Patients who start antiretroviral therapy when their CD4 cell count dipped below 500 cells/mm3 are less likely to develop an AIDS-defining illness than individuals who start treatment with a CD4 cell count of 350 cells/mm3, an international team of investigators report in the Annals of Internal Medicine.
However, initiating HIV treatment with a CD4 cell count of approximately 500 cells/mm3 did not reduce the risk of all-cause mortality.
“If the goal is to prevent AIDS-defining illness or death, our findings support cART [combination antiretroviral therapy] initiation once the CD4 cell count decreases below 500 cells/mm3,” comment the investigators.
Importantly, the investigators did not gather information on the impact of earlier treatment on the risk of serious, but non-fatal, non-AIDS related illnesses.
The authors of an accompanying editorial suggest that the results of the study should be treated with “caution,” and that doctors should have “frank conversations with their patients about what we do and what we don’t know about starting cART.”
Nevertheless, results of the study will undoubtedly inform the debate about the best time to start antiretroviral therapy.
Treatment guidelines in Europe currently recommend that AIDS-free patients should start therapy when their CD4 cell count is in the region of 350 cells/mm3. However, US guidelines advocate treatment when an individual’s CD4 cell count falls under 500 cells/mm3.
Large randomised trials are currently underway to try and determine the optimum time to start HIV therapy. However, their results are not expected for several years. Because of this continuing uncertainty investigators from the HIV-CAUSAL Collaboration undertook a prospective observational study involving approximately 21,000 adult patients enrolled in cohorts in Europe and the US.
All the patients had a CD4 cell count above 500 cells/mm3 when they entered the study, and none had developed an AIDS-defining illness. The patients were recruited between 1996 and 2009. At the time of entry to the study, the patients had a median CD4 cell count of 660 cells/mm3.
The risk of all cause mortality and the risk of AIDS-related illness or death was compared between patients who started HIV treatment when their CD4 cell count was 500 cells/mm3 or above; between 350-499 cells/mm3; 200-349 cells/mm3; and below 200 cells/mm3.
A total of 390 patients developed an AIDS-defining illness or died before their CD4 cell count fell below 500 cells/mm3. HIV therapy was started by 2893 patients when their CD4 cell count was above 500 cells/mm3, and 9296 maintained a CD4 cell count above this level without the need for treatment.
The remaining 8292 patients experienced a fall in their CD4 cell count to below 500 cells/mm3 after a median of nine months.
There was no evidence that starting HIV therapy at CD4 cell counts around 500 cells/mm3, or 350 cells/mm3 significantly reduced the risk of all-cause mortality compared to initiating treatment at a CD4 cell count of 200 cells/mm3. This was equally low for all patients.
However, there was clear evidence that starting therapy at higher CD4 cell counts reduced the risk of AIDS-related illnesses or death.
Compared to patients who started treatment when their CD4 cell count fell below 500 cells/mm3, individuals initiating therapy when their CD4 cell count was below 350 cells/mm3 were 38% more likely to develop AIDS (hazard ratio [HR], 1.38; 95% CI, 1.23-1.56). Furthermore, patients who first took therapy when their CD4 cell count was below 200 cells/mm3 were 90% more likely to develop an AIDS-defining illness (HR = 1.90; 95% CI, 1.67-2.15).
Five-year survival rates were 98% for patients with a CD4 cell count around 500 cells/mm3, 98% for patients with a CD4 cell count around 350 cells/mm3 and 97% for individuals with a CD4 cell count of approximately 200 cells/mm3. AIDS-free survival rates were 92%, 92% and 88% respectively.
The investigators calculated that “approximately 48 patients would need to initiate cART when their CD4 cell count decreased below 500 cells/mm3 rather than 350 cells/mm3 to prevent 1 new case of AIDS-defining illness or death during the first 5 years.”
They add, “however, we estimated little change in all-cause mortality rates between the 500-350 threshold.”
Heart, kidney, and liver disease are now important causes of illness among people with HIV. The investigators acknowledge that a limitation of their study was lack of information on “serious nonfatal events other than AIDS-defining illnesses.”
The authors of the accompanying editorial comment that the study “is a robust, carefully performed analysis that supports the presence of a graded benefit of cART even when the risk for AIDS is low.”
However, they add, “the continuing HIV epidemic and tightening of resources requires that we clarify the absolute benefits, risks and costs of expanding the indications for cART.”
The HIV-CAUSAL Collaboration. When to initiate combined antiretroviral therapy to reduce mortality and AIDS-defining conditions in HIV-infected persons in developed countries. Annals of Internal Medicine, 154: 509-15, 2011.(View free abstract here).
Baker JV et al. If we can’t get what we want, can we get what we need? Optimizing use of antiretroviral therapy in the current era. Annals of Internal Medicine, 154: 563-65, 2011.