphocyte (CD4) cell percentages after 4 years, even in those who restarted therapy.⁵ A similar retrospective study of 136 youth (median age 12.9 years) in the United States found that 38 participants (28%) with histories of treatment interruption had lower CD4 counts and higher HIV RNA levels than participants who had continuous treatment.⁶ A study from the International Epidemiology Databases to Evaluate AIDS Southern Africa, which includes 53,674 children <16 years of age, found that lapses in clinical care of greater than 180 days within the first 6 months of treatment were associated with increased mortality (adjusted hazard ratio [AHR] = 1.52, 95% CI 1.12-2.04); while lapses in care after the first 6 months were not (AHR = 1.05, 95% CI 0.77–‍1.44).⁷

Whether unplanned interruptions occur by accident or necessity (e.g., because of toxicity), all efforts should be made to minimize their duration. If a child will be traveling for an extended period, clinicians can help prevent treatment interruption by ensuring that the child will have access to the necessary drugs during the trip. If the required drugs will not be available at the destination, pharmacies can be asked to dispense extra medication. Additional guidance on supporting adherence can be found in Adherence to Antiretroviral Therapy in Children and Adolescents with HIV.

Structured Treatment Interruptions

Structured treatment interruptions are scheduled periods of time during which ART is not prescribed or administered. This strategy was once considered a method for providing patients with time off ART to reduce the risk of toxicity and costs. Randomized clinical trials of adults with HIV have demonstrated that structured treatment interruptions are associated with significantly higher morbidity and mortality than continuous ART.⁸ Current U.S. Department of Health and Human Services HIV treatment guidelines recommend against planned, long-term structured treatment interruptions in adults (see Discontinuation or Interruption of Antiretroviral Therapy in the Adult and Adolescent Antiretroviral Guidelines).

Few studies have evaluated structured treatment interruption in children. In one trial from Europe and Thailand (PENTA 11), 109 children (median age 9 years) on ART and with virologic suppression were randomized to receive continuous therapy (CT) or to undergo treatment interruption. Although no significant differences in rates of adverse events (AEs) were observed between the two groups at 2 years, 19 of 56 children (34%) in the structured treatment interruption arm met CD4 criteria to restart therapy between 6 and 42 weeks after interruption, suggesting that the time off ART provided by this strategy was ultimately limited.^9,10 The Children with HIV Early Antiretroviral Therapy (CHER) trial in South Africa was designed to determine whether infants who initiated ART early could safely discontinue therapy at either 40 weeks or 96 weeks; infants would reinitiate treatment based on CD4 decline. The median time to the start of continuous ART after interruption was 3 weeks (interquartile range [IQR] 26–45 weeks) among the infants who discontinued ART after 40 weeks, and 70 weeks (IQR 35–109 weeks) among the infants who discontinued ART after 96 weeks.^11,12 A secondary analysis of neurodevelopmental outcomes at age 5 years did not show any significant differences among the children in the different study arms.¹³ However, brain magnetic resonance imaging studies in a subset of participants found that children with HIV on interrupted ART (n = 21) had a thicker cortex than uninfected controls in the left frontal and right insular regions, but children with HIV on CT (n = 25) showed no difference from controls; the clinical significance of these differences is not known.¹⁴ In another randomized trial, 12 of 21 infants in the treatment interruption arm met ART restart criteria within 3 months.¹⁵ In summary, although trials of structured treatment interruptions in children have not shown significant short-term morbidity, the gains in time off ART are limited, and the long-term outcomes remain unknown.

The case of an infant from Mississippi who initiated ART soon after birth and had a prolonged period of time without viremia after an unplanned treatment interruption raised the hope that it may be possible to stop or reduce the intensity of ART (e.g., use fewer agents) in some infants (see Antiretroviral Management of Newborns with Perinatal HIV Exposure or HIV).^16,17 However, the “Mississippi infant” had documented viral rebound after 28 months off ART,¹⁸ and additional reports have emerged of infants who experienced rebound viremia after stopping ART, despite having undetectable HIV DNA and RNA while on ART.^19-21 A South African child aged 9.5 years was reported to have low levels of virus that was not replication competent after receiving ART from approximately 2 to 24 months of age; the factors that led to this outcome remain unknown.²² Future research might identify treatment strategies and diagnostic tests that enable ART to be safely interrupted in some children. “Analytical” treatment interruptions are currently being incorporated into studies of remission in adults and children, but the potential risks and benefits of strategies need to be critically evaluated.^23-25

Currently, the Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV (the Panel) does not recommend treatment interruption as a strategy in clinical settings to confirm diagnosis or to assess remission or cure in infants who reverted to negative serology, tested negative for HIV DNA, or received an initial diagnosis that was based on a single positive nucleic acid test. The Panel encourages providers to consult an expert on pediatric HIV when they are concerned about the validity of the test results that led to treatment initiation in children with HIV.

Short-Cycle Therapy Strategies

One approach, called short-cycle therapy (SCT), schedules 4-day treatment interruptions, rather than waiting to restart ART after CD4 count declines or other AEs occur. In one proof-of-concept study (ATN015), 32 participants (aged 12–24 years) underwent short cycles of 4 days on and 3 days off ART.²⁶ Participants received protease inhibitor–based ART and had at least 6 months of documented viral suppression (defined as a viral load <400 copies/mL) and CD4 counts above 350 cells/mm³. Most participants demonstrated good adherence to the schedule, but 12 participants (37.5%) developed confirmed viral load rebounds >400 copies/mL, and 18 participants (56%) left the study. SCT had no impact on CD4 counts.

The BREATHER (PENTA 16) study sought to examine the safety and benefits of SCT with 5 days on and 2 days off ART; PENTA 16 was a noninferiority trial that randomized 199 children and young adults (aged 8–24 years) for SCT or CT.^27,28 To enroll, participants had to be receiving efavirenz (EFV) plus two nucleoside reverse transcriptase inhibitors, and they had to have been virologically suppressed (defined as a viral load <50 copies/mL) for >12 months. By 48 weeks, six participants (6%) in the SCT arm and seven participants (7%) in the CT arm experienced confirmed virologic failure, which was defined as a viral load >50 copies/mL (difference −1.2%; 90% confidence interval, −7.3% to 4.9%). Of the six participants in the SCT arm who experienced virologic failure, five were able to regain virologic suppression. Two participants in the SCT arm and five participants in the CT arm had major mutations related to resistance to non-nucleoside reverse transcriptase inhibitors at the time of virologic failure. At 48 weeks, the SCT arm had higher D-dimer levels but no other evidence of increased inflammation across a number of other biomarkers. Participants generally reported appreciating the option of SCT.²⁹

A long-term follow-up study of children from the BREATHER study (which included 194 of the original 199 children) suggests comparable virologic failure rates between the SCT and CT arms after a median of 3.6 years; both arms had a failure rate of approximately 16%.³⁰ The participants in the SCT arm experienced a greater number of serious AEs than participants in the CT arm (20 serious AEs in the SCT arm versus 8 in the CT arm, with the primary difference being rate of hospitalizations); however, the arms experienced comparable rates of the Centers for Disease Control and Prevention Grade 3 or 4 AEs. The BREATHER trial suggests that SCT with EFV-based ART may be safe in some adolescents and may yield increased patient satisfaction that could lead to better long-term adherence. However, the Panel currently believes that additional data are needed to decide whether the BREATHER strategy would be safe in different patient populations, with different antiretroviral (ARV) regimens, outside of the context of a trial, and over longer periods.

Conclusion

Cumulative data have demonstrated that treatment interruptions long enough for viremia to recur are generally harmful to children with HIV. Analytic treatment interruptions to assess for remission are employed in research, but not recommended in the clinical context. SCT treatment may be safe and increase satisfaction in some patients, but the Panel concludes that more data are needed before SCT can be recommended for routine use in pediatric populations. Currently, the Panel does not recommend structured treatment interruption in the clinical care of children with HIV; additional studies of treatment-interruption strategies in specific situations are warranted.

References

1. Gibb DM, Duong T, Leclezio VA, 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(5):446-450. Available at: http://www.ncbi.nlm.nih.gov/pubmed/15131469.
2. Saitoh A, Foca M, Viani RM, et al. Clinical outcomes after an unstructured treatment interruption in children and adolescents with perinatally acquired HIV infection. Pediatrics. 2008;121(3):e513-521. Available at: http://www.ncbi.nlm.nih.gov/pubmed/18310171.
3. Siberry GK, Patel K, Van Dyke RB, et al. CD4+ lymphocyte-based immunologic outcomes of perinatally HIV-infected children during antiretroviral therapy interruption. J Acquir Immune Defic Syndr. 2011;57(3):223-229. Available at: http://www.ncbi.nlm.nih.gov/pubmed/21423022.
4. Bartlett AW, Lumbiganon P, Kurniati N, et al. Use and outcomes of antiretroviral monotherapy and treatment interruption in adolescents with perinatal HIV infection in Asia. J Adolesc Health. 2019;65(5):651-659. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31395514.
5. Aupiais C, Faye A, Le Chenadec J, et al. Interruption of cART in clinical practice is associated with an increase in the long-term risk of subsequent immunosuppression in HIV-1-infected children. Pediatr Infect Dis J. 2014;33(12):1237-1245. Available at: http://www.ncbi.nlm.nih.gov/pubmed/24945880.
6. Rakhmanina N, Lam KS, Hern J, Young HA, Walters A, Castel AD. Interruptions of antiretroviral therapy in children and adolescents with HIV infection in clinical practice: a retrospective cohort study in the USA. J Int AIDS Soc. 2016;19(1):20936. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27797320.
7. Davies C, Johnson L, Sawry S, et al. Effect of antiretroviral therapy care interruptions on mortality in children living with HIV. AIDS. 2022;36(5):729-737. Available at: https://www.ncbi.nlm.nih.gov/pubmed/35152225.
8. Strategies for Management of Antiretroviral Therapy Study Group, El-Sadr WM, Lundgren JD, et al. CD4+ count-guided interruption of antiretroviral treatment. N Engl J Med. 2006;355(22):2283-2296. Available at: http://www.ncbi.nlm.nih.gov/pubmed/17135583.
9. Paediatric European Network for Treatment of AIDS. Response to planned treatment interruptions in HIV infection varies across childhood. AIDS. 2010;24(2):231-241. Available at: http://www.ncbi.nlm.nih.gov/pubmed/20010073.
10. Bunupuradah T, Duong T, Compagnucci A, et al. Outcomes after reinitiating antiretroviral therapy in children randomized to planned treatment interruptions. AIDS. 2013;27(4):579-589. Available at: https://www.ncbi.nlm.nih.gov/pubmed/23135172.
11. Violari A, Cotton MF, Gibb DM, et al. Early antiretroviral therapy and mortality among HIV-infected infants. N Engl J Med. 2008;359(21):2233-2244. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19020325.
12. Cotton MF, Violari A, Otwombe K, et al. Early time-limited antiretroviral therapy versus deferred therapy in South African infants infected with HIV: results from the children with HIV early antiretroviral (CHER) randomised trial. Lancet. 2013;382(9904):1555-1563. Available at: http://www.ncbi.nlm.nih.gov/pubmed/24209829.
13. Laughton B, Cornell M, Kidd M, et al. Five year neurodevelopment outcomes of perinatally HIV-infected children on early limited or deferred continuous antiretroviral therapy. J Int AIDS Soc. 2018;21(5):e25106. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29722482.
14. Nwosu EC, Holmes MJ, Cotton MF, et al. Cortical structural changes related to early antiretroviral therapy (ART) interruption in perinatally HIV-infected children at 5 years of age. IBRO Neurosci Rep. 2021;10:161-170. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34179869.
15. Wamalwa D, Benki-Nugent S, Langat A, et al. Treatment interruption after 2-year antiretroviral treatment initiated during acute/early HIV in infancy. AIDS. 2016;30(15):2303-2313. Available at: http://www.ncbi.nlm.nih.gov/pubmed/27177316.
16. Persaud D, Gay H, Ziemniak C, et al. Absence of detectable HIV-1 viremia after treatment cessation in an infant. N Engl J Med. 2013;369(19):1828-1835. Available at: http://www.ncbi.nlm.nih.gov/pubmed/24152233.
17. Persaud D, Luzuriaga K. Absence of HIV-1 after treatment cessation in an infant. N Engl J Med. 2014;370(7):678. Available at: http://www.ncbi.nlm.nih.gov/pubmed/24521123.
18. Luzuriaga K, Gay H, Ziemniak C, et al. Viremic relapse after HIV-1 remission in a perinatally infected child. N Engl J Med. 2015;372(8):786-788. Available at: http://www.ncbi.nlm.nih.gov/pubmed/25693029.
19. Mekonen T, Mulang R, Nghimbwasha H, et al. Structured antiretroviral treatment interruptions in vertically HIV-1 infected children with complete pro-viral DNA PCR reversions in Namibia, following durable viral suppression, led to rapid rebound viremias and significant immunologic destruction. Presented at: AIDS Conference; 2016. Durban, South Africa.
20. Butler KM, Gavin P, Coughlan S, et al. Rapid viral rebound after 4 years of suppressive therapy in a seronegative HIV-1 infected infant treated from birth. Pediatr Infect Dis J. 2014;34(3):e48-51. Available at: http://www.ncbi.nlm.nih.gov/pubmed/25251719.
21. Koofhethile CK, Moyo S, Kotokwe KP, et al. Undetectable proviral deoxyribonucleic acid in an adolescent perinatally infected with human immunodeficiency virus-1C and on long-term antiretroviral therapy resulted in viral rebound following antiretroviral therapy termination: A case report with implications for clinical care. Medicine (Baltimore). 2019;98(47):e18014. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31764816.
22. Violari A, Cotton MF, Kuhn L, et al. A child with perinatal HIV infection and long-term sustained virological control following antiretroviral treatment cessation. Nat Commun. 2019;10(1):412. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30679439.
23. Clinicaltrials.gov. Very early intensive treatment of HIV-infected infants to achieve HIV remission. 2019. Available at: https://clinicaltrials.gov/ct2/show/NCT02140255.
24. Julg B, Dee L, Ananworanich J, et al. Recommendations for analytical antiretroviral treatment interruptions in HIV research trials-report of a consensus meeting. Lancet HIV. 2019;6(4):e259-e268. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30885693.
25. Stecher M, Classen A, Klein F, et al. Systematic review and meta-analysis of treatment interruptions in human immunodeficiency virus (HIV) type 1-infected patients receiving antiretroviral therapy: implications for future HIV cure trials. Clin Infect Dis. 2020;70(7):1406-1417. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31102444.
26. Rudy BJ, Sleasman J, Kapogiannis B, et al. Short-cycle therapy in adolescents after continuous therapy with established viral suppression: the impact on viral load suppression. AIDS Res Hum Retroviruses. 2009;25(6):555-561. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19534628.
27. Butler K, Inshaw J, Ford D, et al. BREATHER (PENTA 16) short-cycle therapy (SCT) (5 days on/2 days off) in young people with chronic human immunodeficiency virus infection: an open, randomised, parallel-group Phase II/III trial. Health Technol Assess. 2016;20(49):1-108. Available at: http://www.ncbi.nlm.nih.gov/pubmed/27377073.
28. Breather Trial Group. Weekends-off efavirenz-based antiretroviral therapy in HIV-infected children, adolescents, and young adults (BREATHER): a randomised, open-label, non-inferiority, phase 2/3 trial. Lancet HIV. 2016;3(9):e421-e430. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27562743.
29. Bernays S, Paparini S, Seeley J, Namukwaya Kihika S, Gibb D, Rhodes T. Qualitative study of the BREATHER trial (Short Cycle antiretroviral therapy): is it acceptable to young people living with HIV? BMJ Open. 2017;7(2):e012934. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28213595.
30. Turkova A, Moore CL, Butler K, et al. Weekends-off efavirenz-based antiretroviral therapy in HIV-infected children, adolescents and young adults (BREATHER): Extended follow-up results of a randomised, open-label, non-inferiority trial. PLoS One. 2018;13(4):e0196239. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29684092.