DILEMMAS IN THE MANAGEMENT OF CO-INFECTION IN HIV-INFECTED CHILDREN

Transcription

1 DILEMMAS IN THE MANAGEMENT OF CO-INFECTION IN HIV-INFECTED CHILDREN E NEL DEPARTMENT OF PAEDIATRICS AND CHILD HEALTH, FHS, STELLENBOSCH UNIVERSITY, SOUTH AFRICA

2 HIV/HBV CO-INFECTION Prevalence of co-infection: 3-19% Limited therapeutic options Often limited resources to monitor patients in areas with the highest burden No routine HBV testing of HIV-infected children in some rcountries in Africa Vaccination response poor No routine antibody titre checking/booster vaccination

3 CASE 7 month old boy Premature (28 weeks) Delivered by CS HIV exposed - ZDV for 6 weeks Formula fed HIV DNA PCR negative at 6weeks

4 CASE At 6 months Failing to thrive Multiple, severe chest infections TB CXR suggestive of PTB Household TB contact Now on TB treatment (RHZ) NOW Repeat HIV PCR: positive Raised liver enzymes (appeared slightly jaundiced)

5 CASE Blood results CD4 count: 3x10 9 /l, percentage 0% HIV viral load: 9X10 6 copies/ml Hep B serology: HBsAg positive; HBeAg positive Hep B viral load: 146 x 10 6 Copies/ml Biochemistry Tot. Protein Albumin Tot. BR Conj. BR ALT AST 79 g/l 37 g/l 47 u/l 30 u/l 47 u/l (ULN 40u/l) 199 u/l

6 QUESTIONS TO CONSIDER General Questions What is causing the abnormal biochemistry? Do we need to treat the HIV? ( Silly Question ) How severe is the liver disease Do we need to treat the Hepatitis B? Additional Questions Do we need to change/stop the anti-tb treatment?

7 CAUSES OF ABNORMAL BIOCHEMISTRY (OTHER THAN HEPATITIS B) HIV IRIS OI s Drugs cart Anti-TB Antibiotics CTX Other (non-hiv related)

8 PHASES OF CHRONIC HEPATITIS B INFECTION* Immune Tolerant Immune Active Inactive HBsAg Carrier HBsAg & HBeAg + HBsAg & HBeAg + HBsAg +/ HBeAg - HBV DNA High (>20 000IU/ml) HBV DNA High (>20 000IU/ml) HBV DNA undetectable (<2 000IU/ml) Little inflammation/necrosis/ fibrosis Inflammation/necrosis/ fibrosis + No/minimal inflammation ALT normal/ marginal elevation No/little progression of liver disease ALT increased Progression to cirrhosis if prolonged ALT normal Low risk for progression to cirrhosis * Reactivation Phase not shown

9 HBV/HIV INTERACTION Chronic infection more likely High HBV DNA levels & Infrequent HBeAg seroconversion Transaminases lower Progression of fibrosis and development of cirrhosis more common Increased drug induced liver injury Severe hepatitis or acute liver failure after introduction of HAART (IRIS?) Accelerated progression of HIV? Liver-related mortality higher

10 WHAT ARE THE GOALS OF TREATMENT OF HIV/HBV CO-INFECTION? 1. Reduce viral replication 2. Minimize liver injury and related consequences (cirrhosis & HCC) 3. Reduce infectivity 4. Decrease HAART toxicity 5. Prevent HBV resistance

11 SELECTION OF CHILDREN FOR HBV TREATMENT (NOT CO-INFECTED) Chronic HBV Immune Tolerant/Inactive Carrier Immune Active No treatment Monitor Rule out other causes of liver disease Liver biopsy Minimal/Mild fibrosis Moderate/Severe inflammation/fibrosis No treatment Monitor Treat Adapted from Jonas, 2010

12 THERAPEUTIC OPTIONS FOR CHRONIC HBV IFN NA Agents with ARV Activity 3-TC (>3yrs*) Agents with no ARV Activity Adefovir (> 12yrs*) Entecavir (>16 yrs*) TDF (not approved for HBV) FTC (adults) Telbivudine (adults) *Approved age for Hep B Treatment (not HIV) No ARV activity at HBV dose

13 THERAPEUTIC AGENTS Pro s Limited duration of treatment No resistance Usually well tolerated IFN 3TC TDF Anti-Hepatitis B & HIV activity Well tolerated Anti-Hepatitis B & HIV activity Little resistance Usually well tolerated by adults Con s Not < 1 year Requires SC Injections In Co-infected patients Most do not meet criteria (high ALT, Low viral load, not perinatal transmission) Limited data in coinfection (adults) Less effective in co-infected patients More toxicity in coinfected patients (adults) Longer duration of treatment required (adults) High resistance > 1 year 20% > 2 years 50% (co-infection) > 4 years 90% (co-infection) May select for HBsAg mutants Not registered in all countries (FDA> 2yrs for HIV, not HBV) Renal toxicity Bone mineralisation No paediatric trials (Hepatitis B) Formulation not suitable Tailor dose & monitor BMD & Renal side-effects?

14 TREATMENT OPTION 1 Initiate ART with no anti-hepatitis B activity Pro s No resistance Con s Hepatitis B IRIS Careful monitoring of liver (biochemistry, liver biopsy, noninvasive measures of fibrosis) Not always feasible in a developing country

15 TREATMENT OPTION 2 Initiate ART with 3TC Pro s Well tolerated/formulation Good initial response Con s Resistance

16 TREATMENT OPTION 3 Initiate ART with 3TC & TDF Pro s Low/no resistance Good Hep B response Con s Not registered No trials Formulation Side-effects Defer until older?

17 TREATMENT OPTION 4 IFN Pro s Limited duration of treatment No resistance Usually well tolerated Con s < 1yr Not suitable: ALT, Viral load Not data in co-infected children Less effective in co-infected adults

18 WHICH OPTION WOULD YOU CHOOSE? Option 1. cart with no HBV activity 2. Include 3TC 3. Include 3TC & TDF 4. IFN 5. Other

19 ALTERNATIVE APPROACHES (WHAT WE WANT/WHAT HAPPENS IN PRACTICE) HBV/HIV Co-infection Better resourced area Poorly resourced area Exclude other liver disease Assess degree of liver involvement (include liver biopsy) 1. HBV status usually not known before starting cart 2.Unable to do liver biopsy 3.Unable to monitor liver biochemistry/function 4. Limited ART available Little inflammation/fibrosis: Liver injury 3TC Sparing regimen Monitor for IRIS or liver disease progression 3TC Regimen Risk of multi-drug resistance? 3TC/TDF 3TC/TDF when indicated Monitor as well as possible When resistance/ flare: TDF add on (if available)

20 CLOSING REMARKS Should all patients be tested for HBV? No clear guidelines for the management of HBV/HIV co-infected children in developing countries Need to individualise management Resources available Drugs available Continued monitoring of patients and modification of management

21 Acknowledgements Dr Leon Levine Dr H Rabie