Art Drugs
Art Drugs
Art Drugs
ss viral RNA is transcribed via RT into a ds proviral DNA that is subsequently incorporated into host cell's genetic material via integrase enzyme. HIV then uses the infected cell's machinery to translate, transcribe, and produce immature viral particles that bud and break from infected cell. For these immature virions to become infectious, the HIV protease enzyme must cleave large precursor polypeptides into functional proteins
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Drugs Abacavir (ABC) Didanosine (ddI) Emtricitabine (FTC) Lamivudine (3TC) Stavudine (d4T) Tenofovir (TDF) Zidovudine (ZDV; formerly azidothymidine [AZT])
MOA Interrupt HIV replication cycle via competitive inhibition of HIV reverse transcriptase and termination of the DNA chain Reverse transcriptase. An HIV-specific DNA polymerase Allows HIV RNA to be transcribed into ss and ultimately ds proviral DNA and incorporated into host-cell genome. Proviral DNA chain elongation is necessary before genome incorporation can occur RNA building DNA Acting as "false blocks causes Chain termination, Nucleus Once incorporated, work by preventing other nucleosides from Host also being incorporated b/c ofCell absence of a 3 OH group.
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MOA of NRTIs
Pharmacokinetics
NRTIs are prodrugs and undergoes phosphorylation by intracellular kinases to exert their activity. Oral bioavailability ranges from 25%-93%, with tenofovir and didanosine on lower end of spectrum. Food does not significantly affect absorption Except didanosine, which must be taken on empty stomach Renal elimination Exception is abacavir, given at normal dose regardless of creatinine clearance. Minimal drug-drug interactions occur. Clinically significant Interactions involve didanosine. With tenofovir, didanosine levels are higher than expected, Didanosine and ribavirin combination should be avoided.
Name
Dosage Form(s)
Adult Dose
Adverse Events
Abacavir
Hypersensitivity reaction (may include fever, rash, nausea, vomiting, diarrhea, malaise, shortness of breath, cough, pharyngitis); patients positive for HLA-B*5701 are at highest risk for hypersensitivity (perform HLA screening before initiating)
Didanosine
>60 kg: 400 mg PO qd Peripheral neuropathy, pancreatitis, nausea, < 60 kg: 250 mg PO qd lactic acidosis Take 30 min ac or 2 hr pc Oral solution: Divide daily dose bid
Name
Lamivudine
Dosage Form(s)
150-mg, 300-mg tablet; 10-mg/mL solution
Adult Dose
300 mg PO qd or 150 mg PO bid
Adverse Events
Minimal toxicity, severe acute exacerbation of hepatitis may occur with HBV-coinfection upon discontinuation
Stavudine
Tenofovir
300-mg tablet
300 mg PO qd
Nausea, vomiting, diarrhea, headache, asthenia, renal insufficiency Nausea, vomiting, headache, asthenia, Anemia, granulocytopenia, myopathy, lactic acidosis, hepatomegaly with steatosis, nail pigmentation, lipid abnormalities, lipoatrophy, hyperglycemia
Zidovudine
300-mg tablet; 100-mg 300 mg PO bid or capsule;10-mg/mL oral 200 mg PO tid solution;10-mg/mL intravenous solution
Drugs First-generation Delavirdine(DLV) Efavirenz (EFV) Nevirapine (NVP) Second-generation Etravirine (ETR) Rilpivirine (RPV)
MOA
HIV reverse transcriptase is a heterodimer composed of 2 subunits (p66 and p51). NNRTIs bind p66 subunit at a hydrophobic pocket distant from active site of enzyme (allosteric site) This noncompetitive binding induces a conformational change in enzyme 1st generation NNRTIs are more rigid in structure Resistance can quickly be developed . 2nd generation NNRTIs have a more flexible structure, Adjust readily and resist mutation more effectively
MOA of NNRTIs
Pharmacokinetics
All utilize cyt P450 for metabolism and exert varying induction and inhibition effects on specific isoenzymes (eg, CYP3A4, CYP2C9). Results in a significant potential for drug-drug interactions Delavirdine primarily uses the 3A4 isoenzyme for metabolism. Nevirapine is metabolized mainly by 3A4 with some secondary metabolism through 2B6. Efavirenz is primarily metabolized through 2B6 and secondarily through 3A4. Etravirine is a substrate of 3A4, 2C9, and 2C19. Highly protein-bound (98-99%), primarily to albumin and alpha1 acid glycoprotein except nevirapine Serum half-lives are fairly extended, ranging (25-55 hours), Except for delavirdine, (2-11 h)
Name
Dosage Form(s)
Adult Dose 400 mg PO tid 600 mg PO qd Take on empty stomach to decrease Adrs
Adverse Events Rash, headache Rash, CNS (eg, somnolence, vivid dreams, confusion, visual hallucinations), hyperlipidemia
Delavirdine 100-mg, 200-mg tab. Efavirenz 600-mg tab.; 50-mg, 200-mg caps
Etravirine
200 mg PO bid
Rash, nausea
Rash, hepatitis
Rilpivirine
25-mg tablet
25 mg PO qd with meal
MOA HIV protease is a 99-amino-acid, aspartic acid protein Responsible for maturation of virus particles late in viral life cycle. Systematically cleaves individual proteins from gag and gag -pol polypeptide precursors into functional subunits for viral capsid formation during or shortly after viral budding from an infected cell. Competitive inhibitors Directly bind to HIV protease and prevent subsequent cleavage of polypeptides.
MOA of PIs
Pharmacokinetics
Significant first-pass metabolism by cytochrome P450 (CYP) 3A4 and 3A5 and intestinal efflux by p-glycoprotein is observed. Highly protein-bound (97-99%), primarily to albumin and alpha1 acid glycoprotein except indinavir, Short serum half-lives, ranging from 1.5-2 hours for indinavir and 7 hours for atazanavir. Significant Interactions with medications cleared through CYP450 isoenzymes Low-dose ritonavir (100-200 mg) is frequently coadministered with other protease inhibitors to block intestinal and hepatic 3A metabolism.
Name
Atazanavir
Dosage Form(s)
Adult Dose
Adverse Events
Indirect hyperbilirubinemia, prolonged PR interval, hyperglycemia, skin rash (20%), hyperlipidemia Rash, nausea, diarrhea, hyperlipidemia, hyperglycemia
100-mg, 150-mg, 200- 400 mg PO qd or mg, 300-mg capsules 300 mg + ritonavir 100 mg PO qd
Darunavir
75-mg, 150-mg, 300- 800 mg qd + ritonavir 100 mg PO mg, 400-mg, 600-mg qd or 600 mg bid + ritonavir 100 tablets mg PO bid 700-mg tab; 50-mg/mL oral sus.
Fosamprenavir
700 mg bid + ritonavir 100 mg PO Rash, nausea, vomiting, bid or 1400 mg PO bid or 1400 mg diarrhea, hyperlipidemia, + ritonavir 100-200 mg PO qd hyperglycemia Sus.: Take without food with RTV: Take with food
Indinavir
100-mg, 200-mg, 400- 800 mg PO q8h Nephrolithiasis, nausea, indirect mg capsules 800 mg PO bid + ritonavir 100-200 hyperbilirubinemia, mg PO bid hyperlipidemia, hyperglycemia Take 1 h ac or 2 h pc;
Dosage Form(s)
Adult Dose
100-mg/25-mg, 200400 mg/100 mg PO bid or mg/50-mg tablets; 800 mg/200 mg PO qd 80-mg/20-mg per mL oral Oral solution: Take with meals solution
Nelfinavir
Ritonavir
Boosting dose for other PIs: 100-400 mg/d Nausea, vomiting, diarrhea, asthenia, Nonboosting dose 600 mg bid hyperlipidemia, oral paresthesias, hyperglycemia
Saquinavir
1000 mg + ritonavir 100 mg PO bid Unboosted not recommended Take with food, or within 2 h pc
Tipranavir
Maraviroc Binding of gp120 HIV surface protein to CD4 receptor induces a structural change that reveals V3 loop of the protein. V3 loop then binds with a chemokine coreceptor (principally either CCR5 or CXCR4), allowing gp41 to insert itself into the host cell and leading to fusion of the cell membranes. Maraviroc selectively and reversibly binds CCR5 coreceptor, blocking V3 loop interaction and inhibiting fusion of cellular membranes.
As some viral strains may use an alternate co-receptor CXCR4 for
entry,
a tropism assay is necessary to confirm that patients virus only uses CCR5 for entry.
Pharmacokinetics 75% protein-bound, primarily to albumin and alpha1acid glycoprotein. Terminal half-life is 15-30 hours. Metabolized through CYP3A4 and is a substrate for efflux pump p-glycoprotein. Dosage adjustment is required when administered in combination with potent inhibitors or inducers of CYP3A4300 mg PO bid Dose 150 mg PO bid (CYP3A4 inhibitors inducers) 600 mg PO bid (CYP3A4 inducers) ADRs
Constipation, dizziness, cough, Pyrexia, Upper respiratory tract infections, Rash, Musculoskeletal symptoms, Abdominal pain, Hepatotoxicity, nasopharyngitis
Fusion Inhibitors
Enfuvirtide, Act extracellularly to prevent fusion of HIV to CD4 or other target cell. Blocks second step in fusion pathway by binding to HR1 region of gp41. Does not allow HR1 and HR2 to fold properly, Thus preventing conformational change of gp41 required to complete final step in fusion process Dose 90 mg SC bid Dose adjustments are not required in patients with renal insufficiency or mild-to-moderate hepatic insufficiency ADRs Injection-site reactions (eg, pain, erythema, induration, nodules) diarrhea, nausea, fatigue, hypersensitivity reactions, increased rate of bacterial pneumonia
Pharmacokinetics
Raltegravir Rapid absorption, taken with or without food. half-life of 10-12 hours Longer half-life in women, 83% bound to plasma proteins Metabolized by uridine diphosphate glucuronyl transferase Other antiretroviral agents may alter metabolism Antacids may decrease absorption by divalent cation binding, Elvitegravir administered with low-dose ritonavir (100 mg) to reduce its first-pass metabolism and systemic clearance. Coadministration results in a 20-fold increase in systemic exposure and a terminal half-life of 10-13 hours. metabolized through CYP3A4 and UGT1A1/UGT1A3. Drug-drug interactions with other medications are likely because of ritonavir Antacids may decrease absorption
Name
Dosage Form(s)
Adult Dose
Adverse Events
Raltegravir
400-mg tablet
Elvitegravir
Name
Combivir Epzicom
Lopinavir + ritonavir
Rilpivirine + tenofovir/emtricitabine Elvitegravir+ cobicistat+ tenofovir + emtricitabine
Kaletra
Complera Stribild
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Therapy options
Standard ART consists of 2 NRTIs in combination with an NNRTI, PI, or integrase inhibitor.
Preferred regimen
NNRTI Based regimen
EFV/TDF/FTC
Alternative Regimens
NNRTI-Based Regimens EFV + ABC/3TC RPV/TDF/FTC RPV + ABC/3TC PI-Based Regimens ATV/r + ABC/3TC DRV/r + ABC/3TC FPV/r (once or twice daily) +ABC/3TC or TDF/FTC LPV/r (once or twice daily) +ABC/3TC or TDF/FTC INSTI-Based Regimen RAL + ABC/3TC
PI Based regimen
ATV/r + TDF/FTC DRV/r (OD) + TDF/FTC
Patient selection
Patients initiating ART should be willing and able to commit to lifelong treatment Should understand benefits and risks of therapy and importance of adherence Patients may choose to postpone therapy, and providers, on a case-by-case basis, May elect to defer therapy based on clinical and/or psychosocial factors.
Clinical Failure:
when the patient has a new AIDS-defining illnessi.e., a new WHO stage 3 or 4 condition--after initiation of ART
Headache Severe or requires narcotics Allergic Reaction Generalized urticaria, angioedema or anaphylaxis
Peripheral Severe discomfort, objective weakness, loss of 2-3 Neuropathy previously present reflexes or sensory dermatomes
Fatigue
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Platelet count
Total Bilirubin Chemistries SCr AST / ALT LFTs Pancreatic Enzymes Lipids Cholesterol * ULN = Upper Limit of Normal
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< 49 x 103/L
> 3-7.5 x ULN*= 3.9-9.75mg/dL > 1.7-2.0 (adult) 5-10 x ULN* = 210-420 U/L, 240-480 U/L > 2-3 x ULN* 8.49- 13.56 mmol/L 1.6-2.0 X ULN
130-400 x 103/L
1.3 mg/dL 1.2 mg/dL 42 U/L , 48U/L
23-85 U/L, 0-160 U/L < 200 mg/dL < 200 mg/dL
liver*
Lipoatrophy (loss of
subcutaneous fat)
*Potentially life-threatening **d4T > ddI, AZT > ABC, TDF, 3TC
didanosine (ddI)
stavudine (d4T)
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CNS symptoms
efavirenz
Stevens-Johnson syndrome*
nevirapine
*Potentially life-threatening
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Liver toxicity*
*Potentially life-threatening
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LIPODYSTROPHY SYNDROME
Main clinical features are peripheral fat loss, central
PIs
Rx
Restorative surgery
Regimen change: PIs to NNRTIs or ABC
Dx
Clinical: N & V, myalgia, abd. Pain & distention, diarrhea, wt loss Lab.
Elevated venous lactic acid Surrogate markers include elevated creatinine phosphokinase (CPK), lactate dehydrogenase (LDH),
Rx
Lactic acid <5mmol/L may not require Therapeutic switch : D4T, ddl, or AZT to ABC,3TC or
Insulin Resistance
Incidence:
30-90% pts on PIs and overt DM occurs in 1-11% with
a mean of 7% in 5yr
Screening:
RBG, FBG and HbA1c after 2-3 mo of the start of PI base regimen
Risk:
Risk of atherosclerosis
Insulin Resistance
Rx
STD RX of type II DM and exercise The two major classes of agents are insulin secretagogues (sulunylureas ) and insulin sensitizing agents ( metformin and
thiazolidinediones / glitazones)
Metformin and glitazones have the potential advantage of improving insulin resistance and decreasing visceral fat
accumulation
Therapeutic switch to non PI base ARV agents
Hyperlipidemia
All PIs appears to have this effect with possible exception of atazanavir;
DX & Rx:
^LDL and TG--PI based ART esp.with retonavir ^TC and HDLEFV & NVP
Rx of hyperlipidemia
Lipid problem Preferred alternative niacin comment Start low dose and titrate upward, watch for myopathy with PIs Combination may increase risk of myopathy Combination may increase risk of myopathy Isolated high LDL Statin
Hepatotoxicity
NRTIs can cause hepatic steatosis, generally after more than 6 months of therapy, probably via mitochondrial toxicity.(D4T!) NNRTIs can cause hepatitis in first 2-3 months of therapy, sometimes as a part of hypersensitivity reaction (NVP>EFV, DLV)-fluminant hepatic necrosis (NVP) PIs can also cause hepatitis by an unknown mechanism, particularly in patients co-infected with hepatitis B or C, raised hepatic aminotransferase concentrations and alcoholism (RTV-the most common, among PIs)
HYPERSENSITIVITY
Is about 100 times more common in HIV Pts than in
general population.
Erythematous maculopapular, pruritic and confluent rash, most ly on body and arms and begins after 1-2 weeks of therapy. SJS or TEN develops in less than 0.3% of patients.
About 50% of ARV hypersensitivity resolves spontaneously despite continuation of therapy. Therapy should be stopped if there is mucosal involvement, blistering, exfoliation, clinically significant hepatic dysfunction
Glucocorticosteroids are ineffective for prevention of nevirapine hypersensitivity. Rechallenge is possible for mild to moderate NNRTI hypersensitivity but not for abacavir,
AST/ALT:
NVP-based ART: 2, 4, and 12 weeks post-initiation, thereafter only as clinically indicated EFV-based ART: 4 and 12 weeks post-initiation, thereafter only as clinically indicated PI-based ART: only as clinically indicated
Glucose and total cholesterol/triglycerides annually only if on PIbased ART Creatinine and creatinine clearance : 3 and 6 months post-initiation and then, if stable, every 6 months (TDF only) RPR (rapid plasma reagin )or VDRL test: after baseline, only as indicated
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Resistance Testing
Two types:
Genotyping Detects drug resistance mutations on virus genome that may make it resistant to certain antiretrovirals
Less expensive Can usually be completed in 1-2 weeks
Phenotyping Measure ability of viruses to grow in presence of various concentrations of antiretroviral drugs
More expensive Generally takes 2-3 weeks to complete
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Resistance Mutations For some drugs (NNRTIs and 3TC), a single mutation causes high-level resistance.
Resistance to these drugs occurs very quickly
For other drugs (most NRTIs and PIs), many mutations must occur before high-level resistance is observed.
Resistance to these drugs occurs more slowly
Cross-Resistance Resistance to one drug can cause resistance to others of the same class
NNRTI: complete cross-class resistance NRTI: partial cross-class resistance PI: partial cross-class resistance
Partly overcome by ritonavir boosting
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