People with weakened immune systems still at risk of treatment failure, even with newer ART regimens

Mareike Günsche |

Delays between acquiring HIV and initiating antiretroviral therapy (ART) often translates to people beginning treatment with weakened immune systems, a scenario that incurs a significantly higher risk that their therapy will fail to suppress the virus. Two new studies suggest that modern integrase inhibitor-based therapies currently recommended as part of first-line ART regimens do not mitigate that risk compared to older formulations.

Narrowing the gap in time between acquiring HIV and starting ART not only increases the success rate of treatment, it also improves people’s health outcomes. Nonetheless, late HIV diagnoses remain a significant problem worldwide. In Europe, for example, almost half of HIV diagnoses occur when people’s CD4 levels have already dropped below 350.

Current recommendations for most people beginning ART for the first time include taking an integrase inhibitor (generally dolutegravir or bictegravir) as the anchor drug, with a nucleoside backbone as part of a three-drug combination. A 2019 analysis that evaluated treatments prescribed between 1994 and 2017 concluded that newer regimens incorporating integrase inhibitors were more successful at achieving undetectable viral loads. However, few studies have specifically investigated whether newer treatments work better in people who initiated their first ART regimen late–specifically, after they had low CD4 levels or high viral loads.


integrase inhibitors (INI, INSTI)

A class of antiretroviral drugs. Integrase strand transfer inhibitors (INSTIs) block integrase, which is an HIV enzyme that the virus uses to insert its genetic material into a cell that it has infected. Blocking integrase prevents HIV from replicating.


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. 

treatment failure

Inability of a medical therapy to achieve the desired results. 

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.

virological suppression

Halting of the function or replication of a virus. In HIV, optimal viral suppression is measured as the reduction of viral load (HIV RNA) to undetectable levels and is the goal of antiretroviral therapy.

Dr Jose Pérez Molina of Madrid’s Hospital Universitario Ramón y Cajal and colleagues performed a meta-analysis to clarify how baseline CD4 levels and viral loads affect the success of integrase inhibitor-based ART regimens in people taking HIV treatment for the first time. The integrase inhibitors included in the regimens analysed were dolutegravir, bictegravir, or raltegravir, and the nucleoside backbones primarily consisted of combinations of tenofovir disoproxil and emtricitabine, tenofovir alafenamide and emtricitabine, and abacavir and lamivudine.

The researchers compared treatment failure—defined as having viral loads greater than 50 after 48 weeks—across 12 randomised clinical trials between groups initiating ART with CD4 levels less than or greater than 200 or viral loads less than or greater than 100,000. From those trials, data from 6,597 participants were used to evaluate the effect of CD4 level and 6846 participants had data to evaluate the effect of viral load on the different ART regimens.

Participants were primarily male (85%) and the median age was 34 years. From the various cohorts, the median percentage of people with CD4 levels less than 200 was 13%, and the median percentage of people with a viral load greater than 100,000 was 26%.

Consistent with previous studies, people with low CD4 levels and high viral loads were more likely to experience treatment failure at 48 weeks after beginning ART, with odds ratios of 1.94 and 1.75, respectively. Similar failure rates were observed after 96 weeks—in both cases the odds ratio was about 1.5.

Put another way, treatment failure occurred in 92 per 1000 people with CD4 counts above 200, rising to 165 per 1000 people with CD4 counts below 200. Failure rates for people with viral loads under 100,000 were 88 per 1000 people and 145 per 1000 people with higher viral loads.

But there were no significant differences when comparing either integrase inhibitor anchor drugs or the nucleoside backbone drugs, suggesting that currently recommended ART regimens fare equivalently when people with already weakened immune systems begin therapy for the first time.

These newer therapies also don’t appear to work better than older regimens in people who begin ART late. The researchers conducted a similar analysis in 2012, primarily comparing how ART regimens with boosted protease inhibitors as the anchor drug fared when started in people with already weakened immune systems. “Ten years later, and with more potent and better-tolerated antiretrovirals, the detrimental effect of low CD4 counts and high viral load on response to ART remains unchanged, with no drug-regimen performing significantly better than the others,” the authors wrote.

In the current study, none of the regimens was associated with a statistically higher likelihood of treatment failure. However, arms with raltegravir exhibited the highest incidence of resistance mutations, suggesting the consequences to failure may differ based on regimen.

A second study made a similar finding that newer regimens do not perform better than older ones in people with weakened immune systems. This study investigated the likelihood to achieve viral suppression after 48 and 96 weeks in participants 17 observational cohorts in Europe and Australia. The cohort included adults who began three-drug ART for the first time between 2014 to 2020. The regimens included the same nucleoside combinations as the previous study as well as regimens anchored with integrase inhibitors (dolutegravir, raltegravir, and elvitegravir), a protease inhibitor (darunavir), or a non-nucleoside reverse transcriptase inhibitor (rilpivirine).

Included in the analysis were 4310 participants, 72% of which started with integrase inhibitor-based regimens (of whom 63% had initiated dolutegravir). Participants were mainly male (84%), White (69%), gay and bisexual (61%), and the median age was 38. When diagnosed, 46% of the participants had CD4 levels below 350 and 36% had viral loads above 100,000.

At 48 weeks, people with CD4 levels below 200 and viral loads above 100,000 were less likely to achieve viral suppression (adjusted odds ratios 0.5 and 0.4, respectively), defined as having a detectable viral load. These negative associations remained at 96 weeks. CD4 levels below 200 were also associated with higher rates of virological failure (adjusted odds ratio of 3.1), defined as two consecutive detectable viral loads. However, no association was found between virological failure and high viral loads when starting ART. These results were generally consistent across anchor drugs (although darunavir and raltegravir were associated with poorer results), suggesting that the effects of starting ART with a weakened immune system are independent of the regimen itself.

Taken together, the two studies confirm the importance of diagnosing HIV and beginning ART as soon as possible to assure people have the best outcome possible. That appears to be the case irrespective of which drugs are included.