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Is there a baseline CD4 cell count that precludes a survival response to modern antiretroviral therapy?
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Therapeutic guidelines advise that 200-350 CD4 cells/l may approximate an irreversible threshold beyond which response to therapy is compromised. We evaluated whether non-immune-based factors such as physician experience and
adherence could affect survival among HIV-infected adults starting HAART.
Analysis of 1416 antiretroviral naive patients who initiated triple therapy between 1 August 1996 and 31 July 2000, and were followed until 31 July 2001. Patients whose physicians had previously enrolled six or more patients were defined as having an experienced physician. Patients who received medications for at least 75% of the time during the first year of HAART were defined as adherent. Cumulative mortality rates and adjusted relative hazards were determined for various CD4 cell count strata. Among patients with < 50 cells/l the adjusted relative hazard of mortality was 5.07 for patients of experienced physicians and was 11.99 among patients with inexperienced physicians, in comparison to patients with [ges] > 200 CD4 cells/l treated by experienced physicians. Similarly, among patients with < 50 CD4 cells/l, the adjusted relative hazard of mortality was 6.19 for adherent patients and was 35.71 for non-adherent patients, in comparison to adherent patients with [ges] >200 cells/l.
The authors conclude survival rates following the initiation of HAART are dramatically improved among patients starting with CD4 counts <200 CD4 cells/l once adjusted for conservative estimates of physician experience and adherence. Our results indicate that the current emphasis of therapeutic guidelines on initiating therapy at CD4 cell counts above 200 cells/l should be re-examined. AIDS 2003; 17(5):711-720. Julio Montaner et al
Our results show that survival rates following the initiation of antiretroviral therapy are dramatically improved among patients starting with CD4 cell counts below 200 cells/l once adjusted for conservative estimates of physician
experience and patient adherence. These data suggest that a CD4 cell count of 200-350 cells/l does not represent an irreversible biological threshold beyond which response to therapy is compromised. Conversely, inappropriate care of
patients with advanced disease and patient non-adherence may be the strongest determinants of patient survival, rather than the time at which antiretroviral therapy is initiated prior to 200 CD4 cells/l. As mortality was elevated among all CD4 strata below 200 CD4 cells/l, however, our data do not support delaying the initiation of HAART below this level, and close follow-up will be necessary to examine if survival differences emerge among patients with baseline CD4 cell counts > 200 CD4 cells/l.
Previous studies have shown that patients are not at immediate risk of death until the CD4 cell count drops below 50 CD4 cells/l, and that AIDS-related opportunistic illnesses (OIs) are rare after the initiation of HAART, except
among patients with less than 50 CD4 cells/l. However, it has also been shown that physicians who have treated less than six HIV-infected patients are significantly less knowledgeable about prescription of prophylaxis against OIs, provision of preventative vaccinations, as well as the treatment of acute OIs. These findings probably explain why physician experience had the largest impact on highly advanced patients, and why physician experience was found to be independent of adherence. Additional evidence that the association between physician experience and survival is attributable to the management of advanced patients and not patient selection factors comes from the fact that physician experience was no longer significant when all-cause mortality was considered. Nevertheless, it was not the objective of the present study to identify the ideal level of experience for the optimal management of HIV-infected individuals, and further study will be required to identify the physician-related factors, such as treatment or prevention of opportunistic infections, that may be responsible for our observations. Although there has been debate about the role of physician experience in the HAART era, to our knowledge, these results are the first to demonstrate an independent effect of physician experience on survival since the widespread use of triple therapy.
Previous studies have demonstrated that measuring daily adherence to antiretroviral therapy can be fraught with difficulties that may over or underestimate a patient's actual exposure to treatment. Although using refill
compliance as a surrogate for adherence has been previously validated, there is likely a very strong conservative bias operating in our study because patients may have been less than optimally adherent to daily treatment despite
receiving >75% medication during the first year of therapy. It has consistently been found that very high daily adherence is required, to achieve an undetectable plasma viral load, to prevent viral rebound, and to prevent the
evolution of resistant virus. Further study will be required to determine the optimal level of adherence which, as illustrated above, is likely to vary depending on the nature of the endpoint selected (virological, immunological, or clinical) as well as the duration of follow-up. In addition, as we have previously discussed, a limitation of the present study is that patients were defined as adherent on the basis of their behavior during the first year
of therapy and then assigned to adherent strata for an analysis of baseline characteristics. Although we adjusted our analyses for pertinent demographic and clinical characteristics, as with all studies of patients treated in observational cohorts, unmeasured differences may exist among study populations and for this reason caution is warranted. However, it was not the objective of the present study to elucidate the level of adherence needed to optimize the outcomes associated with antiretroviral therapy.
In summary, we found that mortality was dramatically altered by very conservative adjustments for physician experience and adherence, suggesting that inappropriate care of advanced patients and patient non-adherence may be the strongest determinants of patient survival, rather than the time at which therapy is initiated prior to CD4 cell counts of 200 cells/l. As mortality was elevated among all CD4 strata below 200 cells/l, our data do not support delaying the initiation of HAART to any level below 200 CD4 cells/l. These results should be useful for the development of therapeutic guidelines, and should be helpful to emphasize the role of physician experience and patient adherence in the treatment of HIV infection.
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