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IAS 2015: START Trial Provides Definitive Evidence of Benefits of Early HIV Treatment

People who start antiretroviral therapy (ART) immediately after an HIV diagnosis -- while their CD4 T-cell count is still high -- rather than waiting until it falls below 350 cells/mm³ have a significantly lower risk of illness and death, according to long-awaited findings from the START trial presented at the 8th International AIDS Society Conference this week in Vancouver and published simultaneously in the July 20 advance edition of the New England Journal of Medicine.

Jens Lundgren from the University of Copenhagen reported that 1.8% of study participants in the immediate treatment group experienced a combined endpoint of serious AIDS-related events, serious non-AIDS events, and death compared with 4.1% in the deferred therapy group -- a 57% reduction. The most common events in both study arms were tuberculosis (TB) and cancer.

These findings suggest that HIV causes persistent immune system damage soon after infection, and "clearly indicate that ART should be provided for everyone regardless of CD4 count," Lundgren told HIVandHepatitis.com.

It is well known that starting ART before CD4 cells fall to low levels dramatically reduces the frequency of opportunistic illness and improves survival. A growing body of evidence shows that earlier treatment is associated with decreased disease progression and death, as well as minimizing the risk of onward transmission of HIV.

But very early treatment can have drawbacks, too, including longer exposure to potentially toxic therapy. In addition, some early treatment critics have expressed concern that people with HIV could be pressured to start treatment before they were ready, in order to benefit others rather than their own health

START Study Design

Investigators with the INSIGHT START Study Group designed the Strategic Timing of Antiretroviral Treatmenttrial to shed more light on the optimal timing of HIV therapy, especially for people with normal CD4 cell counts. The study began wide enrollment in March 2011.

START participants entered the trial with a CD4 count above 500 cells/mm³. They were randomly assigned to either start treatment immediately or to delay therapy until their CD4 count fell below 350 cells/mm³ or they developed symptoms of AIDS. They used a variety of antiretroviral regimens selected by study clinicians.

The study enrolled 4685 HIV-positive adults in 35 countries worldwide, including just over half from low- and middle-income countries. Nearly three-quarters were men and the average age was 36 years. About 45% were white, 30% were black, 14% were Hispanic/Latino, and 8% were Asian. Just over half were men who have sex with men.

At study entry participants had been diagnosed with HIV for a median of 1 year and had never used ART. About a third each had CD4 counts between 500-600 and between 600-700 cells/mm³, with 11% having more than 900 cells/mm³. Pre-treatment HIV viral load was most commonly between 3000 and 30,000 copies/mL, but 10% had >100,000 copies/mL.

Looking at other health risk factors, about a third were current smokers and the median Framingham 10-year cardiovascular risk score was 1.9.

The START trial's Data Safety and Monitoring Board (DSMB) stopped the randomized portion of the trial ahead of schedule in May 2015 when it determined that there was enough evidence to show a significant benefit of immediate treatment. All remaining untreated participants were offered the option to start therapy. They will continue to be followed for long-term outcomes, and a set of sub-studies is looking at specific manifestations including neurological function, artery function, bone density, and liver disease.

At the time the study was halted, participants had been followed for an average of 3 years, accruing a total of 14, 060 person-years of follow-up time. Most (94%) in the immediate arm were on still on treatment and 28% in the deferred arm had started. Retention in START was excellent, according the researchers, and adherence was good once treatment was initiated.

People in the deferred group started ART in a median of 3 years -- less than the predicted 4 years. Nearly a third started ART with a CD4 count of 250-350 cells/mm³, but 8% did not do so until they fell below 250 cells/mm³. The rest did so at higher levels than the trial's treatment-initiation threshold, including 8% who started with more than 750 cells/mm³. Over the course of follow-up people in the deferred therapy group had CD4 counts that were 194 cells/mm³ lower, on average, than those who started treatment immediately.

The researchers used a combined primary endpoint of serious AIDS events, serious non-AIDS events, or death. Serious AIDS events included opportunistic infections and AIDS-defining cancers (cervical cancer, Kaposi sarcoma [KS], and certain types of lymphoma), while serious non-AIDS events included cardiovascular disease, end-stage kidney disease, decompensated liver disease, and non-AIDS cancers (all other malignancies).

Results

• Composite endpoint

o   Looking at the combined endpoint of serious AIDS events, serious non-AIDS events, or death, there were 42 events (1.8%, or 0.60 per 100 person-years [PY]) among people randomized to immediate treatment compared to 96 events (4.1%; 1.38 per 100 PY) in the deferred treatment group -- a 57% lower risk (hazard ratio [HR] 0.43;p<0.001).

• Serious AIDS events

o   There were 14 serious AIDS events (0.20 per 100 PY) in the immediate treatment group and 50 events (0.72 per 100 PY) in the deferred group, for a 72% risk reduction (HR 0.28;p<0.001).

o   The difference in rates of AIDS events became apparent around 24 months and then continued to diverge.

o   TB was the most common AIDS event in both the immediate and deferred treatment arms (6 vs 20 cases, respectively).

o   Opportunistic conditions including lymphoma (3 vs 10 cases), KS (1 vs 11 cases), and Pneumocystis pneumonia (1 vs 5 cases) occurred much more often in the delayed treatment group.

• Serious Non-AIDS Events

o   Turning to serious non-AIDS events -- including deaths due to other non-AIDS causes -- there were 29 (0.42 per 100 PY) in the immediate group and 47 (0.67 per 100 PY) in the deferred group, for a 39% risk reduction (HR 0.61; p=0.04).

o   Here, the curves showing the occurrence of these events "did not split as quickly or markedly" as for AIDS events, Lundgren said.

o   The most frequent non-AIDS events were non-AIDS cancers (9 in the immediate vs 18 in the deferred group) and cardiovascular disease (12 vs 14 cases, respectively); serious liver or kidney disease were rare in both arms (1 case in the immediate arm vs 2 in the deferred arm).

• Deaths

o   Looking at deaths overall, there were 12 (0.17 per 100 PY) in the immediate group and 21 (0.30 per 100 PY) in the deferred group; however, this 42% reduction in risk was not statistically significant (HR 0.58; p=0.13).

o   In both arms the leading cause of death was accidents, violence, or suicide (4 in the immediate and 6 in the deferred arm).

o   There was 1 death due to active HIV/AIDS in the immediate group compared with 4 in the deferred group.

o   Other causes of death were scattered between the groups with very small numbers and "no clear pattern," according to Lundgren.

• Cancer

o   Focusing on cancer, there were 14 cases of any type (0.20 per 100 PY) in the immediate ART group and 39 cases (0.56 per 100 PY) in the deferred group, a 64% risk reduction that was significant (HR 0.36; p=0.001).

o   This difference became apparent after 12-16 months from then on there was a clear separation.

o   AIDS-defining malignancies KS (1 vs 11 cases) and lymphoma (3 vs 10 cases) were much more frequent in the deferred treatment group.

o   For other cancer types the numbers were small and there were no notable differences.

o   This was true for both for cancers caused by infectious agents -- such as human papillomavirus (HPV) for anal and cervical cancer -- and for those with no known infectious cause.

• Cardiovascular Disease

o   Serious cardiovascular disease occurred with similar frequency in the immediate and deferred groups (12 vs 14 cases).

o   There were 3 cardiovascular deaths in the early ART arm compared with 1 in the delayed group, but these numbers are too small to draw conclusions.

o   Lundgren said there is no evidence from this analysis to demonstrates any benefits of early treatment for cardiovascular disease, but this also cannot be ruled out.

• Adverse events

o   Overall rates of serious (grade 4) adverse events, unscheduled hospitalizations, and deaths from any cause did not differ significantly in the immediate and deferred ART arms.

o   However, when these events were combined there was a significant advantage in the early group (HR 0.82; p=0.01).

o   The only specific adverse event with a notable difference was bacterial infections, which were significantly more common in the delayed treatment arm.

o   Despite the long-standing concerns about early ART leading to added side-effects, Lundgren concluded there was "no apparent increased toxicity" seen in this study.

Implications of START

START participants who started immediate treatment saw similar benefits regardless of sex, age, race/ethnicity, or geographic region. Importantly, the benefits of early ART were comparable in wealthy and low- or middle-income countries.

However, the study team acknowledged that the START population was younger than expected and experienced fewer overall events than originally predicted. Further research is needed on complications among people aging with HIV.

Most people in both the immediate and deferred treatment arms spent most of their time in the study with a CD4 count over 500 cells/mm³, and more than two-thirds of serious AIDS and non-AIDS events occurred at this level.

Based on these findings, Lundgren suggested that we cannot rely on CD4 count to fully capture immune deficiencies in early HIV infection. "This trial demonstrates that even in people with high CD4s, there's a hole in the immune system if you're HIV-positive," he explained. With cancer, for example, the normal immune system may provide a surveillance function to capture malignant cells that is weakened in people with HIV.

ART is able to fill those gaps at least partially, but even fully suppressive therapy may not be able to completely reverse immune damage once it's done. Lundgren added that it will be important to develop new types of treatment beyond antiretrovirals aimed at restoring lost immune function.

When the START DSMB halted the trial prematurely, the early findings were provided to the World Health Organization (WHO) panel working on updated global HIV treatment guidelines. WHO announced this week that its forthcoming guidelines will recommend treatment for all, regardless of CD4 count. U.S. guidelines adopted universal HIV treatment in 2012.

"The HIV research community needs to have solid evidence for making global recommendations on treatment," Lundgren told HIVandHepatitis.com. "We want to build an evidence base and not rush it. But now we have evidence that aligns individual benefit and prevention benefit without harm. I'm very happy we were able to provide that evidence and that WHO is responding."

"IAS 2015 will be remembered as the definitive moment when the world agreed earlier initiation of treatment is the best way to preserve the health of people living with HIV, and one of the best tools we have to slow HIV transmission to others," said conference co-chair Julio Montaner of the British Columbia Centre for Excellence in HIV/AIDS. "The new data presented today will inform HIV treatment guidelines worldwide, and inspire governments, funders and health systems to act to save millions more lives."

"We have to translate these findings into programs as quickly as possible," concurred U.S. Global AIDS Coordinator Deborah Birx, speaking on a panel about START's implications after Lundgren presented the findings. "All of us have a moral obligation now."

SEE ALSO: IAS 2015: START Supports ART For All [VIDEO]

7/20/15

References

JD Lundgren, et al. The Strategic Timing of Antiretroviral Treatment (START) Study: Results and their Implications. 8th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention. Vancouver, July 19-22, 2015. Session MOSY03.

JD Lundgren, AG Babiker, F Gordin, et al. (INSIGHT START Study Group). Initiation of Antiretroviral Therapy in Early Asymptomatic HIV Infection. New England Journal of Medicine. July 20, 2015.

Other Sources

National Institute of Allergy and Infectious Disease. NIH-Funded Study: Early Antiretroviral Therapy Prevents Non-AIDS Outcomes in HIV-Infected People. Press release. July 20, 2015.

IAS 2015. Final Study Results Provide Definitive Scientific Evidence to Support Earlier Initiation of HIV Treatment. Press release. July 20, 2015.