Persistent low-level detectable HIV appeared to significantly increase the risk of treatment failure but had no long-term impact on the occurrence of serious health problems in a recent study. Having integrase inhibitors as part of the therapy seemed to be protective against treatment failure in those with low-level detectable virus, Professor Enrique Bernal and colleagues report in the journal AIDS.
Defined in this study as a viral load between 50 and 200 copies persisting over time, low-level detectable HIV has been thought to raise the risk of AIDS-related conditions (by weakening the immune system) and non-AIDS related conditions such as chronic heart disease, kidney disease and some cancers (by keeping the immune system in a state of chronic inflammation). It may also allow the virus to accumulate drug resistance simply by replicating more, which increases its chances of selecting resistant forms potentially leading to more treatment failure. This study confirms the link to treatment failure, but it does not link low-level detectable virus to an increased risk of AIDS-related or non-AIDS related conditions. This is in contrast to a recent study which found the risk to be increased.
The study
The study drew on data gathered from 12,110 people with HIV between 2004 and 2021 from 48 treatment centres in Spain. It included people with HIV who were starting treatment for the first time, had been on treatment for at least a year, and had achieved viral suppression below 50 copies. Those with low-level detectable virus were defined as having between 50 and 200 copies at two consecutive viral load tests; cases where the viral load fell within this range but used to be or later reached higher than 200 copies were excluded from the analysis.
Virological failure (treatment failure, put in simpler terms) was defined when the participants had two consecutive viral load measurements above 199 copies.
Among the eligible participants, 10% had low-level detectable HIV at least once during the follow-up. Most were men. The median age of the group experiencing low level detectable virus was 48 years compared to 44 years for the undetectable group.
Although participants were followed for an average of eight years, the researchers also used statistical modelling to estimate the risk of treatment failure and other outcomes over longer time frames, projecting results out to 15 years.
Factors linked to increased risk of having a low-level detectable virus
Starting treatment with a baseline viral load greater than 100 000 copies, a CD4 count below 200 or taking a protease inhibitor-based regimen seemed to increase the risk of having a low but detectable viral load.
Virological failure
The rate of virological failure was higher for those in the low-but-detectable virus group than the undetectable group – 12.3% as opposed to 4.7%. Further statistical analysis with all factors included revealed a 39% increase in the risk of virological failure for the low-but-detectable group. Other factors that were associated with an increased risk of virological failure were a protease inhibitor-based regimen and baseline viral load greater than 100 000 copies. A CD4 count greater than 200 and starting treatment after 2016 was linked to a 27% and 30% drop in the risk. The 15-year virological failure likelihood of those in the low-but-detectable group was 21% as opposed to 9% for the undetectable group.
Factors linked to lower risk of virological failure with low but detectable virus
The researchers also looked at factors that would reduce the risk of virological failure in those who have low-level detectable virus.
They found that having started treatment past 2012 was protective, suggesting a positive impact of newer treatments being easier to take, having fewer side effects and a higher barrier to resistance. In line with this, regimens based on integrase inhibitors were protective, while those based on protease inhibitors seemed to increase the risk. Interestingly, acquiring HIV in a non-heterosexual way and not via injection drug use also correlated with a lower risk. Being Spanish was also protective, which may simply reflect fewer barriers in access to healthcare.
Probability of developing AIDS-related conditions
Of the participants in the low-but-detectable group, 0.56% developed AIDS during the follow-up, compared to 0.23% for the undetectable group. Modelling 15 years ahead revealed the probability of developing AIDS for those with undetectable viral load to be 0.4%, while it was higher for the low-but-detectable group at 1.06%. None of the differences between the two groups were statistically significant, meaning they could be due to chance.
Probability of developing non-AIDS-related conditions
During the follow-up, 6.2% of all participants developed a non-AIDS-related condition, with no significant difference between the groups. Starting treatment more recently and a CD4 count above 200 significantly was protective against non-AIDS-related conditions. Over 15 years the probability of developing a non-AIDS-related condition was 14.3% for the undetectable group and 16.4% for the low-but-detectable group, which was not a statistically significant difference.
Concluding thoughts
With over 12 000 participants and an average follow-up of eight years, the findings of the study are rather strong. Although the lack of a strong association between low but detectable virus and AIDS and non-AIDS-related conditions feels reassuring, the link between detectable viral load and an increased likelihood of treatment failure is concerning, especially as it is consistent with earlier research.
The current and evolving treatment landscape and newer options offer hope; in most cases low-level detectable viral load may be overcome to avoid risk and perhaps shouldn’t be ignored as benign even if it is only below 200 copies. Integrase inhibitors in particular seem to protect against treatment failure in the context of low-level detectable HIV and should be considered as the preferred treatment option, say the study authors.