3 drug PrEP?

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Dear Bob,
 
From what I have learned, Truvada has two drugs that work to stop reverse transcriptase. If the HIV virus has a mutation that causes one drug to be ineffective, the other drug still has a chance to stop it. My question: Wouldn’t it be theoretically better to have a PREP regimen that uses THREE different drugs? Or is the chance of HIV having mutations to both drugs in Truvada extremely rare and so therefore two is safe enough…?
 
Counting Drugs
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Dear Counting ,
Resistance to both of the drugs in truvada is very rare.  Furthermore, HIV resistance to one of the drugs (emtricitabine aka FTC) makes the virus more susceptible to the other drug (tenofovir aka TDF) so the combination of both drugs may still have high levels of activity in suppressing the virus.  Moreover, resistance to the drugs is typically partial, so that the drugs preserve some activity against the virus after resistance has occurred.  Finally, HIV that becomes resistant to either or both drugs in truvada has lower capacity to replicate, spread, and cause disease.  So, HIV loses a lot when it adapts to the drugs.
A PrEP tablet that contains three drugs might be available some day.  Such a tablet would be helpful mainly if the 3 drugs were as safe and well tolerated and inexpensive as the current tablet.
For now, PrEP with two drugs has been shown to be safe and highly effective when used.  PrEP with one drug (tenofovir) was also effective, although possibly not as effective as truvada which as two drugs.
Drug resistance can occur if he person is already infected with HIV before starting PrEP.  Nonetheless, drug resistance is rare compared with the number of HIV infections that are prevented by PrEP.  HIV that is resistant to one or both components of truvada can be treated with a variety of combination therapy regimens.
My colleague, Teri Liegler, and I wrote a commentary on drug resistance and PrEP published in the Journal of Infectious Disease.
Bob
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April 15, 2015

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