Some have greater risk reduction than others – study

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Starting antiretroviral therapy soon after HIV diagnosis led to better outcomes than delayed treatment in all population subgroups in the START trial.

Researchers reported at the 21st International AIDS Conference (AIDS 2016) recently in Durban that some people saw greater risk reductions, including those over age 50, those with a lower CD4:CD8 ratio and higher viral load, and those with cardiovascular risk factors.

Evidence has accumulated in recent years showing that starting HIV treatment promptly, rather than waiting for the CD4 T-cell count to fall below a certain threshold, is associated with reduced disease progression and death. Some of the most definitive evidence comes from the large START trial, which randomly assigned people with high CD4 counts to either immediate or deferred therapy.

At last year’s International AIDS Society Conference, START investigators reported that people who initiated treatment immediately after diagnosis had a significantly lower risk of illness and death than those who waited until their CD4 count fell below 350 cells/mm3.

At AIDS 2016, Jean-Michel Molina from the University of Paris Diderot presented further findings from the trial looking at benefits of early treatment in different subgroups based on demographics, disease status, and other risk factors.

START enrolled 4685 previously untreated HIV-positive adults with CD4 counts above 500 cells/mm3; the median was about 650, but 11% had more than 900. Nearly three-quarters were men and the average age was 36 years. Participants came from 35 countries, including about half from low and middle-income countries; about 45% were white, 30% were black, 14% were Hispanic/Latino, and 8% were Asian. Median pre-treatment viral load was approximately 12,800 copies/mL, though 10% had over 100,000 copies/mL. About 6% had hepatitis B or C coinfection, 2% had high Framingham cardiovascular risk, and nearly a third were smokers.

The investigators looked at a combined primary endpoint of serious Aids events, serious non-Aids events, or death in pre-specified population subgroups (except for the CD4:CD8 ratio analysis, which was added later). They calculated event rates per 100 person-years (PY), absolute risk reduction (ARR) associated with immediate treatment, and the number of people who needed to start immediate ART in a year to prevent a single event (number needed to treat, or NNT).

Overall, there were 42 of these events (0.60 per 100 PY) among people randomised to immediate treatment compared to 96 events (1.38 per 100 PY) in the deferred therapy group – a hazard ratio of 0.43, or 57% lower risk. Absolute risk reduction worked out to 0.78 per 100 PY and the number needed to treat was 128.

Looking at demographic subgroups, all groups showed a relative risk reduction, or proportional change in risk with immediate ART. Hazard ratios were generally similar, ranging from 0.18 to 0.85, indicating that everyone benefitted from early treatment. But absolute risk reduction, considering actual numbers of events, revealed greater differences across groups.

Broken down by age, absolute risk reduction ranged from 0.49 for those under 30 years, to 0.66 for those age 30-49, to 2.24 for those age 50 and older. While 206 people under 30 and 151 people age 30-49 would need to be treated to prevent one event, this fell to just 45 for the over-50s – a statistically significant difference (p=0.01).

Men and women had an absolute risk reduction of 0.74 and 0.93, respectively, and a number needed to treat of 136 and 108, respectively – not a significant difference (p=0.63). Risk reduction was also statistically similar for racial/ethnic groups (ARR 0.70 for blacks and 0.92 for whites; NTT 142 and 109, respectively, p=0.69) and for high-income and low/middle-income countries (ARR 0.86 vs 0.69; NTT 116 vs 144, p=0.62).

Analysing by baseline disease status, people with a CD4 count 800. Numbers needed to treat were 91, 147, and 196, respectively, which was not a significant difference (p=0.41). Categorising by CD4:CD8 ratio, however, did show a highly significant difference: absolute risk reduction was 1.67 for those with a ratio <0.5, 0.47 for those with 0.5-0.8, and .040 for those with >0.8 (NTT 60, 214, and 248, respectively, p=0.005).

Looking at baseline viral load, absolute risk reduction was just 0.10 for those with 50,000 copies/mL. Numbers needed to treat were 992, 122, and 67, respectively – the largest numerical difference, but just short of statistical significance (p=0.06).

Finally, people with a low Framingham 10-year risk of heart disease had an absolute risk reduction of 0.36, compared to 0.90 for those with medium risk and 1.45 for those with high risk. Numbers needed to treat were 276, 111, and 69, which again did not reach the threshold for significance (p=0.13).

“In asymptomatic ART-naive adults with >500 CD4+ cells/mm3, immediate ART was superior to deferred ART across all sub-groups with similar relative risk reduction,” the researchers concluded, noting that higher absolute risk reduction and lower NNT were found for participants older than 50 years, with HIV RNA levels >50,000 copies/ml, with CD4:CD8 ratios <0.5, and with Framingham 10 year risk score >10%.

The investigators did not analyse subgroups that had fewer than 10 events in both study arms combined, but nevertheless cautioned that “NNT estimates can be unstable when event rates are small, and need to be interpreted with caution.”

Based on these findings, they suggested that people in the groups that saw greater absolute risk reductions “might be prioritised for immediate access to ART” in settings where universal prompt treatment for everyone diagnosed with HIV is not yet feasible.

They emphasised that immediate treatment also reduces HIV transmission risk, which should be considered along with the number needed to treat when assessing the cost effectiveness of ART.

Molina said that these results are from univariate analyses and the team is currently working on a multivariate analysis to shed light on how these factors interact with each other. They hope to use this data to develop a risk scoring system.

Abstract 2016
Background: The START trial showed that immediate antiretroviral therapy (ART) in asymptomatic adults with >500 CD4 cells/mm3 reduces the risk of primary events (a composite of serious AIDS, serious non-AIDS conditions or death) by 57% vs. deferring ART until CD4 < 350. We investigated which subgroups benefitted most from immediate treatment. Methods: Within subgroups defined by 8 predefined baseline characteristics (Figure), we estimated event rates for the START primary endpoint, and the number need to treat (NNT) immediately for one year to prevent one event compared with the deferral strategy. Using proportional hazards models, we estimated hazard ratios (HR) of immediate versus deferred ART within subgroups, and tested for interactions between treatment groups and subgroups to assess heterogeneity of the treatment effect across subgroups. Results: Among the 4685 participants followed for a mean of 3.0 years, the event rates (absolute risk) for the primary endpoint in the immediate and deferred ART arms were 0.6 and 1.38 per 100 PY, respectively, NTT=128. Across all 8 subgroups, HRs consistently favored the immediate arm (Figure). While HRs were similar across subgroups (p>0.25 for all interactions), the event rates and reductions in absolute risk were higher among older participants (NNT=50 for age >50 years), those with higher baseline HIV RNA level (NNT=67 for HIV RNA >50,000 copies/mL), higher Framingham risk score (NNT=69). There is a trend towards lower NNT among participants with lower baseline CD4 levels.
Conclusions: In asymptomatic ART-naïve adults with >500 CD4 cells/mm3, immediate ART was superior to deferral across all subgroups, with similar relative risk reduction. Due to higher absolute risk, older participants, those with higher plasma HIV RNA level, lower baseline CD4 count, and higher Framingham risk score will benefit more from immediate treatment. Immediate ART also reduces transmission risk, which is essential for cost-effectiveness considerations, but not reflected in NNT.

Authors
JM Molina, B Grund, F Gordin, I Williams, M Schechter, M Losso, M Law, E Ekong, N Mwelase, A Skoutelis, MJ Wiselka, L Vanderkerckhove, T Benfield, D Munroe, J Lundgren, J Neaton, INSIGHT START Study Group

Abstract 2015
Background: Data from randomized trials are lacking on the benefits and risks of initiating antiretroviral therapy in patients with asymptomatic human immunodeficiency virus (HIV) infection who have a CD4+ count of more than 350 cells per cubic millimeter.
Methods: We randomly assigned HIV-positive adults who had a CD4+ count of more than 500 cells per cubic millimeter to start antiretroviral therapy immediately (immediate-initiation group) or to defer it until the CD4+ count decreased to 350 cells per cubic millimeter or until the development of the acquired immunodeficiency syndrome (AIDS) or another condition that dictated the use of antiretroviral therapy (deferred-initiation group). The primary composite end point was any serious AIDS-related event, serious non–AIDS-related event, or death from any cause.
Results: A total of 4685 patients were followed for a mean of 3.0 years. At study entry, the median HIV viral load was 12,759 copies per milliliter, and the median CD4+ count was 651 cells per cubic millimeter. On May 15, 2015, on the basis of an interim analysis, the data and safety monitoring board determined that the study question had been answered and recommended that patients in the deferred-initiation group be offered antiretroviral therapy. The primary end point occurred in 42 patients in the immediate-initiation group (1.8%; 0.60 events per 100 person-years), as compared with 96 patients in the deferred-initiation group (4.1%; 1.38 events per 100 person-years), for a hazard ratio of 0.43 (95% confidence interval [CI], 0.30 to 0.62; P<0.001). Hazard ratios for serious AIDS-related and serious non–AIDS-related events were 0.28 (95% CI, 0.15 to 0.50; P<0.001) and 0.61 (95% CI, 0.38 to 0.97; P=0.04), respectively. More than two thirds of the primary end points (68%) occurred in patients with a CD4+ count of more than 500 cells per cubic millimeter. The risks of a grade 4 event were similar in the two groups, as were the risks of unscheduled hospital admissions.
Conclusions: The initiation of antiretroviral therapy in HIV-positive adults with a CD4+ count of more than 500 cells per cubic millimeter provided net benefits over starting such therapy in patients after the CD4+ count had declined to 350 cells per cubic millimeter.

Authors
The INSIGHT START Study Group

HIV and Hepatitis material
AIDS2016 abstract
New England Journal of Medicine abstract


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