HIV long term complications

Transcription

1 HIV long term complications 4th Asian Conference on Hepatitis & AIDS May 2015, Xi'an, China Kees Brinkman Amsterdam The Netherlands

2 NL 2012: known (0,1%) treatment 85% (all) China 2011: known (0,06%) treatment 76% (in need)

3 Registered HIV diagnoses in Netherlands (end 2012) Number per year since 1996: Stable number new registered diagnoses at around 1100 per year 2011: 1047, projected : 947, projected 1051 Cumulative number since 1996: 20,761 HIV-1 infected individuals with a registered date of diagnosis 294 children (0-12 yr), 195 adolescents (13-17 yr), 20,272 adults ( 18 yr). 17,006 currently in care

4 Registered HIV diagnoses(end 2012) Transmission risk groups: 67% MSM 27% heterosexuals 1% IDU Age at time of diagnosis: MSM 45 yrs: 31% yrs: 12% yrs: 29% Heterosexuals 45 yrs: 32% yrs: 30%

5 cart: virologic & immunologic success in treatment-naïve patients HIV viral load: CD4 cell count: end of 2012: 87% of HIV+ use cart

6 AIDS and death AIDS down significantly since cart, but still occurs Mortality overall still higher than in gender- and agematched general population AIDS Mortality Mortality of patients successfully treated from an earlier stage of infection approaches that of general population

7 Causes of death SHM report 2013 AIDS remains major cause 25% (late presentation) Shift to non-aids causes - NADM (malignancies) and cardiovascular Ageing population more comorbidities

8 mortality in HIV in NL % death naieve cart a b years f rom starting cart 2009 SHM database; Luuk Gras e c d a: AIDS b: NADM c: CVD d: non-natural e: liver related

9 estimated life expectancy in NL asymptomatic at 24 wks treatment non HIV HIV v Sighem et al; AIDS 2010; a years lived years to live life expectancy age at 24 weeks [years]

10 Increasing age of patients in care SHM end 2013: N= 17,750 life in care Median age of patients in care = 47 years 50 years or older 1996: 9% 2014: 39% (37% in 2013) 13% 60 years Increase in age-related comorbidities

11 normal ageing genetic background environment behaviour

12 normal ageing, CD4 & inflammation CD4 count area above the curve = immunodeficiency 500 inflammation age (years)

13 ageing = inflamm-ageing de Martinis concept: more inflammation = more co-morbities/ageing

14 CD4, HIV & inflammation CD4 count AIDS HIV age (years)

15 CD4, HIV, cart, & inflammation CD4 count more inflamm- ageing?? = more co-morbidities? HIV cart age (years)

16 multimorbidity and HIV cohort HIV vs non-hiv (matched) Schouten J et al. Clin Infect Dis. 2014;

17 Comorbidities and ageing: HIV vs non-hiv (matched) Significantly more cardiovascular disease (CVD) and chronic kidney disease in HIV-infected group Schouten J et al. Clin Infect Dis. 2014;

18 CD4, early cart & inflammation? CD4 count less inflamm- ageing?? = less co-morbidities? HIV cart age (years)

19 HIV & ageing cart toxicity? HIV itself immunodeficiency chronic inflammation >> risk factors? smoking, drugs, sunlight, etc co-factors: HCV / HBV STD s

20 anti-retroviral targets gp-120 HIV CCR5 CCR5 blockers CXCR4 maturation inhibitor fusion inhibitor CD4 reverse transcriptase NRTI s Non-NRTI s integrase protease protease inhibitors Integrase inhibitors (INSTI)

21 toxicities of cart NRTI s mitochondrial? (AZT, d4t, ddi) kidney, bones? (TDF, ABC) other? NNRTI s: skin, brain? PI s: diarrhea, skin, lipids, kidney stones INSTI: none (??)

22 Mixed genetics of mitochondria ndna encoded proteins mtdna encoded proteins mitotox.kb 22

23 Normal situation Polymerase mtdna mtdna mtdna encoded protein function mitochondrion

24 NRTIs polymerase γ theory Polymerase mtdna mtdna mtdna encoded protein dysfunction mitochondrion NB: more pathways to cause mitochondrial dysfunction

25 Mitochondrial Toxicity in Human Cells Birkus et al., Gilead Sc., AAC 2002; 46: relative [mtdna] [%] HepG2 cell-line (9 days) 0,1 0, NRTI concentration [µm] ddc ddi d4t AZT 3TC ABC TNF

26 mitochondrial dysfunction clinical symptoms â neurological: polyneuropathy â myopathy AZT â cardiomyopathy AZT, ddi, ddc â liver: steatosis, lactic acidosis â gastro-intestinal: pancreatitis, vomiting â hematological: pancytopenias â nephrological: prox. tubular dysfunction â adipocytes: lipodystrophy ddc, ddi, d4t AZT, ddi, d4t AZT d4t, AZT ddi, d4t (TDF)

27 glucose lactic acidosis pyruvate + NADH lactate acid + NAD + FFA triglycerides Acetyl CoA NADH ketone bodies NAD + O 2 OXPHOS Krebs cycle ATP CO 2 + H 2 O NAD + mitochondrion

28 lipo-atrophy: d4t Carr A, et al. New Engl J Med 1998; 33:

29 Replication DNA pol α DNA pol δ DNA polymerases nucleus telomerase & NRTIs Replication DNA pol γ Repair DNA pol β DNA pol ε n DNA HIV DNA mt DNA mitochondria reverse transcriptase HIV RNA

30 unknown NRTI toxicity? β-polymerase inhibition: less DNA repair? no clinical data telomerase inhibition: shortening of telomeres: ageing? 2 recent studies: yes

31 conclusions hiv patients normal life-expectancy more inflamm-ageing accelerated ageing? more co-morbidities increased toxicities: NRTI s!! mitochondrial toxicity other DNA polymerases DNA repair? telomeres?