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C5 Case Study Session of Three Long-Term Survivors with HIV Disease Jayaweera
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C5 Case Study Session of Three Long-Term Survivors with HIV Disease Jayaweera

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  • Toxo
  • TC LDL HDL TG ABC/3TC ATV/r 29 13 8 24 EFV 40 21 12 15 p-value <0.001 0.26

C5 Case Study Session of Three Long-Term Survivors with HIV Disease Jayaweera C5 Case Study Session of Three Long-Term Survivors with HIV Disease Jayaweera Presentation Transcript

  • Case Reports on Long term Survivors D.T Jayaweera M.D. Professor of Medicine Infectious Diseases University of Miami School of Medicine
  • Case Study - 1
  • Case Study
    • 35 year old W/M presented for possible liver transplantation in Jan 2005.
    • He had been diagnosed with HIV over 10 years ago and now he was in end stage AIDS with hemophilia, HCV/ HBV.
    • His Child Pugh class was C and the MELD Score was over 28.
  • Case Study
    • The CD4 cell count was 69 cells/mm3 and the HIV VL was over 100,000 copies/ml
    • Patient had severe ascites.
    • His bilirubin was over 17 mg% and his Albumin was 2 g/dl, and the INR was 2.4. The other labs were unremarkable.
  • Audience Response Questions
    • The factors affecting the Child Pugh score include the following.
    • 1. INR, bilirubin and Ascites
    • 2. INR, creatinine, bilirubin and hemoglobin
    • 3. ALT, bilirubin, creatinine, hemogobin
    • 4. INR, bilirubin and ascites, ALT
    • 5. INR, bilirubin and ascites, creatinine encephalopathy,
  • Audience Response Questions
    • The factors affecting the Child Pugh score include the following.
    • 1. INR, bilirubin and Ascites
    • 2. INR, creatinine, bilirubin and hemoglobin
    • 3. ALT, bilirubin, creatinine, hemogobin
    • 4. INR, bilirubin and Ascites, ALT
    • 5. INR, bilirubin and Ascites, creatinine encephalopathy ,
  • Child-Pugh Score
  • Child-Pugh Score Calculator Measure 1 point 2 points 3 points units Bilirubin <34 (<2) 34-50 (2-3) >50 (>3) μ mol/l (mg/dl) Albumin >35 28-35 <28 g/l INR <1.7 1.71-2.20 > 2.20 no unit Ascites None Mild Severe no unit Encephalopathy None Grade I-II (or suppressed with medication) Grade III-IV (or refractory) no unit
  • MELD SCORE
    • MELD uses serum bilirubin , creatinine , and INR to predict survival.
    • If the patient has been dialyzed twice within the last 7 days, then the value for serum creatinine used should be 4.0
    • 3 month mortality is :
    • 40 or >40 — 100% mortality
    • 30 – 39 —- 83% mortality ; 20 – 29 — 76% mortality 10–19 — 27% mortality <10 — 4% mortality
  • Case Study
    • This patient was on ddI, D4T and Epivir
    • He was intolerant to Lopinavir due to his hemophilia as it caused joint bleeds.
    • The HIV phenotype was pan sensitive to the PI class, and few mutations on NRTIs and NNRTIs.
    • Patients medications were changed
  • Audience Response Questions
    • Based on the phenotype this patient would be best treated with the following (this is 2005)
    • 1. Lopinavir/r, abacavir, epivir
    • 2. fosamprenavir/ ritonavir / abacavir, epivir
    • 3. Atazavir, combivir
    • 4. Efavirenz, truvada
    • Any Boosted PI with truvada
  • Audience Response Questions
    • Based on the phenotype this patient would be best treated with the following (this is 2005)
    • 1. Lopinavir/r, abacavir, epivir
    • 2. fosamprenavir/ ritonavir / abacavir, epivir
    • 3. Atazavir, combivir
    • 4. Efavirenz, truvada
    • Any Boosted PI with truvada
  • Critical decisions
    • What HAART regimen would you start?
    • Will you consider a liver transplant in this patient?
    • What complications do you anticipate if he gets a liver transplant?
    • How will hemophilia affect the transplant and transplant affect the hemophilia?
  • Is HBsAg present? Is IgM anti-HBc present? Is HBeAg or HBV DNA present? Is anti-HBs present? Chronic Hepatitis Acute Hepatitis Replicative HBV infection Non-replicative HBV infection Recovered or vaccinated +/- anti-HBc No HBV infection No Yes Yes Yes Yes No No No Anti-HBc +/- no yes
  • Clinical Liver Disease and HBV Genotype Duong TN, et al. Journal of Medical Virology. 2004;72:551–557. Diagnosis, n (%) Genotypes N Asymptomatic carrier Chronic hepatitis Liver cirrhosis HCC Genotype A 11 8 (72.7) 3 (27.3) 0 0 Genotype B 14 10 (71.4) 3 (21.4) 0 1 (7.2) Genotype C 350 129 (36.8) 126 (36.0) 50 (14.3) 45 (12.9) Genotype D 38 32 (84.2) b 6 (15.8) a 0 0 a a P <0.05 vs genotype C. b P <0.001 vs genotype C.
  • Treatment of HBV in HIV
    • Always start with emtricitabine/tenofovir
    • If the patient has been on lamivudine add tenofovir
    • If the patient is on Epzicom change to emtricitabine/tenofovir
    • If the patient has renal failure or low GFR <60 it is safer to use lamivudine or emtricitabine with entecavir than using dose adjusted emtricitabine/tenofovir
  • To reduce the risk for transmission, HBsAg-positive persons should:
    • Use condoms to protect nonimmune sex partners.
    • Refrain from donating blood, plasma, tissue, or semen.
    • HBsAg-positive pregnant women should be advised their newborns to receive hepatitis B vaccine and hepatitis B immune globulin
    • To protect the liver HBsAg-positive persons should be advised to avoid or limit alcohol consumption, vaccination against hepatitis A.
    • 15%--25% of persons with chronic HBV infection are at risk for premature death from cirrhosis and liver cancer,
  • Management Roadmap According to 24 Week Virologic Response Add another drug without cross resistance Monitor every 3 months Add another drug or Continue Monitor every 3 months Continue Monitor every 6 months Inadequate response >10 4 copies/mL Complete response <300 copies/mL Partial response 300-10 4 copies/mL Week 24: Early predictors of efficacy Keeffe et al. Clin Gastroenterol Hepatol, 2007
  • Monitoring for Drug Resistance
    • All patients
    • HBV DNA and ALT at baseline and at 3 months after starting therapy (assess antiviral efficacy)
    • Mild liver disease
    • HBV DNA and ALT q 6 mo for first 2 years; thereafter q 3 mo and at any change in therapy
    • Advanced liver disease/cirrhosis
    • HBV DNA and ALT q 3 mo with clinical evaluation
    Locarnini S, et al. Antiviral Ther. 2004;9:679-693.
  • Hepatitis B Virus Wild Type and Mutants
    • Wild type
      • Usual HBeAg (+) hepatitis
    • Precore mutation (27% U.S. patients) 1
      • Abolishes HBeAg production
    • Core promoter mutation (44% U.S. patients) 1
      • Down-regulates HBeAg production
    • Treatment-induced mutations 2
      • Lamivudine: L180M +/- M204V/I (YMDD)
      • Adefovir: N236T and A181V
      • Entecavir: I169, T184, S202 and M250 (LAM R patients)
      • Telbivudine: M204I
    1 Chu CJ, et al. Gastroenterology. 2003;125:444-451. 2 Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006;4:936-962.
  • Case Study
    • This patient was started on fosamprenavir/ ritonavir / truvada and after 2 days due to excessive vomiting this was changed to atazanavir/ ritonavir/truvada/fusion inhibitor.
    • After 4 weeks the VL came down to 3940 and the CD4 cell count went up to 97cells/mm3
    • Insurance refused to pay for surgery and after many appeals agreed and the transplant was performed within 6 weeks of the first encounter
  • Case Study
    • Post transplant, patient was started on steroids, PPI and prograf
    • Prograf ( for immunosuppression) is metabolized via CYP P450 3A4 system
    • Post operative GFR decreased to < 40
    • Patient made an unremarkable recovery.
  • Audience Response Questions
    • Following are true:
    • 1. Atazanavir can not be used with PPI and hence need to be changed
    • 2. Truvada should be given to treat HBV
    • 3. Hemophilia will be cured by liver transplant
    • 4. 1 and 2 are correct
    • 5. All are correct
  • Audience Response Questions
    • Following are true:
    • 1. Atazanavir can not be used with PPI and hence need to be changed
    • 2. Truvada should be given to treat HBV
    • 3. Hemophilia will be cured by liver transplant
    • 4. 1 and 2 are correct
    • 5. All are correct
  • Case Study
    • The patient had an uneventful post op period and at the end of one year the CD4 cell count had increased up to 149 cells and the HIV VL was 3900 /mm3
    • Patient managed to get Darunavir on compassionate access program and with that the VL came down to<50 copies
    • It was noted that HBV VL, with e ag positive at the beginning had the HBV VL undetectable at one year.
  • ARTEMIS: Darunavir + Ritonavir Versus Lopinavir/Ritonavir Mills A, et al. 48 th ICAAC. Washington, DC, 2008. Abstract H-1250c. All patients received emtricitabine/tenofovir DF. Virologic failure: >50 copies/mL. * P =0.0437 versus lopinavir/r. † P <0.001 for non-inferiority to lopinavir/r. ‡ P =0.023 versus lopinavir/ritonavir. Week 96 Outcomes Darunavir + RTV (n=343) Lopinavir/r (n=346) Virologic failure (%) 12* 17 HIV RNA <50 copies/mL (%) 79 † 71 By baseline HIV RNA <100K copies/mL > 100K copies/mL 81 (n=226) 76 ‡ (n=117) 75 (n=226) 63 (n=120)
  • ARTEMIS: 96-Week Tolerability Results All patients received emtricitabine/tenofovir DF. * P <0.001 versus lopinavir/r. † P =0.0016 versus lopinavir/r. ‡ P <0.0001 versus lopinavir/ritonavir. Mills A, et al. 48 th ICAAC. Washington, DC, 2008. Abstract H-1250c. Darunavir + RTV (n=343) Lopinavir/r (n=346) Grade 2-4 adverse events Diarrhea Nausea Rash (all types) 4* 2 3 11 3 1 Grade 2-4 lipid abnormalities Total cholesterol LDL-C Triglycerides 18 † 18 4 ‡ 28 15 13
  • Case Study
    • Two years ago when raltegravir was made available the fusion inhibitor was discontinued and he was given raltegravir 400mg twice a day
    • Patient tolerated this very well.
    • Now it is 5 years since his liver transplant
  • Case Study
    • We have cured him of his HEMOPHILIA
    • We have completely suppressed HIV with the VL being continuously undetectable for the last 4 years.
    • We have completely suppressed HBV and he has HBV surface AB Positive
    • His HCV is still active and we are awaiting new treatment for HCV.
  • Problems Associated with Liver Transplantation in HIV
    • Immune suppression and T cell activation
    • Drug Interactions - PK interactions
    • Prescribing errors
    • Co infection with HCV and HBV
    • Use of antacids
    • Renal problems
  • Case Study - 2
  • Case Study
    • 37Y old AAF was 1 st seen in Jan 97 with HIV. She had tested + in 1996. Risk – Hetero sexual and crack use. She had a P/H psoriasis and HSV
    • Quit Crack and ethanol abuse in 1996 . Patient started on AZT/3TC/Crixivan , Zithromax and pentamadine (prophylaxis)
    • Allergy to bactrim
    • Psoriasis treated with steroid creams.
    • She was never really compliant. Had an abusive partner
  • Case Study
    • VL was 5000-200,000/ml CD4 36 -52/ml
    • Changed to Efavirenz, ddI and Ziagen in 7/99
    • Admitted to Hospital with PCP in 4/2000
    • Changed to Efavirenz, ddI, D4T and Ziagen 5/00
    • 1/01 changed to kaletra 3 bid/amprenavir 4 bid/Zerit/epivir 1/01 and 6/01 CD4 13/ml HIV VL >760k
    • Depression – started Effexor
  • Case Study
    • 2/02 Kaletra/abacavir/videx EC/viread CD4 21 VL >750K
    • 2/03 Viramune/videxEC/viread/ziagen CD4 59/ml, VL 148911/ml
    • 5/03 admitted to JMH with headache and right sided hemi paresis CT brain and brain biopsy were done later
    • Developed sudden onset of left eye blindness
  •  
  • Audience Response Questions
    • Based on these findings most likely diagnoses will include
    • CNS toxoplasmosis
    • CNS lymphoma
    • CMV retinitis
    • Retinal detachment
    • 2 and 3 only
    • All of the above except 5.
  • Audience Response Questions
    • Based on these findings most likely diagnoses will include
    • CNS toxoplasmosis
    • CNS lymphoma
    • CMV retinitis
    • Retinal detachment
    • 2 and 3 only
    • All of the above except 5.
  • Case Study
    • CT scan of the brain showed multiple ring enhancing lesions.
    • Patient was diagnosed with CNS toxoplasmosis and started on sulfadiazine/pyrimethamine and folinic acid.
    • After treating for 2-3 weeks the CNS lesions improved except for one lesion.
    • Brain biopsy was done and it showed CNS lymphoma.
  • Case Study
    • The patient was seen by the ophthalmologist and diagnosed CMV retinitis and was started on gancyclovir. Few days later she developed right eye blindness which was diagnosed as retinal detachment but treated was unsuccessful.
    • This patient had been non complaint with HAART medications and having CNS toxo, lymphoma and CMV retinitis and hence, it was decided top send the patient to hospice.
  • Case Study
    • Patient RTC from hospice and requested “ not to give up on her”
    • Started treatment for CNS Lymphoma with IL2, Radiation to th ebrain, GCV/ HAART with high dose AZT, RTX to the brain
    • Responded to this regimen. 1/04 Kaletra/ invirase/Fuzeon/combivir and later changed to high dose Kaletra
    • CD 4 then increased to 116(9%) and VL decreased to 4620 /ml
  • Case Study
    • Patient later enrolled in a study and received Darunavir/ritonavir/truvada / fuzeon and the HIV VL became undetectable and the CD4 slowly went up to 761/ml (29% )
    • This patient was always obese. Her height was 5 feet 6 inches and the weight 180 lbs. During this time this patient became obese and the obesity continued to get worse to 380lbs with hyperlipidemia, hypertension and diabetes.
  • What is the cause of increased lipids in HIV patients?
    • HIV?
    • Untreated HIV is associated with high TG and low HDL and LDL, similar to other chronic inflammatory diseases
    • Treatment?
    • LDL-C tends to go up with virtually all regimens
    • PIs: boosted PI regimens increase TG and non – HDL-C, but HDL-C typically increases as well
    • NNRTIs: Increase HDL-C
      • EFV greater LDL-C and TG increases than NVP
    • NRTIs: d4T increases TG more TDF (and ABC)
    • New classes: MVC and RAL do not appear to adversely affect lipids
  • Newer drugs are more lipid friendly STARTMRK Metabolic Study: RAL vs EFV
    • Randomized, double-blind study comparing RAL vs EFV, both with TDF/FTC
    • Week 96 lipids (all pts, n=563)
      • EFV increased TC, HDL-C, LDL-C, TG, and glucose sig more than EFV
      • No sig difference in total/HDL chol ratio
    • Dexa substudy (n=111)
      • Overall, limb fat increased over time
      • By week 96, 3/37 pts on RAL, 2/38 on EFV had >20% loss of limb fat
    DeJesus E, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 720. ‡ p <0.001 * P =0.025 ‡ ‡ ‡ ‡ * 18.2 17.0 18.1 17.7
    • Raltegravir Group 55 40 37
    • Efavirenz Group 56 46 38
    Number of Contributing Patients Mean Percent (%) Change (SE) in Appendicular Fat Over Time
  • Q1. After starting antiretroviral therapy, which one of the following increases more your total cholesterol?
    • TFV/FTC/EFV
    • TFV/FTC/ATZ/r
    • ABC/3TC/EFV
    • ABC/3TC/ATZ/r
  • Q1. After starting antiretroviral therapy, which one of the following increases more your total cholesterol?
    • TFV/FTC/EFV
    • TFV/FTC/ATZ/r
    • ABC/3TC/EFV
    • ABC/3TC/ATZ/r
  • A5224s design: Metabolic substudy of A5202 A5224s
  • LIPIDS A5202: ATV/r vs. EFV Median Changes in Fasting Lipids (mg/dL) In low HIV RNA stratum, in comparison between ABC/3TC vs. TDF/FTC: significantly greater increase in TC, LDL, HDL with both EFV and ATV/r; greater increase in TG with ATV/r Median Change in Fasting Lipids (Week 48, mg/dL) Daar E, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 59LB. TC LDL HDL TG ABC/3TC ATV/r 29 13 8 24 EFV 40 21 12 15 P-value <0.001 0.002 <0.001 0.26 TDF/FTC ATV/r 10 2 5 14 EFV 22 10 8 13 P-value <0.001 0.002 <0.001 0.26
  • Case Study
    • Later changed to Darunavir/isentress/truvada and the last CD4 cell count is 741 (32%) and VL <50 copies.
    • Patients was also started on a diet, exercise, lipitor for hyperlipidemia and metformin for type 2 diabetes mellitus. Hypertension was treated with lisinopril
    • Diabetes, hypertension, an lipids are under control but the weight has not come down.
  • Case Summary
    • PROBLEMS 5-10
    • years ago
    • End stage AIDS
    • CNS toxo plasmosis
    • CNS lymphoma
    • CMV retinitis
    • Non compliance with medications
    • Drug abuse (crack cocaine)
    • PROBLEMS now
    • Morbid obesity is 63.
    • Hypertension
    • Diabetes type 2
    • HIV
  • D.T Jayaweera M.D. Professor of Medicine Infectious Diseases Thank You