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Rationale use of ARVs and need for Pharmacovigilance

Rationale use of ARVs and need for Pharmacovigilance . Dr Jagdish Chandra, MD, FIAP Director Professor of Pediatrics Nodal Officer, Regional Pediatric ART Centre, Kalawati saran Children’s Hospital, Lady hardinge Medical College, New Delhi <jchandra55@gmail.com>.

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Rationale use of ARVs and need for Pharmacovigilance

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  1. Rationale use of ARVs and need for Pharmacovigilance Dr Jagdish Chandra, MD, FIAP Director Professor of Pediatrics Nodal Officer, Regional Pediatric ART Centre, Kalawati saran Children’s Hospital, Lady hardinge Medical College, New Delhi <jchandra55@gmail.com>

  2. President Clinton inaugurated Pediatric ART Centre on Nov 30th, 2006

  3. Follow-up on ART: died Trans out Alive and well

  4. Pharmacovigilance:definition: • "The science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other possible drug-related problems”. • WHO 2008 • Its concerns have been widened to include herbals, traditional and complementary medicines, blood products, biologicals, medical devices and vaccines"

  5. Pharmacovigilance: • An arm of patient care and aims at getting the best out­come from drug use • 4 points: • Detection • Assessment • Understanding • Prevention Interventions to counter AE or treat

  6. Pharmacovigilance: methods • Passive surveillance / spontaneous/ voluntary • Most common form of pharmacovigilance. • Commonly referred to as “reporting” • No active measures taken to look for and report AEs other than the encouragement of staff • Dependent on the initiative and motivation of reporters.

  7. Active /proactive • Active measures are taken to detect adverse events • Best done prospectively by active follow-up, or • Retrospectively by screening patient records. • Referred to as “hot pursuit” or “cohort event monitoring (CEM)”.

  8. Minimum reporting requirements (WHO 2009) • An identifiable source of information or reporter • An identifiable patient • Name(s) of the suspected product(s) • A description of the suspected reaction(s)

  9. Categories of relationship: • Certain (or definite) • Probable • Possible • Unlikely • Unclassified (or conditional) • Unassessable

  10. ART in India: NACO Guidelines • 2NRTI + 1NNRTI as FDC, is the preferred first-line ART • Thymidine-based NRTI component (Zidovudine or Stavudine) is the chief first line option • Lamivudine is the key NRTI in all the first line regimens • Nevirapine is the preferred NNRTI • Nevirapine is substituted with Efavirenz in patients with HIV and TB co-infection, being treated with Rifampicin containing chemotherapy

  11. Pharmacovigilance of ARVs: significance • ART has to be continued life long. • ART has to be strictly adhered to • Non-adherence can lead to drug resistance • Limited options for second line ART • Need for co-administration of drugs for treatment or prophylaxis of OIs increasing chances of interactions • Development of adverse effects (AE) may lead to non-compliance and non-adherence • Damage to confidence in national ARV programme

  12. Adverse effects of ARVs: • The major AEs of ARVs are; • Lipodystrophy (Stavudine, PIs) • Anemia and neutropenia (ZDV) • Hypersensitivity reactions (NVP) • Acute pancreatitis (Stavudine, lamivudine) • Hepatic dysfunction (NVP) • Lactic acidosis (lamivudine) • Altered bone structure (osteopaenia and osteoporosis), muscle damage (myopathy) of the newborn

  13. Lipodystrophy: General observations: • HIV disease is associated with • Early decrease in HDL-C, • Followed by decrease in LDL-C, • Then increase in TG • Increased VLDL-C • HIV lipoatrophy (more affecting lower limbs) associated with stavudine • Addition of PI leads to further increase in TG • LPV/r use associated with significantly increased TG, VLDL-C but not LDL-C • TG increases with Ritonavir use but not with indinavir or nelfinavir

  14. Lipodystrophy: • HC was significantly associated with multiple PIs and undetectable viral load • Carter RJ et al JIDS 2006 • Higher viral load was protective (50,000 vs. #400copies/mL; HR = 0.59, 95% CI: 0.39 to 0.90) • Tassiopoulos K et al JAIDS2008;47:607–614 • Effect of drug use or restoration to health?? • Carl Grunfeld 2010 The changes predispose to coronary vessel disease

  15. Physical changes:

  16. Such changes may lead to non-compliance Erosion of confidence in National Programmes

  17. Increased risk of CVD: CVD rates California community What has changed ? Intervention to counter AE or treat Year HIV HIV +ve -ve 96-97 2.5 1.3 98-99 3.3 1.5 00-01 2.8 1.4 02-03 3.3 1.7 04-05 3.1 1.9 06-07 2.5 2.0 • Lipid lowering therapy users increased from 1.5% in 96-97 to 33.5% in 06-08 • Pi treated 1.5 to 30.5 % • Pi naïve 1% to 6.4 %

  18. Anemia in HIV and ZDV: • Anemia in HIV may result from: • Anemia of chronic infection • Nutritional deficiency: • Anorexia • Depression/ psychological causes • Dysphagia • Poor absorption • Immune hemolysis • HIV associated • Other viral infections • Bone marrow suppression • Human Parvo virus B19 infection

  19. Anemia in HIV and ZDV: • Study I: • Severe anemia accounted for a rate of 4.4/100 pts of AZT discontinuation, • Commonest cause of HAART regimen modification • Study II: • At 3 months follow-up: • 28.5% developed anemia • 18.7% had severe anemia necessitating blood transfusion • 69.6% had moderate anemia • 11.6% had mild anemia

  20. Agrawal et al Indian J Med Res, 2010, 132: 386-389 • 1256 patients on ZDV, • 203 (16.2%) developed anemia (<8 g%). • Severe anaemia (<6.5 g%) in 100 (7.9%) • Mean duration for fall of Hb- 3.66 ± 3.9 mo • Mean duration for increase in Hb after substitution was 1.26 ± 0.78 mo • In 191 (94.4%) patients anemia occurred within 6 mo • Anemia was: • Normocytic, normochromic in 42 % • Macrocytic 58 % • BMA in 27 patients • Normocellular in 18 (66.6%) patients. • Dysplastic changes in 8 (30%) patients in myeloid line and 7 (28%) in erythroid line.

  21. Anemia in HIV and ZDV • NACO Recommendation: • ZDV based ART to be started only if patient has Hb 9 gm/dl or more ------------------------------------------------------------------- • ZDV pediatric combination was available at KSCH ART centre since Jan 2010. • 14/43 eligible children were started on ZDV based ART of these 4 shifted to STV • Due to Anemia • ART153- after 1 Month • ART127- after 26 days • Due to Anemia and Leucopenia • ART126-after 6 weeks • ART128- after 6 months

  22. 5 Yr/Male MTCT, Clinical stage-3, CD4-163 at start of ART Started on STV+LMV+NVP-12.01.10 20.01.10 Developed repeated vomiting 01.02.10 Severe umbilical region pain S.amylase 61, USG abd-Bulky head of pancreas CECT Abdomen-Bulky head & tail of pancreas, no peri-pancreatic collection

  23. 02.02.10 Stop ART 03.03.10 Restart ART-ZDV+LMV+NVP

  24. Case 2: 6 yrs/Male, MTCT Baseline CD4-5 started on STV+LMV+NVP-21.01.09 12.02.09 developed severe pain abdomen & vomiting, S amylase-75 ART stopped w.e.f. 13.02.09 due to stavudine induced pancreatitis and referred to KSCH for further management CT scan abdomen pancreatic pseudocyst-3.5x2.2 Restarted ART on 22.01.09 on ZDV based regime.

  25. Pancreatitis: • Related to mitochondrial toxicity with NRTI • Diadinosine (ddi) and Stavudine most frequently cited in case reports • Relative risk of pancreatitis twice as great with the combination of Stavudine and ddi as with ddi alone • Increased risk: • With alcohol use • With ribavirin use • Diagnosis: • Amylase usually twice normal+ lipase elevated, or • Amylase thrice normal

  26. Lactic Acidosis: • Reported with NRTI treatment • Mild to moderate in 15-35 % • Symptomatic, severe LA in 1.7-25 cases per 1000 patient yrs • Mechanism: • NRTIs inhibit mitchondrial DNA polymerase which results in deranged oxidative phosphorylation and lactate homeostasis • Mild Symptoms: asthenia, anorexia, fever/ hypothermia, hepatomegaly, deranged LFT, low HCO3 and elevated lactate levels • Severe: intractable LA, coma and multi-organ failure • Treatment: supportive, withdrawal of drug

  27. Lactic Acidosis: • 223 pts • 174 patients on NRTI treatment, • 12 patients treated without NRTIs • 37 patients not treated • Mild hyperlactataemia: • 42 (19%) • 38/42 (90%) NRTI-treated • 4/42 (10%) received no treatment (P<0.05). • Risk factors • NRTI-treatment as a group (P=0.03) and • Elevated ALT (P=0.008). • Stavudine-containing (P=0.004) and a zalcitabine-containing (P=0.07) regimen most notably associated • Vrouenraets et al Antivir Ther. 2000;7:239-44.

  28. Management of Drug Toxicity

  29. Management of Drug Toxicity Alternative First LIne ART

  30. Dr A K Dutta, Dir Prof and HOD Pediatrics Prof Anju Seth, Prof of Pediatrics Prof Praveen Kumar, Prof of Pediatrics Dr Rohini Gupta, SMO ART Centre Dr Sandip Ray, PG Ms Rajni, Data Manager, ART Centre Mr S.Satish, Nurse, ART Centre Acknowledgements:

  31. Thank you for being a wonderful audience

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