11

HIV Treatment Update

Todd Correll, PharmD, BCPSClinical Pharmacy Specialist, Infectious Diseases/HIV

University of North Carolina HospitalsNovember 2006

Objectives

• Provide an update on DHHS HIV treatment naïve guidelines

• Discuss the currently approved antiretrovirals

• Describe treatment options for opportunistic infections

HIV Life Cycle

Illustration by David Klemm

Goals of Therapy & Strategies to Achieve Goals

Improvement of quality of life

Reduction of HIV-related morbidity and mortality

Restoration and/or preservation of immunologic function

Maximal and durable suppression of viral load

Selection of ARV regimen Preservation of future

treatment options Rational sequencing of

therapy Maximizing adherence Use of resistance testing

in selected clinical settings

StrategiesStrategiesGoalsGoals

Indications for Antiretroviral Initiation

Clinical Category

CD4 cell count

HIV RNA

Recommendation

Symptomatic (AIDS)

Any value Any value TREAT

Asymptomatic AIDS

<200 cells/mm3

Any value TREAT

Asymptomatic 200 to 350 cells/mm3

Any value Offer treatment;

pros vs cons

Asymptomatic >350 cells/mm3

>100K c/mL

TREAT

Asymptomatic >350 cells/mm3

<100K

c/mL

Defer therapy

Antiretroviral Combinations Not Recommended as Initial Therapy

Reason for Avoidance Medication/Regimen

↑ rate of virologic failure • ddI + TDF + NNRTI

Inferior antiviral activity • Delavirdine• Unboosted SQV

↑ incidence of toxicities • d4T + ddI• RTV 600 mg Q12h

↑ pill burden/dosing frequency • APV (w/ or w/out RTV)• Unboosted IDV• NFV + SQV

Lack of treatment-naïve data • TPV• DNV• T-20

Antiretroviral Combinations Not Recommended Anytime

• Monotherapy– Except for the perinatal HIV transmission prevention

• Dual NRTI• 3 drug regimens not recommended

– ddI + TDF + NNRTI– ABC + TDF + 3TC– ddI + TDF + 3TC

• NNRTI-based regimens– Efavirenz in pregnancy → category D– Nevirapine initiation → ↑ risk of hepatotoxicity

• women with a CD4 count > 250 cells/mm3• men with a CD4 count > 400 cells/mm3

High rates of virologic failure

Antiretroviral Combinations Not Recommended Anytime

• NRTI backbone– ddI + d4T → toxicities– d4T + AZT → drug antagonism– FTC + 3TC → drug antagonism

• PI combinations– APV + FPV → FPV is the prodrug of APV– APV oral solution in children, pregnancy, renal/hepatic

failure– APV oral solution + RTC oral solution → propylene

glycol toxicity– ATV + IDV → ↑ risk of elevated total bilirubin

Antiretroviral Components in Initial Therapy: NNRTIs

ADVANTAGES• Less fat

maldistribution and dyslipidemia than in PI-based regimens

• PI options preserved for future use

DISADVANTAGES• Resistance - single

mutation• Cross-resistance

among NNRTIs• Rash; hepatotoxicity• Potential drug

interactions (CYP450)

Antiretroviral Components in Initial Therapy: PIs

ADVANTAGES• Longest prospective

data• NNRTI options

preserved for future use

DISADVANTAGES• Metabolic complications

(fat maldistribution, dyslipidemia, insulin resistance)

• Greater potential for drug interactions (CYP450), especially with ritonavir

ART Options

NRTIs (Nucleoside OR Nucleotide Reverse Transcriptase Inhibitors, aka “Nukes”)

NNRTIs (Non-Nucleoside Reverse Transcriptase Inhibitors, aka “Non-Nukes”)

PIs (Protease Inhibitors)

Fusion (or Entry Inhibitors)

ART agents in additional classes currently in development

-Integrase Inhibitors-CCR5 Antagonists-CXCR4 Antagonists

NNRTI

’’8787 ’’9191 ’’9292 ’’9494 ’’9595 ’’9696 ’’9797 ’’9898 ’’9999 ‘‘0000’’8888 ’’8989 ’’9090

NRTINRTI

PIPI

Approved Antiretrovirals

NorvirNorvir

InviraseInvirase

CrixivanCrixivan

FortovaseFortovase

KaletraKaletraViraceptViracept

ZiagenZiagen

CombivirCombivir

VidexVidex

HividHivid

ZeritZerit

EpivirEpivir

TrizivirTrizivir

Rescriptor

SustivaViramune

’’0101

VireadViread

EmtrivaEmtriva

FuzeonFuzeon

ReyatazReyataz

‘‘0202 ‘‘0303’’9393

AgeneraseAgenerase

LexivaLexiva

TruvadaTruvada

EpzicomEpzicom

FIFI

AZTAZT

AptivusAptivus

PrezistaPrezista

AtriplaAtripla

Mechanism of Action

Nucleoside analogs (like AZT below) are activated after being phosphorylated so that they can be incorporated into the viral DNA strand by reverse transcriptase.

Since TDF is a nucleotide, it does NOT have to be phosphorylated prior to being incorporated into the growing viral DNA strand.

After incorporation of

the NRTI, viral DNA

synthesis will be

terminated.

FDA Black Box WarningsNRTI Warning

AZT■ Lactic acidosis and steatosis.■ Hematologic toxicities including neutropenia & anemia.■ Myopathy

ddI■ Fatal and nonfatal pancreatitis; hold ddI if pancreatitis suspected; D/C if confirmed.■ Lactic acidosis and steatosis.■ Fatal lactic acidosis in pregnant women with ddI + d4T.

d4T■ Lactic acidosis and steatosis.■ Fatal lactic acidosis in pregnant women with ddI + d4T.■ Fatal and nonfatal pancreatitis with ddI + d4T+ HU.

3TC ■ Lactic acidosis and steatosis.■ Acute HBV exacerbation upon discontinuation.

ABC

■ Fatal hypersensitivity reactions reported.■ S/S are fever, rash, fatigue, and GI and respiratory Sx. If suspected, ABC should be D/C and should NOT be restarted.■ Lactic acidosis and steatosis.

TDF ■ Lactic acidosis and steatosis.• Acute HBV exacerbation upon discontinuation.

FTC ■ Lactic acidosis and steatosis.■ Acute HBV exacerbation upon discontinuation.

NRTIsDrug Standard

Dose*Dosage forms

Combos Common Side Effects

Zidovudine (ZDV/AZT) Retrovir

300mg bid* 300mg tab, 100mg cap, iv oral soln

Combivir, Trizivir

Fatigue, malaise, HA, myalgia, anemia, GI

Lamivudine (3TC) Epivir

150mg bid* or 300mg qd

150, 300mg tab, oral soln

Combivir, Epzicom, Trizivir

Well tolerated

Emtricitabine(FTC) Emtriva

200mg qd* 200mg cap Truvada,Atripla

Well tolerated

Didanosine (ddI) Videx

400mg EC qd*†

125,200,250,400mg cap, pwdr for soln

Pancreatitis, peripheral neuropathy, LA/HS

*dose reduce for renal dysfunction† dose reduce for weight <60 kg

NRTIs

Drug Standard Dose*

Dosage forms

Combos Common Side Effects

Stavudine (d4T) Zerit

40mg bid*† 15,20,30,40 mg cap,oral soln

Peripheral neuropathy, Dylipidemia, LipodystrophyPancreatitis, LA/HS

Abacavir (ABC) Ziagen

300mg bid, 600mg qd

300mg tabs, oral soln

Trizivir, Epzicom

hypersensitivity

Tenofovir(TDF) Viread

300mg qd* 300mg tabs Truvada,Atripla

Few SEs, potential renal dysfxn.

* dose reduce for renal dysfunction† dose reduce for weight <60 kg

NRTI Combination Products

Drug Standard Dose Dosage Form

Combivir(AZT + 3TC)

1 tablet BID* 300/150 mg tablet

Trizivir (AZT + 3TC + ABC)

1 tablet BID* 300/150/300 mg tablet

Epzicom(ABC + 3TC)

1 tablet QD* 600/300 mg tablet

Truvada(TDF + FTC)

1 tablet QD* 300/200 mg tablet

*Use of individual components instead of combination products may necessary in patients with renal dysfunction.

Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) Inhibit reverse transcriptase by a mechanism that is

different from that of NRTIs nevirapine (NVP)

delavirdine (DLV)

efavirenz (EFV)

Use caution when coadministering PIs (modify dose and closely monitor in order to minimize P450 interactions and complications)

X

I can stop that HIV reverse transcriptase!

RT

Mechanism of Action

These agents directly bind to reverse transcriptase to inhibit its making DNA from the HIV’s RNA.

NEVER use NNRTIs as monotherapy in order to ↓

development

of rapid

resistance!

RT

X

FDA Black Box Warnings

NNRTI Warning

NVP

■ Severe, life-threatening hepatotoxicity including fulminant and cholestatic hepatitis, hepatic necrosis & hepatic failure.■ Severe, life-threatening, and even fatal skin reactions. Monitor intensely during the first 12 wk to detect hepatotoxicity and skin reactions.

DLV ■ None

EFV ■ None

http://aidsinfo.nih.gov/guidelines/adult/AA_032304.pdf

NNRTIs

Drug Standard Dose

Dosage forms

Combos Common AEs

Delavirdine (DLV) Rescriptor

400 mg tid 100mg tab, 200mg cap

Suboptimal data on efficacy; potent CYP3A inhibitor

rash

Nevirapine (NVP) Viramune

200 mg qd x 14 d then200 mg bid

200mg tabs, Oral susp

CYP3A inducer, auto inducer

rash, hepatotoxicity

Efavirenz (EFV) Sustiva

600 mg qhs 50, 100, 200mg cap, 600mg tab

CYP3A inducer, potency similar to PIs

Vivid dreams, drowsiness, CNS SEs, rash (including Stevens Johnson)

Atripla

• Triple combination tablet containing:– Emtricitabine 200 mg – Tenofovir 300 mg– Efavirenz 600 mg

• Bilayer tablet– Do not crush– Do not cut in half

• First “complete regimen” tablet• Dose: 1 tablet at bedtime

Atripla Bioequivalence

TFV

0 12 24 36 48 60 725

50

500

1000

TestReference

Time (hrs)

TF

V P

lasm

a C

on

cen

trat

ion

(ng

/mL

)

FTC

0 24 48 72 961

10

100

1000

5000

Test

Reference

Time (hrs)

FT

C P

lasm

a C

on

cen

trat

ion

(ng

/mL

)

EFV

0 72 144 216 288 360 432 50410

100

1000

5000

Test

Reference

Time (hrs)

EF

V P

las

ma

Co

nc

en

tra

tio

n(n

g/m

L)

Protease Inhibitors:Mechanism of Action

Protease cleaves HIV precursor proteins (gag/pol polyproteins) into active proteins that are needed to assemble a new, mature HIV virus. This enables new viral particles to “break off” from infected host cells.

PIs prevent this cleavage and inhibit the assembly of new HIV viruses within infected host cells.

PI

HIV-1 Protease

XHIV

FDA Black Box WarningsPI Warning

SQV ■ None

RTV ■ Co-administration with certain medications may cause serious or life-threatening events.

IDV ■ None

NFV ■ None

APV ■ Large amount of the excipient propylene glycol in oral soln (contraindicated in pregnant women, pts< 4y, pts with renal or hepatic failure, and pts treated with disulfiram or metronidazole)

LPV ■ None

ATV ■ None

TPV ■ Reports of clinical hepatitis & liver decompensation including some fatalities have occurred; risk of intracranial bleeding

DNV None

FOS ■ None

http://aidsinfo.nih.gov/guidelines/adult/AA_032304.pdf

Protease InhibitorsDrug Dose Pill burden Dosing info

Saquinavir (Invirase)

1000 mg + RTV 100 mg BID

2(500mg) caps/1(100mg cap) BID

Take with food

Nelfinavir (Viracept)

1250 mg BID750 mg TID

2(625mg) tabs BID3(250mg) tabs TID

Take with food

Indinavir(Crixivan)

800mg + RTV 100 BID

800 mg TID

2 (400mg) caps +1(100mg cap) BID

2 (400 mg) caps TID

Drink 7-8 glasses of water per day

Fosamprenavir(Lexiva)

1400 mg BID1400 mg + RTV 200 QD

700 mg + RTV 100 mg BID

2 (700mg) tabs BID2 (700mg) tabs + 2 (100 mg) caps QD

1 (700mg) tabs + 1 (100 mg) caps BID

Take with food

Amprenavir (Agenerase)

600 mg + RTV 100 mg BID1200 mg + RTV 200 mg QD

Available as 50 mg capsules and liquid

Liquid contains propylene glycolAvoid concomitant with ritonavir liquid

Protease Inhibitors

Drug Dose Pill burden Dosing info

Lopinavir/ritonavir (Kaletra)

400mg/100mg QD400mg/100mg BID

4 tabs QD2 tabs BID

Take with or without food

Atazanavir(Reyataz)

400mg QD

300mg + RTV 100mg QD

2 (200mg) QD

2 (150mg) + 1 (100mg) QD

Take with food; avoid PPI

Tipranavir(Aptivus)

500mg + RTV 200mg BID 2 (250mg) caps +2( 100mg cap) bid

Take with food

Darunavir(Prezista)

600mg + RTV 100mg BID 2 (300mg) tabs+ 1 (100 mg) caps BID

Take with food

Protease InhibitorsDrug Side

EffectsBioavailability/Protein Binding

Metabolizingenzymes

Saquinavir GI intolerance 4%/98% 3A substrate

Nelfinavir diarrhea 20-80%/99% P450 inhibitor/inducer/ substrate

Indinavir Nephrolithiasis; GI intolerance

30%/60% 3A substrate

Fosamprenavir GI symptoms, rash

Poor/90% 3A inducer/ substrate

Lopinavir/ritonavir GI symptoms, rash

Poor/99% 3A inhibitor/ substrate; 2D6 inhibitor

Atazanavir ↑bilirubinemia good/86% 3A and UGT1A1 inhibitor; 3A substrate

Darunavir N/V, rash, HA ----------- 3A inhibitor, 3A substrate

Tipranavir GI symptoms↑ LFTs, lipids,

rash

Unknown/99% 3A inhibitor/ substrate

Entry Inhibitors Fusion inhibitors [Fuzeon (enfuvirtide, T20)]

Attachment Inhibitors

Chemokine co-receptor antagonists

See Kilby and Eron, NEJM 2003;348:2228-38

Enfuvirtide (T-20) (Fuzeon)

FDA-approved fusion inhibitor; 36 AA peptide

Dose: 90 mg sc bid side effects:

injection site rxn (common); hypersensitivity reactions (uncommon); eosinophilia (10% >700; 2% >1400); ↑increased risk of pneumonia on phase III

studies

Enfuvirtide: Injection Site Reactions

• Painful• Erythematous• Nodular• Pruritic• Last for ~7 days• DO NOT REINJECT

SITE UNTIL NODULE DISAPPEARS!!!!

Common Opportunistic Infections

CD4 cell count Opportunistic Infection

< 500 cells/mm3 Tuberculosis

VZV

HSV

Recurrent bacterial infections

< 250 cells/mm3 Thrush

< 200 cells/mm3 PCP

< 100 cells/mm3 Toxoplasmosis gondii

< 50 cells/mm3 Cryptococcus meningitis

MAC

CMV

Pneumocystis jiroveci (PCP)

• Ubiquitous fungus• Historic mortality of 20-40% in HIV pt• Incidence has declined since HAART• Clinical Presentation

– DOE/SOB fulminate pneumonia– Fever– Nonproductive cough– Poor oxygenation status/respiratory acidosis

Pneumocystis jiroveci (PCP)Treatment of

ChoiceAlternative Discontinue

Primary Prophylaxis

Bactrim DS QD

Dapsone 100 mg QD

Atovaquone 750 mg BID

CD4 > 200 x 3 months

Secondary Prophylaxis

Bactrim DS QD

Dapsone 100 mg QD

Atovaquone 750 mg BID

CD4 > 200 x 3 months

Treatment Bactrim 15 mg/kg in divided doses

Moderate-severe

•Pentamidine 4 mg/kg IV QD

Mild-moderate

•Dapsone 50 mg + TMP 15 mg/kg in divided doses

•Primaquine 30 mg base + clindamycin 600 mg Q6h

Treat for 21 days followed by secondary prophylaxis

If PaO2 < 70 initiate prednisone 40 mg BID x 5 days; 40 mg QD x 5 days; 20 mg QD x 11 days

Mycobacterium Avium Complex

• Non-TB Mycobacterium spp• Occurs in highly immunocompromised patients• Clinical symptoms depend on organ system

involved– General fever, malaise, lymphadenoapthy– Pulmonary SOB, cough, DOE– GI colitis, abdominal pain– Bone anemia, bone marrow suppression

MACTreatment of

ChoiceAlternative Discontinue

Primary Prophylaxis

Azithromycin 1200 mg Q week

Clarithromycin 500 mg BID

CD4 count >100 cells/mm3

Secondary Prophylaxis

N/A N/A N/A

Treatment Clarithromycin 500 mg BID + ethambutol 20 mg/kg QD ± rifabutin 300 mg QD*

Fluoroquinolone

Amikacin

D/C therapy if a minimum of 12 months of MAC therapy, pt is asx and CD4 count > 100 cells/mm3 for at least 6 months

Rifabutin has drug interactions with PI; dose reductions may be necessary

Toxoplasmosis gondii

• Protozoa causing reactivation disease– 15% of adults are toxoplasmosis IgG positive– 90% of HIV-infected patients are IgG positive

• Clinically presented as an encephalitis with ring-enhancing lesions on CT/MRI– Seizures, altered MS, coma– Multiple lesions

• Often hard to clinically differentiate CNS lymphoma and toxoplasmosis

Toxoplasmosis gondiiTreatment of Choice Alternative Discontinue

Primary Prophylaxis

Bactrim DS QD •Dapsone 50 mg QD + pyrimethamine 50 mg Q week + leucovorin 25 mg Q week

•Atovaquone 1500 mg QD

CD4 >200 x 3 months

Secondary Prophylaxis

Bactrim DS QD •Dapsone 100 mg QD

•Atovaquone 750 mg BID

CD4 > 200 x 6 months

Treatment Pyrimethamine 75 mg QD + sulfadiazine

1-2 g Q6h + leucovorin 25 mg QD

(clindamycin 600 mg IV q6h may be used in sulfa allergic patients)

• Atovaquone 750 mg BID

• Atovaquone + Pyrimethamine 75 mg QD

+ leucovorin 25 mg QD

• Atovaquone + sulfadiazine 1-2 g Q6h

+ leucovorin 25 mg QD

Treatment for at least 6 weeks; rescan to determine CT/MRI improvement

Bactrim 10 mg/kg IV in divided doses in patients who cannot take PO formulations

Cryptococcus• Fungus- yeast• Commonly presents as meningitis or menigoencephalitis

– Seizures– Altered MS– HA, fever

• CSF results– High opening pressure– Lymphocyte predominance– Normal/slightly low glucose– Mild elevation of protein– Organism growth

• Cryptococcus titers

CryptococcusTreatment of

ChoiceAlternative Discontinue

Primary Prophylaxis

None None N/A

Secondary Prophylaxis

Fluconazole 200 mg CD4 > 100-200 x 6 months

Treatment Amphotericin B 0.7 mg/kg + flucytosine 100 mg/kg/d x 14 days

Fluconazole 400 mg QD x 6 weeks

Fluconazole 800 mg QD

6 Rules to Live By1. Per Gretchen- your job is not to screw these

patients up (she will hunt you down!)2. 2 ART is a bad idea; 1 ART is a REALLY bad

idea; Combination therapy is a GREAT IDEA3. The ID clinic note can help you4. Nexium (aka Purple crack) is WHACK

- SIGNIFICANT interaction with atazanavir

5. If Dr. Van der Horst is your attending, do not pass go, do not collect 200 dollars and just follow instructions

6. When in doubt, call 216-0626