The INSIGHT START Trial: Is “Early” Antiretroviral Rx “Better” Than “Later”?

Researchers from around the world are celebrating the completion of the START cohort enrollment. START-which stands for Strategic Timing of AntiRetroviral Treatment-is a large, randomized trial attempting to determine whether it is “better” (by reducing the occurrence of serious morbidity and mortality events) to start antiretroviral therapy “early” (before the CD4⁺ lymphocyte count drops to under 500/mL), or later, when the CD4⁺ lymphocyte count drops below 350/mL.

Currently, the US Department of Health and Human Services (DHHS) Panel on Antiretroviral Guidelines for Adults and Adolescents recommends that antiretroviral therapy be started on every HIV-infected person, regardless of CD4⁺ lymphocyte count. However, the strength of that recommendation varies based on the CD4⁺ lymphocyte count and is weakest for counts above 500/mL. Importantly, randomized clinical trials have shown that starting antiretroviral therapy when the CD4⁺ lymphocyte count drops to 350/mL is better than waiting for the count to drop to 200/mL, but there have been no randomized trials designed to answer the question of whether it is beneficial to start therapy even earlier. In addition, most other guidelines from around the world, including the British HIV Association guidelines, recommend waiting until the CD4⁺ cell count drops to 350/mL before initiating therapy in most HIV-infected individuals.

START opened to enrollment in April 2009 and is being conducted at 222 clinics in 35 countries around the world. Enrollment was completed last December, with a total of 4688 participants. Follow-up is expected to continue until late 2016. In other words, we will have to wait 3 more years for the “answer.” Nevertheless, close examination of the baseline characteristic of this large cohort has revealed many interesting and potentially important observations.

As a bit of background, there are accumulating data (at least at lower CD4⁺ lymphocyte counts) that ongoing HIV replication is a significant independent risk factor for heart, kidney, and liver disease, due to the body’s attempt to fight HIV by secreting a number of proinflammatory cytokines, such as interleukin-6 (IL-6), which leads to a state of chronic inflammation. Consequently, any additional risk factors in this cohort, such as high rates of cigarette smoking, obesity, or elevated cholesterol levels might be expected to lead to significant morbidity in a relatively short period. As such, events observed in this cohort likely will mirror events seen in clinical practice.

So what are the important baseline characteristics of the cohort? To begin with, the average age of the cohort at enrollment was 36 years, with about a 2-year age difference between enrolled men (35 years old) and enrolled women (37 years old). Women made up 27% of the cohort. CD4⁺ lymphocyte count at enrollment was over 650/mL in both men and women, with an average HIV RNA copy number of around 14,000 copies/mL. On average, the cohort had been diagnosed with HIV infection 1 year earlier, and likely had been infected within 1 to 3 years before diagnosis. Ten percent had been infected with a virus showing some degree of resistance to antiretroviral therapy: resistance to the non-nucleoside reverse transcriptase inhibitor (NNRTI) class was most common. Thirty percent of the cohort is black, 14% Hispanic, 8% Asian, and 48% non-Hispanic white.

More interestingly, about 32% are current smokers, and an additional 13% are former smokers. An estimated 7% of the cohort already shows evidence of emphysema (COPD), the incidence of which typically is increased in HIV-infected persons, because of HIV’s COPD-like effect on lung parenchyma. Of the cohort, 3% have diabetes, 19% are hypertensive, 17% are obese (as are 30% of those enrolled from North America), and 8% are hyperlipidemic. Over 50% of the cohort have at least 1 risk factor for cardiovascular disease.

These data mirror what most of us in the US see in our HIV patient population: a diverse group with multiple comorbid conditions that require substantial attention to manage. It is not surprising then, that in the US, an HIV-infected person is more likely to die of a “non–HIV- related” condition than of an AIDS-defining condition. Antiretroviral therapy has had a substantial impact on the latter, but not much of an effect on the former.

Overall, the START trial is off to a great “start,” having enrolled a diverse population of recently infected individuals. The study is likely to answer definitively one of the most important clinical questions involved in HIV management: when is the optimal time to start antiretroviral therapy. All of us will have to wait 3 years for the answer.