People with HIV still running out of treatment options – not always because of resistance

Mareike Günsche |

Around one in ten people with HIV developed limited treatment options – which meant that they could no longer take a standard three-drug antiretroviral combination – during approximately five years of follow-up, a large study has found.

The most common reason for discontinuing previous antiretrovirals and needing a non-standard regimen was inability to tolerate drugs in the previous regimen, not virological failure of treatment. The study followed people who had been on treatment for at least five years, not people who were new to treatment, and those who developed limited treatment options had been taking antiretrovirals for a median of 13.5 years.

The study findings emphasise that new antiretroviral agents are needed not only because of the emergence of drug resistance but also because comorbidities among people with HIV mean that some antiretrovirals are either poorly tolerated or are unsuitable for use by people with multiple health conditions.



The presence of one or more additional health conditions at the same time as a primary condition (such as HIV).

reverse transcriptase

A retroviral enzyme which converts genetic material from RNA into DNA, an essential step in the lifecycle of HIV. Several classes of anti-HIV drugs interfere with this stage of HIV’s life cycle: nucleoside reverse transcriptase inhibitors and nucleotide reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs). 


A precursor to a building block of DNA or RNA. Nucleosides must be chemically changed into nucleotides before they can be used to make DNA or RNA. 

drug resistance

A drug-resistant HIV strain is one which is less susceptible to the effects of one or more anti-HIV drugs because of an accumulation of HIV mutations in its genotype. Resistance can be the result of a poor adherence to treatment or of transmission of an already resistant virus.


Relating to the heart and blood vessels.

In the past, people with limited treatment options were often referred to as highly treatment-experienced, but as Dr Laura Waters told the British HIV Association’s 2023 spring conference, people with HIV can have limited treatment options without having taken lots of antiretrovirals. This may occur if they have acquired drug-resistant HIV, if they can’t tolerate some antiretrovirals or if they have co-morbidities that restrict their treatment options. Resistance to three drug classes can arise after taking only two regimens, she pointed out, if prescribers don’t carefully consider the risks of treatment failure when choosing a second-line regimen.

Definitions of limited treatment options vary. European AIDS Clinical Society guidelines specify that people have limited treatment options when they have resistance to at least two antiretroviral drug classes and/or cannot be treated with a regimen containing two to three active drugs from the four major classes of antiretrovirals. British HIV Association guidelines say that people are judged to have limited treatment options when a fully suppressive regimen cannot be constructed. The US DHHS guidelines offer no definition.

What proportion of people with HIV have limited treatment options? To investigate this question, Professor Amanda Mocroft and colleagues in the RESPOND cohort collaboration combined cohort data from 17 cohort studies in Europe, Australia, Argentina and Israel.

Using treatment records only, as drug resistance data were not available, they looked at the incidence of new cases of limited treatment options in people who had been taking antiretroviral treatment for at least five years. The study excluded people who already had limited treatment options at baseline (2,794 people).

In this study, limited or exhausted treatment options were defined as:

  • requiring two anchor agents (such as dolutegravir or darunavir) in a three-drug regimen, or
  • taking a two-drug regimen consisting of anchor agents (but not rilpivirine combined with dolutegravir or cabotegravir), or
  • taking a regimen of at least three nucleoside reverse transcriptase inhibitors.

Anyone taking a regimen containing two nucleoside reverse transcriptase inhibitors and a third drug from a different class was considered to be taking standard treatment.

The study population consisted of 23,827 people with HIV, on treatment for at least five years and with a CD4 count and viral load measurement in the previous year. Just under three-quarters (73%) were male, 69% were White and the majority (72%) had been living with HIV for 15 years or less. Participants were followed for a median of 5.5 years.

During 130,061 person-years of follow-up, 9% of participants developed limited treatment options (an incidence of 1.66 per 100 person-years of follow-up). Prior to developing limited treatment options, participants had been exposed to a median of seven antiretrovirals after a median of 13.5 years of treatment. Of those who developed limited treatment options, 48% were taking two anchor agents with a third drug, 31% were on a two-drug regimen (containing darunavir in 62% of cases) and 15% were taking three nucleoside reverse transcriptase inhibitors. Almost everyone taking more than two drugs was taking either lamivudine, emtricitabine and/or tenofovir disoproxil.

Overall, only 27% of participants who developed limited treatment options had discontinued an antiretroviral agent due to the failure of any previous regimen. Participants more often discontinued antiretrovirals in their previous regimen because they could not tolerate them (54%).

Developing limited treatment options was not associated with an increased risk of death after adjusting for age and CD4 count and the same was true for cardiovascular disease and non-AIDS-defining malignancies. However, the risk of subsequently developing chronic kidney disease was 47% higher in people who developed limited treatment options.

"The most common reason for discontinuing previous antiretrovirals was inability to tolerate the drugs, not virological failure."

The risk of developing limited treatment options was higher for people with previous cardiovascular disease or chronic kidney disease, as well as in people with CD4 counts below 350 and people with a history of an AIDS diagnosis. People in southern Europe and Argentina had a slightly raised risk of developing limited treatment options compared to people in central Europe.

The risk of developing limited treatment options was lower in the period 2018-2021 compared to the period 2012-2014, possibly because second-generation integrase inhibitors (dolutegravir and bictegravir) with higher barriers to the development of resistance had become available.

“The lower rates of imited/exhausted treatment options in an aging population with an increasing prevalence of comorbidities and extensive ART history is a positive finding and potentially reflects more individualised clinical management with an increased awareness of potential ART-related toxicities, comorbidities, and drug-drug interactions,” the authors conclude.


Mocroft A et al. Heavy ARV exposure and exhausted/limited ARV options: predictors and clinical outcomes. AIDS, published online, 11 December 2023.