Godelieve de Bree Internist infectiologist immunologist Amsterdam University Medical Center AMC the Netherlands EECA INTERACT November 2019 Outline The changing HIV pandemic Development in treatment of HIV and life expectancy ID: 780102
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Slide1
Non-Aids related co-morbidities
Godelieve de BreeInternist-infectiologist, immunologistAmsterdam University Medical Center (AMC), the NetherlandsEECA INTERACT November 2019
Slide2Outline
The changing HIV pandemicDevelopment in treatment of HIV and life expectancyCo-morbidities in HIV infection
Co-
morbidities
Slide3Historical perspective of HIV treatment
1995
1987
2000-2002 onwards
‘Late’ cART era
HIV well controlled, long-term prognosis improved
Multiple ART regimens: greater choice of equally highly effective HAART
Improved drug safety + tolerability, but ongoing burden of chronic toxicity (e.g. lipoatrophy, metabolic syndromes)
prevention
and
treatment options
Advocacy focused on drug tolerability, long-term outcomes
and specific management of complications
’Pre’ cART era
‘Early’ cART era
HIV well controlled, long-term prognosis improved
Multiple ART regimens:
↑
choice but? relative efficacy
Drug toxicity assumes more importance, but efficacy paramount
Advocacy focused on access + improved therapy tolerability
+ long-term outcomes
HIV uncontrolled/poorly controlled, poor long-term prognosis
High-dose mono/dual NRTI therapy: limited treatment options
Issues of drug toxicity outweighed by need for survival benefit
Advocacy focused on access to therapy
Slide4Antiretroviral therapy 2016: > 25 options, 6 classes
Nucleoside and nucleotide RTIs (NRTI)
Zidovudine, AZT
Abacavir, ABC
Lamivudine, 3TC
Didanosine, ddI
Stavudine, d4T
Tenofovir, TDF
Emtricitabine, FTC
AZT/3TC
AZT/3TC/ABC
ABC/3TC
TDF/FTC
TAF/FTC
Non nucleoside NRTIs (NNRTI)
Delavirdine (DLV)
Nevirapine, NVP
Efavirenz, EFV
EtravirineRilpivirinedoravirineFusion inhibitors:
Enfuvirtide, ENF or T20
Protease inhibitors (PIs)Indinavir, IDV Saquinavir, SQV Nelfinavir, NFV Amprenavir, APV Atazanavir, ATV Fosamprenavir, FPV
Lopinavir/ritonavirTipranavir Darunavir Darunavir/cobicistat Atazanavir/cobicistatRed – combination agents
EVG/cobi/FTC/TAFRPV/FTC/TAFBic/FTC/TAFTDF/3TC/DRVRPV/DGVSingle pill regimensEFV/FTC/TDF RPV/FTC/TDFEVG/cobi/FTC/TDFDTG/ABC/3TCCCR5 receptor blockerMaravirocIntegrase inhibitor (INSTI)Raltegravir, RALElvitegravir, EVGDolutegravir, DTGBictegravir
Slide5Development in HIV treatment
Pallela
NEJM 1998
Slide6cART has dramatically increased life span
Marcus JAIDS 2016
HIV positive
HIV negative
Slide7Marcus JAIDS 2016
A gap remains
Slide8Survival probability is lower in PLWH
Croxford
Lancet
Publ
Heath 2017
1997-2002
2003 - 2007
2008-2012
Standardized mortality ratio 2.2
Slide9START trial
INSIGHT START study group NEJM 2015
Slide10Time to first primary event
INSIGHT START study group
NEJM 2015
Primary endpoints: AIDS related serious events and non-AIDS related serious events (including death)
Composite primary end point in 42 of immediate treatment group and 96 in deferred treatment group
Slide11CVD and cancer most frequent non-AIDS events
INSIGHT START study group NEJM 2015
Slide12Causes of death in HIV-positive individuals
D.A.D. study Smith Lancet 2014
Liver
related
CVD
related
Non AIDS
cancer
Other
AIDS related
Slide13Death related to AIDS and non-AIDS cancer
Smith Lancet 2014
total study population
patients with viral load <400
9%
23%
non-AIDS related cancer
Slide14Serious non-AIDS comorbidities
cART does not lead to a full restoration of healthNon-AIDS comorbidities:non-AIDS malignanciescardiovascular diseasekidney diseaseliver diseaseosteopenia / osteoporosisneurocognitive disease
Slide15Chronic inflammation in cART treated HIV
Deeks Lancet 2014
Slide16Kuller
Plos Med 2008
Slide17Inflammation and mortality
Kuller Plos Med 2008
Slide18Persistent inflammation under cART
Kroeze
JID 2019
before cART
during cART
Slide19Persistent inflammation under cART
Wada
AIDS 2015
Slide20Higher inflammation is associated with CVD
Nordell J Am Heart 2014
Slide21Serious non-AIDS comorbidities
Slide22Increased risk of having myocardial infarction
Freiberg JAMA Int Med 2013
Veterans ageing cohort
(2003-2009)
82459 participants
HIV infected versus HIV negative
Slide23Global burden of cardiovascular disease in PLWH
Shah Circulation 2018
Slide24Feinstein
Circulation 2019
Slide25Cardiovascular risk HIV vs traditional risk factors
Feinstein Circulation 2019
Slide26Feinstein
Circulation 2019
Slide27Management of CVD in HIV
Feinstein
Circulation
2019
Slide28Renal involvement in HIV infection
Glomerular-dominantPodocytopathy, classic HIVANImmune complex mediatedTubulointerstitial-dominantTubulointerstitial injury in HIVANAcute tubulointerstitial (toxic cART)Drug induced other than cART
Direct parenchymal infection
Immunologic dysfunction-related tubulointerstitial inflammation
Other inflammation in context of HIV
Vascular
Other (diabetic nephropathy, age related)
Swanepoel Kidney International 2018
Slide29HIVAN glomerulopathy
Swanepoel Kidney Int 2018
Collapse of glomerulus due to FCGS
Casts and tubular atrophy
Slide30HIVAN is associated with apoL1
Pays
Curr
Opin
Imm 2009Kasembeli
JASN 2015
Slide31Tubulo-interstitial nephritis with Tenofovir
Swanepoel Kidney Int 2018
Acute
Irregular epithelial lining and edema
Chronic
Fibrosis and inflammation
Slide32Glomerular
capillary
hypertension
Increased filtration of plasma proteins
Excessive tubular reabsorption
Nuclear signals for NF-kB-dependent and independent vasoactive and inflammatory genes.
Corresponding protein products then released into interstitium
Tubular cell transdifferentiation
Fibroblast proliferation
Fibrogenesis
Increased glomerular permeability to macromolecules
Proteinuria
Lymphocyte/macrophage infiltration
Reduction of nephron numbers
Renal injury
Glomerulo-
sclerosis
Renal scarring
Remuzzi & Bertani, N Engl J Med 1998
Inflammation
Toxic
Direct viral
Slide33Steeper decline in eGFR in HIV
Kooij
JID 2017
Slide34Riskfactors and etiology of kidney disease in HIV
Slide35Management of kidney disease in HIV infection
Swanepoel Kidney Int 2018
Slide36Conclusion and implications
HIV is changing into a chronic diseaseEarly start of treatment is crucialBut even with adequate viral control patients are susceptible for non-AIDS related co-morbidities
Access to cART
Infrastructure also for diagnosis and management of non-AIDS related co-morbidities
Guidelines for cardiovascular risk managment adapted for HIV
Slide37Slide38Slide39Persistent immune activation under cART
Guihot AIDS 2016
Cellular immune
activation
: CD38, HLA-DR
Inflammation
serum: IP-10, sCD14, MIG
Slide40Number of new infections and AIDS related deaths
2019 global AIDS update UNAIDS
In 2018:
37.9
mlln
people living with HIV
1.7
mlln new HIV infections770.000 deaths from AIDS related illness