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)