Challenges in HIV-HBV co-infection Dr Gail Matthews MBChB MRCP FRACP PhD Clinical Academic And Senior Lecturer, Kirby Institute, UNSW Australia & St Vincent’s Hospital, Sydney Australia

Disclosures Gilead: Advisory Board, Honoraria, Research Grants, Travel Sponsorship BMS: Speaker fee, Travel Sponsorship Abbvie: Advisory Board, Honoraia Merck: Speaker fee, Research Grants, Travel Sponsorship Roche: Travel Sponsorship, Speaker fee

HIV-HBV: a huge global burden HIV 35 m HIV-HBV ~2.6 million HBV 250-350 m Kourtis AP et al. N Engl J Med 2012;366:1749-1752.

13 years of tenofovir (TDF) Meta-analysis 23 studies 550 HIV-HBV patients on TDF Increasing suppression over follow-up in majority Little evidence of resistance Price et al, PLOs One 2013

All guidelines recommend TDF-containing ART as preferred regimen WHO ARV guidelines 2013

General agreement on when to start CD4< 500 CD4 >500 DHSS (US)  WHO Evidence of severe chronic liver disease EACS (Europe) If HBV DNA > 2000 IU/ml or ALT elevated BHIVA (UK) HBV DNA > 2000 IU/ml OR F=>2 by TE or biopsy

If the majority of HIV-HBV infected individuals can be treated with a highly potent drug with no resistance what are the challenges remaining?

Challenges remain …in resource limited settings …in resource rich settings

Challenges in resource limited settings Diagnosis and monitoring Access Mother-child transmission

Challenges in resource limited settings Diagnosis and monitoring Access Mother-child transmission

Lack of access to routine testing and monitoring World Hepatitis Alliance/WHO global survey 2009: Testing for HBV and/or HCV >50% people live in countries with no free testing Only 4% low-income countries have ready access to testing Testing accessible to >50% Testing anonymous Free to all Free to some Africa 20% 40% 10% 27% SE Asia 29% 14% Europe 86% 55% Easterbrook et al Sem Liv Dis 2012

Lack of access to routine testing and monitoring Limited access to HBsAg testing means many co-infected individuals not identified pre-ART Little understanding of natural history of co-infection in RLS Liver disease fibrosis assessment not readily available Widespread absence of virological monitoring by HBV DNA testing

Challenges in resource limited settings Diagnosis and monitoring Access Mother-child transmission

Access to TDF in LMIC is restricted First line ART in low and middle income countries 2008 Towards universal access. WHO progress report 2009

Although use is improving Trends in d4T, AZT and TDF use in first-line antiretroviral therapy regimens for adults in low- and middle-income countries, 2006–2011 Global update on HIV treatment 2013. WHO Tanzania: 3% HIV and 17% HIV/HBV on TDF regimen Hawkins IAC 2012

Challenges in resource limited settings Diagnosis and monitoring Access Mother-child transmission

Preventing mother-child transmission Screening of pregnant women for HBV is not routine in many countries Despite WHO Expanded Program of Immunisation universal infant vaccination is not ‘universal’ 56% in SE Asia 47% in India 57% Nigeria WHO expanded program of immunisation

Global and regional infant vaccination rates WHO/UNICEF estimates of third dose of HBV vaccine coverage 1989-2010 Thurz et al Nature Gastro 2012 ; 9; 492-494

Preventing mother-child transmission Screening of pregnant women for HBV is not routine in many countries Universal infant vaccination is not ‘universal’ 56% in SE Asia 47% in India 57% Nigeria High HBV viral loads in HIV infected women increase the likelihood of perinatal transmission even in the setting of immunisation – TDF-containing ART should be prioritised

Challenges in resource rich settings Suboptimal efficacy Toxicity Eradication

Challenges in resource rich settings Suboptimal efficacy Toxicity Eradication

8-10% remain viraemic on tenofovir Efficacy is never 100% 8-10% remain viraemic on tenofovir ? 78% optimal suppression over 7 years Boyd et al Hepatology 2014 De Vries Slujis Gastroenterology 2010

Patterns of suboptimal response to TDF based therapy in HIV-HBV 165 HIV -HBV coinfected individuals followed for median of 4 years HBV DNA detectable in 20% study visits Persistent viraemia (n=25) Viral rebound (n=13) Blipper (n=24) Matthews CID 2012

Factors associated with detectable HBV DNA On truvada based therapy at least 6 months Undetectable HIV RNA < 400 c/ml OR 95% CI p-value Age (per 10 yrs) 0.90 0.48, 1.69 0.74 HBeAg positive 12.06 3.73, 38.98 <0.0001 <95% adherent 2.52 1.16, 5.48 0.02 HAART <2 yrs 2.64 1.06, 6.54 0.04 CD4 < 200 cells/mm3 2.47 1.06, 5.73 Long term adherence is always a challenge Matthews CID 2012

Drivers of HBV viraemia on TDF? Neither genotypic or phenotypic resistance have been definitively described Replication or reservoir release? Virological (UDPS, SGA) and immunological studies may give insight

Challenges in resource rich settings Suboptimal efficacy Toxicity Eradication

TDF associated with bone and kidney toxicity 17 eligible studies, including 10,889 participants, and found that TDF-containing ART regimens were associated with a significantly greater loss of kidney function than were ART regimens not containing TDF. We also found a significantly higher risk of acute renal injury associated with TDF use. Change in glomerular filtration rate (in mL/min) calculated using the Cockcroft-Gault formulation (CG-GFR), for tenofovir disoproxil fumarate (TDF) therapy versus no treatment. BICOMBO 2009 refers to the study by Martinez et al [41], HEAT 2009 refers to the study by Smith et al [44], and HOPS 2007 refers to the HIV Outpatient Study by Young et al [20]. The other studies are indicated by first author and date of publication [16–19, 34, 37, 38, 40]. ART, antiretroviral treatment; CI, confidence interval; MD, mean difference; NNRTI, nonnucleoside reverse-transcriptase inhibitor; RCT, randomized controlled trial; RPI, ritonavir-boosted protease inhibitor. A small but significantly increased risk of acute renal injury associated with TDF-containing regimens (risk difference, 0.7%; 95% CI, 0.2–1.2; statistical heterogeneity absent: I2=0%). There was a significantly greater loss of kidney function over the course of treatment among those receiving TDF-containing ART, compared with control subjects (mean difference [MD] in CG-GFR, 3.92 mL/min; 95% confidence interval [CI], 2.13-5.70 mL/min) Cooper R D et al. Clin Infect Dis. 2010;51:496-505, Bedimo AIDS 2012 26(7) 825-831

Strategies when TDF is contra-indicated? Reduce dose TDF Switch to entecavir (caution if LAM-R) Adefovir plus entecavir (?kidney disease) Peg-interferon (?advanced liver disease) ? Tenfovir Alafenamide (TAF)

Challenges in resource rich settings Suboptimal efficacy Toxicity Eradication

The final challenge Science 2014, 343, 1212-1213

Challenges at many levels Implications of persistent viraemia Management and incidence of flare Options for switch Cure strategies Virological Immunological New agents for cure Burden of disease Understanding natural history Role of GT Occult HBV HCC Access to drug National testing policies Universal and birth dose vaccination Policy/ advocacy Epidemiology Basic science Clinical research