www.ias2013.org kuala lumpur, malaysia, 30 june - 3 july 2013 hiv/hbv co-infection in a teenager -...
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www.ias2013.org Kuala Lumpur, Malaysia , 30 June - 3 July 2013
HIV/HBV co-infection in a teenager - challenges in the context of drug resistance
and toxicity
2/06/13Anna Turkova
Imperial College NHS Trust, UKPENTA
www.ias2013.org Kuala Lumpur, Malaysia , 30 June - 3 July 2013
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
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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
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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
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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
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A year later..
• Symptomatic:• Recurrent respiratory infections• Parotid enlargement, lymphadenopathy
• CD4 340, VL 10,000
• Started on Kivexa + ATZ/r (HLA-B*5701 negative)• VL 43,780 → <50, CD4 340 → 254
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8 weeks after ART started..
• Arthropathy
• Persistent pain in small joints• Mild swelling of a few metacarpal joints• Swollen Achilles tendons + bilateral
subcutaneous nodules
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Voting cards
Recurrent arthropathy - ?cause
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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...
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ART musculoskeletal side effects
ARV Musculoskeletal SE How common?
ABC myalgia (10%), arthralgia uncommon
3TC arthralgia common
TDF reduced bone density uncommon
FTC elevated creatine kinase common
RTV myalgia, arthralgia common
ATZ muscle atrophy, arthralgia, myalgia
uncommon
Lopinavir myalgia, arthralgia, back pain, muscle weakness and spasms
common
1. Truvada + LPV/ritonavir 2. Kivexa + ATZ/ritonavir
http://www.medicines.org.uk/emc/
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Impression
• ART-related arthropathy - ?ritonavir
• ART stopped
• Symptoms resolved
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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
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Routine screening
• HBsAg - positive
• Repeat serology and HBV viral load:– HBsAg positive– Anti-HBc total positive
• Anti- HBc IgM negative– HBeAg positive– HBV VL 916x106c/ml (= 270x106IU/ml)
– Anti-HDV negative
ART changed to Atripla
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2006 2009 2010 2011
CD4 330 Kaletra
&Truvada
4/52joint pain
ART stopped by
parents
CD4<350, ART re-started: Kivexa +
ATZ/r
HBsAg – PosAnti-HBc – PosHBV 916x106
cop/ml
CD4 198
Kivexa+NVP→Atripla
8/52Arthropathy,(?ritonavir)
ART stopped
Timeline
HBsAg neg
CD4 540
∆ HIV, age 8 yrs
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Voting cards
When & how did she acquire HBV?
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Time of acquisition of HBV?• It is a new infection as• She was HBsAg neg 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..
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HBV serology and VL
HIV VL, c/ml
Oct-06
Dec-06
Feb-07
Apr-07Jul-0
7
Sep-07
Nov-07
Feb-08
Apr-08
Jun-08
Aug-08
Nov-08
Jan-09
Mar-0
9
Jun-09
Aug-09
Oct-09
Jan-10
Mar-1
0
May-10
Aug-10
Oct-10
Dec-10
Feb-11
May-11
Jul-11
Sep-11
Dec-11
0
100
200
300
400
500
600
700
50
20,050
40,050
60,050
80,050
100,050
120,050
5387
CD4ALTHIV VL
TDF+FTC+LPV/r Kivexa+ATZ/r
Kivexa+NVP→Atripla
HBsAg NegHBsAg negHBV-DNAinsufficient
HBsAg posHBeAg posAnti-HBe negHBV VL 916x106c/ml
ALT
CD4
HIV VL
HBsAg negAnti-HBs negAnti-HBc posHBeAg negAnti-HBe posHBV-DNA neg
HBsAg posHBV-DNA1636 c/mlCD4
cell/mmᶟALT, IU/L
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Impression..• Reactivation of HBV infection
– Associated with CD4 decrease– Coincided with stopping of Truvada
• Previous occult Hep B HBsAg neg , +/- 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 treatmentMost likely time of acquiring HBV – childhood,
Most likely route of infection – horizontal
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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
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A year later..‘HIV undetectable, HBV increasing’
July 2012 Apr 2013Jul 20111
2
3
4
5
6
7
8
9
HBV VLLog10
cop/ml
• 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
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Voting cards
What is the cause of suboptimal response to anti-HBV treatment?
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Suboptimal response to anti-HBV treatment..
• Adherence is the issue.. • The most likely reason
is HBV resistance
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Addressing adherence..
July 2012 Apr 2013Jul 20111
2
3
4
5
6
7
8
9
HBV VLLog cop/ml• 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
HBV=40 cop/ml
Adherence addressed
→ 5,087 c/ml ( =874 IU/ml)
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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
(FOTO 2, RCT in Uganda 3, ongoing BREATHER trial)
• TDF and FTC have a shorter plasma half life 1
1 Taylor et al, AIDS 20122 Cohen et al, AIDS Society 20083 Reynolds et al, ICAAC 20084 Delaney et al. AAC 2006
TDF has intracellullar ½ life of• 150h in lymphocytes 1
• 96+/-6 h in hepatocytes 4
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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)
Dahari eta al. Hepatology 2009
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HBV resistance testing
• HBV genotyping showed– Genotype E– A Met to Arg change was noted at codon 204– M204R– Mutations at this codon (M204V/I) are associated
with resistance to lamivudine, telbivudine and emtricitabine
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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)
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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 resistance
in vitro 3 • TDF phenotypic resistance has not been
documented in co-infected patients with up to 5 years of follow-up
1 Lada et al, Liver Int 20122 Snow-Lampart A et al, Hepatology 2011 3 Matthews G. Curr Opin Infect Dis 2007
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2 years on Atripla‘HIV undetectable, HBV fluctuating’
July 2012 Apr 2013Jul 20111
2
3
4
5
6
7
8
9
HBV VLLog10
cop/ml• 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
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Voting cards
To intensify or not to intensify?
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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
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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
Plaza et al. AIDS 2013
1 De Vries-Sluijs et al. Gastr 20102 Childs et al. AIDS 20133 Plaza et al.AIDS 2013
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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 diseaseChilds et al, AIDS 2013
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If my patient develops TDF toxicity what would you advise to do?
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Voting cards
In a child with HIV/HBV co-infection and TDF intolerance
what options are there?
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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
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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 19962 Sokal et al. Gastroenterology 19983 Lau GK. Med J Malaysia 2005
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Other anti-HBV antivirals?Entecavir Adefovir Dipivoxil
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Entecavir, AdefovirEntecavir• 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
Adefovir Dipivoxil• 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
1 Jonas et al. Hepatology 2008 2 Pwlowska et al. Eur J Clin Microbiol Infect Dis 2012
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Entecavir, AdefovirEntecavir• 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
Adefovir Dipivoxil• 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
1 Jonas et al. Hepatology 2008 2 Pwlowska et al. Eur J Clin Microbiol Infect Dis 2012
No significant interactions with antiretrovirals
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Summary• HBV reactivation occurs in HIV-infected
children and adults with immunosuppression
• For HBV screening in children - to include HBsAg, anti-HBc and anti-HBs – to rule out past HBV infection– to choose appropriate ART– to vaccinate unprotected
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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)