Editors' ChoiceHIV/AIDS

How Much Do Drugs Matter?

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Science Translational Medicine  05 Feb 2014:
Vol. 6, Issue 222, pp. 222ec25
DOI: 10.1126/scitranslmed.3008566

Antiretroviral drugs have increased life expectancy and improved quality of life for HIV-infected patients. However, although these drugs suppress HIV replication in the blood, they do not eliminate HIV-infected cells. Hence, current treatment cannot cure the infection and must be lifelong. Indeed, even treated HIV-infected patients have persistent immune system abnormalities, including incomplete immune restoration, chronic inflammation, and their sequelae. One explanation for these ongoing complications is that viral replication may persist in the lymphatic tissues, the network of immune cells located in the lymph nodes, gut, and other organs in which most HIV is produced and stored.

Fletcher et al. explored the hypothesis that antiretroviral drug concentrations may be insufficient to completely suppress HIV replication in lymphatic tissues. The authors followed 12 HIV-infected patients who were starting antiretroviral therapy and collected their blood, lymph node, and gut samples at frequent intervals over 6 months. The authors used specialized techniques to measure antiretroviral drug concentrations inside the immune cells in these tissues. Interestingly, the drug levels inside immune cells from the lymphatic tissues were lower than inside immune cells from the blood. The authors then sought to determine whether these drug levels were suppressing virus replication in the lymphatic tissues. They measured the amount and location of virus produced in the lymphatic tissues and found, in four out of nine patients with sufficient data for analysis, evidence that the virus was continuing to replicate in these tissues, even when it was fully suppressed in the blood. Last, the authors found a direct correlation between drug levels and the quantity of viral replication in the tissues.

This study demonstrates that HIV continues to replicate in the lymphatic tissues of some HIV-infected patients receiving therapy despite suppression of viral replication in the blood. Additionally, the study supports that low concentrations of anti-HIV drugs may contribute to this ongoing replication in the tissues. This study importantly suggests that strategies to improve drug penetration into lymphatic cells could overall reduce viral replication. Fully suppressing viral replication in all sites could improve the long-term consequences of HIV infection and provide the first step toward a cure.

C. V. Fletcher et al., Persistent HIV-1 replication is associated with lower antiretroviral drug concentrations in lymphatic tissues. Proc. Natl. Acad. Sci. U.S.A., published online 27 January 2014 (10.1073/pnas.1318249111). [Full Text]

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