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EACS 2015: START Substudies Show More Bone Loss with Early ART, But No Differences in Lung or Neurocognitive Function

Participants who started antiretroviral therapy (ART) soon after HIV diagnosis in the large START trial showed a greater decrease in bone density at the hip and spine compared to those who deferred treatment, researchers reported at a joint session of the 15th European AIDS Conference and the 17th International Workshop on Co-morbidities and Adverse Drug Reactions in HIVlast week in Barcelona. There was no significant difference in the likelihood of fractures, however, and 2 other START substudies saw no differences in lung function or neuropsychological performance between people randomized to immediate or deferred ART.


Starting antiretroviral treatment before development of serious immune system damage greatly reduces the risk of HIV disease progression and death, but early treatment can potentially also have drawbacks including longer exposure to toxic drugs. The INSIGHT START (Strategic Timing of Antiretroviral Treatment)trial was designed to address the long-standing controversy over the optimal timing of HIV treatment, especially for people who still have high CD4 counts.

Briefly, START enrolled 4685 HIV-positive adults in 35 countries who entered the trial with a CD4 count above 500 cells/mm3. They were randomly assigned to either start treatment at study entry or delay therapy until their CD4 count fell below 350 cells/mm3 or they developed AIDS-related symptoms.

Overall, nearly three-quarters were men and the group was quite young (average age 36 years). They had good immune function at baseline, with a median CD4 count of 651 cells/mm3. Over the course of follow-up, the CD4 count of people in the deferred group was 194 cells/mm3 lower, on average, than that of the immediate group.

The START Data Safety and Monitoring Board stopped the randomized portion of the trial ahead of schedule in May 2015 after it determined that there was already enough evidence to show a benefit of immediate treatment. At that point, the average follow-up time was 3 years.

The primary START results, presented this summer at the International AIDS Society Conference in Vancouver and published in the August 27 New England Journal of Medicine, showed thatparticipants randomized to start ART soon after HIV diagnosis had a significantly lower risk of illness and death than those who waited. The immediate treatment group not only had a 72% lower risk of AIDS-related infections and malignancies compared to the deferred group, but also were 39% less likely to experience serious non-AIDS events (heart, liver, and kidney events and non-AIDS cancers) or death.

The START design included several substudies looking at the effects of early versus deferred therapy on specific outcomes known or suspected to be associated with HIV infection or its treatment, including bone density, lung function, and neurocognitive function.

Bone Density Substudy

Jennifer Hoy from Monash University and the Alfred Hospital in Melbourne presented findings from the START bone mineral density (BMD) substudy. This analysis included 193 people randomized to the early ART group and 204 in the deferred ART group.

Substudy participants underwent dual X-ray absorptiometry (DXA) scans of the lumbar spine, total hip, and femoral neck at baseline and annually thereafter. The researchers looked atZ-scores, a measure of deviation from BMD norms for people of the same age, sex, and race, as well as T-scores, based on the norm for young white women.

Participants were followed at 33 study sites and 16 radiology centers in Brazil and Peru (38%), India and Thailand (30%), South Africa (11%), Europe (9%), Australia (8%), and the U.S. (4%). This distribution differed from the START study as a whole, which had more than 200 sites, with 33% in Europe and just 8% in Asia. As in the full population, 26% were men, but the substudy participants were a bit younger (32 vs 36 years), more likely to be Asian (32% vs 8%) or Latino (24% vs 14%), and less likely to be black (19% vs 30%) or white (20% vs 45%); this is relevant because racial/ethnic groups have different bone density norms.

Looking at known or potential risk factors for low bone density, 19% were current smokers, 4% were heavy drinkers, 12% reported recreational drug use, 4% had hepatitis C virus (HCV) coinfection, and 13% of the women were menopausal. Body weight and kidney function were normal (median BMI 24; median eGFR 114 mL/min). Baseline Z-scores were below the norm (-0.3 for the hip; -0.8 for the spine). More than a third (38%) met the criteria for low BMD, 3% had osteoporosis, and 8% reported previous fractures.

People in the immediate arm were on any antiretrovirals for 95% of the total follow-up time, compared with 18% in the deferred arm; they were exposed to tenofovir disoproxil fumarate (Viread, also in Atripla and other single-tablet regimens) for 79% and 15% of follow-up time, respectively. Protease inhibitor use was uncommon (19% and 3% of follow-up time).


  • Over a mean follow-up period of 2.2 years, total spine BMD decreased in the immediate ART arm during the first year (by about 2.0%) and then stabilized, while remaining about the same in the deferred arm (less than -0.5% decline).
  • Total hip BMD continued to decline over 3 years in both arms, but the percentage loss was greater in the immediate compared to the deferred group (about -2.0% vs -0.5% at 12 months and -3.5% vs -2.0% at 36 months).
  • These differences were statistically significant for spine BMD at 12, 24, and 36 months, and for hip BMD at 12 and 24 months (only about 30% of participants had the third year DXA).
  • Overall estimated mean differences were -1.6% for spine BMD and -1.5% for hip BMD -- that is, 1.6% and 1.5% lower in the immediate group -- both of which were significant.
  • Comparing people who were actually on or off ART (rather than group assignment), the mean differences were larger: -2.2 for spine BMD and -2.1% for hip BMD, again both significant.
  • Having a lower CD4 count was associated with greater bone loss at the spine, while longer time since HIV diagnosis was the major factor affecting hip bone loss; however, the only significant risk factor in an adjusted analysis was using a protease inhibitor in the first ART regimen.
  • 7 people in the immediate ART group and 4 in the deferred group (1.72 and 0.90 per 100 person-years [PY]) were diagnosed with osteoporosis, giving a hazard ratio of 2.0 or twice the risk, but the difference was not significant.
  • In the main START study (not just the substudy), 57 people in the immediate arm and 50 in the deferred arm sustained fractures (0.71 and 0.81 per 100 PY), a hazard ratio of 1.16 that again was not significant.
  • Minimal trauma fractures -- those that occur due to bone fragility rather than traumatic injury -- were actually less common in the immediate ART group (0.18 vs 0.32 per 100 PY; hazard ratio 0.57), but this also was not significant.

In summary, this analysis showed "significantly greater loss of BMD at both the hip and spine in those randomized to immediate ART," the researchers concluded, but there was "no evidence of difference in development of osteoporosis between groups (or fractures in the main START study)."

START Pulmonary Substudy 

Ken Kunisaki from the University of Minnesota presented results from the START pulmonary substudy, which compared changes in lung function in the immediate and deferred ART groups.

Chronic obstructive pulmonary disease (COPD) is an emerging HIV comorbidity, Kunisaki noted as background. Observational studies have shown that people with HIV are at higher risk for COPD, but there is conflicting evidence about whether ART is associated with elevated risk. The underlying mechanisms are unclear, but could be related to inflammation, increased risk of pneumonia and other lung infections, changes in lung microbiota, and perhaps antiretrovirals themselves, he said.

In this substudy participants had spirometry tests done at baseline and annually thereafter. Spirometry is used to assess lung function by measuring the amount of air inhaled and exhaled. The primary measure in this analysis was the change in forced expiratory volume, or the amount of air a person can blow out in 1 second (FEV1). FEV1 typically peaks around age 25 and then declines over time; a level below 30% of the maximum is disabling. Results were stratified by smoking status.

This substudy included 518 people randomized to the early ART group and 508 in deferred ART group. Again, the distribution differed from the study as a whole, with about 30% each in Africa and Europe, 19% in South America, and about 10% each in Asia and the U.S. About 70% were men and the median age was 36 years. About 60% had never smoked, 28% were current smokers, and 11% were former smokers.


  • Over a median follow-up time of 2.0 years, FEV1 slope showed "absolutely no difference" between the immediate and deferred ART arms for either smokers or non-smokers, Kunisaki reported.
  • Among smokers, FEV1 fell by -34 mL/year in the immediate ART group and by -31 mL/year in the deferred group, a difference that was not statistically significant.
  • There was also no significant difference between treatment arms among non-smokers, -29 vs -22 mL/year, respectively -- though the smokers did see larger declines than non-smokers in both arms.
  • Turning to self-reported lung function using the standardized St George’s Respiratory Questionnaire for COPD (SGRQ-C), scores fell by -1.1 in the immediate ART arm and by -0.5 in the deferred arm among smokers, and fell by -1.1 while rising by +0.4 among non-smokers; neither difference was significant.
  • Looking at specific domains for symptoms, activity, and impact, the only significant difference was worsening symptoms reported by smokers in the immediate ART group (-2.9 vs +1.6).

Though changes were small and mostly not significant, it is notable that among non-smokers scores for all 3 domains and the overall SGRCQ-C fell in the immediate ART arm -- indicating improvement -- while rising in the deferred arm.

"Immediate vs deferred ART has no impact on lung function decline" in HIV-positive people with CD4 counts above 500 cells/mm3, the researchers concluded. "Immediate ART can be offered without concern for increasing COPD risk in these patients."

Neurology Substudy

Finally, Richard Price from the University of California at San Francisco presented findings on behalf of the START neurology substudy, which looked at changes in performance among 592 participants randomized to early or deferred ART.

Participants in this substudy completed neuropsychological tests measuring various aspects of neurological function at baseline, at months 4, 8, and 12, and then annually. The researchers compared mean changes in QNPZ-8 scores, an average score encompassing 8 tests of fine motor control, processing speed, verbal learning, verbal memory, and "executive" function, or overall management of cognitive function.

Participants in this substudy came from South America (42%), Europe (25%), Thailand (15%), the U.S. (14%), and Australia (4%). Two-thirds were men and the median age was 34 years. About 8% had a prior psychiatric diagnosis and 5% reported alcoholism or drug dependence. They were described as a "high functioning" group, with 76% being employed and 80% having had either vocational training or college/university education; this is relevant because past research has shown a link between neurocognitive performance and education level.


  • Over 2 years of follow-up, QNPZ-8 scores rose in parallel from baseline, increasing by similar amounts in the immediate and deferred ART groups; Price noted that this likely reflects a "practice effect" seen when people repeatedly take the tests.
  • The estimated difference between the groups was -0.01, which was not statistically significant.
  • By month 60, scores in the immediate arm rose more steeply while those in the deferred group declined, but there were only a small number of participants still being followed at that point and Price said this divergence "shouldn’t be paid attention to."

This study showed "no overall neurocognitive advantage (or disadvantage) for immediate ART initiation in asymptomatic treatment-naive individuals with high CD4 counts," the researchers concluded. These findings suggest that there is both a "low incidence of ART-preventable neurocognitive impairment" in this population and a low incidence of neurocognitive decline while off treatment, as well as "no clear evidence of neurotoxicity."

In response to a question Price said that use of efavirenz (Sustiva) -- an antiretroviral known to cause central nervous system side effects -- was very common. No obvious effects of efavirenz were noted, but this is being analyzed further.


Taken together, these studies offer reassurance that early ART does not lead to serious or clinically significant adverse outcomes, though the greater bone loss in the immediate arm is cause for concern. On the other hand, the substudies also did not reveal major advantages for immediate ART with regard to bone, lung, or neurological outcomes.

A limitation of all these substudies is that START enrolled a relatively young population with recent HIV diagnosis and good immune function. Observational studies that have seen higher rates of cardiovascular, neurological, and other conditions among people with HIV have generally looked at older groups of patients, and problems may increase in this group as they age.

Also, as noted, the randomized portion of START was stopped early, so the average 3 years of follow-up was shorter than expected. Researchers are continuing to follow participants to look at longer-term outcomes, and cardiovascular and liver substudies are also underway. But now that both arms have been advised to start treatment, the differences between them are likely to diminish over time.



J Hoy, B Grund, M Roediger, et al (INSIGHT START Bone Mineral Density Substudy Group). Effects of Immediate Versus Deferred Initiation of Antiretroviral Therapy on Bone Mineral Density: A Substudy of the INSIGHT Strategic Timing of Antiretroviral Therapy (START) Study. 15th European AIDS Conference and 17th International Workshop on Co-morbidities and Adverse Drug Reactions in HIV. Barcelona, October 21-24, 2015. Abstract ADRLH-62.

KM Kunisaki, DE Niewoehner, G Collins, et al (INSIGHT START Pulmonary Substudy Group. Lung Function Decline in HIV: Effects of Immediate versus Deferred ART Treatment on Lung Function Decline in a Multi-site, International, Randomized Controlled Trial. 15th European AIDS Conference and 17th International Workshop on Co-morbidities and Adverse Drug Reactions in HIV. Barcelona, October 21-24, 2015. Abstract PS1/1.

E Wright, B Grund, K Robertson, R Price (INSIGHT START Neurology Substudy Group). No Difference between the Effects of Immediate versus Deferred ART on Neuropsychological Test Performance in HIV-positive Adults with CD4+ Cell Counts above 500 cells/μL: The Strategic Timing of Anti Retroviral Treatment (START) Neurology Substudy. 15th European AIDS Conference. Barcelona, October 21-24, 2015. Abstract PS10/6.

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