Provision of Isoniazid Preventive Therapy (IPT) as part of the comprehensive TB/HIV prevention intervention for people living with HIV & AIDS was recommended by WHO in 2011. Literature shows that Isoniazid (INH) associated hepatotoxicity is a common drug adverse event among people taking INH, and that it’s associated with a high risk of mortality. These case series document INH associated hepatotoxicity in HIV-infected children receiving IPT in a resource constrained setting. They also further describe the challenges and lessons learnt while providing routine IPT among HIV-infected children in a resource-limited setting where laboratory tests for liver function monitoring are not performed routinely. The case series describe observed cases which presented to the Mildmay Uganda HIV/AIDS clinic between December 2013 and March 2014. The findings demonstrate that: 1) there was a 1.5% INH related hepatotoxicity incidence among children of four to ten years old; 2) 20% death rate—one out of the five children died and; 3) hepatotoxicity events on average occurred at 10.8 weeks after INH initiation while at the same time, all the cases had liver enzymes elevated above 10 times the upper normal limit values and reported late for medical intervention. The insidious onset of symptoms and signs of INH related hepatotoxicity coupled with lack of adequate resources needed to manage the condition were the major challenges to provision of routine IPT among children living with HIV in resource-limited settings in sub-Sahara Africa. Clinical vigilance, continuous education of clients and caretakers about the side effects or adverse events of INH and routine laboratory examination of liver function tests during follow-up of IPT in HIV-infected children are recommended to enhance early detection and prompt management of IPT associated hepatotoxicity.
World Health Organization (WHO) recommended provision of Isoniazid Preventive Therapy (IPT) among people living with HIV as part of the TB prevention interventions in 2011 [
Although the burden of childhood TB among people living with HIV in Uganda is unknown, at Mildmay Uganda―a specialized HIV & AIDS care and treatment centre [
Case 1
A seven-year-old girl who initiated Highly Active Anti-retroviral Therapy (HAART) in 2007 and IPT in August 2013 developed INH hepatotoxicity which was later complicated by encephalopathy. She was reported dead one week after discharge from the In-Patient Unit. In 2007, she initiated Stavudine, Lamivudine and Nevirapine as HAART, but Stavidine was later substituted for Zidovudine in 2009 due to policy change phasing out Stavudine. Eleven weeks after initiation of INH, she reported to the clinic in company of her caretaker with a history of cough, fatigue and poor appetite for two weeks; and yellow eyes, passing dark urine, abdominal pains, nausea and vomiting and swelling of the face for one week. On physical examination, the patient was lethargic and deeply jaundiced with a puffy face, but not febrile. There was no abdominal tenderness and the liver was not palpable. The abdominal ultrasound scan showed mild increase in liver parenchymal echogenicity with a rough echotexture but normal size and contour. Liver function tests indicated markedly raised transaminases, 30 to 40 fold above the upper normal limits. Renal function tests were within normal range while Hepatitis B and C tests were negative. Urinalysis showed Bilirubin 2+ and urobilinogen 33 micromol/l. A diagnosis of INH Hepatotoxicity was made basing on history, physical examination findings, Liver function test and abdominal ultrasound scan results. The Patient was admitted for supportive care and management of toxicities. On the day of admission, the patient stopped INH and Pyridoxine, and Nevirapine was also led out.
For the first three days of admission, the patient remained stable without new complaints. On the 4th day of admission, the patient’s condition deteriorated mainly characterized by acute urinary retention, and reduced level of consciousness with Glasgow Coma Scale of 11/15. A diagnosis of INH hepatotoxicity with encephalopathy was made due to reduced level of consciousness. All drugs were stopped and the patient was given Lactulose, animal protein free diet feeding by the nasal gastric tube and Intravenous rehydration with normal saline. The patient however, experienced fluctuating levels of consciousness and episodes of aggressiveness. She later improved on supportive treatment and become clinically well―Glasgow Coma scale 15/15, she was able to carry on the activities of daily living and play. She was discharged on the 14th day of admission off all drugs and on an animal protein free diet with a review date of one week. Liver function test results on discharge were as follows: Alkaline Phosphatase (U/L): 387; Aspartate transaminase (U/L): 415.3; Alanine transaminase (U/L): 382.6; and Total Bilirubin (µmol/l): 352.7. Total Bilirubin, was twenty times higher than the normal limits, while Aspartate and Alanine transaminases were each ten times higher than the normal limits. Unfortunately, she fell sick before the appointment date and got admitted at a private Hospital in town where she died. There was no postmortem report from the hospital.
Case 2
A seven-year-old male reported to the clinic four weeks after initiating INH with a short duration (five days) history abdominal pain associated with passing of semi-formed stools. He had a skin rash which did not involve mucous membranes, neither the eyes nor the mouth. The child had initiated HAART (Zidovudine, Lamivudine and Nevirapine) at the age of one month while in a study setting in 2007, failed on first line HAART after nine months and was switched to second line, Didanosine, Abacavir and Lopinavir/Ritonavir. He had received Single dose Nevirapine at birth for Prevention of Mother to Child Transmission of HIV. Later Didanosine was substituted for Lamivudine in 2011 due to policy change to phase out Didanosine. At the time of diagnosis with the INH hepatotoxicity he had been on Abacavir, lamivudine and Lopinavir/Ritonavir for two years, and the diagnosis was made basing on the liver function test results, which were nine times the upper normal limit. The patient continued with HAART uninterrupted and was managed as an out-patient with supportive treatment. Monitoring liver function tests results done on the fourth day after stopping INH were within normal range: Aspartate transaminase (U/L): 36.8; Alaline transaminase (U/L): 33.2; and Total Bilirubin (µmol/l): 3.5. Currently, the child is well and continuing with HAART.
Case 3
A seven-year-old HAART naïve HIV positive female receiving HIV care developed severe INH associated hepatotoxicity, 21 weeks (five months) after taking IPT. She had received HIV care since 2007 for a period of about seven years. She reported to the clinic with a four-day history of fever, abdominal pain, vomiting and passing yellow coloured urine. There was no history of diarrhea and cough. Review of other systems had no significant symptoms and she had no previous history of having a liver disease. On medical examination, she was afebrile and deeply jaundiced. Liver function and bilirubin tests were done and results were raised above the normal upper limits, 40 times for the liver transaminases and 4 times for total bilirubin. Hepatitis B and C tests were also done and results were negative. A diagnosis of severe INH associated hepatotoxicity was made and the child was admitted to the paediatric inpatient unit at Mildmay Uganda for In-patient care. All medications were stopped and the child was managed by giving intravenous fluid and an animal protein free diet for supportive management. The child improved and was discharged after two weeks of admission. Liver function test results on discharge were as follows: Alkaline Phosphatase (U/L) 332.7, Aspartate transaminase (U/L): 44.2; Alaline transaminase (U/L): 69.8; and Total Bilirubin (µmol/l): 8.3. After INH hepatotoxicity resolved, she continued with Cotrimoxazole as prophylaxis for other HIV related opportunistic infections while at the same time preparation for HAART initiation began as per the Uganda National guidelines [
Case 4
A 12-year-old HIV positive female receiving HIV care and treatment (for seven years) developed severe INH associated hepatotoxicity 14 weeks after initiation of IPT. She initiated HAART in 2006 on Zidovudine, Lamivudine and Nevirapine regimen. She reported with a two weeks’ history of fever and headache. On medical examination, she was afebrile and had marked conjunctiva jaundice. She was not anaemic and the systemic examination was normal. Liver function tests were done and results indicated raised liver transaminases five times the upper limit. Abdominal ultrasound scan indicated mild hepatomegally. Blood test results for malaria, Hepatitis B and C were negative. A diagnosis of INH associated hepatotoxicity was made and the child was admitted for In-patient supportive care on the paediatric ward. All medications were stopped, and the patient was given intravenous fluids and restricted animal protein diet. While admitted the liver enzymes kept rising and Prothrombin Time was done to determine the severity of liver damage. Prothrombin Time was 71.6 Seconds, fivefold higher than the upper normal limit (normal range: 9.8 - 14.2). International Normalized Ratio (INR) was 6.5, two-fold higher than the upper normal value (normal ratio range: 2 - 3). However, there was no history of bleeding tendencies. The patient was given Vitamin K. Prothrombin Time and INR results after ten days of admission were 20.7 seconds and 1.69 respectively. The patient was discharged on the 18th day after admission. Liver function test results on discharge were as follows: Alkaline Phosphatase (U/L): 287; Aspartate transaminase (U/L): 75.2; Alaline transaminase (U/L): 61.2; and Total Bilirubin (µmol/l): 111.5. After being discharged from the ward, she continued to attend clinical reviews in the Out-patient department on Cotimoxazole. HAART was restarted three months later after Alkaline Phosphatase, Aspartate transaminase, Alanine transaminase and Total Bilirubin levels had normalized.
Case 5
A four-year-old HIV positive boy was brought in by a care taker, seven weeks after initiating IPT with a five-day history of anorexia, yellow eyes, passing of yellow urine, abdominal pain and general body weakness. He had received HIV care since 2011 and HAART (Zidovudine, Lamivudine and Efavirenz) for 15 months. The child also had a past medical history of pulmonary TB disease in 2012 (2RHZ/4RH) and completed treatment. Test results were negative for hepatitis, and malaria. Liver enzymes were raised about twenty-fold above the upper normal limits. A diagnosis of INH associated hepatotoxicity was made, the child immediately stopped INH. The caretaker was advised on modifying the diet and restricted animal protein. HAART and Cotrimoxazole were continued uninterrupted and the patient was managed on ambulatory basis in the out-patient clinic without admission. Liver Function Tests normalized within eight days after stopping INH. Results were: Alkaline Phosphatase (U/L) 208, Aspartate transaminase (U/L) 44.7, Alanine transaminase (U/L) 16.8 and Total Bilirubin (µmol/l) 5.5.
A summary of the baseline characteristics of the 5 children prior to initiation of IPT is shown in
INH associated hepatotoxicity has previously been reported among people taking TB treatment and IPT, but mainly in developed countries [
Sex (M/F) | Age (Years) | CD4 cells (Absolute Count) | Percentage CD4 (CD3+ CD4+/CD45+) | ART Status (Yes/No) | ART Regimen When Initiating IPT | |
---|---|---|---|---|---|---|
Case 1 | F | 7 | 839 | 43 | Yes | Lamivudine, Zidovudine, Nevirapine |
Case 2 | M | 7 | 1564 | 35 | Yes | Abacavir, Lamivudine, Lopinavir/Ritonavir |
Case 3 | F | 7 | 528 | 24 | No | Naive |
Case 4 | F | 12 | 1193 | 38 | Yes | Zidovudine, Lamivudine Nevirapine |
Case 5 | M | 4 | 1478 | 38 | Yes | Zidovudine, Lamivudine, Efavirenz |
estimated at 0.1 percent and is rare in individuals younger than 20 years of age [
On average, the duration between starting IPT and presentation of cases to the clinic was 11.4 weeks. The findings of these case series are consistent with previous findings in the literature which indicate that hepatotoxicity occurs several weeks after initiating INH, usually after one month [
Except for one child (Case 3) who was HAART naive, the other cases were on ARVs. As previously noted by Weisiger’s finding [
It is recommended that INH (and other hepatotoxic drugs) be withheld in case a patient’s transaminase exceed 3 times the upper limit of normal level if associated with symptoms or 5 times the upper limit of normal if the patient is asymptomatic [
The case series demonstrate that a high incidence of INH associated hepatotoxicity may occur among HIV positive children receiving routine IPT, given as part of the comprehensive HIV care and treatment. Furthermore, children affected are more likely to present late to the clinics or hospitals for appropriate medical interventions. Since the onset of hepatotoxicity symptoms and signs may be insidious after starting IPT, cases are more likely to become severe due to delayed or missed diagnosis, hence carrying a high fatality risk or poor prognosis requiring in-patient care and skilled medical staff―which is most often not readily available in resource-limited settings. This fact underscores the need for: 1) vigilance during clinical visits’ assessment to identify hepatotoxicity signs and symptoms and; 2) continuous education about the side effects and adverse events of INH among patients and caretakers of patients taking IPT. These interventions in turn improve suspicion, early detection and reporting of INH related adverse events both in the health facilities and in the community or at home. In addition, clinical monitoring alone has limitations in ensuring safety and earlier identification of organ damage, hence necessitating routine examination of liver function tests during the course of routine IPT. There is a need for research to: a) explore the effect or interaction of Nevirapine with INH in a bigger quantitative study and; b) assess possible risk factors or determinants of INH hepatotoxicity among HIV infected children taking routine IPT.
Authors acknowledge the dedicated staff at the Mildmay Uganda Peadiatric Department who provided expertise care to the cases discussed in this paper. Caretakers and clients are also acknowledged for their resilience and active participation while working together with the medical team to save lives. Provision of comprehensive HIV, TB & HIV services including routine IPT at Mildmay Uganda is supported by the Cooperative Agreement Number 1UG2PS002909-01 from the Centers for Disease Control and Prevention (CDC).
Informed assent was obtained from the caretakers for all the five children―copies of the assent forms are available for review by the Editor in Chief of this journal.
The authors declare that they have no competing interests.
All authors made equally substantial and intellectual contributions during the writing process of this paper.
The contents of this manuscript are solely the responsibility of the authors and do not represent the official views of the CDC.
AIDS: Acquired Immunodeficiency Syndrome
ART: Antiretroviral Therapy
CDC: Centers for Disease Control and Prevention
HAART: Highly Active Anti-retroviral Therapy
HIV: Human Immunodeficiency Syndrome
INH: Isonicotinic Acid Hydrazide or Isoniazid
INR: International Normalized Ratio
IPT: Isoniazid Preventive Therapy
TB: Tuberculosis
WHO: World Health Organization