Post on 07-Apr-2018
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Failure and change to second line
Prepared By: Dr. Wut Yi
STO, C&S
BI-MM
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Indications for Switching
Toxicity
New Problem (TB, Pregnant)
Failure
Virologic failure
Immunologic failure
Clinical Failure
Difficulty adhering to the regimen Current antiretroviral regimen is suboptimal
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FDA-Approved Drugs for HIV Therapy
NNRTIs
Delavirdine (DLV)
Efavirenz (EFV)
Nevirapine (NVP)
PIs
Amprenavir (APV) discontinued
2004
Atazanavir (ATV)Darunavir (DRV)
Fosamprenavir (FPV)
Indinavir (IDV)
Lopinavir/ritonavir (LPV/RTV)
Nelfinavir (NFV)
Ritonavir (RTV)Saquinavir (SQV hgc)
Tipranavir (TPV)
Abacavir (ABC)
Didanosine (ddI)
Emtricitabine (FTC)
Lamivudine (3TC)
Stavudine (d4T)Tenofovir (TDF)
Zalcitabine (ddC) withdrawn 2005
Zidovudine (ZDV)
3TC/ABC
3TC/ABC/ZDV
3TC/ZDVFTC/TDF
NRTIs
Fusion Inhibitors (FIs)
Enfuvirtide (ENF)
Maraviroc (CCR5 inhibitor)
Multiple Class
EFV/FTC/TDF
Integrase InhibitorsRaltegravir
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RESPONSE TO TREATMENT
Virological
Immunological
Clinical
Falling and then
undetectable viral load
Rise in CD4 count
(10/month)
Weight gainand rise in Karnofski score
Symptoms, PPE less
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How to detect treatment failure
Asymptomatic withCD4 < 200
(Monitor Adherence)
WHO class III or IV
Clinical monitoringevery month
CD4 every 6 months
Clinical monitoring atleast every month
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How to detect?
Reason for failure1. Treatment failure
no optimal treatment
regimen
non-adherence
bad absorption, druginteractions
Resistance
HIV-2
2. Other reasons
side effects of ARVs or
other drugs
IRIS
OI or other HIV relatedproblems.
Non-HIV relatedproblems
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How to detect?
MonitoringAdherence(Importance
*100000000)
Monitoring Viral Load 6 monthsapart
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How is ART failure defined?
Clinical:
New/recurrent OI or malignancy after
6 months on ARTBeware IRIS
Immunological:
Fall CD4 to pre-treatment level, or
50% fall from peak level, after 6months ART, persistant CD4 countsbelow 100/mm3
CD4 repeated 3 months apart
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How is ART failure defined?
Virological failure
Plasma viral load above 5000 copies/ml in
a person on ART
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Immunogical Success
Increase in CD4 count at 12 weeks: 10-50cells/mm
Increase in CD4 count at 16-32 weeks: 30-50cells/mm
Increase in CD4 count/year: 80-150 cells/mm
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Remember
CD4 counts can vary significantly and donot always predict virological failure
20% with no CD4 increases have undetectable VL(Ukraine 14/15 pts with no significant CD4 hadundetectable VL)
40% with immunological failure have undetectableVL
40-70% of those with virological failure dont have
immunological failure Infection, pregnancy, alcohol, stress
CD4 alone is not a reliable method to
assess effectiveness of ART
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Remember
Despite immunological and virological failure, patients doclinically very well for years
only 1/3 have immunological failure after 3 years of virilogicalfailure if the ART continued
Long-term outcomes on 2nd and 3rd line regimens areinferior to 1st line regimens
1st mean 11 months, 2nd mean 7 months
No FDC, o pill burden, food restrictions, side-effects
Options for 2nd line therapy are limited Registration, cost, cold-chain
rapid changes can quickly use up all ARV options
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Remember
If failure is due to poor adherence, then changing therapywill have no benefit
Always exclude co-existent OI or IRIS
If possible, clinical or immunological failure should alwaysbe confirmed with a viral load measurement of >1000copies/ml prior to changing to a second-line regimen
Failure due to ARV resistance will not occur before 12months of ART for treatment nave patients, and 6months of ART for treatment experienced patients.
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When to Change
Should be a combination of bothclinical and immunological failure
Decision to change to 2nd line made bydoctor in consultation with HIV specialist
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ABC or 3TC (sAZT)#
ddI or TDF
EFV or NVPNRTI sparing option if the triple NRTIapproach were used in first-linetherapy
Standard second-line option if NRTI/NNRTIapproach were used in first-line therapy
Second line ARV drugs in adults and adolescents
PI/r*
* Ritonavir-boosted PIs (ATV/r, FPV/r, IDV/r, LPV/r and SQV/r) are considered as the key component in second-line regimens and its
use should be reserved for this situation. LPV/r is the only PI currently available as a FDC and a new formulation that doesn't need
refrigeration was recently launched. In the absence of a cold chain and where the new LPV/r formulation is not available, NFV can be
employed as the PI component but it is considered less potent than a RTV-boosted PI.
# The use of 3TC (AZT) are listed for strategic use as resistance to both drugs is predicted to be present following failure on the
respective first-line regimen listed. 3TC will maintain the M184V mutation which may potentially decrease viral replicative capacity as
well as induce some degree of viral resensitization to AZT or TDF; AZT may prevent or delay the emergence of the K65R mutation.However, it must be stressed that the clinical efficacy of this strategy in this situation has not been proven.
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ABC or 3TC (sAZT)#
ddI or TDF
EFV or NVPNRTI sparing option if the triple NRTIapproach were used in first-linetherapy
Standard second-line option if NRTI/NNRTIapproach were used in first-line therapy
Second line ARV drugs in adults and adolescents
PI/r*
* Ritonavir-boosted PIs (ATV/r, FPV/r, IDV/r, LPV/r and SQV/r) are considered as the key component in second-line regimens and its
use should be reserved for this situation. LPV/r is the only PI currently available as a FDC and a new formulation that doesn't need
refrigeration was recently launched. In the absence of a cold chain and where the new LPV/r formulation is not available, NFV can be
employed as the PI component but it is considered less potent than a RTV-boosted PI.
# The use of 3TC (AZT) are listed for strategic use as resistance to both drugs is predicted to be present following failure on the
respective first-line regimen listed. 3TC will maintain the M184V mutation which may potentially decrease viral replicative capacity as
well as induce some degree of viral resensitization to AZT or TDF; AZT may prevent or delay the emergence of the K65R mutation.However, it must be stressed that the clinical efficacy of this strategy in this situation has not been proven.
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ABC or 3TC (sAZT)#
ddI or TDF
EFV or NVPNRTI sparing option if the triple NRTIapproach were used in first-linetherapy
Standard second-line option if NRTI/NNRTIapproach were used in first-line therapy
Second line ARV drugs in adults and adolescents
PI/r*
* Ritonavir-boosted PIs (ATV/r, FPV/r, IDV/r, LPV/r and SQV/r) are considered as the key component in second-line regimens and its
use should be reserved for this situation. LPV/r is the only PI currently available as a FDC and a new formulation that doesn't need
refrigeration was recently launched. In the absence of a cold chain and where the new LPV/r formulation is not available, NFV can be
employed as the PI component but it is considered less potent than a RTV-boosted PI.
# The use of 3TC (AZT) are listed for strategic use as resistance to both drugs is predicted to be present following failure on the
respective first-line regimen listed. 3TC will maintain the M184V mutation which may potentially decrease viral replicative capacity as
well as induce some degree of viral resensitization to AZT or TDF; AZT may prevent or delay the emergence of the K65R mutation.However, it must be stressed that the clinical efficacy of this strategy in this situation has not been proven.
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How can we minimize ART failure?
Do not prescribe ART at the first visit
Financial problem
Follow up regularly
Regimen and dosage(take right time, right dose andreduce pill burden)
Adherence
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AZT
300 mg BID
Side Effects(SE):y Nausea, vomiting,HA, fatigue - common, early
y Later: anemia, leukopenia, GI, myositis, insomnia
y Pigmentation of nail beds, lactic acidosis, fatty Liver
Food Interactions: None with or without food is ok
Food decreases AZT-related nausea
Use non-AZT regimen if initial Hb
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DDI (Didanosine)
Tabs 200 mg BID for wt >/= 60 kg
125 mg BID for wt < 60 kg
If use buffered tablets, 2 or more tablets
must be used at each dose to provideadequate buffer
Tablets must be chewed or dissolved
y Powder--slightly different absorption and doses
y QD dosing: 400 mg/d for >/=60 kg, 250mg
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DDI toxicity
Peripheral Neuropathy
Nausea
Diarrhea, abdominal pain
Pancreatitis Lactic acidosis, fatty liver
Not combined with D4T (combined toxicity)
Not combined with Tenofovir (drug interactions)
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TDF
300 mg (one pill) once daily Nucleotide
eliminates a phosphorylation step foractivation
Reduce dose of DDI if taken concomitantly Side effects (Rare):
nausea/vomiting, diarrhea, anorexia
can be associated with lactic acidosis,
pancreatitis, hepatotoxicity, worsening renalfailure (? genetic)
Resistance Pattern:Slow--Multiple mutations
Activity against Hepatitis B
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Abacavir (ABC)
Dosing: 1 x 300mg tablet BID
Food Interactions: no food interactions
Toxicity
Diarrhea,Nausea, Headache all mild
Lactic acidosis, fatty liver (rare)
Allergic reaction (HSR) : 5%
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ABC
Systemic symptoms: feels sick, fever, malasie
Rash, GI, Respiratory
Peak day around day 11
Symptoms related to doses
Decision to stop because ofHSR isforever. Irrevocable. Therefore make it
wisely. Role of initial education, partnership.
Have patient return any unused ABC.
Future: Genetic Testing for who will havereaction
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FTC
Flourinated 3TC-very similar
Dosing: 1 x 200mg capsule QD
Food Interactions: no food interactions
Activity against Hepatitis B
Toxicity
Mild abdominal discomfort
Occasional nausea
Hyperpigmentation
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Preferred boosted PI
Lopinavir/ritnavir
Atazanavir/ritonavir
( Ritonavir boosted= increase the drug level ofother PI
= increase dosing interval
= slow mutation and slow resistant)
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Kaletra (Lip/r)
Dose: 400/100mg twice daily (Thermostable formulation: 2tablets twice daily; old formulation: 3 tablets twice daily)
Advantages of the thermo-stable formulation: lower pill
burden, no food restriction. Generally well-tolerated Most common adverse effects : nausea and diarrhoea,
increase of hepatic transaminases Class adverse reactions: insulin resistance, fat accumulation
and hyperlipidaemia
can increase the risk of nephrotoxicity with TDF If given with rifampicin need to increase the dose to
533/133mg twice daily, and monitor closely for hepatitis (riskincreased).
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Third line
Darunavir (DRV)
Ritonavir
Raltegravir
Etravirine (ETV)