May 20, 2002
I tested positive in 1991, started therapy in 1992 and am now resistant to virtually all the NRTIs and NNRTIs. Prior to now, I have not been on any PI.
In early March 2002, I changed my medication to Viracept, Viread and Epivir. (Epivir was part of a failing regimen a few years ago.) Within 4 weeks of the change, my viral load decreased to 151 from about 20K. (It was as high as 120K in 1999 and subsequently dropped after a change in regimen but was never below 500 prior to now.) My doctor seems to be satisfied with this decline and does not seem to be concerned whether or not the VL gets under 50. When I said Id like to get it under 50, he indicated that may be difficult to achieve.
My doctor says he likes Viracept as an initial PI because its resistance profile leaves more PI options available later on. My concern is that Viracept may not be the most potent PI available. Because Viread is virtually the only NRTI that Im sensitive to, and, having never been undetectable, I dont want to waste it on a sub-optimal regimen.
I go back for lab work in one week. Is my doctor on the right course or are my concerns well-founded? Should I expect to see an improvement in the VL to less than 50? If the VL does not drop to undetectable, do you think I should switch to another PI (or two)?
| Response from Dr. Cohen
Like you, I am pretty concerned if the viral load is not less than 50 copies on a regimen, especially when in this situation. The reason for this is clear -- when the viral load goes below 50 it very often means the regimen is potent enough to be durable for years, and far longer than what is seen when the viral load is above 50 copies. And when the viral load is above 50 copies, then HIV is growing and creating more and more resistance mutations over time to eventually "learn" how to ignore this regimen as well, as it apparently has done with your prior combos. And since, as you describe, you only have the PI class to fully rely on, making the PI combo maximally effective is the best way you have to ensure a very durable response, one that might last years or even decades.
While it is true that the viral load rebound on viracept/nelfinavir is one that usually can be followed by other PIs, this strategy is a bit controversial - since the next PI combo may not be as successful after nelfinavir resistance in ways that are subtle and hard to fully predict. When we rely on sequencing we risk the cost of any cross resistance, not only to the PI used, but to the NRTIs used as well. And if there is basically one good swing at the bat left, it is worth being very sure that relying on sequencing is the better option versus going for full suppression.
So it comes down to what the options are for full suppression at this point, since if they are lousy, you are doing the best we've got. But there is progress on that front. The usual options include either one "boosted" PI (one that is given with a low dose of norvir/ritonavir to increase the blood level and therefore the potency), or even two boosted PIs in combination. We are still learning which approaches are best, but there are several being studied. For example, we in our group are in the midst of a study where we are using the combination of two boosted PIs: Kaletra - (a boosted PI that has the ritonavir already in the capsule) plus saquinavir (using either the Fortovase or the Invirase version) at a dose of between 800 and 1000 mg twice daily. And this dual PI approach appears to be very successful and often well tolerated especially with the benefit of having some options in how we use this combo (for example, using invirase may have fewer GI side effects for some people than does fortovase). These dual PI combination may even be potent enough to stand alone without the epivir/viread addition, although some people may need the additional potency from one or both of the NRTIs. (Note that in the past viracept was studied for two-PI combos but those stopped as better tolerated dual PI combinations have been identified since then. We presented our initial results of this combo at the recent retroviral conference - the web site is attached at the end, and the abstract is under the first author's name of Hellinger.)
Since the mono or dual boosted PI approach may be more likely to get to <50, should you switch now or wait to see if your current approach is good enough? One approach is to do it now, but it is also possible to wait to see if this does work - switching soon after noting that your viral load either does not get to below 50, or is increasing back up after getting there, likely would not "cost" too much in terms of PI class resistance. But that means monitoring regularly like every 2 or 3 months to be sure that you know when you are rebounding and then have the opportunity to change. At least, that is one way to minimize any chance for PI resistance.
Until any switch, please note that nelfinavir is a more successful drug when taking with food - in turns out that for this drug, food is the best booster we have - so eat when you take it!
One more point. You didn't mention your CD4 count. Another controversy in our field is whether there is any benefit to being off meds for a while - especially prior to any changing. There are two large US studies testing this - since a pause may minimize some of the damage done by cross resistance; at least, that is what the studies are trying to learn. You can learn more about that on the cpcra web site - the MDR trial or the SMART trial.
Hope that helps.
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