HIV anno Vroeg of laat behandelen? Eric C.M. Van Gorp ErasmusMC & Slotervaart hospital

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1 HIV anno 2010 Vroeg of laat behandelen? Eric C.M. Van Gorp ErasmusMC & Slotervaart hospital

2 Vragen en dilemma s anno 2010 Medicatie; Veiligheid & Effectiviteit Beschikbaarheid medicatie Het Zwitsers standpunt!? Individueel vs gemeenschapsbelang Co-infecties Lange termijn complicaties; screening wat, wie en wanneer? Starten met behandeling; vroeg of laat? Stigmata anno 2010

3 HIV and stigma

4 Emerging infectious diseases

5 HIV

6 HIV

7 HIV epidemie in NL HIV infections in the Netherlands AIDS in the Netherlands More HIV-infections, less aids

8 Wanneer starten ART? Toxiciteit ART op lange termijn vs Effecten van chronische infectie

9 Toxiciteit Toxicity 58.3% Virological failure 14.1% n = 312 Other 8.0% Non-adherence 19.6%

10 Onbehandelde HIV-infectie

11 Starten behandeling CD4 Lympho cytes HIV RNA load Symptom-free phase weeks (?) years 2 3 years Infection with HIV First symptoms Slide: Sven Danner

12 No therapy Mono-therapy % of patients progressing Months JAMA 1998 & CMAJ 1999

13 No therapy Mono-therapy Dual-therapy % of patients progressing Months JAMA 1998 & CMAJ 1999

14 No therapy Mono-therapy Dual-therapy % of patients progressing Triple therapy Months JAMA 1998 & CMAJ 1999

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16 2010 anti-retrovirals nucleoside- RT-inhibitors Non-nucleoside RT-inhibitors Protease inhibitors others zidovudine nevirapine saquinavir/r T-20 didanosine efavirenz ritonavir CCR-5 inhibitors lamivudine TMC-125 Indinavir/r intergrase inhibitors stavudine nelfinavir (IL-2) abacavir fos-amprenavir/r tenofovir lopinavir/r emtricitabine atazanavir/r tipranavir/r TMC-114/r

17 Behandelopties anno 2010 Behandeling van verleden tot heden Wanneer starten met ART? Welke combinatie?

18 Doel behandeling Direct Verlagen virale load (bij voorkeur tot niet-detecteerbaar) Verhogen aantal CD4-cellen Beide surrogaateindpunten! Indirect Voorkomen complicaties a.g.v. verminderd immuunsysteem: opportunistische infecties maligniteiten overlijden

19 Resistentie! Viralereplicatie is slordig, dus continu foutjes in aanmaak viraal RNA! Per toeval kunnen foutjes onstaan die coderen voor resistentie! Resistente vormen zijn in het algemeen minder fit dan wildtype virus! Dus:!! Onder optimale selectiedruk door ART nauwelijks virusreplicatie en dus geen resistentie! Onder sub-optimale selectiedruk: resistent virus groeit uit, wildtype repliceert niet, dus resistentie!

20 Klasse resistentie Resistentie voor een middel in een klasse, zorgt vaak voor (gedeeltelijke) resistentie voor alle middelen in die klasse Opties voor vervolgbehandeling daarom beperkt

21 Therapieontrouw: hoofdoorzaak falen therapie

22 Therapietrouw Therapietrouw is essentieel Eenmaaldaags schema s Counselling Pillendozen SMS-service Plus apotheek

23 Lange termijn complicaties HIV drug side effects/ toxicity chronic tiredness livertoxicity renal disease (HIV related/toxicity) HIV and cancer risk for opportunistic and co-infections osteoporosis/-necrosis pulmonary hypertension metabolic complications/ lipodystrophia venous thrombo-embolic complications (VTE) Risk on cardio-vascular Disease (CVD)

24 HIV en het metabool syndroom diabetes Dyslipidaemie overgewicht hypertensie MS gerelateerd aan pre-existente factoren, HIV infectie, ART of combinatie

25 Dyslipidaemia 60% patienten op ART In HIV triglycerides > HDL< with HAART Chol > LDL > Associatie met oudere PI s Atherogeen patroon Indicatie voor start statines furthermore statines do have anti-inflammatory effects, effects the endothelium and coagulation cascade, which may be beneficial

26 Metabool Syndroom Lipid abnormalities Disordered glucose metabolism Mitochondrial toxicity Body fat redistribution Bone Disorders

27 Veneuze en arteriele complicaties Risk on Venous Thrombo-embolic Events (VTE) Risk on VTE 2-10x increased compared to healthy population (Risk for DVT 0.1% per year; ranging 0.001% in childhood to 1% in the elderly) Risk on (arterial) Cardio-Vascular Disease (CVD) Positive association between duration of exposure HAART and risk of MI; every year of HAART use 26% increase in the rate of MI per year during the fisrt 6 years

28 Risico op VTE en CVD Pro-thrombotic state resulteert in occlusie Ischaemic heart disease Cerebro Vascular accident (CVA) Deep venous thrombosis Pulmonary embolism

29 Chronische vermoeidheid Prevalence 37-80% Quality of life Pulmonale hypertensie Greater risk of developing pulmonary hypertension in HIV infection both in the pre and post ART period 0.5 % HIV infected patients/ 1-2 per 1 million persons in general population

30 Osteopenie/ Osteoporose Decreased bone mineral density (BMD) initially reported in HIV+ on PIs (plus NRTIs) Multifactorial etiology: HIV, cytokines, endocrine factors, liver disease, smoking,? antiretrovirals Osteonecrose Avascular necrosis = aseptic necrosis = osteonecrosis Associated with corticosteroid use, possibly duration of antiretroviral therapy & immune recovery

31 HIV en maligniteiten Cirion Before ART! Kaposi sarcoma non hodgkin lymphoma anal: x 3 liver: x 5 lung: x 3 skin: x 20 All cancer: x 2.6

32 HIV & maligniteiten en ART Cirion After ART! Decreased incidence rates No./1000 HIV infected people J Natl Cancer Inst. 2000; 92:

33 Overige maligniteiten Cirion Other cancer relatively new problem emerging after HAART limited amount of studies more aggressive disease more rapid progression more refractory to treatment more drug toxicities -> increased mortality types involved cervical cancer (HPV related) anal carcinoma (HPV related) lung carcinoma skin carcinoma types probably NOT influenced by HIV breast cancer colon carcinoma

34 Overige maligniteiten Cervical cancer (HPV related) Screening PAP smear after diagnosis of HIV Repeat PAP 6 months later if both negative, annual PAP low threshold for colposcopy Anal cancer (HPV related) anal PAP screening? not yet recommended, guidelines coming up! Lung cancer stop smoking!! low threshold chest X-ray surgery: treat like non-hiv chemotherapy: avoid toxic drug combinations radiotherapy: consider conformal Every year a PAP smear Quit for Good

35 HIV and cognitive disorders Despite the decreasing incidence of HAD in recent years, cogni5ve impairment is the most common CNS complica5on in people with HIV/AIDS. Delirium is the most common cogni5ve disorder in hospitalized pa5ents with AIDS. The prompt diagnosis of cogni5ve impairment/demen5a and delirium may significantly decrease morbidity and mortality.

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37 Vragen Welke cognitieve dysfunctie? Hoe te diagnostiseren? Pathogenese? Behandel opties?

38 Diagnostische tools Anamnese Screening Neuropsychologisch assessment MRI CSF analyse HIV RNA Immune activatie markers

39 HIV dementia scale

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41 Looking over the horizon Relevantie van screening patienten ter voorkoming van ontwikkelen lange termijn complicaties Wat zijn de relevante risico factoren in deze specifieke patienten populatie?

42 EASC treatment guidelines The European AIDS Clinical Society (EACS) released updated HIV treatment guidelines. According to the new but may benefit from sooner. The new guidelines place more emphasis on screening and management of chronic age- related such as and, as well as treatment of co- diseases including B and C and tuberculosis.

43 Starten ART anno 2010 In 2006, WHO recommended that all patients start ART when their CD4 count falls to 200 cells/mm3 or lower, at which point they typically show symptoms of HIV disease. Since then, studies and trials have clearly demonstrated that starting ART earlier reduces rates of death and disease. WHO is now recommending that ART be initiated at a higher CD4 threshold of 350 cells/mm3 for all HIV-positive patients, including pregnant women, regardless of symptoms.

44 CD4 Lympho cytes HIV RNA load Symptom-free phase weeks (?) years 2 3 years Infection with HIV First symptoms

45 Afgenomen morbiditeit en mortaliteit na vroege start ART Meerder studies tonen positief effect van vroeg behandeling op klinische eindpunten - verbeterde overleving - verminderde incidentie maligniteiten - verminderde incidentie CVD - Verbeterde afweer, minder co-infecties (TBC) Vraag blijft of start behandeling bij CD4 getal > 350 verdere reductie geeft

46 Vroege start ART Verbeterde overleving = afgenomen mortaliteit Afgenomen (co)morbiditeit Afgenomen transmissie risico s

47 Het Zwitserse standpunt Mensen met hiv, in een vaste stabiele relatie met iemand zonder hiv, hebben een uiterst kleine kans om hiv over te dragen als ze: 1.een antiretrovirale behandeling ondergaan en hun medicijnen strikt volgens de voorschriften innemen, met regelmatige controle door een arts 2.geen andere soa hebben 3. de hoeveelheid virus in hun bloed al minstens een half jaar niet meer meetbaar is.

48 HIV anno 2010 Focus op lange termijn overleving Co morbiditeit; Aging Transmissie risico s; Controle SOA s Effectieve geneesmiddelen; bijwerking neutraal Vroeg-behandeling

49 The End