Delaying treatment changes when first-line ART fails costs lives, says South African study

Antiretroviral drugs to treat HIV infection. Image by NIAID. Creative Commons licence.

Promptly switching antiretroviral therapy (ART) when individuals have viral rebound saves lives, according to an important study published in the American Journal of Epidemiology. Delayed switching more than doubled the risk of death over five years and was especially dangerous when a person had a CD4 cell count below 100.

The research involved people in South Africa who received ART between 2004 and 2017.

“We have shown that an early switch of regimen is highly beneficial in terms of reduced mortality,” comment the authors. “Patients with low CD4 counts at time of failure are at particularly high risk of increased mortality, whereas a moderate delay in healthy patients comes with a comparatively lower risk.”


second-line treatment

The second preferred therapy for a particular condition, used after first-line treatment fails or if a person cannot tolerate first-line drugs.

treatment failure

Inability of a medical therapy to achieve the desired results. 

first-line therapy

The regimen used when starting treatment for the first time.

viral rebound

When a person on antiretroviral therapy (ART) has persistent, detectable levels of HIV in the blood after a period of undetectable levels. Causes of viral rebound can include drug resistance, poor adherence to an HIV treatment regimen or interrupting treatment.

detectable viral load

When viral load is detectable, this indicates that HIV is replicating in the body. If the person is taking HIV treatment but their viral load is detectable, the treatment is not working properly. There may still be a risk of HIV transmission to sexual partners.

The research is of immediate significance to ART treatment programmes in South Africa and other resource-limited settings. The investigators suggest that individuals with a detectable viral load should have their CD4 cell count measured regularly (currently guidelines do not recommend CD4 cell monitoring in stable ART-treated individuals). They also emphasise that a delay between a first and confirmatory test of virological failure is associated with increased mortality risk. “This points to the importance of either accelerating confirmation of virological failure in patients with advanced immunological-suppression, or to consider switching at the first evidence of viraemia if cost and regimen-sparing are no longer important considerations,” write the researchers.

In 2017 an estimated 4.4 million people in South Africa were taking ART. But as the number of individuals taking treatment has increased, so too has the number of those experiencing first-line treatment failure and therefore needing to switch to second-line therapy.

First-line therapy usually consists of two-NRTIs plus an NNRTI; second-line treatment retains the same two-drug NRTI backbone, usually in combination with a protease inhibitor. Virological failure is defined as two consecutive viral load measurements above 1000 copies/ml, with the tests ideally conducted four weeks apart.

Changes to treatment after virological failure should be made as quickly as possible. However, this does not always happen. Reasons typically include concerns about adherence, limited availability of viral load monitoring and the cost of second-line treatments.

An international team of researchers led by Dr Helen Bell-Gorrod of the University of Sheffield wanted to see if there was a relationship between delayed treatment changes and the risk of death. They also wanted to determine the extent to which this was affected by CD4 cell count.

To answer these question they looked at the records of approximately 8000 people living with HIV who started standard first-line ART between 2004 and 2017.

The primary end point was mortality as recorded in patient files and the South African national registry. Information was gathered on the date of a first viral load measurement above 1000 copies/ml and the interval until the confirmatory measurement. Data were also gathered on age, sex, CD4 cell count and HIV disease stage.

The median time between the start of ART and treatment failure was approximately 3.3 years. The median time between treatment failure and switch of treatment was 121 days. This means that individuals typically stayed on a regimen that was not suppressing viral load for an average of four months.

"The study highlights the importance of early treatment switch, particularly for patients with low CD4 cell counts at failure."

During follow-up, 52% of people switched treatment and 12% died. A fifth of individuals who never switched had a viral load above 100,000 copies/ml when treatment failure was confirmed.

The probability of switching treatment was highest for individuals with a low CD4 cell count, high viral load and higher frequency of visits to their healthcare provider.

Immediate switch, compared to no treatment change, was calculated to reduce the mortality risk by 60% (95% confidence interval 0.33-0.48). Changing therapy within 60 days of virological failure reduced the mortality risk by 48%, meaning that even a short delay in starting a new treatment combination could have serious repercussions.

 The consequences of not switching from failing regimens were made starkly clear when the investigators calculated the impact of various treatment switch scenarios on five-year mortality rates.

  • If everyone changed treatment immediately at the first sign of viral rebound, 11% of all patients would die within five years.
  • If everyone remained on a failing combination, the mortality rate more than doubled to 27%.
  • If everyone remained on a failing combination, mortality among people with a CD4 cell count below 100 would be 50%, and 18% for those with a CD4 cell count above 200.

“Our study highlights that it often takes a long time to switch patients to second line treatment in South Africa,” comment Dr Bell-Gorrod and colleagues. “It is no surprise that delayed treatment switch may affect patient’s health. However, according to our results, earlier switch is of particular benefit when switching after the first signs of failure, i.e. the first viral load > 1000 copies/ml, for those who go onto confirmed failure.”

The investigators acknowledge that doctors may be reluctant to switch patients who have problems with adherence. However, in other instances, rapid treatment changes are likely to be beneficial.

“Our study highlights the importance of early treatment switch, particularly for patients with low CD4 cell counts at failure,” conclude the researchers.


Bell-Gorrod H et al. The impact of delayed switch to second-line antiretroviral therapy on mortality, depending on failure time definition and CD4 count at failure. American Journal of Epidemiology, online ahead of print, March 27 2020.

doi: 10.1093/aje/kwaa049

Full image credit: 'Antiretroviral drugs to treat HIV infection'. Image by NIAID. Available at: under a Creative Commons licence CC BY 2.0.