Category Archives: 6.1. Perspective

6.1. Perspective

Christian Hoffmann –

The development of antiretroviral therapy has been one of the most dramatic evolutions in the history of medicine. Few other areas have been subject to such fast progress and sometimes short-lived trends. Those who have experienced the rapid developments of the last few years have been through many ups and downs.

The early years, from 1987-1990, brought great hope and the first modest advances using monotherapy (Volberding 1990, Fischl 1990). But when the results of the Concorde Study arrived (Hamilton 1992, Concorde 1994) both patients and clinicians plunged into a depression that would last several years. AZT (zidovudine) was first tested on humans in 1985, and was introduced as a treatment in March 1987 with great expectations. Initially it did not seem to be very effective, at least as monotherapy. The same was true for the nucleoside analogs ddC (zalcitabine), ddI (didanosine) and d4T (stavudine) which were introduced between 1991 and 1994. The lack of substantial treatment options led to a debate that lasted for several years about which nucleoside analog should be used, when, and at what dose. One typical question was, “Should the alarm clock be set to go off during the night for a sixth dose of AZT?”

Many patients infected during the early and mid-80s were dying. Hospices were established as well as support groups and ambulatory nursing services. One became accustomed to AIDS and its resulting death toll. There was, however, definite progress in the field of opportunistic infections (OI) – cotrimoxazole, pentamidine, gancyclovir, foscarnet and fluconazole saved many patients’ lives, at least in the short-term. Some clinicians started to dream of a kind of “mega-prophylaxis”. But the general picture was still tainted by an overall lack of hope. Many remember the somber, still mood of the IXth World AIDS Conference in Berlin in June 1993. Between 1989 and 1994 little had changed.

Then in September 1995, the preliminary results of the European-Australian DELTA Study (Delta 1995) and the American ACTG 175 Study (Hammer 1996) attracted attention. It became apparent that combination therapy with two nucleoside analogs was more effective than monotherapy. Indeed, the differences made in the clinical endpoints (AIDS and death) were highly significant. Both studies demonstrated that it was of great importance to immediately start treatment with two nucleoside analogs, as opposed to using the drugs sequentially.

This was by no means the final breakthrough. By this time, the first studies with protease inhibitors (PIs), a completely new class of drugs, had been under way for several months. PIs had been designed in the lab using the knowledge of the molecular structure of HIV and protease and their clinical value was initially uncertain. Preliminary data, along with many rumors, were circulating. Great impatience pervaded patients and clinicians. By the fall of 1995, a fierce competition had started up between three companies: Abbott, Roche and MSD. The licensing studies for the three PIs, ritonavir, saquinavir and indinavir, were pursued with intense effort. The monitors of these studies lived for weeks at the participating clinical sites. Deep into the night, case report files were perfected and thousands of queries were answered. These efforts led to fast track approval for all three PIs between December 1995 and March 1996 – first saquinavir, followed by ritonavir and indinavir – for the treatment of HIV.

Many clinicians (including this author) were not really aware of what was happening during these months. AIDS remained ever-present. Although the incidence of AIDS had dropped by half between 1992 and 1996, many were still dying. Doubts remained. Hopes had already been raised too many times in the previous years by alleged miracles. Early in January 1996, during the 5th AIDS convention in Munich, other topics were higher on the agenda: palliative medicine, pain management, even euthanasia. Here and there a few speeches on “new approaches”, nothing much. Faint and latent optimism was the highest of emotions anyone dared show. Noone dared to proclaim a breakthrough.

In February 1996, during the 3rd Conference on Retroviruses and Opportunistic Infections (CROI) in Washington, many caught their breath as Bill Cameron reported the first data from the ABT-247 Study during the late breaker session. The auditorium was absolutely silent. Riveted, listeners heard that the mere addition of ritonavir oral solution decreased the frequency of death and AIDS from 38% to 22% (Cameron 1998). These results were sensational in comparison to everything else that had been previously published.

The World AIDS Conference in Vancouver a few months later in June 1996, where the great potential of PIs became fully apparent, developed into a celebration. Even regular news channels reported in great depth on the new “AIDS cocktails”. The strangely unscientific expression “highly active antiretroviral therapy” (HAART) began to spread irreversibly.

By this time, David Ho, Time magazine’s “Man of the Year” in 1996, had shed light on the hitherto completely misunderstood kinetics of HIV with his breakthrough research (Ho 1995, Perelson 1996). A year earlier, Ho had already initiated the slogan “hit hard, hit early”, and almost all clinicians were now taking him at his word. With the new knowledge of the incredibly high turnover of the virus and the relentless daily destruction of CD4 T cells, there was no longer any consideration of a latent phase – and no life without antiretroviral therapy. In many centers almost every patient was treated with HAART. Within only three years, 1994-1997, the proportion of untreated patients in Europe decreased from 37% to barely 9%, whilst the proportion of patients on HAART rose from 2% to 64% (Kirk 1998).

Things were looking good. By June 1996, the first non-nucleoside reverse transcriptase inhibitor nevirapine was licensed and hence a third drug class introduced. One now had a great selection of medications at hand. Most patients seemed to tolerate the drugs. 30 pills a day? Not much of a problem, if it helped. And how it helped! The number of AIDS cases was drastically reduced. Within only four years, between 1994 and 1998, the incidence of AIDS in Europe was reduced from 30.7 to 2.5 per 100 patient years – i.e., to less than one tenth of what it was. Some of the most feared opportunistic infections now only rarely occurred (Mocroft 2000). HIV-specialized ophthalmologists began looking for new areas of work. The large OI trials, planned only a few months before, faltered due to a lack of patients. Hospices, which had been receiving substantial donations, shut down or changed their focus. The first patients began to leave the hospices and went back to work; ambulatory nursing services shut down. Patients with other diseases occupied AIDS wards.

In early 1997, some patients began to complain of an increasingly fat stomach, but was this not a good sign after years of wasting and supplementary nutrition? The lower viremia was thought to use up far less energy. It was assumed that, because patients were less depressed and generally healthier, they would eat more. At most, it was slightly disturbing that the patients retained thin faces. However, more and more patients also began to complain about the high pill burden.

In June 1997, the FDA published the first warning about the development of diabetes mellitus associated with the use of PIs. In February 1998, CROI in Chicago finally brought home the realization among clinicians that protease inhibitors were perhaps not as selective as had long been believed. One poster after another, indeed whole walls of pictures, showed fat abdomens, buffalo humps, thin legs and faces. A new term was introduced at the beginning of 1998 which would influence antiretroviral therapy for years to come: lipodystrophy. And so the old medical saying was shown to hold true for ART as well: all effective drugs have side effects. The actual cause of lipodystrophy remained completely unclear. Then, in early 1999, a plausible hypothesis emerged from the Netherlands, mitochondrial toxicity (Brinkmann 1999). It has become an ubiquitous term in HIV medicine today.

The dream of eradication (and cure), widely hoped for in the beginning, was eventually abandoned. Mathematical models were evidently not real life. In 1997, it was estimated that viral suppression with a maximum duration of three years was necessary; in this time it was predicted that all infected cells would die. Since then, the duration has constantly been adjusted upwards. More recent estimates have evolved to around 60 to 70 years (Silicano 2003). These numbers show just one thing: HIV will not be cured with standard ART for some time to come. More recent studies have come to the sobering conclusion that HIV remains detectable in latent infected cells, even after long-term suppression. Regardless, we need to talk about being able to cure the disease someday, however utopian it may seem now. We will never get there without a vision.

In fact, today’s reality seemed impossible ten years ago: HIV infection is a chronic disease which, although incurable, is controllable lifelong with therapy, even in patients with resistant virus. CCR5 antagonists as well as integrase inhibitors have opened up new possibilities of treatment. It has become increasingly possible to lower viral loads below detection in most patients. The pioneer drugs maraviroc and raltegravir have shown to be well-tolerated, even to the degree of causing distrust. The new drug classes will bring about fundamental changes to current ART. The dogma of always using two nucleoside analogs as the backbone of every therapy may start to change. Many of the currently widespread drugs will disappear over the next few years. The end of HIVID®, Agenerase® or Fortovase® is just the beginning. Veteran agents like AZT, d4T, ddI, nelfinavir or indinavir are not recommended by guidelines anymore although they served us in HIV management in the nineties. Will we be needing saquinavir, fosampranavir, nevirapine or even efavirenz and lopinavir as much as we do today five years from now?

A normal life expectancy seems possible today. Therapy is likely to last for decades. This will pose a tremendous challenge for patients, physicians and for the pharmaceutical industry. The comfortable situation at present doesn’t mean one can lean back. New drugs are urgently needed. However, there is still uncertainty about whether modern drugs will stand the test of time over decades. Effects on the heart, kidney, bones and other organs in an aging HIV population are difficult to foresee. Supposing a cure is delayed in coming, over the decades one will need a longer breadth, and the range of drugs has to increase. It will not be easy for new drugs to prevail as the example of vicriviroc has shown. How do you prove the advantages of a new drug over other successful therapies today? Approval for new drugs is becoming more strict and the market is tightening. Already one can observe the pharmaceutical industry’s caution. The days are over when a HIV drug got from the laboratory to the market within five years. New strategies are needed.

At the same time, the simple question of “when to start” with ART remains unanswered. Instead of David Ho’s recommendation from the nineties “hit hard, hit early”, today we hear “hit HIV hard, but only when necessary” (Harrington 2000). This sounds sensible. However, when is it actually necessary? At a count of 350 CD4 T cells? What roles do the following play: viral load, CD4 T cell changes, CD4 percentages, age, gender, host elements and viral tropism? What about acutely infected patients? These strategically important questions will hopefully find some answers through big studies like START that are underway now. Until then, this issue requires great sensitivity.

HIV clinicians are well-advised to keep an open mind to new approaches. Those who do not make an effort to broaden their knowledge often at conferences will not be able to provide adequate treatment for their patients in a field that is still growing and learning and changing direction every two to three years. Those who adhere strictly to evidence-based medicine and only treat according to guidelines are quickly outdated. HIV medicine is ever-changing. Treatment guidelines remain just that, and are often out of date by the time of publication. There are no laws set in stone. However, those who confuse therapeutic freedom with random choices, and assume that data and results coming from basic research can be ignored are also missing the point. Individualized treatment is not random treatment. It cannot be stressed enough that clinicians are also responsible for the problem of poor adherence. Even if many experienced clinicians have come to disregard this, every patient has the right to know why they are taking the therapy they are on or, indeed, why certain therapies are not an option. The more they understand their therapies, the better the long-term results.

HIV remains a dangerous opponent. Patients and clinicians must tackle it together.

References

Brinkman K, Smeitink JA, Romijn JA, Reiss P. Mitochondrial toxicity induced by nucleoside-analogue reverse-transcriptase inhibitors is a key factor in the pathogenesis of antiretroviral-therapy-related lipodystrophy. Lancet 1999,  354:1112-5.

Brodt HR, Kamps BS, Gute P, et al. Changing incidence of AIDS-defining illnesses in the era of antiretroviral combination therapy. AIDS 1997, 11:1731-8.

Cameron DW, Heath-Chiozzi M, Danner S, et al. Randomised placebo-controlled trial of ritonavir in advanced HIV-1 disease. Lancet 1998, 351:543-9.

Concorde: MRC/ANRS randomised double-blind controlled trial of immediate and deferred zidovudine in symptom-free HIV infection. Lancet 1994, 343:871-81.

Delta: a randomised double-blind controlled trial comparing combinations of zidovudine plus didanosine or zalcitabine with zidovudine alone in HIV-infected individuals. Lancet 1996, 348: 283-91.

Fischl MA, Parker CB, Pettinelli C, et al. A randomized controlled trial of a reduced daily dose of zidovudine in patients with the acquired immunodeficiency syndrome. N Engl J Med 1990; 323:1009-14.

Hammer SM, Katzenstein DA, Hughes MD et al. A trial comparing nucleoside monotherapy with combination therapy in HIV-infected adults with CD4 cell counts from 200 to 500 per cubic millimeter. N Engl J Med 1996, 335:1081-90.

Harrington M, Carpenter CC. Hit HIV-1 hard, but only when necessary. Lancet 2000, 355:2147-52.

Ho DD. Time to hit HIV, early and hard. N Engl J Med 1995, 333:450-1.

Ho DD, Neumann AU, Perelson AS, Chen W, Leonard JM, Markowitz M. Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection. Nature 1995, 373:123-6.

Kirk O, Mocroft A, Katzenstein TL, et al. Changes in use of antiretroviral therapy in regions of Europe over time. AIDS 1998, 12: 2031-9.

Mocroft A, Katlama C, Johnson AM, et al. AIDS across Europe, 1994-98: the EuroSIDA study. Lancet 2000, 356:291-6.

Perelson AS, Neumann AU, Markowitz M, Leonard JM, Ho DD. HIV-1 dynamics in vivo: virion clearance rate, infected cell life-span, and viral generation time. Science 1996, 271:1582-6.

Siliciano JD, Kajdas J, Finzi D, et al. Long-term follow-up studies confirm the stability of the latent reservoir for HIV-1 in resting CD4+ T cells. Nature Med 2003;9:727-728.

Volberding PA, Lagakos SW, Koch MA, et al. Zidovudine in asymptomatic HIV infection. A controlled trial in persons with fewer than 500 CD4-positive cells per cubic millimeter. N Engl J Med 1990, 322:941-9.

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Filed under 6. ART 2011, 6.1. Perspective, Part 2 - Antiretroviral Therapy