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Delaying Treatment More than 12 Months after HIV Infection Reduces CD4 Cell Recovery

People with HIV who start antiretroviral therapy (ART) more than a year after seroconversion have a lower likelihood of regaining normal CD4 T-cell counts, researchers reported in the November 24 online edition of JAMA Internal Medicine. "If full restoration of immunologic and clinical health is our goal, then the present study tells us that the best chance we have is to start antiretroviral therapy within 12 months of infection," according to an accompanying editorial.

It is now widely accepted that HIV treatment should begin before an individual's CD4 count falls below 350 or 500 cells/mm³, but there is still controversy about whether to start sooner. Many experts now favor initiating ART as soon as possible after infection, but others are concerned that the benefits of early treatment may not outweigh the risks.

One potential benefit of starting therapy early is maintaining good immune function, indicated by a normal CD4 cell count. But the optimal timing of treatment relative to infection is not well understood.

Jason Okulicz from the Uniformed Services University of Health Sciences and colleagues looked at the influence of ART timing on normalization of CD4 counts, immune function, and risk of progression to AIDS.

This study included 1119 participants in the U.S. Military HIV Natural History Study who had documented approximate dates of seroconversion and who achieved virological suppression on ART. More than 95% were men, whites and blacks were about equally represented, and the median age at ART initiation was 31 years. The median time between estimated seroconversionand study entry was approximately 10 months.

The researchers analyzed biomarkers of T-cell activation, dysfunction, and responsiveness. Ability to respond to hepatitis B virus (HBV) vaccination was also assessed as an indicator of immune function. They looked at normalization of CD4 counts to >900 cells/mm³ -- the median level in a survey of HIV negative populations -- as well as diagnosis of AIDS-defining conditions.

Results

• 26.1% of participants started ART 12 months or less from their estimated date of seroconversion, and 57.6% within 12 months after study entry.
• Overall, 30.9% of participants achieved CD4+ T-cell normalization.
• Among study participants who started ART within 12 months after their estimated date of seroconversion, 38.4% achieved normalized CD4 counts.
• Among those who delayed treatment until more than 12 months after estimated seroconversion, the proportion with normalized CD4 counts fell to 28.3%, a significant difference.
• Incrementally higher levels of CD4 cell recovery -- <500, 500-899, and >900 cells/mm³ -- were associated with stepwise decreases in the risk of progression to AIDS.
• Greater CD4 cell recovery was also associated with markers of immune activation, dysfunction, and responsiveness becoming closer to those seen in HIV negative people.
• People with CD4 counts of 500-899 cells/mm³had T-cell activation levels lower than those of people with <500 cells/mm³, but similar to those of people with >900 cells/mm³.
• Participants with CD4 counts of 500 cells/mm³ or higher at study entry were twice as likely to achieve CD4 cell normalization than those with lower levels (adjusted odds ratio 2.00).
• Participants with CD4 counts of 500 cells/mm³ at the time of ART initiation were 4 times more likely to experience CD4 cell normalization (adjusted odds ratio 4.08).
• Among participants with CD4 counts <500 cells/mm³ at study entry, earlier ART did not substantially improve the likelihood of CD4 normalization, as it did among people with >500 cells/mm³.
• However, even among people with a CD4 count of >500 cells/mm³ at both study entry and ART initiation, the likelihood of CD4 cell normalization was 80% lower among those who started treatment more than 12 months after seroconversion (adjusted odds ratio 0.20).
• ART initiation within 12 months of the estimated date of seroconversion was associated with:

o   Significantly lower risk of AIDS (7.8% vs 15.3%);

o   Reduced T-cell activation (12.0% vs 15.6% CD4+HLA-DR+ effector memory T-cells);

o   Increased hepatitis B vaccine responsiveness (67.9% vs 50.9%).

"Deferral of ART beyond 12 months [after] the estimated date of seroconversion diminishes the likelihood of restoring immunologic health in HIV-1-infected individuals," the study authors wrote.

"[I]f a critical goal of HIV care is restoration of immunologic health, our data indicate that normalization of CD4+ counts may be an important therapeutic target, since attainment of this CD4+ benchmark during viral load-suppressive ART was associated with maximal reductions in the AIDS risk, suppression of T-cell activation and dysfunction, and restitution of T-cell responsiveness," they elaborated in their discussion.

"[S]ince we found that immunologic deficits persisted, despite CD4+ normalization during viral load-suppressive ART compared with HIV-uninfected persons, adjunctive therapies that specifically target these functional gaps in full immune reconstitution are needed," they added. "Potentially, these residual immunologic deficits may render HIV-infected persons susceptible to non-AIDS comorbidities."

"[T]he capacity for CD4+ normalization is retained if the duration of untreated infection is short and the CD4+ count at ART initiation is 500 cells/[mm³] or more," they continued. "Participants with a study entry CD4+ count of 500 calle/[mm³] or more compared with less than 500 cells/[mm³] had increased CD4+ normalization, but this immunologic advantage was greatly diminished if the interval between the [estimated date of seroconversion] and ART initiation was more than 12 months, regardless of whether ART was subsequently initiated when CD4+ counts were still 500 cells/[mm³] or more or deferred until the levels had declined to less than 500 cells/[mm³]."

"[W]e demonstrated in the present study that there is a narrow time window after acquiring HIV infection within which commencement of ART favors CD4+ normalization," they concluded. "Achieving CD4+ normalization is an imminently feasible therapeutic goal, provided ART is started within 12 months of the [estimated date of seroconversion] at higher CD4+ counts (>500 cells/[mm³])."

A public health strategy that includes frequent HIV testing for people at risk and prompt initiation of ART after diagnosis "may offer the best chance for rapidly terminating the progressive immune damage...that constrains optimal immune reconstitution with ART," they recommended.

"This important study reminds us that the goal of HIV therapy should be full restoration of immune function and not just suppression of viral replication," Timothy Schacker from the University of Minnesota stressed in an accompanying editorial.

"If full restoration of immunologic and clinical health is our goal, then the present study tells us that the best chance we have is to start antiretroviral therapy within 12 months of infection,"he wrote. But this study has "provided the clearest signal to date that we will not restore immunity with the drugs we have available. Under ideal conditions only approximately one-third of the patients who receive treatment could achieve this goal. Most of the 35 million people infected with HIV live in conditions where only a few will have the opportunity to start therapy within 12 months of seroconversion."

"We need better formulations of antiretroviral drugs that fully suppress virus replication in tissues," Schacker concluded. "However, we also need adjunctive therapies that eliminate the causes of persistent immune activation and restore lymphoid tissues to their normal anatomy and function."

11/25/14

References

JF Okulicz, TD Le, BK Agan, et al. Influence of the Timing of Antiretroviral Therapy on the Potential for Normalization of Immune Status in Human Immunodeficiency Virus 1-Infected Individuals. JAMA Internal Medicine. November 24, 2014 (Epub ahead of print).

TW Schacker. Defining Success With Antiretroviral Therapy. JAMA Internal Medicine. November 24, 2014 (Epub ahead of print).

Other Source

JAMA. Delaying ART in Patients with HIV Reduces Likelihood of Restoring CD4 Counts. Media advisory for November 24, 2014.