Toxicity & Resistance

Dr. Guido van den BerkDecember 2009

Sint Maarten

HIV[e]EDUCATION

NRTI NRTI +

PI

or

NNRTI(the “NRTI backbone”)(the “NRTI backbone”)

� Combination of at least 3 drugs, usually:

› 2 NRTIs (the “NRTI backbone”), plus:

› 1 NNRTI or 1-2 PIs

� Therapy with only one or two agents

allows HIV to overcome therapy through

resistance mutations

According to the November 2008 DHHS

guidelines for the use of ART. Which of the

following statements is true regarding

initial ART:

Zid

ovudin

e-la

m...

Ten

ofovi

r-em

tr...

Abac

avir

plu

s ...

Sta

vudin

e plu

s...

0% 0%0%0%

A. Zidovudine-lamivudine (Combivir) plus efavirenz

B. Tenofovir-emtricitabine (Truvada) plus ritonavir (norvir) plus Darunavir

C. Abacavir plus tenofovir plus lamivudine

D. Stavudine plus lamivudine plus lopinavir-ritonavir

A. Zidovudine-lamivudine (Combivir) plus efavirenz

B. Tenofovir-emtricitabine (Truvada) plus ritonavir (norvir)

plus Darunavir

C. Abacavir plus tenofovir plus lamivudine

D. Stavudine plus lamivudine plus lopinavir-ritonavir

�Class specific

� Drug specific

� Patients A,B and C recently started HAART :

� A) AZT, 3TC, Nevirapine

� B) Abacavir, 3TC, Lopinavir/ritonavir

� C) Tenofovir, Emtricitabin, Efavirenz

� Patient A develops anemia. What is the most probable cause ?

1. AZT

2. 3tc

3. nevirapine

Patient A develops anemia. What is the most probable cause ?

AZT

3tc

nev

irap

ine

0% 0%0%

1. AZT

2. 3tc

3. nevirapine

� Patients A,B and C recently started HAART :

� A) AZT, 3TC, Nevirapine

� B) Abacavir, 3TC, Lopinavir/ritonavir

� C) Tenofovir, Emtricitabin, Efavirenz

� Patient A develops rash. What is the most probable cause ?

� 1. azt

� 2. 3tc

� 3. nevirapine

Patient A develops rash. What is the most

probable cause ?

azt

3tc

nev

irap

ine

0% 0%0%

1. azt

2. 3tc

3. nevirapine

� Patients A,B and C recently started HAART :

� A) AZT, 3TC, Nevirapine

� B) Abacavir, 3TC, Lopinavir/ritonavir

� C) Tenofovir, Emtricitabin, Efavirenz

� Patient B develops diarrhea. Which medicine is the most probable

cause ?

� 1. abacavir,

� 2. 3tc

� 3. lopinavir / ritonavir

Patient B develops diarrhea. Which

medicine is the most probable cause ?

abac

avir,

3tc

lopi

navir

/ ri

...

0% 0%0%

1. abacavir,

2. 3tc

3. lopinavir / ritonavir

� Patients A,B and C recently started HAART :

� A) AZT, 3TC, Nevirapine

� B) Abacavir, 3TC, Lopinavir/ritonavir

� C) Tenofovir, Emtricitabin, Efavirenz

� Patient c develops night mares. What is the most probable cause ?

� 1) his wife

� 2) tenofovir

� 2) emtricitabin

� 3) efavirenz

Patient c develops night mares. What is

the most probable cause ?

His

wife

teno

fovi

r

em

tric

itabin

efa

vire

nz

0% 0%0%0%

1. His wife

2. tenofovir

3. emtricitabin

4. efavirenz

� Patients A,B and C recently started HAART :

� A) AZT, 3TC, Nevirapine

� B) Abacavir, 3TC, Lopinavir/ritonavir

� C) Tenofovir, Emtricitabin, Efavirenz

� Patient C develops renal insufficiency. What is the most probable

cause ?

� 1) tenofovir

� 2) emtricitabin

� 3) efavirenz

Patient C develops renal insufficiency. What is the most probable cause ?

teno

fovi

r

em

tric

itabin

efa

vire

nz

0% 0%0%

1. tenofovir

2. emtricitabin

3. efavirenz

� Rash Nevirapine > Efavirenz

� Hepatotoxicity Nevirapine > Efavirenz

� Efavirenz:

› Psychogenic side effects

› Teratogenic effects

90

Синдром Стивенса-Джонсона

� GI effects

� Lipodystrophy

› Lipoatropy

› dyslipidemia

› Insulin resistance, diabetes

Changes in fat distributionChanges in fat distribution

�� Subcutaneous fat wastingSubcutaneous fat wasting

�� Fat accumulationFat accumulation

–– intraintra--abdominal fatabdominal fat

–– localisedlocalised

–– breast enlargementbreast enlargement

–– buffalo humpbuffalo hump

–– lipomatalipomata

Metabolic complicationsMetabolic complications

�� DyslipidemiaDyslipidemia

�� Insulin resistanceInsulin resistance

�� Diabetes mellitus Diabetes mellitus (rare)(rare)End points should be considered separatelyEnd points should be considered separately

Objective measures Objective measures (DEXA, CT)(DEXA, CT) crucialcrucial

Lipoatrophy- hollow cheeks

80

Lipoatrophy- loss of

subcutaneousfat in the legs of a

woman

� GI problems

� Mitochondrial toxicity with:� Lactic acidosis

� Myelopathy

� (Cardio) myopathy

� Distal polyneuropathy (“d-drugs”)

� Pancreatitis

� Hepatitis

� Lipodystrophy

Nucleoside action in mitochondriaNucleoside action in mitochondria

Polymerase -Gamma

mtDNA mtDNA mtDNA

nDNA

N

O

R

M

A

L

N

R

T

I

s

mtDNA mtDNA

Proteins encoded by

nDNA

Brinkman K et al. Lancet 1999; 354: 1112-1115

ZDV 3TC D4T DDC DDI

Neuropathy

Myopathy

Cardiomyopathy

Pancreatitis

Hepatitis

Lactic acidosis

Bone marrow

depression

++

+

+

+

++

+

+

+/-

+/-

++

+

+

+

++

+

+

+

++

+

++

+

+

Incidence of Myocardial Infarction Incidence of Myocardial Infarction

aaccording to ccording to cARTcART EExposurexposure

Events

PYFU

16 17 20 41 61 62 51 47 30

11815 7105 9027 12098 14892 14394 11351 7935 5853

Total

345

94469

RR per year of cART:Univariable: 1.16 [1.11-1.21] Adjusted: 1.16 [1.09-1.23]

None <1 1-2 2-3 3-4 4-5 5-6 6-7 >70

1

2

3

4

5

6

7

8

cART-Exposure (yrs)

MIs

per

1000 P

Y (

95%

CI)

NEJM April 2007

None <1 1-2 2-3 3-4 4-5 5-6 >60.5

1

2

4

8

PI-Exposure (yrs)

RR

(95%

CI)

Relative Rate of MI according to

PIPI Exposure – Adjusted for NNRTINNRTI

Adjusted RR* per year of PI: 1.16 [1.10-1.23]

�: Adjusted for sex, age, cohort, calendar year, prior CVD, family history of

CVD, smoking, body-mass index, NNRTI exposure

None <1 1-2 2-3 3-4 >40.5

1

2

4

8

NNRTI-Exposure (yrs)

RR

(95%

CI)

Relative Rate of MI according to

NNRTINNRTI Exposure – Adjusted for PIPI

Adjusted RR* per year of NNRTI: 1.05 [0.98-1.13]

�: Adjusted for sex, age, cohort, calendar year, prior CVD, family history of

CVD, smoking, body-mass index, PI exposure

0.9 1.0 1.1 1.2 1.30.9 1.0 1.1 1.2 1.3

Relative Rate of MI (95% CI)

Effect of Exposure to

PIPI and NNRTINNRTI – before and after

Adjusting for Lipids

RR 1.16

RR 1.10

RR 1.05

RR 1.00

PI exposure

(per additional year)

NNRTI exposure

(per additional year)

�: Adjusted for sex, age, cohort, calendar year, prior CVD, family history of

CVD, smoking, body-mass index, the other drug classFriis-Møller et al NEJM 2007

� 33.347 patiënts (157.912 patiënt years)

› 517 first myocardial infarction

� Out of the 517, in the 6 months before MI:

› 192 used abacavir

› 124 used ddI

� TA`s not associated with increased risk MI

� Recent (<6 mnths) or current abc or ddi

use associated with higher risk MI

� Higher risk no longer observed in patients who had

discontinued abc or ddi > 6 months

Sabin CA et al. Lancet april 2008

2.25

CHD (n = 639)Stroke (n = 195)

Adjusted Relative Rate (95% CI)

ZDV

ddI

d4T

3TC

ABC

RR: 1.40 (P = .005)

RR: 1.63 (P = .0001)

0.50 0.75 1.00 1.25 1.50 1.75 2.00

Sabin CA et al. Lancet april 2008

Sabin CA et al. Lancet april 2008

EMEA :

After examination of all currently available data, the EMEA and the

national competent authorities have considered that, presently,

no definitive conclusion can be drawn on the potential

association between abacavir or didanosine use and the risk of

myocardial infarction

FDA:

The FDA has stated that it regards the D:A:D study findings as

incomplete as they did not include an analysis of abacavir’s

chief competitor, tenofovir (Viread), nor another important

antiretroviral drug, FTC (emtricitabine, Emtriva)

ddIddI

d4Td4T

ddI / d4TddI / d4T

ddI / HUddI / HU

d4T / ddI / HUd4T / ddI / HU

RRRR

1.001.00

1.401.40

1.891.89

7.807.80

2.112.11

95% CI95% CI

––

0.40 0.40 –– 4.904.90

0.47 0.47 –– 7.577.57

1.74 1.74 –– 34.9234.92

0.56 0.56 –– 13.5313.53

� Neurotoxic agents› “d-drugs” (ddC, ddI, d4T)

� Isoniazid, dapsone, vincristine

� Diabetes mellitus

� Alcoholism

� Vitamin B12 deficiency (rare)

PinprickPinprickNormalNormalDiminishedDiminishedLostLost

HyperesthesiaHyperesthesia

contact sensitivitycontact sensitivity

↑↑↑↑↑↑↑↑ or normal knee reflexesor normal knee reflexes

↓↓↓↓↓↓↓↓ ankle reflexesankle reflexes

↓↓↓↓↓↓↓↓ pin, temperature, vibrationpin, temperature, vibrationStrength normalStrength normal

•The common reasons to switch:

➡ Toxicity

➡ Virological failure

� Causes of treatment failure include:› Patient factors

(CD4 nadir, comorbidities)

› Drug resistance

› Suboptimal adherence

› ARV toxicity and intolerance

› Pharmacokinetic problems

› Suboptimal drug policy

� Virologic failure:› HIV RNA >400 copies/mL after 24 weeks

› >50 copies/mL after 48 weeks

› >400 copies/mL after viral suppression

� Immunologic failure:› Failure to achieve and maintain adequate CD4 increase despite virologic suppression

Resistance

? ???

�Most copies of HIV

are the same in the

body

�Part of HIV will be

“naturally” resistant to

ARV

� General principles:› Add at least 2 (preferably 3) fully active agents to an optimized background ARV regimen� Determined by ARV history and resistance testing

› 1 active drug should not be added to a failing regimen (drug resistance is likely to develop quickly)

� 3TC has a unique mutation, M184V, which is commonly seen when failing regimen with 3TC

› A single mutation is enough to significantly decrease 3TC antiviral effect

› If mutation M184V is present emtricitabine is also failing

(identical mutation)

�AZT and d4T have almost identical mutations and universal cross resistance

� K65R (Tenofovir resistance)

�The K103N or Y188L mutation alone

prevents the clinical utility of all NNRTIs

�NVP and EFV have universal cross

resistance

�NVP or EFV should not be part of

second line regimen after failing NNRTI

first line treatment