Although there are 4 reasons to suspend treatment temporarily, pulse therapy appears to be the most promising.
• Immunization One rationale for STI, when used with patients who have prolonged virologic control, is to stop therapy to let the virus come back and “immunize” the patient in a fashion analogous to a vaccine. The theory seemed good, but has not proven successful, and most have abandoned this tactic except with the rare patient who was treated very early in the course of the disease. • Treatment failure A rationale for discontinuing
treatment when it has failed due to drug resistance is to allow growth of “wild type virus” that is sensitive to antiretroviral agents. The theory, that STI would permit a new round of therapy against sensitive virus, has not proven successful for possibly predictable reasons. In many or most patients, the resistant strains are minority species that quickly become the dominant strains under renewed antiviral pressure.
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• Intermittent therapy The plan with intermittent therapy is to periodically discontinue treatment on a prearranged schedule, such as 1 week on and 1 week off or 5 days of treatment followed by a weekend off. The theory is that when therapy is discontinued there is usually sustained viral suppression for 10-14 days and treatment is restarted while the virus is still suppressed. This strategy could potentially reduce treatment-associated side effects and cost. Although the initial experience has been limited but promising, the strategy cannot be recommended until more substantial experience is gained.
• Pulse therapy With this strategy, therapy is discontinued when the CD4 cell count increases to a level that makes the patient and physician comfortable doing so and is restarted when the CD4 count declines to a worrisome level. Initial experience has generally been that the viral load returns within 2 weeks and the CD4 cell count declines rapidly and then plateaus. Most experts restart therapy when the CD4 cell count reaches 350/mm3, but this strategy has not been
systematically studied. Nevertheless, it does appear that there is no penalty in terms of resistance and the period off therapy is often 1-2 years, depending to a large extent on the CD4 cell count at the time treatment is discontinued and on the pre-therapy CD4 nadir. The patient must be warned that viral loads will return to pre-therapy levels, with important implications for risk of HIV transmission to others.
KEY POINTS
The major indicator for the speed of progression in early stage disease is the viral load, which dictates the speed of CD4 cell decline. The major indicator for the risk of HIV-associated complications is the CD4 cell count.
ART is directed toward preventing HIV-associated complications and
hospitalizations and improving quality of life and survival.
ART does not cure HIV infection, is expensive, is associated with substantial risks of short-term and long-term toxicity, and requires a level of adherence that is unmatched with any other antimicrobial therapy.
ART is recommended when there are HIV- associated symptoms or when the CD4 count is <200-350/mm3.
The standard of practice for ART is 3 or 4 drugs representing 2 classes.
The major objective of ART is to inhibit HIV as reflected by viral load. Successful antiviral therapy is defined as a viral load of <50 c/mL by 16-24 weeks, usually accompanied by an increase in the CD4 cell count of 100-150/mm3/year.
Failed therapy is defined as virologic (viral load >400 c/mL twice after 24 weeks), immunologic (CD4 count fails to increase by >25-50/mm3 at 6-12 months), or clinical (new AIDS-defining OI after >3 months of therapy).
Treatment is changed for drug intolerance (substitution) or virologic failure
(selection by resistance tests).
The 3 factors that consistently predict outcome are CD4 cell count, patient adherence, and provider experience.
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SUGGESTED RESOURCES
Deeks SG, Hirschel B. Supervised interruptions of antiretroviral therapy. AIDS. 2002;16:S157-169.
Hirsch MS, Brun-Vezinet F, Clotet B, et al. Antiretroviral drug resistance testing in adults with Human Immunodeficiency Virus type 1: 2003 recommendations of an International AIDS Society – USA panel. Clin Infect Dis. 2003;37:113-128. Lawrence J, Mayers DL, Hullsiek KH, et al. Structured treatment interruption in patients with multidrug-resistant human immunodeficiency virus. New Engl J Med. 2003;349:837-846.
Mellors JW, Munoz A, Giorgi JV, et al: Plasma viral load and CD4+ lymphocytes as prognostic markers of HIV-1 infection. Ann Intern Med. 1997;126:946-954. Palella FJ, Delaney KM, Moorman AC, et al: Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. N Engl J Med. 1998;338:353-360.
Panel on Clinical Practices for Treatment of HIV Infection. Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents. Washington DC: U.S. Department of Health and Human Services. Nov 10, 2003. Available at http://www.aidsinfo.nih.gov.
Yeni PG, Hammer SM, Hirsch MS et al. Treatment for Adult HIV Infection: 2004 recommendations of the International AIDS Society–USA Panel. JAMA. 2004; 292:251-265.
Youle M. Strategies of HIV Management – When to start. AIDS. 2002;16:S145-149.
WEBSITES
AIDSInfo: http://www.aidsinfo.nih.gov Accessed 11/03 (Several treatment guidelines are continuously updated at this U.S. Department of Health and Human Services website)