Does choice of antiretroviral drugs matter for inflammation?

ABSTRACT

Introduction: The massive implementation of combination antiretroviral therapy (cART) has forever changed the landscape of HIV infection. This unprecedented success has turned HIV infection into a manageable chronic disease. The increased survival of people living with HIV is, however, shadowed by a high burden of aging-related comorbidities. The pathogenic basis underlying this excess of co-morbid conditions is most likely a persistent inflammatory and immune activation state, despite an optimal control of HIV replication, which in turn has largely been attributed to bacterial or bacterial products translocation from the gut.

Area covered: This review is focused on the relationship between cART and the chronic inflammatory and immune activation status in otherwise virologically well-controlled people living with HIV (PLWH). Particular focus will be placed on the differences, if any, between distinct cART modalities, with emphasis on less-drug cART regimens, and especially on dual therapies.

Expert opinion: Research to address the increased inflammatory and immune activation status of cART-treated, HIV-infected patients, should focus on adjuvant means of therapy, rather than on the cART regime itself. With current antiretrovirals, no difference between dual and triple regimens has been demonstrated, provided that virological and immunological outcomes be non-inferior.

KEYWORDS:

• HIV infection
• combination antiretroviral therapy
• triple therapy
• dual therapy
• inflammation
• immune activation
• cytokines
• IL-6
• IL-1b
• TNF-a
• CD4/C8 ratio

Article highlights

• Advances in combination antiretroviral therapy (cART) have drastically increased the life expectancy for persons living with HIV, transforming HIV management into long-term care with lifelong cART exposure.

• Less-drug cART regimens, including NRTI-sparing ones, have been evaluated as an alternative treatment in specific populations to decrease drug exposure and toxicities in both cART-naive and experienced patients.

• Persistent inflammation and immune activation (IIA) in the setting of virologically-controlled HIV infection is well-documented, seems to have a multifactorial origin, including ongoing low-level viral replication, the coinfection with other chronic viruses, immune dysregulation, and translocation of the intestinal microbial flora into the systemic circulation.

• It is known that persistent IIA is a predictor of clinical events and mortality in persons living with HIV.

• Although several studies suggest adequate efficacy with less adverse events with dual antiretroviral strategies, there is concern that treating patients with less than three drugs might lead to a loss of a supposed control of IIA.

• To date, there is no evidence that dual behave differently from triple antiretroviral regimes in terms of inflammation and immune activation in PLWH

Acknowledgments

The funding sources were not involved in the design of the study, in the collection and analysis of data or in writing the report. All authors had access to the data used and the lead author reviewed the full data report. The full study data were available to all authors. The decision to submit the paper for publication was made by PD.

Author contributions

P Domingo, MG Mateo, M Gutierrez, and F Vidal designed the review. P Domingo, MG Mateo, and F Vidal contributed to the coordination and oversight of the review. All authors participated in data interpretation. The manuscript was drafted by P Domingo and MG Mateo. All authors provided input to the report and approved the final version of the manuscript.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work has been partially funded by Fondo de Investigaciones Sanitarias (FIS PI13/0796, PI14/0700, PI14/0063, PI016/0503, PI17/0420 & PI17/0498), Ministerio de Sanidad, Politica Social e Igualdad (EC11-293), Programa de Suport als Grups de Recerca AGAUR (2014 SGR 250, 2017 SGR 948), and Red de Investigación en SIDA RD012/0017/0014, RD12/0017/0005 integrated in the National RDI Plan and cofinanced by the ISCIII-Subdirección General de Evaluación and FEDER; FEDER (Fondo Europeo de desarrollo Regional; otra manera de hacer Europa) and by the Gilead Fellowship Program (I Convocatoria de Proyectos de Investigación en VIH y Hepatitis 2013, GLD 1300168, and II Convocatoria de Proyectos de Investigación en VIH y Hepatitis GLD 2014/00923.