People who start antiretroviral therapy (ART) immediately after the diagnosis of HIV seropositivity, while its CD4 cell count is still high, rather than waiting until it drops below 350 cells / mm3 have a risk significantly lower in sick and go to death, in line with the long-awaited findings of the study START. The final study and its findings were presented on Monday at the Eighth Conference International AIDS Society (IAS 2015) in Vancouver, Canada, and published simultaneously with the Edit 20 July before issue of the New England Journal of Medicine.
Professor Jens Lundgren of the University of Copenhagen reported that 1,8% of the study participants, the group with the start of immediate treatment experienced a combined endpoint of serious diseases related to AIDS, severe cases of AIDS and death, compared with 4,1% in Group Deferred therapy - a reduction of 57%. The most common event in both study arms were tuberculosis (TB) and cancer.
These findings suggest that HIV causes persistent damage to the immune system soon after infection, and "clearly indicate that the ART (Antiretroviral Therapy) should be prescribed to all citizens regardless of CD4 count," said Lundgren to aidsmap.
[Results] "clearly indicate that HAART should immediately be prescribed for all infected people, regardless of CD4 count." Jens Lundgren
It is well known that the prescribed HAART before the CD4 cell counts fall to low levels dramatically reduces the frequency and incidence of opportunistic infections and increases the survival improving greatly on the quality of life. An increasing body of evidence shows that early treatment is associated with a less progression of disease and death as well as minimize the risk of subsequent transmission of HIV.
But the very early treatment of HIV can also have disadvantages, including increased time of exposure to the potentially toxic antiretroviral therapy. In addition, some of the critical early treatment expressed concern that people with HIV can be pressured to start treatment before they are ready [psychologically], to benefit others rather than treat, really, of their own health.
The Estuto design START
Researchers with the START INSIGHT Study Group conceived the strategic distribution of antiretroviral treatment in order to shed more light on the question that seeks to find the ideal time for early treatment of HIV infection, especially for people with cell count CD4 in the normal range. The study started wide application [of volunteer patients] in March 2011.
Participants enrolled in the START study lived with a CD4 cell count above 500 cells / mm3. They were randomly assigned to start treatment immediately or with a delay in the initiation of therapy until his CD4 count drops below 350 cells / mm3, or who have developed AIDS symptoms at some time prior to this fall count. They used a wide range of varieties of antiretroviral regimens selected for the clinical study.
Study participants 4685 adults living with HIV in 35 countries worldwide, including just over half of middle and low income countries. About three-quarters were male and the average age was 36 years. About 45% were white, 30% were black, 14% were Hispanic or Latino and 8% were Asian. Just over half were men who have sex with men.
At baseline, participants had been diagnosed with HIV from an average of a year and had never used HAART. About a third had CD4 count between 500 600 and 600 and 700 between cells / mm3 with 11% having more than 900 cells / mm3. Patients who started with immediate treatment had a viral load count more often between 3.000 and 30.000 copies / ml, however 10% had a viral load greater than 100.000 copies / ml.
Primary study results
Monitors the safety and study data (DSMB - In English) determined the study design of the stop ahead of schedule in May 2015 when determined that there was insufficient evidence to show a significant benefit of early treatment. The option to start treating all remaining untreated to study participants was offered. They will continue to be followed to observe the long-term treatment results, and there are a number of sub-studies that takes a look at the specific manifestations including neurological function, arterial function, bone densitometry and liver function.
"The global community of researchers of HIV disease needed evidence about the actual effectiveness and benefits of early treatment. Now we have evidence about the overall benefits of the treatment and the prevention with PrEP without causing damage to individuals "; said Jens Lundgren
At the time the study was stopped, the participants were followed for an average of three years, accumulating a total of 14.060 person-years of time for follow-up. Most (94%), in the immediate therapy arm was also joined in treatment and 28% in deferred arms had started treatment after discontinuation [...] the study. The retention in the study START [grip] was "excellent," according to the researchers, and adherence was always good as was the treatment started.
People in the group started in deferred treatment after an average of three years; less than expected, which would be after four years. Nearly one third had the top ART CD4 with a cell count of between 250-350 cells / mm3 but 8% did not until the count dropped below 250 cells / mm3. The rest did so at higher levels than the average of the experimental START treatment including 8% more than that started with 750 cells / mm3. During tracking people in the therapy group were delayed until the treatment CD4 counts were, on average, 194 cells / mm3, or even lower, than those who started treatment immediately.
First, the combined search with a primary endpoint of serious diseases related to AIDS, severe AIDS-related illnesses or death, recorded 42 these events (1,8%, or by 0,60 100 person-years [PV]) among people in blocks randomized to immediate treatment compared to 96 events (4,1%; 1,38 100 PY) in the deferred treatment group, of 57% lower risk (hazard ratio [HR] 0,43 CI 95 0,30-0,62%, p <0,001). The researchers also analyzed the outcome of individual subjects. Serious events related to AIDS, such as opportunistic infections and AIDS-defining illnesses, such as cancers (cervical cancer, Kaposi's sarcoma [KS] and some types of lymphoma), although serious events unrelated to AIDS have been included such as cardiovascular disease, kidney disease, decompensated liver disease and cancer without unrelated to AIDS (all other cancers).
Serious events related to AIDS
There was 14 serious events related 'to AIDS in the immediate early arm and events were identified (by 0,20 100 PY) and 50 events (0,72 100 PY) in the deferred group of 72% risk reduction (HR 0,28, 95-0,15 IC0,50% p <0,001). The difference in rates of AIDS become apparent around 24 months and then continued to diverge, Lundgren.
Looking at the types of events, TB was the most common event, both in the immediate treatment as in deferred (6 20 vs cases, respectively). Including opportunistic conditions like lymphoma (3 10 cases vs), Kaposi's sarcoma (1 11 cases vs) and Pneumocystis pneumonia (1 5 vs cases) that occurred more frequently in the late treatment arm. This was true even though most people in the lengthy treatment of early group spent most of his time in the study, with a CD4 cell counts well above the traditional "danger zone" below 200 350 or cells / mm3 .
Serious events unrelated to AIDS
Returning to the serious events not related to AIDS, including deaths due to other causes not related to AIDS, which were 29 events (0,42 in.) 100 PY) in the immediate group and 47 events (0,67 100 PY) in the deferred group of 39 % reduction in risk (HR = 0,61, 95% CI: 0,38-0,97, p = 0,04). Here, the curves for the occurrence of these events "did not fly apart quickly or sharply" said Lundgren.
Frequently unrelated to AIDS were events like câncecancro (9 early group vs immediate 18 in the deferred treatment group) and cardiovascular disease (vs 12 14 cases, respectively). Severe liver and kidney diseases were rare in both arms (1 case in the immediate arm vs 2º in the deferred arm).
Looking across the board for the deaths (there were 12 (0,17 100 inch PY) in the immediate and 21 group (0,30 100 PY) in deferred Reducing 42% in the risk of death was not statistically significant (HR 0,58;. IC95% 0,28- 1,17, p = 0,13).
In both arms, the main cause of death was accidents, violence or suicide (four in the immediate group and six in the deferred arm). There was one death due to HIV / AIDS in the immediate group compared with four in the delayed group. But there are other causes of death that were spread between the two groups with very few and "no clear pattern" according to Lundgren.
Cancer and cardiovascular disease
Concentrating in relation to cancer, there 14 cases of any kind (0,20 100 PY) in the immediate treatment group and 39 cases (0,56 100 PY) in the deferred group, 64% risk reduction which was statistically significant (HR 0,36 ; IC95 0,19-0,6%, p = 0,001). This difference became apparent after 12-16 months and, thereafter, there was a clear separation, Lundgren said.
Malignant disease related to AIDS, Kaposi's sarcoma (1 11 vs cases) and lymphoma (3 10 vs cases) were more frequent in the deferred treatment group. But for other types of cancers the numbers were small and there were no notable differences. This was true for both cancers caused by infectious agents such as human papilloma virus (HPV) anal, cervical cancer as well as those with any known infectious cause.
Serious cardiovascular events occurred with similar frequency in the immediate and deferred treatment groups (12 14 cases vs). There were three deaths from cardiovascular disease at the start of ART, compared with an arm in the late group, but these numbers are too small to draw conclusions. Anyway, Lundgren said, there is no evidence in this study that can demonstrate the benefits of early treatment in cardiovascular disease, but it also can not be ruled out.
Finally, the researchers looked at adverse events in the study, assessing the group treated with HAART and the group of untreated participants. Separately, the serious adverse event rates (grade 4) 0, with hospital admissions and unscheduled deaths from any cause did not differ significantly in the immediate treatment group and delayed group. However, when these events were combined, it has a significant advantage in the early treatment group (HR = 0,82; p = 0,01). The only adverse events were remarkable difference bacterial infections that were significantly more common in late treatment arm.
Despite long concerns about beginning HAART, leading to addition of side effects, Lundgren said he had "no apparent increase in toxicity," in this study.
Implications of START STUDY
Participants who began treatment immediately saw similar benefits, regardless of gender, age, race / ethnicity or geographic region. Importantly, the benefits of antiretroviral therapy were comparable in rich countries, middle-income poor.
However, study team acknowledged that the participants were younger than expected and events in general, were more present in less experienced people than originally planned. Further studies are needed on complications among older people with HIV.
As noted, most people both in the immediate arm as in the deferred treatment begins spent most of his time in the study, with a CD4 cell count above 500 cells / mm3, and more than two thirds of adverse events, in with and without AIDS occurred in the count level.
Based on these findings, Lundgren suggested that we can not rely on CD4 cell count to capture fully immune deficiencies in early HIV infection.
"This study shows that even in people at high CD4s, there is a hole in the immune system if you are HIV-positive," he explained. ART is able to fill these gaps, at least partially, but still does not eliminate completely therapy and may not be able to completely reverse the damage to the immune system once it is started. Lundgren said to be important for the development of new types of treatments in addition to antiretroviral aimed restore lost immune function.
When the start DSMB prematurely discontinued the trial, initial results have been provided for the World Health Organization (WHO) working on the overall panel updated guidelines for the treatment of HIV. The WHO announced this week that its forthcoming guidelines recommend treatment for everyone regardless of CD4 count.
"The community of treatments against HIV researchers need solid evidence to guide treatment guidelines for HIV," Lundgren told aidsmap.com. "We want to build an evidence base and there is no rush. But now we have evidence that line the individual benefit and prevention for the benefit of society without harming the treated individuals. I am very happy we were able to provide proof and that WHO is responding. "
"2015 of the IAS will be remembered as the defining moment when the world awoke to learn that early treatment of HIV infection is the best way to preserve the health of people living with HIV, and one of the best tools we have to stop the slow transmission of HIV, "said co-chair of the conference Julio Montaner of the British Columbia Centre for Excellence in HIV / AIDS. "The new data presented today will inform treatment guidelines for HIV 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," agreed the coordinator of the Global Response to AIDS Deborah Birx, speaking on a panel about the study's implications START after Lundgren present the results. "We all have a moral obligation now."
Translated from Original START trial Provides definitive evidence of the benefits of early HIV treatment written by Liz Highleyman in a collaboration between the Aidsmap eo HIVandHepatites.Com by Claudio Souza, Reviewed by Mara Macedo in July 22 2015
Lundgren JD et al. Initiation of Antiretroviral Therapy in HIV Infection Early Asymptomatic. New England Journal of Medicine. July 20, 2015.
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.