Important note: Information in this article was accurate in March 2000. The state of the art may have changed since the publication date.
In certain countries the standard of care for people with HIV infection is usually early treatment with powerful combination therapy or HAART. This approach to treatment is founded on certain assumptions that are now being challenged by a number of leading doctors in Britain and the United States. According to leading British researcher Dr. Brian Gazzard, the main problems connected with the current "hit hard, hit early" approach relate to the following issues:
In a recent article in the Annals of Internal Medicine, Dr. Keith Henry describes in detail what he considers to be the key problems with the assumptions that inform current treatment guidelines. We outline some of his thoughts below.
Assumption: Therapy is simple enough for long-term use.
Implicit in the current approach to anti-HIV therapy is the assumption that people can take their complicated regimens as directed-a behaviour called adherence-for long periods of time. The problem with this assumption is that long-term adherence for chronic illnesses is generally difficult. This is likely true for AIDS as well. Moreover, excellent levels of adherence are needed to achieve success in treating HIV/AIDS. One study of adherence produced the following results:
Clearly, simpler and more effective therapies are needed.
Assumption: Therapy is safe for long-term use.
Side effects associated with HAART appear to be "extremely complex." Strange changes in body shape, altered metabolism, increased risk of diabetes, cardiovascular disease and liver damage are only some of the side effects encountered by patients.
The long-term side effects of HAART are not known.
To help their patients cope with side effects some doctors prescribe drugs to reduce cholesterol levels, hormones to reduce changes in body shape and still more drugs to relieve nerve pain. The long-term toxicity of such a chemical soup is also not clear. Moreover, some of these drugs may interact with anti-HIV medications.
Assumption: HIV causes irreversible damage to the immune system.
Several studies have clearly shown that HAART allows the immune system to repair much of the damage caused by HIV. Indeed, some people who were previously dependent on anti-infective drugs to prevent life-threatening infections can, as a result of HAART, stop taking prophylaxis such as Bactrim/Septra, ganciclovir and other drugs.
Researchers have noticed that in most people who are HIV-positive, the immune system quickly loses its ability to produce an effective immune response against HIV. Preliminary and controversial findings from several small studies suggest that early treatment may help preserve a certain level of the immune system's anti-HIV activity. Whether this anti-HIV activity can (a) delay the fall in CD4+ counts or (b) the appearance of AIDS-related symptoms remains to be seen.
Assumption: Use of potent therapy results in complete long-term viral suppression.
Unfortunately, this is not the case for most people. Even among people whose viral load in the blood is below the limit of detection, HIV continues to be produced in other parts of the body.
Assumption: Potent therapy prevents the emergence of viral resistance.
Outside the carefully controlled world of a clinical trial, viral resistance has actually become a serious problem for patients, many of whom have been taking potent therapies.
Assumption: Results from population-based surrogate marker studies apply to individual patients.
Analyses of the relationship between CD4+ cell counts, viral load and the development of life-threatening complications are an essential part of the argument supporting the early use of anti-HIV therapy. Unfortunately, such information was collected in the time before HAART was available and the use of preventive medications (prophylaxis) was not widespread. Instead of looking at who is at risk for developing AIDS, Dr. Henry asserts that it is just as important to identify patients who are not at risk for AIDS-related illnesses.
Using this frame, Dr. Henry took another look at data from the study ACTG 175. He noted that subjects in that study who had fewer than 300 CD4+ cells and a viral load below the 10,000 copy mark "had only a 4% chance of [developing an AIDS-related illness] over a three-year period while receiving [nukes alone]."
Therefore, over a three-year period, it may be reasonable for some people to take no therapy while being monitored very closely. For others, it may be reasonable to use a simple regimen of nukes alone.
Assumption: Full suppression of HIV will lead to a possible cure.
This assumption, perhaps more than any other, fuelled the early excitement, hope and support for the "hit hard, hit early" approach. However, more recent studies suggest that a cure is not possible with currently available treatments.
Assumption: Virologic failure (rising viral load) of therapy would quickly lead to decreasing CD4+ cell counts and the appearance of symptoms of AIDS.
Several studies have noted that over a 12 to 18 month period, virologic failure occurs without a corresponding drop in CD4+ cell counts. Doctors who followed the guidelines would therefore have changed their patients' regimens before they were at high risk for AIDS-related events. In some cases, this has occurred in patients who were never at high risk for the rapid appearance of AIDS developing strains of HIV that were resistant to available drugs.
In light of the problems with the current approach to anti-HIV therapy, other approaches need to be assessed. Now that HAART is here, patients are going to be alive for much longer than in the time before HAART. Long-term treatment strategies tailored to individual needs are therefore needed. Dr. Henry's suggestions include the following options:
1. Gazzard BG. Antiretroviral treatment guidelines in Britain and the USA: moving closer? Medscape HIV/AIDS 2000;6(1):
http://www.medscape.com/Medscape/HIV/journal/2000/v06.n01/mha0127.gazz/
2. Henry K. The case for more cautious, patient-focussed antiretroviral therapy. Annals of Internal Medicine 2000;132:306-311.
3. Gallant JE. Strategies for long-term success in the treatment of HIV infection. Journal of the American Medical Association 2000;283:1329-1334.
4. Junghans C, Low N, Chan P, et al. Uniform risk of clinical progression despite differences in utilization of highly active antiretroviral therapy: Swiss HIV cohort study. AIDS 1999;13(18):2547-2444.
5. Brivet FG, Nion I, Mégarbane B, et al. Fatal lactic acidosis and liver steatosis associated with didanosine and stavudine treatment: a respiratory chain dysfunction? Journal of Hepatology 2000;32:364-365.
6. Connick E, Lederman MM, Kotzin BL, et al. Immune reconstitution in the first year of potent antiretroviral therapy and its relationship to virologic response. Journal of Infectious Diseases 2000;181:358-363.
7. Malhotra U, Berrey MM, Huang Y, et al. Effect of combination antiretroviral therapy on T-cell immunity in acute human immunodeficiency virus type 1 infection. Journal of Infectious Diseases 2000;181:121-131.
8. Schacker T, Little S, Connick E, et al. Rapid accumulation of human immunodeficiency virus (HIV) in lymphatic tissue reservoirs during acute and early HIV infection: implications for timing of antiretroviral therapy. Journal of Infectious Diseases 2000;181:354-357.
9. Furtado MR, Callaway DS, Phair JP, et al. Persistence of HIV-1 transcription in peripheral-blood mononuclear cells in patients receiving potent antiretroviral therapy. New England Journal of Medicine 1999;340:1614-1622.
10. Sharkey ME, Teo I, Greenough T, et al. Persistence of episomal HIV-1 infection intermediates in patients on highly active anti-retroviral therapy. Nature Medicine 2000;6(1):76-81.
11. Ramratnam B, Mittler JE, Zhang L, et al. The decay of the latent reservoir of replication-competent HIV-1 is inversely correlated with the extent of residual viral replication during prolonged anti-retroviral therapy. Nature Medicine 2000;6(1):82-85.
12. Dornadula G, Zhang H, VanUitert B, et al. Residual HIV-1 RNA in blood plasma of patients taking suppressive highly active antiretroviral therapy. Journal of the American Medical Association 1999;282:1627-1632.
13. Prins JM, Jurriaans S, van Praag RME, et al. Immuno-activation with anti-CD3 and recombinant human IL-2 in HIV-1-infected patients on potent antiretroviral therapy. AIDS 1999;13:2405-2410.
14. Davey RT, Bhat N, Yoder C, et al. HIV-1 and T cell dynamics after interruption of highly active antiretroviral therapy (HAART) in patients with a history of sustained viral suppression. Proceedings of the National Academy of Sciences USA 1999;96(26):15109-15114.
15. Descamps D, Flandre P, Calvez V, et al. Mechanisms of virologic failure in previously untreated HIV-infected patients from a trial of induction-maintenance therapy. Journal of the American Medical Association 2000;283:205-211.
16. Havlir DV, Hellmann NS, Petropoulos CJ, et al. Drug susceptibility in HIV infection after viral rebound in patients receiving indinavir-containing regimens. Journal of the American Medical Association 2000;283:229-234.
17. Markowitz M. Resistance, fitness, adherence, and potency: mapping the paths to virologic failure. Journal of the American Medical Association 2000;283(2):250-251.
18. Deeks SG. Failure of HIV-1 protease inhibitors to fully suppress viral replication. Implications for salvage therapy. Advances in Experimental Medicine and Biology 1999;458:175-182.
19. Kaul R, Plummer FA, Kimani J, et al. HIV-1-specific mucosal CD8+ lymphocyte responses in the cervix of HIV-1-resistant prostitutes in Nairobi. Journal of Immunology 2000;164:1602-1611.
20. Ho DD. Time to hit HIV, early and hard. New England Journal of Medicine 1995;333(7):450-451.
21. Mezzaroma I, Carlesimo M, Pinter E, et al. Clinical and immunologic response without decrease in virus load in patients with AIDS after 24 months of highly active antiretroviral therapy. Clinical Infectious Diseases 1999;29:1423-1430.
22. Palella FJ, Delaney KM, Moorman AC, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. New England Journal of Medicine 1998;338:853-860.
23. Hockett RD, Kilby JM, Derdeyn CA, et al. Constant mean viral copy number per infected cell in tissues regardless of high, low or undetectable plasma HIV RNA. Journal of Experimental Medicine 1999;189(10):1545-1554.
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