Human Immunodeficiency Virus

Deanne Tabb, PharmD, MT (ASCP)

Infectious Disease Specialist

Objectives

• Review epidemiology and transmission of HIV• Describe the clinical presentation of HIV

infection• Discuss diagnostics for HIV identification• Interpret surrogate markers commonly utilized in

HIV care• Construct the lifecycle of HIV• Identify criteria for initiating antiretroviral therapy

Objectives

• Discuss goals of therapy

• Review recommendations for initial antiretroviral selection

• Highlight agents used for PEP

• Review pharmacologic therapy

• Review newer agents in the pipeline

• Examine opportunistic infection prophylaxis and treatment

Adult and Children estimated to be living with HIV/AIDS

WHO UNAIDS AIDS epidemic update, December 2005

AIDS Rates2004

Modes of TransmissionRisk of transmission after single exposure to HIV

infected source

Needle Sharing

Percutaneous (occupational exposure)

Receptive anal intercourse

Insertive anal intercourse

Receptive vaginal intercourse

Insertive vaginal intercourse

Exposure

0.67%

0.3 – 0.4%

0.1 – 3%

0.03%

0.08 – 0.2%

0.03 – 0.09%

Risk/ 10,000 exposures

Am J Med 1999; 106:323. MMWR 1998; 47(RR17);1-14.

Virus Characteristics

• Retrovirus• > 109 to 1010 virus particles produced on a daily

basis• Half-life of infected cell approximately 1-2 days• 1/3 to ½ of circulating virus replaced each day

• HIV lacks 3’-5’ exonuclease proofreading capability• Cannot repair defects in genetic code• Estimated 1 error per viral genome transcribed

Goals of Therapy

• Reduce HIV-related morbidity/mortality

• Improve quality of life

• Restore and preserve immunologic function

• Maximally and durably suppress viral load– Goal < 50 copies HIV RNA/ mL (undetectable)– Prevention of viral resistance

Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents.

(DHHS) Updated October 2006.

Definition of Failure

• Virologic failure: – Confirmed HIV RNA level > 50 c/mL after 48-weeks

HAART (ultra-sensitive assay) – HIV RNA level > 400 c/mL after 24-weeks of HAART

• Immunologic failure: failure to increase CD4 count by 25-50 cells/mm3 above baseline over the first year of therapy

• Clinical failure: occurrence of HIV related events > 3 months after starting ART

An Update and Review of Antiretroviral Therapy Pharmacotherapy 2006;26(8):1111-33

Natural History/Time Course• Acute retroviral syndrome symptoms present in 40-90%• Typically occur within 5-30 days of exposure• Typically resolves within 14 days of onset• Severity ranges from mild to severe• Symptoms

• Malaise, myalgia (54%), night sweats, fever (96%), headache (32%), N/V/D (~30%), neurologic (12%)

• Signs• Cervical lymphadenopathy (74%), mucocutaneous ulceration,

rash (70%), weight loss (13%), oral candidiasis (12%)

Natural History/Time Course

• Approximately 2.6 days from initial cellular infection to release of formed virus particles from target cell

• After primary infection, plasma viremia (HIV RNA) markedly increases• Peaks within 30 days of exposure

• Latency of virus in lymph nodes– Asymptomatic for years– Median time from initial infection to an AIDS diagnosis

8 years

Surrogate Markers

• Plasma RNA (PCR)

• CD4 cell counts

CD4 Cell count % CD4

> 500/mm3 > 29

200 – 500/mm3 14-28

< 200/mm3 <14

Natural History in Patient Without HAART

Ann Intern Med 1996;124:654

Immune Defense

• The major target of HIV is the CD4 cell

• High variability in CD4 rate of decline– Rampant loss to < 200 within 2 years– CD4 > 500 at > 8yrs (chronic nonprogressors)– Average decline CD4 50 mm3 /yr

– Rate of decline is inversely proportional to viral clearance by cytotoxic T cells (CD8)

Diagnosis

• Enzyme-linked Immunosorbent Assay (EIA)• Detects antibodies against HIV-1• >99 % sensitive and >98% specific• Optimal time to perform 2 months post-exposure• Positive EIA repeated

• Confirmatory Western Blot• Positive confirmatory test with EIA +• Negative confirmatory test, most likely not infection

– Repeat confirmatory test– Re-test in 3-6 months– Perform viral load assay

Factors That Influence Rate of Progression

• Cytotoxic T-lymphocyte response

• Defective virus

• Genetic susceptibility of receptor sites

• Age - Duration of survival is inversely correlated with age

• Major Histocompatibility genes

• Plasma HIV RNA level (set point)

PrognosisProgression to AIDS or Death

0 - 49 cells/mm3

50 - 99 cells/mm3

100 - 199 cells/mm3

200 - 349 cells/mm3

> 350 cells/mm3

16 % 20%

12% 16%

9.3% 12%

4.7% 6.1%

3.4% 4.4%

CD4 T cell count

3 yr-probability

VL <105 VL >105

HIV Life Cycle and Drug Targets

Reverse Transcriptase Inhibitors

Integrase Inhibitors

Protease Inhibitors

Entry Inhibitors

MOA

• NRTIs– interfere with reverse transcriptase thus inhibiting viral

replication

• NNRTIs– bind directly to reverse transcriptase halting the

addition of DNA to the growing chain

• PIs– interfere with the enzyme protease which is

responsible for cleaving viral precursors necessary for new viral replication

MOA

• Entry and Fusion Inhibitors– bind to gp41 subunit of the viral envelope glycoprotein

preventing conformational changes required for fusion of viral and cellular membranes (blocking HIV from entering human cells)

• Integrase Inhibitors– Inhibit viral integration into host DNA

• CCR5 coreceptor antagonists– block viral entry

• Maturation Inhibitors– block HIV maturation by inhibiting the final step in the

processing of the HIV Gag protein

Pretreatment Evaluation

• Complete medical history, physical examination, lab evaluation– Presence of co-

infection– Assess overall health

status

• Optional tests:– GC/Chlamydia– x-ray if indicated

• Laboratory evaluation– HIV antibody test– CD4 T cell count– Plasma HIV RNA– CBC, BMP, LFT’s,

U/A, RPR or VDRL, PPD, Toxo IgG, Hepatitis panel, PAP smear for women, fasting glucose and lipids, viral genotype

Utilization of Drug Resistance Testing in Clinical Practice

• Persons with acute HIV infection

• Persons with chronic HIV infection

• Genotypic analysis preferred for naïve

• Suboptimal viral load reduction

• In cases of virologic failure– Should perform while patient on failing

regimen (or within 4 weeks of discontinuation)– Viral load > 1,000 copies/mL

Methods to Achieve Readiness to Start HAART

• Patient-related:– Negotiate plan/regimen– >2 visits ensure readiness– Recruit family/friends– Use memory aids– Address drug/ETOH abuse

mental illness

• Provider/Team-related:– Educate: goals, pills, food

effects, side effects– Assess adherence– Ensure off-hour access– Utilize full health care team –

ensure medication refills

• Provider/Team-related cont:– Consider impact of new

diagnosis on adherence– Provide team training updates– Monitor adherence and

intensify when needed

• Regimen-related:– Avoid drug interactions– Simplify regimen– Inform patient about SE– Anticipate and treat SE

Pocket Guide Adult HIV/AIDS Treatment January 2006; The Johns Hopkins AIDS Service

When to Start HAARTClinical Category CD4T Cell Count Plasma HIV RNA Recommendation

AIDS-defining illness or severe

symptomsAny value Any value Treat

Asymptomatic

CD4 T cells

< 200/mm3 Any value Treat

Asymptomatic

CD4 T cells

> 200/mm3 but

< 350/mm3

Any value

Treatment should be offered following full

discussion of pros/cons

Asymptomatic

CD4 T cells

> 350/mm3

> 100,000 Most clinicians recommend

deferring therapy, but some will treat

Asymptomatic CD4 T cells

> 350/mm3

< 100,000 Defer therapy

Considerations for Selecting an Initial Regimen

• Factors to consider include• Comorbidities

• Liver/renal disease• Depression• Cardiovascular disease• Diabetes mellitus

• Pregnancy status• Adherence

• Pill burden• Dosing regimens• ADEs• Food restrictions

• Drug interactions• Resistance mutations

Pharmacotherapy 2006;26(8):1111-33. JAMA, August 16, 2006 – vol 296, No. 7.

HAART

• Highly Active Antiretroviral Therapy• Triple drug regimen, combining agents

from different classes• 2 Nucleoside Reverse Transcriptase Inhibitors

(NRTI)PLUS• Non-Nucleoside Reverse Transcriptase

Inhibitors (NNRTI) OR• Proteus Inhibitor (PI)

Currently Available Antiretroviral Therapy

• Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

• Efavirenz (EFV)• Nevirapine (NVP)• Delavirdine (DLV)

• NucleoSIDE Reverse Transcriptase Inhibitors (NRTIs)

– Zidovudine (AZT)– Lamivudine (3TC)– Abacavir (ABC)– Didanosine (ddI)– Stavudine (D4T)– Zalcitabine (ddC)– Emtricitabine (FTC)

• NucleoTIDE Reverse Transcriptase Inhibitors (NRTI)

• Tenofovir (TDF)

• Protease Inhibitors (PIs)• Ritonavir (RTV)• Amprinavir (APV)• Indinavir (IDV)• Nelfinavir (NFV)• Saquinavir (SQV)• Lopinavir/Ritonavir (LPV/r)• Atazanavir (ATV)• Fosamprenavir (fAPV)• Tipranavir (TPV)• Darunavir (DRV)

• Fusion Inhibitors• Enfuvertide (T-20)

Starting RecommendationsTreatment-naive

Column A Column B

NNRTI PI 2-NRTIPreferred

( order)

Efavirenz Atazanavir + ritonavir (AIII)

(AII) Fosamprenavir +ritonavir BID (AII)

Lopinavir/ritonavir BID (AII)

Tenofavir/emtracitabine (AII)

Zidovudine/lamivudine (AII)

Alternative

( order)

Nevirapine Atazanavir (unboosted) (BII)

(BII) Fosamprenavir (unboosted) (BII)

Fosamprenavir +ritonavir q Day (AII)

Lopinavir/ritonavir q Day (BII)

Abacavir/lamivudine (BII)

Didanosine + lamivudine (BII)

Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents.

(DHHS) Updated October 2006.

Special Considerations

Hepatitis Co-infection

• HBV– Tenofovir, Lamivudine, Emtricitabine– Hepatocellular inflammation “Flares”– LMV or FTC add entecavir– In early HIV, If treating HBV only: adefovir or

entecavir

• HCV– ART excluding ddI with ribavirin (↑LA/PA)

Pregnancy

• Avoid ART during 1st trimester• Preferred:

– AZT + 3TC or FTC (nRTIs) +– NFV 1,250 mg po bid or SQV/r 800/100 (PI)

• Do not use – Efavirenz – teratogenic – Nevirapine - ↑ hepatotoxicity in CD4 > 250 - caution

• Prevention of perinatal transfer– Intra-partum: AZT 2 mg/kg; 1 mg/kg/h until delivery– Post-partum: (Infant) AZT syrup 2 mg/kg po q6h or

1.5 mg/kg IV q6h x 6 wks

Pocket Guide Adult HIV/AIDS Treatment January 2006; The Johns Hopkins AIDS Service

HCW PEP

• Initiate as soon as possible• 2-drug regimens

– Basic: 3TC or FTC plus AZT, d4T or TDF– Expanded: basic + LPV/r (alt: ATV, FPV,

IDV/r, SQV/r or NFV– SE management and counseling sheets

• Expert consultation• HCW serology: Baseline, 6 wk, 12 wk, 6

mo +/- 12 mo

NucleoSIDE Reverse Transcriptase

Inhibitors

Zidovudine (AZT, ZDV)/Retrovir®FDA approved 1987

Formulations Normal

dose

Food Requirements

Dose adjust T ½

Intracellular T1/2

Caps 100 mg

Tabs 300 mg

IV 10 mg/mL

Syrup 10 mg/mL

300 mg PO bid or 200 mg PO tid

None Crcl < 10 and HD: 300 mg Q Day

1.1 hrs

7 hours

• Unique AE: BM suppression (↑ MVC anemia or neutropenia)

• Class AE: GI intolerance, HA, LA, hepatic steatosis

• Combinations: Combivir (AZT+3TC); Trizivir (AZT+3TC+ ABC)

Didanosine (ddI)/ Videx EC®FDA approved 1991

Formulations Normal

dose

Food Requirements

Dose adjust T ½

Intracellular T1/2

> 60 kg 400 mg PO/day

Take ½ hr before or 2 hr after meal (food ↓ bioavial 55%)

< 60 kg 250 mg PO/day With TDF 200 mg/day

1.1 hrs

7 hours

• Unique AE: pancreatitis, peripheral neuropathy

• Class AE: Lactic acidosis (LA), hepatic steatosis

• Avoid combinations: with stavudine (d4T) due to ↑AE

Capsules 125, 200, 250, 400

Zalcitabine (ddC)/ Hivid®

Formulations Normal

dose

Food Requirements

Dose adjust T ½

Intracellular T1/2

0.75 mg po tid

NoneCrcl < 50; 0.75 bid; <10 and HD 0.75/day

1.2 hr

• Unique AE: Peripheral neuropathy, stomatitis

• Class AE: Lactic acidosis (LA), hepatic steatosis, pancreatitis

• Not routinely used due to TID dosing/peripheral neuropathy

• Avoid combination with d4T (↑ peripheral neuropathy)

Tabs: 0.375, 0.75 mg

Stavudine (d4T) Zerit®

Formulations Normal

dose

Food Requirements

Dose adjust T ½

Intracellular T1/2

> 60 kg 40 mg po bid;< 60kg 30 mg po bid

None Crcl < 50 adjust dose based on weight

1.0 hr

7.5 hr

• Unique AE: ↑ LA and hepatic steatosis, or lypodystrophy

• Class AE: peripheral neuropathy, pancreatitis

• Avoid combination wit ddI, antagonistic with AZT

Capsules 15,20,30, 40

1mg/ml oral solution

Lamivudine (3TC)/ Epivir®

Formulations Normal

dose

Food Requirements

Resistance T ½

Intracellular T1/2

150 mg po bid or 300 mg po/day

None 5-7 hr

18 hr

• Class AE: LA with hepatic steatosis

• Approved for treatment of HepB; dose 100 mg po/day

• Combinations:

• Combivir 3TC + ZDV Epzicom 3TC + ABC

• Trizivir 3TC + ZDV + ABC

Tabs: 150, 300

10 mg/ml oral solution

Combivir

M184V

Abacavir (ABC)/ Ziagen®

Formulations Normal

dose

Food Requirements

Dose adjust T ½

Intracellular T1/2

300 mg po bid or 600 mg po/day

NoneETOH ↑ ABC 41%

1.5 hr

12-26 hr

• Unique AE: hypersensitivity (fever, rash, N/V/D, fatigue, malaise, dyspnea, cough)

• STOP taking immediately; do not re-challenge, fatal anaphylaxis

• Class AE: GI intolerance, HA, LA, hepatic steatosis, lipodystrophy

Tabs: 300 mg

20 mg/ml oral solution

Emtricitabine (FTC) Emtriva® FDA approved 2003

Formulations Normal

dose

Food Requirements

Dose adjust T ½

Intracellular T1/2

200 mg po/day or 240 mg po/day solution

None 10 hr

>20 hr

• Unique AE: hyperpigmentation of palms and soles

• Approved for HepB

• Combinations:

• Truvada FTC + TDF (one tablet/day)

• Atripla EFV + FTC + TDF (FDA approved first once-a-day 3-drug combination tablet – July 2006)

Caps: 200 mg

10 mg/ml oral solution

Crcl < 50: 200 mg/48h; <30 200 mg/72h; < 15 or HD 200 mg/96h

Truvada

NucleoTIDE Reverse Transcriptase

Inhibitor

Tenofovir (TDF)/ Viread® FDA approved 2001

Formulations Normal

dose

Food Requirements

Dose adjust T ½

Intracellular T1/2

300 mg po/day None 17 hr

>60 hr

• Unique AE: RI, ARF

• Class AE: LA, hepatic steatosis, HA, D/N/V

• Combinations:

• Truvada FTC + TDF (one tablet/day)

• Atripla EFV + FTC + TDF (FDA approves first once-a-day 3-drug combination tablet – July 2006)

Tabs: 300 mg Crcl < 50: 300 mg/48h; <30 300 mg/2 x wk; HD 300 mg/ wk

Viread

Non-Nucleoside Reverse Transcriptase

Inhibitors

Efavirenz (EFV)/ Sustiva® FDA approved 1998

Formulations Normal

dose

Food Requirements

Dose adjust T ½

Intracellular T1/2

600 mg

po qhs

Empty stomach preferred; high fat meal ↑ by 39 and 79%

40-55 hrs

• Unique AE: Rash, morbilliform (15-27%) – discontinuation not required unless blistering and desquamation present (1.7%). Onset ~ 11 days, duration ~ 14 days. CNS AE: confusion, dizziness, insomnia, abnormal dreams, hallucinations, nightmares, depersonalization (transient usually subside 2-4 weeks following initiation); False-positive cannabinoid test

• Class AE: GI intolerance, HA, ↑LFTs

• Do not use in pregnancy; teratogenic

• Combination: Atripla TM – with FTC + TDF

Caps: 50, 100, 200 mg

Tabs: 600 mg

CYP 3A4 inducer/inhibitor;

Hepatic metabolism, renal and hepatic

excretion

Efavirenz

Nevirapine (NVP)/ Viramune®

Formulations Normal

dose

Food Requirements

Dose adjust T ½

Intracellular T1/2

200 mg po/day x 14 days then 200 mg po/bid

None 25-30 hr

• Unique AE: Maculopapular red rash on face, trunk, limbs (17%), and fatal hepatotoxicity (↓ incidence by titrating dose)

•↑ incidence hepatotoxicity in women with CD4 count >250

• 7% require discontinuation

• Class AE: GI intolerance and HA

Tabs: 200 mg

10 mg/ml oral suspension

CYP 3A4 inducer (autoinduction)

Nevirapine

Delavirdine (DLV) Rescriptor®

Formulations Normal

dose

Food Requirements

Dose adjust T ½

Intracellular T1/2

400 mg po tidNone; separate from antacids by 1 hour

5.8 hrs

• Unique AE: Rash (18%), maculopapular, red on trunk and arms. Usual duration = 2 weeks, discontinuation not required unless accompanied by fever, swelling, mucous membrane involvement or arthralgias.

• Class AE: GI intolerance, HA, ↑LFTs

• Dose adjustments required when used with PIs

• Not routinely used in clinical practice

Tabs: 100,

200 mg

100 mg tabs in > 3oz water to make slurry

CYP 3A4 inhibitor; Hepatic metabolism,

renal and hepatic excretion

Protease Inhibitors

PI Considerations

• 10 PIs• Factors: dosing frequency, food and fluid

requirements, pill burden, drug interaction potential, baseline hepatic function, toxicity profile, propensity to cause metabolic abnormalities

• Ritonavir: potent CYP450 3A4 inhibitor– Exploited for PK properties w/other PIs– Increased level of AE when used as single PI

PI Class Considerations

• Class AE– Significant GI

intolerance– HA– ↑ Tg & TChol– Hyperglycemia– Lipodystrophy– Hepatotoxicity, ↑LFTs

• Contraindications– Rifampin– Midazolam, triazolam– Simvastatin, lovastatin– St. John’s wart

Amprenavir (APV)/ Agenerase®

Formulations Normal

dose

Food Requirements

Dose adjust Half-life

1400 mg bid oral solution

w/ or without food; avoid high

fat meal

(↓AUC 21%)

7.1-10.6 hrs

• Unique AE: GI intolerance, hepatotoxicity, oral parethesias, rash – APV is a sulfonamide; watch for sulfa allergies

• Oral solution contains propylene glycol: contraindicated in pregnant women, children < 4 years old, patients with hepatic or renal failure, and patients treated with disulfuram or metronidazole

• Caution: anticonvulsants, methadone

Caps: 50 mg

15 mg/mL oral solution(not interchangeable)

Not recommended in patients with hepatic or renal

failure

Fosamprenavir (fAPV) LexivaTM

FDA approved 2003

Formulations Normal

dose

Food Requirements

Dose adjust

1,400 mg bid

None

H2 blockers and PPIs may ↓ absorption

• Adverse effects: GI intolerance, rash (17%), HA, hyperlipidemia, ↑LFTs, hyperglycemia, fat maldistribution, possible increased bleeding episodes in patients with hemophilia

• 700 mg fosamprinavir = 600 amprenavir

• Coadministration with EFV use fAPV boosted regimen only

• PI-experienced patient (q day dosing not recommended)

• Caution: see amprenavir

Tabs:

700 mg

CYP 3A4 inh/sub/ind

Boosted should not be used w/ hepatic impairment; not

recommended in severe

liver disease

Boosted

dose

1,400 mg + 200 mg RTV q day, fAPV 700 mg +

100 mg RTV bid

Atazanavir (ATV)/ ReyatazTM

Formulations Normal

dose

Food Requirements

Dose adjust

400 mg q day

Take w/ food

↑ AUC

Avoid use w/ H2 blockers, PPIs

• Unique AE: ↑ indirect hyperbilirubinemia, jaundice, GI intolerance, rash, ↑ PR interval -1st degree heart block

• Possible increased bleeding episodes in patients with hemophilia

• Neutral effects on lipids and blood glucose compared with other PIs

• Caution: indinavir, irinotecan

Caps: 100, 150, 200 mg

CYP 3A4 inhibitor/substrate

300 mg Q day in liver disease

Boosted

dose

300 mg + 100 mg RTV (w/ TDF or

EFV)

Indinavir (IDV)/ Crixivan®

Formulations Normal

dose

Food Requirements

Dose adjust

800 mg q 8h

Unboosted: take 1h before or 2h after; may take w/ skim milk or

low-fat meal

• Unique AE: nephrolithiasis (ADV crystals); drink > 48 oz. water/day, ↑ indirect bilirubin, dry skin, mouth, eyes, alopecia, metallic taste, hemolytic anemia

• Class AE: GI intolerance, hyperlipidemia, hyperglycemia, fat maldistribution

• Caution: azoles, clarithromycin, oral contraceptives, anticonvulsants

Caps: 200, 333, 400 mg

None in renal

Mild/moderate hepatic insufficiency

600 mg q8h

Boosted

dose

800 mg + RTV 100 or 200 mg

q12h

Lopinavir + Ritonavir (LPV/r)/ Kaletra®

Formulations Normal

dose

Food Requirements

Dose adjust

Two tablets or 5mL bid

Four tablets or 10 mL q day (naïve pts)

Tabs: None

Oral solution: take with food

• Unique AE: GI intolerance, esp. diarrhea with once daily, ↑ LFT’s

• Class AE: Hyperlipidemia (esp. hypertriglyceridemia), hyperglycemia, fat maldistribution, ↑ bleeding episodes in patients with hemophilia

• Caution: rifampin, oral contraceptives, atorvastatin AUC ↑ 6x, pravastatin levels ↑ 33% (no dose change), azoles (max dose 200 mg ketoconazole/day), anticonvulsants, atovaquone

Tabs: 200/50 mg

400/100 mg/5mL (42% alcohol)

No dose adjustments

Dosing Modifications

For tx experienced:

w/ EFV or NVP three tablets

bid

Saquinavir (SQV), Invirase®

Hard gel capsulesFormulations Normal

dose

Food Requirements

T ½

serum

1000 mg + 100 mg RTV bid

Take within 2 hours of a meal

• Adverse Events: GI intolerance (N/D), HA, ↑ LFTs

• Class AE: Hyperlipidemia (esp. hypertriglyceridemia), hyperglycemia, fat maldistribution, ↑ bleeding episodes in patients with hemophilia

• Note: Boosted Invirase better tolerated than Fortavase (no longer available)

• Caution: Dexamethasone, anticonvulsants, methadone, ketoconazole, grapefruit juice, clarithromycin

Tabs: 500 mg

Caps: 200 mg hard gel

1-2 hours

Dosing Modifications

CYP3A4 inhibitor

Nelfinavir (NFV)/ Viracept®

Formulations Normal

dose

Food Requirements

T ½

serum

1,250 mg bid or 750 mg tid

Take with meal or snack

• Adverse Events: diarrhea/loose stools 10-30% (can treat with Psyllium or loperamide),↑ LFTs

• Class AE: Hyperlipidemia (esp. hypertriglyceridemia), hyperglycemia, fat maldistribution, ↑ bleeding episodes in patients with hemophilia

• Caution: atorvastatin ↑ 74%, rifampin, methadone, anticonvulsants, oral contraceptives

• Note: safe in pregnancy

Tabs: 250 mg or 625 mg

Powder: 50 mg/mL

3.5 – 5

hours

Dosing Modifications

CYP3A4 inhibitor and

substrate

Tipranavir (TPV)/ Aptivus®

FDA approved 2005

Formulations Normal

dose

Food Requirements

Storage

500 mg + 200 mg RTV bid

Take with food

• Adverse Events: Hepatotoxicity, skin rash (TPV has a sulfonamide moiety), Rare cases of fatal and nonfatal intracranial hemorrhages

• Caution: atorvastatin ↑ 9-fold, rifampin, methadone, anticonvulsants, oral contraceptives, no data with azoles – do not exceed 200 mg daily of azole, TPV contains alcohol avoid use of flagyl/disulfuram

• Miscellaneous drug interactions: Abacavir, AZT, loperamide, antacids

• Note: new option for treatment experienced patients

Caps: 250 mg Refrigerated

Room temp: 60 days

Dosing Modifications

CYP3A4 inhibitor and

substrate

Darunavir (DRV) PrezistaTM

Formulations Normal

dose

Food Requirements

T ½serum

600 mg + 100 mg RTV bid

Take with food

• Adverse Events: Skin rash (7%) – DRV has a sulfonamide moiety (SJS/erythema multiforme), GI intolerance N/D, HA, ↑ LFTs,

• Caution: atorvastatin use lowest possible dose, rifampin, methadone, anticonvulsants, oral contraceptives, no data with azoles – do not exceed 200 mg daily of azole, Paroxetine & setraline AUC ↓

• Note: new option for treatment experienced patients

Tabs: 300 mg 15 hours

Dosing Modifications

CYP3A4 inhibitor and

substrate

Entry Inhibitors

Enfuvirtide (T20)/ FuzeonTM

• Dose: 90 mg (1mL) SC bid to upper arm, abdomen, anterior thigh

• Storage: reconstituted solution should be refrigerated and used within 24-hours

• Adverse Events: – local injection site reactions in all patient (~3% require

discontinuation) – pain, erythema, induration, nodules, cysts, pruritus, ecchymosis

– ↑ rate of bacterial pneumonia– Hypersensitivity reaction (<1%); do not rechallenge

Maraviroc (Selzentry) FDA approved August 2007

• Treatment experienced CCR5-tropic MDR-HIV-1 strains • Considerations: tropism testing, not recommended in

dual/mixed CXCR4-tropic HIV-1, pediatrics, and treatment naïve

• Dosing:– 300 mg bid– 150 mg bid if given with PIs except tipranivir/ritonavir, delavirdine,

ketoconazole, itraconazole, clarithromycin, and telithromycin– 600 mg bid if given with efavirenze, rifampin, carbamazepine,

phenobarbital, and phenytoin• Adverse Events:

– Cough, fever, rash, abdominal pain, respiratory infections, rhinitis, dizziness, edema, sleep disorder

– Serious events < 2%: hepatic cirrhosis or failure, viral meningitis, osteonecrosis, rhabdomyolitis

– Lab abnormalities: ↑ bilirubin, amylase/lipase, AST/ALT

Newer Agents Coming to Market

Investigational Agents

• Nucleoside Reverse Transcriptase Inhibitors– AVX754 (apricitabine)– Elvucitabine– KP-1461– Racivir– Fozivudine tidoxil

• Non-nucleoside Reverse Transcriptase Inhibitors– TMC125 (etravirine)– TMC278 (rilpivirene)

aidsinfo.nih.gov

Investigational Agents

• Entry and Fusion Inhibitors– AMDO70– PRO 140– Peptide T– SCH-D (vicriviroc)– TNX-355– BMS-488043– PRO 542

• Integrase Inhibitors– GS 9137– MK-0518 (raltegravir)

• CCR5 coreceptor antagonists (Phase I)

• Maturation Inhibitors (Phase II)

aidsinfo.nih.gov

Agents not Recommended as Initial Therapy

Drug Reasons for not recommendingDarunavir (boosted) Lack of data in treatment-naïve

Delavirdine Inferior virologic efficacy; tid dosing

ddI + tenofovir ↑rate of virologic failure, rapid selection of resistance, potential for CD4 decline

Enfuvirtide No trial experience in naïve, SC bid

Indinavir (unboosted) Tid with meals; fluid requirements

Indinavir (boosted) High incidence of nephrolithiases

Ritonavir mono PI High pill burden, GI intolerance

Saquinavir(unboosted) ↑ pill burden, Inferior virologic efficacy

Tipranavir (boosted) Lack of data in treatment-naïve

Zalcitabine-AZT Inferior virologic efficacy, ↑ AE than alt

Agents not Recommended at Any Time

Drug Reasons for not recommendingMonotherapy NRTI or NNRTI

Rapid development of resistance

Dual-NRTI Rapid development of resistance

Triple NRTI ↑ early virologic non-responseAtazanavir +Indinavir Additive hyperbilirubinemia

DDI + stavudine ↑ LA with hepatic steatosis +/- pancreatitis in pregnancy (fatal)

Efavirenz in pregnancy TeratogenicEmtricitabine + 3TC Similar resistance profile3TC + Zalcitabine In vitro antagonismD4T + Zalcitabine Additive peripheral neuropathy

D4T + AZT Antagonistic effect on HIV-1

Changing Therapy

• Toxicity/intolerance• Single-substitution naïve

patients• Stop all• Symptomatic management• Lipid lowering agents• Structured treatment

interruptions

• Inconvenience

• First regimen failure– Ensure 2 preferably 3

active agents

• Multiple regimen failure – If 2 active agents not

available continue current regimen

– Investigational agents– Lamivudine/emtricitabine

retain some activity even when resistant (M184V or L44I substitution)

Pharmacotherapy 2006;26(8):1111-33. JAMA, August 16, 2006 – vol 296, No. 7.

Activity of ART with Mutations

ART Mutation ResultNRTIs Q151M

Q151M + M184V

T69S insertion + TAMs

T69S + M184V

Multiple drug resistance, sensitive to LMV and tenofovir

May be sensitive to only tenofovir

Multidrug resitance likely

May have activity against tenofovir

Lamivudine-emtricitabine

M184V

TAMs

Resistant

Sensitive

Stavudine- zidovudine

TAMs = M41L, D67N, K70R/Q/N, T215F/Y

Decreased activity with increased number of mutations

Abacavir

Tenofovir

L74V

TAMs

Tams + M184V

K65R

K65R + M184V

Resistant

Decreased activity with ↑ number of mutations

Activity may be resensitized with M184V

Resistant

Activity may be resensitized to tenofovir, AZT, D4T

PI L90M, L10I, 154V, M46I, 184V

Primary mutations, ↑ mutations = MDR

NNRTIs K103N Class resistance

An Update and Review of Antiretroviral Therapy Pharmacotherapy 2006;26(8):1111-33

Salvage Therapy

• Structured treatment interruptions

• Multi-drug Rescue– Drug selection based

on past exposure and resistance

– Give as many as possible

– Foscarnet induction

• Mega-HAART– Typically 5-9 drugs

• Boosted PI (not 3)• 1-2 NNRTIs• Several NRTIs• hydroxyurea

• Adherence > 95% required

3rd International Workshop on Salvage Therapy for HIV infection HIV/AIDS eJournal 6(3),2000

Opportunistic Infections in HIV

Frequency of Initial AIDS-Defining Diagnosis

Pneumocystis Jirvoveci 42 75-85

HIV wasting syndrome 11 70-90

Candida esophagitis 15 20-30

Kaposi’s sarcoma 11 15-25

HIV-associated dementia 4 40-70

Disseminated CMV 4 80-90

Toxoplasmosis encephalitis 3 5-15

Disseminated MAC 5 30-40

Lymphoma 4 3-5

Chronic mucocutaneous herpes simplex 1 10-25

Cryptococcus meningitis - 8-12

Cryptosporidiosis 2 5-10

Tuberculosis 5 4-20

% among all without proph1997 %

Prevention of OI

TB (latent) PPD + (> 5mm) INH 300 mg/day

+ pyridoxin 50 mg/day

PCP CD4 < 200/mm3 TMP-SMX 1 DS or SS/day

or CD4% <14, thrush

Toxoplasmosis CD4 < 100/mm3 TMP-SMX 1 DS/day

+ anti-Tox IgG

MAC CD4 < 50/mm3 Azithromycin 1200 mg/wk

Clarithromycin 500 mg bid

Varicella Exposure to VZIG 6.25 mL IM < 96 hr

chickenpox/zoster

Disease Indication Preferred Regimen

Pocket Guide Adult HIV/AIDS Treatment January 2006; The Johns Hopkins AIDS Service

OI TreatmentPCP Acute therapy

TMP-SMX 15-20 mg TMP/kg/day IV

divided q6-8h or same dose PO x 21

days

Chronic maintenance therapy

TMP-SMX 1-DS or SS PO/day

Alt: Dapsone 100 mg/day

Dapsone 50 mg/day +

pyrimethamine 50 mg and

leukovorin 25 mg PO q/wk

Dapsone 200 mg + pyremethamine

75 mg + leukovorin 25 mg PO/wk

Pentamidine aerosole 300 mg/mo

Atovaquone 1,500 mg PO/day

TMP-SMX 1-DS TIW

Alternatives

For severe PCP:

Pentamidine 4mg/kg IV q/day

Mild-mod:

Dapsone 100 mg PO q/day + TMP 15 mg/kg/day PO (divided tid)

Primaquine 15-30 mg PO q/day + CD 600-900 mg IV q6-8h or CD 300-450 mg PO q6-8h

Other Issues

Indications for CS

PaO2 <70 mm/Hg

Prednisone 40 mg PO bid days 1-5, then q day days 6-10, then 20 mg q day days 11-21

Secondary prophylaxis can be discontinued when CD4 > 200 cells/uL for > 3 months

TE Acute therapy

Pyrimethamine 200 mg PO x1, then

50 mg (< 60 kg) q/day + sulfadiazine

1,000 (<60 kg) PO q6h + leucovorin

10-20 mg PO q/day

Pyrimethamine (leucovorin) + CD 600 mg IV or PO q6h

CS for focal lesion edema

Secondary prophylaxis can be discontinued ss of TE are gone and CD4 > 200 cells/uL for > 6 months

OI Preferred

Treating OI Among HIV-Infected Adults and Adolescents MMWR Dec 17,2004

OI TreatmentMAC At least 2 drugs as initial therapy

Clarithromycin 500 mg PO bid + ETH 15 mg/kg PO q day

Consider adding a 3rd agent for CD4 < 50, high mycobacterial load, or in absence of ART; Rifabutin 300 mg po/day

Chronic maintenance therapy

Clarithromycin 500 mg PO bid + ETH 15 mg/kg/day +/- Rifabutin 300 mg po/day lifelong until sustained immunity

Alternatives

Azithromycin 500-600 mg po q/day

Alt: 3-4th drug in pts with more severe disseminated disease

Ciprofloxacin 500-750 po bid or

Levo 500 mg po/day or

Amikacin 10-15 mg/kg IV q/day

Other Issues

NSAIDS or CS if IRS

Secondary prophylaxis can be discontinued in patients who

completed 12 mo/tx

remain asymptomatic

CD4 > 100 for > 6 mo

Crypto Acute therapy

Ampho B 0.7 mg/kg IV q/day+ flucytosine 25 mg/kg po qid x 2 weeks followed by fluconazole 400 mg po q/day for 8 weeks or until CSF sterile

Chronic maintenance therapy

Fuconazole 200 mg po q/day

Amphotericin or fluconazole 400 -800 po or IV mg/day for less severe disease

Fluconazole + flucytosine

Therapeutic CSF punctures to ↓ ICP

Secondary prophylaxis can be discontinued if asymptomatic and CD4 > 100-200 cells/uL for > 6 months

OI Preferred

Treating OI Among HIV-Infected Adults and Adolescents MMWR Dec 17,2004

Immune Reconstitution Syndrome

• Occurs with CD4 T cell recovery and improved response to antigens

• Presentation: paradoxical worsening• Onset: <1 week to several months• Incidence: 10-25% of patients on ART• Implicating pathogens: Mycobacterial (33%), C.

neoformans, CMV, HBV, HCV, HIV – severe demyelinating leucoencephalopathy in CNS, BK virus – hemorrhagic cystitis

• Management: treat PCP/TB defer ART 1-3 wks depending on CD4 count or use CS

CID 2004;38:1159-66

Final Considerations

• Review all HAART regimens carefully– Right combinations– Doses– drug-drug/food interactions– adherence

• Consider antiretroviral SE and patient CC• Identify needs for OI prophylaxis• Individualize patients counseling needs• Refer patients to HIV clinic