Co-trimoxazole and INH Prophylaxis

Vashini Pillay Paediatric Infectious Diseases Unit

Red Cross War Memorial Children’s Hospital School of Child and Adolescent Health

University of Cape Town

Co-Trimoxazole Prophylaxis (trimethoprim-sulfamethoxazole)

Introduction

• Substantially reduces HIV-related morbidity and mortality • Broad-spectrum prophylactic action against: bacterial pathogens eg: Pneumocystis jirovecii (PJP)

protozoa eg: Plasmodium spp & Isospora belli

• RCT in HIV infected Zambian children showed a highly significant benefit in improving survival and decreasing hospital admissions and severe pneumonias¹

Hazard Ratio 0.57 (95% C/I 0.43 – 0.77) p = 0.0002 1. Chintu C, et al. Lancet 2004; 364: 1865-1871

Co-trimoxazole

• Combination of trimethoprim and sulphamethoxazole

• Trimethoprim: blocks action of dihydrofolate reductase which disrupts folate synthesis in susceptible micro-organisms

• Sulfamethoxazole: inhibit bacterial folic acid synthesis

Co-trimoxazole

• Well absorbed

• Widely distributed

• Trimethoprim excreted in urine

• Sulphamethoxazole metabolised in liver & excreted in urine

Adverse Effects

• Common

- nausea, vomiting, mild skin rashes

• Uncommon - thrombocytopenia, hyperkalemia,

hyponatremia

• Rare - pancreatitis, fulminant hepatitis, renal failure,

Stevens-Johnson syndrome

Severe Adverse Events

If severe adverse event eg: Stevens-Johnson Syndrome

- stop co-trimoxazole

- alternative regimen is Dapsone (2mg/kg/day)

No paediatric formulation (ie: only tablet form available)

Initiation of Prophylaxis (DOH National Guidelines 2010)

• HIV-exposed infants and children <18months - start 4-6 weeks of age - continue until risk of transmission ceases and HIV infection has been excluded • HIV infected children <12months - indicated regardless of CD4 count and clinical status of child • HIV infected children 1 – 5 years - all symptomatic children (WHO clinical Stage 2,3,4) or children with a CD4 <15% or CD4 count <500 cells/mm3 • HIV infected children >6years - any WHO clinical stage + CD4<15% or CD4 count < 200 cells/mm3 OR WHO clinical stage 3 or 4 regardless of CD count

When can we stop Co-trimoxazole (DOH National Guidelines 2010)

• Children <12 months: - remain on prophylaxis • Children 1- 5 years: - CD4% of >/= 15% or CD4 count of >/= 500cells/mm³ on 2 consecutive occasions, 3-6 months apart • Children over 6 years: - CD4% of >/= 15% or CD4 count of >/= 200 mm³ on 2 consecutive occasions, 3-6 months apart

INH Preventative Therapy

Introduction

• Tuberculosis (TB) is a major cause of morbidity and mortality among children infected with HIV

• HIV infected children are much more at risk of contracting and developing TB compared to uninfected children

• Incidence of 24 per 100 (Cape Town, 2007)¹ ² 1. Cotton MF, South African Journal of HIV Medicine 2011: 27 – 30 2. Zar HJ, et al. BMJ 2007; 334:136

Role of INH in TB prevention

• Isoniazid (INH) significantly decreases the risk of developing active TB in HIV infected children

• A recent study has also showed that IPT may offer additional protection to TB on children already on ART¹

1. Frigati LJ, et al. Thorax 2011, doi: 10.1136/thx.2010.156752

Cohort Analysis

• Cohort analysis performed at 2 hospitals in Cape Town from January 2003 – December 2007

• In children infected with HIV:

- INH alone reduced risk of TB by 0.22 (95% CI 0.09-0.53)

- ART alone reduced risk of TB by 0.32 (95% CI 0.07-1.55)

- INH and ART combined reduced risk of TB by 0.11

(95% CI 0.04-0.32)

• In children on ART:

- INH reduced risk of TB by 0.23 (95% CI 0.05-1.00)

Isoniazid

• First line agents used for treatment of active TB as well as for prophylaxis

• Interferes with the synthesis of mycolic acid (specific to mycobacterial cell walls)

• Optimal absorption takes place on an empty stomach

• Metabolised by the liver

• Excreted by the kidneys

Common Adverse Effects

• Hepatotoxicity (< 1% overt hepatitis) -nausea, vomiting, abdominal pain, jaundice, dark urine • Neurotoxicity eg: peripheral neuropathy -dose-dependent -prevention and reversal -treat with Pyridoxine (vit.B6) 25mg daily • Heamatological - thrombocytopenia, neutropenia, heamolytic anaemia

Drug Interactions

• Inhibits cytochrome p450 enzymes

-metabloism of phenytoin and

carbamazepine inhibited

• Warfarin, Theophylline, Alcohol, Corticosteroids

Post-Exposure Prophylaxis

• Exclude active TB • HIV infected children : All children exposed to a source case with drug-sensitive TB • HIV uninfected children: <5years old exposed to a source case with drug-sensitive TB OR Asymptomatic children with a positive mantoux skin test • Administer INH 10-15mg/kg for 6 months • Add vitamin B6 25mg/day • Clinical follow-up

Primary (Pre-Exposure) Prophylaxis

1. Active TB has been excluded

2. Infants/children not commenced on ARV’s within first 3 months of life

3. Mother not on MTCT program and has not been screened for TB

4. Poor record of attending follow-up appointments (therefore unable to regularly screen for TB exposure or signs and symptoms of TB disease)

Primary (Pre-Exposure) Prophylaxis

• Administer INH 10-15mg/kg for 6 months

• Add vitamin B6 25mg/day

• Clinical follow-up

Not yet National Policy