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HIV/HBV co-infection in a teenager - challenges in the context of drug resistance and toxicity

HIV/HBV co-infection in a teenager - challenges in the context of drug resistance and toxicity. 2/06/13 Anna Turkova Imperial College NHS Trust , UK PENTA. 14 yr old young lady. Background Born in Sub-Saharan Africa Arrived to the UK at the age of 6 yrs

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HIV/HBV co-infection in a teenager - challenges in the context of drug resistance and toxicity

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  1. HIV/HBV co-infection in a teenager - challenges in the context of drug resistance and toxicity 2/06/13 Anna Turkova Imperial College NHS Trust, UK PENTA

  2. 14 yr old young lady • Background • Born in Sub-Saharan Africa • Arrived to the UK at the age of 6 yrs • Born at term, fully immunised, BCG + • Normal development • HIV diagnosed at the age of 8 yrs

  3. At the time of HIV diagnosis,8 years of age • Well grown (Wt 91st, Ht 75th) • HBsAg – NEGATIVE • Anti-HCV and anti-HAV – all negative • CD4 540 (22%), HIV VL 97,959 cop/ml • Baseline HIV resistance – wild type virus • Other issues: Difficult rapport with the family, unscreened siblings

  4. Started on ART - age 10 yrs • Indications • Increased Rt parotid gland • CD4 330 cells/mmᶟ • VL 8,000-16,000 cop/ml • Started on Truvada + Kaletra • Excellent response (in 2 weeks) • CD4 330 → 440 • VL 16,051 → <50

  5. 4 weeks after ART started.. • Arthralgia • Low grade fever and persistent joint pain • No obvious joint swelling • WBC 7.1, CRP 64, ESR 118, ALT 52 • Blood culture, throat swabs - neg • ANA, ASOT – neg • Parents: ‘Joint pain is related to ART’ • ART stopped despite medical advice • Arthralgia resolved

  6. A year later.. • Symptomatic: • Recurrent respiratory infections • Parotid enlargement, lymphadenopathy • CD4 340, VL 10,000 • StartedonKivexa + ATZ/r (HLA-B*5701 negative) • VL 43,780 → <50, CD4 340 → 254

  7. 8 weeks after ART started.. • Arthropathy • Persistent pain in small joints • Mild swelling of a few metacarpal joints • Swollen Achilles tendons + bilateral subcutaneous nodules

  8. Voting cards Recurrent arthropathy - ?cause

  9. Recurrent arthralgia/arthropathy post ART • Arthralgia / arthropathy is well known ART – related side effect.. • This is a session on HIV/HBV co-infection • It must be an extrahepatic manifestation • I would re-check her hepatitis serology...

  10. ART musculoskeletal side effects 1. Truvada + LPV/ritonavir 2. Kivexa + ATZ/ritonavir http://www.medicines.org.uk/emc/

  11. Impression • ART-related arthropathy - ?ritonavir • ART stopped • Symptoms resolved

  12. 6 mo after ART interruption, 13 yrs • CD4 <200 (15%), VL 35,000 • Prolonged negotiation with the family – reluctant to restart • Restarted ART: Kivexa + NVP

  13. Routine screening • HBsAg - positive • Repeat serology and HBV viral load: • HBsAgpositive • Anti-HBc total positive • Anti- HBcIgMnegative • HBeAgpositive • HBV VL 916x106c/ml (= 270x106IU/ml) • Anti-HDV negative ART changed to Atripla

  14. Timeline ∆ HIV, age 8 yrs CD4<350, ART re-started: Kivexa + ATZ/r HBsAgneg CD4 540 8/52 Arthropathy, (?ritonavir) ART stopped 2006 2009 2010 2011 HBsAg– Pos Anti-HBc – Pos HBV 916x106 cop/ml CD4 198 Kivexa+NVP→ Atripla CD4 330 Kaletra &Truvada 4/52 joint pain ART stopped by parents

  15. Voting cards When & how did she acquire HBV?

  16. Time of acquisition of HBV? • It is a new infection as • She was HBsAgneg in 2006.. • This makes me think about the modes of acquisition in a teenage girl.. • We need to explore this further with her • I would put my money on HBV reactivation • I would do HBV serology and HBV VL on old samples..

  17. HBV serology and VL Kivexa+ATZ/r Kivexa+NVP →Atripla TDF+FTC+LPV/r HBsAgNeg HBsAgneg Anti-HBs neg Anti-HBcpos HBeAgneg Anti-HBe pos HBV-DNA neg HBsAgneg HBV-DNA insufficient HBsAg pos HBV-DNA 1636 c/ml HBsAgpos HBeAg pos Anti-HBeneg HBV VL 916x106c/ml HIV VL, c/ml CD4 cell/mmᶟ ALT, IU/L CD4 HIV VL ALT

  18. Impression.. • Reactivation of HBV infection • Associated with CD4 decrease • Coincided with stopping of Truvada • Previous occult Hep B HBsAgneg , +/- anti-HBc pos, HBV-DNA <200 IU/ml (The Taormina Consensus 2008) • More common in HIV+ populations • Cross-sectional study in HIV+ adolescents (Thailand) → isolated anti-HBc in 0.8% (4/521) (Aurpibul et al. PIDJ 2012) Retrospectively : both parents - HBV carriers, undetectable on treatment Most likely time of acquiring HBV – childhood, Most likely route of infection – horizontal

  19. Learning points • Hep B screening in HIV+ children should include HBsAg, anti-Hbc (and anti-HBs) • Ask / check HBV status within the family • Those who are negative –vaccinate sooner rather than later • Arthropathy - as the only sign of IRIS occur in HIV/HBV co-infected adults • Usually pts are more immunocompromised • Usually associated with rise of CD4 • Arthropathy persistent, requires treatment with steroids

  20. A year later..‘HIV undetectable, HBV increasing’ • Well • On Atripla • HIV <50 • CD4 200 → 465 • HBV DNA 916x106→ → →18,653 → 268 → 242,132 c/ml (=71,006 IU/ml) HBV=40 cop/ml Jul 2011 July 2012 Apr 2013

  21. Voting cards What is the cause of suboptimal response to anti-HBV treatment?

  22. Suboptimal response to anti-HBV treatment.. • Adherence is the issue.. • The most likely reason is HBV resistance

  23. Addressing adherence.. • Admits to struggle to take the medicine every night • Misses ≥2 doses every week • After addressing adherence • HBV VL 916x106→ 256,034 → 4,141 →18,653 → 268 → 242,132 → 754 Adherence addressed HBV=40 cop/ml Jul 2011 July 2012 Apr 2013 → 5,087 c/ml ( =874 IU/ml)

  24. Could incomplete adherence be the reason for fluctuating HBV-DNA when HIV remains undetectable? • EFV has a long plasma half life (36-100 hrs)1 and can suppress HIV for few days off ART • HIV VL remains suppressed with weekends off ART (FOTO2, RCT in Uganda3, ongoing BREATHER trial) • TDF and FTC have a shorter plasma half life 1 • TDF has intracellullar ½ life of • 150h in lymphocytes1 • 96+/-6 h in hepatocytes4 1 Taylor et al, AIDS 2012 2 Cohen et al, AIDS Society 2008 3 Reynolds et al, ICAAC 2008 4 Delaney et al. AAC 2006

  25. Different HBV DNA decline profiles can be observed in patients during drug therapy • Complex interplay between HBV and host immunity • Many contributing factors • HBV-DNA viral load • Resistance • Adherence • Proportion of infected hepatocytes • Inflammation • Host immune response • CCC HBV-DNA (resistant to antivirals) Lamivudine and famciclovir Pegylated IFN2a Adefovirdipivoxil (D) Lamivudine and famciclovir (E) Slow rebound Dahari eta al. Hepatology 2009

  26. HBV resistance testing • HBV genotyping showed • Genotype E • A Met to Arg change was noted at codon204 • M204R • Mutations at this codon (M204V/I) are associated with resistance to lamivudine, telbivudine and emtricitabine

  27. Does resistance to 3TC matter? • Very common in HIV/HBV patients • 50% by 2yrs, 90% by 5yrs in adults with HBV monotherapy with 3TC • 75% of Thai adolescents reported to have M204V/I (Aurpibul et al. PIDJ 2012) • 3TC/FTC resistance mutations (L180M, M204V/I) confer decreased response to entecavir (Pessoa et al. AIDS 2008) • TDF is effective in suppressing HBV DNA independently of the presence of 3TC/FTC resistant virus (Schmutz et al. AIDS 2006; Lee et al, CROI 2012)

  28. Resistance to TDF • Has not been convincingly described • Sequencing doesn’t provide an explanation for suboptimal responses to tenofovir 1,2 • A194T mutation imparts partial TDF resistancein vitro 3 • TDF phenotypic resistance has not been documented in co-infected patients with up to 5 years of follow-up 1Lada et al, Liver Int 2012 2 Snow-Lampart A et al, Hepatology 2011 3Matthews G. CurrOpin Infect Dis 2007

  29. 2 years on Atripla‘HIV undetectable, HBV fluctuating’ • On Atripla for 2 yrs • HIV RNA <50 c/ml • HBV DNA 5,087 c/ml (=874 IU/ml) • Would you intensify HBV treatment? HBV=40 cop/ml Jul 2011 July 2012 Apr 2013

  30. Voting cards To intensify or not to intensify?

  31. Would you consider intensification of treatment with additional anti-HBV antivirals in this case? • I would consider adding additional anti- HBV drugs • I would continue with Atripla

  32. Response to TDF • HIV/HBV patients take longer to achieve undetectable viral load • 31-87% respond by 48 w • 90% by 5 yrs 2 • Most of the patients achieve undetectable viral load by 3-5 yrs 1,2,3 1 De Vries-Sluijs et al. Gastr 2010 2 Childs et al. AIDS 2013 3 Plaza et al.AIDS 2013 Plaza et al. AIDS 2013

  33. What are the factors contributing to delayed response? • High HBV-DNA level is the main predictor of delayed virological response • Higher HBV-DNA in HIV/HBV patients • Intensification is not required in delayed responders • Intensification may be considered in patients with advanced liver disease Childs et al, AIDS 2013

  34. If my patient develops TDF toxicity what would you advise to do?

  35. Voting cards In a child with HIV/HBV co-infection and TDF intolerance what options are there?

  36. In a child with HIV/HBV co-infection and TDF toxicity/intolerance what options are there? • Stop TDF leave on modified ART and monitor for progression of liver disease • Stop TDF and consider PEG-IFN

  37. IFN-α • HBV-monoinfected children - 26 - 28% - clearance HBV DNA1,2 • Response better with high ALT (x1.5-2) • Genotype A, B respond better • Less effective in HIV/HBV patients (adult data) • PegIFN-α more efficacious than IFN-α3 (adult data) • PegIFN-α – not approved for HBV treatment in children • Side effects: flu-like symptoms, myalgias, rash 1 Torre et al. CID 1996 2 Sokal et al. Gastroenterology 1998 3 Lau GK. Med J Malaysia 2005

  38. Other anti-HBV antivirals? Entecavir AdefovirDipivoxil

  39. Entecavir, Adefovir Entecavir AdefovirDipivoxil Labelled for use in children >12 yrs RCT, n=173, better than placebo only in 12-18yr old, 23% HBV DNA <1000 c/ml 1 Lower virological efficacy compared to Entecavir,TDF Greater nephrotoxicity than with TDF NOT an option in TDF toxicity • Labelled for use in children children >16yrs • Studies on establishing doses for children are ongoing • High virological efficacy • High genetic barrier to resistance • Genetic barrier to entecavir is lowered by exposure to 3TC • Safety profile (in adults) is comparable to TDF 1 Jonas et al. Hepatology 2008 2 Pwlowska et al. Eur J ClinMicrobiol Infect Dis 2012

  40. Entecavir, Adefovir Entecavir AdefovirDipivoxil Labelled for use in children >12 yrs Lower virological efficacy compared to TDF Greater nephrotoxicity than with TDF RCT, n=173, better than placebo only in 12-18yr old, 23% HBV DNA <1000 c/ml NOT an option in TDF toxicity • Labelled for use in children children >16yrs • RCT in children is ongoing • Paed study on experienced children 40% undetectable at 24w (88% HBeAg-ve, 23% HBeAg+ve) 2 • High virological efficacy • High genetic barrier to resistance • Genetic barrier to entecavir is lowered by exposure to 3TC • Well tolerated in adults and children No significant interactions with antiretrovirals 1 Jonas et al. Hepatology 2008 2 Pwlowska et al. Eur J ClinMicrobiol Infect Dis 2012

  41. Summary • HBV reactivation occurs in HIV-infected children and adults with immunosuppression • For HBV screening in children - to includeHBsAg, anti-HBcand anti-HBs • to rule out past HBV infection • to choose appropriate ART • to vaccinate unprotected

  42. Summary • Monotherapy with 3TC/FTC should be avoided • In children with TDF intolerance options are limited • off label entecavir may be considered in older ones? (RCT results in children are awaited)

  43. Thank you! • Acknowledgements: • Paediatric ID team at St Mary’s • Gareth Tudor-Williams • Caroline Foster • Hermione Lyall • Sam Walters • Adult ID at St Mary’s • Graham Cooke • Virology • Emilie Sanchez

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