HIV: Mortality Gap Narrowed, But Not Closed

Individuals initiating human immunodeficiency virus (HIV) care in the U.S. had higher mortality rates over subsequent years than the general U.S. population—however, researchers found that from 1999-2017, the gap decreased.

HIV-related mortality has been trending downwards since 1996 as more effective treatments and evolving care guidelines improved patients’ treatment options; however, “the extent to which persons entering HIV care in the United States have higher risk for death over the following years compared with peers in the general population over the same period remains unclear,” Jessie K. Edwards, PhD, of the University of North Carolina at Chapel Hill, North Carolina, and colleagues wrote in Annals of Internal Medicine.

To help elucidate this difference, Edwards and colleagues compared the cumulative risk for all-cause mortality over five years among individuals entering HIV care from 1999-2017 at U.S. sites affiliated with the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) against the general population.

“Persons entering HIV care in the United States had higher mortality over the subsequent years than those with similar demographic characteristics and geographic context in the general U.S. population, but this disparity decreased over calendar years between 1999 and 2017,” they found. “By the latest period examined (2011 to 2017), 5-year mortality for someone starting care was only 2.7 percentage points higher than among persons of the same age, sex, race/ethnicity, and county in the general population. In later years of the study, mortality risks for persons in NA-ACCORD after 1 year in care were similar to 1-year mortality risks in the general population.”

While this decrease in mortality is a step in the right directions, the study authors noted that it will be important to address the gaps that remain.

“These gaps could reflect the effects of prolonged immunodeficiency in persons who present late to care or persistent immune activation and subsequent end-stage chronic diseases even among those who are successfully treated,” they noted. “Antiretroviral medications have adverse effects that may contribute to mortality risk, and the interplay between HIV and aging-related comorbidities and co-infections may accentuate differences in mortality, especially in older populations. Uptake by clinicians and patients of standard preventive interventions, such as smoking cessation and lipid and cancer screening, may have lagged in persons with HIV, especially in earlier periods, and improved over time. Quantifying the elevation in mortality observed for persons in HIV care in the era of modern treatments will inform efforts to address both AIDS and non–AIDS-related consequences of HIV infection and long-term [antiretroviral therapy] ART.”

In an editorial accompanying the study, Marshall J. Glesby, MD, PhD, and Roy M. Gulick, MD, MPH, both of Weill Cornell Medicine in New York City, noted that it is important, when placing these study results into context, to consider that the sample was limited to patients initiating HIV treatment in the U.S., “a resource-rich country, which limits generalizability to all people living with HIV. Data from the Centers for Disease Control and Prevention indicate that 14% of people with HIV in the United States remain undiagnosed, and only 58% receive continuous medical care. Although the mortality gap relative to the general population seems to be narrowing over time, this trend is predicated on prompt diagnosis and receipt of ongoing appropriate care.”

They also pointed out that the Covid-19 pandemic has the potential to widen the mortality gap, because SARS-CoV-2 infection and mortality appear to be higher among HIV patients. “Furthermore, global rates of HIV viral suppression with antiretroviral therapy could be reduced due to lockdowns, quarantining, and supply chain disruptions,” they added.

For their observational cohort study, Edwards and colleagues pulled data on 82,766 (84% male; 46% non-Hispanic Black; 16% Hispanic; median age 42 years) adult patients entering HIV clinical care from 1999-2017 at 13 U.S. NA-ACCORD sites, along with a subset of subjects from the general population matched on calendar time, age, sex, race/ethnicity, and county using U.S. mortality and population data from the National Center for Health Statistics.

The primary study outcome was five-year all-cause mortality, as estimated using the Kaplan-Meier estimator of the survival function.

Overall, 7,796 deaths occurred within five years of entry into care among eligible participants in NA-ACCORD,” they found. “Five-year mortality was 10.6% among persons entering care and 2.9% among the matched U.S. population. Mortality over the first five years after entry into care decreased substantially over time, from 14.5% among those entering care between 1999 and 2004 to 5.0% among those entering care between 2011 and 2017. Over the same period, mortality decreased less in the matched U.S. population, from 3.4% between 1999 and 2004 to 2.3% between 2011 and 2017.”

In other words, the difference in five-year mortality between HIV patients and the general U.S. population dropped from 11.1 percentage points from 1999-2004, to 2.7 percentage points from 2011-2017.

Edwards and colleagues speculated that differences in mortality rates persist, even in “the era of safe, simple, and effective ART,” for at least four reasons:

• While universal immediate treatment has been recommended for HIV patients in the U.S. since 2012, not everyone entering care can start treatment immediately.
• “Treatment alone is not a panacea.” While treatments have improved over time, “they remain imperfect, are only effective when adhered to, and may increase risk for adverse events with prolonged exposure.”
• Even when patients are on ART, HIV may be a factor in non-AIDS-related comorbidities and mortality, “particularly among persons who enter care with advanced immunosuppression or at older ages.”
• Individuals with HIV may have a higher prevalence of other risk factors for mortality, including smoking, substance use, and comorbidities.

Regardless of the cause, Glesby and Gulick concluded that there is “a clear need to close this mortality gap further. Prompt diagnosis of HIV and rapid initiation of antiretroviral therapy are pillars of the Ending the HIV Epidemic strategy in the United States. Although the standard of care remains daily oral antiretroviral medications, a long-acting injectable antiretroviral regimen was recently approved by the U.S. Food and Drug Administration, and other strategies being developed include weekly oral regimens, subcutaneous agents, implants, and patches that could enhance long-term adherence. Reducing mortality is a key goal, but it is also important to improve quality of life in people with HIV, which may be adversely affected by comorbidities and aging-related issues.

“The past 40 years of the epidemic saw remarkable progress in improving survival in people living with HIV; with ongoing commitment and innovations, further gains can be anticipated,” they added.

Study limitations included only basing mortality estimates on HIV patients entering care at NA-ACCORD sites; some of the mortality differences between the study groups may have resulted from residual differences in geography not captured by the matching variables; county of residence was subject to misclassification; and NA-ACCORD may have failed to capture all deaths among participants.

1. While individuals initiating human immunodeficiency virus (HIV) care in the U.S. still have higher mortality rates over subsequent years than the general U.S. population, the gap decreased substantially from 1999-2017.

2. Researchers concluded that quantifying the elevation in mortality observed for persons in HIV care in the era of modern treatments will inform efforts to address both AIDS and non–AIDS-related consequences of HIV infection and long-term antiretroviral therapy (ART).

John McKenna, Associate Editor, BreakingMED™

Cat ID: 339

Topic ID: 338,339,339,730,27,192,151,925