Download Pharmacovig

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
<[email protected]>
President Clinton inaugurated Pediatric ART
Centre on Nov 30th, 2006
Follow-up on ART:
died
Trans out
Alive and well
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 outcome from drug use
 4 points:
Detection
Assessment
Understanding
Prevention
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 noncompliance and non-adherence
 Damage to confidence in national ARV programme
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
Physical changes:
Such changes may lead to non-compliance
Erosion of confidence in National Programmes
Increased risk of CVD:
CVD rates California community
Year
HIV
+ve
HIV
-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
What has changed ?
 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 %
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, CD4163 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
02.02.10
03.03.10
Stop ART
Restart ART-ZDV+LMV+NVP
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 zalcitabinecontaining (P=0.07) regimen most notably associated

Vrouenraets et al Antivir Ther. 2000;7:239-44.
Management of Drug Toxicity
Grade
Management
1
Transient or mild discomfort; no limitation of
activities; no medical intervention required
2
Mild to moderate limitation of activity; some
assistance may be needed; no/ minimal medical
intervention required
3
Marked limitations of activity; some assistance
required; minimal intervention +? hospitalization
4
Extreme limitation of activity; significant
assistance required; significant medical
intervention/therapy required; hospitalization
Management of Drug Toxicity
Grad
e
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,
Alternative First LIne ART
23-May-17
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
Thank you
for being a wonderful audience