Delayed antiretroviral therapy initiation linked to decreased immunologic recovery in HIV

1. Postponed introduction of antiretroviral therapy (ART) beyond 12 months of HIV-1 estimated seroconversion was linked with a lower proportion of CD4+ normalization.

2. Earlier initiation of ART was also associated with decreased risk of AIDS and better immune function, including increased responsiveness to the hepatitis B virus (HBV) vaccine.

Evidence Rating Level: 2 (Good)

Study Rundown: Attaining an undetectable HIV viral load is associated with patient immunologic recovery and thus is the goal of antiretroviral therapy (ART). However, no previous studies have examined the influence of time to initiating ART on achieving optimal immunologic health within a more real-life clinical setting. This study aimed to investigate the influence of commencing ART after 12 months of the estimated date of seroconversion (EDS) on normalization of CD4+ counts, AIDS risk and immune function using participants in the US Military HIV Natural History Study (NHS).

A larger proportion of patients with HIV-1 achieved CD4+ normalization after receiving ART within 12 months of EDS compared to if ART was started after 12 months. Higher incremental CD4+ count was also associated with a stepwise decrease in AIDS risk and return to levels of normal immune activation, dysfunction and responsiveness. Initiation of ART within 12 months was associated with a significantly lower risk of AIDS, reduced T-cell activation and increased responsiveness to the hepatitis B virus (HBV) vaccine. Strengths of this study include examining the impact of ART initiation in a real-life clinical setting using the NHS. Limitations include that the cohort consisted largely of young males (95.3%) and thus limits the generalizability to women and older adults with HIV-1. Additionally, despite being a well-constructed retrospective observational study, one cannot determine causation.

Click to read the study, published today in JAMA Internal Medicine

Relevant Reading: WHO 2013 Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection

In-Depth [retrospective cohort]: This retrospective cohort study used the US Military HIV Natural History Study (NHS) cohort of 5,402 HIV-infected US military personnel. Each of the 4 primary outcomes was evaluated in their own NHS subsets: 1,119 participants were used to determine CD4+ normalization and AIDS risk, 124 participants were used to determine T-cell activation, dysfunction and responsiveness, and 374 participants were used to determine HBV serologic response. CD4+ normalization was defined as at least 900 cells/mL. The EDS was defined as the midpoint between the dates of the last documented negative and first positive HIV test. Antiretroviral therapy initiation was referred back to the EDS and/or the entry into the cohort.

CD4+ normalization was achieved in 38.4% of participants who started ART within 12 months of EDS, compared to 28.3% in those initiating ART greater than 12 months after EDS (P<0.001). NHS participants who had a study-entry level of greater than 500 cells/µL had a better trajectory of immunologic recovery. However, this was also modified by timing of ART initiation: earlier ART initiation resulted in better immunologic recovery. Initiation of ART greater than 12 months after EDS was also associated with a higher risk of AIDS (15.3% vs 7.8%, p=0.002), and reduced responsiveness to the HBV vaccine (50.9% vs 67.9%, p=0.07).

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