Download d4T/ 3TC

Humphrey Shao MD, MHS
Goals of ART
 Eradication of HIV?
Not possible with currently available
ARV medications
ART Goals & Tools to Achieve Them
 Improved quality of life
 Reduction of HIV-related
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morbidity and mortality
Restoration and/or
preservation of
immunologic function
Maximal and durable
suppression of viral load
Prevention of vertical
transmission
Prevention of transmission
to sexual partners
 Selection of ARV regimen
 Preservation of future
treatment options
 Rational sequencing of
therapy
 Maximizing adherence
 Use of resistance testing in
selected clinical settings
Baseline Evaluation
 Complete History & Physical exam.
 Laboratory testing:
 HIV antibody
 CD4 cell count
 Plasma HIV RNA
 Resistance test (genotype)
 CBC, chemistry profile, BUN, Cr, transaminase
 Fasting glucose and lipids
 RPR or VDRL
 Hepatitis A, B, C serology
 Toxoplasma IgG
Before Initiating ART: Additional Tests
 Tuberculin skin test (TST) or IFN-γ
release assay
 Chest X ray (if symptoms, or positive TST
or IFN-γ release assay)
 Gynecologic exam with Pap smear
 Testing for chlamydia and gonorrhea
 Ophthalmology exam (CD4 count
<100 cells/µL)
Considerations in Initiating ART
 Willingness of patient to begin and the
likelihood of adherence
 Degree of immunodeficiency
(CD4 cell count)
 Plasma HIV RNA
 Risk of disease progression
 Potential benefits and risks of therapy
Considerations in Initiating ART (2)
 ART should be considered lifelong therapy
 Interruption of ART is not recommended,
except for serious toxicities or inability to take
oral medications
 Usually causes immediate virologic rebound, with
CD4 decline
Use of CD4 Cell Levels to Guide Therapy Decisions
 CD4 count
 The major indicator of immune function
 Most recent CD4 count is best predictor of disease
progression
 CD4 count usually is the most important
consideration in decision to start ART
 Important in determining response to ART
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Adequate response: CD4 increase 100-150 cells/µL per year
 CD4 monitoring
 Check at baseline (x2) and at least every 3-6 months
Use of HIV RNA Levels to Guide
Therapy Decisions
 HIV RNA:
 Less important than CD4 count, but may influence
decision to start ART and determine frequency of CD4
monitoring
 Critical in determining response to ART
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Goal of ART: HIV RNA below limit of detection
(ie, <40 to <80 copies/mL, depending on assay)
 RNA monitoring:
 Check at baseline (x2)
 Immediately before initiating ART
 2-8 weeks after start or change of ART
 Every 3-4 months with stable patients
When to Start
ART
 Potent ART may improve and/or preserve of immune
function in most patients with virologic suppression,
regardless of baseline CD4 count
 ART indicated for all with low CD4 count or symptoms
 Earlier initiation of ART may result in better immunologic
responses and better clinical outcomes
 Recommended ARV combinations are considered to be
durable and tolerable
 Exact CD4 count at which to initiate therapy not known, but
evidence points to starting at higher counts
 Current recommendation: ART for all patients with CD4
counts of <350 cells/µL, certain others regardless of count
Indications for ART
Treat all:
 History of AIDS-defining illness
 CD4 count of <200 cells/µL
Strong evidence of decreased mortality and
morbidity if ART is given to patients with symptoms
of AIDS or CD4 counts of <200 cells/µL
Indications for ART
(2)
Treat all:
 CD4 counts of 200-350 cells/µL
Data suggest risk of AIDS-related events and nonAIDS-defining conditions is higher in this range than
at >350 cells/µL
Indications for ART
(3)
Treat all (regardless of CD4 count):
 Pregnant women
 To treat maternal infection and reduce risk of
perinatal transmission
 HIV-associated nephropathy (HIVAN)
 Not clearly related to CD4 decline; ART may
preserve renal function
 HBV coinfection, if HBV treatment is needed
 TNF + 3TC or FTC is recommended
 If ART is not started, HBV therapy should not
include agents that may select for resistance to
ARVs
Indications for Initiating ART:
Chronic Infection
Clinical Category and/or
CD4 Count
 History of AIDS-defining illness
 CD4 count of <350 cells/µL
 Pregnant women
 HIV-associated nephropathy
 Hepatitis B coinfection, when
HBV treatment is indicated*
Recommendation
Initiate ART
* Treatment with fully suppressive drugs active against both HIV and HBV is
recommended.
Indications for Initiating ART:
Chronic Infection (2)
Clinical Category and/or
CD4 Count
CD4 count of >350 cells/µL,
asymptomatic, without
conditions listed above
Recommendation
Optimal time to initiate ART is
not well defined; consider
individual patient characteristics
and comorbidities
Potential Benefits of Early
Therapy (CD4 count >350 cells/µL)
 Maintain higher CD4; prevent irreversible immune
system damage
 Decrease risk of HIV-associated complications
 eg, TB, NHL, KS, peripheral neuropathy,
HPV-associated malignancies, HIV-associated cognitive
impairment
 Decrease risk of nonopportunistic conditions and
non-AIDS-associated conditions
 eg, CV, renal, and liver disease; malignancies; infections
 Decrease risk of HIV transmission
Potential Risks of Early Therapy
(2) (CD4 count >350 cells/µL)
 ARV-related side effects and toxicities
 Drug resistance (caused by ART failure)
 Inadequate time to learn about HIV, treatment,
and adherence
 Increase in total time on ART; greater chance of
treatment fatigue
 Current ART may be less effective or more toxic
than future therapies
 Transmission of ARV-resistant virus, if
incomplete virologic suppression
Current ARV Medications
NRTI
PI
Fusion Inhibitor
 Abacavir (ABC)
 Didanosine (ddI)
 Emtricitabine
(FTC)
 Lamivudine (3TC)
 Stavudine (d4T)
 Tenofovir (TDF)
 Zidovudine (AZT,
ZDV)
 Atazanavir (ATV)
 Darunavir (DRV)
 Fosamprenavir
(FPV)
 Indinavir (IDV)
 Lopinavir (LPV)
 Nelfinavir (NFV)
 Ritonavir (RTV)
 Saquinavir (SQV)
 Tipranavir (TPV)
 Enfuvirtide (ENF, T-20)
NNRTI
 Delavirdine (DLV)
 Efavirenz (EFV)
 Etravirine (ETR)
 Nevirapine (NVP)
CCR5 Antagonist
 Maraviroc (MVC)
Integrase Inhibitor
 Raltegravir (RAL)
Initial Treatment: Choosing
Regimens (2)
 Considerations:
 Comorbidities (eg, liver, psychiatric, or cardiovascular disease;
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tuberculosis; pregnancy)
Adherence potential
Dosing convenience (eg, pill burden, dosing frequency)
Potential adverse effects
Potential drug interactions
Pregnancy potential
Results of drug resistance test
Gender and CD4 count, if considering NVP
HLA B*5701 testing, if considering ABC
ARV Components in Initial
Therapy: NNRTIs
ADVANTAGES
 Long half-lives
 Less metabolic toxicity
(dyslipidemia, insulin
resistance) than with
some PIs
 PI options preserved
for future use
DISADVANTAGES
 Low genetic barrier to
resistance – single
mutation
 Cross-resistance among
most NNRTIs
 Rash; hepatotoxicity
 Potential drug
interactions (CYP450)
ARV Components in Initial
Therapy: PIs
ADVANTAGES
 Higher genetic barrier to
resistance
 PI resistance uncommon
with failure (boosted PI)
 NNRTI options preserved
for future use
DISADVANTAGES
 Metabolic complications
(fat maldistribution,
dyslipidemia, insulin
resistance)
 GI intolerance
 Potential for drug
interactions (CYP450),
especially with RTV
ARV Components in Initial
Therapy: Dual-NRTI Pairs
ADVANTAGES
 Established backbone of
combination therapy
 Minimal drug
interactions
DISADVANTAGES
 Lactic acidosis and
hepatic steatosis
reported with most
NRTIs (rare)
ARV Components in Initial Therapy:
NRTIs
ADVANTAGES
DISADVANTAGES
 Established backbone of
 Lactic acidosis and hepatic
combination therapy
steatosis reported with most
NRTIs (rare)
 Minimal drug interactions
 PI and NNRTI preserved for  3-NRTI regimens show
inferior virologic response
future use
compared with EFV- and
IDV-based regimens*
* 3-NRTI regimen of ABC + 3TC + ZDV to be used only when a
preferred or alternative NNRTI- or PI-based regimen cannot or
should not be used as first-line therapy.
The Patient’s First HAART
Start when the patient (not the provider) is emotionally,
psychologically and intellectually ready to start.
Explain the natural progression of HIV infection.
Explain the way the ARV’s work against the HIV.
Know the preferences and concerns of the patient.
Introduce the adequate ARV regimens according to her/his
needs.
HAART IS NOT AN EMERGENCY
The Doctor’s First HAAART
Start with the best regimen for the patient:
Most tolerable.
Best chance for adherence.
Most adequate for the patient’s lifestyle and habits.
The most salvageable.
HAART IS NOT AN EMERGENCY
THE COMBO’S:
WHAT TO START WITH?
The Combo’s
 The MoHSW recommends the following drugs for first
line treatment:
 • Zidovudine (AZT)
 • Stavudine (d4T)
 • Lamivudine (3TC)
 • Emtricitabine (FTC)
 • Tenofovir (TDF)
 • Nevirapine (NVP)
 • Efavirenz (EFV)
The Combo’s
 The following drug combinations can be made out of
these drugs
 AZT+3TC+NVP
 • AZT+ 3TC+EFV
 • d4T+3TC+NVP
 • d4T+3TC+EFV
 • TDF+FTC+EFV
 • TDF+FTC +NVP
 • TDF+3TC+EFV
 • TDF+3TC+NVP
The Combo’s
 Note: The following drugs may appear in fixed drug
combinations (FDC):
 • AZT+3TC, e.g. Combivir or Duovir
 • AZT+3TC+NVP, e.g. Duovir N
 • d4T+3TC+NVP, e.g. Triomune
 • TDF+FTC+EFV, e.g. Atripla
 • TDF+3TC
 • TDF+FTC, e.g. Truvada
Measurement of Adherence
 No gold standard
 Patient self-report overestimates adherence,
but is associated with viral load responses and
is most useful method in the clinic setting
 Self-report of suboptimal adherence is strong
indicator of nonadherence
Predictors of Good
Adherence
 Emotional and practical supports
 Convenience of regimen
 Understanding of the importance of adherence
 Belief in efficacy of medications
 Feeling comfortable taking medications
in front of others
 Keeping clinic appointments
 Severity of symptoms or illness
Adverse Effects: NRTIs
 All NRTIs:
 Lactic acidosis and hepatic steatosis
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Higher incidence with d4T
(d4T > ddI = ZDV > TDF = ABC = 3TC = FTC)
 Lipodystrophy
(higher incidence with d4T)
Adverse Effects:
NNRTIs
 All NNRTIs:
 Rash
 Drug-drug interactions
 NVP: hepatotoxicity (may be severe and life-
threatening); rash including Stevens-Johnson
syndrome
 EFV: neuropsychiatric, teratogenic in primates
(FDA pregnancy class D)
Adverse Effects: PIs
 All PIs:
 Hyperlipidemia
 Insulin resistance and diabetes
 Lipodystrophy
 Elevated LFTs
 Possible increased bleeding risk in
hemophiliacs
 Drug-drug interactions
First Line Regimen- d4T/ 3TC/ NVP
Minor side effects:
 Headaches, nausea, gastro-intetestinal disorder insomnia
Manage symptomatically
Major side effects:
 Immediate: peripheral neuropathy, hepatitis,
pancreatitis, skin reactions
 Long term: lactic acidosis, lipodystrophy syndrome
Example: peripheral neuropathy
[due to d4T]
Step-wise series of actions:
 Minimise possible risk factors
 Symptomatic: amitryptiline; NSAIDS
 Reduce dose d4T/3TC/NVP [40mg-30mg]
 If no better then may have to stop or consider referral
to a centre for alternative first line regimen
Example: drug-induced hepatitis
[due to NVP]
 Stop ARV therapy if clinical evidence of hepatitis or if
AST > 5 times upper limit
 If evidence of hepatitis (ie jaundice) then safest thing
is to STOP ARV therapy
 DO NOT give d4T/3TC/NVP again
 When better consider referral and substitute with
alternative first line regimen
Example: drug-induced pancreatitis
[due to stavudine or rarely lamivudine]
• Suspect if patient develops severe abdominal pain,
nausea and vomiting
• Diagnosis is difficult in district hospitals: amylase
/ US/ CT scan
• Either refer patient or stop therapy: if referral
takes time then STOP
Example: drug-induced skin rash
[due to Nevirapine]
 In first two weeks of ART:
• observe either in or out of hospital
• dose of nevirapine stays at 200 mg daily
• try anti-histamines
• if rash improves or stays stable increase NVP dose
to 200 mg twice a day
• if rash deteriorates or mucous membranes are
involved then STOP nevirapine
Example: drug-induced skin rash
[due to Nevirapine]
 After the first two weeks of ART:
• any skin problem needs hospital assessment
• if just itching then add anti-histamine and
continue ARV therapy
• if rash occurs carefully assess and rule out other
causes
• if rash worsens and if mucosal membranes
involved STOP ART
Changing Antiretroviral Therapy
 Drug adverse events – Toxicities, including:
 • Intolerable side effects
 • Drug interactions
 • During pregnancy if the patient is on EFV
 Treatment failure including:
 • Clinical failure – occurrence or persistence of HIV
related OIs
 • Immunological failure
 • Virological failure
Types of Antiretroviral Drugs
 The currently existing and commercially available
antiretroviral drugs fall into the following five main
categories:
 Binding and Fusion Inhibitors
 Nucleoside reverse transcriptase inhibitors (NRTIs)
 Non-nucleoside reverse transcriptase inhibitors
(NNRTIs)
 Nucleotide reverse transcriptase inhibitors (Nucleotide
analogues)
 Protease inhibitors (Pls)