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Report from the HAARTland

April 1999

A note from The field of medicine is constantly evolving. As a result, parts of this article may be outdated. Please keep this in mind, and be sure to visit other parts of our site for more recent information!

This year's Sixth Conference on Retroviruses and Opportunistic Infections, held in Chicago January 31 to February 4, presented a mixed bag of new data on the treatment of HIV disease. Depending on whose needs were at stake, conference presentations provided either encouragement by offering a number of potentially improved first line therapy options, or frustration by showing few prospects for people who have already exhausted current therapy options. If there was any bottom line message appropriate for everyone, it was that making the best possible use of currently available therapies remains the most important challenge faced by every HIV-infected person.

Options for "Third Line" Therapy?

Good news at the far reaches of the HIV therapy experience -- for people who have become unresponsive or intolerant to all currently available therapies -- was limited perhaps to one small study of a single drug. An initial dose-ranging study of the new fusion inhibitor, T-20 (pentafuside), gave the drug to one of the most difficult patient populations ever treated in a clinical trial setting. Volunteers in the study had previously used an average of nine drugs, including three protease inhibitors. Despite the high level of resistance to previously used treatments, people using T-20 showed at least some significant suppression of HIV, even when it was used alone (i.e. not in combination with other anti-HIV medications). There were, of course, serious limitations to this finding and no one suggests that the drug should be used alone. The details of the success and tribulations of the T-20 study are described in "Third Line Therapy Options."

"If there was any bottom line message appropriate for everyone, it was that making the best possible use of currently available therapies remains the most important challenge faced by every HIV-infected person."

The next glimmer of hope for people losing their response to current therapies involved a surprising finding in a French study. The study suggested that the new protease inhibitor, amprenavir, might work better than other protease inhibitors in people who previously developed resistance to another drug of this class. The usefulness of this finding, however, may be limited to people who have had prior experience with only one other protease inhibitor. Data from studies with people who had become unresponsive to multiple protease inhibitors weren't nearly as encouraging. More about amprenavir can be found in the box "Expanded Access Programs."

Most other news for people in need of third line therapy (people who have failed two or more previous treatment combinations) centered on the use of a combination of a large number of drugs. While typical antiviral regimens use three or at most four drugs, new third line regimens employ anywhere from five to nine drugs. While a few small studies employing this methodology reported seemingly encouraging results, many scientists and clinicians remain skeptical about long-term tolerance and adherence to the extremely complex dosing requirements the drugs require. Still, it's nice to know that something appears to work. More information can be found in "Third Line Therapy Options."

Beyond these meager examples, hope for the person with extensive prior use of anti-HIV therapy came only from a sprinkling of reports about new drugs in early stages of development, most commonly new protease inhibitors and new non-nucleoside reverse transcriptase inhibitors (NNRTIs). The sponsors of these experimental drugs often assert the hope that the drugs will be active despite prior resistance to other drugs in the same class. However, history suggests that such claims are all too easy to make in early stages of drug development and vastly more difficult to prove in later clinical applications.

"Class-Sparing" Initial (First Line) Therapy

For people just starting therapy, the outlook is somewhat improved. Debate continues about the various "protease inhibitor-sparing" regimens and the even newer "NNRTI and protease inhibitor-sparing" regimens. In general, the goal of these "class-sparing" regimens is to save one or more classes of antiviral drugs for later use, hopefully delaying side effects and achieving a longer period of effective treatment. The first protease inihibitor-sparing regimen was described nearly two years ago at the Vancouver conference. A study of nevirapine (Viramune®) plus two older nucleoside drugs, AZT (zidovudine, Retrovir®) and ddI (didanosine, Videx®), appeared to suppress virus to below the limit of detection of HIV RNA tests for about a year. Though this early study used a less than ideal combination, it clearly demonstrated that three-drug combinations without a protease inhibitor could be effective, at least for a number of people just beginning therapy. The concept was bolstered by reports the following year of an ongoing study of efavirenz (Sustiva®) plus two nucleosides (AZT and 3TC). After 48 weeks, this combination now appears to be roughly equivalent in potency to a typical protease inhibitor-based three-drug combination.

This year, additional studies with nevira-pine-based or delavirdine-based (Rescriptor®) three-drug combinations seemed to confirm the picture. Due to differences in how the studies were run and analyzed, however, it is not currently possible to say whether any one NNRTI makes a better basis for combinations than others. Even more importantly, each of the three NNRTIs differs somewhat in side effects, drug interactions and cost, which suggests that choosing one will always be a somewhat individual choice.

Why would anyone want to use a NNRTI combination instead of protease inhibitor combination? Proponents of this approach hope to solve three problems. First, the NNRTI class is generally easier to use than protease inhibitors (PIs), making adherence easier and more likely. Second, there is a growing concern about long-term side effects associated with protease inhibitors, such as the various forms of fat redistribution. If these problems are truly caused by PIs, then it might make sense to use an alternative regimen as first line therapy. That way, the side effects of PIs could be delayed. Third, preserving the use of potent PIs for later use might offer a better long-term strategy, allowing people to fully utilize the benefits of two other classes of drugs before moving to the PIs.

However, not everyone agrees that starting treatment with a NNRTI-based combination is the wisest approach, even if it seems to work fairly well. Critics point out that only protease inhibitor-based combinations have thus far demonstrated long-term viral suppression for three years or more, while PI-sparing regimens have only been tested for a year. Another concern is that using a NNRTI as first line therapy will probably eliminate this whole class of drugs later in the course of HIV infection. This is particularly a concern if a person needs third line therapy after protease inhibitors have begun to fail. For people at this end of the treatment spectrum, often the only thing that works is a combination of many drugs, including first time use of the NNRTI class of drugs. If the NNRTI drugs were used earlier (to the point of failure), there is almost nowhere else to turn for third line therapy. Therefore, many physicians and researchers believe it may be more important to preserve the NNRTI class for later use. The arguments on both sides of the issue seem reasonable.

So if using a NNRTI combination to "spare" the protease inhibitor for later use might not be the wisest strategy, what about combinations that spare both the NNRTI and PI classes for later use? If sparing one class of drugs has some advantages, why not spare two classes? Studies have already begun to test this approach. These NNRTI and PI-sparing regimens employ three-drug regimens made up entirely of nucleoside analogue drugs (NARTIs), or two NARTIs plus hydroxyurea. Some of these studies have shown fairly impressive success in suppressing virus below the limit of detection in a majority of users. None, however, have yet reported results beyond 24 weeks. If this kind of regimen can effectively keep viral levels below the limit of detection in most people for a year or more, this may present an important option for wringing the longest possible period of success from the currently available drugs. These studies are described in "Class-Sparing Treatment Therapies."

Of course, no strategy satisfies everyone. Still another group of researchers wonders whether the best overall approach might simply be to combine all three current classes of drugs into a single, highly potent mix. Theoretical arguments suggest this approach might lead to the best and longest suppression of HIV. But when such a regimen fails, it runs the risk of using up all three classes of drugs at once.

Whatever the answer, the overall message here seems to be that there are now several viable approaches for starting first line therapy. Each has theoretical advantages and disadvantages, but there are no long-term studies which can tell us which makes for the best long-term strategy. Read more about these and other initial therapy options in "Options for First Line Therapy."

Coping with Long-Term Therapy

Many patients and physicians had high hopes that the Chicago conference would provide greater understanding of the side effect problems facing people on aggressive combination therapy. Concerns have reached a serious level about a class of side effects generally referred to as metabolic complications in therapy. The most widely discussed complication is the syndrome of effects sometimes called lipodystrophy, simply translated as a disturbance in the way the body processes fats. The effects of lipodystrophy include obvious physical effects such as the following:

  • the accumulation of hard fatty deposits at the top of the spine (buffalo hump),

  • loss of fat or wasting in the face and limbs (facial/limb wasting),

  • accumulation of fat in the abdomen (or protease paunch, though it may not be strictly related to PIs),

  • breast enlargement, in both women and men.

Related phenomena detected by lab tests include elevated cholesterol and triglyceride levels, insulin resistance and diabetes.

Despite an entire symposium devoted to these troubling issues, most people came away from the Chicago Conference disappointed since so little new information was offered. For the most part, presentations were simply updates or restatements of others made last summer in Geneva. There was still no agreement about the exact cause or mechanism of the problems, and widespread disagreement on how often they occur.

Little encouraging treatment information was offered. A few very small studies suggested that switching from protease inhibitors to NNRTI-based combinations might help, but the data were scarce and over-promoted. The long delay in addressing these concerns points to a possible problem in the current oversight of newly approved drugs-no one seems to be responsible for tracking the consequences of unforeseen side effects.

Perhaps the only positive note on this subject came from a very preliminary laboratory study at Glaxo Wellcome. Their initial data seem to define a mechanism faulting some, but not all, protease inhibitors. If their data are correct -- and this is a large IF -- they suggest that at least one protease inhibitor [theirs, amprenavir (Agenerase®)] might not contribute to lipodystrophy. But this is exactly the rub: it's too early to know if they are right and too easy to question their objectivity until further data is available. Nonetheless, hints in their early data support the possibility that there may be a difference with this drug. Time will tell.

There was considerable discussion about another aspect of long-term therapy, namely how to get people off therapy altogether. The reason for addressing the topic seem clear: it is highly unlikely that people will be able to remain on the current drugs for a lifetime. Aside from the accumulation of side effects, large numbers of people are reporting great weariness with constant adherence to drug regimens. A few years may be possible, but more and more people are pessimistic about their ability to "stay with the program" for the rest of their lives.

Two different discussions are underway among researchers about the issue of "going off therapy." Unfortunately, media reporting on the subject has lumped the two very different concepts together. In fact, they are two entirely different theories that apply to entirely different patient populations. For a more thorough discussion of pulsed therapy and strategic interruptions of therapy, see "Pulsed Therapy and Structured Interruptions of Treatment."

Yet another concern associated with long-term therapy is the broad question of how long it will continue to work, even under the best circumstances. A positive note was sounded in recent data from an early study of indinavir (Crixivan®). After three years, about two-thirds of the study participants were able to stay on therapy and maintain viral load levels below the limit of detection. Although most researchers saw this as surprisingly good news, at least one major media outlet instead chose to characterize it as a sign of failure, proclaiming instead that one-third had failed therapy after three years. Certainly, the glass is more than half full, so the media pessimism was surprising. It is highly unlikely that any researcher in recent years would have been sufficiently confident to predict continued success for three years for two-thirds of people using the new drugs. Apparently, the media expected 100% success.

Perhaps more encouraging was the finding that even though an increasing number of people were "failing" on therapy -- defined today as having detectable viral load -- most continued to do well clinically. In fact, many of the people "failing" based on viral load measures actually saw their CD4+ cell counts continue to rise long afterward. Whether this is a unique property of protease inhibitors or an indictment of our current definition of "failure" is unclear. It is likely some of both.

A final but sobering note on long-term therapy was the widely discussed -- but still anecdotal -- observation that the rate of new opportunistic infections was indeed increasing, and in all likelihood, so too is the death rate. Current public figures do not yet reflect these apparent trends, but public figures tend to lag nearly a year behind.

"The 'hit it hard, hit it early' mantra of 1996 looks increasingly naïve today in terms of long-term complications of therapy and the lack of new treatment options that work well after initial therapies fail. Knowing what we do today, there is a reasonable case to be made for delaying therapy somewhat to avoid starting people on the cycle of potential side effects and drug resistance any earlier than necessary."

Impact on Treatment Strategies

The current state of knowledge of HIV treatment, as presented at the Sixth Conference on Retroviruses and Opportunistic Infections, raised more questions about treatment strategy, but did little or nothing to answer them. People just beginning therapy for the first time clearly have the greatest number of options ever available. Yet selecting from among those options impacts all future choices for second and third line therapy.

The most obvious dilemma centers around the optimal time to use the NNRTI class of drugs represented by efavirenz, nevirapine and delavirdine. Data suggest that they can be used effectively in first line therapy, but that doesn't necessarily mean this is the best time to use them. For now, they also play a critical and unique role for people who have become resistant to a first or second line protease inhibitor regimen. If the NNRTIs are used in early, first line therapy, by definition they won't be useful later. Just which strategy results in the longest possible life is unclear and there are no data to guide this decision.

It is also unclear whether the best initial overall strategy, is (1) a three-drug, all-nucleoside (NARTI) regimen; (2) a mix of a NNRTI and two NARTIs; (3) a protease inhibitor and two NARTIs; or (4) a regimen which combines one or more classes of drugs. There is logic, if not data, to support all these choices. Yet each has different consequences later on down the line. Please refer to the Drug ID Chart below for assistance.

Drug Identification Chart

Protease Inhibitors (PIs)
AMP amprenavir Agenerase® Glaxo Wellcome
IDV indinavir Crixivan® Merck
NFV nelfinavir Viracept® Agouron
SQVhgc saquinavir hard gel capsule Invirase® Hoffman La Roche
SQVsgc saquinavir soft gel capsule Fortovase® Hoffman La Roche
RTV  ritonavir Norvir® Abbott Labs
Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
DLV delavirdine Rescriptor® Pharmacia & Upjohn
EFV efavirenz Sustiva® Dupont Pharma
NVP nevirapine Viramune® Boehringer Ingelheim
Nucleoside Analog Reverse Transcriptase Inhibitors (NARTIs)
ABC abacavir Ziagen® Glaxo Wellcome
AZT zidovudine Retrovir® Glaxo Wellcome
AZT+3TC --- Combivir® Glaxo Wellcome
ddC zalcitabine Hivid® Hoffman La Roche
ddI didanosine Videx® Bristol-Myers Squibb
d4T stavudine Zerit® Bristol-Myers Squibb
3TC lamivudine Epivir® Glaxo Wellcome
Nucleotide Analog Reverse Transcriptase Inhibitor (NtARTI)
ADV adefovir Preveon® Gilead Sciences
Ribonucleotide Reductase Inhibitor (RRI)
HU   hydroxyurea Hydrea® Bristol-Myers Squibb

People struggling with lipodystrophy problems face similar, uncharted courses of action. Should they abandon an effective PI regimen for an alternative based on a NNRTI or three NARTIs? What about switching to a different protease inhibitor, such as amprenavir?

Another strategy question looms over the fundamental issue of when to start therapy in the first place. The "hit it hard, hit it early" mantra of 1996 looks increasingly naïve today in light of the long-term complications of therapy and the lack of new treatment options that work well after initial therapies fail. Knowing what we do today, a reasonable case can be made for delaying therapy somewhat to avoid starting people on the cycle of potential side effects and drug resistance any earlier than necessary. In truth, the actual data from 1996 never recommended treatment for all HIV-infected people, nor did any other guideline. Yet many physicians interpreted the words of researchers to suggest exactly that. This question is further complicated by recent data demonstrating that men and women tend to have somewhat different levels of viral load at equivalent CD4+ cell counts. That leads to debate about whether there should be gender differences in deciding when to start therapy. For more information on "Gender Difference in Viral Load," see article.

"A final but sobering note on long-term therapy was the observation that the rate of new opportunistic infections was going up, and in all likelihood, so too is the death rate. Current public figures do not reflect these apparent trends, but they tend to lag nearly a year behind."

For the foreseeable future, there is no reason to expect clear answers to any of these questions, since little is being done to answer them. The lack of long-term "strategy" trials -- proposed here and by other activists many years ago -- continues to haunt the field of HIV research, forcing people with HIV/AIDS and physicians to make no more than best guess decisions about many critical issues. In this context, it is far too easy to have decisions influenced by drug company promotions, advertising and simplistic physician preferences.

Perhaps more than at any other time in the history of the epidemic, people today need to be as well informed as possible about the issues they face. There is no one right answer for everyone, and everyone must understand the implications and long-term consequences of the choices they make. Clearly, patient empowerment and knowledge may be more important today than any individual medication offered for the treatment of HIV disease.

Back to the Project Inform Perspective April 1999 contents page.

A note from The field of medicine is constantly evolving. As a result, parts of this article may be outdated. Please keep this in mind, and be sure to visit other parts of our site for more recent information!

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This article was provided by Project Inform. It is a part of the publication Project Inform Perspective. Visit Project Inform's website to find out more about their activities, publications and services.
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