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"Missed A Dose" follow-up
Jul 28, 2004

Hi, Dr. Pierone. Thanks for your response on Jun 27, 2004 to my "Missed A Dose" posting, in which I expressed my concern over my first (and only) missed dose of Sustiva-Viread-Epivir in my six months of treatment. Your words were very comforting. And you were right: I did achieve undetectable status at my last visit! Feel like I have a new lease on life.

Just one follow-up question, though... One of the hardest parts of dealing with HIV is reconciling conflicting information from various sources. In your most recent response to me, you wrote: "Sustiva has been shown to maintain adequate levels in the blood for antiviral activity for 1 to 2 weeks (sometimes longer). Viread has adequate levels at least several days and Epivir levels persist for 1 or 2 days."

You went on to mention some unfinished studies investigating various days-on/days-off strategies for my particular drug regimen currently being investigated, though you were very clear that such studies are "not ready for prime time" and that 100% adherence remains critical.

I'm confused, though, by a recent posting in the "Drug Resistance and Staying Undetectable" forum, in which Dr. Renslow Sherer of U of C Hospitals wrote: "Sustiva has the longest half-life, up to 40 hours. Tenofovir also has a long half life that allows for once daily dosing, e.g. 26 hours. Epivir has a shorter half life, 4-6 hours, in the plasma, but has been shown to be effective when used twice daily, and more recently once daily, due to the accumulation of active drug in the intracellular compartment... Both efavirenz and lamivudine are genetically vulnerable, i.e. a single mutation leads to resistance, and with both drugs this can occur very quickly, i.e. within hours or days of an inadequate blood level of drug."

So now I'm worried again that my one missed dose may have done me serious damage in the long run. Can you clarify the situation for me? Does Dr. Renslow's response reflect older information, whereas yours reflects the "new data regarding the forgiveness of contemporary regimens" you mentioned. Or is there genuine disagreement among you docs about this issue?

As always, thanks for your invaluable assistance.

Best, D

Response from Dr. Pierone

The information between the two posts is not inconsistent, but looks at different aspects of pharmacology. The half life of a drug states how many hours (on average) it takes for the body to clear 1/2 of the initial level from the blood stream. If a drug like Sustiva has a 40 hour half life, one still has 1/2 the drug levels at 40 hours, 1/4 of original levels at 80 hours, 1/8 at 120 hours, etc. The original blood levels of Sustiva are way above the minimal inhibitory concentration (MIC) of the virus; this is why antiviral activity is maintained for 1 to 2 weeks.

Similar calculations can be done for Epivir and Viread using the intracellular half life numbers. So half life is only part of the story; absolute drug levels, intracellular concentration, intracellular half life, and minimum concentrations of the drug necessary to inhibit viral replication all contribute to the effectiveness of a regimen and how "forgiving" it is of missed doses. So you have no need to worry about the missed dose since this regimen is more forgiving than others.

less potent less toxic combinations
timing of drugs

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