What drug will not be effective if the HIV viral strain uses the CXCR4 coreceptor?
Maraviroc. It inhibits binding of gp120 by antagonizing CCR5
What drug prevents fusion of the HIV particle with the host cell after the particle has bound gp120 to CD4 and CCR5?
Enfuvirtide (IV). This peptide locks gp41 in the extended conformation, keeping it away from the cell’s plasma membrane and preventing fusion.
Drug with questionable efficacy in preventing fusion of HSV to host cells? Drug with questionable efficacy in preventing acidification necessary to release influenza A RNA into host cell by blocking M2 proton channel.
Docosanol (HSV) and amantadine/rimantidine (influenza A)
How does AZT (azidothymidine/zidovudine) work?
It is a prodrug and gets phosphorylated 3x on the 5’ end. Reverse transcriptase recognizes it as a nucleotide and incorporates it into the DNA. There is no 3’ phosphate group to polymerize from and transcription is terminated.
What drugs fall into the nucleoside reverse transcriptase inhibitor class? Which ones can cross-over to treat HBV?
Zidovudine, lamivudine (HIV + HBV), emtricitabine (HIV + HBV), abacavir, tenofovir disoproxil (nucleotide), didanosine and stavudine.
Why do all nucleoside reverse transcriptase inhibitors have the possible side effect of lactic acidosis?
Although they are specific for reverse transcriptase, they can also have an effect on polymerase gamma in the mitochondria. Mitochondrial deficiency can lead to lactic acidosis due to inefficient oxidative phosphorylation.
What should you do before giving patients abacavir for anti-retroviral HIV therapy?
Genotype for HLA-B*5701 due to increased risk for hepatomegaly.
Nucleoside reverse transcriptase inhibitors that work for HBV but not HIV
Entecavir and telbivudine. Note that even though HBV is a dna virus, it uses RNA template and reverse transcriptase to replicate itself. Tenofovir, a nucleotide reverse transcriptase inhibitor also works and patients may develop rebound HBV when discontinued.
Resting cells have a less active thymidine kinase and thus the nucleoside reverse transcriptase inhibitors are not effective because they do not get phosphorylated. What drugs can you use in the resting cells?
Tenofovir is a nucleotide analogue that is converted to the di and tri phosphate form in resting cells. It then competitively inhibits HIV reverse transcriptase by terminating transcription due to absence of 3’ phosphate groups.
Side effect to look out for with tenofovir
What drug is a DNA polymerase inhibitor used to treat CMV that is resistant to ganciclovir and forscarnet?
Cidofovir, it is a cytosine nucleotide analogue that causes chain termination
Cytosine nucleotide analogue being used to treat Ebola
What drugs can you prescribe to someone taking a nucleoside reverse transcriptase inhibitor that will not interact or compete with them, but will also act on the reverse transcriptase?
Non-nucleoside reverse transcriptase inhibitors: nevirapine, rilpivirine, etravirine, efavirenz, delavirdine “look for the internal vir” but remember that maraviroc and enfuvirtide are exceptions to the rule.
Non-nucleoside reverse transcriptase inhibitor that is a teratogen
What do you want to do before prescribing non-nucleoside reverse transcriptase inhibitor?
Genotype, many HIV strains are resistant to these drugs.
How do the HIV protease inhibitors work?
They prevent Gag/Pol processing and prevent the virions from becoming infectious.
What are the HIV protease inhibitors?
“DAN FLIRTS”: Darunavir, Atazanavir, Nelfinavir, Fosamprenavir, Lopinavir, Indinavir, Ritonavir, Tipranavir, Saquinavir.
Why do you often combine ritonavir with other protease inhibitors?
All protease inhibitors are CYP3A4 substrates. Ritonavir is the best inhibitor of CYP3A4 and effectively increases the relative concentration of the other protease inhibitors by inhibiting CYP3A4.
Why might atanazavir be a more desirable protease inhibitor than the others?
Protease inhibitors cause lipodystrophies with increased LDL, decreased HDL, increased triglycerides, hyperglycemia and insulin resistance. Atanazavir does this the least of all the protease inhibitors.
What should you try if a patient has HIV that is resistant to a protease inhibitor?
Try a different protease inhibitor. Resistance to one does not mean it will be resistant to another protease inhibitor.
How do you know a protease inhibitor is for HCV and not HIV?
They end in evir (boceprevir, telaprevir, simeprevir)
What drugs block HIV DNA incorporation into host DNA?
Raltegravir, elvitegravir and dolutegravir are all integrase inhibitors.
What are acyclovir and valaciclovir used for? How do they work? How does it differ from the nucleoside reverse transcriptase inhibitors used for HIV?
HSV chain terminators (no 3’ hydroxyl group). Note that this drug is not phosphorylated by host enzymes, only by infected cells that have the thymidine kinase encoded by HSV.
How are zanamivir and oseltamivir effective in treating influenza A and B?
Neuraminidase inhibitors prevent the cleavage of hemagglutinin by neuraminidase from the infected cells.
1st line drugs for CMV infection in an HIV-infected patient
Ganciclovir and valganciclovir. These are substrates for the enzyme phosphotransferase and cause chain termination after they are phosphorylated.
2nd line drugs for CMV and/or HSV infection in an HIV-infected patient? 3rd line?
2nd: Foscarnet (mimics inorganic pyrophosphate and inhibits HSV & CMV DNA polymerase) 3rd: Cidofovir (inhibits viral DNA polymerase).
Old treatment for HCV
IFN (upregulates cytokines to cause proliferation of CD8 response) and ribavirin (chain terminator).
Current treatment for HCV
Protease inhibitors and sofosbuvir (inhibits HCV RNA synthesis b/c its a nucleotide analogue)