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मुखपृष्ठ एड्स निदान Terms and Concepts of AIDS - Immune Reconstitution

Terms and Concepts of AIDS - Immune Reconstitution

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Terms and Concepts of AIDS
Immune Reconstitution
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Immune Reconstitution
The immune response to antiretroviral therapy is quantitative (CD4 response) and qualitative (antigen/microbe specific). The initial response is an increase in CD38+ MO+ (memory) cells followed after six months by increases in CD38+ MA+ (naive) cells including naive cells of thymic origin. The biologic impact of immune reconstitution has been shown by:
  1. An inflammatory response ascribed to immunologic reaction to selected microbial antigens.
  2. The safety in discontinuation of prophylaxis for selected OIs.
  3. Control of several chronic, untreatable opportunistic infections, and
  4. An impressive decline in virtually all HIV–associated complications except lymphomas. With regard to the inflammatory reactions, the “Immune reconstitution syndrome” has been observed with the following pathogens: M. avium, M. tuberculosis, M. kanasii, herpes simplex, herpes zoster, hepatitis and CMV. Chronic, relatively untreatable infections that can be controlled with immune reconstitution include Molluscum contagiosum, PML, CMV, cryptosporidiosis, and microsporidiosis. OI prophylaxis that may be suspended with adequate criteria for immune reconstitution according to the CDC/IDSA 1999 guidelines are primary PCP prophylaxis, primary MAC prophylaxis and secondary CMV prophylaxis (MMWR 1999,48:RR–10).
Salvage or rescue regimens containing >6 antiretroviral regimens. Some of the drugs are “Re–cycled”. The rationale is that patients with multiple drug exposure and failures are unlikely to have viruses that are resistant to all drugs. Preliminary results show some success with this approach, the main concerns are the need for extraordinary motivation, high rates of intolerance and cost. Immune–based Therapy: Treatment intended to achieve immune reconstitution that does not involve antiretroviral agents. The most advanced in development through clinical trials are IL–2 and gp120 depleted inactivated HIV vaccine (Remune). Trials of IL–2 therapy show robust CD4 responses using doses of 5–7.5 MIU bid IM or SC x 5 days every 8 weeks, most studies have been carried out in patients with baseline CD4 counts >200/mm3 (Lancet 1999, 535:1923). Remune is given to stimulate HIV–specific CTL response for improved immune regulation of HIV, preliminary results document immune response, but have not confirmed clinical benefit. Similar disappointing preliminary results were obtained with a recombinant gp160 vaccine (Lancet 1999, 353:1735).

Trial Analysis
Results of most clinical trials are presented in “Intent–to–treat” analysis or “As–treated” analysis using virologic end points of <500 c/mL or <50 c/mL. In an intent–to–treat analysis, the numerator is the number achieving the desired end point, and the denominator is all patients randomised to that treatment arm, patients who discontinue the trial and those with missing data are counted as failures. With “As–treated analysis”, the numerator is the number who achieve the desired end point, and the denominator is the number continuing the trial to that time point. In this analysis, patients who change therapy due to treatment failure, discontinue the trial due to side effects, or have other reasons for missing data are excluded from the analysis.

Intent–to–treat analysis
Is generally viewed as more scientifically valid and preferred. In a review of 17 HIV therapeutic trials, A. Hill, et al [6th Conf. On Retroviruses, Chicago, 1999, Abstract #394] showed that the mean percent achieving “Virologic success” was 81% by as treated analysis using <500 c/mL as the therapeutic goal, and 52% by intent–to–treat analysis using <50 c/mL as the therapeutic goal. This represents a 29% difference (a range of 15–46% for individual studies) that may not be readily detected by the casual observer.

Drug holiday
Simultaneous discontinuation of antiretroviral drugs. Prior studies show this usually results in a viral rebound in 3–31 days (AIDS 1999, 13:F79). The HIV strains are usually “Wild–type”, the HIV RNA plasma levels usually rise rapidly to the pretreatment levels, and immunologic deterioration with CD4 decline is rapid and substantial.

It is unfortunate that the cure theory was deemed plausible due to its impact on patient perceptions of the benefits of therapy. Virtually all studies show viral rebound within 12 weeks after discontinuing therapy despite no detectable virus for 2–3 years with HAART (NEJM 1999, 340:1605, Nat Med 1999, 5:512).




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