Page 162 - HIV/AIDS Guidelines

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However, in patients with baseline CD4 counts <50 cells/mm (17% of the study population), the rate of AIDS
or death was lower in the earlier therapy group than in the later therapy group (8.5 vs. 26.3 cases per 100
person-years, a strong trend favoring the earlier treatment arm, P = 0.06). For all patients, regardless of CD4
cell count, earlier therapy was associated with a higher incidence of IRIS and of adverse events that required a
switch in ARV drugs than later therapy. Two deaths were attributed to IRIS. 6
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In the CAMELIA study, which was conducted in Cambodia , patients who had CD4 counts <200 cells/mm 3
were randomized to initiate ART at 2 weeks or 8 weeks after initiation of TB treatment. Study participants had
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advanced HIV disease, with a median entry CD4 count of 25 cells/mm ; low BMIs (median = 16.8 kg/m ),
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Karnofsky scores (87% <70), and hemoglobin levels (median = 8.7 g/dl); and high rates of disseminated TB
disease. Compared with therapy initiated at 8 weeks, ART initiated at 2 weeks resulted in a 38% reduction in
mortality (P = 0.006). A significant reduction in mortality was seen in patients with CD4 counts ≤50 cells/mm 3
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and in patients with CD4 counts 51 to 200 cells/mm . Overall, 6 deaths associated with TB-IRIS were reported.
The ACTG 5221 (STRIDE) trial, a multinational study conducted at 28 sites, randomized ART-naive patients
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with confirmed or probable TB and CD4 counts <250 cells/mm to earlier (<2 weeks) or later (8–12 weeks)
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ART. At study entry, the participants’ median CD4 count was 77 cells/mm . The rates of mortality and AIDS
diagnoses were not different between the earlier and later arms, although higher rates of IRIS were seen in the
earlier arm. However, a significant reduction in AIDS or death was seen in the subset of patients with CD4
counts <50 cells/mm who were randomized to the earlier ART arm (P = 0.02).
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In each of these 3 studies, IRIS was more common in patients initiating ART earlier than in patients starting
ART later, but the syndrome was infrequently associated with mortality. Collectively these 3 trials demonstrate
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that in patients with active TB and with very low CD4 cell counts (i.e., <50 cells/mm ), early initiation of ART
can reduce mortality and AIDS progression, albeit at the risk of increased IRIS. These findings strongly favor
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initiation of ART within the first 2 weeks of TB treatment in patients with CD4 cell counts <50 cells/mm (AI).
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The question of when to start ART in patients with CD4 counts ≥50 cells/mm is also informed by these
studies. The STRIDE and SAPiT studies—in which the patients with CD4 cell counts ≥50 cells/mm were
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relatively healthy and with reasonable Karnofsky scores (note the SAPiT study excluded patients with
Karnofsky scores <70) and BMIs—demonstrated that ART initiation in these patients can be delayed until 8
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to 12 weeks after initiation of TB therapy (AI for CD4 counts 51–500 cells/mm and BIII for CD4 counts
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>500 cells/mm ).
However, the CAMELIA study, which included more patients who were severely ill than the STRIDE and
SAPiT studies, showed that early initiation of ART improved survival both in patients with CD4 counts ≤50
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cells/mm and in patients with CD4 counts from 51 to 200 cells/mm . In a multivariate analysis, age >40
years, low BMI (<16), low Karnofsky score (<40), elevated aspartate aminotransferase (AST) level (>1.25 x
the upper limit of normal [ULN]), disseminated and MDR TB were independently associated with poor
survival; whereas in a univariate analysis, hemoglobin <10g/dl also was associated with poor survival.
Thus, recently published results from the three clinical trials are complementary in defining the need for ART
and use of CD4 count and clinical status to inform decisions on the optimal time to initiate ART in patients
with HIV and TB disease. Earlier initiation of ART within 2 to 4 weeks of TB treatment should be strongly
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considered for patients with CD4 cell counts from 50 to 200 cells/mm who have evidence of clinical disease
of major severity as indicated by clinical evaluation, low Karnofsky score, low BMI, low hemoglobin, low
albumin, or organ system dysfunction (BI). Initiation of ART within 2 to 4 weeks also should be considered
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for patients with CD4 counts >200 cells/mm who present with evidence of severe disease (BIII).
Of additional importance, each of the above studies demonstrated excellent responses to ART, with 90% and
>95% of participants achieving suppressed viremia (HIV RNA <400 copies/mL) at 12 months in the SAPiT
Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents J-14

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