Risks and benefits of reducing the number of drugs to treat HIV-1 infection

ABSTRACT

Introduction: Despite the efficacy and safety of antiretroviral therapy, new treatment options are needed to address the concerns of patients and physicians regarding long-term toxicities, costs, and convenience of lifelong antiretroviral therapy. To achieve this goal, one strategy is to reduce the number of drugs in the antiretroviral regimen.

Areas covered: We review the recent evidence on the efficacy and safety of reduced drug regimens and their potential risks and benefits. There is currently strong evidence showing that some two-drug regimens have a comparable efficacy and short-term safety compared to standard three-drug regimens. The fixed-dose combination of dolutegravir/lamivudine is already an alternative for many treatment-naïve and virologically suppressed HIV-1 infected adults supported by large randomized clinical trials. The co-formulation dolutegravir plus rilpivirine is also a switch strategy for maintenance therapy. Long-acting injectable cabotegravir plus rilpivirine has already regulatory approval, and islatravir plus doravirine is an expected option in the near future. Some two-drug regimens have not been as successful.

Expert opinion: Long-term safety issues of these two-drug regimens remain to be determined, but with the overwhelming evidence available in virological control and short-term safety, the potential benefits of some of these two-drug regimens appear to outweigh the risks.

KEYWORDS:

• HIV
• antiretroviral therapy
• highly active
• simplification
• dual therapy
• two-drug regimen
• nucleoside sparing
• reduced-drug regimens

Abbreviations

2DR, two-drug regimen; 3DR, Three-drug regimen; 3TC, lamivudine; ABC, abacavir; AE, adverse event; ART, antiretroviral therapy; ATV, atazanavir; BIC, bictegravir; CAB, cabotegravir; COBI or c, cobicistat; DRV, darunavir; DTG, dolutegravir; DOR, doravirine; FTC, emtricitabine; HBV, hepatitis B virus; HIV, human immunodeficiency virus; INSTI, integrase strand transfer inhibitors; ISL, islatravir; LPV, lopinavir; MVC, maraviroc; NGS, next-generation sequencing; NNRTI, non-nucleoside reverse transcriptase inhibitor; NRTI, nucleoside/nucleotide reverse transcriptase inhibitor; PI, protease Inhibitor; PI/b, boosted protease inhibitor; PLWH, people living with HIV; RAL, raltegravir; RAM, resistance-associated mutation; RDR, reduced-drug regimen; RPV, rilpivirine; RTV or r, ritonavir; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate; VF, virological failure; VL, viral Load.

Article highlights

• Some two-drug NRTI-sparing regimens have shown in large phase 3 randomized clinical trials their efficacy, safety and durability compared to standard 3DRs. This challenges the idea that 3DRs ought to be the treatment of choice for all HIV-1 infected persons.

• For many treatment-naïve HIV-1 infected adults, DTG plus 3TC is already an alternative. ISL plus DOR is currently on phase III clinical trials.

• For many virologically suppressed HIV-1 infected adults, DTG plus 3TC and DTG plus RPV are already valid alternative regimens. Additionally, a PI/b plus 3TC may be an alternative for selected patients, and soon long-acting injectable CAB plus RPV will be available.

• Some issues of these 2DRs are to be defined better, especially their long-term safety and the potential impact of historical drug-RAMs.

• Immunity to HBV should be confirmed before considering a 2DR.

• However, the preliminary information is reassuring, and the potential benefits in tolerance, long-term toxicities, drug-interactions, cost-effectiveness, and patients’ compliance and quality of life, appear to outweigh the potential risks of 2DRs.

This box summarizes key points contained in the article.

Declaration of interest

J Cadiñanos has been granted with a Río Hortega contract by the National Institute of Health Carlos III (CM19/00059) outside the submitted work. JR Arribas has received advisory fees, speaker fees and grant support from Viiv, Janssen, Gilead, MSD, Teva, Alexa, and Serono. R Montejano is supported by Juan Rodés contract by the National Institute of Health Carlos III (JR18/00030) outside the submitted work. R Montejano reports personal fees and non-financial support from MSD, Janssen, ViiV and Gilead, outside the submitted work. R De Miguel reports personal fees (speaker fees) and non-financial support from Janssen, ViiV and Gilead, outside the submitted work. The authors have no other 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

A reviewer on this manuscript is involved in drug studies, both investigator-led, as well as pharma-sponsored ones, using Gilead, ViiV, J&J and Merck drugs used in dual regimens; ViiV has provided financial support to one of the investigation lead studies; Gilead, ViiV and Merck have sponsored drug. All other peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.