Similar rate of severe clinical outcomes with two drug vs three drug HIV treatment combinations


A large study from across Europe and Australia has shown similar results for severe clinical outcomes when comparing two drug and three-drug regimens to treat HIV. Clinical outcomes investigated included death, AIDS and cancer and showed no statistically significant differences in these outcomes between two drug and three-drug regimens.

The data published in Clinical Infectious Diseases is the first large observational study of real-world clinical outcomes for people switching to two-drug regimens. While further studies are needed to research virological failure and drug resistance when switching to two-drug regimens, this research shows promising results to potentially decrease the number of drugs taken by people living with HIV.

The analysis only included people who were already receiving treatment for HIV who switched to one of nine eligible two-drug combinations included in the study, which were chosen to reflect the currently prescribed two-drug regimens used in real-world settings. All contained either an integrase inhibitor or a boosted protease inhibitor. The most commonly used combination was dolutegravir with lamivudine (23% of the participants on two drugs), with the second most common being raltegravir with boosted darunavir (20%). The comparison group on three drugs had to use one of the same medications from the two-drug treatments as the third drug. In this group the most common treatment was dolutegravir with two nucleoside reverse transcriptase inhibitors (NRTIs), which was taken by 47%.


statistical significance

Statistical tests are used to judge whether the results of a study could be due to chance and would not be confirmed if the study was repeated. If result is probably not due to chance, the results are ‘statistically significant’. 

observational study

A study design in which patients receive routine clinical care and researchers record the outcome. Observational studies can provide useful information but are considered less reliable than experimental studies such as randomised controlled trials. Some examples of observational studies are cohort studies and case-control studies.

end-stage disease

Final period or phase in the course of a disease leading to a person's death.

boosting agent

Booster drugs are used to ‘boost’ the effects of protease inhibitors and some other antiretrovirals. Adding a small dose of a booster drug to an antiretroviral makes the liver break down the primary drug more slowly, which means that it stays in the body for longer times or at higher levels. Without the boosting agent, the prescribed dose of the primary drug would be ineffective.

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.

Other studies have previously looked at inflammation and the immune system to try to compare the use of two-drug vs three-drug regimens, rather than real-world clinical outcomes. The clinical outcomes included in this trial were death, AIDS, cancer unrelated to AIDS, severe cardiovascular disease, end-stage liver disease and end-stage kidney disease. When the results were analysed, they were adjusted to account for participants’ different backgrounds and other health conditions, prior to starting the trial. The participants were predominantly male (72%) of White ethnicity (82%).

In total, 9791 people were included – 1088 people switching to two-drug regimens and 8703 switching to three drugs. The participants were each followed up for an average of 2.6 years.

During the study 619 severe clinical events occurred, the most common of which were death (186) and non-AIDS related cancer (130). Initial data showed the number of severe events was higher for those on two-drug regimens, however it was found that the median age in the group using two-drugs was almost five years greater (53 years vs 48 years). When adjusted for the older age in the two-drug group, the incidence ratio was 1.08 (p = 0.54), which is not statistically significant. Further analysis which excluded two-drug treatments that are not currently clinically recommended by guidelines also showed no difference to their corresponding three-drug treatments.

In those patients whose viral load was not suppressed when they changed treatment, there were actually fewer events in the group using two drugs compared to three. However, this may be because of a relatively lower number of other medical conditions in this group, making them healthier overall. A comparison of viral load suppression in the two-drug and three-drug groups was not done as part of this study.

The researchers recognised that there were several different factors which could make interpreting the results difficult, especially because of the relatively low number of some of the events studied. There were also large amounts of data missing, such as smoking status, which could have had a significant effect on the outcome.

The advantages of taking fewer medications include fewer side effects and less risk of drug interactions. These regimens may also be cheaper and involve fewer pills.

Irrespective of the different analysis models used, the data consistently suggested that the likelihood of a severe clinical outcome remained the same whether using two drugs or three. However, each individual severe clinical outcome requires further investigation. It is also important to ensure that other factors are accounted for, particularly the ability to maintain viral load suppression with two-drug regimens and the potential effects on resistance mutations. As the investigators point out, “further research on resistance barriers and long-term durability of two drug-regimens is needed.”