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Humphrey Shao MD, MHS
Goals of ART
Eradication of HIV?
Not possible with currently available ARV medications
ART Goals & Tools to Achieve ThemImproved quality of lifeReduction of HIV-related
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 adherenceUse of resistance testing
in selected clinical settings
Baseline Evaluation
Complete History & Physical exam.Laboratory testing:
HIV antibody CD4 cell count Plasma HIV RNAResistance test (genotype)CBC, chemistry profile, BUN, Cr, transaminaseFasting glucose and lipidsRPR or VDRLHepatitis A, B, C serologyToxoplasma IgG
Before Initiating ART: Additional Tests Tuberculin skin test (TST) or IFN-γ
release assayChest X ray (if symptoms, or
positive TST or IFN-γ release assay)Gynecologic exam with Pap smearTesting for chlamydia and
gonorrheaOphthalmology 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 RNARisk of disease progressionPotential 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 medicationsUsually causes immediate virologic
rebound, with CD4 decline
Use of CD4 Cell Levels to Guide Therapy DecisionsCD4 count
The major indicator of immune function Most recent CD4 count is best predictor of
disease progressionCD4 count usually is the most important
consideration in decision to start ART Important in determining response to ART
Adequate response: CD4 increase 100-150 cells/µL per year
CD4 monitoringCheck at baseline (x2) and at least every 3-
6 months
Use of HIV RNA Levels to Guide Therapy DecisionsHIV 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 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 ART2-8 weeks after start or change of ARTEvery 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 countART indicated for all with low CD4 count or symptomsEarlier initiation of ART may result in better
immunologic responses and better clinical outcomesRecommended 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 countsCurrent 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 illnessCD4 count of <200 cells/µL
Strong evidence of decreased mortality andmorbidity 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 non-
AIDS-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 functionHBV coinfection, if HBV treatment is
neededTNF + 3TC or FTC is recommendedIf 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/orCD4 Count
Recommendation
History of AIDS-defining illness CD4 count of <350 cells/µL Pregnant women HIV-associated nephropathy Hepatitis B coinfection, when
HBV treatment is indicated*
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
Recommendation
CD4 count of >350 cells/µL, asymptomatic, without conditions listed above
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 complicationseg, TB, NHL, KS, peripheral neuropathy,
HPV-associated malignancies, HIV-associated cognitive impairment
Decrease risk of nonopportunistic conditions and non-AIDS-associated conditionseg, 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 toxicitiesDrug resistance (caused by ART failure)Inadequate time to learn about HIV,
treatment, and adherenceIncrease in total time on ART; greater
chance of treatment fatigueCurrent ART may be less effective or
more toxic than future therapiesTransmission of ARV-resistant virus, if
incomplete virologic suppression
Current ARV MedicationsNRTI Abacavir (ABC) Didanosine (ddI) Emtricitabine (FTC) Lamivudine (3TC) Stavudine (d4T) Tenofovir (TDF) Zidovudine (AZT, ZDV)
NNRTI Delavirdine (DLV) Efavirenz (EFV) Etravirine (ETR) Nevirapine (NVP)
PI Atazanavir (ATV) Darunavir (DRV) Fosamprenavir (FPV) Indinavir (IDV) Lopinavir (LPV) Nelfinavir (NFV) Ritonavir (RTV) Saquinavir (SQV) Tipranavir (TPV)
Fusion Inhibitor Enfuvirtide (ENF, T-20)
CCR5 Antagonist Maraviroc (MVC)
Integrase Inhibitor Raltegravir (RAL)
Initial Treatment: Choosing Regimens (2)
Considerations:Comorbidities (eg, liver, psychiatric, or
cardiovascular disease; tuberculosis; pregnancy)Adherence potentialDosing convenience (eg, pill burden, dosing
frequency)Potential adverse effectsPotential drug interactionsPregnancy potentialResults of drug resistance testGender and CD4 count, if considering NVPHLA B*5701 testing, if considering ABC
ARV Components in Initial Therapy: NNRTIs
ADVANTAGESLong half-livesLess metabolic
toxicity (dyslipidemia, insulin resistance) than with some PIs
PI options preserved for future use
DISADVANTAGESLow genetic barrier
to resistance – single mutation
Cross-resistance among most NNRTIs
Rash; hepatotoxicityPotential drug
interactions (CYP450)
ARV Components in Initial Therapy: PIs ADVANTAGESHigher genetic barrier to
resistancePI resistance uncommon
with failure (boosted PI)NNRTI options
preserved for future use
DISADVANTAGESMetabolic
complications (fat maldistribution, dyslipidemia, insulin resistance)
GI intolerancePotential for drug
interactions (CYP450), especially with RTV
ARV Components in Initial Therapy: Dual-NRTI PairsADVANTAGESEstablished
backbone of combination therapy
Minimal drug interactions
DISADVANTAGESLactic acidosis
and hepatic steatosis reported with most NRTIs (rare)
ARV Components in Initial Therapy: NRTIsADVANTAGESEstablished backbone of
combination therapyMinimal drug interactionsPI and NNRTI preserved
for future use
DISADVANTAGESLactic acidosis and
hepatic steatosis reported with most NRTIs (rare)
3-NRTI regimens show inferior virologic response 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 HAARTThe Patient’s First HAARTStart 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 EMERGENCYHAART IS NOT AN EMERGENCY
The Doctor’s First HAAARTThe Doctor’s First HAAARTStart 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 EMERGENCYHAART IS NOT AN EMERGENCY
The Combo’sThe 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’sThe 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’sNote: 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 standardPatient self-report overestimates
adherence, but is associated with viral load responses and is most useful method in the clinic settingSelf-report of suboptimal adherence is
strong indicator of nonadherence
Predictors of Good Adherence
Emotional and practical supportsConvenience of regimenUnderstanding of the importance of
adherenceBelief in efficacy of medicationsFeeling comfortable taking
medicationsin front of others
Keeping clinic appointmentsSeverity of symptoms or illness
Adverse Effects: NRTIsAll NRTIs:
Lactic acidosis and hepatic steatosisHigher incidence with d4T
(d4T > ddI = ZDV > TDF = ABC = 3TC = FTC)
Lipodystrophy(higher incidence with d4T)
Adverse Effects: NNRTIs
All NNRTIs:RashDrug-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 diabetesLipodystrophy Elevated LFTsPossible increased bleeding risk in
hemophiliacsDrug-drug interactions
First Line Regimen- d4T/ 3TC/ NVPMinor side effects:
Headaches, nausea, gastro-intetestinal disorder insomnia
Manage symptomatically
Major side effects:Immediate: peripheral neuropathy,
hepatitis, pancreatitis, skin reactionsLong term: lactic acidosis, lipodystrophy
syndrome
Example: peripheral neuropathy[due to d4T]
Step-wise series of actions:Minimise possible risk factorsSymptomatic: amitryptiline; NSAIDSReduce 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 againWhen 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 InhibitorsNucleoside reverse transcriptase inhibitors
(NRTIs)Non-nucleoside reverse transcriptase
inhibitors (NNRTIs)Nucleotide reverse transcriptase inhibitors
(Nucleotide analogues)Protease inhibitors (Pls)