HIV & comorbiditeiten Steven Callens, MD PhD Ghent University Hospital
Content Veroudering Cardiovasculair lijden HIV associated neurological disease (HAND) Hepatitis C Kanker
ATHENA: Older Pts Becoming More Prevalent in the HIV-Positive Population ATHENA: Observational cohort of 10,278 HIV-positive pts in the Netherlands Modeling study projections: Proportion of HIV-positive pts 50 yrs of age to increase from 28% in 2010 to 73% in 2030 Median age of HIV-positive pts on combination ART to increase from 43.9 yrs in 2010 to 56.6 yrs in 2030 Smit M, et al. Lancet Infect Dis. 2015;15:810-818. Proportion of HIV-Positive Pts 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 2010 2015 2020 2025 2030 > 70 yrs of age 60-70 yrs of age 50-60 yrs of age 40-50 yrs of age 30-40 yrs of age < 30 yrs of age
Veroudering Mediane leeftijd van patienten on opvolging: Vrouwen 38 jaar in 2006, 43 jaar in 2015 Mannen 43 jaar in 2006 en 46 jaar in 2015. Ongeveer 20% is ouder dan 50 jaar WIV 2016
Interplay of Age With Morbidity HIV infection Antiretroviral treatment Aging Behavioural choices Risk of comorbidities increases as individuals get older HIV does not cause these illnesses However, HIV and/or ART may increase the risk
HIV-geïnfecteerde volwassenen hebben veel traditionele risicofactoren voor kwetsbaarheid en andere geriatrische syndromen. Polypharmacy Clinical Aging and Geriatric Syndromes (frailty/sarcopenia, neurocognitive decline) Social isolation Chang et al., Archives of Gerontology and Geriatrics, 2012
Leeftijd ART- HIV en Comorbiditeit Agravatie van metabole, renale, and hematologische afwijkingen? Toxiciteit? Nefaster verloop van voorafbestaande afwijkingen?? Minder reserve Nauwgezette klinische en biologische opvolging
NA-ACCORD: Immunologic but Not Virologic Response Decreased in Older Pts Analysis of pts who received initial ART with a boosted PI or NNRTI-based regimen in 19 cohort studies (NA-ACCORD; N = 12,196) Cumulative Incidence of HIV-1 RNA 500 copies/ml 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 Cumulative Incidence of HIV-1 RNA 500 c/ml in First 2 Yrs After Starting ART 18 to 30 yrs 30 to 40 yrs 40 to 50 yrs 50 to 60 yrs 60 yrs 0 2 4 6 8 10 12 14 16 18 20 22 24 Mo From ART initiation Cumulative Incidence of CD4+ 100 cells/mm³ 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 Cumulative Incidence of CD4+ Cell Count Increase of 100 cells/mm³ in First 2 Yrs After Starting ART 18 to 30 yrs 30 to 40 yrs 40 to 50 yrs 50 to 60 yrs 60 yrs 0 2 4 6 8 10 12 14 16 18 20 22 24 Mo From ART initiation Althoff KN, et al. AIDS. 2010;24:2469-2479.
HIV is gerelateerd met kwetsbaarheid Kooij, K. W., Wit, F. W. N. M., Schouten, J., van der Valk, M., Godfried, M. H., Stolte, I. G., Reiss, P. (2016). HIV infection is independently associated with frailty in middle-aged HIV type 1-infected individuals compared with similar but uninfected controls. Aids, 30(2), 241 250. http://doi.org/10.1097/qad.0000000000000910
HIV is gerelateerd met kwetsbaarheid Kooij, K. W., Wit, F. W. N. M., Schouten, J., van der Valk, M., Godfried, M. H., Stolte, I. G., Reiss, P. (2016). HIV infection is independently associated with frailty in middle-aged HIV type 1-infected individuals compared with similar but uninfected controls. Aids, 30(2), 241 250. http://doi.org/10.1097/qad.0000000000000910
Treating HIV Does Not Fully Restore Life Expectancy Losina et al. CID 2009
Survival of HIV-positive patients starting antiretroviral therapy between 1996 and 2013: a collaborative analysis of cohort studies The Lancet HIV DOI: (10.1016/S2352-3018(17)30066-8)
Drug-Drug Interacties HMG-CoA reductase inhibitors (statins) Antiarrhythmic agents (e.g. amiodarone) Drugs that inhibit gastric acidity Anticonvulsants Warfarin Selective serotonin reuptake inhibitors Erectile dysfunction agents
Management van de oudere patiënt met HIV Infectie Optimalizatie van adherence Vermijden van interactie tussen medicijnen Kanker Screening PAP smear, mammofrafie Prostate exam HCC, lung cancer
Samenvatting Mogelijk wat kortere levensduur Zeker bij lagere CD4 cellen Merkers voor inflammatie blijven hoger bij HIV geïnfecteerde populatie Beter bij vroege therapie? Veel co-morbiditeiten Door leeftijd Door HIV Door ART Door levenssttijl (roken, alcohol) Noodzaak aan vroege diagnose en behandeling
HIV diagnose bij ouderen Artsen hebben minder kans en grijpen minder de kans om hiv-gerelateerde risicofactoren te bespreken met oudere volwassenen HIV-geassocieerde symptomen en andere ziekten worden versterkt door leeftijd Late presentatie voor diagnose en zorg Patel D. Curr Inf Dis Rep 2011 Gebo KA. Drugs Aging 2006 Lindau ST. NEJM 2007 MMWR Recomm Rep 2006
Late diagnose van HIV Infectie Minder routine screening voor HIV Risico op HIV wordt verkeerd ingeschat Minder kennis over veilige sexuele contacten Artsen durven niet denken aan SOA bij ouderen Overlappende symptomen van OI en leeftijdgebonden aandoeningen Grabar,S: JAC; Jan 2006 Patel D. Curr Inf Dis Rep 2011
Behandeling en Prognose Leeftijd als onafhankelijke voorspeller van de klinische progressie op cart Beduidend langzamer CD4 cel regeneratie Virale onderdrukking en therapietrouw moeilijker (comorbiditeit & Sociaal) Hinkin, CH: AIDS 2001; 15:1576-9 Grabar,S: JAC; Jan 2006; 57:4-7
Mythe : HIV over 50 Senioren hebben geen sex en dus geen risico voor HIV Seksueel verlangen neemt af na de leeftijd van 50 Meer dan 50% van de personen boven de 50 jaar oud hebben twee keer seks per maand In 1999 AARP enquête (leeftijd 64-74%) 1/3 van de mannen ¼ van de vrouwen Seks hebben minstens een keer per week Kaiser network.org About.com AIDS/HIV
Cardiovasculair aandoeningen in oudere patiënten met HIV Microvasculaire risico factoren for CVA verhoogd bij HIV infectie Dyslipidemie Endotheliale dysfunctie Pro-inflammatoire status
Myocard Infarctie in HIV+ versus HIV- Mean MI rate = 11 v 7 per 1000 person years RR=1.7 Langer HIV = Hoger risico Triant J, et al. Clin Endocrinol Metab. 2007.
Cardiovascular complications of HIV ART and myocardial infarction Langer ART = Hoger Risico MI incidence according to duration of ART exposure Friis-Moller N, et al. D:A:D. NEJM 2003.
Cardiovascular risk factor changes by treatment group START trial. Jason V. Baker et al. J Am Heart Assoc 2017;6:e004987 2017 Jason V. Baker et al.
Cardiovascular disease in HIV Relative Hazard 1 2 3 4 5 6 CVD hazard in D:A:D* Reduce sysbp 10 mmhg Reduce TC 1 mmol/l Stop smoking 40 45 50 55 60 65 age *relative to 40 y.o. HIV+ male Petoumenos K for D:A:D. 20 th CROI 2013.
CVD complicaties van HIV: Te onthouden Stoppen met roken! Monitor en behandel hypertensie Monitor en behandel dyslipidemie en diabetes Gezond eten en beweging, gewicht onder controle houden Monitor en behandel HIV-infectie Volgens de richtlijnen there is no evidence to support use of specific ART regimens for PLHIV with high-risk for CVD
HIV associated neurologic disease HAND
Background HIV is neurotropic and invades the nervous system from the time of primary infection HIV-associated dementia is an AIDS-defining illness Recognition of minor and asymptomatic neurocognitive impairment in HIVinfected persons Overall prevalence of HIV-associated neurocognitive disorders (HAND) has not decreased with cart HAND is associated with increased mortality and morbidity 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention 2013 Chiodi F, et al. Brain Pathology 1991;1:185 91 Gray F, et al. Brain Pathol 1996;6:1 15
Typical features of HIV-associated dementia Cognitive impairment Behavioural abnormalities Motor dysfunction o o o o o o o o o o o o o o Mental slowness or loss of mental stamina Memory problems Poor concentration and comprehension Apathy Lethargy Diminished emotional response Reduced gregariousness Depression Agitation/increased irritability Unsteady gait Poor balance Incoordination Abnormal tone Tremors 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention 2013 Navia BA, et al. Ann Neurol 1986;19:517 24
Neuropsychological impairment in the era of cart HIV- Associated Dementia Mild Neurocognitive Disorder Asymptomatic Neurocognitive Impairment HIV infection without cognitive impairment CHARTER Study (n=1,555 HIV-infected adults) 52% had NP impairment: HAD 2%, MND 12%, ANI 33% 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention 2013 Heaton RK, et al. Neurology 2010;75:2087 96
Impact van HAND Verminderde overleving Verminderde zelfzorg en kwaliteit van leven Verminderde werk performantie, hogere kans op werkloosheid Suboptimale adherence Verminderd vermogen tot besturen van een voertuig en meer ongevallen Significant persoonlijk, economische en maatschappelijke kost 1. Sevigny JJ, et al. Arch Neurol 2007;64:97 102; 2. Vivithanaporn P, et al. Neurology 2010;75:1150 8; 3. Heaton RK, et al. J Int Neuropsychol Soc 2004;10:317 31; 4. Heaton RK, et al. Psychosom Med 1994;56:8 17; 5. Woods SP, et al. Arch Clin Neuropsychol 2008;23:257 70; 6. Hinkin CH, et al. Neurology 2002;59:1944 50; 7. Marcotte TD, et al. J Clin Exp Neuropsychol 2006;28:13 28 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention 2013
Probleem met de diagnose van HAND De meerderheid slechts milde symptomen Beperkte symptomen worden niet gerelateerd aan HAND HIV artsen zijn geen neuroloog of geriater moeilijke (h)erkenning Screening is moeilijk en kan tijdrovend zijn Beperkte toegang tot neuropsychologische testing 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention 2013
Screening instruments voor HAND Mini-Mental State Examination HIV Dementia Scale International HIV Dementia Scale Montreal Cognitive Assessment (MoCA) Medical Outcomes Study HIV Health Survey (MOS-HIV) Other screening protocols 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention 2013
Co-morbiditeiten confounding factoren Co-infections Hepatitis B/C, toxoplasma, CMV, cryptococcus, tuberculosis, malaria, meningitis Medications Drugs with CNS effects, psychotropic medications, adverse effects of cart Aging Substance use Alcohol, opiates Psychiatric disorders Mood and anxiety disorders, depression, bipolar disorders, personality disorders, schizophrenia Systemic/Metabolic disorders Anemie, diabetes, dyslipidaemias, B12 deficiency 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention 2013
Wanneer denken aan HAND Minder heldere anamnese Circumstantiality (conversation drift) Perseveratie Woordvindingsstoornissen, paraphrasie Afwezigheid van details Emotionele instabiliteit Overschatting Verminderde adherence 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention 2013
Nagaan van functioneel vermogen Zelf rapportage of omgeving Zelfzorg nagaan (ADL) Shopping, food preparation, laundry, housekeeping, transport, use of telephone (IADL) Medications, financial management, werk performantie or efficientie Toegenomen nood aan assistentie 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention 2013
EACS guidelines for HAND diagnosis All patients without highly confounding conditions Screening for NCI: 3 questions Normal Clear symptoms and/or signs of NCI and no highly confounding conditions Abnormal IADL questionnaire Abnormal NP Examination Abnormal Normal Normal Repeat 3 questions after 2 yrs 3 questions 1. Do you experience frequent memory loss (e.g. do you forget the occurrence of special events even the more recent ones, appointments, etc.)? 2. Do you feel that you are slower when reasoning, planning activities, or solving problems? 3. Do you have difficulties paying attention (e.g. to a conversation, a book, or a movie)? Neurological examination Brain MRI CSF examination Additional causes of NCI other than HIV excluded HAND diagnosis (HAD, MND) EACS Guidelines Nov 2012 [www.europeanaidsclinicalsociety.org]
Behandeling voor HAND Uitsluiten en behandelen van omkeerbare aandoeningen Optimalisatie van ART : Ondetecteerbaarheid in bloed en CSF Genotypische resistentie testing CPE score of ART regimen Overweeg ART toxiciteit Cognitive revalidatie Support to activities of daily living 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention 2013
CNS Penetration-Effectiveness (CPE) score ranking 2010 CPE Score Drug Class 4 3 2 1 NRTIs Zidovudine Abacavir Emtricitabine NNRTIs Nevirapine Delavirdine Efavirenz Protease Indinavir/r Darunavir/r Inhibitors Fosamprenavir/r Indinavir Lopinavir/r Entry/Fusion Inhibitors Integrase Inhibitors Maraviroc Raltegravir Didanosine Lamivudine Stavudine Etravirine Atazanavir Atazanavir/r Fosamprenavir Tenofovir Zalcitabine Nelfinavir Ritonavir Saquinavir Saquinavir/r Tipranavir/r Enfuvirtide 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention 2013 /r = ritonavir boosted 1. Letendre S. Top Antivir Med 2011;19:137 42 2. Tozzi V, et al. J Acquir Immune Defic Syndr 2009;52:56 63
In the context of earlier ART institution, adherence, and longstanding viral suppression, will the incidence of HAND remain as high? If so, does this reflect the effect of the viral reservoir and sanctuary, the self-perpetuating inflammatory cascade, or both? 2. Can screening tests and biomarkers be optimized to assess for early stages of HAND and can treatments prevent the progression to more severe subtypes? 3. Can early sensitive plasma, CSF, and imaging biomarkers of CNS impairment be used to improve therapeutic clinical trials? Can a combination of methods provide a more holis- tic concept of HAND pathogenesis? Can these methods be applied to patient care in the clinic? 4. Can the early institution of ARVs limit the development of the CNS reservoirs and prevent the inflammatory milieu from developing? 5. Can improved CNS penetration and efficacy, in particular with the use of maravirocenriched regimes, whilst maintaining systemic viral suppression, reduce the incidence of HAND? 6. Can novel cellular and molecular therapies, targeting recently understood pathogenic pathways, improve therapeutic efficacy 1 Carroll A, Brew B. HIV-associated neurocognitive disorders: recent advances in pathogenesis, biomarkers, and treatment. F1000Research 2017; 6: 312.
Samenvatting HAND is frequent en wordt frequent gemist High index of suspicion en routine screening vragen helpen met diagnose Er zijn (beperkte) interventies mogelijk 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention 2013
HCV epidemie 185 miljoen mensen zijn geïnfecteerd 80% chronisch geïnfecteerd > 350.000 mensen sterven ieder jaar 4.5 miljoen mensen zijn gecoïnfecteerd met HIV Vooral IDU > heteroseksuele populatie > MSM Snellere progressie naar cirrhosis
Life Cycle of the Hepatitis C Virus (HCV) and Targets of Therapy. Liang TJ, Ghany MG. N Engl J Med 2013;368:1907-1917.
Treatment Algorithm for HCV Infection, According to Genotype. Liang TJ, Ghany MG. N Engl J Med 2013;368:1907-1917.
MSM: Modeling the effect of behavioral and treatment interventions 1 Salazar-Vizcaya L, Kouyos RD, Zahnd C, et al. Hepatitis C virus transmission among human immunodeficiency virus-infected men who have sex with men: Modeling the effect of behavioral and treatment interventions. Hepatology 2016; 64: 1856 69.