Study START sub-studies show very few or no worsening in the pulmonary and neurocognitive functions

Ken Kunisaki, presenting at EACS 2015. Photo by Liz Highleyman, hivandhepatitis.com
Ken Kunisaki, presenting at EACS 2015. Photo by Liz Highleyman, hivandhepatitis.com

Participants initiating antiretroviral therapy (ART) soon after diagnosis of HIV seropositivity at the start of the large study showed no difference in lung function or neuropsychological performance when compared to people who were entirely randomized to initiate antiretroviral therapy (ART) According to two studies presented last week in the 15thEuropean AIDS Conference Barcelona, ​​Spain.

Um related study showed that the early initiation of treatment in the START study was associated with a greater loss of bone mass over time.

Initiating antiretroviral treatment before the development of serious damage to the immune system significantly reduces the risk of progression of HIV disease and death, but early treatment may potentially also have drawbacks, including increased exposure to the toxicity of antiretroviral drugs. A study called INSIGHT noted that, in relation to the START study (strategic distribution of antiretroviral Strategic Timing of Antiretroviral Treatment) Was designed to address the long controversy over the optimal time for treatment of HIV, especially for people who still have high counts of CD4.

The main results of START, the presented last summer in the Northern Hemisphere the Vancouver International AIDS Society Conference and published in 27 in August in New England Journal of Medicine, Showed that participants randomized to start ART soon after diagnosis of HIV seropositivity had a significantly lower risk of disease and death than those who expected a significant drop in CD4 count. The immediate treatment group not only had a 72% lower risk of AIDS-related infections and cancers also related to AIDS compared to those who postponed the start of ART, but also were 39% less likely to suffer serious events unrelated to AIDS (heart, liver and kidney events and cancers unrelated to AIDS) or death.

The initial project includes several sub-studies looking at the effects of early treatment versus delayed start on specific outcomes known or suspected to be associated with HIV infection or its treatment, including bone density, pulmonary function and cognitive function.

Lung substudy related to the study START

Lungs healthyKen Kunisaki, the University of Minnesota presented lung results since the beginning of the sub-study, which compared the changes in lung function in groups where the HAART scheme is immediate or delayed.

Chronic obstructive pulmonary disease (COPD) is an emerging comorbidity related to HIV infection, Kunisaki noted, as background. Observational studies have shown that people with HIV are at increased risk for COPD, but there is conflicting evidence as to whether ART is associated with increased risk or not. The underlying mechanisms are unclear and, in the meantime, may be related to chronic inflammation, increased risk of pneumonia and other lung infections, as well as changes in the pulmonary microbiota and, perhaps, antiretroviral activity, he said.

In this substudy, participants had spirometry done online and thereafter annually. Spirometry is used to assess lung function by measuring the amount of inhaled and exhaled air. The main measure for this analysis was the change in forced expiratory volume, ie the amount of air a person can blow in the first second (VEF1). VEF1 generally has the capacity peaks around the 25 years of age and then decreases over time; a level below 30% of the maximum is considered disabling. The results were stratified by smoking.

This substudy included 518 people randomized to the early group of immediate ART and 508 in the deferred group starting ART. The distribution of participants in the substudy differed from the study as a whole, with about 30% in Africa and Europe, 19% in South America, and about 10% in Asia and the US. About 70% were male and the average age was 36 years. About 60% had never smoked, 28% were smokers and 11% were former smokers.

During an average follow-up period of 2,0 years, the slope of the VEF1 showed "Absolutely no difference" between the arms of the immediate treatment group and delayed start of ART for both smokers and non-smokers, demonstrated Kunisaki.

Among smokers, VEF1 fell by -34 ml / yr in the immediate ART group and by -31 ml / yr in the deferred group, a difference that was not statistically significant (p = 0,83). There was also no significant difference between treatment arms among nonsmokers, -29 vs -22 ml / year, respectively (p = 0,56) - although smokers demonstrated falls greater than nonsmokers in both arms of the study

Turning to the self-reported respiratory difficulty with normalized pulmonary function, the St George's Respiratory Questionnaire (SGRQ-C), scores decreased - 1,1a for the immediate ART arm and - 0.5 on the deferred arm among smokers, and fell in - 1,1 + 0,4 while elevated among non-smokers; statistically significant difference. Looking at specific domains for symptoms, activity, and impact, the only significant difference was that it worsened in the symptoms reported by smokers in the immediate ART initiation group (-2,9 vs. significant (+ 1,6). most of them non-significant, it is notable that among nonsmokers the scores of all three domains of the SGRQ and the COPD set fell in the immediate ART arm, indicating improvement - during the rise in the deferred initiation arm. the early-onset ARV arms vs. early deferral of ART have no impact on the decline in lung function "in people living with HIV and who have CD4 counts above 500 cells / mm3, the researchers concluded." Immediate ART may be offered without the concern of increasing the risk of COPD in these patients. "

Sub-study Related to Neurology

Neuron cellFinally, Richard Price, the University of California, San Francisco, presented the findings on behalf of the sub START child neurology which analyzed the evolution in performance between 592 random participants to start immediate or deferred ART

Participants in the substudy, neuropsychological tests completed with the aim of measuring different aspects of the baseline neurological function, 4º months, and 8º 12º months, and then yearly. The researchers compared changes in average QNPZ-8 scores, a score of averaged over eight fine motor control testing, processing speed, verbal learning, verbal memory and "executive function," or comprehensive monitoring of cognitive functions.

Participants in this substudy came from South America (42%), Europe (25%), Thailand (15%), United States (14%) and Australia (4%). Two-thirds were males and the mean age was 34 years. About 8% of them had previous psychiatric diagnosis and 5% reported alcoholism or drug dependence.

They were described as "a high-functioning group", with 76% being employed and 80% not having received any vocational training or attended college and / or university or higher education; this is relevant because previous research has shown a link between neurocognitive performance and level of schooling.

Over the two-year follow-up, QNPZ-8 scores increased in parallel from the baseline, increasing in similar amounts in the arms of the early-onset and delayed-start study of ART. Note that Price probably reflects a "practice" seen when people do the tests several times. The estimated difference between the two groups was -0,01, which was not statistically significant. By the 60th month, the scores on the arm of immediate ART increased sharply, while the participants in the deferred group start group decreased, but there were only a small number of participants and they are still being followed up to this point and Price said "that this divergence must be followed closely. "

This study showed "a non-global cognitive advantage (or disadvantage) between the immediate beginning of arms of ART in asymptomatic patients between individuals" naïve "with high count CD4," the researchers concluded. These findings suggest that there is a "low incidence of" preventive ART "for cognitive impairment" in this population and a low incidence of cognitive decline and treatment, as "there is no clear evidence of neurotoxicity. '

In response to a question, said the use of efavirenz (Sustiva) - A component of some antiretroviral therapy regimens known for tropism for the central nervous system and causes psychosomatic side effects - was very common among participants. It was observed that "There is no obvious effects of efavirenz"But it is being analyzed in more detail (Translator's note: This statement is almost like that cover the sun with a sieve because my experience in my service via app whats shows often intense suffering and degeneration of the patients state of mind that make the use of efavirenz and few months ago, a mistake, I received a box of Efavirenz and, thinking there had been a change in treatment, I took ONE of these Efavirenz tablets and the experience was BAD).

Consecutive

Taken together, these studies offer the guarantee that the beginning HAART does not lead to serious or clinically significant adverse outcomes, but most bone loss observed in the immediate start arm It is cause for concern (Here is a complete study in English and elsewhere). On the other hand, the sub-studies also do not reveal major immediate advantages for ART in terms of bone, lung or neurological outcomes.

A limitation of all these sub-studies is that they get registered with a relatively young population with newly diagnosed HIV and good immune function. Observational studies saw higher rates of cardiovascular disease, neurological and other conditions among people with HIV have observed, in general, groups of older patients, and problems can increase in this group as they age.

In addition, as noted, the random part of the postponed start was discontinued early, so that the mean, three-year follow-up was lower than expected. Researchers continue to follow participants and observe the long-term results and the substudies of cardiovascular and liver diseases are also underway. However, now that both arms have been advised to begin treatment, the differences between them are likely to decrease over time.

Produced by Liz Highleyman for Aidsmap in collaboration with hivandhepatitis.com

Translated by Claudio Souza.

Reviewed by Mara Macedo

References

Kunisaki KM et al. 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, ​​abstract PS1 / 1, 2015.

Wright E et al. (Price R presenting) The difference between the effects of immediate versus deferred ART on neuropsychological test performance in HIV-positive ddults with CD4 + cell counts above 500 cells / uL: the Strategic Timing of Antiretroviral Treatment (START) substudy neurology. 15thEuropean AIDS Conference. Barcelona, ​​abstract PS10 / 6, 2015.

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