Incomplete viral suppression at 6 months increases 10-year mortality risk

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A viral load as low as 400 copies/ml six months after starting HIV therapy is associated with a substantial ten-year mortality risk, investigators from the University of North Carolina-Chapel Hill, Gillings School of Public Health, the Harvard TH Chan School of Public Health, the University of California – San Francisco, NorthWestern Medicine Feinberg School of Public Health and the University of Alabama at Birmingham report.

People with a viral load between 400 and 999 copies/ml had a 20% mortality risk, similar to the 23% risk observed in people with a viral load between 1,000 and 4m copies/ml. In contrast, the mortality risk was only 14% for individuals who rapidly achieved complete viral suppression – a viral load below 20 copies/ml.

“A single viral load measurement collected six months after initiating antiretroviral therapy (ART) remains highly informative regarding the risk of death over 10 years,” write the authors.

The aim of ART is rapid and sustained suppression of viral load to below the limit of detection (between 50 to 20 copies/ml depending on testing assay). Treatment guidelines suggest that viral load should be undetectable six months after the initiation of treatment. Newer antiretroviral drug combinations, especially those containing an integrase inhibitor, suppress viral load more rapidly.

Ongoing low-level viral replication despite therapy is associated with the emergence of drug-resistant virus, causing treatment failure and an increase in the risk of HIV- and non-HIV-related illnesses. Small increases in viral load once complete suppression has been achieved, above the limit of detection on occasional tests, so-called viral load `blips`, do not predict treatment failure and are not problematic. This study looked at the failure of treatment to achieve viral suppression after six months.

Analysing viral load measurements taken six months after ART initiation, a team of US investigators sought to determine the level of low-level viraemia (up to 1000 copies/ml) which was associated with an increased risk of all-cause mortality over ten years.
Their study population consisted of approximately 8000 adults who initiated ART between 1998 and 2014. Study participants were followed until death or for up to ten years.

Median age at baseline was 40 years; 83% of participants were male; 62% were in the men who have sex with men risk group; 45% were white and 12% reported ever injecting drugs. The median pre-ART viral load was 75,000 copies/ml and the median year of ART initiation was 2007. Approximately a third of people had been diagnosed with Aids before starting treatment.

The median period of follow-up was 6.2 years, during which time there were 863 deaths.
Over half (57%) of viral load measurements six months after starting therapy were below 20 copies/ml, with 15% measured at 1000 copies/ml or higher.

As expected, compared to a viral load below 20 copies/ml, a viral load above 999 copies/ml was strongly associated with an increased risk of all-cause mortality over ten years (HR = 1.96; 95% CI, 1.56-2.46). A slightly increased risk of mortality was discernible at a viral load as low as 130 copies/ml (HR = 1.39; 95% CI, 1.02-1.88).

“While we observed an increased hazard of death with low-level viral loads, discernible at 130 copies/ml,” write the authors, “this association was largely driven by the elevated mortality risk experienced by patients with viral load between 400 and 999 copies/ml.”
The average ten-year mortality risk for people with a viral load below 20 copies/ml was 13%, similar to the 14% risk observed in individuals with a viral load between 20 and 400 copies/ml. The ten-year mortality risk was 20% for people with a viral load between 400 and 999 copies/ml, comparable to the 23% risk for people with a viral load of 1000 copies/ml or higher.

“Low-level viral loads between 400 and 999 copies/ml shortly after starting ART appear to place patients at a significantly higher 10-year risk of death than patients with viral loads under 20 copies/ml, and occurrences of viral loads in this range may need to be treated similarly as viral load that exceed 1000 copies/ml,” conclude the authors. “Given the importance of rapidly achieving virologic suppression after initiating treatment, further investigation of the causes of unsuppressed viral loads between 400 and 999 copies/ml is warranted.”

The authors suggest that incomplete viral suppression six months after starting treatment may be a marker for several problems. Apart from lack of adherence to treatment or poor retention in care, incomplete viral suppression might be a consequence of undetected drug resistance, or of drug-drug interactions that lead to low levels of antiretroviral drugs. Planning in advance to prevent these problems from undermining treatment, and prompt investigation of any problems, are likely to improve the chances of viral suppression.

Abstract
Objective: To determine whether there is a threshold of detectable HIV RNA under 1,000 copies/mL after antiretroviral therapy initiation associated with 10-year all-cause mortality.
Design: This study included nearly 8,000 patients from a US-based multicenter clinical cohort who started antiretroviral therapy between 1 January 1998 and 31 December 2013. Viral load was assessed six months after initiation of therapy. Patients were followed from six months after therapy initiation (between 1 July 1998 and 30 June 2014) until death, and data were administratively censored after 10 years or on 31 December 2014.
Methods: We used nonparametric multiple imputation to account for left-censored viral load measurements, Cox proportional hazards models to estimate all-cause mortality hazard ratios, Nelson-Aalen cumulative hazard estimates to construct risk curves, and inverse probability of exposure weights to standardize estimated hazard ratios and risk curves to the total study population.
Results: Plots of standardized hazard ratio estimates and 95% confidence intervals indicated there was no demonstrable viral load threshold between 30 and 500 copies/mL associated with a marked increase in 10-year mortality. The standardized 10-year risk of mortality among patients with viral loads between 400 and 999 copies/mL six months after starting treatment was comparable to the risk of mortality among patients with viral loads between 1,000 and 4 million copies/mL (20% vs. 23%).
Conclusion: Incomplete suppression of plasma HIV RNA six months after starting therapy is associated with substantial 10-year all-cause mortality risk, highlighting the importance of rapid viral load suppression after therapy initiation.

Authors
Lee, Jennifer S; Cole, Stephen R; Richardson, David B; Dittmer, Dirk P; Miller, William C; Moore, Richard D; Kitahata, Mari; Mathews, Christopher; Mayer, Kenneth; Geng, Elvin; Achenbach, Chad J; Eron, Joseph J Jr

Aidsmap material
AIDS abstract


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