Hoping for a Holiday: Structured Treatment Interruptions

Not too long ago, the idea of stopping anti-HIV therapy was a laughable notion. After all, possible eradication of the virus was at stake. But the hope of curing HIV using highly active antiretroviral therapy (HAART) has faded. Still, experts continued to warn against stopping therapy, including short-term drug holidays. There was a threat that nasty drug-resistant strains of the virus would emerge, along with the possibility that immune function would quickly decline and send patients' health spiraling downwards.

Preliminary results of several small studies reported at the recent 7th Conference on Retroviruses and Opportunistic Infections (CROI) suggest that not only may drug holidays be feasible and safe, but they may also be good for the immune system. While proving these suggestions will require a fair amount of additional research (none of the recent reports offer any guarantees), a dose of springtime optimism is certainly in the air.


Let's face it. HAART is not all that its cracked up to be. For people who started therapy "early," that is, while their viral loads were low and CD4+ cell counts were high, popping pills every day in the face of side effects has been a herculean task. At the same time, there are also patients who desperately needed therapy to bring their high viral loads down and CD4+ cell counts out of the red. Now that many of these folks have been saved, that is, have seen their viral load stay undetectable and their CD4+ cell counts linger at healthy levels, a fundamental question remains: "Why do I need to stay on this stuff?"

It's not at all clear what comes next. There are a number of different possibilities, all of which will drive research over the next few years. Researchers might prove that all patients, once they've started therapy, should remain on it. Another avenue to explore is the possibility of treating HIV like many other chronic diseases, initiating therapy when the immune system shows signs of damage or when a patient experiences symptoms of HIV disease, then stopping therapy when their health improves. And let's not forget new treatments, including novel anti-HIV drugs and immune-based therapies, that may prove to be the magic bullet everyone is waiting for.

In essence, figuring out how to treat HIV remains in a constant state of uncertainty. Structured treatment interruptions, more commonly referred to as "drug holidays," represent the first experimental approach to break with the current HAART model. While drug holidays are by no means ready for the "real world" of HIV care (in other words, they are not yet considered to be safe or effective enough for patients to try them at home) they are definitely the research trend to watch in the coming months.

Structured Treatment Interruptions

While it would be nice to think that patients "sick of it all" were the driving force behind structured treatment interruption (STI) research, the scientific rationale can actually be traced back to a phenomenon seen in a single patient living in Germany. A few years ago, Dr. Franco Lori, a researcher with labs in Pavia, Italy and Georgetown, reported on the highly irregular circumstances of an unnamed patient who, after a series of interruptions in his drug therapy, appeared to have cleared HIV from his body.

". . .the present message remains clear: do not try a drug holiday at home, at least not without the cooperation and direct supervision of a health-care provider."

The "Berlin Patient," as he has come to be known by the world, was participating in a clinical trial for recently infected patients. He entered the study approximately two months after an unsafe sexual experience which, as he feared, resulted in HIV infection. Once enrolled, he started a triple-drug regimen involving indinavir (Crixivan), ddI (Videx), and hydroxyurea (Hydrea), but went off of his drugs after two weeks due to a bacterial infection. He stopped his medication for three days, and predictably, saw his viral load increase. After restarting therapy, his viral load became undetectable. Four months later, he developed hepatitis A, causing his liver enzymes to increase dramatically, requiring that he go off therapy again. But this time, his viral load did not rebound; it stayed undetectable. While he opted to start therapy yet again after his hepatitis got better, he changed his mind and has been off therapy ever since and continues to enjoy an undetectable viral load.

Has he been cured? Dr. Lori says no. He still has a traceable amount of HIV in his lymph nodes. Instead, it appears as if the immune system of this very lucky patient has been able to keep his HIV in check, much like other viral infections that are never totally eradicated from the body (e.g., varicella, the virus responsible for chickenpox).

While no one is sure why this happened, Dr. Lori and his colleagues have offered an intriguing hypothesis. HAART is designed to drastically reduce the amount of virus in the body. While this is definitely a good thing with respect to protecting the immune system from additional damage, it may prevent the immune system from doing what it should be doing in terms of fighting HIV. Perhaps with so little virus in the blood and the lymph nodes, the immune system "forgets" that HIV is there. In turn, it calls off cells programmed to search and destroy the virus. If HAART is stopped, the virus comes back with a vengeance. If HAART is not restarted, the amount of virus will grow considerably, often to levels that overwhelm the immune system.

The key, Dr. Lori argues, is to keep the amount of virus at a controllable level, just enough to keep the immune system active, but not enough to dominate it. This may have been what happened during the brief breaks, the structured treatment interruptions, in the Berlin Patient's therapy. During the first three-day STI, it's possible that just the right amount of virus was released and then controlled to spark the immune system. Then, upon stopping therapy the second time, the immune system was ready and waiting, able to control HIV on its own.

Fast-Forward: New Data

Unfortunately, the Berlin Patient is still a unique case. No other patient who has taken an STI, whether in a clinical trial or more discreetly with a doctor, has come close to achieving this level of success. But, in light of some new data presented at CROI in early February, STIs may still offer some benefits.

Dr. Lori presented one study that received a considerable amount of attention, this time involving a cohort of nine patients taking hydroxyurea in combination with ddI, a relatively weak regimen in comparison to the triple-drug therapies used by most people. For the sake of seeing what would happen upon stopping therapy, these patients were compared to a group of eight patients being treated with a protease inhibitor-based regimen (HAART) who also elected to do an STI.

Seven of the eight patients receiving HAART had undetectable viral loads while on therapy. Within six weeks after the STI, five of these patients saw their viral load increase to levels above 100,000 copies/mL. Among patients receiving only hydroxyurea and ddI, only one of whom had an undetectable viral load while on therapy, none saw their viral load increase to levels greater than 10,000 copies/ mL during the six-week period off treatment.

In discussing these results, Dr. Lori suggested that hydroxyurea and ddI succeeded in keeping patients' viral loads low, but not undetectable. This allowed for small amounts of the virus to circulate in the blood and in the lymph nodes, keeping the immune system stimulated and ready to kick in once therapy was stopped. This might also explain why the HAART-treated patients saw a dramatic increase in viral load, along with a decrease in their CD4+ cell counts, after stopping therapy; keeping levels of the virus low allowed for the immune system to be caught off guard once therapy was halted.

In another study, Dr. Lydia Ruiz and her colleagues in Spain randomized 25 patients -- all of whom had undetectable viral loads for more than two years while on HAART -- either to continue on therapy or to undergo an STI. Therapy was interrupted for 30 days or until patients saw their viral loads increase to levels greater than 3,000 copies/mL, whichever came first. After 30 days off therapy, treatment was resumed for an additional 90 days followed by a second STI.

". . .STIs are by no means fail-proof and may in fact be dangerous in some cases."

After the first STI, viral load failed to rebound in two of the patients during the 30-day drug holiday. Upon restarting therapy, all patients who took a drug holiday did so without any problems -- their viral load went undetectable again and it did not appear that any had developed drug resistance while off therapy. Thus, while more data are needed to see what happens to the patients' viral loads and CD4+ cell counts during and after the second STI, these early results suggest that STIs may be safe. That is, there does not appear to be any immediate danger associated with STIs in patients who have undetectable viral loads upon stopping therapy, at least in these 25 Spanish patients.

Also of interest was a late-breaking report from an international team comprised of researchers in New York, Switzerland, and Spain. According to their report, ten HIV-infected patients treated with HAART for 52 weeks, all of whom had undetectable viral loads for at least 32 weeks, underwent three STIs (one month each) separated by six months of the same triple-drug therapy.

While therapy was stopped three times during this study, upon restarting therapy, all patients were able to drive their viral loads to undetectable levels each time. This helps to confirm Dr. Ruiz' finding that STIs may at least be safe for patients with undetectable viral loads while on therapy. But the news doesn't stop there. An interesting thing occurred in four of the nine patients during the second STI. While their viral loads increased significantly within a few weeks, the amount of virus in their blood samples began to drop all by themselves. What's more, CD4+ and CD8+ cells collected from these patients during the second STI had taken on important HIV-specific characteristics that are not usually present in people who are either on HAART or have yet to start treatment.

Data from a study conducted at Massachusetts General Hospital in Boston have also added to the current level of optimism. Enrolled in this study were seven newly infected patients who were treated with HAART and willing to undergo two STIs lasting two months each. After the first STI, all seven patients saw major increases in their viral loads. But during the second STI, their viral loads failed to go any higher than 5,000 copies/mL. According to the presenters of these results, it seemed as if HAART followed by STIs during the earliest days of HIV infection could help preserve necessary components of the immune system needed to control the virus. Because these immune responses aren't usually seen in most HIV-infected patients, these results are of major interest.

The Message to Go

Now that the foundation has been laid -- we have preliminary data suggesting that STIs might be safe for people who have been on HAART and have undetectable viral loads -- it's time to do some heavy-duty research. It will be important to determine if STIs are safe for people who have been on anti-HIV therapy and have a detectable viral load upon deciding to temporarily stop treatment. As for the potential benefits of STIs, a number of questions remain:

  1. Do STIs help patients recover from side effects, such as lipodystrophy?

  2. Will STIs help boost the immune system's response to HIV for prolonged periods of time? Will these immune responses help slow HIV's destructive activity in the body?

  3. Can STIs be used in combination with immune-based therapies to help boost the immune system responses to HIV even more and help patients live longer healthier lives without anti-HIV drugs?

It's not entirely clear if the data presented at CROI will convince anyone of anything. The results are preliminary and have yet to be duplicated by large clinical trials. Results of these studies are eagerly awaited. And while the race is on to address the uncertainties of STIs, the present message remains clear: do not try a drug holiday at home, at least not without the cooperation and direct supervision of a health-care provider.

According to one case report presented at CROI, an STI can go terribly wrong. The report came from researchers at the University of Alabama in Birmingham and involved a patient who secretly stopped therapy due to financial reasons on the same day he received a vaccination against the flu. Even though the patient had an undetectable viral load and a CD4+ count of almost 750 cells/mm3, his viral load shot up to more than 1 million copies/mL and his CD4+ count dropped to 164 cells/mm3 within three weeks. What's more, the patient required hospitalization due to flu-like symptoms. While the reason for this lightening-fast progression of HIV disease has not been fully evaluated, it's likely that the flu vaccine had a lot to do with it (vaccines have been shown to have a strong effect on viral load in patients not taking anti-HIV therapy). Still, this case report warns that STIs are by no means fail-proof and, may in fact be dangerous in some cases.

Tim Horn is the executive editor of The PRN Notebook_, published by Physicians' Research Network in New York, and a member of CRIA's Research Advisory Committee._