Should HIV controllers take HIV treatment?

There exists a very small proportion – less than 1% – of people living with HIV who, without taking antiretroviral therapy (ART), spontaneously maintain their viral load below an undetectable level for several years, or maybe decades. These people are referred to as HIV controllers.

In this population, HIV control is favoured by an unusual response of the immune system. This may include the presence of specific molecules called human leucocyte antigens (HLA) which rest on the surface of cells, in order for the immune system to identify them as the body’s own and not attack them. HIV control is also probably achieved through the combination of several other mechanisms, including the resistance of the person’s CD4 cells and macrophages.

HIV controllers are defined by virological criteria. Some HIV controllers also meet the definition of Long-Term Non-Progressors who maintain a high level of CD4 cells during several years without ART.

If you are an HIV controller, you may be wondering if international guidelines that recommend treatment for all people living with HIV apply to you.

As there are specific issues for HIV controllers, a number of factors should be carefully considered before starting ART. Based on scientific evidence, this page should help you broaden your understanding of the pros and cons of starting ART if you are an HIV controller.

What is an HIV controller?

The definition of an HIV controller varies from one study to another. However, it is always based on a viral load cut-off and the duration of control.

Individuals who maintain their viral loads below 50 copies can be referred to as elite controllers, while those who do so below 2000 copies may be called viraemic controllers.

How long does viral control need to be maintained for a person to be considered a controller? Definitions range from three viral loads below a given cut-off within 12 months, to the last five viral loads being below a cut-off for at least five years.

Nevertheless, two definitions of HIV control are widely used.

• A person who has never taken ART and has at least two viral loads below 50 copies within one year.
• A person who has never taken ART and more than 90% of all their viral loads are below 400-500 copies for over five (or ten) years. 

These definitions matter. For example, what is observed in elite controllers will not necessarily be seen in viraemic controllers, whose detectable viral loads greatly increase the risk of serious health issues and of a substantial CD4 decline over time.

It is also important to keep in mind that there can be important differences between individuals who are defined as controllers using the same criteria.

Reasons to consider taking ART

According to a French team of experts led by Professor Olivier Lambotte, the following situations are reasons for HIV controllers to consider starting ART. If you are facing one or several of them, you may want to have a thorough discussion with your doctor around these issues.

Basic information on CD4 and viral load

• Loss of viral control: the loss of the immune system’s control of HIV, due to reduced function of CD4 cells, CD8 cells and macrophages, can lead to an increase in viral load on two or more tests.
• Persistent, low-level viral replication, suggested by blips (low but detectable viral load results). Blips may suggest the loss of viral control.
• Wanting to reduce the HIV transmission risk. Although no HIV transmissions from an HIV controller has ever been reported, an HIV controller might feel more comfortable using ART as a ‘treatment as prevention’ tool.
• A decline in the CD4 cell count. Especially when starting from an already low level, this is not uncommon among controllers and may raise concerns. For example, a skewed CD4/CD8 ratio predicts the emergence of non-AIDS health issues in people living with HIV. Also, the loss of CD4 cells has been linked to viral blips and low-level viral replication.
• Persistent, excessive immune activation. This is associated with poor outcomes in people living with HIV, such as the loss of CD4 cells, even when viral load is repeatedly undetectable. Immune activation may trigger chronic inflammation, which is associated with the development of co-morbidities. However, it can be challenging to decide to start ART based on immune activation, since its thresholds still need to be defined, and since inflammation biomarkers are not available in routine medical care.
• Having a co-morbidity such as cardiovascular disease or cancer might be a clinical reason to start ART. In people living with HIV, most co-morbidities develop due to chronic HIV inflammation, which can be controlled with ART. However, it is not clear if controllers are at greater risk for co-morbidities than HIV-positive people on ART, or than HIV-negative people.

Importantly, all these situations are often inter-related. For example, low-level viral replication is often accompanied by the loss of CD4 cells, an increase in immune activation and chronic inflammation. This is another reason to review your situation with your doctor as precisely as possible.

The team of experts have made some suggestions of what to do in specific clinical scenarios:

• Detectable viral load above 1000 copies: start ART.
• Viral load consistently between 50 and 1000 copies, plus decrease in CD4 cell count or CD4/CD8 ratio: start ART.
• Viral load consistently between 50 and 1000 copies, plus stable CD4 cell count or CD4/CD8 ratio: close follow-up.
• Intermittent viral blips, plus decrease in CD4 cell count or CD4/CD8 ratio: start ART.
• Intermittent viral blips, plus stable CD4 cell count or CD4/CD8 ratio: close follow-up.

Some other scenarios should generate a discussion between the doctor and the patient:

• Undetectable viral load, plus decrease in CD4 cell count or CD4/CD8 ratio: consider treating any non-HIV related co-morbidities.
• Cardiovascular disease, obesity, smoking, hepatitis C or B: consider treating co-morbidities.
• Cancer: consider starting ART.

The effect of ART on HIV controllers

A handful of studies have looked at the outcomes of ART in HIV controllers.

In terms of CD4 cell counts, they have reported:

• An increase of CD4 cells in controllers, though smaller by around 50 CD4 cells than increases seen in non-controllers.
• In another study, seemingly smaller increases in CD4 cells among controllers with a viral load of less than 400 copies at the start of ART, as compared with non-controllers with viral loads of 400-1000 copies, but the reduction in viral load was similar in both groups.  
• In 34 controllers treated with ART for a median duration of 15 months, the CD4 cell count rose significantly but this increase was lower than that seen in non-controllers with detectable viraemia. Controllers did not have such a rapid increase in CD4 cells soon after starting ART.

You or your doctor may also be interested in the potential of ART to reduce HIV reservoirs. Latent reservoirs are groups of cells that are infected with HIV but do not produce new HIV for many months or years. They are established at the earliest stage of HIV infection and can continue to survive even when the person is on ART (a phenomenon called residual inflammation). Latently infected cells may be reawakened to begin actively reproducing HIV, therefore triggering an activation of the immune response.

What have studies of HIV reservoirs in controllers starting ART taught us so far?

• In a study of four elite controllers with high CD4 counts, ART led to a profound depletion of reservoirs containing able-to-replicate HIV, but did not have any relevant effects on inflammatory markers.
• In a study of 16 HIV controllers with no symptoms and a viral load below 400 copies, the investigators found:

1. a significant decrease of HIV-DNA in the blood, but not in the rectum.
2. as important, a decrease of HIV-RNA, both in the blood and the rectum.
3. an overall reduction of immune activation markers, though not all of them.

•  In 35 controllers, a significant decline in specific CD8 T-cells (positive for CD38 and HLA-DR, known markers of the CD8s that control HIV) was observed, as well as a decline in IP-10 (an inflammatory marker), probably reflecting a reduced presence of HIV in the reservoir.

This small body of data is mostly from viraemic controllers, rather than elite controllers. It indicates that, in controllers, ART is associated with a reduction of the viral replication and of immune activation. However, it’s worth noting that the data do not clearly tell us whether ART decreases the size of HIV reservoirs or the occurrence of non-AIDS-related co-morbidities. 

Should all HIV controllers take ART?

Trying to answer this important question naturally takes us back to the definitions of HIV controllers.

One study of 52 controllers who never had a detectable viral load during their follow-up (measured with a routine assay whose detection limits varied from 500 to 10 copies), indicate that these patients may simply not need ART. As a matter of fact, these patients did not show CD4 decreases or disease progression, and for most, in the first years of being HIV-positive, had had lower HIV-RNA and DNA loads than patients presenting loss of control. In addition, further HIV-DNA load decreases have been observed in some controllers.

In controllers who have a low – but detectable – viral load, starting ART appears to be effective in the control of both HIV and immune activation. But of course, the other clinical factors described above must be taken into account when considering ART.

Additionally, your doctor should consider your willingness and readiness to start lifelong treatment. In the discussion, it will be worth asking whether you would ever be able to stop treatment, if you do start, and how you would be followed up afterwards. Make sure you get information about potential drug side effects; this is one of the main concerns of some HIV controllers.

Conventional ART is one treatment option. However, you may also discuss with your doctor the opportunity for you to join a clinical trial testing a new therapeutic approach, such as immunomodulatory strategies: new anti-CMV medications, statins, new drugs that target inflammation and the ageing of the immune system.

Whether or not you end up deciding to start an already approved or experimental treatment, this decision must be made in an environment where you feel comfortable to ask questions and have them answered. Experts strongly recommend that doctors who follow HIV controllers adopt individualised and patient-centred approaches when discussing ART with their patients.