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Dr Katja Doerholt

3 rd Annual Conference of the Children’s HIV Association ‘ Young People and HIV: Back to the Future’. Dr Katja Doerholt. St George’s Hospital, London. Friday 15 May, The Bridgewater Hall, Manchester. Update on cardiovascular, bone and renal toxicity Changing views. Katja Doerholt.

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Dr Katja Doerholt

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  1. 3rd Annual Conference of the Children’s HIV Association ‘Young People and HIV: Back to the Future’ Dr Katja Doerholt St George’s Hospital, London Friday 15 May, The Bridgewater Hall, Manchester

  2. Update on cardiovascular, bone and renal toxicityChanging views Katja Doerholt

  3. Outline of Presentation Update on side effects of antiretroviral therapy (ART): Lipids, lipodystrophy syndrome and coronary heart disease (CHD) Kidney Bone Summary

  4. Problem - Cause How much is………

  5. Metabolic changes and Coronary heart disease (CHD)

  6. HIV – ART - Coronary heart disease (CHD) • HAART has been associated with • Metabolic abnormalities • Concerns about the potential of HAART to significantly increase the risk of CHD despite conflicting evidence • ?drug holiday possibly good idea • Then came the SMART results

  7. HIV - ART - CHD BUT Smart Treatment interruption (TI) with more time on lower cd4 cell count were at a significantly elevated risk of serious complications (2.1 vs. 1.4%, p = 0.04) incl. heart attack, stroke and kidney or liver disease ?increased level of inflammation responsible?

  8. Further publications HOPS and 2 large cohorts (WHIS & MACS) reported • cardiovascular risk group and baseline CD4 count < 350 cells/mm3 were independently associated with cardiovascular disease D.A.D • MI appears mainly PI driven, since 2001 reduced, NNRTI not associated with increased risk of MI

  9. Data in children/YP

  10. Miller et al. Case control study, Miami • 42 HIV positive children and age and sex matched control • HIV positive children had higher TG, total and LDL cholesterol levels, lower HDL • Study authors concluded, • "Children infected with HIV have adverse cardiac risk profiles compared with NHANES controls • Antiretroviral therapy has a significant influence on these factors.”? Do we know this? What about HIV?

  11. Further paediatric studies • Morphologic and metabolic abnormalities in vertically HIV-infected children and youth, LA • height, weight, total and limb fat were lower than in controls • high prevalence of lipid abnormalities among those on Pis and evidence of developing insulin resistance • These factors could accelerate lifetime risk for cardiovascular disease BUT PI group had lower CD4 baseline ? Toxicity ? HIV?? Increased inflammation

  12. Further paediatric studies • Immunological recovery and metabolic disorders in severe immunodeficiency HIV type 1-infected children on HAART, Spain • ?unclear selection of kids, biased • Low prevalence of insulin resistance among HIV-infected children receiving NNRTI-based HAART in Thailand • Insulin resistance is uncommon among children receiving NNRTI-based HAART and is unrelated to lipodystrophy • NRTIs and PIs are more associated with insulin resistance then NNRTIs

  13. Further paediatric studies • Lipid and glucose alterationsin HIV-infected children beginning or changing ART • Initiation or change in ART associated with significant increases in lipid measures and insulin resistance • Favorable lipid changes associated with CD4%  • Regimens with NNRTI and PI are associated with worse lipid profiles than regimens that contain only 1 • Lipodystrophy and metabolic changes in HIV-infected children on NNRTI-based ART, Thailand • More than half developed LD at 144 weeks after HAART • Dyslipidaemia occurred in 11-12% of children • Is resistin a link between highly active antiretroviral therapy and fat redistribution in HIV-infected children

  14. Further paediatric studies • Active surveillance of body fat changes and metabolic abnormalities in HIV-infected children and adolescents in Europe: first round results • 56% overall prevalence of lipodystrophy syndrome • 3x more severe fat loss than severe fat gain • 31% had dyslipidaemia • 29% had both dyslipidaemia and body fat alterations • One of the few paediatric studies with large number of children/YP

  15. Biomarkers • Biomarkers of Vascular Dysfunction in HIV-infected Children with and without Hyperlipidemia • HIV+ children with and without Hyperlipidaemia show greater levels of biomarkers than controls • These changes may reflect vascular dysfunction and may be associated with elevated cardiovascular risk over the long-term. • Differences are pronounced in coagulant and endothelial dysfunction.

  16. The ABC story

  17. D.A.D.: Abacavir (ABC) and MI • D.A.D. (Data Collection on Adverse Events of Anti-HIV Drugs) cohort • Almost doubles the risk of MI if recent ABC • But overall risk low without ABC 1.6% over 5yrs • High risk patients much increased risk compared to other groups of Framingham definition

  18. Smart: ABC and MI MI: about a 4-fold risk for those on ABC hsCRP levels were 27% higher and IL-6 levels were 16% higher in those on ABC (both p = 0.02). ddI no increased risk of CVD SMART authors "This adverse effect appears to be only clinically relevant to consider among patients with elevated underlying cardiovascular risk.” ABC might cause cardiovascular problems, perhaps through drug-induced inflammation.

  19. ACTG A5001/ALLRT : ABC and MI No Association of Abacavir (ABC) use with Risk of Myocardial Infarction (MI) or Severe Cardiovascular Disease Events (SCVD)  Older age was significantly associated with increased risk of MI. Older age, a history of hypertension (HTN), and a family history of CVD significantly associated with increased risk of SCVD events" 

  20. Metabolic changes and Coronary heart disease (CHD)

  21. Renal toxicity

  22. Tenofovir TDF TDF in adults well tolerated but patients with pre existing renal problems more likely to have side effects Renal toxicity from proximal renal tubular dysfunction, renal failure and nephrogenic diabetes insipidus Few data in kids

  23. Adult data • Long-term follow-up data of 1111 adults from 2 Gilead RCTs 903 and 934 • Small differences in glomerular filtration rate over time were noted but no clinically relevant renal disease by 144 weeks • Duke • 35 of 744 patients taking tenofovir developed nephrotoxicity (7.5%). • Significant independent predictors of nephrotoxicity in future • PI use, chronic pain (NSAID), hypertension • If TDF as part of NNRTI low risk for nephrotoxicity

  24. TDF CHIPS Cohort & case controle study Cohort data TDF generally well tolerated 12 children (7.5 %) stopped TDF due to side effects incl. 5 renal events hypophosphataemia in the 10 cases on TDF occurred at median 18 months (IQR 17 to 20) post-TDF start Clinic follow up often do not collect renal tubular data Overall incidence was about 3% with biggest risk factor current TDF

  25. Bone

  26. Adult data • First-line PI-containing Regimens Enhance Decreased Bone Mineral Density Greater than NNRTI-containing Regimen in HIV-1-infected Patients: A Substudy of the HIPPOCAMPE–ANRS 121 TrialC • Before starting ARV, osteopenia was present in 31% of patients • Decrease in lumbar spine BMD worse in PI regimens • Prospective Evaluation of Bone Mineral Density among Middle-aged HIV-infected and -uninfected Women • Highlights role of traditional risk factors for loss of bone mineral density, age, smoking, depression, opoids

  27. Adult data • Risk Factors for Reduced Bone Mineral Density in HIV-infected Individuals in the Modern HAART • Age, BMI, ethnicity and low CD4 count

  28. Adult data • First-line PI-containing Regimens Enhance Decreased Bone Mineral Density Greater than NNRTI-containing Regimen in HIV-1-infected Patients: A Substudy of the HIPPOCAMPE–ANRS 121 TrialC • Before starting ARV, osteopenia was present in 31% of patients • Decrease in lumbar spine BMD worse in PI regimens • Prospective Evaluation of Bone Mineral Density among Middle-aged HIV-infected and -uninfected Women • Highlights role of traditional risk factors for loss of bone mineral density, age, smoking, depression, opoids

  29. Paediatric studies • Long-term Effect of HAART Containing Tenofovir on Bone Mass in HIV-infected Children and Adolescents: A 48-Month Longitudinal Assessment • No BM deterioration in HAART regimens with TDF

  30. Conclusions • Studies support the recent shift toward earlier treatment before significant immune dysfunction develops • benefits of maintaining a high CD4 cell count may be beyond avoidance of AIDS-related OI • Contradictions probably due to • different study designs and populations • observational methods with limitations in controlling confounding • limited follow-up periods • the absence of HIV negative control subjects • Most paediatric studies had only small number of children

  31. Conclusions Need for long term follow up of CHIPS / AALPHI and large European collaborations Still awaiting case definition for lipodystrophy syndrome Should we look for other inflammatory marker as predictor Watch the space re cardiovascular disease

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