Case study: HIV drug resistance in a 13 year old boy, a multicausal problem

Estudio de caso: resistencia a los medicamentos contra el VIH en un niño de 13 años, un problema multicausal

Background: In 2011, at least 34 million people live with HIV. HIV vertical infected children require close follow-up from all the way through diagnosis to treatment and management of complications.

Case summary: This is the case of a 13-year-old male patient with HIV (vertical transmission) diagnosed at 4 months old. His HIV diagnosis was made in the context of opportunistic manifestations of immunodeficiency because his mother did not access prenatal check-ups. He developed AIDS sequelae such as spastic paraparesia derived from HIV myelopathy and CMV retinitis due to immunodeficiency; these diseases presented in first two years of life. After three years from HAART initiation, the patient was exposed to inadequate HAART (ritonavir without another protease inhibitor), and experienced a first change of therapy due to virological failure. Subsequent treatment regimens —a sum of 7— presented failures in their formulation and this, along with delays due to administrative issues, led to the patient developing multiresistance to most of antiretrovirals given. The patient died mainly from multiorganic failure due to HIV and wasting syndrome.

Conclusion: Congenital HIV is a fundamental issue in public health. It is a preventable disease, and perinatal management, including diagnosis and treatment, is a must. Treatment has demonstrated effectiveness when it is given with proper schemes and adherence. Administrative barriers led to failures in treatment and this affects the prognosis of any patient with HIV. This case is an example that highlights the relationship between virological and clinical failures with health system barriers, in HIV infected children. Managing gaps in diagnosis, antiretroviral administration, and follow up of HIV infected children translates into the prognosis of future adolescents and adults.

Antecedentes: en 2011, al menos 34 millones de personas viven con el VIH. Los niños infectados con VIH vertical requieren un seguimiento cercano desde el diagnóstico hasta el tratamiento y el tratamiento de las complicaciones.

Resumen del caso: este es el caso de un paciente masculino de 13 años con VIH (transmisión vertical) diagnosticado a los 4 meses de edad. Su diagnóstico de VIH se realizó en el contexto de manifestaciones oportunistas de inmunodeficiencia porque su madre no accedió a controles prenatales. Desarrolló secuelas del SIDA tales como la paraparesia espástica derivada de la mielopatía por VIH y la retinitis por CMV debido a la inmunodeficiencia; estas enfermedades se presentaron en los primeros dos años de vida. Después de tres años desde el inicio de HAART, el paciente estuvo expuesto a TARGA inadecuado (ritonavir sin otro inhibidor de proteasa) y experimentó un primer cambio de terapia debido a falla virológica. Los regímenes de tratamiento subsiguientes -una suma de 7- presentaron fallas en su formulación y esto, junto con retrasos debidos a problemas administrativos, llevaron al paciente a desarrollar una resistencia múltiple a la mayoría de los antirretrovirales administrados. El paciente murió principalmente por falla multiorgánica debido al VIH y al síndrome de desgaste.

Conclusión: el VIH congénito es un problema fundamental en la salud pública. Es una enfermedad prevenible y el tratamiento perinatal, incluidos el diagnóstico y el tratamiento, es obligatorio. El tratamiento ha demostrado efectividad cuando se administra con esquemas y adherencia adecuados. Las barreras administrativas condujeron a fallas en el tratamiento y esto afecta el pronóstico de cualquier paciente con VIH. Este caso es un ejemplo que destaca la relación entre las fallas virológicas y clínicas con las barreras del sistema de salud, en los niños infectados por el VIH. La gestión de las brechas en el diagnóstico, la administración de antirretrovirales y el seguimiento de los niños infectados por el VIH se traduce en el pronóstico de futuros adolescentes y adultos.

HIV DRUG RESISTANCE IN A 13 YEAR OLD BOY, A MULTICASUAL PROBLEM

Carol Páez-Canro1, 2,

Julián Porras-Villamil3

1. MD, MSc Clinical epidemiology.

Faculty of Medicine,

Universidad Nacional de Colombia.

2. Asistencia Científica de Alta Complejidad SAS.

3. Medical student,

Faculty of Medicine,

Universidad Nacional de Colombia.

Correspondence to:

Carol Páez Canro. Bogotá D.C., Colombia.

Email : cpaezc@unal.edu.co

ABSTRACT

Keywords: HIV, children, HIV drug resistance.

CLINICAL CASE: DESCRIPTION

The following data was extracted from the complete patient’s clinical history, interviews with relatives and the Foundation coordinator.

The patient was the product of third pregnancy of a 27-year-old mother. The patient’s mother did not access HIV testing during pregnancy or antenatal care, and we have no information about why she did so. The patient was born at term in a public hospital by vaginal birth. An HIV test was not performed at birth. The patient’s parents worked as street vendors and were diagnosed with HIV infection at same time as their son. There is no information about lactation. Mother died by the time the patient was 1 year old due to AIDS related complications (tuberculosis and wasting syndrome). The father continued to live but had sequelae of neurotoxoplasmosis. The patient’s two siblings are not infected. By age of 2, the patient entered a foundation for HIV infected children in Bogotá, where they assumed responsibility for his comprehensive care until death. The patient was affiliated to the contributive health regime, his health care was provided in multiple institutions, but mainly in a third level hospital where he was attended by a pediatric infectologist.

The patient was diagnosed with HIV infection stage C3 by the age of 1 after multiple hospitalizations. His exams showed severe immunodeficiency and multiple opportunistic diseases (pulmonary tuberculosis, myelopathy from HIV with spastic paraparesia and CMV retinitis, malnutrition, Pneumocystis jirovecii pneumonia). All this clinical information was validated by specialists through the clinical history. The confirmation test for HIV (western blot) authorization was made with six months of delay. Table 2 shows viral loads and CD4 cell counts over the span of his life as related to ARV regimens.

The first ARV regimen lacked potency (Zidovudine, Didanosine and ritonavir without another protease inhibitor because of a lack of oral solution presentations), leading to incomplete suppression of viral replication, which was interpreted as virological failure. Multiple empirical ARV regimens were given until a necessary viral genotypification was ordered at the age of seven —with a two years delay between when the exam was ordered and when it was actually carried out—. Genotypification showed resistance to all known NRTI’s and to PI. Further genotypifications showed new mutations and polymorphisms that confer resistance to almost all ARVs. Table 1 shows the history of antiretroviral resistance mutations and polymorphisms.

Date	Age	Viral Load	Cd4	Art
01/04/2001	17 months	>500.000 copies/mL (Log > 5.70)	185	Zidovudine + didanosine + ritonavir
22/02/2002	2 years, 4 months	800.000 copies/mL	219	Lopinavir/ritonavir + nevirapine + zidovudine
16/06/2004	4 years, 7 months	No data	272
11/08/2004	4 years, 9 months	210785 copies/mL (Log 5.32)	444	Stavudine + Lopinavir/ ritonavir + lamivudine
30/03/2005	5 years, 5 months	>500.000 copies/mL (Log > 5.70)	408
02/09/2005	5 years, 10 months	423 copies/mL (Log 2.62)	320
01/02/2006	6 years, 3 months	28934 copies/mL (Log 4.46)	261
30/11/2006	7 years, 1 months	358.215 copies/mL (Log 5.55)	338
09/10/2007	7 years, 11 months	>500.000 copies/mL (Log > 5.8)	108	Lopinavir/ritonavir + lamivudine + efavirenz
03/08/2009	9 years, 9 months	405.169 copies/mL (Log 5.61)	15
02/09/2010	10 years, 10 months	201.177 copies/mL	313
08/11/2010	11 years	864.917 copies/mL	113
06/01/2011	11 years, 2 months	646.186 copies/mL (Log 5.81)	165	Raltegravir + Etravirine+ Enfuvirtide + Maraviroc
29/06/2011	11 years, 8 months	110.864 copies/mL (Log 5.04)	7
01/07/2012	11 years, 9 months	185.006 copies/mL (Log 5.27)	4	Raltegravir + Tenofovir/ emtricitabine + darunavir
10/01/2013		44.002 copies/mL (Log 4.64)	14

Table 1. Immunovirologic tests and ARV.

Antiretroviral Group	Mutations And Polymorphisms
Reverse transcriptase inhibitors	M41L, D67N, K70R, Y181C, T215Y, K219E, M184V, T69E, M184, G190A, Y188L, T215F/V
Protease inhibitors	A71V, I54L, I62V, I84V, L10F, L33F, L63P, L90M, M36I, M46L, V82A, K20R, F53L/F, Q58E, K43T, I13V, L89V, V11I, E35D, H69R, G73S

Table 2. Antiretroviral resistance mutations and polymorphisms.

6 months after the genotype results, CD4 had decreased to 66 cell/uL with consequent clinical deterioration that required further hospitalizations. Rescue therapy was initiated, but viral load (VL) continued to rise. A tropism test for the CCR5 co-receptor recommended the use of Maraviroc, a novel therapy that represented an option; however there was a 4 month suspension of ARV because of delay in supply.

The patient received a 5-month treatment with Maraviroc and Enfuvirtide. The VL decreased to 1/8 of the prior count. Nevertheless, the CD4 count continued to decrease from 165 to 7 cells. A new genotypification showed prior resistance plus probable or emergent resistance to NRTI and Non-nucleoside retrotranscriptase inhibitors (NNRTIs). New VL and CD4 cell counts confirmed persistence of virological failure. After one last AR change, the case was presented at a bioethical committee of the last institution where he was attended. They recommended suspension of all ARV drugs because of its lack of effectiveness and administration of analgesia for pain relief in the context of palliative care. The patient died after a complicated respiratory infection 4 months after ARV discontinuation.

DISCUSSION

This case represents the consequences of the mismanagement of an HIV infected patient at several levels. The first one was the missed opportunity for HIV prenatal diagnosis in his mother while she was pregnant. Poverty due to informal employment affects the access to HIV tests because the economic resources are limited and often they are invested in food and living instead. It is necessary to ensure that all pregnant women access HIV and syphilis tests during antenatal controls, hopefully in first trimester, one way to do this is by rapid point of care tests that do not require administrative authorization or other administrative barriers. Also, HIV tests must be administered during the third trimester and labor.

The second level of failure was directly related to the empiric administration of multiple ARTs to this patient before genotypic evaluation for HIV ART resistance. The elevated viral load and the positive selection induced by multiple empiric antiretrovirals resulted in multidrug ART resistance, as has been demonstrated in several studies (9 - 11). As in adults, the genotype is an accurate measure for determining the best ART for each patient when virological failure is detected. As such, it must be made as soon as the failure is diagnosed (30).

Drug resistance cases in children may become a public health problem since they behave as regular adolescents and adults, with a high risk of spreading the infection, leading to the consequences that that implies (31, 32). The delay in health services and the excess of administrative procedures that are present in Colombia’s health system affects the clinical course of pathologies such as HIV and AIDS related complications. This leads to cases undertreated sequelae and the loss of life expectancy, especially in children.

Due to the great capacity of the HIV virus to acquire resistance to drugs, it is necessary to provide the best of care to HIV patients, and especially prenatally infected pediatric patients, in terms of early diagnosis, HIV resistance evaluations, and ART treatment (33). This includes the availability of resistance testing to select the best ARV combination for each patient and a multidisciplinary approach to determine the best course of management in cases of reactivation and re-emergence of latent virus when the conditions are favorable.

CONCLUSION

This case highlights the challenge of middle and low income countries in the diagnosis, evaluation, and treatment of HIV infected children. There is a peremptory need to continue efforts to guarantee antenatal controls and HIV tests for all pregnant women. Women in poverty must be a priority for these programs. Physicians that treat HIV positive children must be trained in this specific issue, Clinical Practice Guidelines must be taken account, especially now that guidelines were published in 2015 with evidence-based recommendations. The adherence to guidelines will lead to fewer undertreated children and a better quality of life for this population.

The access to health system services must be assured in order to apply the guideline’s recommendations, especially when diagnostic procedures and antiretrovirals are not included in the health plan. There must be an adequate approach to management including not only the treatment of sequelae and the complications of pathologies but also prevention.

REFERENCES

1. Ruddox V, Mathisen M, Otterstad JE. Prevalence and prognosis of non-specific chest pain among patients hospitalized for suspected acute coronary syndrome - a systematic literature search. BMC medicine. 2012;10:58.

2. UNAIDS report on the global AIDS epidemic 2013. Available on: http://www.unaids.org/en/ dataanalysis/knowyourresponse/countryprogressreports/ 2012countries/ce_CO_Narrative_Report[ 1].pdf [Review November 23rd 2013].

3. Ettenger A, Barnighausen T, Castro A. Health insurance for the poor decreases access to HIV testing in antenatal care: evidence of an unintended effect of health insurance reform in Colombia. Health Policy Plan. 2014;29(3):352-8.

4. CLOSING THE TREATMENT GAPFOR CHILDREN WITH HIV8-12 DECEMBER, GENEVA, SWITZERLAND, can be accesed at http://www.who.int/hiv/pub/toolkits/flyer-peadriatic- hiv-dec2014.pdf.

5. Viani RM, Araneta MR, Deville JG, Spector SA. Decrease in hospitalization and mortality rates among children with perinatally acquired HIV type 1 infection receiving highly active antiretroviral therapy. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2004;39(5):725-31.

6. Sanchez JM, Ramos Amador JT, Fernandez de Miguel S, Gonzalez Tomee MI, Rojo Conejo P, Ferrnado Vivas P, et al. Impact of highly active antiretroviral therapy on the morbidity and mortality in Spanish human immunodeficiency virus-infected children. The Pediatric infectious disease journal. 2003;22(10):863-7.

7. Usuga X, Montoya CJ, Landay AL, Rugeles MT. Characterization of quantitative and functional innate immune parameters in HIV-1-infected Colombian children receiving stable highly active antiretroviral therapy. J Acquir Immune Defic Syndr. 2008;49(4):348-57.

8. Arrivillaga M, Ross M, Useche B, Springer A, Correa D. Applying an expanded social determinant approach to the concept of adherence to treatment: the case of Colombian women living with HIV/AIDS. Women’s health issues : official publication of the Jacobs Institute of Women’s Health. 2011;21(2):177-83.

9. GARCIA, Ricardo et al. Reducción de la transmisión madre hijo del VIH en Colombia: dos años de experiencia nacional, 2003-2005. Biomédica [online]. 2005, vol.25, n.4 [cited 2015-04- 28], pp. 547-564 . Available from: <http://www. scielo.org.co/scielo.php?script=sci_arttext&pid= S0120-41572005000400015&lng=en&nrm=iso>. ISSN 0120-4157.

10. MNSyPS. Perfil epidemiológico a 31 de diciembre de 2011. Perfil epidemiologico del VIH/SIDA Colombia 2012. 2012.

11. Castro Díaz J. VII Estudio Nacional Centinela de VIH en Gestantes: Informe de Resultados 2009. INS. 2009.

12. Barrios Acosta ME, Díaz Amaya JG, Koller SH. [A Colombian institutional response to Colombian children infected with HIV/AIDS]. Cien Saude Colet. 2013;18(2):507-16.

13. Miguez-Burbano MJ, Baum MK, Page B, Moncada M, Shor-Posner G. Risk of HIV-1 infection in runaway children in Colombia. Lancet. 1993;342(8869):498.

14. Bustamante A, Elorza M, Cornejo W. Clinical characteristics of HIV-infected children seen at a University Hospital in Medellin, Colombia, 1997-2005. Iatreia;20(4):354-361, dic. 2007. tab.

15. Lizarazo J, Chaves O, Agudelo C, Castañeda E. Comparison of Clinical Findings and Survival Among HIV Positive Patients and HIV-Negative with Cryptococcal Meningitis in a Tertiary Care Hospital. Acta Med Colomb; 37(2): 49-61, abr.-jun. 2012. ilus, tab.

16. López P, Caicedo Y, Rubiano L, Cortés C, Valencia A et al. Metabolic alterations with anti-retroviral highly effective therapy in positive children for VIH, Cali, Colombia. Infectio; 13(4): 283-292, dic. 2009.

17. Siuffi M, Angulo M, Velasco C, López P, Dueñas V, Rojas C. Relation between viral load and CD4 versus Cryptosporidium spp. in feces of children with AIDS. Colomb. méd; 37(1): 15-20, ene.-mar. 2006.

18. Practice Coo. Scheduled Cesarean Delivery and the Prevention of Vertical Transmission of HIV Infection. American College of Obstetricians and Gynecologists. 2010(234):1-4.

19. Connor EM, Sperling RS, Gelber R, Kiselev P, Scott G, O’Sullivan MJ, et al. Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. Pediatric AIDS Clinical Trials Group Protocol 076 Study Group. The New England journal of medicine. 1994;331(18):1173-80.

20. Kind C, Rudin C, Siegrist CA, Wyler CA, Biedermann K, Lauper U, et al. Prevention of vertical HIV transmission: additive protective effect of elective Cesarean section and zidovudine prophylaxis. Swiss Neonatal HIV Study Group. AIDS (London, England). 1998;12(2):205-10.

21. Mandelbrot L, Le Chenadec J, Berrebi A, Bongain A, Benifla JL, Delfraissy JF, et al. Perinatal HIV-1 transmission: interaction between zidovudine prophylaxis and mode of delivery in the French Perinatal Cohort. Jama. 1998;280(1):55-60.

22. The mode of delivery and the risk of vertical transmission of human immunodeficiency virus type 1--a meta-analysis of 15 prospective cohort studies. The International Perinatal HIV Group. The New England journal of medicine. 1999;340(13):977-87.

23. NIH. Panel on Treatment of HIV-Infected Pregnant Women and Prevention of PerinatalTransmission. Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health andInterventions to Reduce Perinatal HIVTransmission in the United States. Available athttp://aidsinfo.nih.gov/contentfiles/lvguidelines/ PerinatalGL.pdf. Accessed (27/02/2015, 09:42pm). 2015.

24. Almeida FJ, Berezin EN, Rodrigues R, Safadi MA, Arnoni MV, Oliveira C, et al. Diversity and prevalence of antiretroviral genotypic resistance mutations among HIV-1-infected children. Jornal de pediatria. 2009;85(2):104-9.

25. Prevalence and Predictors of HIV Drug Resistance Among US Children and Youth with Perinatal HIV. Abstract # 897. Available on: http://www. croiconference.org/sites/all/abstracts/897.pdf [Review October 5th 2014].

26. Leal E, Janini M, Diaz RS. Selective pressures of human immunodeficiency virus type 1 (HIV-1) during pediatric infection. Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases. 2007;7(6):694-707.

27. Prevalence and Predictors of HIV Drug Resistance Among US Children and Youth with Perinatal HIV. Abstract # 897. Available on: http://www. croiconference.org/sites/all/abstracts/897.pdf [Review October 5th 2014].

28. Bunders M, Cortina-Borja M, Newell ML. Age-related standards for total lymphocyte, CD4+ and CD8+ T cell counts in children born in Europe. The Pediatric infectious disease journal. 2005;24(7):595-600.

29. Domachowske JB. Pediatric human immunodeficiency virus infection. Clinical microbiology reviews. 1996;9(4):448-68.

30. World Health Organization Generic Protocol for surveillance of initial drug-resistant HIV-1 among children < 18 months of age newly diagnosed with HIV. WHO/HIV/2012.17. Available on: http:// apps.who.int/iris/bitstream/10665/75202/1/ WHO_HIV_2012.17_eng.pdf ?ua=1. [Review October 1st 2014].

31. Foster C, Judd A, Tookey P, Tudor-Williams G, Dunn D, Shingadia D, et al. Young people in the United Kingdom and Ireland with perinatally acquired HIV: the pediatric legacy for adult services. AIDS patient care and STDs. 2009;23(3):159-66.

32. Judd A, Doerholt K, Tookey PA, Sharland M, Riordan A, Menson E, et al. Morbidity, mortality, and response to treatment by children in the United Kingdom and Ireland with perinatally acquired HIV infection during 1996-2006: planning for teenage and adult care. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2007;45(7):918-24.

33. Patel K, Hernan MA, Williams PL, Seeger JD, McIntosh K, Van Dyke RB, et al. Long-term effectiveness of highly active antiretroviral therapy on the survival of children and adolescents with HIV infection: a 10-year follow-up study. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2008;46(4):507-15.