Rationale use of ARVs and need for Pharmacovigilance
Dr Jagdish Chandra, MD, FIAPDirector Professor of PediatricsNodal Officer, Regional Pediatric ART Centre, Kalawati saran Children’s Hospital,Lady hardinge Medical College,New Delhi<[email protected]>
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"
An arm of patient care and aims at getting the best out come from drug use
4 points:DetectionAssessment UnderstandingPrevention Interventions to
counter AE or treat
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.
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)”.
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)
Categories of relationship:
Certain (or definite)
Probable
Possible
Unlikely
Unclassified (or conditional)
Unassessable
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
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
Adverse effects of ARVs: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
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
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. #400 copies/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
Increased risk of CVD:Increased risk of CVD:
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 %
CVD rates California community What has changed ?
Intervention to counter AE or treat
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
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
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.
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
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
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.
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
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
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.
Grade Management
1Transient or mild discomfort; no limitation of activities; no medical intervention required
2Mild to moderate limitation of activity; some assistance may be needed; no/ minimal medical intervention required
3Marked limitations of activity; some assistance required; minimal intervention +? hospitalization
4Extreme limitation of activity; significant assistance required; significant medical intervention/therapy required; hospitalization
Management of Drug Toxicity
Apr 19, 2023
Grade
Advice on ART
1 Changes of ART should be avoided; Observe
2 Changes of ART should be avoided; Observe
3 Usually necessary to discontinue the drug, it may be possible to cautiously re-administer the drug
4
Discontinue all the drugs and hospitalise The offending drug should not be re-administered. After improvement, institute the alternate ART regimen,
Management of Drug Toxicity
Alternative First LIne ART
Acknowledgements:
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
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