Page 44 - HIV/AIDS Guidelines

ART. However, unmeasured confounders for which adjustment was not possible may have influenced the
analysis.

The ART Cohort Collaboration (ART-CC) included 45,691 patients from 18 cohort studies conducted
primarily in North America and Europe. Data from ART-CC showed that the rate of progression to AIDS
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and/or death was higher when therapy was deferred until CD4 count fell to the 251 to 350 cells/mm range
6
3
than when ART was initiated at the 351 to 450 cells/mm range (risk ratio: 1.28, 95% CI: 1.04–1.57). When
analysis of the data was restricted to mortality alone, the difference between the 2 strategies was weaker and
not statistically significant (risk ratio: 1.13, 95% CI: 0.80–1.60).
In a collaboration of North American cohort studies (NA-ACCORD) that evaluated patients regardless of
whether they had started therapy, the 6,278 patients who deferred therapy until their CD4 counts were <350
cells/mm had greater risk of death than the 2,084 patients who initiated therapy with CD4 counts between
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3
351 and 500 cells/mm (risk ratio: 1.69, 95% CI: 1.26–2.26) after adjustment for other factors that differed
between these 2 groups. 11
Another collaboration of cohort studies from Europe and the United States (the HIV-CAUSAL
Collaboration) included 8,392 ART-naive patients with initial CD4 counts >500 cells/mm who experienced
3
declines in CD4 count to <500 cells/mm . The study estimated that delaying initiation of ART until a patient
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had a CD4 count <350 cells/mm was associated with a greater risk of AIDS-defining illness or death than
3
initating ART with a CD4 count between 350 and 500 cells/mm (HR: 1.38, 95% CI: 1.23–1.56). There was,
3
however, no evidence of a difference in mortality (HR: 1.01, 95% CI: 0.84–1.22).
A collaboration of cohort studies from Europe, Australia, and Canada (the CASCADE Collaboration)
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included 5,527 ART-naive patients with CD4 counts in the 350 to 499 cells/mm range. Compared with
patients who deferred therapy until their CD4 counts fell to <350 cells/mm , patients who started ART
3
immediately had a marginally lower risk of AIDS-defining illness or death (HR: 0.75, 95% CI: 0.49–1.14)
and a lower risk of death (HR: 0.51, 95% CI: 0.33–0.80). 12

Randomized data showing clinical evidence favoring ART in patients with higher CD4 cell counts comes
from a small subgroup analysis of the SMART trial, undertaken primarily in North and South America,
Europe, and Australia, which randomized participants with CD4 counts >350 cells/mm to continuous ART
3
or to treatment interruption until CD4 count dropped to <250 cells/mm . In the subgroup of 249 participants
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3
who were ART naive at enrollment (median CD4 count: 437 cells/mm ), participants who deferred therapy
until CD4 count dropped to <250 cells/mm had a greater risk of serious AIDS- and non-AIDS-related events
3
than those who initiated therapy immediately (7 vs. 2 events, HR: 4.6, 95% CI: 1.0–22.2). 13
HPTN 052 was a large multinational, multicontinental (Africa, Asia, South America, and North America)
randomized trial that examined whether treatment of HIV-infected individuals reduces transmission to their
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uninfected sexual partners. An additional objective of the study was to determine whether ART reduces
clinical events in the HIV-infected participants. This trial enrolled 1,763 HIV-infected participants with CD4
counts between 350 and 550 cells/mm and their HIV-uninfected partners. The infected participants were
3
randomized to initiate ART immediately or to delay initiation until they had 2 consecutive CD4 counts less
than 250 cells/mm . At a median follow-up of 1.7 years, there were 40 events/deaths in the immediate
3
therapy arm versus 65 events/deaths in the delayed arm (HR: 0.59, 95% CI: 0.40–0.88). The observed
difference was driven mainly by the incidence of extrapulmonary TB (3 events in the immediate therapy arm
vs. 17 events in the delayed therapy arm). The difference in mortality rates observed between the immediate
and deferred therapy arms (10 vs. 13 deaths, respectively; HR: 0.77, 95% CI: 0.34–1.76) was not significant.
Collectively, these studies suggest that initiating ART in patients with CD4 counts between 350 and 500
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cells/mm reduces HIV-related disease progression; whether there is a corresponding reduction in mortality is

Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents E-3

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