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

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


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


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


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


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


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


8 weeks after ART started..

• Arthropathy

• Persistent pain in small joints• Mild swelling of a few metacarpal joints• Swollen Achilles tendons + bilateral

subcutaneous nodules


Voting cards

Recurrent arthropathy - ?cause


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...


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/


Impression

• ART-related arthropathy - ?ritonavir

• ART stopped

• Symptoms resolved


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


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


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


Voting cards

When & how did she acquire HBV?


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..


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-08Jun-08

Aug-08

Nov-08Jan-09

Mar-09Jun-09

Aug-09

Oct-09Jan-10

Mar-10

May-10

Aug-10

Oct-10

Dec-10

Feb-11

May-11Jul-1

1

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


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 treatment

Most likely time of acquiring HBV – childhood,Most likely route of infection – horizontal


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


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


Voting cards

What is the cause of suboptimal response to anti-HBV treatment?


Suboptimal response to anti-HBV treatment..

• Adherence is the issue.. • The most likely reason

is HBV resistance


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)


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


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


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


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)


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


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


Voting cards

To intensify or not to intensify?


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


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


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


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


Voting cards

In a child with HIV/HBV co-infection and TDF intolerance

what options are there?


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


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


Other anti-HBV antivirals?Entecavir Adefovir Dipivoxil


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


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


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


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)


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

Documents

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