Slower time to AIDS and TB in immediate-treatment arm of HPTN 052
People who started antiretroviral therapy (ART) immediately in the randomized HPTN 052 trial had a significantly slower time to an AIDS disease and to tuberculosis than did people who delayed treatment [1]. The group that started ART immediately--at a CD4 count above 350--also had a lower rate of all new diseases assessed in this 2-year analysis.
HPTN 052 randomized HIV-positive adults with a CD4 count between
350 and 550 to start ART immediately or to wait until their
count fell below 250 or they had an AIDS illness [2]. People who
started ART immediately had a 96% lower risk of transmitting HIV
to their partner in this 1763-couple trial. Study participants
who started ART at a higher CD4 count also had a lower risk of
AIDS-related complications, especially extrapulmonary
tuberculosis, in this initial analysis.
The new analysis looked more closely at clinical outcomes
through 2 years of follow-up in this international trial. The
study considered long lists of primary clinical events (death,
WHO stage 4 HIV disease, tuberculosis, severe bacterial
infection, serious cardiovascular/vascular disease, serious
liver disease, end-stage renal disease, non‐AIDS
malignancy, and diabetes mellitus) and secondary clinical events
(WHO stage 2 or 3 HIV disease, malaria, renal insufficiency,
hepatic transaminitis, lipodystrophy, dyslipidemia,
hypertension, peripheral neuropathy, lactic acidosis, and
thrombocytopenia).
Follow-up of the 1761 HIV-positive people in this analysis (886
in the immediate-ART arm and 875 in the delayed arm) lasted for
a median of 2.1 years (interquartile range [IQR] 1.6 to 2.9).
During follow-up, 213 people (24%) in the delayed arm started
ART. Median CD4 count when ART began stood at 442 in the
immediate-treatment group and 229 in the delayed-treatment
group. In this analysis, treated people in the delayed group
took ART for a median of 1 year (IQR 0.5 to 1.7).
During that time 134 people (7.6%) experienced at least one
clinical event, including 26 deaths and 21 non-AIDS events.
Proportions of study participants who had at least one primary
event were 6% in the immediate-treatment group and 9% in the
delayed-treatment group. People in the delayed arm had a 37%
higher risk of a primary event (hazard ratio [HR] 1.37),
indicating a strong trend favoring immediate ART (95% confidence
interval [CI] 0.97 to 1.93, P = 0.07). Risk of a
primary event did not differ by continent, gender, or
pretreatment CD4 count above or below 450.
Compared with the immediate-treatment group, the
delayed-treatment group had a significantly shorter time to an
AIDS-defining disease (P = 0.03) and to tuberculosis
(P = 0.02). TB incidence was significantly higher in
the delayed group (1.8 per 100 person-years, 95% confidence
interval [CI] 1.3 to 2.6, versus 0.8 per 100 person-years, 95%
CI 0.5 to 1.3, P = 0.009).
In multivariate analysis, delayed treatment raised the risk of a
primary event 39%, but that heightened risk fell just short of
statistical significance (95% CI 0.98 to 1.96, P =
0.06). Four variables did independently predict a primary event
in this analysis: age 40 or older (HR 2.42, 95% CI 1.17 to 4.98,
P = 0.017), each 10-fold higher pretreatment viral load
(HR 1.34, 95% CI 1.06 to 1.69, P = 0.013), grade 2 or
worse hemoglobin deficiency (HR 2.17, 95% CI 1.10 to 4.27,
P = 0.025), and hepatitis B coinfection (HR 1.85, 95%
CI 1.03 to 3.31, P = 0.04). An analysis that considered
time-updated CD4 count determined that every 50-cell higher
count lowered the risk of a primary event 10% (HR 0.90, 95% CI
0.85 to 0.95, P < 0.001).
The most frequent AIDS diagnoses were TB (2% in the immediate
arm versus 4% in the delayed arm), serious bacterial infection
(2% versus 1%), and a WHO stage 4 event (1% versus 2%). Time to
a first AIDS-defining disease was significantly faster in the
delayed-treatment arm (P = 0.03).
Secondary events arose in 298 people (34%) in the immediate arm
and 317 people (36%) in the delayed arm. Incidence of secondary
events was significantly higher in the delayed arm (25 versus 21
per 100 person-years, P = 0.05).
Primary event incidence was also higher in
the delayed arm, but the difference from the immediate arm was
not significant (4.5 versus 3.5 per 100 person-years,
P = 0.18).
Incidence of any primary or secondary event was significantly
higher in the delayed group (29 versus 25 per 100 person-years,
P = 0.02). That meant the risk of any event was 20%
lower in the immediate-treatment arm (incidence rate ratio 0.8,
P = 0.02). This difference could be traced to
conditions directly related to HIV infection, such as TB, herpes
virus infection, herpes zoster, Candida, and skin conditions.
New non-AIDS diagnoses were rare in HPTN 052, and rates were
similar in the two trial arms: incidence 0.6 per 100
person-years in the immediate arm and 0.4 per 100 person-years
in the delayed arm (P = 0.51).
The HPTN 052 team proposed that "the combined treatment and
prevention benefits of ART support early initiation" of
therapy.
References
1. Grinsztejn B, Hosseinipour M, Swindells S, et al.
Effect of early versus delayed initiation of antiretroviral
therapy (ART) on clinical outcomes in the HPTN 052 randomized
clinical trial. XIX International AIDS Conference. July 22-27, 2012.
Abstract
THLBB05.
2. Cohen MS, Chen YQ, McCauley M, et al. Prevention of HIV-1
infection with early antiretroviral therapy. N Engl J Med.
201;365:493-505. http://www.nejm.org/doi/full/10.1056/NEJMoa1105243.
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