Pharmacokinetics of nucleoside/nucleotide reverse transcriptase inhibitors for the treatment and prevention of HIV infection

ABSTRACT

Introduction

Despite dramatic increases in new drugs and regimens, a combination of two nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) remains the backbone of many regimens to treat HIV.

Area covered

This article summarizes the pharmacokinetic characteristics of approved NRTIs that are currently in the international treatment and prevention guidelines.

Expert opinion

Compared to other NRTIs, tenofovir alafenamide fumarate (TAF) is more advantageous in terms of potency and safety. It is therefore a preferred choice in combination with emtricitabine (FTC) in most HIV treatment guidelines. The efficacy of the two-drug combination of NRTI/Integrase strand-transfer inhibitor, i.e. lamivudine/dolutegravir has been approved as an option for initial therapy. This regimen however has some limitations in patients with HBV coinfection. The two NRTI combinations tenofovir disproxil fumarate (TDF)/FTC and TAF/FTC have also been approved for pre-exposure prophylaxis (PrEP). Interestingly, a promising long-acting nucleoside reverse transcriptase translocation inhibitor, islatravir, formulated for implant was well tolerated and remained effective for up to a year, suggesting its potential as a single agent for PrEP. In the next decade, it remains to be seen whether NRTI-based regimens will remain the backbone of preferred ART regimens, or if the treatment will eventually move toward NRTI-sparing regimens to avoid long-term NRTI-toxicity.

KEYWORDS:

• HIV
• nucleoside reverse transcriptase inhibitors
• nucleotide reverse transcriptase inhibitor
• pharmacokinetics

Article highlights

• A three-drug combination therapy with two NRTIs plus a third agent from another antiretroviral class remains the gold-standard ART.

• Sustained adherence remains a major hurdle for the success of HIV treatment and prevention.

• Oral PrEP with TDF/FTC is recommended for individuals at risk for HIV and adherence to PrEP, and its use is highly correlated with efficacy.

• Most NRTIs are well tolerated and less likely than other ARV to cause significant drug interactions.

• The intracellular levels of active anabolites are more clinically relevant than the plasma levels of NRTIs. Characterization of the intracellular pharmacokinetic parameters of NRTI anabolites will provide a better understanding of drug activity.

This box summarizes key points contained in the article.

Acknowledgments

The authors thank Professor David Back at the Department of Clinical and Molecular Pharmacology, University of Liverpool for his valuable comments and suggestions on their manuscript.

Declaration of interest

K Ruxrungtham has served as a consultant for ViiV, Merck, and Mylan. He has had paid speaking engagements with ViiV, Mristol-Myers Squibb, Merck, Roche, Jensen-Cilag, GlaxoSmithKline, Thai GPO, and Mylan Lab Limited. 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

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

Additional information

Funding

This paper was not funded.