VHS Infectious Diseases Medical Centre DirectorSite LeaderChennai Antiviral Research and Treatment CART Clinical Research Site Clinical AdvisorClinton Health Access Initiative Chennai India ID: 1032780
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1. Dr. N. KumarasamyChief & DirectorVHS- Infectious Diseases Medical CentreDirector/Site Leader-Chennai Antiviral Research and Treatment (CART) Clinical Research SiteClinical Advisor-Clinton Health Access InitiativeChennai, IndiaAdvanced HIV Disease-Clinical considerations
2. Natural History of HIV disease in Resource limited settings3 about 6mths // 5 10 yrsAcute HIVOpportunisticinfectionsasymptomaticCD4 countcells/ul800200HIV RNAcopies/ml10^610^2†Virologic set-point Varies from patient to patientHIV antibodiesKumarasamy, et al. Clin Infect Dis 2003
3. Natural History of Human Immunodeficiency Virus Disease in Southern India80% had one or more AIDS defining opportunistic infection when presented for care
4. Co-factorsOR95% CIP-value HIV associated illness Pulmonary TB PCP Cryptococcal Toxoplasmosis Co-infection HCV3.524.476.982.577.841.96-6.322.67-7.514.1-11.971.27-5.21.61-38.22<0.001<0.001<0.0010.010.01Co-factors relating to progression of patients with HIV disease: Kumarasamy et al., CID Jan 2003
5. Cohen MS, Chen YQ, McCauley M, Gamble T, Hosseinipour MC, Kumarasamy N et al, NEJM, 2011TREAT ALLINSIGHT Study group.Initiation of ART in early asymptomatic HIV infection. NEJM 2015
6. IeDEA-COHERE: Results based on 951 855 adults from 55 countries after imputation of missing dataDoes not include “re-starters” after interruptionGlobally, in 2015, 37% of people starting ART did so at CD4 cell count <200 cells/mm3Proportion of people with advanced HIV disease starting ART by sex and country income group, 2010–2015
7. WHO Guidelines
8. Case Definition: A paradoxical deterioration in clinical status after initiating highly active antiretroviral therapy (HAART) attributable to the recovery of the immune response to latent or subclinical infectious or non-infectious processesOther NomenclatureImmune reconstitution inflammatory syndrome (IRIS)Immune restoration/restitution/recovery diseaseimmune rebound illnessImmune reconstitution syndrome
9. Incidence of Immune Reconstitution Syndrome
10. When to start ART in TB?A5221/ STRIDECAMELIASAPIT806660429SitesAfrica, Asia, S Am, N AmCambodiaS. AfricaArmsImm vs 8-12 wkImm vs 8 wk Early vs 24 wkEndptDeath/AIDS <50 CD4 DeathDeathCD4 (IQR)77 (36,145)25 (11,56)150 (77, 254)Havilr- NEJM 2011, Blanc- NEJM 2011, Abdool Karim, NEJM, 2011
11. Randomized clinical trial in Zimbabwe; ART started within 72 hours vs. 8 weeks after initiation of fluconazole alone for treatment of CM (Makadzange C, et al. Clin Infect Dis 2010)Trial stopped by the DSMB due to increased HR for death (HR 2.85) in the early ART armRandomized clinical trial in Uganda, South Africa (COATS) in patients with CM After 7-11 days of treatment with amphotericin B + fluconazole, patients were randomized to start ART within 48 hours or > 4 weeksTrial stopped by the DSMB due to increased mortality in the early ART armCryptococcal Meningitis and Antiretroviral Therapy
12. Diagnosis: Overviewhttp://apps.who.int/iris/bitstream/handle/10665/260399/9789241550277-eng.pdf?sequence=1Lumbar puncture facilitate CSF examination and controlling of intracranial pressure
13. WHO recommendations: Treatment of HIV associated CMInduction therapy: Preferred regimen1 week:- Amphotericin B deoxycholate (1.0mg/kg/day)- Flucytosine (100mg/kg/day divided into four doses)Followed by 1 week of fluconazole1200mg/kg/day: Adults12mg/kg/day (Maximum 800 daily): Children and adolescents ART should be deferred by 6 weeks from the initiation of antifungal treatmenthttp://apps.who.int/iris/bitstream/handle/10665/260399/9789241550277-eng.pdf?sequence=1
14. Cytomegalovirus (CMV) vitritis following ART-IRIS
15. REMSTART resultsMfinanga S. Lancet 2015;385:2173-82There was a 28.4% reduction in mortality with community support and CrAg screening (18% versus 13%)34% of all mortality occurred in the first monthAbout half of the reduction in mortality was from community support and half from pre-emptive treatment of cryptococcal antigenemiaPatients with a positive CrAg had much higher mortality (32% versus 13%), even with preemptive fluconazole.
16. REALITY Trial – enhanced prophylaxisHakim J. NEJM 2017;377:233-45Research study in Uganda, Zimbabwe, Malawi and KenyaAdults and children >5 years with CD4 <100 cells randomized to receiveRoutine care with cotrimoxazole and ART, orEnhanced prophylaxis with ARTINH/B6/cotrimoxazole FDCFluconazoleAzithromycinAlbendazoleAlthough the median CD4 was only 37 cells, almost half were asymptomatic16
17. 17MortalityWeeks since randomizationThere was a reduction in mortality, from 12.2% to 8.9%, at 24 weeks with enhanced prophylaxisThe main mortality benefit for prophylaxis was for reductions in mortality from cryptococcus infections and “unknown”. It was felt that most of the “unknown” causes of death were severe bacterial infections, which caused death at home where diagnosis was not possible.REALITY resultsHakim J. NEJM 2017;377:233-45
18. The new Unitaid/CHAI AHD initiative will reduce morbidity and mortality and improve cost efficiencies by accelerating access to affordable, optimal AHD products
19. Advanced HIV: diagnosis, treatment and prevention