A study conducted by researchers at the Institute for HIV Research, the UDE School of Medicine and the University Hospital in Essen collapsed with a potential toxicity of integrase inhibitors. Inhibitors of incorporation (INSTI) are a preferred drug for inclusion in antiretroviral treatment regimens given its tolerability, efficacy and high strength barrier. Indeed, INSTI has been found to improve and prolong the lives of millions of people living with HIV who suffer from side effects and resistance to treatment. However, recent data from the laboratory show that INSTI may not be as safe as it was proposed.
The researchers found that INSTI had a dramatic effect on the activity of the immune system cells and specifically reduced the activity and function of CD4 T helper cells. This involved a reduced proliferation and proliferation of these cells. As HIV itself attacks and destroys CD4 helper cells, the study raises concerns about whether this class of drugs is the best long-term option for HIV treatment. Interestingly, other HIV drugs, including protease inhibitors (PIs) or reverse transcriptase inhibitors ((N) NRTIs) or drugs, did not show these results.
In addition, there was also a difference between the INSTI class of medicines. While eltvegravir (EVG) and docetagravir (DTG) had a significant effect on cellular function, raltegravir did not show any effect. To further understand the source of reduced T cell T cell proliferation and proliferation, the researchers studied the effect of drugs on mitochondria. Mitochondria are important organelles of cells in our body that produce energy for cellular function. In fact, INSTI interferes with the electron transport chain of mitochondria, seriously damaging their respiratory capacity and thus slowing down cellular activity.
The impact of DTG and EVG on cellular functions is probably systematic. However, CD4 T cells are metabolically highly reactive and so small effects can be more easily detected in these cells compared to others. "
Professor Dr. Hendrik Streeck, Senior Writer
Indeed, in particular, DTG has repeatedly been suspected of possible serious side effects. In 2018 drug regulators warned of possible harm to babies born to women who took dolutegravir during early pregnancy. Preliminary findings from the Tsepamo study in Botswana showed a slightly increased risk of neural tube defects. The results led to a safety alert and stopped the plans to introduce DTG-based therapy in some countries in Sub-Saharan Africa. Now, several emerging studies have linked INSTI with significant weight gain further increasing potential safety concerns for these drugs. "INSTI is a big drug category and has helped millions of people worldwide, but our study requires greater pharmacovigilance for possible serious long-term toxicity," says Professor Streeck. "In particular, given the wide use of INSTIs, prospective studies are needed to determine the wider clinical implications of our findings."
University of Duisburg-Essen
Korencak, M. et al. (2019) Effect of HIV infection and antiretroviral therapy on immune cell functions. Journal of Clinical Investigation Insight. doi.org/10.1172/jci.insight.126675
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