Early treatment in the HPTN 052 study of treatment as prevention reduced
serious illness by around 40%, delegates at the Sixth International AIDS Society
conference heard – but the effect was almost entirely accounted for by fewer
cases of extrapulmonary tuberculosis.
There was no significant difference in deaths, or in the rate of serious
bacterial infections or of pulmonary tuberculosis.
The HPTN 052 study was designed to determine whether early treatment for an
HIV-infected person would reduce the risk of HIV transmission to his or her
The study showed that early antiretroviral treatment – started at a CD4 count
between 350 and 550 cells/mm3 – reduced the risk of HIV transmission
to uninfected partners by at least 96%.
However, the study also collected information on a number of other endpoints:
death, illness , virological and immunological responses to treatment. These
data will provide important information on the potential benefits of early
treatment in settings where bacterial infections and tuberculosis are more
prevalent than in North America and Europe.
The study will also provide information on any differences in rates of
clinical or immunological disease progression between different regions of the
world, or between men and women. Some studies, but not all, have suggested
faster rates of disease progression in sub-Saharan Africa.
The study enrolled 1763 HIV-infected individuals with CD4 counts between 350
and 550 cells/mm3. Participants were randomised either to receive
immediate antiretroviral treatment or to defer treatment until their CD4 cell
count fell below 250 cells/mm3 on two separate tests. This was the
level at which treatment was recommended to begin in national guidelines during
the study recruitment period. The study recruited participants in Malawi, India,
Zimbabwe, Botswana, South Africa, Kenya, Thailand, the US and Brazil.
The median CD4 count at enrolment was 446 cells/mm3 and the median
viral load 4.4 log10 copies/ml (25,000 copies/ml).
Differences between Africa and other regions
Although the proportion of HIV-positive men and women recruited to the study
was equal across the study population as a whole, sites in Africa recruited a
larger proportion of women than men (58 vs 40%, p< 0.0001), reflecting the
higher rates of engagement in care by women in sub-Saharan Africa as a
consequence of earlier HIV diagnosis through antenatal programmes.
African sites also recruited a larger proportion of participants in the 18 to
24 age group (20 vs 15%, p=0.003). African participants had slightly lower viral
loads (4.4 vs 4.5 log10 HIVRNA, p=0.006).
Although there was no significant difference in baseline CD4 count between
regions, Africans in the deferred treatment arm were less likely to reach the
CD4 threshold that indicated they needed to start treatment. Participants in the
deferred arm outside the Africa region were 40% more likely to start treatment,
but when the hazard ratio was adjusted for confounding factors this difference
ceased to be statistically significant (aHR 1.30, 95% CI 0.9-1.8, p= 0.06).
The median time to starting treatment in the deferred arm was 3.25 years
outside Africa, compared to 4.1 years in Africa.
Overall, 21% of participants in the deferred arm needed to start treatment
during the follow-up period (n=184), an incidence rate of 12 per 100
person-years of follow-up. However, among Africans the rate of treatment
initiation was 9 per 100 person-years, compared to 15 per 100 person-years of
follow-up in participants at non-African sites.
Unsurprisingly, the factors significantly associated with the need to start
treatment in the deferred treatment arm were lower CD4 count or higher viral
load at enrolment (adjusted hazard ratio per increase of 100 CD4 0.6; 95%
CI,0.5-0.7) and higher log10 HIV RNA (adjusted hazard ratio per log
increase 1.5; 95% CI, 1.2-1.8).
Overall, 75% of patients in the deferred arm who initiated treatment did so
because of a decline in CD4 cell count.
Among those who initiated treatment immediately (886 patients), at a median
CD4 count of 442 cells/mm3, 90% had an undetectable viral load (below
400 copies/ml) after one year of treatment. They experienced a mean CD4 cell
increase of 158 cells/mm3, to 603 cells/mm3.
In the delayed-treatment group, the median CD4 count at treatment initiation
was 225 cells/mm3, and the median time to treatment initiation in the
deferred arm was 3.5 years. After one year, 93% had an undetectable viral load
(below 400 copies/ml) and CD4 cell counts had risen by a mean of 191
cells/mm3, to 418 cells/mm3.
Virologic failure was rare; only 5% in the immediate-treatment arm and 2.7%
in the deferred-treatment arm experienced virologic failure. Of these, 67% in
the immediate arm and 60% in the deferred arm switched to second-line
The effect of early treatment on clinical outcomes was very clear.
Early treatment significantly reduced the risk of clinical illness, but there
was no difference in the risk of death between the two study arms.
Primary endpoint clinical events were defined as:
Around 7% of participants received cotrimoxazole prophylaxis against
bacterial infections, and around 4% received isoniazid preventive therapy to
prevent the development of active TB.
A total of 105 participants developed a primary clinical event during 3304
person-years of follow-up. Forty primary events occurred in the immediate arm
(2.4 per 100 PY), compared to 65 in the deferred arm (4.0 per 100 PY, hazard
ratio 0.59, 95% CI: 0.40 - 0.88, p=0.01.)
Early treatment did not significantly reduce the risk of developing pulmonary
tuberculosis. There were 14 cases of pulmonary TB in the immediate-treatment arm
(0.8 per 100 PY), compared with 16 in the delayed-treatment arm (0.9 per 100
PY). Pulmonary TB cases were diagnosed at a median CD4 count of 521 in the
immediate-treatment arm and 295 in the delayed-treatment arm.
In contrast, early treatment did significantly reduce the risk of
extrapulmonary TB. Three cases were diagnosed in the immediate-treatment arm
(0.2 per 100 PY), at a median CD4 count of 443, compared to 17 in the
delayed-treatment arm (1 per 100 PY), at a median CD4 count of 342.
Bacterial infections occurred somewhat more frequently in the
immediate-treatment arm (19 vs 13, 1.1 vs 0.8 per 100 PY). In each arm the most
common bacterial infection was pneumonia, and the difference between arms was
chiefly driven by four cases of sepsis in the immediate-treatment arm. Three
participants in the immediate arm each experienced more than one bacterial
There was no significant difference in the death rate between arms: ten
occurred in the immediate arm and 13 in the deferred arm. Deaths were largely
attributed to causes other than HIV in the immediate arm: 3 suicides, one
stroke, and three unknown causes, with only three deaths due to infection
(leptospirosis, TB and sepsis) in the immediate arm. Almost half the deaths in
the delayed arm were of unknown cause, with two accidental deaths, one stroke
and only two deaths due to infection.
There was no significant difference in severe adverse events between the two
arms (14% in each), nor any difference in the distribution of types of adverse
event between the two arms.
Grinsztejn B et al. Effects of early versus delayed initiation of
antiretroviral therapy (ART) on HIV clinical outcomes: results from the HPTN 052
randomised clinical trial. Sixth International AIDS Society Conference on
HIV Pathogenesis, Treatment and Prevention, Rome, abstract MOAX0105, 2011.
Hosseinipour MC et al. Immunologic and virologic disease progression and
responses to ART across geographic regions: outcomes from HPTN 052 study.
Sixth International AIDS Society Conference on HIV Pathogenesis, Treatment and
Prevention, Rome, abstract MOAX0104, 2011.