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Reverse-transcriptase inhibitor

Reverse transcriptase inhibitors (RTIs) are a class of antiretroviral drugs that target the reverse transcriptase enzyme, a key viral protein essential for the replication of retroviruses such as human immunodeficiency virus type 1 (HIV-1). By inhibiting this enzyme, RTIs prevent the conversion of the virus's single-stranded RNA genome into double-stranded DNA, thereby blocking viral integration into the host cell's genome and subsequent production of new virions.^[1] These medications are classified into two primary subclasses: nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), which act as substrate analogs that incorporate into the growing DNA chain and cause chain termination due to the absence of a 3'-hydroxyl group, and non-nucleoside reverse transcriptase inhibitors (NNRTIs), which bind directly to a hydrophobic pocket on the enzyme, inducing a conformational change that inhibits its polymerase activity.^[1] Primarily indicated for the treatment of HIV-1 infection, RTIs also have applications in managing hepatitis B virus (HBV) for certain NRTIs and in pre-exposure and post-exposure prophylaxis to prevent HIV acquisition after high-risk exposures.^[1] The development of RTIs revolutionized HIV management, with zidovudine (AZT), the first NRTI, receiving U.S. Food and Drug Administration (FDA) approval in 1987 as the inaugural antiretroviral therapy, significantly reducing mortality and perinatal transmission rates despite initial monotherapy limitations.^[2] In contemporary highly active antiretroviral therapy (HAART) regimens, RTIs form the backbone, typically combining two NRTIs with an NNRTI, protease inhibitor, or integrase strand transfer inhibitor to achieve viral suppression, restore immune function, and minimize drug resistance emergence through multi-drug approaches.^[1] Common NRTIs include tenofovir disoproxil fumarate, emtricitabine, and abacavir, while NNRTIs encompass efavirenz, rilpivirine, and doravirine; these are administered orally in fixed-dose combinations for improved adherence and efficacy.^[1] Although effective, RTIs carry risks such as mitochondrial toxicity from NRTIs (e.g., lactic acidosis, lipodystrophy) and hypersensitivity reactions or neuropsychiatric effects from NNRTIs, necessitating monitoring and genotype-guided selection to counter resistance mutations like those at the M184V or K103N positions in reverse transcriptase.^[1] Ongoing research explores long-acting formulations and novel RTIs to enhance tolerability and address resistance in resource-limited settings.^[1]

Overview

Definition and role

Reverse transcriptase inhibitors (RTIs) are a class of antiviral medications that specifically target and inhibit the enzyme reverse transcriptase (RT), an RNA-dependent DNA polymerase essential for the replication of retroviruses. This enzyme catalyzes the conversion of single-stranded viral RNA into double-stranded DNA, a critical step that allows the viral genome to integrate into the host cell's DNA. By blocking this process, RTIs disrupt the viral life cycle at an early stage, preventing the production of new infectious virions and limiting the spread of infection.^[1] The primary role of RTIs is to halt retroviral replication by interfering with reverse transcription, thereby inhibiting the integration of viral DNA into the host genome and subsequent viral protein synthesis. This mechanism is particularly vital for treating infections caused by human immunodeficiency virus types 1 and 2 (HIV-1 and HIV-2), where RT serves as the key enzymatic bridge between the viral RNA genome and host cellular machinery. In HIV, RT exists as a heterodimer composed of p66 and p51 subunits; the larger p66 subunit houses both the polymerase domain, responsible for nucleotide incorporation during DNA synthesis, and the RNase H domain, which degrades the RNA template in RNA-DNA hybrids to facilitate strand displacement. The p51 subunit provides structural support without catalytic activity.^[3] RTIs also play a significant role in managing hepatitis B virus (HBV) infection, a hepadnavirus that employs a related multifunctional RT. In HBV, the RT domain within the viral polymerase protein performs both reverse transcription of pregenomic RNA to minus-strand DNA and subsequent DNA-dependent DNA polymerization to complete plus-strand synthesis, all within the viral capsid. This dual functionality underscores the enzyme's central importance in HBV replication, making it a prime target for inhibitors that suppress chronic infection.^[4]

Therapeutic significance

Reverse-transcriptase inhibitors (RTIs) form a cornerstone of antiretroviral therapy (ART) for HIV, enabling sustained viral suppression, CD4+ T-cell immune recovery, and reduced risk of HIV transmission by achieving undetectable viral loads.^[1] As part of WHO-recommended first-line regimens, such as dolutegravir plus tenofovir disoproxil fumarate and lamivudine or emtricitabine, RTIs are integral to treating all individuals with HIV regardless of CD4 count. In chronic hepatitis B virus (HBV) management, particularly among HIV-HBV coinfected patients, RTIs like tenofovir and entecavir suppress viral replication to prevent progression to liver complications, including cirrhosis, end-stage liver disease, and hepatocellular carcinoma.^[5] Sustained HBV suppression with these agents reduces hepatocellular carcinoma risk by approximately 58% in large cohort studies.^[5] RTIs have contributed to major public health milestones, including a 70% decline in global AIDS-related deaths from 2.1 million in 2004 to 630,000 in 2024, driven by expanded ART access that incorporates these drugs.^[6] In pre-exposure prophylaxis (PrEP), combinations like tenofovir disoproxil fumarate-emtricitabine reduce HIV acquisition risk by 66% to 75% among high-risk populations when adherence is maintained.^[1] RTIs are routinely combined with other antiretroviral classes, such as boosted protease inhibitors (e.g., darunavir/ritonavir plus tenofovir-emtricitabine), to provide a high genetic barrier to resistance, minimize viral rebound, and ensure long-term virologic suppression in treatment-naive and experienced patients.^[7] This multi-class approach prevents the emergence of drug-resistant HIV variants, supporting durable immune reconstitution and improved clinical outcomes.^[7]

Mechanism of Action

Core inhibition process

Reverse transcription is a critical step in the retroviral replication cycle, where the viral single-stranded RNA genome is converted into double-stranded DNA by the viral enzyme reverse transcriptase (RT). The process begins with priming, in which a host transfer RNA (tRNA) binds to the primer-binding site (PBS) near the 5' end of the viral RNA, providing a 3'-OH group for initiating DNA synthesis. RT's polymerase domain then extends this primer by adding deoxynucleoside triphosphates (dNTPs), synthesizing the minus-strand strong-stop DNA (~100–150 nucleotides long) complementary to the 5' repeat (R) region and part of the unique 5' (U5) sequence. This is followed by first-strand transfer, where the newly synthesized DNA anneals to the 3' end of the RNA via R region complementarity, allowing elongation to continue toward the 5' end of the RNA template.^[8] Concurrently, RT's RNase H domain degrades the RNA strand in the RNA:DNA hybrid, except for the polypurine tract (PPT), which serves as a primer for plus-strand DNA synthesis. The plus-strand strong-stop DNA is synthesized from the PPT, copying the PBS and unique 3' (U3) region, followed by second-strand transfer using PBS complementarity. Elongation of both strands proceeds using the opposite strand as template, culminating in termination with the formation of a double-stranded DNA molecule flanked by long terminal repeats (LTRs), ready for integration into the host genome. This cycle can be simplified as:

\text{RNA (viral genome)} + \text{dNTPs} \xrightarrow{\text{RT polymerase}} \text{dsDNA (provirus)}

The RNase H activity ensures template removal, preventing interference with subsequent steps.^[8]^[9] Reverse transcriptase inhibitors (RTIs) block this process by targeting RT, preventing the synthesis of proviral DNA and thus halting viral replication. These inhibitors bind either to the enzyme's active site, competing with natural dNTP substrates, or to allosteric sites, inducing conformational changes that distort the active site. This interference halts nucleotide incorporation into the growing DNA chain or blocks chain elongation, with relative selectivity for the viral enzyme over host DNA polymerases, although NRTIs can inhibit mitochondrial DNA polymerase gamma due to structural similarities in substrate binding.^[1]^[10] RTIs disrupt key steps across the cycle: at initiation, they impair stable tRNA primer binding to the PBS, preventing formation of the RT-tRNA-RNA complex needed for (-) strand priming; during elongation, they inhibit dNTP addition by occupying the polymerase site or altering its geometry, stalling DNA chain extension; and at termination, they preclude completion of dsDNA synthesis, blocking LTR formation and proviral maturation. Overall, this targeted inhibition ensures selective disruption of reverse transcription while sparing host nucleic acid synthesis.^[10]^[8]

Class-specific variations

Reverse-transcriptase inhibitors (RTIs) exhibit class-specific variations in their mechanisms of interaction with the reverse transcriptase (RT) enzyme, diverging from the core polymerization process where natural dNTPs are incorporated into nascent DNA.^[1] Nucleoside analogs, classified as nucleoside reverse transcriptase inhibitors (NRTIs), function through competitive inhibition by mimicking natural deoxynucleoside triphosphates and serving as chain terminators upon incorporation into the viral DNA chain, lacking the 3'-hydroxyl group necessary for further phosphodiester bond formation.^[11] In contrast, non-nucleoside reverse transcriptase inhibitors (NNRTIs) act as non-competitive inhibitors by binding allosterically to a hydrophobic pocket approximately 10 Å from the active site, inducing conformational changes that distort the enzyme's polymerase domain and prevent proper substrate alignment.^[12]^[13] A key distinction within nucleoside-based inhibitors lies in their activation requirements: NRTIs, derived from nucleosides, must undergo sequential intracellular phosphorylation by host kinases to their active triphosphate forms before competing with natural dNTPs, whereas nucleotide reverse transcriptase inhibitors (NtRTIs) are nucleotide monophosphate analogs that bypass the initial phosphorylation step, entering cells as pre-activated forms.^[14]^[11] NNRTIs specifically target a conserved hydrophobic pocket adjacent to the RT active site, stabilizing an inactive enzyme conformation that inhibits both RNA- and DNA-dependent DNA polymerization activities.^[12] Emerging nucleoside reverse transcriptase translocation inhibitors (NRTTIs) incorporate into the DNA primer but feature a 4'-substituent that sterically hinders the post-incorporation translocation step, delaying the enzyme's movement to the next template position and blocking subsequent nucleotide addition.^[15]^[16] These structural impacts further differentiate RTI classes: allosteric NNRTIs lock RT in a rigid, inactive form that reduces catalytic efficiency without directly competing for the nucleotide-binding site, while portmanteau inhibitors, designed as dual-action agents, combine RT inhibition—often via nucleoside analog mechanisms—with integrase strand transfer inhibition through separate binding domains, targeting multiple viral lifecycle stages.^[13]^[17]^[18]

Classification

Nucleoside/nucleotide analogs (NRTIs/NtRTIs)

Nucleoside reverse transcriptase inhibitors (NRTIs) and nucleotide reverse transcriptase inhibitors (NtRTIs) represent the foundational class of substrate-competitive reverse transcriptase inhibitors, structurally resembling natural nucleosides or nucleotides to interfere with viral DNA synthesis. NRTIs, such as zidovudine (AZT) and lamivudine (3TC), are nucleoside analogs that lack a 3'-hydroxyl group on the deoxyribose moiety, mimicking deoxynucleosides but preventing further chain elongation once incorporated.^[1] These prodrugs enter host cells via passive diffusion or carrier-mediated transport and must undergo sequential phosphorylation by cellular kinases—thymidine kinase for the first step, followed by thymidylate kinase and nucleoside diphosphate kinase—to form the active triphosphate form that competes with endogenous deoxynucleotide triphosphates (dNTPs) for binding to the reverse transcriptase active site.^[1] In contrast, NtRTIs like tenofovir disoproxil fumarate (TDF) are nucleotide monophosphate analogs already bearing a phosphonate group, bypassing the initial kinase-dependent phosphorylation and requiring only two additional steps to reach their active diphosphate form, which enhances intracellular accumulation and potency in certain cell types.^[11] The mechanism of action for both NRTIs and NtRTIs involves competitive incorporation into the growing viral DNA chain during reverse transcription, where the absence of a 3'-OH group on the analog prevents formation of the 5'-3' phosphodiester bond, resulting in premature chain termination and inhibition of viral replication.^[1] This substrate analog approach exploits the reverse transcriptase's lack of proofreading activity, leading to stalled DNA synthesis without affecting host polymerases to the same extent due to differences in substrate affinity and cellular dNTP concentrations.^[19] Zidovudine (AZT), the first FDA-approved RTI in 1987, exemplifies this class as a thymidine analog that was pivotal in establishing NRTIs as a cornerstone of HIV therapy.^[20] Other key NRTIs include emtricitabine (FTC), a cytidine analog with high potency and a favorable resistance profile when combined with other agents, and lamivudine (3TC), which shares structural similarity to FTC but is dosed differently for specific indications.^[21] For NtRTIs, tenofovir alafenamide (TAF), a prodrug of tenofovir, offers improved pharmacokinetics with targeted delivery to lymphocytes, reducing plasma exposure and associated renal toxicity compared to TDF.^[22] Due to the shared reliance on reverse transcriptase for replication in hepatitis B virus (HBV), which utilizes an RNA-dependent DNA polymerase akin to HIV's enzyme, several NRTIs and NtRTIs have been approved for HBV management. Lamivudine (as Epivir-HBV) was the first oral nucleoside analog approved by the FDA in 1998 for chronic HBV in adults, demonstrating viral suppression through chain termination similar to its HIV activity.^[23] Tenofovir disoproxil fumarate (Viread) received FDA approval for chronic HBV in 2008, providing durable suppression in treatment-naive and lamivudine-resistant patients, while tenofovir alafenamide (Vemlidy) was approved in 2016 as a less nephrotoxic alternative for compensated liver disease.^[24] These approvals highlight the dual utility of nucleoside/nucleotide analogs across retroviral and hepadnaviral infections.^[11]

Non-nucleoside inhibitors (NNRTIs)

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) represent a chemically diverse class of antiretroviral agents that target HIV-1 reverse transcriptase through non-competitive inhibition. These compounds, including structures such as diarylpyrimidines (e.g., etravirine), benzoxazinones (e.g., efavirenz), and dipyridodiazepinones (e.g., nevirapine), bind to a hydrophobic allosteric pocket approximately 10 Å from the enzyme's active site.^[25]^[26] This binding induces a conformational change in the reverse transcriptase, distorting its p66 subunit and rigidifying the thumb and fingers subdomains, which prevents the polymerase domain from undergoing the necessary movements for DNA polymerization.^[27] Unlike nucleoside analogs, NNRTIs do not require intracellular activation and act allosterically to lock the enzyme in an inactive state.^[28] Key NNRTIs include nevirapine, approved in 1996 as the first in its class, featuring a dipyridodiazepinone core with high oral bioavailability (>90%) and a long half-life (25-45 hours).^[26]^[29] Efavirenz, approved in 1998, is a benzoxazinone derivative that became a cornerstone of initial HIV therapy due to its potency (Ki = 2.93 nM) and once-daily dosing.^[29] Etravirine, a second-generation diarylpyrimidine approved in 2008, offers improved flexibility in its horseshoe-like conformation, enabling activity against some mutant strains resistant to earlier NNRTIs.^[29] Doravirine, a third-generation agent approved in 2018, exhibits exceptional potency (EC50 = 0.6-10 nM across subtypes) and a high genetic barrier to resistance, making it suitable for treatment-naïve and experienced patients.^[30]^[29] NNRTIs demonstrate high potency at low doses, often requiring only 100-600 mg daily, with rapid absorption (Tmax 1-5 hours) and extensive hepatic metabolism primarily via CYP3A4 and CYP2B6 isoforms.^[26]^[30] This metabolism leads to significant drug-drug interactions; for instance, efavirenz and nevirapine induce CYP3A4 autoinduction, reducing their own exposure over time and potentially altering levels of coadministered drugs like protease inhibitors.^[26] Advantages of NNRTIs include the absence of need for phosphorylation, simplifying their pharmacokinetics compared to nucleoside analogs, and their ability to achieve substantial viral load reductions (e.g., >1 log10 copies/mL within weeks in efavirenz-based regimens).^[26]^[27] These properties contribute to their role in combination therapies for effective HIV suppression.^[27]

Emerging classes (NRTTIs and portmanteau)

Nucleoside reverse transcriptase translocation inhibitors (NRTTIs) represent an innovative subclass of reverse transcriptase inhibitors that differ from traditional nucleoside analogs by blocking the translocation step of the reverse transcriptase enzyme after nucleotide incorporation into the viral DNA chain, thereby halting further elongation more effectively.^[15] This mechanism provides a higher genetic barrier to resistance compared to standard NRTIs, as it requires multiple mutations for viral escape.^[31] A leading example is islatravir (MK-8591), a deoxyadenosine analog developed by Merck, which has demonstrated potent antiretroviral activity in preclinical and early clinical studies.^[32] Development of islatravir faced a temporary pause in late 2021 due to concerns over reduced lymphocyte counts observed in some participants, leading to a U.S. FDA clinical hold; however, trials resumed in September 2022 with a modified lower-dose regimen (0.5 mg or 0.75 mg daily oral).^[33] By 2025, phase 3 trials, such as those evaluating once-daily oral combinations with doravirine (DOR/ISL), have shown non-inferior virologic suppression to standard three-drug regimens in virologically suppressed adults, with ongoing studies exploring long-acting subcutaneous implants and vaginal rings for HIV treatment and prevention to reduce daily pill burden.^[34] Another NRTTI candidate, MK-8527, is currently in phase 3 clinical trials as of 2025 for once-monthly oral HIV-1 pre-exposure prophylaxis (PrEP), with similar translocation inhibition properties.^[35] Portmanteau inhibitors, also known as dual-action or hybrid inhibitors, are multifunctional molecules engineered to simultaneously target HIV reverse transcriptase and integrase, aiming to enhance efficacy and simplify regimens by addressing multiple viral life cycle stages in a single compound.^[36] These agents typically incorporate structural motifs from established RT inhibitors (such as HEPT derivatives) and integrase strand transfer inhibitors (like raltegravir analogs) to bind both enzymes, potentially increasing the resistance barrier through synergistic inhibition.^[37] Examples include rationally designed hybrids such as 3-hydroxy-3-phenylpropanoate ester-AZT conjugates and caffeoyl-anilide scaffolds, which have shown promising dual inhibitory activity in biochemical assays but remain in early investigational stages without advanced clinical progression as of 2025.^[38]^[39] Azvudine, an NRTI-like nucleoside analog, exemplifies emerging applications beyond traditional HIV therapy; approved in China in 2021 for treating high-viral-load HIV-1 infections in combination regimens, it gained conditional approval in 2022 for mild-to-moderate COVID-19 due to its inhibition of viral RNA-dependent RNA polymerase, though its HIV role continues to expand in real-world use.^[40]^[41] Overall, these emerging classes offer advantages like extended dosing intervals and reduced resistance potential, supporting efforts to improve long-term adherence in HIV management.^[42]

Clinical Applications

HIV treatment and prevention

Reverse-transcriptase inhibitors (RTIs) form the backbone of first-line antiretroviral therapy (ART) for HIV treatment in adults and adolescents, typically combined with an integrase strand transfer inhibitor such as dolutegravir. According to the 2023 ART clinical guidelines aligned with World Health Organization (WHO) recommendations, the preferred regimen is tenofovir disoproxil fumarate (TDF) plus lamivudine (3TC) or emtricitabine (FTC) with dolutegravir (DTG), known as TLD or equivalent formulations, initiated as soon as possible after diagnosis regardless of CD4 count or viral load.^[43] This combination achieves rapid viral suppression in over 90% of adherent patients within six months, improving immune function and reducing transmission risk.^[44] Alternative backbones, such as abacavir (ABC) plus 3TC, may be used in cases of tenofovir intolerance, but TDF- or tenofovir alafenamide (TAF)-based pairs remain standard due to their efficacy and availability in fixed-dose combinations.^[44] In HIV prevention, oral pre-exposure prophylaxis (PrEP) regimens rely heavily on nucleoside RTIs, with Truvada (TDF/FTC) as the established option, reducing HIV acquisition risk by approximately 99% among adherent users engaging in sexual activity.^[45] Daily dosing is recommended, with protective efficacy building over 7 days for receptive anal sex and 21 days for receptive vaginal sex or injection drug use.^[46] Descovy (TAF/FTC), an alternative for those at risk primarily through sex (excluding cisgender women), offers comparable efficacy but with a more favorable renal safety profile, showing statistically significant improvements in estimated glomerular filtration rate (eGFR) and reduced proximal tubular dysfunction compared to Truvada in the DISCOVER trial.^[47] This makes Descovy preferable for individuals with baseline renal concerns, though monitoring remains essential for both.^[47] For pediatric and special populations, RTI-based regimens require weight- and age-based dosing adjustments to optimize efficacy and minimize toxicity. In infants and children, preferred first-line ART includes two NRTIs such as zidovudine (ZDV) plus 3TC or ABC plus 3TC, combined with DTG for those weighing ≥3 kg, with dispersible tablets facilitating administration in young children.^[48] Neonates exposed to HIV perinatally receive ZDV monotherapy for 2-6 weeks if low-risk (maternal viral load <50 copies/mL) or triple therapy (ZDV + 3TC + nevirapine) if high-risk, reducing transmission rates to <2%.^[48] In prevention of mother-to-child transmission (PMTCT), pregnant individuals with HIV are prescribed ART including a dual NRTI backbone like TDF/FTC or TAF/FTC plus DTG from conception, achieving MTCT rates below 1% with viral suppression.^[49] Adolescents follow adult dosing (e.g., ≥35 kg for TDF/FTC + DTG), with adjustments for pubertal changes or co-morbidities.^[48] Monitoring RTI-containing ART involves regular assessment of virologic and immunologic response to ensure long-term success. The primary target is sustained viral suppression, defined as HIV RNA <200 copies/mL, confirmed by two measurements at least 3 months apart after ART initiation, with optimal suppression below the assay's limit of detection (typically <20-50 copies/mL).^[50] CD4 recovery is expected at 50-150 cells/mm³ in the first year, averaging 50-100 cells/mm³ annually thereafter until stabilization above 500 cells/mm³, guiding prophylaxis against opportunistic infections.^[50] Viral load testing occurs at baseline, 4-12 weeks post-initiation, then every 3-6 months, with more frequent checks in pediatrics or high-risk cases to detect early failure.^[51]

Hepatitis B management

Reverse-transcriptase inhibitors (RTIs), particularly nucleoside and nucleotide analogs, play a central role in managing chronic hepatitis B virus (HBV) infection by targeting the viral reverse transcriptase, a key enzyme in HBV replication. These agents inhibit the reverse transcription of pregenomic RNA into DNA, thereby preventing the formation and amplification of covalently closed circular DNA (cccDNA), the persistent viral reservoir in infected hepatocytes. Approved RTIs for HBV include lamivudine, adefovir dipivoxil, tenofovir disoproxil fumarate (TDF), and tenofovir alafenamide (TAF), which are nucleotide/nucleoside analogs that compete with natural substrates to chain-terminate viral DNA synthesis. In comparison, entecavir, another nucleoside analog, exhibits high potency against HBV polymerase (with reverse transcriptase activity) but is often preferred over older RTIs like lamivudine and adefovir due to a lower risk of resistance development.^[52]^[1]^[53]^[54] The primary treatment goals for chronic HBV using RTIs are to achieve profound suppression of HBV DNA to undetectable levels in serum, normalize alanine aminotransferase (ALT) levels to reduce hepatic inflammation, and prevent disease flares or progression to cirrhosis and hepatocellular carcinoma. These objectives are pursued through long-term or indefinite oral therapy, as current RTIs do not eradicate cccDNA, leading to high relapse rates upon discontinuation. For instance, tenofovir-based regimens are favored for their high genetic barrier to resistance, enabling sustained viral suppression in most patients without frequent monitoring for breakthroughs. Guidelines from the American Association for the Study of Liver Diseases (AASLD; 2025), European Association for the Study of the Liver (EASL; 2025), and WHO (2024) have expanded treatment criteria to include a broader range of patients, such as those with cirrhosis (regardless of ALT or HBV DNA), immune-active disease (elevated ALT and HBV DNA >2,000 IU/mL), immune-tolerant phase if age >40 years or significant fibrosis (≥F2), family history of hepatocellular carcinoma, or other risk factors, emphasizing entecavir or tenofovir as first-line options over lamivudine or adefovir monotherapy due to resistance concerns.^[55]^[56]^[57]^[58] In patients with HBV and HIV co-infection, dual therapy incorporating RTIs addresses both viruses simultaneously, with tenofovir combined with lamivudine (or emtricitabine) as a core component of antiretroviral therapy (ART) to suppress HBV replication while treating HIV. This approach leverages the overlapping activity of these agents against both retroviral reverse transcriptases, achieving HBV DNA suppression in over 90% of cases when integrated into fully suppressive ART regimens, though lifelong treatment is typically required to prevent HBV flares. AASLD and EASL guidelines specifically endorse tenofovir-based ART for co-infected individuals to minimize resistance and hepatic complications.^[59]^[60]

Investigational and other uses

Reverse-transcriptase inhibitors (RTIs) have been investigated for applications beyond HIV and hepatitis B, particularly in treating other viral infections associated with RNA-dependent polymerases or retroviral mechanisms. Azvudine, a nucleoside analog RTI approved in China in 2022, targets the RNA-dependent RNA polymerase of SARS-CoV-2, which shares functional similarities with reverse transcriptase in its template-switching activity. Phase 3 clinical trials demonstrated that azvudine reduced hospitalization duration and rates in patients with mild-to-moderate COVID-19, with one study reporting a significant decrease in all-cause mortality by 28 days compared to standard care.^[61]^[62]^[63] Real-world data from 2024-2025 further confirmed its efficacy in shortening viral clearance time and improving clinical outcomes during Omicron variant surges, positioning it as a potential oral option for acute respiratory viral infections.^[64]^[65] In the context of human T-lymphotropic virus type 1 (HTLV-1), zidovudine combined with interferon-alpha has shown substantial activity against adult T-cell leukemia/lymphoma (ATLL), a retroviral malignancy driven by HTLV-1 reverse transcriptase. This regimen induces high response rates in leukemic subtypes, with a global meta-analysis establishing it as the gold standard first-line therapy due to improved survival outcomes over single-agent chemotherapy.^[66]^[67] Phase 2 trials combining zidovudine with other agents, such as belinostat, continue to explore enhanced efficacy in HTLV-1-associated ATLL, highlighting the role of RT inhibition in controlling proviral load and leukemic progression.^[68]^[69] RTIs have seen limited investigational use in other retroviral models, particularly simian immunodeficiency virus (SIV) infections in nonhuman primates, which serve as preclinical systems for studying retroviral latency and cure strategies akin to HIV. In SIV-infected rhesus macaques, early initiation of RTI-containing antiretroviral regimens has been employed to model viral suppression and reservoir persistence, providing insights into post-treatment control without eradicating the virus entirely.^[70]^[71] These models demonstrate the challenges of RTI penetration into sanctuary sites like the central nervous system, informing rare retroviral infections in humans, though clinical translation remains exploratory. Emerging research focuses on long-acting nucleoside reverse transcriptase translocation inhibitors (NRTTIs), such as MK-8527, which offer potential for broad-spectrum antiviral activity through extended dosing intervals and improved pharmacokinetics. Preclinical and phase 1 data indicate MK-8527's potency against HIV-1 reverse transcriptase, with ongoing trials evaluating its role in long-acting formulations for PrEP and treatment, potentially extending to other RNA viruses.^[15]^[72] For hepatitis D virus (HDV) co-infection with HBV, investigational trials as of 2025 incorporate NRTIs like tenofovir as a backbone alongside novel agents, such as capsid inhibitors, to suppress HBV replication and indirectly control HDV viremia in compensated liver disease patients.^[73] These approaches aim to achieve functional cure in HBV/HDV dual infections, with phase 2 studies reporting improved virologic responses when NRTIs are intensified with entry or assembly inhibitors.^[74]

Resistance Mechanisms

NRTI/NtRTI resistance

Resistance to nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs/NtRTIs) in HIV primarily arises through two main mechanisms: discrimination and excision, both mediated by mutations in the reverse transcriptase (RT) enzyme that alter its interaction with these drugs. Discrimination involves mutations that reduce the enzyme's affinity for the analog triphosphate compared to the natural deoxyribonucleotide triphosphate (dNTP), allowing RT to preferentially incorporate the natural substrate. A classic example is the M184V mutation in the RT active site, which decreases incorporation of lamivudine and emtricitabine by up to 100-fold while only modestly affecting viral replication fitness. This mutation exemplifies kinetic discrimination, where the altered geometry of the dNTP-binding pocket favors dNTPs over NRTI triphosphates. The excision mechanism, conversely, enhances the removal of the incorporated NRTI monophosphate from the DNA primer terminus via phosphorolysis, using ATP as a pyrophosphate donor to reverse the polymerization step. Thymidine analog mutations (TAMs), such as M41L, D67N, K70R, L210W, T215Y/F, and K219Q/E, confer resistance to zidovudine and other thymidine analogs by repositioning RT to facilitate this excision, increasing the removal rate by 10- to 100-fold depending on the drug. These mutations often accumulate sequentially, with T215Y/F being particularly potent when combined with others, leading to high-level resistance. Beyond these, multidrug resistance complexes like the Q151M pathway (involving A62V, V75I, F77L, and F116Y alongside Q151M) impair incorporation and enhance excision for multiple NRTIs, including zidovudine, didanosine, and stavudine, reducing susceptibility by over 20-fold across the class. The K65R mutation, common with tenofovir and abacavir, primarily acts via discrimination by altering the RT's ability to position the analog's sugar ring, resulting in 2- to 5-fold decreased incorporation efficiency. These mutations can overlap; for instance, K65R may coexist with TAMs, compounding resistance profiles. Detection of NRTI/NtRTI resistance typically relies on genotypic assays that sequence the RT gene to identify these mutations, correlating them with phenotypic assays measuring the 50% inhibitory concentration (IC50) shift, where a >1.5-fold increase indicates reduced drug susceptibility. Clinically, such resistance leads to cross-resistance within the NRTI/NtRTI class—for example, M184V confers hypersusceptibility to tenofovir but resistance to lamivudine—necessitating regimen switches to integrase inhibitors or boosted protease inhibitors to maintain viral suppression. In treatment-experienced patients, up to 50-70% may harbor TAMs or Q151M complexes, underscoring the need for resistance testing to guide therapy.

NNRTI resistance

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) exert their antiviral effect by binding to a hydrophobic pocket near the active site of HIV-1 reverse transcriptase (RT), inducing conformational changes that inhibit enzyme activity. Resistance to NNRTIs primarily arises from mutations in this binding pocket, which alter the pocket's structure and reduce drug affinity. The K103N mutation, one of the most common, substitutes lysine with asparagine at position 103, disrupting key electrostatic interactions between the RT and NNRTIs like efavirenz (EFV), leading to a 20- to 50-fold increase in the 50% inhibitory concentration (IC₅₀) for first-generation NNRTIs. Similarly, the Y181C mutation replaces tyrosine with cysteine at position 181, eliminating π-π stacking interactions essential for binding nevirapine (NVP) and other NNRTIs, resulting in over 50-fold resistance to NVP. These single-point mutations confer high-level resistance due to the low genetic barrier of the NNRTI binding site, allowing rapid selection under drug pressure.^[75] First-generation NNRTIs, such as EFV and NVP, exhibit a low barrier to resistance, with mutations like K103N and Y181C emerging quickly in treatment-naïve patients, often within months of initiation. In contrast, second-generation NNRTIs like etravirine (ETR) and rilpivirine (RPV) possess higher genetic barriers, maintaining activity against viruses harboring K103N or Y181C through flexible binding that accommodates pocket distortions; for instance, ETR retains susceptibility against K103N isolates with IC₅₀ values below 10 nM in many cases. However, cross-resistance remains a challenge, as combinations like K103N + Y181C can confer broad resistance across the class.^[29]^[76] Certain NNRTI resistance mutations impose a fitness cost on the virus, reducing RT enzymatic efficiency and replication capacity in the absence of drug, which can facilitate reversion to wild-type upon treatment interruption. The L100I mutation, often selected by EFV, slightly impairs viral fitness (relative replication fitness of 0.93 compared to wild-type), while the double mutant K103N + L100I exhibits even greater impairment (relative fitness of 0.84), though this can be partially compensated by secondary mutations like L74V. These fitness deficits contribute to the lower clinical prevalence of L100I despite its potency in conferring resistance.^[77] Management of NNRTI resistance involves genotypic testing to guide regimen optimization, with strategies including switching to second-generation NNRTIs if susceptibility persists or transitioning to alternative classes like integrase strand transfer inhibitors (INSTIs) or boosted protease inhibitors to achieve virologic suppression. In treatment-experienced patients, ETR-based regimens can salvage up to 50% of cases with single NNRTI mutations. Transmitted NNRTI resistance remains a concern, with 2023 surveillance data indicating an intermediate prevalence of 7.8% overall for pretreatment drug resistance, predominantly driven by NNRTI mutations like K103N in newly diagnosed individuals.^[78]^[79]^[80]

Resistance in emerging classes

Emerging classes of reverse transcriptase inhibitors, such as nucleoside reverse transcriptase translocation inhibitors (NRTTIs) and portmanteau inhibitors, demonstrate enhanced resistance profiles compared to traditional NRTIs and NNRTIs, primarily due to novel mechanisms that impede common viral escape strategies. NRTTIs like islatravir function by delaying the translocation step in reverse transcription after nucleotide incorporation, which reduces the efficacy of the viral excision mechanism responsible for resistance to conventional NRTIs.^[81] This delayed translocation limits the virus's ability to remove the inhibitor from the DNA chain, thereby elevating the genetic barrier to resistance.^[81] The primary resistance mutation to islatravir is M184V in the reverse transcriptase enzyme, which confers only a modest 6- to 7-fold reduction in susceptibility, in contrast to the high-level resistance (often >100-fold) observed with this mutation against lamivudine or emtricitabine.^[81] Preclinical models indicate slower emergence of M184V under islatravir selection pressure compared to approved NRTIs, attributed to the inhibitor's differentiated binding and translocation dynamics that maintain partial antiviral activity even in mutated strains.^[82] A 2022 study highlighted islatravir's high barrier to resistance, requiring multiple mutations (e.g., M184V combined with A114S) to achieve substantial (>30-fold) reductions in potency, underscoring its robust preclinical profile against wild-type and pre-existing NRTI-resistant HIV-1 variants.^[81] Portmanteau inhibitors, which combine reverse transcriptase inhibition with targeting of integrase or other viral enzymes in a single molecule, further raise the resistance barrier through dual-action mechanisms that disrupt multiple stages of the HIV lifecycle.^[36] By necessitating simultaneous mutations in both the reverse transcriptase and integrase genes for full evasion, these agents reduce the probability of viable resistant variants emerging, as compensatory changes in one enzyme often impair function in the other.^[36] However, integrase mutations, such as those affecting the catalytic DDE motif (Asp64, Asp116, Glu152), can compound resistance to the reverse transcriptase component, potentially diminishing overall efficacy if cross-talk between enzymes facilitates viral adaptation.^[36] Ongoing preclinical and clinical trials emphasize combining these emerging classes with existing antiretrovirals to further mitigate resistance risks, with monitoring focused on mutation accumulation in treatment-experienced patients.^[83] For instance, islatravir paired with doravirine or lenacapavir shows complementary profiles that maintain suppression against NRTI-experienced strains, highlighting the potential for synergistic barriers in real-world applications.^[83]

Adverse Effects

Short-term side effects

Reverse-transcriptase inhibitors (RTIs) are associated with various short-term side effects that are typically acute and reversible upon discontinuation or adjustment of therapy. These effects vary by drug class and individual agent, often including gastrointestinal, neurological, dermatological, and renal symptoms that emerge within weeks to months of initiation.^[84] Nucleoside/nucleotide reverse-transcriptase inhibitors (NRTIs/NtRTIs) commonly cause gastrointestinal disturbances and headaches. For zidovudine (AZT), nausea and vomiting occur in 18.8% to 89% of patients, headaches in 15% to 38%, and diarrhea in 7% to 78%.^[85] Tenofovir disoproxil fumarate (TDF) is linked to renal issues, including proximal tubulopathy in 2% to 5% of users, manifesting as acute kidney injury or tubular dysfunction.^[86] Non-nucleoside reverse-transcriptase inhibitors (NNRTIs) frequently induce dermatological and central nervous system (CNS) effects. Nevirapine causes rash in 15% to 20% of patients, with a risk of severe hypersensitivity reactions such as Stevens-Johnson syndrome in approximately 0.3%.^[87]^[88] Efavirenz is associated with CNS symptoms, including vivid dreams and insomnia, reported in over 50% of patients.^[89] Among emerging RTIs, islatravir (MK-8591) has shown mild gastrointestinal upset, such as diarrhea, in clinical trials, alongside headache and decreased lymphocyte count as common adverse events. Development of once-monthly islatravir for HIV prevention was discontinued due to lymphocyte declines, though lower-dose formulations are in Phase 3 for treatment as of 2025.^[90]^[90] Management of these short-term effects involves dose adjustments, symptomatic treatment, or switching agents to mitigate risks. For instance, transitioning from TDF to tenofovir alafenamide (TAF) reduces renal and bone-related effects due to TAF's lower plasma exposure and improved intracellular delivery.^[91] Discontinuation of the offending drug is recommended for severe reactions like rash or tubulopathy, with prompt substitution to an alternative RTI.^[1]

Long-term toxicities

Long-term toxicities associated with reverse-transcriptase inhibitors (RTIs), particularly nucleoside reverse-transcriptase inhibitors (NRTIs), arise primarily from prolonged exposure and can involve mitochondrial dysfunction, skeletal and renal impairment, hepatic reactivation in specific infections, and metabolic alterations affecting cardiovascular health.^[92] These effects necessitate ongoing monitoring, such as regular assessment of lactate levels, bone mineral density (BMD), renal function, and lipid profiles, with mitigation strategies including drug switches to less toxic alternatives.^[93] Mitochondrial toxicity is a key concern with NRTIs, stemming from their inhibition of mitochondrial DNA polymerase gamma, which leads to depleted mitochondrial DNA and impaired cellular energy production.^[92] This manifests as lipodystrophy (subcutaneous fat loss, especially in the face and limbs), peripheral neuropathy, myopathy, and severe lactic acidosis.^[92] Stavudine, a thymidine analog NRTI, was particularly implicated, with high rates of lipodystrophy (up to 20-30% in long-term users) and rare but fatal lactic acidosis, prompting its discontinuation in many guidelines by the mid-2010s due to these risks.^[92] With modern NRTIs like tenofovir or abacavir, the incidence of symptomatic lactic acidosis has dropped to less than 1% (approximately 1-10 cases per 1,000 patient-years), reflecting improved safety profiles and reduced thymidine analog use.^[94] Bone and renal toxicities are prominent with nucleotide NRTIs such as tenofovir disoproxil fumarate (TDF), which can impair proximal tubular function and phosphate reabsorption, leading to Fanconi syndrome, reduced glomerular filtration rate, and BMD loss.^[95] Long-term TDF use is associated with 1-3% greater BMD reduction at the hip and spine compared to other NRTIs in the first year of therapy, with cumulative losses reaching 5-10% over 5 years in some cohorts, particularly among treatment-naïve individuals or those with risk factors like low body weight.^[96] These effects contribute to increased fracture risk, though clinical significance varies.^[96] Switching to tenofovir alafenamide (TAF), a prodrug with lower plasma concentrations, mitigates these risks, showing BMD stabilization or gains (e.g., +1-2% at the spine after 48 weeks) and reduced renal toxicity.^[96] In patients with hepatitis B virus (HBV) mono-infection treated with NRTIs like lamivudine or tenofovir, discontinuation can trigger severe HBV reactivation and hepatic flares due to rebound viral replication.^[93] This occurs in rates of approximately 5-30% post-cessation, with lower incidence (around 5%) observed in recent studies following tenofovir discontinuation, particularly in HIV/HBV coinfected patients as of 2025.^[93]^[97] This can potentially lead to decompensation, acute liver failure, or death if not promptly addressed. Close monitoring of alanine aminotransferase and HBV DNA levels (every 1-3 months initially) is essential, with immediate reinitiation of therapy recommended upon flare detection to prevent life-threatening outcomes.^[93] Cardiovascular risks from non-nucleoside RTIs (NNRTIs), such as efavirenz, involve dyslipidemia, including elevated triglycerides and low-density lipoprotein cholesterol, which may accelerate atherosclerosis over years of use.^[98] Efavirenz-based regimens are linked to a 10-20% increase in total cholesterol and triglycerides compared to integrase inhibitors, though the overall cardiovascular disease risk with RTIs remains lower than with older protease inhibitors.^[98] Switching to newer NNRTIs like doravirine can improve lipid profiles, reducing these long-term concerns.^[99]

History and Development

Early discovery and approval

The discovery of reverse transcriptase as a therapeutic target for retroviruses stemmed from foundational work in the early 1970s. In 1970, Howard Temin and David Baltimore independently identified the enzyme reverse transcriptase in RNA tumor viruses, demonstrating that genetic information could flow from RNA to DNA, challenging the prevailing central dogma of molecular biology.^[100]^[101] This breakthrough, recognized with the 1975 Nobel Prize in Physiology or Medicine shared with Renato Dulbecco, highlighted reverse transcriptase as a key vulnerability in retroviral replication, paving the way for targeted inhibitors.^[100] The first reverse-transcriptase inhibitor, zidovudine (AZT), originated from earlier anti-cancer research but was repurposed for HIV. Synthesized in 1964 by Jerome Horwitz at the National Cancer Institute (NCI) as a potential chemotherapeutic agent, AZT initially showed limited efficacy against leukemia and was shelved.^[102]^[2] In 1985, following in vitro studies demonstrating its inhibition of HIV reverse transcriptase, NCI-initiated phase I clinical trials tested AZT in patients with AIDS, revealing improved immune function and viral suppression at tolerable doses.^[103] These early trials marked the shift toward antiretroviral therapy amid the escalating HIV epidemic. AZT received accelerated U.S. Food and Drug Administration (FDA) approval on March 19, 1987, as the first antiretroviral drug for treating AIDS and AIDS-related conditions, based on a pivotal placebo-controlled trial showing reduced mortality and disease progression.^[104]^[102] Subsequent nucleoside reverse-transcriptase inhibitors (NRTIs) followed: didanosine (ddI) in October 1991 for patients intolerant to or progressing on AZT, and zalcitabine (ddC) in June 1992 under the FDA's accelerated approval pathway for advanced HIV disease.^[105]^[106] Early use of these inhibitors as monotherapy revealed significant limitations. AZT monotherapy often failed due to rapid emergence of HIV resistance mutations in reverse transcriptase, with clinical deterioration observed within months in many patients during the late 1980s and early 1990s.^[107] Additionally, high doses of AZT (up to 1200 mg daily) caused substantial toxicity, including severe anemia from bone marrow suppression, affecting up to 30% of recipients and necessitating transfusions or dose reductions.^[2]^[108] The success of NRTIs against HIV prompted their exploration for other retroviral infections, notably hepatitis B virus (HBV). Lamivudine, approved by the FDA in 1995 for HIV as an NRTI, demonstrated potent activity against HBV reverse transcriptase in clinical studies, leading to its approval in 1998 specifically for chronic hepatitis B treatment, where it achieved viral suppression in over 90% of patients within weeks.^[109]^[110] The late 1990s also saw the approval of the first non-nucleoside reverse transcriptase inhibitors (NNRTIs), expanding RTI options. Nevirapine received FDA approval in June 1996, followed by delavirdine in April 1997 and efavirenz in September 1998. These agents, combined with NRTIs, were key components of the initial highly active antiretroviral therapy (HAART) regimens introduced around 1996, which markedly reduced HIV-related mortality and morbidity.^[111]

Modern advancements and future directions

Since the early 2000s, the development of second- and third-generation non-nucleoside reverse transcriptase inhibitors (NNRTIs) has significantly improved treatment options for HIV patients with resistance to first-generation agents like efavirenz. Etravirine, approved by the U.S. Food and Drug Administration (FDA) in January 2008, was the first such agent, demonstrating efficacy in treatment-experienced adults harboring NNRTI-resistant strains through its ability to bind a more flexible pocket in the reverse transcriptase enzyme.^[112] Rilpivirine, approved by the FDA in May 2011 for treatment-naïve adults, offers a favorable tolerability profile with once-daily dosing and activity against certain efavirenz-resistant mutants, reducing viral loads comparably to efavirenz in phase 3 trials.^[113] Doravirine, approved by the FDA in August 2018, represents a third-generation NNRTI with a higher barrier to resistance, maintaining potency against key mutants like K103N and Y181C, and showing non-inferior virologic suppression in combination regimens for both naïve and virologically suppressed patients.^[114] These agents have expanded salvage therapy options, with real-world data confirming their role in regimens for multidrug-resistant HIV.^[115] Advancements in long-acting formulations have addressed adherence challenges associated with daily oral therapy. The FDA approved cabotegravir, an integrase strand transfer inhibitor, in combination with rilpivirine as a monthly intramuscular injection (Cabenuva) in January 2021 for virologically suppressed adults, marking the first complete long-acting injectable regimen with sustained viral suppression rates exceeding 90% at 48 weeks in phase 3 studies.^[116] This every-two-month dosing option, expanded in 2022, further improves convenience without compromising efficacy.^[117] Islatravir, a nucleoside reverse transcriptase translocation inhibitor (NRTTI), is under investigation in long-acting formats, including subcutaneous implants and once-weekly oral combinations with doravirine or lenacapavir; phase 3 trials as of 2025 report non-inferior viral suppression and minimal impact on lipids or weight compared to standard three-drug regimens.^[34] These formulations enhance patient retention in care, particularly in resource-limited settings. The scope of reverse transcriptase inhibitors (RTIs) has broadened beyond HIV to other viral infections. Azvudine, a nucleoside analog RTI, received conditional approval in China in July 2022 for mild-to-moderate COVID-19, where it inhibits SARS-CoV-2 RNA-dependent RNA polymerase by chain termination, reducing hospitalization risks and viral clearance time in real-world studies of over 1,000 patients.00117-5.pdf) Next-generation NRTTIs, such as islatravir, are being explored for their potential to target HIV latency models; preclinical data indicate that NRTTIs with prolonged intracellular retention may enhance reservoir reduction when combined with latency-reversing agents, though clinical translation remains in early phases as of 2025.^[118] Looking ahead, artificial intelligence (AI) is accelerating the design of dual RTIs that target both the polymerase and RNase H domains, with machine learning models predicting novel compounds active against resistant strains and optimizing pharmacokinetics for better bioavailability.^[119] Gene-editing technologies, such as CRISPR/Cas9 targeting CCR5 or HIV proviral DNA, are emerging as adjuncts to RTIs in cure strategies; in animal models, combining dual CRISPR editing with antiretroviral therapy achieved up to 40% higher rates of viral elimination from reservoirs compared to ART alone, paving the way for functional cures in clinical trials by 2025.^[120] These innovations promise more durable suppression and potential eradication of persistent HIV infection.

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