What’s New inWhat s New in Antiretroviral Therapy?Antiretroviral Therapy?

Sasisopin Kiertiburanakul, MD, MHS

Division of Infectious DiseasesDepartment of Medicine Faculty of Medicine Ramathibodi HospitalFaculty of Medicine Ramathibodi Hospital Mahidol University

Rotating RCPT, Uttaradit (July 8, 2010)

Outline

• Patient evaluation and assessmentPatient evaluation and assessment• When to start• What to start• How to monitorHow to monitor

P ti t E l ti dPatient Evaluation and AssessmentAssessment

History Takingy g

• Estimate the duration of HIV infectionEstimate the duration of HIV infection– Timing of HIV seroconversion? or

Wh th fi t HIV di i ?– When was the first HIV serodiagnosis?• Risk factor• Past HIV-related illness

Herpes zoster– Herpes zoster – Constitutional symptoms

• Fever, weight loss, diarrhea– OI: TB, PCP, cryptococcosis, CMVy

History Takingy g

• Prior antiretroviral therapypy– Response to each regimen (CD4, viral load),

toxicities, adherence, and prior resistance test , , presults

– ARV during pregnantg p g• Other diseases

Hepatitis malignancy DM HT CVD– Hepatitis, malignancy, DM, HT, CVD,….• Other medications, vaccinations• Social, sexual, and family histories

– Tobacco, alcohol, heroin,…, , ,– Sex partners, sex practices

Physical Examinationy

• General: fever, appearanceGeneral: fever, appearance• Oral cavity• HEENT: retinitis, lymphadenopathy• Lung: dyspnea adventitious sound(s)Lung: dyspnea, adventitious sound(s)• Abdomen: mass, organomegaly• Skin: PPE, seborrheic dermatitis,

papulonecrotic lesions, mollusgum-likepapulonecrotic lesions, mollusgum like lesion, psoriasis, zoster scarA it l i ti• Anogenital examination

Baseline Evaluation

HIV disease Serum chemistryHIV disease characterization

• CD4 cell count

Serum chemistry• LFT• BUN/CrCD4 cell count

• HIV RNA (virus load)• BUN/Cr• FBS• Lipid profiles

Hematology Serological tests• CBCWomen

g• Syphilis (VDRL/RPR)• Hepatitis B and C

• Pregnancy test• Pelvic examination

Hepatitis B and C

OthersCXR UAPelvic examination • CXR, UA

When to Start?When to Start?

Thai Guideline 2008Clinical Presentations CD4 Count Recommendation

(cells/mm3) AIDS-defining illness Any Treat

Symptoms* Any Treat

Asymptomatic <200 Treaty pAsymptomatic 200-350 Defer treatment, follow

up CD4 every 3 hmonths

Asymptomatic >350 Defer treatment, follow up CD4 every 6up CD4 every 6

months*unexplained fever or diarrhea > 2-4 wks, >10% unexplained weight loss, oral

Sungkanuparph S et al. J Med Assoc Thai 2008;91:1925-36.

p , p g ,candidiasis, or PPE

WHO Guideline 2009: Key Messages

• The best time to start ART is before patients pbecome unwell or develop their first opportunistic infection

• Promote earlier treatment, when CD4 count <350 cells/mm3 regardless of symptoms<350 cells/mm , regardless of symptoms

• ~ 1-2 years’ additional exposure to ARTAdh i t t t t l d d• Adhering to treatment vs. prolonged and healthier life

• Rates of death, morbidity and HIV and TB transmission are all reduced

http://www.who.int/hiv

Thai Guideline 2010

Clinical Presentations CD4 Count (cells/mm3)

Recommendation

AIDS defining illness Any TreatAIDS-defining illness Any Treat

HIV-related symptoms* Any Treat

Asymptomatic <350 TreatAsymptomatic >350 Deferred treatment,

follo p CD4 e er 6follow up CD4 every 6 months

Pregnancy Any Discontinued afterPregnancy Any Discontinued after delivery, if CD4 >350

**oral candidiasis, PPE, unexplained fever or diarrhea >2 weeks, >10% unexplained weight loss in 3

Sungkanuparph S et al. Asian Biomed 2010. (in press)

months, or herpes zoster involved >2 dermatomes

AIDS-defining Illnessg• Esophageal candidiasis • Lymphoma

• Tuberculosis • Non-tuberculosis mycobacteria,

disseminated/extrapulmonary

• Kaposi’s sarcoma • Cervical cancer • Progressive multifocaldisseminated/extrapulmonary

• Pneumocystis carinii pneumonia • Cryptococcosis, extrapulmonary

Progressive multifocal leukoencephalopathy

• HIV wasting syndrome• HIV encephalopathy (AIDSyp , p y

• Histoplasmosis, disseminated or extrapulmonaryP i illi i

• HIV encephalopathy (AIDS dementia complex)

• Penicilliosis• Toxoplasmosis • CytomegalovirusCytomegalovirus• Recurrent pneumonia, recurrent• Salmonella septicemia

DHHS Guideline 2009 Clinical Conditions CD4 Count

( ll / 3)Recommendation

(cells/mm3) History of AIDS-defining illness Any Treat

Asymptomatic <350 TreatPregnant women* Any TreatHIV-associated nephropathy Any Treat

HBV co-infection when HBV treatment indicated

Any Treattreatment indicated

Asymptomatic without specific conditions above

350-500 55% voted for strong recommendation (A)conditions above recommendation (A)

Asymptomatic without specific conditions above

>500 50% voted favor starting ART (B)

Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents Department of Health and Human Services. December 1, 2009. http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf

Earlier Initiation of HIV TreatmentBenefit Limitations• Reduction in mortality and/or

AIDS-related morbidity• Reduction in HIV-related

• Drug toxicity• Quality of life• Drug resistance

morbidity– Nephropathy– Hepatitis co-infection

Drug resistance• Nonadherence to therapy• Cost

I f t tp

– Cardiovascular disease– Malignancies– Neurocognitive decline

• Infrastructures

Neurocognitive decline– Age and treatment-related

immune reconstitution– T-cell activation andT cell activation and

inflammation• Prevention of HIV transmission

CD4 <200 CD4 <350

Other Factors

• Patients’ willingness and readinessPatients willingness and readiness• Adherence potential• Family planning status • Co-morbidity or conditions: OI liverCo morbidity or conditions: OI, liver

disease, depression or mental illness, cardiovascular disease chemicalcardiovascular disease, chemical dependency, pregnancy

• Potential drug interactions with other medicationsmedications

What to Start?What to Start?

Antiretroviral Agents 2010gNRTI NNRTI PI

abacavir (ABC) delavirdine (DLV) atazanavir (ATV)

didanosine (ddI) efavirenz (EFV) darunavir (DRV)didanosine (ddI) efavirenz (EFV) darunavir (DRV)

emtricitabine (FTC) etravirine (ETV) fosamprenavir (FPV)

l i di (3TC) i i (NVP) i di i (IDV)lamivudine (3TC) nevirapine (NVP) indinavir (IDV)

stavudine (d4T) Entry Inhibitor lopinavir/r (LPV/r)

tenofovir (TDF) enfuvirtide (T20) nelfinavir (NFV)

zidovudine (AZT) CCR5 Antagonists ritonavir (RTV)zidovudine (AZT) CCR5 Antagonists ritonavir (RTV)

Integrase Inhibitors maraviroc (MVC) saquinavir (SQV)

raltegravir (RAL) tipranavir (TPV)

Antiretroviral Regimensg

• 2 NRTIs + NNRTIs2 NRTIs NNRTIs – NNRTI-based regimens

2 NRTI 1 2 PI• 2 NRTIs + 1-2 PIs – PI-based regimensg

• 2 NRTIs + INSTIntegrase based regimens– Integrase-based regimens

ARV Combinations: Basic Regimens

2 NRTI + NNRTI/Boosted PIs

Non-Thymidine

2 NRTI + NNRTI/Boosted PIs

Thymidine NNRTI orNon Thymidine Analog+

Thymidine Analog

NNRTI orBoosted PIs+

3TCAZTd4T

EFV or NVP

ATV+rDRV/rLPV/

ddIFTC

LPV/r SQV/r

ABCTDF

Thai HIV Guidelines 2010

Recommendation NRTI NNRTI PI

Preferred AZT + 3TC EFV or LPV/rPreferred AZT + 3TC TDF + 3TC TDF/FTC

EFV or NVP

LPV/r

TDF/FTC

Alternative ABC + 3TC d4T 3TC

- ATV/r d4T + 3TC ddI + 3TC

SQV/r DRV/r

Sungkanuparph S et al. Asian Biomed 2010. (in press)

WHO Guideline 2009: Key Messages

• Greater use of more patient-friendlyGreater use of more patient friendly treatment regimensP i l h t f d4T• Progressively phase out use of d4T as a preferred first-line therapy option – Avoid disabling and disfiguring side effects

and reduce costs of managing these toxicitiesg g

• Move to less toxic alternatives such as AZT and TDFAZT and TDF

• NNRTI: EFV or NVP

http://www.who.int/hiv

DHHS Guideline 2009Recommendation NRTI NNRTI PIPreferred

(pregnant women)

TDF/FTC EFV ATV/rDRV/r

AZT/3TC LPV/r(p g ) AZT/3TC LPV/r

Alternative (ABC or AZT) + 3TC EFV ATV/rLPV/rLPV/r

AZT + 3TC NVP

TDF/FTC SQV/rTDF/FTC SQV/rLPV/r

Acceptable ddI + (3TC or FTC) EFVp ( )

(ABC or AZT) + 3TC ATV

Use with caution ABC + 3TC or TDF/FTC NVP

Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents Department of Health and Human Services. December 1, 2009. http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf

Use with caution ABC + 3TC or TDF/FTC NVP

Combined Pill by GPOy

• ZilarvirZilarvir– AZT 300 mg, 3TC 150 mg

L t i • Lastavir– d4T 30 mg, 3TC 150 mgg g

• GPO-VIR S30d4T 30 mg 3TC 150 mg NVP 200 mg– d4T 30 mg, 3TC 150 mg, NVP 200 mg

• GPO-VIR Z250– AZT 250 mg, 3TC 150 mg, NVP 200 mg

Factors to Consider Regimen for Thais

• Health insurance systemHealth insurance system • Inexpensive• Access to HIV care• Co-morbidityCo morbidity• Concurrent OI and its treatment• ART during pregnancy• Efficacy• Efficacy

What Not to Use

• Monotherapy with NRTIpy• Dual-NRTI regimens • Triple NRTI regimens (with exception)• Triple-NRTI regimens (with exception) • d4T + ddI• d4T + AZT• TDF + ddI• ATV + IDV• EFV in first trimester of pregnancy• EFV in first trimester of pregnancy• NVP in women with CD4 >250 or men with CD4

400 ll / 3>400 cells/mm3

Common Adverse Effects: NRTIs

• Zidovudine: headache, GI intolerance,Zidovudine: headache, GI intolerance, bone marrow suppressionT f i h d h GI i t l l• Tenofovir: headache, GI intolerance, renal impairment, Fanconi syndrome

• Stavudine: peripheral neuropathy (PN), pancreatitispancreatitis

• Didanosine: PN, GI intolerance, pancreatitis

• Abacavir: hypersensitivity reactionAbacavir: hypersensitivity reaction

Common Adverse Effects: NNRTIs

• Nevirapine: hepatotoxicity, rash includingNevirapine: hepatotoxicity, rash including Stevens-Johnson syndromeEf i hi t i t t i• Efavirenz: neuropsychiatric, teratogenic, false positive cannabinoid test

40 Years Old Businessman

• Fever, weight loss, and Rt. axilla mass 4Fever, weight loss, and Rt. axilla mass 4 weeksN l CXR• Normal CXR

• CD4 23 cells/mm3• Pus AFB positive

S HRZE• Start HRZE

Q3: 4 weeks Later, What Next?

• A. Wait for another 4 weeks, then startA. Wait for another 4 weeks, then start ARTB W it til l t TB t t t• B. Wait until complete TB treatment

• C. Start ART with NVP-based regimeng• D. Start ART with EFV-based regimen

E S ART i h PI b d i• E. Start ART with PI-based regimen

Treatment of TB/HIV Co-infection

CD4 cell count Recommendation CommentsCD4 cell count (cells/mm3)

Recommendation Comments

<200 Start TB treatment Start ART Recommended ART<200 Start TB treatment. Start ART as soon as TB treatment is tolerated (after 2 weeks)

Recommended ART

200-350 Start TB treatment. Start one of the ART regimen after intensive phase of TB

Recommended ART

intensive phase of TB treatment (if severely compromised start earlier)

>350 Start TB treatment Defer ART

ART Regimen in Patients with TB

• EFV containing regimensEFV containing regimens– EFV is contra-indicated in pregnant women or

women of child bearing potential withoutwomen of child bearing potential without effective contraceptionD f EFV i 600 /d f i ht <60– Dosage of EFV is 600 mg/day for weight <60 kg and 800 mg/day for weight >60 kg1

• NVP is an alternative to EFV for patient who has taken rifampicin p– Lead-in NVP for the first 14 days is not

necessarynecessary

1. Sungkanuparph S et al. J Med Assoc Thai 2008;91:1925-36.

Patients with active TB hasnewly diagnosed HIV infectionnewly diagnosed HIV infection

Rifampicin containingRifampicin-containing drug regimen

St t ART t l tART is

not indicated nowART is

indicated

Start ART at least 2 weeks-2 monthsafter TB treatment

ART with EFV based regimen Alternatively useART with EFV-based regimen(alternative NVP-based regimen)

Alternatively use non refampcin-based

drug regimen

Re-evaluated after complete Any standard ART regimensp

TB treatment Any standard ART regimens

HIV/TB Co-infection

HIV-infected PatientsHIV infected PatientsNew active TB established

Continuationof ART

NNRTI-based regimen PI-based regimen g(EFV or NVP)

g

Rifampicin-containing

drug regimen

Alternatively use non rifampicin-containing

drug regimendrug regimen drug regimen

IRIS: Definition

• Immune recovery inflammatory syndrome y y y• Collection of inflammatory disorders associated

with paradoxical worsening of pre-existingwith paradoxical worsening of pre existing infectious processes following the initiation of HAART in HIV-infected individualsHAART in HIV infected individuals

• Systemic or local inflammatory reactions may occur at the site or sites of preexisting infectionoccur at the site or sites of preexisting infection

• Preexisting infections P i l di d d d– Previously diagnosed and treated

– Subclinical and later unmasked by the host's regained it t t i fl tcapacity to mount an inflammatory response

Timing of ART in the Setting of OI

• Early ART in hopes of • Deferring ART in order to d th i k f IRISreducing the risk of AIDS-

related morbidity and mortality

decrease the risk of IRIS• Poor absorption of

therapeutic drugs duringmortality• Earlier immunologic

recovery

therapeutic drugs during acute or advanced HIV-related infection

– Faster resolution of OI • Additive toxicities of multiple therapeutic agentsagents

• Drug interactions• Problem of differentiatingProblem of differentiating

IRIS from other simultaneously present ill i f tiillnesses or infections

When to Start HAART after OI?

• No consensus…When???• Absent any contraindications, early HAART

initiation should be strongly considered in theinitiation should be strongly considered in the AIDS patient with OI

• Cryptosporidiosis microsporidiosis PML and• Cryptosporidiosis, microsporidiosis, PML, and Kaposi sarcoma

HAART h ld b t t d ibl– HAART should be started as soon as possible• TB, MAC, PCP, and cryptococcal meningitis

– Waiting a response to OI therapy– Improve signs and symptoms of the diseases

When to Start HAART after OI?• TB

– 4-8 weeks after starting anti-TB• PCPPCP

– After completion of anti-PCP (21 days)• Cryptococcal meningitis• Cryptococcal meningitis

– 8-10 wks after treatmentToxoplasmosis• Toxoplasmosis– After completion treatment (6 weeks)

• MAC– 4-8 weeks after treatment and negative blood

culture

Treatment Goal of HAART

• Reduce HIV-related morbidity and prolongReduce HIV related morbidity and prolong survivalI lit f lif• Improve quality of life

• Restore and preserve immunologic p gfunction

• Maximally and durably suppress viral load• Maximally and durably suppress viral load• Prevention vertical HIV transmission

Goal of Therapypy

Vi l l d

els

CD4

Viral load

ve L

eve CD4

Rel

ativ

<50copies/mL at 6 month

Limit of Detectionat 6 month

Months Years After HIV Infection

Acute HIV infection

Monitoringg

• Clinical monitoringClinical monitoring• Adherence assurance/counseling• Immunological monitoring

Vi l i l it i• Virological monitoring• Drug resistant testingDrug resistant testing• Therapeutic drug monitoring

Monitoring: Thai Guideline 2010gLaboratory During the first year After the first year Noteinvestigations

CBC, CD4 6, 12 month Every 6 month

Viral load First regimen: Every 12 month Before changing the regimen6, 12 month (every 6 month,

if possible)

ART changing after f il 6 12 th

Every 12 monthfailure: 6, 12 month

FBS 6, 12 month Every 6 month

ALT 6, 12 month Every 6 month At 3 month if starting NNRTIs

Cr* 6, 12 month Every 6 month Every 6 month, if use TDF or IDV

Lipid profile (TC, TG, LDL, HDL)

6, 12 month Every 6 month

Urinalysis - - Every 6 month, if use TDF or IDV

CXR - - Repeat, if indicated

Pap smear 12 month Every 12 month Repeat, if indicatedPap smear 12 month Every 12 month Repeat, if indicated

Sungkanuparph S et al. Asian Biomed 2010. (in press)

Laboratory Monitoring Schedule: DHHS

Entry to care Follow up before ART

ART initiation or switchbefore ART or switch

CD4 cell count every 3-6 months

HIV RNA every 3-6 monthsHIV RNAResistance testing optional

Hepatitis B serology if not immune and HBsAg negHBsAg neg

Basic chemistry every 6-12 months

Liver function test every 6-12 months

CBC every 3-6 months

Lipid profile if normal, annually

Fasting glucose if normal, annually

Urinary analysisif t ti EFVPregnancy test if starting EFV

Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents Department of Health and Human Services. December 1, 2009.http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf

Conclusions

• Appropriate patient assessmentAppropriate patient assessment• Early treatment initiation is associated with

b fit th i kmore benefits than risk– Asymptomatic with CD4 <350 cells/mm3

• Use less toxic drugsA i t ti i f ART i iti ti i• Appropriate timing of ART initiation in patients with OI

• Appropriate monitoring • Patients should be identified early• Patients should be identified early