Last year's meeting piqued the interest of the HIV community, the media, and the general public thanks to much-heralded presentations by Dr. David Ho and others. This year, with considerably less hype, many of these same researchers gathered to emend and modify their earlier predictions amid mixed reports, some of treatment successes, some of therapeutic failures.
Perhaps the most inspiring and encouraging information to come from the 5th Conference on Retroviruses concerns the improved survival rates for AIDS patients and the dramatic decreases in the incidence of opportunistic infections that have been seen since the widespread adoption of highly-active antiretroviral therapies. Although some groups did report modest improvements in survival rates before the advent of protease-inhibitor-containing regimens, truly remarkable increases in survival have been seen since the protease inhibitors won F.D.A. approval and triple-combination therapy became the standard of care. This trend, first reported at last year's meeting, has been seen across the board (see "C.D.C. reports substantial drop in AIDS deaths," in Vol. 3, No. 2 of HIV Newsline).
As might be expected, the most significant benefits of highly-active antiretroviral therapy, or HAART, are seen in folks who have never been on therapy before. As a long-term survivor of AIDS -- and a long-time veteran of antiretroviral therapy -- I sometimes liken treatment decisions to playing a poker game. Some things we know, many things we don't, and everything is a gamble. Being antiretroviral-naïve is a bit like being dealt a wild card. Each of us is dealt one, which we can use at any time. That wild card is initial therapy, and we can play it early in the game or hold it back until the stakes are higher. It gives us a better chance of winning one of the hands we are dealt, but that doesn't mean we won't win other hands.
Having played my own wild card during the days of AZT monotherapy -- which gives you an idea of how many moons I have been on therapy -- I sympathize and identify with AIDS patients who have also used their wild cards, and who complain that data from clinical studies conducted in antiretroviral-naïve patients aren't relevant to their situation. They want to know what drug combinations work best in people like themselves, people who have been through a dozen different drug combinations in the last dozen years.
We may get dealt only one wild card, but that doesn't mean that there are no more good cards to play once we've used our best one -- and we need to know what those winning combinations are. (One potential winner is described in the Newsline section of this issue: see "Superior Six-Pack.") As more drugs become available -- and more people with HIV live longer -- clinical research will have to give greater consideration to "real world" uses of these therapies.
This question has perplexed the AIDS community from the moment AZT became available. There are those who argue forcefully that the best approach is to hit the virus as hard as possible as early as possible, in the hope that the virus can be knocked out before it entrenches itself in the bone marrow, lymph nodes, and other so-called sanctuary sites. Others, recognizing that even the most aggressive therapy does not eliminate all the virus in a person's body -- and knowing that resistance develops over time to all antiretroviral agents -- have argued that it is better to delay therapy until viral load begins to rise (indicating that the immune system is weakening and needs assistance in its all-out war against HIV).
At the 5th Conference on Retroviruses this all-important question was addressed by Dr. Bruce Walker and others who have studied how newly infected individuals respond to HAART. According to these researchers, the sooner HAART is initiated after HIV infection occurs, the more likely one is to stave off significant immune damage. Dr. Walker observed that much of this damage is done in the days and weeks following acute infection. If potent combination antiretroviral therapy is begun during this narrow "window of opportunity," a considerable amount of immune function can be preserved. According to Dr. Walker, HAART will not "cure" someone who has been recently infected with HIV, but it may well convert that person from a "rapid progressor" to a "long-term non-progressor." And in the absence of a cure, that is an extremely desirable goal.
Dr. Walker's findings provide a rationale for very early, very aggressive treatment of individuals who have just been infected with HIV, but these findings offer little rationale for aggressive treatment of individuals who have passed beyond the stage of primary infection. At that point the initial damage has already been done to the immune system, and in such individuals a stable CD4 count and low viral load may mean that the damaged immune system is effectively suppressing most of the virus that is being produced in the body. Of course, treatment should be considered for those whose viral load remains high after acute infection.
During this period of virtual equilibrium, which can last for years or even decades, people with HIV may want to defer HAART therapy. Some are even suggesting that individuals in this situation may want to begin therapy with a combination of two or more nucleosides, or two nucleosides and a non-nucleoside reverse-transcriptase inhibitor -- deferring use of the more potent, protease-inhibitor-containing combinations until a later date.
On the antiretroviral front, study after study presented at this year's conference showed that the first protease inhibitor a person takes has the best anti-HIV activity. Subsequent regimens, even those that contain one or more new protease inhibitors, are likely to be less effective, due to cross-resistance among all currently available compounds. These findings reinforce the importance of developing a treatment strategy, taking into consideration not only the first but also the second and third regimen that will be used. It also reinforces how important it is to choose a powerful initial regimen -- and then to adhere to it. This is clearly not the time to save the best for last!
A number of the presentations made at this year's retrovirus conference reported on the effectiveness of multidrug regimens that include more than one protease inhibitor. We already know that when ritonavir (Norvir®) and the soft-gel formulation of saquinavir (Fortovase®) are taken together, the two drugs act synergistically: you get a many-fold increase in the levels of active drug in the bloodstream with no increase in side effects. It appears that other protease inhibitors may also act synergistically when taken together. Expect reports on these combinations in the Newsline section of this publication in the months to come.
In addition, preliminary data on twice-daily dosing of both nelfinavir (Viracept®) and indinavir (Crixivan®), when taken as part of certain multidrug regimens, suggest that this dosing schedule may be as effective as the currently approved thrice-daily schedule (see "Simpler Is Better" in the Newsline section of this issue). This is great news for all of us on combination therapy: the less complicated our daily dosing schedule is, the less chance there is that we will miss taking our prescribed pills at the prescribed times.
For treatment-experienced patients, the data showed that even those of us who have moved from monotherapy to dual therapy to three- and four-drug combination therapy can derive some benefit from some of the new antiretroviral regimens. As we reported in the last issue of AIDS Care, researchers have found that even extensively pretreated individuals respond to the combination of d4T and 3TC (see "Combination of d4T and 3TC proves effective in patients whose previous antiretroviral treatment has made them resistant to AZT," Vol. 2, No. 1). This two-nucleoside combination appears to be a viable alternative for people who are intolerant of, or resistant to, AZT. As more concrete findings are made available, we will summarize them for you in the newsline section of AIDS Care.
Perhaps the most interesting news on the treatment front concerns hydroxyurea. Although hydroxyurea is not an antiretroviral agent, it appears to enhance the effectiveness of some anti-HIV therapies. In a small study that included a number of antiretroviral-experienced patients, volunteers took hydroxyurea in combination with ddI and d4T. The response to this novel combination was excellent, and one treated patient has no detectable virus in his bloodstream 12 months after he stopped taking the three-drug combination (see "Help from Hydroxyurea" in the Newsline section of this issue). These dramatic results, if confirmed in larger studies, would make hydroxyurea plus ddI an important adjunct to current therapies, particularly in patients who have been extensively treated and have fewer therapeutic options.
The long-term side effects of chronic antiretroviral therapy are a matter of increasing concern to the AIDS community, especially now that people with HIV are living longer thanks to HAART. One new and previously unreported result of long-term therapy is what HIV experts call lipodystrophy, meaning the accumulation of unusual fatty deposits on the back and belly. Nicknamed "protease paunch" when it occurs on the lower abdomen and "buffalo hump" when it occurs on the upper back, this anatomical abnormality appears to be more of a cosmetic problem than a health threat.
An entire section at this year's retrovirus conference was dedicated to reports of this treatment-related phenomenon, which can also include thickening of the torso, breast enlargement and, paradoxically, wasting of the arms and legs. Some of these changes were so dramatic that several affected women appeared to be in the last stages of pregnancy (see "Combination therapy can lead to unusual fat deposits," Vol. 2, No. 1).
In general, these changes appear to involve nothing more than fat redistribution. Curiously, "protease paunch" and "buffalo hump" tend to occur in patients who are responding well to therapy. Several researchers have noted that this condition is not specific to any one class of antiretroviral agent; they report that they saw it in a few patients prior to the approval of the protease inhibitors.
It has been suggested that perhaps these fatty deposits are some sort of autoimmune response, triggered by the immune reconstitution that occurs with HAART, but Dr. David Cooper has proposed that "protease paunch" and other accumulations of fat are a lipid-binding problem that is indeed caused by protease inhibitor therapy. At the moment, the cause or causes are unknown. Until we better understand this phenomenon, people living with these disfiguring fat deposits will rightly be concerned about the long-term implications of these physiological changes.
Not all effects of antiretroviral therapy are negative. One entirely positive ancillary effect of HAART has been a steep decline in the rates of all opportunistic infections in patients on combination therapies that contain a protease inhibitor. Overall, the incidence of OIs has dropped a whopping 70% since the protease inhibitors became widely available two years ago.
An even more remarkable result of HAART has been the resolution of symptoms or actual eradication of certain OIs that were once regarded as incurable. In the last issue of AIDS Care we reported the possible cure of MAC infections in people with advanced HIV disease, and we noted that some patients with CMV retinitis have had their symptoms resolve as a result of HAART therapy (see "HAART therapy leads to resolution of MAC infection," Vol. 2, No. 1). There have also been reports that HAART has a positive therapeutic impact on such previously untreatable OIs as progressive multifocal leukoencephalopathy, cryptosporidiosis, and microsporidiosis.
This is incredibly exciting news for those of us who have been living with HIV for many years. In the short term, it may mean that we can eventually stop taking the drugs now used to prevent or treat potentially fatal OIs. In the long term it may mean that our risk of dying will be reduced even if our antiretrovirals do not work indefinitely. After all, it is opportunistic infections, not HIV infection itself, that cause death, and if we can reduce or even eliminate some of these potential threats to our health we may benefit even if there is a resurgence of viral activity.
It is important to remember that even though the incidence of OIs has fallen sharply, opportunistic infections remain a potential threat to people with advanced HIV disease, especially those with CD4 counts below 50 -- and no one should abandon OI prophylaxis or suppressive therapy without consulting an expert on HIV infection. For those who respond well to HAART, some level of immune recovery does appear to occur, but this immune reconstitution, as it is called, does not happen immediately -- and we are not at all sure that the CD4 cells that are regained with HAART are as a good as the ones lost to HIV infection. We do know that HAART often fails to suppress subclinical infections that have not manifested prior to the initiation of therapy, and in some cases the initiation of HAART has caused unusual inflammatory reactions and active infections (see "You may be at heightened risk for MAC when you begin combination therapy," Vol. 2, No. 1).
As a person living with AIDS, I came away from the 5th Conference on Retroviruses and Opportunistic Infections with a lot of valuable information -- and two observations, which I believe are shared by many in the AIDS community. The first is that this important meeting has become so large, and so dominated by specific agendas, that important and informative research often gets shunted off center stage. The need for novel approaches and fresh thinking is crucial at this point in the epidemic, and it will only become more crucial as people with HIV live longer -- and, in the process, develop resistance to most of the drugs now available to them. The organizers of next year's retrovirus conference should take a position of strong leadership -- by choosing speakers and symposium topics that showcase the most creative minds and promote the most fruitful dialogue.
My second observation is that this year's conference proved to be a kind of coming of age for immunology. As the meeting progressed it became increasingly evident that future AIDS research must focus even more on the impact that HIV has on the immune system -- because therein lies the key to transforming HIV into a manageable, perhaps even a curable, disease. A few years ago the principal focus of research was the virus itself. This year's retrovirus meeting showed us that if we really want to conquer HIV we must expand our vision to include the host and target for the virus -- the immune system itself.
Dawn Averitt is founder of WISE (Women's Information Service and Exchange).