15/05/2014. When to Start HBV Treatment? Il trattamento precoce delle infezioni da HIV HBV e HCV nello scenario delle nuove opportunità terapeutiche

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1 Il trattamento precoce delle infezioni da HIV HBV e HCV nello scenario delle nuove opportunità terapeutiche Andrea Antinori INMI L Spallanzani IRCCS, Roma When to Start HBV Treatment? Benefits Likelihood of Adverse outcome without treatment Long lasting response Patient s ageand and preference Costs Risks Adverse effects Drug resistance Likelihood of adverse outcome without treatment Activity and stage of liver disease at presentation Risk of cirrhosis/hcc in the next 1 2 yrs Likelihood of long term benefit with treatment 4 Phases of Chronic HBV Infection Cost-effectiveness of an early treatment to prevent long term HBV-related complications ALT activity Current Understanding of HBV Infection HBeAg Anti HBe HBV DNA Phase Immune Tolerant Immune Clearance Inactive Carrier State Liver Minimal inflammation and fibrosis Chronic active inflammation Mild hepatitis and minimal fibrosis Reactivation Active inflammation Optimal treatment times Yim HJ, et al. Natural history of chronic hepatitis B virus infection: what we knew in 1981 and what we know in 25. Hepatology. 26;43:S173 S181. Copyright John Wiley & Sons, Inc. All Rights Reserved. Post, Health Affairs 211 1

2 Early cure also provide markedly reduction of mortality rates Even after 5 years, the early care scenario could be considered cost-effective Post, Health Affairs 211 Post, Health Affairs 211 HBV Screening Algorithm Cost-effectiveness of Screening for Chronic Hepatitis B Infection in the United States Assess HBsAg Positive Negative CHB* Assess anti HBs Negative (no antibodies) Positive (antibodies present) Evaluate for treatment Vaccinate *Time from positive HBsAg test to diagnosis of CHB is 6 mos. Keeffe EB, et al. Clin Gastroenterol Hepatol. 28;6: Immune to HBV Screening followed by treatment with a low cost, high resistance nucleoside or nucleotide was cost effective ($29,23 per QALY). Sensitivity analyses revealed that screening costs <$5, per QALY in extremely low risk populations unless the prevalence of chronic HBV infection is <.3%. The 2% threshold for prevalence of chronic HBV infection in current Centers for Disease Control and Prevention/US Public Health Service screening guidelines is cost effective. Eckman MH, et al. Clin Infect Dis, 211 2

3 Screening and early treatment of migrants for chronic infection is cost-effective Dynamic course of HCV infection Early detection and treatment of people with HBV infection can have a large impact on liver related health outcomes. Systematic screening for chronic HBV infection among migrants is likely to be costeffective, even using low estimates for HBV prevalence, participation, referral, and treatment compliance. Veldhuijzen, Gastroenterology 21 In most regions of the world, the full impact of HCV infection is projected to rise as disproportionately affected age cohorts cross thresholds of infection duration or age that increase disease risk. The most detailed modeling has occurred for the United States. Assuming that cirrhosis and HCC incidences start to climb after 3 years of infection and as persons reach more than years of age, it is anticipated that the prevalence of both forms of disease will sharply increase in the next decade. Thomas DL. Nat Med, 213 Outcomes associated to HCV infection Delayed versus immediate treatment for patients with acute hepatitis C We randomly allocated patients with symptomatic acute hepatitis C (1:1) to receive immediate treatment with: pegylated interferon alfa 2b (1.5 μg/kg) for 24 weeks (group A), or delayed treatment with pegylated interferon alfa 2b (1.5 μg/kg) plus ribavirin (>1.6 mg/kg) if HCV RNA was positive after 12 weeks of observation (group B); Patients with asymptomatic acute hepatitis C received immediate treatment with pegylated interferon alfa 2b for 24 weeks without randomisation (group C). Need of treatment Treatment effectiveness Deterding K, et al. Lancet Infect Dis, 213 3

4 Advantage of immediate antiviral therapy within 2 months after HCV transmission, regardless of IL28B polymorphism EASL Clinical Practice Guidelines 214 Management of hepatitis C virus infection Deuffic Burban S, et al. JHepatol, 213 All treatment naïve patients with compensated chronic liver disease related to HCV, who are willing to be treated and who have no contraindications to treatment, should be considered for therapy. Treatment should be scheduled, rather than deferred, in patients with advanced fibrosis (METAVIR score F3 to F4) and in those patients with clinically significant extrahepatic manifestations (symptomatic cryoglobulinemia or HCV immune complexes nephropathy). For patients with minimal or no fibrosis the timing of therapy is debatable, and treatment may be deferred pending the development and availability of new therapies. The decision to defer treatment for a specific patient should also consider the patient s preference and priorities, the natural history and risk of progression, the presence of comorbidities and the patient s age. Patients who have treatment deferred should be assessed on a regular basis for evidence of progression, to reconsider the indication for treatment, and to discuss new therapies as they emerge. Key Factors in Deciding to Treat or Wait Chronic HCV infection Factors that affect the decision to treat now or delay therapy Patient factors Urgency to treat Likelihood of response HCV genotype Treatment experience IL28B genotype Degree of fibrosis Patient motivation Treatment factors Efficacy of current options Safety of current options Duration of therapy Pill burden, dosing frequency Future options and their timelines Shiffman ML & Benhamou Y, Liver International, 213 4

5 Early treatment of HCV infection may lead to SVR Hepatitis C virus (HCV) replication cycle The time of the start of the therapy is a significant factor in determining the outcome. The analysis revealed four phases when the sensitivity of the infection to drug treatment differs. Further, we added a perturbation term in the model to simulate the drug treatment period and predict the outcome when the therapy is carried out during each of the four phases. The study shows that while the infection may be difficult to treat in the late phases, the therapy is likely to result in SVR if it is carried out in the first or second phase. Thus, development of newer and more sensitive screening methods is needed for the early detection of the infection. Moreover, the analysis predicts that the drug that blocks new infections is more effective than the drug that blocks the virus production. Potentially druggable host and viral factors involved in the HCV replication cycle are depicted in green (host) and blue (viral). A selection of approved compounds and compounds in development are shown. Roman numerals in brackets indicate the current clinical phase of development. Gupta S, et al. PLoS One, 212 Manns MP, et al. Nat Rev Drug Disc, 213 Current and upcoming treatment options for HCV Efficacy With Sofosbuvir + P/R in Tx- Naive GT1/4/5/6 Patients: Phase III Trials Single arm study of sofosbuvir + P/R for 12 wks SVR12 According to GT SVR12 According to Fibrosis Level 92 SVR12 (%) SVR12 (%) Selection of anti HCV drugs in advanced development A schematic of drugs approved for treating hepatitis C virus (HCV) infection as well as drugs in advanced development with tentative future launch dates. Evolution of treatment of HCV The percentage of treatment naive patients chronically infected with hepatitis C virus (HCV) achieving sustained virological response (SVR) with evolving treatment. Manns MP, et al. Nat Rev Drug Disc, n/n = 261/292 27/28 7/7 GT1 GT4 GT5/6 Lawitz E, et al. N Engl J Med. 213;368: /273 43/54 No Cirrhosis Cirrhosis 5

6 Effect of IFN-sparing or IFN-free regimens on future treatment options for hepatitis C IFN-Free Therapy for Tx-Naive GT1 HCV: Regimens Effective in Both Subtypes AVIATOR [1] : ABT 45/RTV + ABT ABT RBV 12 wks 24 wks 96 9 LONESTAR [2] : SOF/LDV FDC 8 wks SOF/LDV + RBV 8 wks SOF/LDV FDC 12 wks AI [3] : Daclatasvir + Asunaprevir + BMS for 12 wks 92 MK MK mg + RBV MK MK mg + RBV MK MK mg C WORTHY 12 wk regimens [4] : SVR12/24 (%) n = Trembling PM, et al. Nat Rev Gastroenterol Hepatol Kowdley K, et al. EASL 213. Abstract Lawitz E, et al. AASLD 213. Abstract Everson GT, et al. AASLD 213. Abstract LB Lawitz E, et al. AASLD 213. Abstract 76. High rates of SVR by once-daily oral daclatasvir plus sofosbuvir among genotype 1 HCV previously untreated patients Treatment Decisions in Late 213: Genotype 1 SOF or SMV + P/R Oral regimens Overall, 211 patients received treatment. High rates of sustained virologic response at week 12 were observed among patients with HCV subtypes 1a and 1b (98% and %, respectively) and those with CC and non CC IL28B genotypes (93% and 98%, respectively), as well as among patients who received ribavirin and those who did not (94% and 98%, respectively). Sulkowksi MS, et al. N Engl J Med, 214 Moderate/advanced fibrosis Naive Relapsers Previous IFN unwilling pts Extrahepatic features Acute hepatitis C (P/R) Patient choice Mild fibrosis Previous treatment failures IFN ineligible Everyone? 6

7 Clinical category AIDS defining or symptoms Pregnancy HBV, HCV When to start cart? Guidelines Update CD4 cells/m DHHS IAS USA EACS CNA SIMIT m 3 WHO 131 BHIVA 136 GESIDA 147 CNS ANRS Any Any Any Treat (AI) Treat (AI) Treat (AI) Treat Treat (AI) Treat (AI) Treat (AI) Treat (AI) Treat (AI) Treat (AI) Treat (AI) Treat Treat (AI) Treat (AI) Treat (AI) Treat (AI) Treat HBV (AIII) Treat (AII/CIII) Treat or consider only if CD4 <5/mm 3 Treat or consider only if CD4 <5/mm 3 Treat (AII) Treat (AIII) SPARTAC Trial Primary end point according to interval between seroconversion and randomization 366 HIV individuals with PHI. Primary end point was a CD4+ count of less than 35 cells per cubic millimeter or long term ART initiation. Other clinical conditions Any TB HIVAN HIVAN HIVAN, Malignancies, HAND HIVAN, Malignancies, HAND, CVD HIVAN, Malignancies, HAND HIVAN, Malignancies, HAND, CVD Malignancies Asymptomatic <35 Treat (AI) Treat (AI) Treat (AI) Treat Treat (AI) Treat (AI) Treat (AI) Treat (AI) Asymptomatic 35 5 Treat (AII) Treat (AII) Treat (AI) treatment Treat (AII) Generally defer Treat (AII) Treat (AII) Asymptomatic >5 Defer Treat as moderate Treat as moderate treatment Treat only on individual basis (AII/BIII) Generally defer Treat as moderate Treat as moderate Prevent sexual transmission Any Treat (AI) treatment Treat PHI treatment (GPP) Treat (AI/BIII) 1. WHO consolidated guidelines onthe use of antiretroviral drugs for treating and preventing HIV infection. June DHHS Guidelines 213 Available at 3. ARV Treatment of Adult HIV Infection. 212 Recommendation of the IAS USA panel. JAMA 212;38: EACS Guidelines 213. Available at 5. Linee Guida Italiane sull utilizzo dei farmaci antiretrovirali e sulla gestione diagnostico clinica delle persone con infezione da HIV 1, 213. Available at: 6. BHIVA Guidelines 212 Updated 213. HIV Medicine (214), 15 (Suppl. 1), GESIDA. Documento de consenso de Gesida/Plan Nacional sobre el SIDA respecto al tratamiento antirretroviral en adultos infectados por el virus de la inmunodeficiencia humana. Actualización enero CNS ANRS. Prise en charge médicale des personnes vivant avec le HIV. Rapport 213 The SPARTAC Trial Investigators, N Engl J Med, 213 ANRS VISCONTI Study Post-Treatment HIV-1 Controllers with a Long-Term Virological Remission after the Interruption of Early Initiated Antiretroviral Therapy Post treatment controllers (PTCs) have very low levels of cell associated HIV DNA which keep decreasing after treatment interruption for some patients. A. Levels of cell associated HIV 1 DNA (median and IQR) in 6 PTCs at PHI, just before or at treatment interruption (TI), and the last available obtained at a median of 6 years after cart discontinuation (Last). B. The evolution of cell associated HIV DNA after treatment interruption in PBMCs from 8 PTCs. The slope of the evolution of HIV DNA levels after treatment interruption was calculated by linear regression (lines) of the available sequential measures (symbols). Five PTCs experienced a decline of their cell associated HIV DNA levels (left); two PTCs maintained stable levels and a positive slope was calculated for OR3 (right). Risk of clinical progression or death for deferring cart at CD4 level than 35-5 Cohort N. partecipants AIDS or Death Consistency Death alone Consistency NA ACCORD (N Engl J Med, 29) ART CC/When to start (Lancet, 29) 17,517 n.a. n.a. Deferred cart at CD4 35 5: HR 1.69 ( ) 24,444 Deferred cart to CD4 lower than : HR 1.28 ( ) yes Deferred cart to CD4 lower than : HR 1.13 (. 1.) yes no Saez Cirion A, et al. PLoS Pathogens, 213 HIV CAUSAL (Ann Intern Med, 211) CASCADE (Arch Intern Med, 211) 2,971 Compared with initiating cart at CD4 cell count threshold 5/mm3, HR for 35/mm 3 threshold:1.38 ( ) 9,455 In CD4 stratum , cart initiation associated with ahr:.75 ( ) yes no Compared with initiating cart at CD4 cell count threshold 5/mm 3, HR for 35/mm3 threshold:1.1 ( ) In CD4 stratum , cart initiation associated with ahr:.51 (.33.) no yes 7

8 Changing Criteria for Antiretroviral Therapy Initiation in DHHS Guidelines START Design HIV infected adults, ART naive with CD4+ cell counts > 5 cells/mm 3 CD4+Count, cells/mm 3 > < 2 or symptomatic Offer if VL > 2K Offer if VL > 55K if VL K in certain groups* Offer if if VL if in VL > 2K > 55K VL K certain groups* Offer if VL > 2K Offer, but controversy exists Offer after discussion with patient Treat Treat Treat Treat Treat Treat Treat Treat Treat Treat Treat Treat *Pregnant women, patients with HIV associated nephropathy, and patients with HBV that requires treatment. 5% of panel members recommended starting antiretroviral therapy; 5% of members viewed treatment as optional. Wilkin T, et al. Available at: Early ART Group Immediately initiate i i ART N=2, Deferred ART Group Df Defer ART until CD4+ <35 cells/mm 3 or symptoms develop N=2, Primary endpoint: Serious AIDS & serious non AIDS disease Current Status: >3, randomised; randomisation ends 1 st quarter 213/ study < 215. Life expectancy of people who started cart in 2-28 by CD4 cell count group at start of cart compared with that of UK population The effect of HIV infection and its treatment on inflammation and immunosenescence Many of the T cell characteristics associated with immunosenescence including thymic dysfunction, T cell activation, and a reduced T cell regenerative potential are more common among individuals who fail to exhibit robust CD4+ T cell gains during therapy than among those who achieve a normal CD4+ T cell count. Because a low CD4+ T cell count on therapy is a consistent proximal predictor of non AIDS morbidity, these observations collectively suggest that HIV associated immunosenescence contributes to persistent immunodeficiency and the early onset of age associated diseases The persistent inflammation during therapy is probably due to a number of factors, including ongoing HIV production (if not HIV replication), increased copathogen load (particularly CMV, but likely other herpesviruses as well), translocation of lipopolysaccharide (LPS) across a damaged gut mucosa, loss of T regulatory cells and other immunoregulatory cells, and the irreversible fibrosis of the thymus and lymphoid infrastructure May M, et al. BMJ, 211 Deeks SG, Annu Rev Med, 211 8

9 HPTN 52: Multivariate Analysis of Factors Associated With Linked Transmissions 1,763 sexually active sero discordant heterosexual couples (54% from Africa). HIV 1 infected subjects with CD4 counts between 35 and 55 cells/mm3 were randomly assigned in a 1:1 ratio to receive ART either immediately (early therapy) or after a decline in the CD4 count <25 cells/mm3 or the onset of HIV 1 related symptoms (delayed therapy). The primary prevention end point was linked HIV 1 transmission in HIV 1 negative partners. Variable HR 95% CI Treatment, immediate vs delayed Baseline CD4+ count, per cells/mm 3 increment Baseline HIV 1 RNA, per 1 log 1 c/ml increment Baseline condom use, % vs < % Sex of infected partner, male vs female % 2% The Continuum of HIV Care in Various Settings Engagement in HIV Care 1,178,35 ~11, 149,9 % 941,95 % ,32 79 % 62 % HIVinfected HIVdiagnosed No data 4, , United States 1 British Columbia, Canada 2 France 3 328, To achieve a reduction in HIV transmission, HAART programs must ensure the effectiveness and quality of a cascade of services from testing and referral to care to ensuring ongoing adherence to HAART 2 Large US cohorts have found that women, IVDU, younger and non white patients were less likely to achieve virologic suppression, and may require targeted outreach along the cascade of care 4,5,6 *US 2 copies/ml, BC and France < 5 copies/ml Linked to HIV care Retained in HIV care On ART 52 Suppressed viral load* Cohen MS, et al. N Engl J Med. 211;365: Adapted from CDC, MMWR 211;: Adapted from Nosyk B, et al. CROI 213; Atlanta, GA. # Costagliola D, et al. CROI 213; Atlanta, GA. #13 4. Althoff K, et al. CROI 213; Atlanta, GA. # Novak R, et al. CROI 213; Atlanta, GA. #132a 6. Horberg M, et al. CROI 213; Atlanta, GA. #