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<jchandra55@gmail.com>

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

Follow-up on ART:

Alive and well

diedTrans out

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

Physical changes:

Such changes may lead to non-complianceErosion of confidence in National Programmes

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

02.02.10 Stop ART03.03.10 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 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

Thank youfor being a wonderful audience