Pulmonary Arterial Hypertension in Pa)ents with HIV Infec)on: New Thoughts, BeGer Outcomes

Transcription

1 Pulmonary Arterial Hypertension in Pa)ents with HIV Infec)on: New Thoughts, BeGer Outcomes Hap Farber, MD Director, Pulmonary Hypertension Center Boston University School of Medicine

2 Disclosures Consultant: Gilead, Actelion, United Therapeutics, Ikaria, Bayer, Bristol-Myers Grant support: United Therapeutics, Gilead Speakers bureau: Bayer, Gilead, Actelion

3 Talk Outline Overview PAH: where HIV-PAH fits Demographics of HIV-PAH Pathogenesis of HIV-PAH Treatment of HIV-PAH

4 Case (History) Patient admitted to MICU (12/07) b/o respiratory failure and severe right heart dysfunction (by ECHO in ED); presumed acute PE. According to sister, progressive DOE/SOB over 1y, with dramatic worsening last 2 wks According to sister, HIV+ since 1997 (last CD4 >900; VL <1000); no previous ARV

5 Case (Studies) EKG: RAD, RVH w/ strain, RAE D-dimer: 4036 ECHO: Small LV compressed by extremely dilated RV IVS flattening throughout cardiac cycle w/ paradoxical septal motion LVEF 55% RV function severely reduced w/ RVH Severe (4+) TR RVsp 102; hepatic flow reversal and dilated IVC w/ blunted respirophasic variation Impaired LV relaxation No intracardiac shunt

6 CTPA: Case (Studies) Cardiomegaly (enlarged RV and RA) Enlarged PA No acute or chronic PE Mediastinal and axillary LAN V/Q: no acute or chronic PE ANA, RF: neg Hepatitis screen: neg HRCT: no parenchymal disease CD4 947; VL 336 c/ml

7 RHC: RA 12 RV 89/10 PAP 94/45 (64) PCWP 8 PAsat 51% CO/CI (TD) 3.5/1.9 CO/CI (Fick) 3.3/1.8 PVR 1279 SVR 1782 Case (RHC)

8 Classification of Pulmonary Hypertension (Nice, 2013) 1. Pulmonary arterial hypertension 1.1 Idiopathic PAH 1.2 Heritable PAH BMPR ALK-1, ENG, SMAD9, CAV1, KCNK Unknown 1.3 Drug and toxin induced 1.4 Associated with: Connective tissue disease HIV infection Portal hypertension Congenital heart diseases Schistosomiasis 1 Pulmonary veno-occlusive disease and/or pulmonary capillary hemangiomatosis 1 Persistent pulmonary hypertension of the newborn (PPHN)

9 Introduction: HIV-PAH Pulmonary hypertension in HIV disease first reported in 1987 Initially reported in patients with classic hemophilia & HIV infection Subsequent cases imply that pulmonary hypertension related to HIV infection Approximately 250 cases reported

10 Demographics: HIV-PAH Incidence approximately 0.5% HIVinfected patients (6-12 fold >IPAH) Same incidence before and after availability of ARV Relationship of ARV to occurrence of HIV-PAH

11 Prevalence of HIV-PAH in Current Era 7,648 consecutive patients from French HIV centers Mean duration of HIV infection: 10 years 86% receiving current ARV therapy 377 patients (9.66%) with unexplained dyspnea 35 patients (0.46%) diagnosed with PAH by right heart catheterization Sitbon O et al. Am J Resplr Crit Care Med. 2008;177:

12 Demographics: HIV-PAH Mean age: 32 years Male to female ratio: :1 HIV risks: IVDU (42-50%) MSM (20-25%) Hemophilia (13%) Heterosexual sex (10%)

13 Clinical Features: HIV-PAH Dyspnea main presenting symptom No correlation with history of OI, CD4 count or HIV viral load Correlated with duration of HIV infection (>6y)

14 Clinical Features: HIV-PAH Older studies: PAH more aggressive in HIV patients PAH more lethal in HIV patients Newer studies: Seemingly not as lethal with advent of pulmonary vasodilators

15 Comparison of HIV-PAH & IPAH HIV-PAH IPAH Age at diagnosis 32 ± 5 42 ± 7 Male-to-female ratio PAP mean systolic 1.6:1 1:3 or 1:4 65 mm Hg 76 mm Hg PAP mean 52 ± 10 mm Hg 66 ± 18 mm Hg Time to diagnosis 6 months 2.5 years Median survival 1.3 years 2.6 years

16 Prognosis: HIV-PAH Older studies: 34% died within 5d of diagnosis 1y survival 50-60% Survival poorer in WHO III-IV (28% at 3y) vs WHO I-II (84% at 3y) 72% HIV-PAH direct cause of death Newer studies: good response to pulmonary vasodilators (any drug class)

17 1 Survival in PAH Percent Survival CHD CVD HIV PPH Portopulm McLaughlin V et al. CHEST, 2004 Years

18 Survival in HIV-PAH Degano et al. AIDS 2010; 24:

19 Long-term Survival of PAH in the REVEAL Registry Benza et al. Chest. 2012; 142:

20 Prognosis: HIV-PAH CD4 >200 Epoprostenol (Flolan )?ARV relationship to survival

21 Pathological Features: HIV-PAH 85% with plexogenic pulmonary arteriopathy (20%-80% in IPAH) Also thrombotic-fibrotic, thromboembolic

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23 Pathogenesis: HIV-PAH HIV: no direct infection of endothelial cells or smooth muscle cells No evidence of BMPR2 mutations HIV-infected alveolar macrophages HHV-8 Association with HLA-DR6 & HLA-DR 52 HIV viral particles: tat, gp 120, nef

24 Pathogenesis of HIV-PAH

25 Pathogenesis: HIV-PAH (other issues) Intravenous drug abuse Chronic liver disease (hepatitis B, C virus) Coagulation abnormalities

26 Echocardiography: HIV-PAH ECHO compared with right heart catheterization (PH population): False negative rate: <1% False positive rate: >30-40% ECHO accuracy in HIV: No data, but frequent abnormalities (both left- and rightsided)

27 Treatment: HIV-PAH No RCT in HIV-PAH (excluded from trials) Oral vasodilators (calcium channel blocker, bosentan, ambrisentan, sildenafil) Inhaled prostaglandins (iloprost) Intravenous prostaglandins (epoprostenol, treprostinil)

28 Treatment: HIV-PAH Antiretrovirals: True effect of ARV on HIV- PAH unknown; but HIV-PAH was not considered an indication for initiation of ART (in lieu of other indications) Anticoagulation (warfarin): no data

29 ARV Therapy Alone Does Not Improve Hemodynamics in HIV-PAH 1400 PVR (dyne.s.cm -5 ) Baseline Last evaluation Baseline Last evaluation N = 77 HAART only PAH therapy Degano B et al. AIDS. 2010;24:67-75.

30 Treatment: HIV-PAH (Bosentan)

31 PVR After 16 Weeks of Bosentan in HIV-PAH PVR (dyn.sec/cm 5 ) Baseline Week 16 N = 15, P <0.001 vs baseline Sitbon O et al. Am J Resplr Crit Care Med. 2004;170:

32 Long-term Ambrisentan in HIV-PAH Change in 6MWD LOCF and Observed Cohort Analysis Mean Change in 6MWD (m) m +64 m Time (weeks) LOCF, N = OC, N = Mean ± 95% confidence intervals Farber HW et al. Am J Respir Crit Care Med. 2012;185:A4783.

33 Survival with Epoprostenol in HIV-PAH 1.0 Cumulative survival Subject at risk, n P = 0.01 Epoprostenol Conventional therapy Time (months) Epoprostenol Conventional therapy Nunes H et al. Am J Resplr Crit Care Med. 2003;167:

34 Treatment: HIV-PAH (Epoprostenol) Boston Medical Center Patient Age/sex HIV risk factor HIV diagnosis CD4 count 9 ARV therapy 1,9 EPO 2 start date 1 40/F IDU TC 4 /d4t 5 4/ /F IDU TC/d4T 7/ /F IDU TC/d4T 7/ /F IDU None 3/ /M IDU/MSM HAART 7 6/ /M IDU HAART 3/ /M Heterosexual TC/DDI 8 /EFV 1/ /M IDU None 2/ /F Heterosexual ZDV/3TC/EFV 4/ /M MSM ZDV/3TC/EFV 2/ ARV = antiretroviral; 2 EPO = epoprostenol; 3 IDU = injecting drug use; 4 3TC = lamivudine; 5 d4t = stavudine, 6 MSM = men who have sex with men, 7 HAART highly active antiretroviral therapy; 8DDI = ; 9 at baseline.

35 Pulmonary Vascular Resistance at Baseline & After Long-term Epoprostenol Boston Medical Center 1200 PVR (dynes/sec/cm -5 ) Baseline Acute infusion 12 months 24 months 36 months 48 months 60 months 72 months Pt 1 Pt 2 Pt 3 Pt 4 Pt 5 Pt 6 Pt 7 Pt 8 Pt 9 Pt 10

36 Interactions Between ARV Therapies and PAH Medication Recommended ARV Therapy* Potential Interaction Efavirenz + tenofovir/emtricitabine None expected Atazanavir/ritonavir + tenofovir/emtricitabine Or Darunavir/ritonavir + tenofovir/emtricitabine Increases drug levels of bosentan, macitentan, sildenafil, tadalafil, riociguat Raltegravir + tenofovir/emtricitabine None expected

37 Interactions and Dosing Recommendations in Patients Receiving HIV PIs PAH medication Interaction Ambrisentan No interaction. No dose adjustment required. Bosentan Macitentan Increases bosentan trough levels. Dose adjust to 62.5 mg once daily or every other day depending on tolerability. Contraindicated with ritonavir. Doubles exposure to macitentan. Avoid concomitant use with PIs.

38 Interactions and Dosing Recommendations in Patients Receiving HIV PIs PAH Medication Interaction Sildenafil Tadalafil Substantially increases sildenafil serum levels. Coadministration with PIs is contraindicated Substantially increases tadalafil serum levels. Coadministration with PIs should be avoided as tadalafil exposure effectively eliminates PI. If absolutely necessary, start dose at 20 mg once daily, and follow drug levels if possible or virologic parameters Riociguat Increases riociguat exposure and may result in hypotension. Consider starting dose 0.5 mg 3 times daily when initiating riociguat in patients receiving ritonavir. No information of riociguat effect on ARV.

39 Treatment: HIV-PAH Tcherakian, et al. Curing HIV-associated pulmonary arterial hypertension. Eur Respir J. 2012;39:1045. Bosentan in 2 patients (one for 5y; one for 1.5y)

40 Case (Outcome) Epoprostenol initiated w/ hemodynamic and clinical improvement Now walks several blocks on flat ground, can climb 5 flights of stairs, and back to work part-time Most recent CD4 884; VL 437, no ARV Current epoprostenol dose: 16 g/kg/min (no dose increase since 6/08)

41 Conclusions: HIV-PAH HIV patients living longer HIV patients with dyspnea of unclear etiology should be evaluated for PAH HIV-PAH may become an increasing cause of morbidity and mortality Better understanding of pathogenesis of HIV- PAH Role of ARV in HIV-PAH Treatment of HIV-PAH (interactions w/ ARV; exclusion from trials)

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