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Early HIV treatment and isoniazid prophylaxis: why TEMPRANO results do not yet support universal ART at CD4 counts >500

Simon Collins, HIV i-Base

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The TEMPRANO study presented as an oral late breaker looked at timing of TB prophylaxis and the timing of ART in TB-endemic countries. Even though the study concluded that ART should be started at CD4 counts above 500 cells/mm3, the results were to some extent historical and highlight the continued importance of the ongoing START study.

TEMPRANO was sponsored by the French ANRS and conducted in nine clinics in Abijan, Ivory Coast. It used a 2×2 factorial design to look at both timing of ART and use of isoniazid preventive therapy (IPT) for TB. [1]

Although WHO guidelines recommend (IPT) to all HIV positive people, in resource-limited settings this is often limited by the difficulty of ruling out active TB and a concern for developing drug resistance. In TEMPRANO, early ART involved starting treatment at any CD4 count below 800 cells/mm3 and WHO-ART was based on the current WHO guidelines.

Importantly for interpreting the results, the WHO guidelines changed the CD4 criteria for starting treatment during the course of the study from 200 (March 2008 to December 2009) to 350 (December 2009 to July 2012) and then to 500 (July 2012 to December 2014).

The study enrolled 2076 HIV positive adults with a CD4 count <800 cells/mm3 who were not yet eligible for ART, and 2056 participants were included in the final analysis.

The four study arms were: (1) early-ART with IPT, (2) early-ART without IPT, (3) WHO-ART with IPT and (4) WHO-ART without IPT. The IPT was once-daily isoniazid (300 mg) for 6 months, starting one month after study entry. ART was tenofovir/FTC plus efavirenz or lopinavir/r; or plus AZT if coinfected with HIV-2.

The primary endpoint was severe HIV-related morbidity. This was defined as all cause-mortality, any AIDS-defining event, severe bacterial diseases, and non-AIDS cancers. Other grade 3-4 morbidities were secondary endpoints.

Baseline criteria were balanced between arms and included: 78% women, median age 35 (IQR: 30-42), 90% were WHO stage 1 or 2, and 35% were positive for latent TB using Quanti-FERON IGRA test. Median CD4 count (cells/mm3) was 465 (IQR: 369-573) and was <350 in 21%, 350-500 in 38% and >500 in 41% of participants. Median viral load was 4.7 log copies/mL (IQR: 4.0-5.3) with 25% <10,000 copies/mL and 25% >120,000 copies/mL.

During a median follow-up time of 29.9 months (IQR: 29.9, 30.0), 597 (58%) of the WHO-ART arms started ART and 927 (90%) of the IPT arms used IPT and 94% of these (868/927) completed 6 months. Only 54 participants (2.6%) were lost to follow up.

There were significantly fewer events that independently favoured the use of early-ART (6.6% vs 11.4%, p=0.0002) and IPT (7.2% vs 10.7%, p=0.005), with a 44% reduction with early ART and a 35% reduction with IPT, see Table 1.

Table 1: Severe morbidity in TEMPRANO study at 30 months
% events n Rate / 100 PY adj HR p
WHO ART 11.4% 111 4.9
Early ART 6.6% 64 2.8 0.56 0.0002
No IPT 10.7% 104 4.7
IPT 7.2% 71 3.0 0.65 0.005

Over 30 months there were 204 events and 47 deaths, see Table 2. The most common event was TB (85/204) with 41/85 in the WHO ART arm with no IPT. Half the TB events were pulmonary. Bacterial events (56/204) were largely pneumonia (23/56) or isolated bacteremia (13.56). There were very few AIDS-related cancers (n=5), non-AIDS cancers (n=4) or other serious non-AIDS events (n=7).

In an analysis of participants who enrolled with a baseline CD4 count >500 cells/mm3 (849/2056 participants), early ART was associated with a significant 44% reduced risk (10.1% vs 5.8%; aHR 0.56, p=0.03). However, the 39% reduction with IPT (9.7% vs 6.1%; aHR 0.61, p=0.56) was not statistically significant.

However, early ART was associated with a higher risk of the secondary endpoints of serious grade 3/4 events during the first six months of ART (aHR 1.92, p=0.007). After six months, this was reduced compared to the WHO ART arm (aHR 0.74, p=0.03). In the IBT analysis, there were no significant differences in grade 3/4 events either during the first six months (aHR 0.80, p=0.36) or later (aHR 1.01, p=0.97).

Of the 40 TB strains isolated during follow-up, 5/40 were resistant to isoniazid alone and 4/40 were multidrug resistant to at least isoniazid and rifampicin, with no significant difference by IPT arm.

Although the study concluded that starting ART with a CD4 >500 cells/mm3 reduced HIV morbidity, the presenter did not clarify that much of the follow-up time was compared to waiting until CD4 counts <200 cells/mm3, which is already known to be suboptimal.

Table 2: Breakdown of serious events in TEMPRANO study (n=2056)
Overall(n=2056) WHO ART (n=511) WHO ART + IBT (n=512) Early ART (n=515) Early ART + IPT (n=518)
Total events 204 75 60 41 28
All cause death 47 16 10 13 8
TB (pulmonary, disseminated) 85 (43, 42) 41 (20, 21) 16 (4, 12) 17 (11, 6) 11 (8, 3)
Bacterial 56 14 28 7 7
AIDS cancers 5 1 2 1 1
non-AIDS cancers 4 0 3 0 1
Other non-AIDS events 7 3 1 3 0

Comment

The TEMPRANO study is one of the key studies looking at treatment strategies and this seven year study is a significant achievement. However, understanding the comparator group in these results is essential before any conclusion can be made about starting ART at CD4 counts above 500 cells/mm3.

This CD4 >500 analysis includes approximately 1200 people who were enrolled before January 2010 when the WHO guidelines still recommended deferring treatment until the CD4 counts dropped to 200 cells/mm3. [2] Although the study concluded that starting with a CD4 count >500 cells/mm3 reduced HIV morbidity, this was against a comparator of <200 cells/mm3 for much of the follow-up time. Further analysis is needed before any comment can be made on whether any benefit was seen compared to starting at 350 cells/mm3.

This further analysis is essential given that the ongoing international START study, with site in both developed and resource-limited settings, compares the risks and benefits of starting >500 to 350 cells/mm3, with results due in 2017. [3]

Importantly, TEMPRANO used three different deferral strategies, and only a limited number of people were randomised after the CD4 count for starting ART in the deferred arm was raised to 350 cells/mm3. Additionally, the presentation at CROI did not detail how closely participants in the deferral arm kept to the protocol. In earlier randomised controlled trials, including the Haiti trial [4], many people in the deferred arm started treatment at much lower CD4 counts than the protocol recommended, and led to increased HIV-related events at CD4 counts <200 cells/mm3.

It is important that the TEMPRANO and START research teams are working collaboratively to compare designs of the two studies, including applied deferral strategies, assessment of adherence to the strategy and endpoints. As part of this, START will be able to present additional analysis to the START Data and Safety Monitoring Board on sub groups in TEMPRANO that resemble the START design (i.e. >500 vs 350 cells/mm3 analysis).

References:

  1. Danel C et al. Early ART and IPT in HIV-infected African adults with high CD4 count (Temprano Trial). 2015 Conference on Retroviruses and Opportunistic Infections (CROI 2015), 23-26 February 2015, Seattle. Oral late breaker abstract 115LB.
    Abstract:
    http://www.croiconference.org/sessions/early-art-and-ipt-hiv-infected-african-adults-high-cd4-count-temprano-trial
    Webcast:
    http://www.croiwebcasts.org/console/player/25757?mediaType=slideVideo&
  2. TEMPRANO study cumulative enrolment.
    http://mereva.isped.u-bordeaux2.fr/temprano/
    http://mereva.isped.u-bordeaux2.fr/temprano/html/temprano_documents/fichiers/Temprano%20study%20enrollment%20curve_20130109.pdf (PDF)
  3. Strategic Timing of AntiRetroviral Treatment (START) study.
    http://insight.ccbr.umn.edu/start
  4. Severe P et al. Early versus standard antiretroviral therapy for HIV-infected adults in Haiti. N Engl J Med 2010; 363:257-265 (15 July 2010). DOI: 10.1056/NEJMoa0910370
    http://www.nejm.org/doi/full/10.1056/NEJMoa0910370