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
Use of resistance testing in selected clinical settings
Indications for Antiretroviral Initiation TREAT >100K c/mL >350 cells/mm 3 Asymptomatic Defer therapy <100K c/mL >350 cells/mm 3 Asymptomatic Offer treatment; pros vs cons Any value 200 to 350 cells/mm 3 Asymptomatic TREAT Any value <200 cells/mm 3 Asymptomatic AIDS TREAT Any value Any value Symptomatic (AIDS) Recommendation HIV RNA CD4 cell count Clinical Category
Antiretroviral Combinations Not Recommended as Initial Therapy
APV (w/ or w/out RTV)
NFV + SQV
↑ pill burden/dosing frequency
Lack of treatment-naïve data
d4T + ddI
RTV 600 mg Q12h
↑ incidence of toxicities
Inferior antiviral activity
ddI + TDF + NNRTI
↑ rate of virologic failure Medication/Regimen Reason for Avoidance
GS 934: Study Design TDF QD FTC QD Efavirenz QD (N = 255) Non inferiority Trial, Primary Endpoint < 400 c/mL at Week 96 Time to Loss of Virologic Response (TLOVR) CBV BID Efavirenz QD (N = 254) Week 144 Stratification by HIV RNA >10,000 c/mL Any CD4 count Adequate Renal and Hepatic Function at baseline FTC/TDF Fixed dose combination tablet was not used Gallant JE, et al. XVI IAC Toronto, Canada, Aug. 13-18, 2006; Abst. TUPE0064. ARV-naïve patients randomized 1:1 Week 144 * FDA-required endpoint, similar to ITT Missing = Failure, Switch = Failure. Requires confirmation for success, used by FDA for presentation in U.S. Prescribing Information of newly approved antiretrovirals 241 Median CD4 (cells/mm³) 233 5.0 Median Viral Load (log 10 copies/mL ) 5.0 37 Age (Median) 36 87% Male 86% Baseline Characteristics
Major inclusion criteria: ART naïve, Any CD4 orHIV RNA >2000 copies/mL Riddler S, et al., XVI IAC Toronto, Canada, Aug. 13-18, 2006; Abst THLB0204 . 753 pts randomized in open label design *Virologic failure defined as early (rebound or lack of suppression by 1 log10) or late (failure to suppress to <200 copies/mL or rebound) **Regimen Completion defined as virologic failure or d/c secondary to any treatment related discontinuation of any component
EFV vs. LPV/r vs. LPV/r + EFV 96 Week Outcomes (ITT) Patient Percent Riddler S, et al. XVI IAC Toronto, Canada, Aug. 13-18, 2006; Abst. THLB0204. EFV vs. LPV: p=0.006 EFV vs. LPV/EFV: p=0.5 LPV vs. LPV/EFV: p=0.13 CD4+ Cell Count Change from BL: +239 vs. +285 vs. +268 (p=0.01) EFV vs. LPV: p=0.003 EFV vs. LPV/EFV: p=0.123 LPV vs. LPV/EFV: p=0.183
Time to Virologic Failure Adjusted p values (threshold for significance <0.016) LPV/EFV vs LPV: 0.13 LPV/EFV vs EFV: 0.5 LPV vs EFV: 0.006 Log Rank P-Values: A vs B p=0.099; A vs C p=0.371; B vs C p=0.004 Regimen Censored Failed Total MEDIAN A – LPV+EFV 177 73 250 - B – LPV+3TC+NRTI 159 94 253 - C – EFV+3TC+NRTI 190 60 250 - Proportion Not Failed Time in Weeks From Randomization Riddler S, et al. XVI IAC Toronto, Canada, Aug. 13-18, 2006; Abst. THLB0204. 0 8 16 24 32 40 48 56 64 72 80 88 96 104 112 120 128 136 144 152 1.0 0.8 0.6 0.4 0.2 0.0 LPV EFV LPV/ EFV
Time to Regimen Completion Proportion Not Failed Time in Weeks From Randomization Adjusted p values (threshold for significance <0.016) LPV/EFV vs LPV: 0.13 LPV/EFV vs EFV: 0.5 LPV vs EFV: 0.02 Log Rank P-Values: A vs B p=0.101; A vs C p=0.708; B vs C p=0.028 Regimen Censored Failed Total MEDIAN A – LPV+EFV 145 105 250 133 B – LPV+3TC+NRTI 126 127 253 106 C – EFV+3TC+NRTI 156 94 250 - Riddler S, et al. XVI IAC Toronto, Canada, Aug. 13-18, 2006; Abst. THLB0204. 0 8 16 24 32 40 48 56 64 72 80 88 96 104 112 120 128 136 144 152 1.0 0.8 0.6 0.4 0.2 0.0 LPV EFV LPV/ EFV
ARV Resistance Mutations (Preliminary Analysis) +some genotype assays pending ++30N, 32I, 33F, 46I, 47A/V, 48V, 50L/V, 82A/F/L/S/T, 84V, 90M Riddler S, et al. XVI IAC Toronto, Canada, Aug. 13-18, 2006; Abst. THB0204. * P < 0.05 compared to LPV; ** P<0.05 compared to EFV; *** P<0.05 compared to LPV/ EFV 2 0 0 Major PI mutations ++ 2** 2** 8 20 52 94 LPV 2 10*** Mutations in 2 classes 27* 16 NNRTI mutations 4 11*** NRTI mutations 18 13 Any PI mutations 39 33 Genotypic assays + 73 60 Observed VF LPV/ EFV EFV Patient Samples
Antiretroviral Combinations Not Recommended Anytime
Except for the perinatal HIV transmission prevention
3 drug regimens not recommended
ddI + TDF + NNRTI
ABC + TDF + 3TC
ddI + TDF + 3TC
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
ddI + d4T -> toxicities
d4T + AZT -> drug antagonism
FTC + 3TC -> drug antagonism
APV + FPV -> FPV is the prodrug of APV
APV oral solution in children, pregnancy, renal/hepatic failure
JB is a 35 y/o female HIV-infected patient who was diagnosed. Her baseline CD4 count was 137 cells/mm 3 and HIV RNA viral load was 68,980 copies/mL. PCP prophylaxis was initiated. All other labs with normal limits.
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
FDA Black Box Warnings Warning NRTI ■ Lactic acidosis and steatosis. ■ Hematologic toxicities including neutropenia & anemia. ■ Myopathy AZT ■ Lactic acidosis and steatosis. ■ Acute HBV exacerbation upon discontinuation. FTC
■ Lactic acidosis and steatosis.
Acute HBV exacerbation upon discontinuation.
TDF ■ 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. ABC ■ Lactic acidosis and steatosis. ■ Acute HBV exacerbation upon discontinuation. 3TC ■ Lactic acidosis and steatosis. ■ Fatal lactic acidosis in pregnant women with ddI + d4T. ■ Fatal and nonfatal pancreatitis with ddI + d4T+ HU. d4T ■ 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. ddI
NRTIs *dose reduce for renal dysfunction † dose reduce for weight <60 kg 125,200,250,400mg cap, pwdr for soln 200mg cap 150, 300mg tab, oral soln 300mg tab, 100mg cap, iv oral soln Dosage forms Pancreatitis, peripheral neuropathy, LA/HS Well tolerated Well tolerated Fatigue, malaise, HA, myalgia, anemia, GI Common Side Effects 400mg EC qd * † Didanosine (ddI) Videx Truvada, Atripla 200mg qd* Emtricitabine (FTC) Emtriva Combivir, Epzicom, Trizivir 150mg bid * or 300mg qd Lamivudine (3TC) Epivir Combivir, Trizivir 300mg bid * Zidovudine (ZDV/AZT) Retrovir Combos Standard Dose* Drug
NRTIs * dose reduce for renal dysfunction † dose reduce for weight <60 kg hypersensitivity Trizivir, Epzicom 300mg tabs, oral soln 300mg bid, 600mg qd Abacavir (ABC) Ziagen Few SEs, potential renal dysfxn. Truvada, Atripla 300mg tabs 300mg qd* Tenofovir (TDF) Viread Peripheral neuropathy, Dylipidemia, Lipodystrophy Pancreatitis, LA/HS 15,20,30,40 mg cap,oral soln 40mg bid * † Stavudine (d4T) Zerit Common Side Effects Combos Dosage forms Standard Dose* Drug
NRTI Combination Products * Use of individual components instead of combination products may necessary in patients with renal dysfunction. 600/300 mg tablet 1 tablet QD* Epzicom (ABC + 3TC) 300/200 mg tablet 1 tablet QD* Truvada (TDF + FTC) 300/150/300 mg tablet 1 tablet BID* Trizivir (AZT + 3TC + ABC) 300/150 mg tablet 1 tablet BID* Combivir (AZT + 3TC) Dosage Form Standard Dose Drug
JB and her physician decided to initiate therapy because of her low CD4 count and high viral load. Zidovudine + lamivudine + efavirenz was initiated. Her CD4 cell count increased from 88 cells/mm3 to 167 cells/mm3 in 3 months. Her viral load was undetectable. Although she reports she takes her medications every day, she stated she recently began to feel fatigued and experiencing headaches.
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 ↓
FDA Black Box Warnings http://aidsinfo.nih.gov/guidelines/adult/AA_032304.pdf Warning NNRTI ■ None EFV ■ None DLV ■ 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. NVP
NNRTIs Vivid dreams, drowsiness, CNS SEs, rash (including Stevens Johnson) CYP3A inducer, potency similar to PIs 50, 100, 200mg cap, 600mg tab 600 mg qhs Efavirenz (EFV) Sustiva rash, hepatotoxicity CYP3A inducer, auto inducer 200mg tabs, Oral susp 200 mg qd x 14 d then 200 mg bid Nevirapine (NVP) Viramune rash Suboptimal data on efficacy; potent CYP3A inhibitor 100mg tab, 200mg cap 400 mg tid Delavirdine (DLV) Rescriptor Common AEs Combos Dosage forms Standard Dose Drug
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 X HIV
FDA Black Box Warnings http://aidsinfo.nih.gov/guidelines/adult/AA_032304.pdf
DNV ■ Reports of clinical hepatitis & liver decompensation including some fatalities have occurred; risk of intracranial bleeding TPV ■ None ATV Warning PI ■ None FOS ■ None LPV ■ 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) APV ■ None NFV ■ None IDV ■ Co-administration with certain medications may cause serious or life-threatening events. RTV ■ None SQV
Protease Inhibitors Take with food 2 (700mg) tabs BID 2 (700mg) tabs + 2 (100 mg) caps QD 1 (700mg) tabs + 1 (100 mg) caps BID 1400 mg BID 1400 mg + RTV 200 QD 700 mg + RTV 100 mg BID Fosamprenavir (Lexiva) Liquid contains propylene glycol Avoid concomitant with ritonavir liquid Available as 50 mg capsules and liquid 600 mg + RTV 100 mg BID 1200 mg + RTV 200 mg QD Amprenavir (Agenerase) Drink 7-8 glasses of water per day 2 (400mg) caps + 1(100mg cap) BID 2 (400 mg) caps TID 800mg + RTV 100 BID 800 mg TID Indinavir (Crixivan) Take with food 2(625mg) tabs BID 3(250mg) tabs TID 1250 mg BID 750 mg TID Nelfinavir (Viracept) Take with food 2(500mg) caps/ 1(100mg cap) BID 1000 mg + RTV 100 mg BID Saquinavir (Invirase) Dosing info Pill burden Dose Drug
Protease Inhibitors Take with food 2 (300mg) tabs + 1 (100 mg) caps BID 600mg + RTV 100mg BID Darunavir (Prezista) Take with food 2 (250mg) caps + 2( 100mg cap) bid 500mg + RTV 200mg BID Tipranavir (Aptivus) Take with food; avoid PPI 2 (200mg) QD 2 (150mg) + 1 (100mg) QD 400mg QD 300mg + RTV 100mg QD Atazanavir (Reyataz) Take with or without food 4 tabs QD 2 tabs BID 400mg/100mg QD 400mg/100mg BID Lopinavir/ritonavir (Kaletra) Dosing info Pill burden Dose Drug
Protease Inhibitors 3A inhibitor, 3A substrate ----------- N/V, rash, HA Darunavir 3A and UGT1A1 inhibitor; 3A substrate good/86% ↑ bilirubinemia Atazanavir 3A inhibitor/ substrate; 2D6 inhibitor Poor/99% GI symptoms, rash Lopinavir/ritonavir 3A inhibitor/ substrate Unknown/99% GI symptoms ↑ LFTs, lipids, rash Tipranavir 3A inducer/ substrate Poor/90% GI symptoms, rash Fosamprenavir 3A substrate 30%/60% Nephrolithiasis; GI intolerance Indinavir P450 inhibitor/inducer/ substrate 20-80%/99% diarrhea Nelfinavir 3A substrate 4%/98% GI intolerance Saquinavir Metabolizing enzymes Bioavailability/ Protein Binding Side Effects Drug
25 y/o WM diagnosed with HIV 7/06. CD4 count is 88 cells/mm3 and HIV RNA viral load is 140,000 copies/mL. Prophylaxis for opportunistic infections was initiated. Other pertinent labs include negative hepatitis serologies, Toxoplasmosis IgG negative, G6PD normal. Other other laboratory values are within normal limits.
Pneumocystis jiroveci (PCP) If PaO2 < 70 initiate prednisone 40 mg BID x 5 days; 40 mg QD x 5 days; 20 mg QD x 11 days Bactrim 15 mg/kg in divided doses Bactrim DS QD Bactrim DS QD Treatment of Choice Treat for 21 days followed by secondary prophylaxis
MAC Rifabutin has drug interactions with PI; dose reductions may be necessary Clarithromycin 500 mg BID + ethambutol 20 mg/kg QD ± rifabutin 300 mg QD* N/A Azithromycin 1200 mg Q week Treatment of Choice 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 Fluoroquinolone Amikacin Treatment N/A N/A Secondary Prophylaxis CD4 count >100 cells/mm3 Clarithromycin 500 mg BID Primary Prophylaxis Discontinue Alternative
Clinically presented as an encephalitis with ring-enhancing lesions on CT/MRI
Seizures, altered MS, coma
Often hard to clinically differentiate CNS lymphoma and toxoplasmosis
Toxoplasmosis gondii Bactrim 10 mg/kg IV in divided doses in patients who cannot take PO formulations 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) Bactrim DS QD Bactrim DS QD Treatment of Choice Treatment for at least 6 weeks; rescan to determine CT/MRI improvement