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Being Alive
Success Out of "Failure": Good News for Many with Still-Detectable Viral Loads
Walt Senterfitt
April 5, 1998
Being Alive 1998 Apr 5: 1

We have rapidly come to accept "undetectable" viral loads as the gold standard for successful HIV treatment. The quicker one's viral load reaches undetectability the better. Rapid undetectability on the newer "ultrasensitive" tests is best of all. A measurable viral load after it was once undetectable is regarded as a sign of "failure." Never reaching undetectability is also considered "failure," though perhaps of a milder sort.

It certainly is discouraging news for the person with HIV or AIDS to hear these words from one's provider. What to do in cases of drugs failing is a big challenge at the moment, with no clear answers. Generally, the preferred choice is to switch to another drug combination, ideally a combination containing no drugs that one has taken before. Frequently, though, a switch in regimen, with, say a different protease inhibitor, has disappointing results. For those who have had AIDS for some time, and have taken most available drugs earlier, this option may not even be available.

Two recent studies show that even with "failure" indicated by a rising viral load, many people continue to have "success" in terms of lasting T-cell rises and freedom from OIs (opportunistic infections). In technical medical terms, this status is called "virologic but not clinical or immunologic failure." One of these studies, presented at the Chicago Retrovirus Conference, was by Dr. Steve Deeks of San Francisco General Hospital and the other was recently published as a letter in the British medical journal, The Lancet, by the Swiss HIV Cohort Study based in Lausanne.

San Francisco General Study Last fall, we were all discouraged to hear reports of Dr. Deeks' presentation at a scientific meeting (ICAAC). His review of medical charts of people treated with combination therapy at San Francisco General Hospital showed that more than half were later "failing" or again had detectable and/or rising viral loads. The media picked up the story with flamboyant sound bites like "protease no good for more than half." We in the HIV community press tried to go to some lengths to explain that this group comprised mostly people who started with fairly low T-cell counts and had extensive prior exposure to antiviral medications in mono- and double-combination therapies. In other words, they started with a high level of drug resistance and already severely damaged immune systems.

Since then (and after feeling badly about the discouraging effect of the news coverage of his ICAAC presentation), Dr. Deeks has taken a closer look at those 150 or so "virologic failure" patients at San Francisco General. This group all had two or more consecutive detectable viral load measurements (500 or more copies per ml) after having been on treatment with a protease-containing combination for at least 6 months. For those who had a recorded viral load before starting combination therapy, the average viral load before starting was about 70,000 and the average T-cell count was 82. Then he looked at their records for a period covering an average of 18 months, including at least 12 months after the second detectable viral load.

The results were better than he expected. Overall, only three had died, all from causes that had begun before protease inhibitor therapy was started. Furthermore, there were only eight new AIDS-defining events: two lymphomas, two PCP, one cryptococcal meningitis, one KS, one PML and one invasive aspergillus. There were no new cases of CMV or MAC.

For analyzing T-cell increases, he divided the group into three categories: those whose viral loads came down and stayed down on combination therapy but never reached undetectability (called durable responders); those whose viral load dropped at least one log at one point but later rose to be close to baseline or higher (transient responders); and those whose viral load never dropped as much as one log after starting treatment (non-responders).

After 18 months on treatment, each category still had average T-cell counts higher than what they started with. The non-responders had a T-cell rise of 50, the transient responders had a rise of more than 100, and the durable responders had over 150. The fact that new illnesses were much rarer than would have been expected gives indirect evidence that these T-cell rises were not just empty numbers, or ineffective T-cells, but were associated with a real restitution of some immune function.

Dr. Deeks was careful to point out the limitations of his study-it was retrospective in nature and the period of follow up was fairly short. We do not know how long the benefit will last.

The Swiss Cohort Study The Swiss HIV Cohort Study has found rates of virologic failure in advanced and drug-experienced PWAs similar to that found at San Francisco General and other study centers. About 49% of people in this cohort taking HAART (highly active antiretroviral therapy) did not achieve undetectable viral loads, that is, viral loads below 500 copies per ml.

Their Lancet letter (in the issue dated March 7, 1998) described all 101 patients in their study who started HAART before February 1997 and received the drugs for at least three months. The baseline for this group was an average T-cell count of 162; 66% had shown evidence of virologic failure on their previous mono- or dual-therapy regimens. After 12 months, 93% of the whole group had higher T-cell counts than they began with, but 49 of them had detectable viral loads.

At the end of one year, those who became undetectable and stayed that way had an average increase of 138 T-cells. Those who were transiently undetectable did almost as well with an average T-cell rise of 130.

The real surprise came in looking at the 49 who were never undetectable the whole year. For the 33 who continued taking their medications anyway, the average T-cell increase was 105-not that far below those who reached undetectability. Even the 16 who stopped or interrupted treatment (for an average of 55 days) had an average rise at the end of the year of 57 T-cells.

The study compared these rises to their cohort's experience before the coming of HAART. The average number of T-cells lost per year was 60. With double-combination nucleoside therapy, the decline stopped, but the gains were small-no more than 40 T-cells after one year. The authors rightly inferred from this comparison that something else must be going on with HAART besides viral suppression.

They looked at 15 of the patients with continued detectable viral loads but T-cell rises and found that all 15 had quite an accumulation of drug-resistance mutations. They speculate, therefore, that heavily-mutated viruses may be less "fit" for reproduction or causing damage to the immune system and/or that small reductions in viral load and a break in the killing of T-cells may allow time for the immune system to make small but significant restorations.

Practical Implications In practical terms, these studies give new hope to those who have exhausted all their antiviral drug choices and still have detectable viral loads. They give reason to stay on therapy, if one can tolerate it and if no better options are available as yet, even if viral loads are rising. We cannot expect these benefits in T-cell counts to last indefinitely, but they may well give tens of thousands of people enough immune system boost to hang on until more drugs are available and we know how to use them better. Keep taking your medicine! Although OIs seem to go way down with these T-cell rises coupled with detectable viral loads, they do not cease entirely. The means there is no reason yet to stop taking prophylaxis as otherwise indicated, and this is particularly important for those with low T-cells and small or no rises in T-cells on HAART. Don't stop your prophylaxis! The increasing evidence that accumulating drug-resistant mutations costs the virus a lot in terms of its capacities for deadliness is heartening indeed (pardon the pun). This is the time for increased research attention to resistance, and to practical studies of how to measure resistance better and how to use resistance assays in day-to-day decision making. Up to now, HIV has gradually worn out our valiant and pretty-damn-effective immune systems. Maybe we are about to turn the tables. We're gonna wear your ass out, HIV! It is also time to up the ante on looking for immune boosters and immune restoration strategies. These studies amplify what we are hearing from a hundred sources: it is not just the virus (stupid!) but also the immune system. We still have much yet to learn about how HIV actually damages and destroys immune systems. A more promising way to put it is the flip side: we have much more to learn about how to strengthen and restore immune systems. Let's get on with it.

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