Immediate ART during Early HIV Infection May Delay Disease Progression

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People who started combination antiretroviral therapy (ART) within 6 months of HIV infection were less likely to experience large CD4 cell decreases or AIDS-related illnesses during follow-up, although viral load set point could not be evaluated, researchers reported in the December 15, 2011 Journal of Infectious Diseases.

HIV persists long-term in the body in part because it can hide in viral "reservoirs," including resting memory T-cells and anatomic sites such as the gut and brain. Researchers have long hypothesized that if anti-HIV drugs are started very early after infection -- before these reservoirs are established -- disease progression might be slowed or halted, but study results have been mixed.

Christine Hogan and fellow investigators with the Setpoint Study (ACTG A5217) compared the effects of immediate versus deferred antiretroviral treatment in people who acquired HIV within 6 months, a period known as primary infection.

During the typical course of untreated infection, viral load reaches very high levels soon after infection, but then settles at a relatively stable level known as the viral set point. In this study, the researchers looked at viral set point as well as immunological (CD4 cell decline) and clinical disease progression.

The study enroll 130 participants (out of a planned 150) who were randomly assigned to either immediately start a 36-week course of ART or else defer therapy according to HIV treatment guidelines in effect at the time (CD4 threshold of 350 cells/mm3). Patients stared or re-started therapy if their CD4 count fell below 350 cells/mm3 on 2 consecutive tests, CD4 cells ever fell below 200 cells/mm3 or 14%, HIV RNA rose above 750,000 copies/mL, or they developed AIDS-related illnesses.

Most participants (nearly 95%) were men, 87% were white, and the median age was 36 years. The median baseline CD4 count was approximately 530 cells/mm3, but 6% had < 200 cells/mm3; about 75% had baseline viral load of 10,000 copies/mL or more.

Results

In June 2009 a Data Safety Monitoring Board reviewed interim data and recommended that the study should be stopped because further follow-up was unlikely to change the findings.

"Progression to meeting criteria for antiretroviral initiation in the [deferred therapy] group occurred more frequently than anticipated, limiting the ability to evaluate virologic set point," the researchers wrote, concluding that "Antiretrovirals during early HIV-1 infection modestly delayed the need for subsequent treatment."

"Treated participants appear to have been protected not only while on treatment but also for a brief period of time thereafter," they elaborated in their discussion. "Thus, a limited period of ART during early HIV-1 infection delayed the need for subsequent initiation of long-term ART."

"Owing to the higher-than-anticipated rates of progression and, consequently, initiation of therapy, the difference in virologic set points between the 2 groups could not be statistically evaluated," they explained, leaving the influence of early treatment on viral set point an unanswered question.

Although the higher-than-expected progression rate prevented them from drawing conclusions regarding set point, they noted that this was "a compelling finding of this study and contributes to the growing body of evidence favoring earlier treatment."                   

"Recently revised treatment guidelines recommend treatment initiation at higher CD4 T-cell count thresholds [now 500 cells/mm3]," the researchers wrote. "These guidelines consider emerging data highlighting the consequences of untreated HIV-1 infection and the potential role of ART in preventing serious non-AIDS conditions, which may result from the persistent immune activation and systemic inflammation associated with uncontrolled viral replication."

"The results of our current study may be of interest to clinicians and patients struggling with the decision of whether to initiate ART during recent HIV infection," they continued. "Our results suggest that if immediate therapy is not begun, progression to meeting standard criteria for ART initiation may occur more rapidly than expected, especially with changing treatment paradigms."

A sub-study of A5217 is currently underway to assess whether immediate versus deferred therapy during early infection affects markers of inflammation and immune activation, which, they said, "may provide further insight into the potential benefits of treating primary infection."

Commentary

In an accompanying editorial, Harout Tossonian and Brian Conway from the University of British Columbia explored the implications of these findings for decisions about when to start treatment.

"Immune preservation and reduction in the latent pool of HIV-1–carrying CD4 T-cells seems to require intervention at the earliest possible time of acute infection," they wrote. "It is difficult enough to identify and engage patients within months of exposure, let alone days or weeks. If this were the standard, it would limit us to offering intervention to the privileged few."

"It is, therefore, heartening that even in those who have become infected as remotely as 6 months before their first presentation, a measurable advantage of immediate treatment can be demonstrated," they continued. "This seems to be achieved at little or no cost to the patient, in terms of either drug-related toxicity or emergence of drug resistance."

"This is very welcome news," National Association of People with AIDS president Frank Oldham stated in an agency press release. "The study supplies scientific confirmation of something we at NAPWA have always believed: the closer we can come to bringing all people living with HIV into treatment, and the earlier they start treatment, the better."

"[W]e have to end the HIV stigma, homophobia, and counterproductive HIV transmission laws that make people afraid to get tested and know their status," added NAPWA Vice President for Treatment Advocacy Stephen Bailous. "Only then will we get the full benefit of our new knowledge that treatment is prevention in populations and early treatment usually means better outcomes for individuals."

12/16/11

References

CM Hogan, V DeGruttola, X Sun, et al. (A5217 Study Team ). The Setpoint Study (ACTG A5217): Effect of Immediate Versus Deferred Antiretroviral Therapy on Virologic Set Point in Recently HIV-1–Infected Individuals. Journal of Infectious Diseases. December 15, 2011 (Epub).

H Tossonian and B Conway. Recent HIV-1 Infection: To Treat or Not to Treat, That Is the Question. Journal of Infectious Diseases. December 15, 2011 (Epub).

Other Sources

Infectious Diseases Society of America. Study Suggests Early ART in Recently HIV-Infected Patients Preferable to Delayed Treatment. Press release. December 16, 2011.

National Association of People With AIDS. NAPWA salutes study showing benefits of starting ARV treatment early. Press release. December 16, 2011.