Drug Failure and Other Pleasant Surprises
As the HIV epidemic enters its third decade, the only thing that we can be truly certain of is that nothing in HIV research is certain. Take, for example, the deafening mantra that ushered in the era of highly active antiretroviral therapy (HAART): keep viral load undetectable for three years and everything will be all right. As usual, things don't work out the way we hope they will. Using mathematical probabilities, we now know that people living with HIV (PLHIV) will need to keep their viral loads undetectable for approximately 23 years in order to clear the virus from their bodies using the drugs that are currently available. Yet, almost 50% of people who started HAART a little over three years ago (in most clinical trials) are now beginning to see their viral loads peek out from their undetectable slumber. Compound this fact with the 23-year hypothesis, and things are beginning to look pretty bad. Or are they?
Drug failure, it turns out, isn't quite as bad as some experts thought it might be. Not too long ago many researchers and clinicians hypothesized that "virologic failure" (an increase in viral load while on HAART) would lead to a rapid decline in T-cells and inevitable disease progression. This, however, has turned out to be precisely not the case for some PLHIV experiencing virologic failure. For a few PLHIV, T-cells are actually continuing to increase, despite the fact that viral load rears its ugly head. This is known as "immunologic discordance." There were several reports at the 6th Conference on Retroviruses and Opportunistic Infections in Chicago in February regarding this particular phenomenon. While it hasn't yet been determined what percentage of PLHIV experience such surprising responses, there have been some intelligent guesses.
In one study involving 2,236 HAART-popping PLHIV in Paris, almost 380 (17%) whose viral loads increased while on therapy saw their T-cells rise as well. After six months, the researchers concluded that these PLHIV were no more likely to progress to AIDS than PLHIV who maintained both undetectable viral loads and high T-cells. But how long does this discordance last? According to two additional studies presented at the Retrovirus conference, at least a year.
One team of researchers at Rush Medical Center in Chicago compared the rates of disease progression -- that is, progression to AIDS -- in three different groups of PLHIV taking HAART. One group consisted of 45 people whose viral loads remained undetectable (<500 copies/mL). Another group consisted of 35 people who saw their viral loads increase to levels between 500 and 10,000 copies/mL. And a third group was made up of 31 people whose viral loads increased to levels above 10,000 copies/mL. Not surprisingly, the best Tcell count increases -- averaging 124 cells higher than before HAART -- were seen in PLHIV whose viral loads remained undetectable for at least 54 weeks of therapy. In PLHIV who saw their viral loads increase to levels between 500 and 10,000, there was still a T-cell increase of approximately 72 cells. After the study statisticians had their say, there didn't appear to be a difference between the two groups in regards to the T-cell counts and risks of disease progression -- even after a year of virologic failure.
A group from the University of California, San Francisco (UCSF) reported similar results in a study of 180 people. After 72 weeks (I 1/2 years) of virologic failure, people's T-cell counts hung in there -- provided that their viral loads didn't increase to levels higher than 10,000 copies/mL. It is important to note, however, that both the Rush Medical Center and UCSF studies found that PLHIV who experienced virologic failure saw their T-cell counts increase more slowly than PLHIV with undetectable viral loads. Still, there doesn't appear to be much of a difference between these two groups, even after a year and a half.
While the cause of immunologic discordance hasn't been determined, there was one preliminary report at the Retrovirus conference indicating that drug-resistant strains of HIV might be to blame. According to the report, drug-resistant virus -- which is the main cause of virologic failure -- is less fit than the healthy, "wild type" virus that most people are infected with. In turn, the drug-resistant virus is slightly disabled and will have a slightly more difficult time causing damage to T-cells and the rest of the immune system.
Do these reports suggest that drug resistance and virologic failure are possibly good things? Not at all. For starters, there is no telling if the drug-resistant strains of HIV will eventually mutate to "self-correct" their faults to provide themselves with a survival advantage especially if HAART is eventually stopped. Second, it might be possible that the increasing T-cells in the presence of rebounding viral load is a bad thing, since T-cells can technically feed the fire that HIV needs to grow. Third, only a small percentage of PLHIV are experiencing immunologic discordance and, even for these people, it isn't clear how long this will last or what the outcome may be. Still, these reports do offer some peace of mind and certainly support the classic saying that every cloud truly does have a silver lining.
Back to the Notes from the Underground Spring 1999 Contents Page.
Late Breaker No. LB9: High Frequency of Antiretroviral Drug Resistance in HIV-1 from Recently Infected Therapy Naïve Individuals
This article was provided by PWA Health Group. It is a part of the publication Notes From the Underground.