Pharm: Antiretrovirals

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goals of HIV pharmacology

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Suppression of viral replication as much as possible for as long as possible
Restore and maintain health of the immune system (keep CD4 count has high as possible)

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Treatment failure is usually the consequence

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non-adherence

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Treatment failure generally requires

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completely new combination of drugs

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Initiate treatment in all patient with CD4 count of

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less than or equal to 350 cells/mm3 (DHHS current guidelines) – all symptomatic pt’s receive tx

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HAART is

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Avoid resistance using combinations of highly active antiretroviral drugs (HAART)

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mnemonic for NRTIs and MtRTIs

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NRTIs
Abacavir
Didanosine
Emtricitabine
Lamivudine
Stavudine
Zalcitabine
Zidovudine


NtRTI
Tenofovir

DAZZLE ST

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mnemonic for NNRTIs

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NEED

delavirdine
efavirenz
nevirapine
etravirine

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mnemonic ofr PIs

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island raft

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which drugs are entry inhibitors

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enfuvirtide (fusion inhibitor)
maraviroc (CCR5 antagonist)

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what are the integrase inhibitors

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raltegravir

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what are the FIXED-DOSE COMBINATION PRODUCTS

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Lamivudine-Zidovudine [Combivir]

Abacavir-Lamivudine [Epzicom]

Abacavir-Lamivudine-Zidovudine [Trizivir]

Emtricitabine-Tenofovir [Truvada]

Efavirenz-Emtricitabine-Tenofovir [Atripla

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Oral
Bioavailability varies; may be affected by fatty meal
Distributed to most body fluids and tissues
Penetration into CSF is varies
Minimal systemic metabolism (exceptions are zidovudine and abacavir) – very few metabolic drug RXNs!
Eliminated by cellular metabolism and by glomerular filtration and active tubular secretion (kidney – think transporters!)
Intracellular half-lives range from 3 to 40 hours allowing once or twice daily dosing (except zalcitabine every 8 hours)

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NRTI

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why does zalcitabine need to be given every 8 hours

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bc it has an intracellular halflife around 3 hours (which is short for its class - NRTIs)

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MOA:
Inhibit incorporation of native nucleotides into the nascent viral RNA-DNA duplex
Terminate elongation of proviral DNA chain (they lack 3' -OH group)

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NRTIs

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what is the significance of the 184V mutation

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reduced susceptibility to lamivudine and emtricitabine; low-level resistance to abacavir, didanosine, and zalcitabine

On the other hand, zidovudine-resistant isolates regain sensitivity to zidovudine


(the mutation hardly ever occurs on its own)

NRTIs

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know the viral resistance to NRTIs

know the important mutation

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NRTIs prevent infection of susceptible cells but do not eradicate the virus from cells that already harbor integrated proviral DNA (like all available antiretroviral drugs)
High level resistance usually requires accumulation of a minimum of 3 to 4 codon substitutions  resistance usually occurs more slowly than with NNRTIs and HIV PIs
Generally follows several mutational patterns
Cross-resistance to multiple nucleoside analogs has been reported following prolonged therapy

184V mutation:  susceptibility to lamivudine and emtricitabine; low-level resistance to abacavir, didanosine, and zalcitabine
On the other hand, zidovudine-resistant isolates regain sensitivity to zidovudine

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toxicities:
Selectivity: they are selective for HIV reverse transcriptase
Low affinity for host DNA polymerases-α and –β
-->
Inhibiting host DNA polymerase-γ (mitochondrial enzyme)
-->
Mitochondrial Toxicity

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NRTIs

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which NRTIs are more likely to cause mitochondrial toxicity

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Didanosine, stavudine, zidovudine, zalcitabine are more likely to cause mitochondrial toxicity.
Tenofovir DF, abacavir, lamivudine, and emtricitabine are less toxic to mitochondria.

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which NRTIs are LESS likely to be toxic to mitochondria

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Didanosine, stavudine, zidovudine, zalcitabine (Not applicable, bc its no longer used) are more likely to cause mitochondrial toxicity.
Tenofovir DF, abacavir, lamivudine, and emtricitabine are less toxic to mitochondria.

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clinical presentation:
Myopathy, peripheral neuropathy, lipodystrophy (predominantly lipoatrophy) and pancreatitis; anemia, neutropenia, and thrombocytopenia are thought to be related to mitochondrial toxicity

Risk factors for the lactic acidosis-steatosis syndrome include female sex, obesity, and prolonged exposure to the drug.
Lactic acidosis with hepatic steatosis are rare and potentially fatal. *****

***** treatment should be suspended in the setting of rapidly rising aminotransferase levels, progressive hepatomegaly, or metabolic acidosis of unknown cause

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Manifestations of Mitochondrial Toxicity

NRTIs

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drug interactions:
Drugs that compete for active tubular secretion --> decr. Clrenal acyclovir; valacyclovir; ganciclovir; cidofovir; adefovir dipivoxil; probenecid

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NRTIs


NRTIs are not substrates of CYPs; zidovudine and abacavir undergo glucuronidation
Pharmacodynamic DDIs: competition or additive toxicities (please see next slide)

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HIV-1, HIV-2, and human T-cell lymphotrophic viruses (HTLV) I and II
Tx HIV infection; prevention of mother-to-child transmission of HIV infection**; post-exposure prophylaxis (needle stick**); mitochondrial toxicity

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Zidovudine

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(rarely used) HIV-1; HIV-2 Peripheral neuropathy; lipatrophy is most strongly associated with stavudine; lactic acidosis and hepatic steatosis can occur

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Stavudine

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HIV-1; HIV-2; HBV Used in Tx of HIV and HBV infection (rebound HBV infection if lamivudine DC’d); among least toxic; no affect on mitochondrial DNA (in vitro)

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Lamivudine

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which NRTIs are least toxic

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emtricitabine
lamivudine

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which NRTIs are usefulagainst HBV (along with HIV)

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lamivudine
emtricitabine
tenofovir

these are also the most commonly used NRTIs

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fluorinated derivative of lamivudine; HIV-1; HIV-2; HBV Used in Tx of HIV inf (rebound HBV infection if lamivudine DC’d); among least toxic; no affect on mitochondrial DNA (in vitro); hyperpigmentation of palms and/or soles reported ***

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Emtricitabine

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Withdrawn from market; 3x-daily administration; low potency; high incidence of adverse effects

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Zalcitabine

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HIV-1; Hypersensitivity syndrome (life threatening) -> should not be given to patients with the HLA-B*5701 genotype******, nor restarted in pt with hypersensitivity reaction;
EtOH --> incr. drug levels

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Abacavir

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HIV-1; HIV-2; HTLV-1 and other retroviruses; degraded by stomach acid **; mitochondrial toxicity; retinal changes, optic neuritis

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Didanosine

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HIV-1; HIV-2; HBV Used in Tx of HIV and HBV infection (rebound HBV infection if lamivudine DC’d); Flatulence***; renal failure, Fanconi syndrome** - toxicity of proximal tubules

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Tenofovir

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PK:
Oral
Variable bioavailability (meal --> incr. efavirenz and etravirine levels)
Highly bound to plasma proteins
All are eliminated by hepatic metabolism
t½ long --> once daily dosing (except delavirdine 3x daily

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NNRTI Pharmacokinetics

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MOA:
Noncompetitive inhibitors
Bind to allosteric site on reverse transcriptase --> conformational change --> decr. activity of the enzyme
Potent activity against HIV-1
(no activity against HIV-2)

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NNRTI

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All – except etravirine – are susceptible to high-level drug resistance caused by single-amino-acid changes in the NNRTI-binding pocket (usually in codons 103 or 181)
Efavirenz or nevirapine can induce resistance and virologic relapse within a few days or weeks if given as monotherapy
Exposure to even a single dose of nevirapine***** in the absence of other antiretroviral drugs is associated with resistance mutations in up to one-third of patients
Cross-resistance: Efavirenz – Nevirapine – Delavirdine
Mutations selected by Etravirine usually are associated with resistance to all of the NNRTIs

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NNRTI

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which of the NNRTIs have a cross resistance

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Efavirenz – Nevirapine – Delavirdine

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Exposure to even a single dose of ____ in the absence of other antiretroviral drugs is associated with resistance mutations in up to one-third of patients

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nevirapine

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Mutations selected by ___ usually are associated with resistance to all of the NNRTIs

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Etravirine

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toxicity:
Rashes: occur frequently with all of this group of drugs, usually during the first 4 weeks of therapy; usually mild and self-limited
Stevens-Johnson syndrome has been reported rarely
Fat accumulation can be seen after long-term use
Fatal hepatitis has been associated with ___ use
Substrates and inducers or inhibitors of metabolic enzymes --> High potential for drug interactions
***

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Fatal hepatitis has been associated with nevirapine use

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Hepatitis: Severe and fatal hepatitis may be more common in women with CD4 counts >250 cells/mm3 especially during pregnancy
Pregnancy: Considered safe to the fetus
DDI: substrate of CYP3A4, and inducer of CYP3A4 and 2B6
 levels of the PIs amprenavir, indinavir, lopinavir, and saquinavir, as well as efavirenz and methadone

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Nevirapine

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Convenient; tolerable; potent
CNS symptoms: dizziness; impaired concentration; dysphoria; vivid or disturbing dreams; insomnia; frank psychosis (avoid in predisposed pt’s)
Pregnancy: the only antiretroviral drug that is unequivocally teratogenic in primates
DDI: substrate, inducer and inhibitor of CYP3A4
efavirenz and/or phenobarbital, phenytoin, carbamazepine concentrations may be decreased; efavirenz may decrease methadone concentrations

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Efavirenz

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Treatment-experienced HIV-infected adults (only indication)
Pregnancy: no evidence of fetal harm in animal studies; available data is insufficient to recommend use in pregnancy
DDI: inducer of CYP3A4 and UGTs; inhibitor of CYP2C9 and 2C19 (maraviroc dose should be doubled when used with etravirine)

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Etravirine

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Not widely used: short t½ and the need for 3x-daily dosing
Pregnancy: teratogenic in some animal studies
DDI: substrate of CYP3A4 and a strong inhibitor of CYP3A4, several others

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Delavirdine

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PK:
Food --> incr. bioavailability of most of the HIV Pis
Highly plasma protein bound; substrates of Pgp
Clearance mainly by CYP3A4
Fecal excretion primarily
t½ varies from 1-2 hours (unboosted saquinavir and indinavir) to 15 hours (darunavir)

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HIV Protease inhibitors

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Potent inhibitor of CYP3A4 and and other CYPs
This property is used to clinical advantage
Low-doses of this drug in combination with other PIs --> incr concentrations and incr. duration of action of the active PI

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"ritonavir boosting"

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MOA:
Reversible inhibitors of HIV-1 and HIV-2 protease
Prevent proteolytic cleavage of HIV gag and pol proteins
-->
Release of immature, noninfectious viral particles

High-level resistance to __ requires accumulation of a minimum of 4 to 5 codon substitutions, which generally takes several months.

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PIs

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toxicities:
The virologic benefits of these drugs must be balanced against short- and long-term toxicities, including the risk of insulin resistance and lipodystrophy.
Nausea, vomiting, diarrhea (generally resolve)
Metabolic effects (just like glucocorticoids - cushing's): central obesity, buffalo hump, peripheral and facial wasting, breast enlargement, and a cushingoid appearance. Concurrent increases in triglyceride and LDL levels, and hyperglycemia and insulin resistance can occur.
Peripheral neuropathy
Skin rashes including Stevens-Johnson syndrome
High potential for drug interactions (please refer to handout)

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HIV PIs Toxicities

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adverse effects:
Hepatotoxocity: potentially fatal, though rare (US Boxed Warning)
Intracranial hemorrhage: potentially fatal, though rare (US Boxed Warning)
Impairs platelet aggregation: Coadministration of anticoagulants, and antiplatelets → ↑ risk of
bleeding
Bleeding episodes reported in patients with hemophilia
Oral solution contains vitamin E; additional vitamin E supplements should be avoided and may
increase the risk of bleeding
↑ Lipids and triglycerides: more likely than with other boosted HIV PIs
Rash: usually transient; discontinue drug if rash is severe
Caution: Avoid in patients with sulfa allergy
Drug interactions: Tipranavir is a substrate, inhibitor, and inducer of CYP enzymes.

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TIPRANAVIR

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High pill burden; generally tolerable; lipodystrophy with long-term use; QT prolongation (saquinavir/ritonavir)

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Saquinavir

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Pharmacokinetic enhancer (low doses); rarely used for antiretroviral effect because of dose-dependent toxicities nausea, vomiting, diarrhea, anorexia, abdominal pain, and taste perversion; peripheral and perioral paresthesias ;  serum total cholesterol and triglycerides

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Ritonavir

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Prodrug of amprenavir  pill burden, better tolerated (dephosphorylated in intestinal mucosa to amprenavir, a nonpeptide); GI effects common; fatigue, depression; rash (may be related to sulfa moiety in structure)

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Fosamprenavir

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Coformulated with ritonavir; GI effects common;  serum cholesterol and triglycerides relatively common
Oral solution contains ethanol / propylene glycol  neonates at risk of toxicity cardiotoxicity (complete AV block, bradycardia, cardiomyopathy), lactic acidosis, CNS depression, respiratory complications, acute renal failure and death

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Lopinavir

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GI effects; unconjugated bilirubinemia (cosmetic effect due to inhibition of UGT)

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Atazanavir

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Nonpeptide; sulfa moiety; rash reported in up to 10% of patients; hepatotoxicity reported

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Darunavir

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Nephrolithiasis and other nephrotoxicity (poorly soluble at higher pH); unconjugated bilirubinemia (inhibition of UGT); lipodystophy syndrome; hyperglycemia; hair loss, dry skin

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Indinavir

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Fatty foods for optimal absorption; CYP2C19 to active metabolite; ritonavir boosting does NOT enhance nelfinavir effects; secretory diarrhea; glucose intolerance, incr. lipids

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Nelfinavir

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Nonpeptide; sulfa moiety; hepatotoxicity (rare but potentially life-threatening); impairs platelet aggregation --> incr. risk of bleeding; vitamin E formulation;incr. lipids and TGs more likely than with other boosted HIV PIs; rash

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Tipranavir

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PK:
Highly variable
Oral, high fat meal --> incr. AUC (no food requirements with raltegravir administration, antiviral effects were maximal at all concentrations at clinical trial doses)
83% bound to plasma proteins
Hepatic glucuronidation mainly by UGT1A1
 Raltegravir is neither a substrate nor an inhibitor or inducer of CYP enzymes
Glucuronide excreted in feces and urine; parent drug excreted in feces;
t½elimination 9-12 hours  2x daily dose

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Raltegravir Pharmacokinetics

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MOA:
It blocks the catalytic activity of the HIV-encoded integrase --> prevents integration of virus DNA into the host chromosome
Humans lack integrase, and human DNA is not known to undergo excision and reintegration

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raltegravir

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activity:
Potent against both HIV-1 and HIV-2
Treatment of treatment-naïve and treatment-experienced adults and adolescents  16 years of age

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Raltegravir Activity

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Resistance
Primary mutations in the integrase gene (Q184R/H/K, or N155H); either mutation can confer 25- to 50-fold changes in drug sensitivity in vitro.
Additional secondary mutations can accumulate and cause high-level resistance, including cross-resistance to investigational integrase inhibitors.

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Raltegravir Resistance

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AEs:
Well tolerated
Headache, nausea, asthenia, and fatigue (most common complaints)
Creatine kinase elevations, myopathy, and rhabdomyolysis have been reported (causal relationship to drug exposure is unproven)
Depression exacerbation has been reported
--> Raltegravir did not increase serum lipids

no CYP interactions

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Raltegravir Adverse Effects

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When used with ___, raltegravir dose should be doubled.

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When used with rifampin, raltegravir dose should be doubled.

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DIs:
Inhibitors or inducers of UGT1A1  potential for pharmacokinetic drug interactions
UGT1A1 induction: Rifampin; Efavirenz; Tipranavir all   raltegravir concentrations
 When used with rifampin, raltegravir dose should be doubled.
UGT1A1 inhibition: Atazanavir   raltegravir concentrations
Other interactions:
Tenofovir + raltegravir --> incr. raltegravir concentrations (mechanism undefined)

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Raltegravir

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Chemistry: 36-amino acid synthetic peptide, sequence derived from a part of the transmembrane gp41 protein of HIV-1 involved in the fusion of the virus membrane with that of the host cell

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Enfuvirtide

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PK: SubQ; bioavailability ~84%; 92% protein binding; proteolytic hydrolysis (CYP isoenzymes do not appear to contribute to metabolism; t½ elimination 3.8 hours  2x daily dose

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Enfuvirtide

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Use: Treatment-experienced adults and children ≥ 6 years old who have evidence of HIV replication despite ongoing antiretroviral therapy, in combination with at least two other active antiretroviral drugs
AE: injection site reaction; pneumonia; not teratogenic (animal)
DDI: No known metabolic drug interactions

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Enfuvirtide

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binds to a hydrophobic groove in the N36 coil of the gp41 subunit of the viral envelope glycoprotein 
Blocks the interaction between the N36 and C34 sequences 
Inhibits the conformational change in gp41 required for membrane fusion 
Inhibits the fusion of HIV-1 virus with CD4 cells

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Enfuvirtide

prevents fusion --> prevents entry!

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Activity: HIV-1
Resistance:
Mutations in the codon of the enfuvirtide binding domain of gp41are associated with resistance
High-level resistance is usually associated with two or more amino acid changes (V38A or N43D substitutions are most common)
It retains activity against viruses that have become resistant to antiretroviral agents of the NRTI, NNRTI, and PI classes

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Enfuvirtide Activity and Resistance

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PK:
Oral
Variable bioavailability 23-33% (dose-dependent); food  AUC but no food requirements (clinical efficacy trials were conducted without food restrictions)
76% plasma protein bound
Hepatic metabolism via CYP3A4 (***)
Fecal and urinary excretion
t½elimination 14-18 hours (LONG**)

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Maraviroc Pharmacokinetics

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MOA:
blocks the binding of the HIV outer envelope protein gp120 to the CCR5 chemokine receptor

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Maraviroc

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Activity: CCR5-tropic strains of HIV only ****
Resistance:
Shift in tropism to CXCR-4 or dual tropism
Mutations in the V3 loop of gp 120 that allow virus binding in the presence of inhibitor

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Maraviroc

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clinical use:
Tx of CCR5-tropic HIV-1 infection in adults and adolescents 16 years of age, in combination with other antiretroviral agents
 Prior to therapy, tropism testing should be performed for presence of CCR5-tropic HIV-1 infection. Therapy not recommended in patients with CXCR4- or dual/mixed tropic HIV-1 infection; efficacy not demonstrated in this population.
AE: generally well tolerated, with little significant toxicity; hepatotoxicity with allergic features (reported)
DDI:
Strong CYP3A4 inducers, eg efavirenz, etravirine, rifampin, carbamazepine, phenytoin, or St. John’s wort --> incr. dose
Strong CYP3A4 inhibitors, eg delavirdine, ketoconazole, itraconazole, clarithromyin  decr. dose

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Maraviroc