Protease inhibitors: opium of the masses?

Background. The development of protease inhibitors (PIs) dramatically changed the landscape of HIV/AIDS treatment. Morbidity and mortality among HIV-infected persons decreased.[1] This much is undeniable. There is reason for concern, however, about the course of events following PI development that call into question what effect PIs have had on AIDS research and how they continue to influence the general direction of HIV/AIDS clinical research and treatment. This article is not intended to "bash" PIs, nor are the objections and concerns presented here intended to negate the obvious clinical benefits derived from the therapy.

Recently Steven Miles, MD, was quoted in Treatment Issues[2] as saying, "Sometimes I'd like to give the community Lithium, because we go from `Oh, therapy is terrible,' to `therapy is wonderful,' to `therapy is terrible' and back again." While there may be members of the community who would benefit from Lithium, especially those whose opinions arise from anecdote, or worse still from their personal experience, there is an equal number of physicians and pharmaceutical officials who also deserve a dose of Lithium for their lack of critical thinking. We need to think objectively about the subject of treatment, take into account the changes that have occurred and let this new perspective guide the choices of where and how the affected community makes its next big push in the development of treatments.

Pharmaceutical companies involved in the development of PIs may protest indignantly that their products are singled out from the larger treatment picture and that the criticisms here unfairly parcel them out. However, the criticisms in this article are not intended to take PIs out of context, rather to analyze them in the context of the whole treatment picture and review how the development of PIs instructed the decisions of where research money has been spent and how efforts have been made. Hopefully this will spark some ideas of how research might change its focus.

"HAART," a deconstructionist's dream. PIs were rationally designed to interfere with the life cycle of HIV, and their success in achieving this goal has led the research, medical and patient communities down what seems like an irreversible dogmatic path of "maximal suppression." Early anecdotal reports of the development of PIs had pharmaceutical company scientists skipping in the halls of hospitals, whispering to the activist corps that they might have found a cure. But even short-term experience with PIs dampened this excitement.

Soon the benefit of combining therapies began to become clearer (the combination trend had actually begun earlier with nucleoside reverse transcriptase inhibitors, NRTIs), and the treatment paradigm of 2 NRTIs and a PI became the unique model by which other therapies were measured. A mad rush by pharmaceuticals to recreate this model with their own product or products followed this defining moment.

As an example of the impact of PIs, before PIs the outlook for non-nucleoside reverse transcriptase inhibitors (NNRTIs) was dim. The rapid resistance that developed when they were used as monotherapy quickly vitiated the potency of NNRTIs. Along the same lines, the idea of combining more than 2 NRTIs was a scary proposition. After PIs, the course was set and everyone began to take seriously the possibility of an antiviral solution to HIV infection. The strategy, christened "highly active antiretroviral therapy," was disingenuously shortened to HAART, an acronym that appeals to the clever and the compassionate, not to mention the sentimental.

In concert with the development of HAART, scientists began to develop viral load measurement. This development helped entrench HAART. Not only was HAART effective, but also scientists and the medical community had the means of "proving" its effectiveness. The paradigm of HAART, now buttressed by the technology of viral load measurement, was supported further by clinical improvement in patients and in some cases their downright "resurrection." No one can complain about that.

The Holy Grail of eradication. Before the advent of HAART, common thought was that once a patient's immune system had deteriorated past a certain point, no antiviral therapy could reconstitute what had been damaged. "We need 2 things," my doctor told me. "A way to stop HIV, but more importantly, a way to restore your immune system."

It was thought that the benefit of PIs was the exclusive purview of those lucky enough to have triple-digit CD4 T cell counts at the moment PIs became available. But again, PIs proved these predictions premature and wrong. Patients with single-digit CD4 T cells started to regain ground and there was a further tendency to equate maximal viral suppression with immune restoration.

The fact that CD4 T cell counts increase to a certain level and unexplainably stop their climb did little to temper the enthusiasm for this theoretical approach equating suppression with restored immunity. The unexpected gift of CD4 T cells to those who never expected to have double-digit, let alone triple-digit, CD4 T cell counts was enough to gloss over the question of why the increase in cells seemed to plateau.

Nor did PI and viral load testing advances address the dilemma of HIV's sequestration in discrete, unreachable compartments. Nor did the clinical advances tell us how such seemingly nonpathogenic viral particles can create such havoc. One could argue that it is not necessary to understand the phenomenon of viral suppression to reap its benefits and in fact, these questions were subsumed beneath the celebration of clinical success. This is understandable given the catastrophic nature of the epidemic and the necessity to act expeditiously. But there is an ongoing danger in the paradigm of HAART as the solution, and it may most clearly manifest itself in these nagging and unanswered questions.

Incomplete immunologic reconstitution, mysterious compartments not reached by therapy, latent reservoirs persisting for a lifetime, new unidentifiable sources of viral replication when HAART is interrupted, cryptic replication and genetic divergence signaling ongoing replication in virus previously thought to be latent--these are some of the new frontiers of the epidemic.[3-9]

Nonetheless, in those early years of the development of HAART, the will to bring this epidemic to an end got the better of us and with this newly found desire was born the idea of eradication. Everyone was stunned in disbelief when the word "eradication" was first uttered in the context of this dreaded disease. At times it became necessary to explain to HIV-infected persons that the word "eradication" meant just that, the complete ridding of HIV from an infected person's body.

No one ever made the blatant assertion that maximal suppression and eradication of HIV would ipso facto result in immune reconstitution. On the other hand, no one did much to dissuade patients from the notion that if HIV replication could be halted, lost immune function could be restored. And the debate of the precise source of CD4 T cells rises in patients able to suppress their virus seemed hardly to make a dent in the enthusiasm of eradication.

Maximal suppression as a tool or an end. The theory of eradication has been discredited at this point. Patients who have been maximally suppressed for years are still not able to rid themselves of HIV. Study after study has proven the impossibility of eradication, at least with current regimens.[10-11]

Yet, whether one agrees that maximal suppression may be part of the answer (and there seems to be an increasing number of clinicians who doubt its absolute necessity), it is clear that viral suppression has given scientists an unprecedented opportunity to learn about the immune system and HIV infection. For instance, virologic suppression has allowed scientists to speculate about the dynamics of HIV infection,[12] and to postulate theories of immune response that bring us closer to an understanding of HIV pathogenesis under HAART and the mechanisms of viral persistence.[13-14]

But the nagging question of whether maximal suppression is merely a tool or end has yet to be answered clearly. Recent reports from Steven Deeks, MD,[15] stating that CD4 T cell response is sustained even after the failure of PI-based regimens lend a further dimension to the issue, posing the question of whether there is some inherent benefit of PIs or PI-based regimens that makes them useful even beyond their obvious mechanism of suppressing HIV. PIs would have to impair the fitness of HIV, make it less pathogenic or be involved in some indirect way such as altering apoptosis (programmed cell death) for this to be true.

Studies like Deeks's are fascinating for what they suggest. Unfortunately, they also feed into the affected person's need to believe and they imply the idea that there is something not yet understood about PIs that makes them inherently good. Still, suggestion is not science and HIV research is full of trends that do not pan out over time.

In fact, the journal AIDS[16] just published an analysis by the British Columbia Centre for Excellence in HIV/AIDS challenging the notion that a PI-based regimen or triple therapy "per se alters the natural history of HIV infection with respect to the relationship between pVL [plasma viral load] and CD4 cell count." After analyzing the results from 3 multinational clinical trials (INCAS, AVANTI-2 and AVANTI-3) they conclude, "The relationship between changes in CD4 cell count and pVL are independent of the specific antiretroviral therapy used, including the potency of the regimen or the drug class(es) included in it. The data provide no evidence for a CD4 cell count benefit unique to PI, at least in the first-line regimens up to 1 year in patients with moderate baseline CD4 cell count." So, it may be that the immunologic phenomenon that results from HAART may be the result of viral suppression and not from some mysterious benefit attributable to any combination of drugs or class of drugs.

The messenger controls the message. Miles's suggestion that the community's attitude towards therapy vacillates between embracing acceptance and disdainful rejection may be true. This pendulum may not only reflect the community's need to distill a simplistic black-and-white message from more nuanced scientific studies, but also it may reflect how scientific messages are shaped and delivered in the fast-paced world of accelerated approval.

PIs are a perfect example of the hype resulting from the twin, and often conflicting, needs of commercial and therapeutic success. Who can forget Roche's commercial touting of saquinavir (Invirase) after studies clearly showed the dose to be suboptimal and patients were experiencing virologic rebounds left and right? Or the harsh reality of the side effects of a full dose of ritonavir (Norvir), not to mention the incalculable drug interactions? How did those early studies not reflect the full extent of these problems? Or Agouron, reporting its registrational study for nelfinavir (Viracept) with numbers that did not account for the patients who never responded to the drug? And even Merck, with its highly conservative 035 study, making every effort to ease the pain of its monumental dosing headache.

Innate to this world of competitive drug development is a need for some degree of secrecy or at least veiling of some sort. Commercial success also requires some glossing of the nicks and scars of the product. Pharmaceutical companies are not the only culprits here. Physicians involved in clinical research, by choice or economic circumstance, are sometimes forced to distort the message.

Of course, drug development does not happen in a vacuum. There are overseeing agencies that mandate certain standards be met. This is where activists have had their greatest impact--in changing the system that now allows for the accelerated approval of agents and their availability before approval. But Federal agencies like the Food and Drug Administration (FDA) have also had their swings, from the approval of nelfinavir without a public meeting to the rejection of adefovir dipivoxil much to the disappointment of many, especially its developer. This may reflect the changing world of drug approval and one cannot help but wonder if accelerated approval is undergoing the maturation and tempering long overdue.

Time tells all. Eventually time and experience tell the true message, no matter how imperceptibly the many forces involved--pharmaceutical companies, clinical researchers and yes, activists--have tried to soften it. The true message of PIs and HAART, judging from the short-term experience, is that they are imperfect strategies with both scientific and practical problems.

The large percentage of patients who experience viral rebound while taking some form of combination therapy (estimated to be as high as 70% or more in urban areas[17,18]) is a testament to the onerous nature of the strategy or its lack of potency. In addition, the emergence of metabolic and morphologic changes that appear to be associated with the use of the therapies have created concerns about the long-term feasibility of keeping people on combination therapy.

To address this burgeoning problem the pharmaceutical industry and clinicians have embarked on a furious effort to simplify dosing and find a way to ameliorate the side effects. Drugs that once required dosing 3 times a day are now being formulated or combined with other therapies to enable twice-a-day or even once-a-day dosing. Drugs with fewer known metabolic and morphologic side effects are being substituted for drugs known to have more of these side effects. Some 15 to 20 studies were reported at the recent XIII International AIDS Conference that in some way tweaked HAART regimens to make them easier to dose or to lessen the side effects.

While all this tweaking of regimens may make some incremental difference in the success of these regimens, it seems unlikely that over a long period of time it will make a difference in the overall success rate.

Thinking outside the box. Tragically, the development of "me-too" drugs is rampant and there appears to be little slowing down of this process. Strategies of drug interruption and pulsing at least challenge the commercial HAART imperative of "all therapy, all the time." These strategies take into account the impracticality of constant dosing and the reality of long-term side effects. Entry inhibitors should be applauded, if for no other reason, for their attempt at a new method of interfering with the HIV life cycle. But these 2 examples are the exception and not the rule.

For the moment, the commercial interests are leading a campaign determined to refine, tweak and polish the imperfect model of HAART. Without eradication the HAART model may be merely a way of postponing some inevitable fate of complications or viral rebound.

Among the strategies that should be re-examined is that of humoral immunity. Some early work by basic scientists has revealed some of HIV's devious machinery that has allowed it to evade the surveillance of the immune system. This type of work should be encouraged and promoted. The drug developers and virologists have had their day in the sun. Perhaps it is time to start letting the immunologists and vaccinologists take center stage.

REFERENCES

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[16.] BC Centre for Excellence in HIV/AIDS. Highly active antiretroviral therapy including protease inhibitors does not confer a unique CD4 cell benefit. The AVANTI and INCAS Study Groups. AIDS. 2000; 14(10): 1383-1388.

[17.] Deeks SG. Hecht FM, Swanson M. et al. RNA and CD4 cell count reponse to protease inhibitor therapy in an urban clinic: reponse to both initial and salvage therapy. AIDS. 1999;13(6):F35-F44.

[18.] Bartlett JG, Gallant JE. Medical Management of HIV Infection. Baltimore, MD: Johns Hopkins University, Department of Infectious Diseases; 2000:51.