Early START results recommend ART for all study participants: starting HIV meds when the CD4 count is above 500 reduces AIDS-related events

1 June 2015. Related: Treatment alerts.

Simon Collins, HIV i-Base

On 27 May 2015, early results from the international Strategic Timing of AntiRetroviral Treatment (START) study were announced by Dr Anthony Fauci, head of the US National Institute of Allergy and Immune Diseases (NIAID). The findings are expected to change HIV treatment guidelines globally. [1]

The results were not anticipated and will have implications for everyone: doctors, researchers, guidelines committees, policy makers and funders – and HIV positive people, whether or not they are yet on treatment.

Timeline for DSMB recommendations

Although only limited findings have been released from START, they show surprises that nobody predicted.

The top-line results are based on data collected up to 13 March 2015. A more detailed analysis will be available in time for the International AIDS Conference being held in Vancouver in July, and will include data to the end of May 2015.

The first surprise is that the results are at least 18 months earlier than expected. This is due to a recommendation from the independent Data and Safety Monitoring Board (DSMB) for the study, who were tracking unblinded results. On 15 May 2015, this small group of experts decided that the primary research question had been definitively answered. Although the overall rate of serious events was low, and involved fewer endpoints than expected, the difference between the two arms of the study was highly significant. Based on pre-defined rules for changing the study, the DSMB recommended that all participants be offered treatment and that follow-up should continue as planned. The continued follow up is important: the START study is therefore still ongoing.

START is a large randomised international study and the size, randomisation and global network involved are all key to the importance of the results. The primary research question was whether the benefits and risks of starting antiretroviral treatment (ART) at high CD4 counts outweighed the benefits and risks of waiting until later. The definition of ‘early’ vs ‘late’ was having a CD4 count above 500 cells/mm³ vs waiting until 350 cells/mm³. Until now, observational cohort studies had reported conflicting results on whether there were clinical advantages of starting earlier and randomised studies had deferring treatment until even lower CD4 cut-offs.

The two groups in START were compared based on the different rates of serious clinical events. These events included important AIDS-related and non-AIDS related illnesses together with deaths from all causes. Numerous sub-studies were included to look at the impact of both HIV and ART on other key areas of health in early infection­ – including on bone heath, neurological function, cardiovascular risks, lung function and quality of life. Although information about the sub studies has not been released, these unblinded results were available to the DSMB when making their recommendations.

Enrolment and patient characteristics

From April 2009 to December 2013, START enrolled 4685 HIV positive people at 211 sites in 35 countries. By the time of the data cut in March for the 2015 DSMB review, the mean follow up time was about 3 years, contributing to 7000 patient years of follow-up.

Baseline characteristics for the main study and related sub-studies have been well described in the annual DSMB open reports and in a recent open access supplement to HIV Medicine. [2, 3]

Age at enrolment ranged from 18 to 81 years, with a median age of 36 (IQR: 29 to 41). Just over half of participants were gay men and more than a quarter were women. Most people were enrolled within a year of their HIV diagnosis (median estimated time 1.0 (IQR: 0.4 to 3.0) years).

START is a global study; with 33% of participants in Europe, 25% in South America or Mexico, 21% in Africa, 11% in the US, 8% in Asia and 2% in Australia.

Given that entry criteria included having a CD4 count >500 cells/mm³, the study enrolled many people at CD4 counts that were significantly higher than expected, with 20% of participants starting above 800 cells/mm³. The median CD4 count was 651 cells/mm³ (IQR: 584-765; range 503 to 2296). Viral load at baseline also showed that this was a group in early infection. Median viral load was about 12,000 copies/mL (IQR: 3,000 to 40,000) and 8% had viral load <400 copies/mL.

The number of other medical complications within this diverse group is important. At baseline, almost one-third were current smokers, half had at least one cardiovascular risk based on the Framingham calculator, almost one in five either had hypertension or were on hypertensive treatment and 8% either had high blood lipids or were on lipid-lowering drugs. Just over 3% had diabetes, were using diabetes treatment, or had high fasting glucose. Prevalence of viral hepatitis was 2.9% and 3.7% for coinfection with hepatitis B and C, respectively. Other important health issues included about that 3% had documented alcohol or substance use issues and 6% had a psychiatric diagnosis (including depression, bipolar and other conditions).

These baseline data suggested that cardiovascular disease (CVD) and non-AIDS cancers would be the most common serious events. START was designed as an endpoint-driven study and modeling projected that 213 serious events would be needed to show that earlier treatment would reduce the risk of events by about one third. The study was expected to run until the end of 2016.

Top line results: ART has greatest impact on HIV-related events

In the press conference, results were released for three separate endpoints, see Table 1 below. The number of events for each endpoint and the relative differences between the early and late treatment groups were also provided. These figures are based on data from March 2015 and so will change slightly when the final dataset become available.

The differences were highly significant for endpoints 1 and 2, but not for endpoint 3.

• The combined endpoint of AIDS, serious non-AIDS or death was reduced by 53% in the early treatment group (HR 0.47; 95%CI 0.32 to 0.68). This was based on 41 vs 86 events in the early vs deferred groups, with rates of 0.60 vs 1.25 per 100 person years (PY).
• The combined endpoint of AIDS or death was reduced by 70%, (HR 0.30; 95%CI 0.17 to 0.55). This was based on 14 vs 46 events in the early vs deferred group, with rates of 0.20 vs 0.66 per 100 PY.
• The combined endpoint of serious non-AIDS events or non-AIDS related deaths was reduced by 33% (HR 0.67; 95%CI 0.42 to 1.09). This was based on 28 vs 41 events in the early vs deferred groups with rates of 0.41 vs 0.59 per 100 PY. This difference is not statistically significant because the 95% confidence intervals cross 1.0.

These preliminary results were not expected. They show that early treatment had a greater impact on HIV-related illnesses than on non-AIDS events. To understand the importance of this finding, the clinical concern behind some treatment guidelines already recommending ART at CD4 counts above 500 cells/mm³ was driven by risk of non-AIDS illnesses. Non-AIDS events include serious heart, liver, kidney disease and non-AIDS cancers.

* PY = patient years, ** NS = non significant

How much better was early and how much worse was late?

It is important that the interim results in Table 1 included information both on relative rates and the absolute number of events. While the relative rates were so highly significant in answering the study question, the absolute number of serious illnesses was low. Less than 3% of participants experienced these problems. More the 97% of participants did not have serious complications over the average three years of follow-up.

This means that fewer participants had to undergo serious event than was initially planned in order to see a difference between early and late ART. Back in 2009, it was thought that 370 endpoint events would be needed. Then in 2013, the study team recalculated that only 213 events would be needed, because the enrolment of people with very high CD4 counts widened the difference of risk in the two groups. [4]

In May 2015, the DSMB announcement showed that the number of endpoints was reduced further, with the study question answered based on only 127 events. This is good for the study and good for participants.

These results highlight that for people who have high CD4 counts but are not on treatment, that the absolute risk of events is still low. START results mean that a discussion about starting ART at the routine visit will be important but that the timeline for starting treatment can be paced.

The most common AIDS-related events were pulmonary tuberculosis (TB), Kaposi’s Sarcoma (KS) and non-Hodgkins Lymphoma (NHL). The most common non-AIDS events were cancer, cardiovascular events and other causes (including traffic accidents, assault, suicide and overdose).

Earlier treatment therefore had a greater impact on reducing the risk of HIV-related events than on reducing non-AIDS events.

The combined results also imply that earlier treatment was not associated with significant harm. This is important for HIV positive people who already started treatment at high CD4 counts. However, results from important secondary endpoints, including virological efficacy, side effects and drug resistance, together with important substudies, will be essential.

Although the results have not been released for each geographical region, it is notable that the overall benefit of earlier ART were found for both high and low/middle-income countries.

Implications and impact of the START results

The START results are likely to have a significant impact for anyone interested in HIV treatment.

• For HIV positive people who are not yet on treatment, the results should make it easier to be treated. The results should reduce the reliance on any CD4 threshold in order to access treatment.
• For HIV positive people currently on treatment, the findings should be reassuring in terms of low risk of serious complications.
• Now that both treatment benefits have the highest grade of evidence supporting earlier treatment, this should also make Treatment as Prevention (TasP) easier to access. The default will be that treatment becomes the routine next step after an HIV diagnosis. It is already common for newly diagnosed individuals to want ART in order to reduce the risk of transmission to sexual partners: this data is reassuring that ART also benefits their health.
• HIV activists have long-demanded evidence for earlier treatment, so it a major achievement from START is to establish such a strong and robust dataset for this evidence. Different national guidelines are likely to become more similar.
• For health professionals, it is difficult to overestimate the importance of the START results given how keenly the study was being followed. Even when the US DHHS treatment guidelines recommended ART at CD4 counts above 500 cells/mm³ in February 2013, this was based on the lowest evidence rating of expert opinion. These guidelines included an important caveat for this recommendation – that definitive evidence would only come from randomised studies such as START. [5]
• Similarly, in July 2013, when the WHO consolidated guidelines (produced for low- and middle-income countries) increased the threshold for ART from a CD4 count of 350 to 500 cells/mm³, this was based on the hoped for merger of clinical, prevention and operational benefits of earlier treatment. [6] The 2015 review of the WHO guidelines is therefore likely to benefit from strong data supporting both clinical and prevention benefits from starting ART at higher CD4 counts. It is important that these finding also come at a time when first-line treatment globally has shifted to wider use of effective and tolerable drugs.
• The clinical benefits from START are similarly likely to change national HIV guidelines that until now have retained CD4 thresholds of 350 cells/mm³ (for the UK) or 500 cells/mm³ (for South Africa, Australia and some European countries including France and Spain).
• Finally, researchers and scientists now have a rich and complex dataset to further explain the pathogenesis of early infection, including hypotheses on risks of immune activation and activation and that challenge earlier assumptions that HIV-related illnesses were not an appreciable risk at very high CD4 counts.

The NIAID press conference is accompanied by a press statement and related Q&A document, both of which are online. [1]

A non-technical i-Base article about the START study and a community Q&A is also online. [7, 8]

Simon Collins is a member of the START Community Advisory Board and was involved as a community advocate from the planning stages of the study.

Comment

Overnight, these results are likely to overturn the 30-year dependence on a CD4 threshold for initiating HIV treatment. They are the crucial missing evidence that will unify the benefits of ART for both treatment and prevention.

This is positive news, with findings similar in low- and high-income country settings, and with the study question answered so much earlier than expected.

It was believed that early ART would be better, as this was a key assumption in the study. Two surprises were (1) the benefits were so significant and (2) that ART reduced AIDS-related at high CD4 counts, rather than non-ADS events such heart, liver, kidney disease and some cancers.

Even people who were vocal in not supporting the START study – and there were a few – did not predict the results. START was driven by a demand for data. One of the most important results is therefore realigning the importance of evidence-based medicine. This outcome is probably as important as finding benefits of early ART.

Follow-up will now continue for all participants. Extending this beyond 2016 might also be warranted, given the unique nature of this cohort.

START is likely to be a source for many further surprises. Further results will be headline news when presented in Vancouver in July.

References:

1. NIAID press announcement and statement. Starting antiretroviral treatment early improves outcomes for HIV-infected individuals, study finds: trial results will likely impact global treatment guidelines, (27 May 2015).
   http://www.niaid.nih.gov/news/newsreleases/topics/Pages/aidsReleases.aspx
2. START Study. DSMB Open reports, 2009-2014.
   http://insight.ccbr.umn.edu/start/index.php?study=start&page=&menu=safety&submenu=DSMB
3. The START Trial Characteristics at Study Entry, HIV Medicine, April 2015, Volume 16, Special Issue: Supplement S1 Pages 1–146.
   http://onlinelibrary.wiley.com/doi/10.1111/hiv.2015.16.issue-s1/issuetoc
4. START study DSMB 10th open report. (15 May 2015).
   http://insight.ccbr.umn.edu/official_documents/START/open_DSMB/START_OpenDSMB_30May2014.pdf (PDF)
5. US Department of Health and Human Sciences (DHHS). Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. February 2013.
   http://www.aidsinfo.nih.gov/guidelines
6. World Health Organization. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection. Recommendations for a public health approach. June 2013.
   http://www.who.int/hiv/pub/guidelines/arv2013/en/
7. Collins S. Breaking news: what do the START results mean for HIV positive people.
   https://i-base.info/breaking-news-what-do-the-start-results-mean-for-hiv-positive-people
8. i-Base Q&A on the START study results.
   https://i-base.info/i-base-qa-on-the-start-study-results