More? HIV Medicine 2007, Chapter 5.1: Download

HIV Medicine
15th edition
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Many patients, who were infected up until the mid-80s, began to die. Hospices were established, as well as more and more 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 - cotrimoxazole, pentamidine, gancyclovir, foscarnet, and fluconazole saved many patients' lives, at least in the short-term. Some clinicians dreamed of a kind of "mega-prophylaxis", but the picture was still tainted by an overall lack of hope. Many remember the somber, almost depressed mood of the IXth World AIDS Conference in Berlin, in June 1993. Between 1989 and 1994, the mortality rates hardly changed. Then, in September 1995, the results of the European-Australian DELTA Study (Delta 1996) and the American ACTG 175 Study (Hammer 1996) attracted attention. It became apparent that two nucleoside analogs were more effective than monotherapy. Indeed, the differences made on the clinical endpoints - AIDS and death - were highly significant. Both studies demonstrated that it was potentially of great importance of starting treatment immediately with two nucleoside analogs, as opposed to using the drugs successively. This was by no means the final breakthrough, but by this time, the first studies with protease inhibitors (PIs), a completely new drug class, had been running for months. PIs had been designed using the knowledge of the molecular structure of HIV and protease - their clinical value was uncertain. Preliminary data, combined with rumours, were already circulating. Patients and clinicians were waiting impatiently. In the fall of 1995, a fierce competition started up between Abbott, Roche and MSD. The licensing studies for the PIs, ritonavir, saquinavir and indinavir, were pursued with a great vigour. The monitors of these studies in the different companies "lived" for weeks in the clinical centers. Deep into the night, case report files had to be perfected and thousands of queries answered. All these efforts led to a fast track approval, between December 1995 and March 1996, for all three PIs - first saquinavir, followed by ritonavir and indinavir - for the treatment of HIV. Many clinicians (including the author) were not really aware of what was happening during these months. AIDS remained ever present. Patients were still dying, as only a relatively small number were participating in the PI trials - and few were adequately treated according to current standards. Doubts remained. Hopes had been raised too many times before by alleged miracle cures. In January 1996, at the 5th Munich AIDS Conference, other topics were more important: palliative medicine, treatment of CMV, wasting, and pain management; euthanasia was even a theme. The few contributions here and there on "new beginnings" produced no more than restrained optimism. 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. Electrified, listeners learned that the mere addition of ritonavir oral solution decreases the frequency of death and AIDS from 38 % to 22 % (Cameron 1998). These were sensational results in comparison to everything else that had been previously published! Although some severely ill patients with AIDS managed to recover during these months, for many the combinations that were now - at the beginning of 1996 - widely used, came too late. Then in June 1996, the World AIDS Conference in Vancouver reported on the new "AIDS cocktails" and the strangely unscientific (and rather ridiculous) expression "highly active antiretroviral therapy" (HAART) began to spread irreversibly. Clinicians were only too happy to become infected by this enthusiasm. Meanwhile, David Ho, Time magazine's "Man of the Year" in 1996, had clarified the hitherto completely misunderstood kinetics of HIV with his breakthrough trials (Ho 1995, Perelson 1996). A year earlier, Ho had already initiated the slogan "hit hard and early", and almost everyone was now taking him by his word. With the knowledge of the high turnover of the virus and the relentless daily destruction of CD4 cells, there was no consideration of a "latent phase" - and no life without antiretroviral therapy. In many centers, almost every patient was treated. Within three years, from 1994-1997, the proportion of untreated patients in Europe decreased from 37 % to 9 %, whilst the proportion of HAART patients rose from 2 % to 64 % (Kirk 1998). A third drug class was introduced in June 1996, with the licensing of the first non-nucleoside reverse transcriptase inhibitor (NNRTI), nevirapine. Nelfinavir, a new PI, also arrived. Most patients seemed to tolerate the pills well. 30 pills a day? No problem, if it helps. And how it helped! The number of AIDS cases diminished. Within four years, between 1994 and 1998, the incidence of AIDS in Europe sank from 30.7 to 2.5/100 patient years - i.e. to less than a tenth. Opportunistic infections (OI) such as CMV and MAC became almost rare (Mocroft 2000). HIV ophthalmologists had to look for new areas of work. The OI trials, planned only a few months before, faltered due to a lack of patients. Hospices, which had been receiving substantial donations, had to shut down or reorientate themselves. Patients left hospices, nursing services shut down; and AIDS wards became occupied by other patients. In 1997, some patients began to complain of a fat stomach, but was this not a good sign after the years of wasting and supplementary nutrition? Not only did the PIs contain lactose and gelatin, but also the lower viremia was thought to use up far less energy. It was assumed that, because patients were less depressed they would eat more. At most, it was slightly disturbing that the patients retained thin faces. However, more and more patients began to complain about the high pill burden. In June 1997, the FDA published a warning about the development of diabetes mellitus associated with the use of PIs. At the CROI in February 1998, a number of posters showed pictures of buffalo humps, thin legs faces. A new term was introduced, which would influence antiretroviral therapy: lipodystrophy. The old medical wisdom was also shown to hold true for HAART: all effective drugs have side effects. The actual cause remained unclear. Then, in early 1999, a new hypothesis emerged from the Netherlands: "mitochondrial toxicity" (Brinkman 1999). It has become a ubiquitous term in HIV medicine today, occupying a whole chapter of this book. A chapter on lipodystrophy is long overdue. The dream of eradication (and a cure), still widely hoped for in the beginning, eventually had to be abandoned In 1997, mathematical models were still based on viral suppression of approximately three years. After this period, it was predicted that all infected cells would presumably have died. Eradication was a magic word. At every conference since then, the period of three years has been adjusted upwards. Nature is not so easy to predict, and more recent studies have come to the sobering conclusion that HIV remains detectable in latent infected cells, even after long-term suppression. Nobody knows how long these latent infected cells survive, and whether even a small number of them would be sufficient for the infection to flare up again as soon as treatment is interrupted. Finally, during the Barcelona World AIDS Conference, experts in the field admitted to bleak prospects for eradication. The most recent estimate for eradication of these cells stands at 73.3 years (Siciliano 2003). Such number games say one thing: HIV will not be curable in the short term. The latent reservoirs will not simply let themselves be wiped out. On the other hand, if the subject of cure is not spoken about, it will never be reached. Although it still seemed utopian ten years ago, it is now realistic to expect to control HIV for the longer term. This results in huge challenges for patients and clinicians. The industry needs to develop improved pill combinations.Fortunately, once-daily regimens are already available, and a complete HAART regimen in a single pill is imminent. CCR5 antagonists and integrase inhibitors are being developed. They may even partially replace the current antiretroviral therapy. In June 2006, HIVIDä was withdrawn from the market - a novelty for HIV medicine. Other long-serving substances will follow. In ten years time, antiretroviral treatment will be completely different. With increasing knowledge of the risks of antiretroviral therapy many treatment recommendations are revised. Instead of "hit hard and early", today we hear "hit HIV hard, but only when necessary" (Harrington 2000). The question of "when to start?" is still the subject of major debate. HIV clinicians are well advised to keep an open mind for new approaches. Those, who do not make a constant effort to broaden their knowledge, will be treating their patients inadequately within a short period of time. Those who adhere strictly to evidence-based HIV medicine, quickly become outdated. HIV medicine is ever changing. Treatment guidelines remain just guidelines. They are often out of date by the time of publication. There are no laws set in stone. HIV remains a dangerous and cunning opponent. Patients and clinicians must tackle it together. The following describes how this can be done. References 1. 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. http://amedeo.com/lit.php?id=10509516 2. 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. http://amedeo.com/lit.php?id=9386808 3. 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. http://amedeo.com/lit.php?id=9492772 4. Concorde: MRC/ANRS randomised double-blind controlled trial of immediate and deferred zidovudine in symptom-free HIV infection. Lancet 1994, 343:871-81. http://amedeo.com/lit.php?id=7908356 5. 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. http://amedeo.com/lit.php?id=8709686 6. 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. http://amedeo.com/lit.php?id=1977079 7. Gulick RM, Mellors JW, Havlir D, et al. 3-year suppression of HIV viremia with indinavir, zidovudine, and lamivudine. Ann Intern Med 2000, 133:35-9. http://amedeo.com/lit.php?id=10877738 8. 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. http://amedeo.com/lit.php?id=8813038 9. Harrington M, Carpenter CC. Hit HIV-1 hard, but only when necessary. Lancet 2000, 355:2147-52. http://amedeo.com/lit.php?id=10902643 10. Ho DD. Time to hit HIV, early and hard. N Engl J Med 1995, 333:450-1. 11. 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. http://amedeo.com/lit.php?id=7816094 12. 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. http://amedeo.com/lit.php?id=9814872 13. Mocroft A, Katlama C, Johnson AM, et al. AIDS across Europe, 1994-98: the EuroSIDA study. Lancet 2000, 356:291-6. http://amedeo.com/lit.php?id=11071184 14. 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. http://amedeo.com/lit.php?id=8599114 15. 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. http://amedeo.com/lit.php?id=12754504 16. 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. http://amedeo.com/lit.php?id=1969115