Human Immunodeficiency Virus Deanne Tabb, PharmD, MT (ASCP) Infectious Disease Specialist
Nov 02, 2014
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