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Prophylaxis for Human Immunodeficiency Virus-Related Pneumocystis carinii Pneumonia
 
 
  Using Simulation Modeling to Inform Clinical Guidelines
 
Comments: the authors of this study found that it is better to delay stopping PCP prophylaxis until CD4s are 300 rather than 200. This prevented additional cases of PCP (9/1000). This is particularly true for patients with lower CD4s before HAART. In patients with an average of 87 CD4s before starting HAART, an additional 34 cases of primary PCP per every 1000 patients were prevented. The authors found delaying stopping prophylaxis to be cost effective as well. Clinical guidelines suggest stopping prophylaxis when CD4s are above 200 for at least 3-6 months. These authors decided to examine using an absolute CD4 count.
 
Sue J. Goldie, MD, MPH; Jonathan E. Kaplan, MD; Elena Losina, PhD; Milton C. Weinstein, PhD; A. David Paltiel, PhD; George R. Seage III, ScD, MPH; Donald E. Craven, MD; April D. Kimmel; Hong Zhang; Calvin J. Cohen, MD, MSc; Kenneth A. Freedberg, MD, MSc
 
Background: Human immunodeficiency virus (HIV)-infected patients receiving highly active antiretroviral therapy (HAART) have experienced a dramatic decrease in Pneumocystis carinii pneumonia (PCP), necessitating reassessment of clinical guidelines for prophylaxis.
 
Methods: A simulation model of HIV infection was used to estimate the lifetime costs and quality-adjusted life expectancy (QALE) for alternative CD4 cell count criteria for stopping primary PCP prophylaxis in patients with CD4 cell count increases receiving HAART and alternative agents for second-line PCP prophylaxis in those intolerant of trimethoprim-sulfamethoxazole (TMP/SMX). The target population was a cohort of HIV-infected patients in the United States with initial CD4 cell counts of 350/無 who began PCP prophylaxis after their first measured CD4 lymphocyte count less than 200/無. Data were from randomized controlled trials and other published literature.
 
Results: For patients with CD4 cell count increases during HAART, waiting to stop prophylaxis until the first observed CD4 cell count was greater than 300/無 prevented 9 additional cases per 1000 patients and cost $9400 per quality-adjusted life year (QALY) gained compared with stopping prophylaxis at 200/無. For patients intolerant of TMP/SMX, using dapsone increased QALE by 2.7 months and cost $4500 per QALY compared with no prophylaxis. Using atovaquone rather than dapsone provided only 3 days of additional QALE and cost more than $1.5 million per QALY.
 
Conclusions: Delaying discontinuation of PCP prophylaxis until the first observed CD4 cell count greater than 300/無 is cost-effective and provides an explicit "PCP prophylaxis stopping criterion." In TMP/SMX-intolerant patients, dapsone is more cost-effective than atovaquone.
 
Arch Intern Med. 2002;162:921-928
 
RESULTS
 
CRITERIA FOR STOPPING PCP PROPHYLAXIS WITH CD4 CELL COUNT INCREASES DURING HAART
 
In HIV-infected patients with initial CD4 cell counts of 350/無 (who were given PCP prophylaxis after their first measured CD4 lymphocyte count <200/無), we considered different strategies to guide the decision to stop or continue PCP prophylaxis once CD4 cell counts increased to greater than 200/無 during HAART. In the base case analysis, we assumed that the risk of PCP was based on the actual new CD4 cell count (ie, fraction of benefit of 1.0). A CD4 cell count stopping criterion greater than 200/無 provided 3.6 months of quality-adjusted life expectancy and cost $5100 per QALY compared with no prophylaxis (Table 2). Discontinuing prophylaxis with a CD4 cell count greater than 300/無 prevented an additional 9 cases of primary PCP per 1000 patients at a cost of $9400 per QALY.
 
For patients starting with lower CD4 cell counts and in the later stages of HIV disease, the clinical benefits of waiting until the CD4 cell count was greater than 300/無 vs greater than 200/無 were much greater. For example, in patients similar to those in the AIDS Clinical Trial Group Protocol 320 (initial mean CD4 cell count, 87/無), delaying discontinuation of prophylaxis until the CD4 cell count was greater than 300/無 prevented an additional 34 cases of primary PCP per 1000 patients compared with stopping at a CD4 cell count greater than 200/無. The cost-effectiveness ratio of this strategy, at $8200 per QALY, was more attractive than the cost-effectiveness ratio of stopping at a CD4 cell count greater than 200/無, thereby dominating the latter strategy.74 In contrast, in a cohort of patients starting with earlier HIV disease (mean CD4 cell count of 500/無), delaying discontinuation of prophylaxis until the CD4 cell count was greater than 300/無 prevented only 5 additional cases of primary PCP per 1000 patients.
 
COMMENT BY AUTHORS
 
Pneumocystis carinii pneumonia prophylaxis was the most important improvement in the standard of HIV care during the first decade of the HIV epidemic, and it played a major role in reducing the rate of progression to AIDS before the availability of other opportunistic infection prophylaxis and HAART.1-3 Its low cost makes it the least expensive HIV medication, and its cost-effectiveness suggests that it offers substantial clinical value for the resources spent.32 There is a convergence of opinion in favor of discontinuing PCP prophylaxis in patients whose CD4 cell counts have increased to greater than 200/無 with HAART.11-28 In HIV-infected patients with initial CD4 cell counts of 350/無 who started PCP prophylaxis after their first measured CD4 lymphocyte count less than 200/無, stopping prophylaxis when the CD4 cell count increased to greater than 300/無 with HAART provided a small additional clinical benefit (eg, 9 cases of primary PCP averted per 1000 patients) compared with stopping at 200/無. However, the additional costs are so low that continued prophylaxis has an attractive cost-effectiveness ratio nonetheless. For patients withmore advanced disease, such as those in AIDS Clinical Trial 320 (CD4 cell counts of 87/無), the incremental benefits of stopping prophylaxis at a CD4 cell count greater than 300/無 rather than greater than 200/無 are much greater (eg, 34 cases of primary PCP averted per 1000 patients). Lower CD4 cell count nadirs may be associated with a greater risk of opportunistic infections in patients with CD4 cell count increases during HAART.65 However, even when we assumed a fraction ofbenefit of 0.0 in those with CD4 cell count nadirs of less then 50/無, the overall cost-effectiveness results were unchanged.
 
Our results, in large part, support recent clinical guidelines.5 The 1999 US Public Health Service-Infectious Disease Society of America Working Group suggested that stopping prophylaxis when the CD4 cell count has been greater than 200/mL for at least 3 to 6 months may be reasonable based on early data showing an extremely low risk of PCP in patients treated successfully with HAART. The analysis we conducted to address this issue involved the critical review of all published studies supporting safe discontinuation in patients with CD4 cell count increases with HAART; in most of these studies, the mean CD4 cell count at the time of discontinuation was greater than 300/無.11-24 Because these clinical studies described the immune status of their study populations using the mean CD4 cell count, we elected to use an absolute CD4 cell count rather than duration of time at a particular CD4 cell count for our primary prophylaxis discontinuation criterion. In fact, the clinical guidelines and our results are quite similar whether there will be a clinically meaningful difference between "a CD4 cell count greater than 200/無 for at least 6 months" and "a measured CD4 cell count of at least 300/無" is a question for future research.
 
The results of this analysis support the following conclusions: (1) Despite the relativelylow risk of PCP in patients successfully treated with HAART, waiting to stop primary PCP prophylaxis until an observed CD4 cell count is greater than 300/無 will prevent PCP cases, is cost-effective, and provides an explicit and easily understandable PCP prophylaxis stopping criterion for patients and providers. (2) Regimens using atovaquone in TMP/SMX-intolerant patients have cost-effectiveness ratios that are much higher than those of well-accepted clinical interventions, and dapsone should be the initial choice for prophylaxis in these patients. These conclusions can be used to refine the optimal approach to PCP prophylaxis as treatment for HIV disease continues to evolve in this era of effective antiretroviral therapy.
 
 
 
 
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