My lab does a lot of research on the pharmacology of HIV drugs, so for those interested, I thought I would follow up our class discussion on drug classes with a few examples of the drugs in each class (generic names) and various pros and cons.
NRTI (Nucleos(t)ide Reverse Transriptase Inhibitors)
Emtricitabine, Lamivudine, Zidovudine, Zidovudine/Lamivudine (Combivir), Didanosine, Tenofovir, Tenofovir/Emtricitabine (Truvada), Stavudine, Abacavir
Target: Blocking HIV RNA transcription to dsDNA by competitively binding to the viral DNA and terminating chain extension.
Pros: Drug binding halts the proliferation of viral DNA, slowing the progression of the virus. If the drugs are at a sufficiently high level intracellularly before infection, can have a prophylactic effect and prevent the initial infection.
Cons: Drug levels must saturate the amount of viral RNA to fully prevent proliferation, otherwise the unimpeded RNA strands could still cause infection. Also, NRTIs have demonstrated mitochondrial toxicity.
NNRTI (Non-Nucleoside Reverse Transcriptase Inhibitors)
Efavirenz, Nevirapine, Etravirine, Delavirdine
Target: Changes conformation of reverse transcriptase, decreasing the activity of the enzyme’s catalytic sites.
Pros: Drug targets the enzyme, instead of the enzyme’s product, which diminishes the possibility of getting fully or partially formed dsDNA.
Cons: As with NRTIs, the drug levels must saturate the enzyme to fully prevent viral proliferation.
PI (Protease Inhibitors)
Indinavir, Ritonavir, Lopinavir/Ritonavir, Atazanavir, Nelfinavir, Tipranavir, Indinavir
Target: Inhibits the viral protease enzyme which cleaves the viral polypeptide coded for by the dsDNA.
Pros: Can be used in all retroviruses. Prevents the dsDNA from being cleaved into its more virulent components which prevents disease proliferation.
Cons: Must be used in combination with other antiretrovirals (usually NRTIs) in order to have full efficacy.
Integrase Inhibitors
Raltegravir
Target: Inhibits integrase, the enzyme which inserts viral DNA into host DNA.
Pros: Can be used to treat multiple retroviruses, not just HIV, including mutated HIV virus. Early results show very good efficacy. Also used in combination with other drug classes to have greater effect in preventing viral proliferation.
Cons: Still early in the ballgame to determine long term effects of the drug. May be best suited as an additional drug in HAART. Prevents last stage of viral addition to host DNA, which may not be the best drug target, as the viral DNA will have already been produced before infection is halted.
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So when a person has a possible exposure, which class of drugs are most effective in preventing infection? (It would seem like the NRTI's would be the best choice) Do they use a combination of classes?
ReplyDeleteDoes this usually work?
Hi Andrea-
ReplyDeleteThat is a good question. There is a lot of research (some of which is still on going) to show the chemoprophylactic potential of the NRTI tenofovir (with and without a helping hand from emtricitabine) in a primate model. Most of these studies show that an NRTI like tenofovir can be successful at decreasing or even preventing viral load if the patient takes a high enough soon enough after the infection event. Chances of successfully preventing infection increase by starting medication as soon as possible (even before) the infection occurs. Essentially, the drug has to have 5 half lives (to build up to a steady state concentration at peak levels) before the virus has a chance to take hold.
Unfortunately, cost is a prohibitive factor, as these drug regimens can cost tens of thousands of dollars, otherwise one could think of preventing viral infection in at risk patients.
For more information, check out papers by Koen Van Rompay, as he has spent most of his career on this subject.
Hi,
ReplyDeleteThis post really hit close to home. My friend is an ED doc in Johannesburg South Africa, and 4 months ago while working on an HIV positive patient who had presented to the ED, had a needle stick exposure. Her post exposure prophylaxis (PEP) included tenofovir. She had nasty side effects, but fortunately she has not sero-converted. I found it interesting that South Africa's standard PEP differs quite considerably from the most recent, "Updated U.S. Public Health Service Guidelines for the Management of Occupational Exposures to HIV and Recommendations for Postexposure Prophylaxis" (http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5409a1.htm). Part of it is a cost issue but I am not sure, how much of it is just reluctance and skepticism on the part of their bureacracies to implement proven PEP therapies.
This is really great information to have, especially for those of us working in the health care industry. Thanks Joseph and Belssing!
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