OTHER ANTI-HIV/AIDS aggie

NUCLEOTIDE INHIBITORS
Tenofovir ( ten-o-four-veer)
TDF
Viread®

Oral
300mg
Given as a prodrug- tenofovir disoproxilfumarate
TDF
an acyclic nucleoside phosphonate analog of adenosine 5'-monophosphate.
It is converted by cellular enzymes to the diphosphate, which is the inhibitor of
HIV reverse transcriptase.
Cross-resistance with other NRTIs may occur, but some AZT-resistant strains retain
susceptibility to tenofovir.
should be taken with a meal to increase bioavailability.
Tenofovir has a long half-life, allowing once-daily dosing.
Serum css achieved within an hour
 Most of the drug is recovered unchanged in the urine, and elimination is by
filtration and active secretion.
Tenofovir is the only NRTI with significant drug interactions.
Tenofovir increases the concentrations of ddI to the point that ddI dosage reductions
are required if the two are given together; however, these two agents are no longer
recommended for combined use.
Tenofovir decreases the concentrations of atazanavir such that atazanavir must be
boosted with ritonavir if given with tenofovir to maintain effective atazanavir
concentrations.
SIDE EFFECTS
Gastrointestinal complaints are frequent and include nausea, diarrhea, and
vomiting.
asthenia
Renal toxicity- ARF, Fanconi syndrome, proteinuria, TN due to drug accumulation
in the PCT
Less common:
Hepatotoxicity
Abd. Pain
flatulence
FUSION INHIBITORS
Aka Entry inhibitors
Include:
Enfluvirtide
Maraviroc
ENFLUVIRTIDE
Fuzeon®
Formely called T-20
Available formulation: P/E
90mg/ml for injection

-binds to gp41 and interferes with its ability to approx. the two membranes.
Enfuvirtide is a 36-amino-acid peptide that binds to gp41, preventing the conformational
change.
Enfuvirtide, in combination with other antiretrovirals, is approved for therapy of treatment-
experienced patients with evidence of viral replication despite ongoing antiretroviral drug
therapy.
As a peptide, it must be given subcutaneously.
Most of the adverse effects are related to the injection i.e pain, erythema, induration, and
nodules, which occur in almost all patients. However, only 3 percent discontinue treatment
because of them.
Enfuvirtide must be reconstituted prior to administration.
It is an expensive medication.
92% plasma protein bound
Metabolism: proteolytic hydrolysis?
Elimination t1/2 : 3.8 hr
Peak conc. 8 hrs
MARAVIROC [MA-RA-VI-ROC]
Selzentry/ Celsentri®
Often ref to as a chemokine receptor antagonist

-binds to CCR5 preventing an interaction with gp120

it is well absorbed orally therefore formulated as an oral tablet.
Maraviroc blocks the CCR5 coreceptor that works together with gp41 to facilitate
HIV entry through the membrane into the cell.
HIV may express either the CCR5 coreceptor or the CXCR4 coreceptor, or both.
A test to determine tropism is required to distinguish the CCR5 from the CXCR4
coreceptor as well as mixed and dual tropic virus.
Only the CCR5-expressing virus can be treated with maraviroc.
Maraviroc is metabolized by cytochromeP450 liver enzymes, and the dose must be
reduced when given with the protease inhibitors.
Adverse effects/precautions
Hepatotoxicity
 may be preceded by a systemic allergic reaction (pruritic rash,
eosinophilia)
Dizziness/postural hypotension
Increased risk of CV events (MI, ischemic events)
 - but generally well-tolerated
INTEGRASE INHIBITORS

Raltegravir, [ral TEG ra veer]

FDA approved in 2007

isentress®
Formely MK-0518
(RAL)
Oral tabs: 200,400 and 600mg
-specifically inhibits the final step in integration of stand transfer of the viral DNA
into our own host cell DNA.
- has a half-life of approximately 9 hours and is therefore dosed twice daily.
-83% protein bound
-The route of metabolism is UGT1A1-mediated glucuronidation, therefore drug
interactions with CYP450 inducers, inhibitors or substrates do not occur.
- is well-tolerated with nausea, headache and diarrhea as the most common side
effects.
Used in paeds ( ages 2-18)

FDA approved for all pts. Though (2009)

In combination with other antiretrovirals, is approved for therapy of treatment-
experienced patients with evidence of viral replication despite ongoing antiretroviral
drug therapy.
ARV UPDATE
Tipranavir (Aptivus®)
 Approved June 2005

Darunavir (Prezista®)
 Approved June 2006

Emtricabine/tenofovir/efavirenz (AtriplaTM)
 Approved August 2006

TMC-125 (Etravirine)
 Investigational NNRTI-available via expanded access program (EAP)
TIPRANAVIR (APTIVUS ®)
Dosage Form
 250 mg capsules

Adult Dose
 500 mg po bid WITH ritonavir 200 mg po bid

Patient Counseling Points

 Take with food (high fat meal preferred)
 Antacids may decrease TPV/RTV absorption (25-29%), consider separating dosing
 Keep in refrigerator or store at room temperature for up to 60 days
 AEs: Hepatotoxicity-monitor LFTs, closely, rash (8-14%) of patients, diarrhea, nausea,
vomiting, rare cases of intracranial hemorrhage
 Caution with sulfa allergy
It is a non-peptide protease inhibitor
Has the ability to inhibit viral replication in cases of resistance to protease inhibitors
DARUNAVIR (PREZISTA ®)
Dosage Form
 300 mg capsules

Adult Dose
 600 mg po bid WITH ritonavir 100 mg po bid

Patient Counseling Points

 Take with food
 AEs: Rash (7%), abdominal pain, constipation, headache
 Caution with sulfa allergy
DA ARUN A VIR
Named after Arun K Ghosh, Illinois
Another protease inhibitor
Indicated for RX naïve and experienced adolesecents and adults
ONE PILL ONCE DALY!
AtriplaTM
(emtricitabine/tenofovir/efavirenz)
 Emtricitabine/tenofovir (Truvada®) + efavirenz
(Sustiva®)
Approved July 12, 2006
First collaborative effort between 2
companies to develop combination pill for
HIV treatment
Not new drugs!
 ETRAVIRINE [ET-RA-VYE-
RINE]
¤is the first second generation NNRTI.
¤HIV strains with the common K103N resistance mutation to the first generation of
NNRTI's are fully susceptible to entravirine.
¤Following oral administration, etravirine is well distributed and bioavailability is
enhanced when taken with a high-fat meal.
¤Although it has a half-life of approximately 40 hours, it is indicated for twice daily
dosing.
¤Etravirine is extensively metabolized to inactive products.
¤ Etravirine is a potent inducer of cytochrome P450; therefore, the doses of
cytochrome P450 substrates may need to be increased when given with etravirine.
oRash is the most common side effect.
oEtravirine is otherwsie well tolerated and does not have the CNS side effects that are
seen with efavirenz
ois pregnany category B.
ois indicated for HIV treatment-experienced, multi-drug resistant adult patients who
have evidence of ongoing viral replication.