I have been undectable for the past two years on a regimen of Viramune and Truvada. My lab blood work is better now than it was before I started meds and all of my liver enzymes are in the normal range. I feel great. I have no side effects and would prefer to be on this regimen for a long time. If/when there is actual viral breakthrough, does a person end up with resistance to just one of the drugs in the regimen or is the entire regimen compromised?

Thanks for the great work on here.

Thank you for this excellent and important question. It would be a good idea for anyone taking ART to understand the answer. Its a long one with an important message at the end, so stay with me.

The answer depends on the regimen you are taking, so it would be a good idea to ask this question of your doctor in regard to your specific regimen.

It also depends on whether you are on your first ever ART regimen (as in your case), or you have been on more than one regimen, and already have experienced some drug resistance.

In general, resistance to all three drugs at the same time is unusual in patients taking their first ever regimen, for two reasons.

First, because the 'genetic barrier' to resistance usually differs between members of an ART regimen, the earliest drug to develop resistance is the one with the lowest barrier to resistance, just as a chain breaks under stress at its weakest link.

Secondly, the time required for an ART regimen to develop resistance depends on both the class of drug in question, and the specific agent within the class.

In general, NRTIs such as AZT, D4T, DDI, and ABC (abacavir) require weeks to months to accumulate resistance mutation. An important NRTI exception is 3TC (lamivudine = Epivir), for which a single mutation causes resistance. (But 3TC is an exception for other reasons as well, in that even with the M184V mutation that causes resistance, the drug still causes a one half log decline in viral load, it causes an advantage for AZT activity and resistance, and as long as it is used it impairs the 'fitness' of the virus, ie its ability to replicate and contribute to HIV disease progression.) The sole nucleotide RT inhibitor, tenofovir (TDF = Viread), also develops resistance in a time frame of weeks to months, some of which cause cross resistance to other NRTIs.

In contrast to the NRTIs, the time to the development of resistance to the NNRTIs is faster, days to weeks. Like 3TC, a single amino acid substitution can confer resistance. Unlike 3TC, once resistance occurs, no antiviral activity remains, and no viral fitness impairment. For this reason, physicians and patients using NNRTI-based regimens such as EFV (efavirenz = Sustiva) or NVP (nevirapine = Viramune)should take great care to ensure the best possible adherence to the regimen, as even small lapses can lead to 'viral breakthrough', i.e. detectable plasma viremia, and rapid resistance, after which the entire NNRTI class has no further value.

The PI class, such as lopinavir/r (Kaletra) and atazanavir (ATV = Reyataz), takes even longer to develop resistance, i.e. months to years, and in some trials of boosted PIs, no PI resistance has been seen even in the few patients with viremia. THis has even led to some clinical trials in which boosted PIs are used alone, with some preliminary success. (Since this is still experimental, no one should consider doing this outside of a clinical trial at present.)

So here's the important message: While its usually the case that resistance is first seen to only one or at most two drugs in the regimen, this situation can be short lived if ongoing viremia continues unrecognized. This means that people on ART should be sure to keep their regularly scheduled clinic appointments and lab test schedule, so that they and their doctors can pick up viremia as early as possible and make the necessary adjustment in the regimen, if any.

As always, talk to your doctor about this issue, and remember that the best way to deal with resistance is to prevent it in the first place by keeping up the best possible adherence and keeping your clinic appointments.