A tale of two patients

Transcription

1 15 th Annual Resistance and Antiviral Therapy Meeting Dr Sanjay Bhagani Royal Free Hospital, London Thursday 29 September 2011, Royal College of Physicians, London A tale of two patients Sanjay Bhagani Dept of HIV Medicine Royal Free Hospital 1

2 Tom 45yr old London MSM Heavy smoker 50 pack/yr history HIV+ February 2005 CD4 628, vl c/ml HBsAg, anti-hbc, anti-hbs negative HCV-Ab negative vaccinated against HAV and HBV November 2006 CD4 249, vl Starts cart Kivexa/EFV January 2007 Progressive SOBOE, fatigue, increasing cough, occ. fevers Radiology 2

3 What s the diagnosis? Infection Granulomatous reaction Lymphoproliferative infiltration Epithelial malignancy Phone a friend.. After BAL TB-PCR neg, cytology unhelpful We phoned a friend Open lung biopsy Necrotic ganulomas with occ. AAFB TB-PCR negative Culture negative 3

4 Tom (2) Anti-mycobacterial therapy for 12 months ARVs switched to ABC/3TC/lopinavir/r Isoniazid, Rifabutin, Pyrazinamide, Ethambutol 2/12 Isoniazid, Rifabutin, Ethambutol - continuation April 2008 (month 11 of anti-mycobacterial Rx) ALT 1315 U/l, AST 630 U/l, Bil 34, PT normal 2/52 later ALT 700 U/l, AST 450 U/l, bil, PT normal Asymptomatic Further hx: doxycycline for NSU 3/52 prior What do you think is going on? Drug induced hepatotoxicity Acute HCV Acute HBV Hep A infection Phone a friend 4

5 Results: HCV IgG negative, HCV RNA negative Hep A total +, IgM negative HBsAg+, HBeAg+, anti-hbc IgM+ Diagnosis Acute HBV Infection But a)vaccinated against HBV in 2005 b) On lamivudine-based cart Tom (3) Retrospective testing Anti-HBs negative in 2007 HBV Pol sequencing M204I, L180M, V173L 5

6 HBV Primary Resistance Mutations Terminal Spacer Pol/RT RNaseH protein (rt1) 692 (rt344) F_V_LLAQ YMDD 845 aa I(G) II(F) LAM resistance LdT resistance ADV/TDF resistance* ETV resistance A B C D E rta18it/v rta181t/v rtm204v/i rtm204i rta181t/v rti169t rtl180m rtm204 rtt184s/a/i/l/g/c/mv rts202g/c/i rtn236t rtm250i/v *Based on in vitro data and therapy switch following emergence of genotypic ADV resistance. Allen MI, et al. Hepatology. 1998;27: Qi X, et al. EASL Abstract 57. Tenney D, et al. Antimicrob Agents Chemother. 2004;48: Telbivudine [package insert]. Locarnini S. IDRW Abstract P2. Qi X, et al. Antivir Ther. 2007;12: van Bommel F, et al. AASLD Abstract 960. Antiviral Resistance Pathways in CHB Pathway Mutation Associated Resistance L-nucleoside rtm204v/i LAM FTC LdT CLV Acyclic phosphonate rtn236t ADV TDF Shared rta181t/v L-nucleosides and acyclic phosphonates (see above) Naive entecavir resistance rtl180m + rtm204v with one of rtt184, S202, or M250 Multidrug resistance Complex patterns, eg, rta181t + rtn236t + rtm250l ETV Multidrug Yuen L, et al. AASLD Abstract

7 Cumulative Rates of Resistance With Oral Agents in Nucleos(t)ide-Naive Patients Not head-to-head trials; different patient populations and trial designs Drug Generation Yr 1 Yr 2 Yr 3 Yr 4 Yr 5 Yr 6 1st LAM 24% 38% 49% 67% 70% 2nd 3rd ADV LdT ETV TDF 0% 3% 11% 18% 4% 17% 0.2% 0.5% 1.2% 1.2% 1.2% 1.2% 0% 0% 0% 29% EASL. J Hepatol. 2009;50: Tenny DJ, et al. EASL Abstract 20. Marcellin P, et al. AASLD Abstract 481. Heathcote E, et al. AASLD Abstract 483. Evolution of HBV resistance to 3TC Primary resistance mutations (rtm204i) Secondary resistance mutations (rtl180m with rtm204v) Compensatory mutations (rtv173l) 100% 50% 0% M0 M1 M10 M12 M14 M16 M18 M20 M22 M24 M26 M30 M32 M34 Months YIDD (M204V) YVDD (M204I) YMDD (WT) 7

8 Evolution of x-resistance with continued Lam mono-therapy Comparative Incidence of HBV Resistance in Patients Treated with ADV or LAM ADV 1,2,* (N236T or A181V) LAM 3 (YMDD ) LAM 4 (YMDD in HIV/HBV) 100% 90% Incidence of Resistance 80% 60% 40% 20% 0% 70% 53% 42% 47% 24% 0% 2% 3.9% year 1 year 2 year 3 year 4 1. Benhamou Y. et al., Lancet (2001) 358: Qi, et al., EASL 2004, Apr 16, 2004, Berlin 3. Lai C.L., et al., Clinical Infectious Diseases (2003) 36: Benhamou Y et al. Hepatology 1999; 30: * Year 4 resistance rate for ADV not yet available 8

9 Indications of Emergence of Drug-Resistant Virus Increasing HBV DNA ( 1.0 log IU/mL) Increasing serum ALT levels Clinical deterioration Increased risk of drugemergent mutations Primary non-response <1 log drop in DNA at week 12 Detectable HBV DNA 24 weeks after start of therapy (L-nucleosides) 48 weeks post ETV/TDF/ADF HBV DNA (log 10 IU/mL) ALT (U/L) Manifestations of Antiviral Resistance Antiviral Treatment Virologic rebound Virologic breakthrough Genotypic resistance Yrs Hepatitis flare Biochemical breakthrough ULN More than just drug resistance Overlapping Pol and S Mutations in Pol changes in S ADASMs Antiviral Drug- Associated S mutations ADAPVEMS Antiviral Drug Associated Potentially Vaccine (and detection) Escape Mutations Associated with L- nucleosides and Entacavir, possibly with adefovir 9

10 Tom - Acute 3TC-resistant HBV infection Date Feb 05 Nov 06 Apr 07 Jan 08 2 May May May Jun Sep 08 Mar 09 HBV serology sagcabsab- sag- sag- cab- cab- sab- sab- sag+ eag+ cigm+ sag+ eag+ sag+ eageab- sag+/- eageab+ sab- sag- eag eab+ sab+ sageageab+ sab++ HBV DNA (cps/ml) 1,674, ,131 6,810 <100 HBV Resistance M204V L180M V173L M204V L180M V173L ARVs ABC 3TC LPV/r TDF FTC LPV/r HIV VL <50 <50 <50 Public Health Significance of Drug-Resistant Strains Can infect naive (anti-hbs-) individuals Individual with chronic HBV treated with nucleos(t)ide analogues Selects for mutants that may not be protected by vaccination Can infect hepatitis B immunized (anti- HBs+) individuals 10

11 Jerry Jerry London HIV MSM HIV HBsAg+, HBeAg+, anti-hbc+, anti-hbe- HCV Ab neg CD4 111, vl c/ml Starts D4T/3TC/Nelfinavir 11

12 Jerry (2) Feb 2008 transfers to the RFH AZT/3TC/Lopinavir/r HBV DNA 1, c/ml eag+, anti-hbe- ALT 22U/l, PT, platelets - normal US scan normal, AFP 5 iu/l FibroScan 6kPA (significant fibrosis ruled out with Normal ALT) Switched to TDF/FTC/Lopinavir/r Jerry (3) August 2008 HBV DNA <100 c/ml eag+, anti-hbe- Continues on TDF/FTC/Lopinavir/r Annual US scans + AFP But.. 12

13 Jerry - results Associated increase in proteinuria Reducing serum phosphate Normal BP Urine RBP/Creat What do we do next? Switch TDF to Entecavir Switch TDF to ADF Stop TDF and Rx with PegIFN Continue TDF and Rx with probenecid Phone a friend. 13

14 Jerry (4) We stop TDF and switch to Entecavir (1mg/day) Continue on 3TC/Lopinavir-r 1 month later HIV RNA <40 c/ml HBV DNA <100 c/ml 4 months later egfr 66ml/min HBV DNA 2859 c/ml (i.e >1 log 10 increase) eag+, anti-hbe- HIV RNA <40 c/ml Re-bound on switching from TDF to ETV Pol sequenced M204V, L180M BUT no S202G, T184G or M205V 14

15 Anti-HBV drugs TBV ETV* TDF* PegIFN Potency LAM* FTC* ADV Nucleosides Nucleotides *Anti-HIV activity Genetic barrier Cumulative probability of virological breakthrough with entecavir NA naïve Lamivudine refractory Percent Year N = N = Mutations: (M204V, L180M) + T184, S202 and/or M250 Colonno, AASLD 2006; Colonno EASL 2007; Colonno Hepatology 2006; Tenney et al Antiimicrob.Agents Chemother

16 Genetic Barrier The number of substitutions needed for primary antiviral drug resistance LAM/LdT: rtm204i ADV: rtn236t Combination of low genetic barrier drugs: at least 2 mutations required ETV: at least 3 mutations required: rtl180m + rtm204v + one of rtt184 or rts202 or rtm250 change Efficacy of Entecavir vs Tenofovir in the Setting of Resistance Similar antiviral activity against nonresistant HBV; efficacy against drug-resistant strains differs Activity According to Resistance Entecavir Tenofovir LAM/LdT resistance Decreased Active ETV resistance -- Active ADV resistance Active Decreased TDF resistance Active -- Lok AS. Hepatology. 2010;52: Slide 24 16

17 Care with patients who have previously been exposed to Lam mono-therapy 6 patients switched from TDF to ETV Lam maintained in 5/6 Rapid rebound in HBV viraemia median 2 months (range 1-11 months) All had baseline L180M + M204V What do we do next? Continue Entacavir and repeat HBV DNA Switch Entacavir to ADF Switch back to TDF on alternate days Stop Entacavir and start PegIFN Phone a friend. 17

18 Jerry (5) Confirmed HBV DNA 2658 c/ml 3 weeks later Switched to TDF alternate days HBV DNA 6 weeks later <100c/ml Renal function 3 months later 69ml/min Adefovir add-on in patients with lamivudine resistance 3-yr cumulative probability 100 Virologic breakthrough* ADV mono ADV+LAM P< % 6% Months * >1 log rebound from nadir Lampertico, Hepatology 2006; Lampertico, Gastroenterology

19 Unanswered questions What is the minimum effective dose of TDF? Does the PK/PD profile of alternate day TDF allow for effective suppression of HBV replication? Is alternate day TDF less tubulo toxic? Is continuing Lam driving reduced efficacy of ETV Multidrug Resistance ADV LAM ADV + LAM ADV + ETV? N236T A181T L180M + A181T + M204V A181T + N236T + M250V Shaw T, et al. EASL Abstract 699. MDR 19

20 Take home messages Ensure HBV vaccination and presence of protective anti-hbs levels Avoid lamivudine monotherapy for HBV treatment Therapy regimens high potency and high genetic barrier (ETV/TDF) Monitor for non-response, slow response and viral rebound For patients with lam resistance TDF offers the best likelihood of re-suppression And they lived happily after 20