HIV controllers may be more susceptible to non-AIDS illnesses compared to people on HIV treatment

Domizia Salusest |

A new study finds that HIV controllers – people who don’t need HIV treatment to maintain viral loads below 400 copies – are twice as likely to experience certain non-AIDS-related health conditions, particularly infections such as bronchitis. The results raise the questions of whether antiretroviral therapy (ART) might benefit some controllers and under what conditions.

Although people with HIV on ART live long, healthy lives, their immune systems often remain activated in a state of chronic inflammation. Beginning ART soon after acquiring the virus has been shown to reduce these effects, but not completely. The result is that many people living with HIV, especially when CD4 levels are relatively low, remain at higher risk of non-AIDS-related health conditions such as cardiovascular disease, cancer, liver and kidney issues, as well as depression and other mental health conditions.

On the other hand, fewer than 1% of people living with HIV are able to maintain viral load control without the use of ART. However, little is known about the susceptibility of these HIV controllers to develop non-AIDS related illnesses compared to those on ART. Though few previous studies have been conducted, the few that have report conflicting results. Some have indicated controllers may remain in a more inflamed state than people on ART, and therefore could be more susceptible to these conditions, while others have shown similar risks between the two groups or lower risk among controllers.

Carmelite Manto from the Université Paris Saclay and colleagues aimed to shed light on the question by reviewing existing data in French cohorts from multiple health centres. To be enrolled in the analysis, controllers had to have had HIV for five years or more and had at least five consecutive viral loads below 400 copies without taking ART. Those on ART were included if they’d maintained undetectable viral loads for at least five years and had initiated treatment within one month of their HIV diagnosis—a criterion that may not represent the wider population of people on ART.

The cohort had 227 controllers and 328 people on ART. Controllers compared to people on ART were more likely to be female (57% versus 14%), of African descent (38% versus 7%), were younger (median age of 45 versus 42), and were more likely to have acquired hepatitis B (46% versus 22%) or hepatitis C (6% versus 3%). The two groups had no significant differences in baseline CD4 levels or CD4/CD8 ratios.

The analysis considered non-AIDS-related conditions such as cardiovascular disease, pulmonary diseases such as pneumonia, liver diseases such as hepatitis, cancer, infections, bone afflictions such as fractures, as well as psychiatric conditions including depression and suicide attempts.

During the five-year observation period, 68 controllers experienced at least one non-AIDS-related illness compared to 62 people on ART. Overall incidence rates of all  of these potential conditions were slightly higher in controllers (7.8 events per 100 person-months versus 5.2). The most common events were non-AIDS-related infections, such as bronchitis, upper respiratory tract infections, gastroenteritis and urinary tract infections, with incidence rates of 4.1 events per 100 person-months in controllers compared to 1.9 in people on ART.


multivariate analysis

An extension of multivariable analysis that is used to model two or more outcomes at the same time.


A mental health problem causing long-lasting low mood that interferes with everyday life.

HIV controllers

A small subset of people living with HIV who are able to control HIV replication in the absence of antiretroviral treatment for an unusually long period of time. However, because HIV continues to replicate in HIV controllers, ART is recommended for controllers who have declining CD4 counts or who develop HIV-related complications. HIV controllers include sub-groups known as elite controllers and viraemic controllers. Around half of HIV controllers can also be described as long-term non-progressors.


Relating to the heart and blood vessels.


A molecule on the surface of some white blood cells. Some of these cells can kill other cells that are infected with foreign organisms.

The researchers performed a multivariate analysis, controlling for year of diagnosis, age, gender, ethnicity, tobacco use, history of these illnesses, hepatitis coinfections, and baseline CD4 counts. The results showed the risk of having any non-AIDS related condition was roughly twice as high in controllers compared to people on ART (adjusted incidence rate ratio, aIRR of 1.93). Age – specifically being 43 years old or older – was the only risk factor associated with a higher risk in controllers (aIRR of 1.7). In addition, the researchers found that controllers were nearly three times as likely to contract a non-AIDS-related infection (aIRR of 2.9).

While previous studies comparing these two groups varied in their results, the authors write that a strength in their analysis is including two to three times more controllers than previously published work. However, the study also had a few limitations, including that the two groups—controllers versus people on ART—exhibited differences in gender, hepatitis coinfections, and intravenous drug use. Another important limitation is that the people on ART were restricted to those beginning ART within one month of diagnosis instead of including people who started ART later.

Nonetheless, the authors argue that their findings raise the question of whether some controllers might benefit from ART. Although they do not advocate prescribing ART to all controllers, it might be considered under specific conditions—particularly if controllers’ CD4 counts decline, or if they lose control of viral load.