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Non-nucleoside reverse transcriptase inhibitors
(NNRTIs): a brief overview of clinically approved drugs
and combination regimens
Murugesan Vanangamudi1, Sonali Kurup2 and
Vigneshwaran Namasivayam3
The non-nucleoside reverse transcriptase inhibitors (NNRTIs)
are allosteric inhibitors of HIV-1 reverse transcriptase and are
classified into generations depending on their discovery and
resistance profiles. The NNRTIs are used in combination
regimens with antiretroviral agents that target two or more
enzymes in the viral life cycle. The combination regimens
usually include a backbone of two nucleoside or nucleotide
reverse transcriptase inhibitors and a third core agent among
the NNRTIs or protease inhibitors. The combination regimens
are maintained over long durations and consequently lead to
long-term problems, including toxicity, drug-drug interactions,
and increasing costs. This brief overview summarizes the
pharmacokinetic profiles for NNRTIs and NNRTI-based
combination regimens.
Addresses
1
Department of Medicinal and Pharmaceutical Chemistry, Sree
Vidyanikethan College of Pharmacy, Tirupathi, Andhra Pradesh 517102,
India
2
College of Pharmacy, Ferris State University, 220 Ferris Drive, Big
Rapids, MI 49301, USA
3
Pharamceutical Institute, University of Bonn, An der Immenburg 4,
53121 Bonn, Germany
Corresponding author: Namasivayam, Vigneshwaran
(vnamasiv@uni-bonn.de)
Current Opinion in Pharmacology 2020, 54:179–187
This review comes from a themed issue on Anti-infectives
Edited by Leonor Huerta Hernández
For a complete overview see the Issue and the Editorial
Available online 14th November 2020
https://doi.org/10.1016/j.coph.2020.10.009
1471-4892/ã 2020 Elsevier Ltd. All rights reserved.
Introduction
The human immunodeficiency virus (HIV) belongs to the
Retroviridae family. The first case of acquired immune
deficiency syndrome (AIDS) due to HIV was reported in
1981 and was characterized by a rare lung infection of
Pneumocystis carinii pneumonia(PCP) now referred to as
Pneumocystis jirovecii pneumonia. The characteristic fea-
ture of AIDS is almost a devastating immune system
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along with high viral load and low CD4+ T-cell counts
(<200 cells/mL of blood) [1]. A total of 37.9 million
people are HIV-positive globally implying a significant
threat to human health [2]. The reverse transcriptase
(RT) enzyme is an essential part of the replication cycle
of HIV, and reverse-transcribes RNA into DNA [1]. Most
antiretroviral drugs (ARD) treat HIV by targeting RT’s
first step. The RT inhibitors include nucleoside reverse
transcriptase inhibitors (NRTIs), nucleotide reverse tran-
scriptase inhibitors (NtRTIs), and non-nucleoside
reverse transcriptase inhibitors (NNRTIs). The NRTIs
and NtRTIs directly interact with the RT active site. The
NNRTIs are non-competitive and bind to the allosteric
hydrophobic pocket [3]. Over 50 diverse chemical groups
have been identified as NNRTIs targeting RT [4] with
US FDA approvals for nevirapine (NVP, delavirdine
(DLV), efavirenz (EFV), etravirine (ETR), rilpivirine
(RPV), doravirine (DOR) and Russian Ministry of Health
(MoH) approval of elsulfavirine (VM-1500A or ESV) [5]
(Figure 1). Efficacy for the NNRTI drug class is reduced
by mutations within or near the NNRTI binding pocket
(NNIBP). Drug resistance poses a considerable challenge
in anti-HIV-1 drug discovery. Among the approved
NNRTIs drugs, EFV, RPV, and DOR are approved in
combination with NRTIs or integrase strand transfer
inhibitor (INSTI) to overcome viral resistance. The
unique antiretroviral mechanism of action, high specific-
ity, and low toxicity of NNRTIs have allowed continued
use as part of drug combination regimens. The newer
NNRTIs are highly active against mutant strains of HIV-
1 compared to the earlier or more traditional NNRTIs.
According to present national and international guide-
lines, three-drug regimens (3DRs) and two-drug regi-
mens (2DRs) of NNRTI with other antiretroviral agents
are recommended HIV therapies [6,7]. This brief review
covers the therapeutic efficiency aspects of NNRTI-
based mono and combination antiretroviral therapy to
suppress patients with HIV-1 infection.
Traditional NNRTIs
The NNRTI, NVP, demonstrated an EC50 of 63 nM
(range: 14–302 nM) against clinical isolates of different
HIV-1 subtypes and circulating recombinant forms
(CRFs). The NNRTIs are lipophilic and highly plasma
protein-bound. Single-point mutations such as L100I,
K101P, K103N/S, V106A/M, V108I, Y181C/I, Y188C/L/
H, G190A, and M230L in RT enzyme reduces the
Current Opinion in Pharmacology 2020, 54:179–187
180 Anti-infectives
Figure 1
Nevirapine (NVP) Efavirenz (EFV)
O N
NH
F F
F O
N N N Cl
O O
O NH
1996 1997 1998
Delavirdine (DLV)
NH
N O O
N NC
NH N Na
O
S
NH O
O
Chemical structures of NNRTI drugs approved by US FDA and Russian MoH.
inhibitory potency of NVP while using longer duration.
The adverse reactions of NVP produced hepatitis, skin
toxicity, and hypersensitivity reactions, especially Ste-
vens-Johnson syndrome, were observed in clinical prac-
tice. Consequently, NVP is considered too toxic for initial
drug regimens and is considered only as an alternative
agent or no longer recommended [8,9]. A high medication
load (three times daily) followed by severe skin rash and a
low genetic barrier to resistance (e.g. L100I, K103N,
Y181C, and P236L) has led to DLV being withdrawn
from the market. The rash was found to be erythematous,
mildly pruritic, and moderately maculopapular [10,11].
Frequent and persistent mental health issues, including
nightmares and an increased risk of suicidal behavior, are
associated with EFV. Skin rash, hyperlipidemia, and
elevated transaminases are also observed. EFV also has
multiple drug interactions and needs a thorough review of
concomitantly administered drugs. As a result, EFV is
considered an alternative NNRTI for combination anti-
retroviral therapy (cART) and is not considered for inclu-
sion in initial combination regimens. The metabolism for
EFV proceeds via extensive cytochrome P450 (CYP)
mediated oxidative metabolism in liver microsomes
resulting in 7- and 8-hydroxy-efavirenz metabolites and
is associated with varied drug interactions. Resistance to
EFV occurs by point mutation like L100I, K101P,
K103N/S, V106M, V108I, Y181C/I, Y188L, G190S/A,
P225H, and M230L, which occur at the catalytic site of
RT.
Current Opinion in Pharmacology 2020, 54:179–187
Rilpivirine (RPV) Doravirine (DOR)
Cl
N O
N
N NH
F C
F F
2008 2011 2017 2018
Etravirine (ETR) Elsulfavirine (ESV)
Cl Cl
H
F N
O
O S
N
Br O
CH3
US FDA
Russian MoH
Current Opinion in Pharmacology
The agent, ETR is highly effective against wild-type
HIV-1 strains (EC50 1.4–4.8 nM), a panel of 32 clinical
isolates (EC50 0.9–1.8 nmol/L) for CRF strains, and HIV-
1 subtype A, B, C, D, F, and H strains (EC50 1.1–1.7 nmol/
L). The elimination half-life of ETR is 30–40 hour is
relatively long due to the high protein binding (99.9%)
[12,13]. The most common adverse effects seen for ETR
include diarrhea, somnolence, headache, insomnia, psy-
chiatric disorders, and a severe rash. Rare but serious
adverse effects including cardiac dysfunction, stroke,
pancytopenia, hypertriglyceridemia, pancreatitis, psychi-
atric and hepatic abnormalities have also been reported
[14–16]. The metabolism of ETR proceeds via CYP3A4,
CYP2C9, and CYP2C19. Additionally, ETR is a CYP2C9
and CYP2C19 inhibitor requiring dose adjustments based
on drug interactions. The NNRTI, RPV, is taken orally as
once daily with the standard dose of 25 mg recommended
for treatment-naive patients with HIV-1 RNA  100,000
copies/mL. However, RPV is not recommended in
patients with HIV-1 RNA viral loads of >100,000 cop-
ies/mL or a CD4+ count <200 cells/mm3 based on the
lower rates of virologic suppression in patients with these
characteristics during the phase III clinical trial program.
The metabolism for RPV proceeds via CYP3A4 and 3A5
to oxygenated RPV and hydroxy-RPV metabolites. RPV
effectively inhibits a broad spectrum of clinical isolates
from HIV-1 genotypes (A1, C, D, F1, G, H), CRFs (AE,
AG, BG) and group M isolates, including isolates with
resistant mutations (K101E, K103N, Y181C, and G190A).
The E138A/G/K/Q/R mutation in combination with the
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 Approved non-nucleoside transcriptase inhibitors and combination regimens Vanangamudi, Kurup and Namasivayam 181
M184I mutation significantly decreases susceptibility to
RPV as well as ETR [17,18]. Significant drug-drug inter-
actions and pH specific drug absorption have led to
contraindications with proton pump inhibitors and
administration with medium to high-calorie meals for
RPV. It has been associated with neurologic and psychi-
atric side effects, QT prolongation, and dose-limiting
cardiotoxicity due to hERG (the human Ether-a-go-go-
Related Gene) inhibition. However, these side effects are
fewer compared to those observed with EFV.
Recently approved NNRTIs
Doravirine
The NNRTI, DOR has exhibited significant inhibition
against wild-type and mutant HIV-1 (Figure 1). The
mutations, K103N, Y181C, and K103N/Y181C, inhibited
at 95% with concentrations of 43, 27, and 55 nmol/L (18.3,
11.5, and 23.4 ng/mL), respectively of DOR. Excellent
inhibition of single mutant strains including A98 G,
E138A/G/K/Q, G190A, K101E/P, K103S, L100I,
P236L, V106M, V108I, G190A V197D, V90I, Y181V,
Y188H/C is observed. Inhibition is not observed for
V106A, Y188L, or F227L HIV-1 mutants. Clinical trials
for DOR have demonstrated more prolonged antiviral
efficacy in patients while comparing to darunavir/ritonavir
and efavirenz-based regimens in DRIVE-FORWARD,
DRIVE-AHEAD, and DRIVE-SHIFT clinical studies.
Once-daily dosing with an elimination half-life of around
15 h, the median time to maximum plasma concentrations
of 1–4 hour, and time to a steady-state concentration of
7 days are reported for DOR. In treatment-naı̈ve patients
(n = 9764), resistant mutations with DOR were very low
(1.4%) with the most prevalent mutations were V108I,
Y188L, H221Y, and Y318F. A superior safety profile for
DOR has resulted in less frequent neuropsychiatric and
cutaneous adverse reactions than EFV. A serious immune
reconstitution inflammatory syndrome can occur with
DOR [19,20,21]. The metabolism for DOR occurs
predominantly via CYP3A4; however, it is neither a
CYP inhibitor nor inducer, and thus has a lower potential
for drug interactions compared to other NNRTIs.
Elsulfavirine
Elsulfavirine (ESV or VM-1500A), is an investigational
NNRTI developed by Viriom, a San Diego-based biotech
company. ESV was approved by the Russian Ministry of
Health (MoH) in 2017 [5] (Figure 1). It is also being
considered for market approvals in various countries in
Asia and Latin American countries. The FDA has
accepted Viriom‘s investigational new drug (IND) appli-
cation filed for ESV based on its longer half-life of T1/2 
9 days, allowing once-weekly treatment. A long-acting
intramuscular or subcutaneous injectable is also being
investigated with an administration schedule of 1–3
months. ESV accumulates in red blood cells (RBCs)
via binding to RBC carbonic anhydrase, serving as a
natural slow-release depot and allowing for a prolonged
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duration of action. This occurrence gives an advantage for
the development of long-acting oral and parenteral for-
mulation [22–26]. A phase-2b clinical trial for ESV at a
dose of 20 mg orally once-daily in combination with
tenofovir disoproxil fumarate (TDF) / emtricitabine
(FTC) is being compared to EFV combination therapy
in treatment-naı̈ve HIV patients. Viral inhibition was
observed in 81% of patients in the elsulfavirine arm
compared to 74% of the patients in the efavirenz arm.
Drug-induced adverse effects were lower in the ESV
group (36.7%) versus the EFV group (77.6%). The
ESV maximum plasma concentration was 148  8 ng/
mL after 6.3 hours in HIV-1 infected patients. ESV has
shown high clinical efficacy of EC50 = 13.8 nM potency
against a broad range of HIV-1 clinical isolates, including
isolates from NNRTI-experienced patients. In clinical
studies, ESV is effective in treatment-naive patients and
patients with HIV isolates that are not controlled by
typical NNRTIs [23,27,28]. Table 1 includes a summary
of the pharmacological features of clinically approved
drugs.
Combination therapies
Because of the rapid development of resistance, NNRTIs
are not used as monotherapy and are used only in combi-
nation with other antiretroviral agents [29,30]. Combi-
nation regimens, including varied classes of antiretroviral
agents that target two or more enzymes in the viral life
cycle, have demonstrated improvements in treatment
outcomes resulting in the approval of novel combination
regimens for antiretroviral therapy [30–33].
Current combination therapy
The approved combination regimens entitled cART typ-
ically include a backbone of two NRTIs or NtRTIs and a
third or core agent from NNRTIs or PIs [33]. Three
NNRTIs, EFV, RPV, and DOR are key components of
the single-tablet regimens (STRs) of fixed-dose combi-
nations (FDCs) [33,34]. The FDCs include an NNRTI in
combination with two RT inhibitors that have been
approved (Table 2). FTC or lamivudine are NRTIs,
while TDF is a NtRTI [34,6,7]. The FDCs improve
effectiveness and provide better resistance profiles.
The FDCs also simplifies dosing, ease of administration,
and improve patient compliance. Seven FDCs have been
approved to date and include Atripla (EFV, FTC, TDF)
approved in 2006, Symfi and Symfi Lo, including EFV,
lamivudine, and TDF, approved in 2018. Complera and
Odefsey include FTC, RPV, and TDF fumarate and
were approved in 2011 and 2016 (Figure 2).
The cART regimens must be maintained over long
durations and, consequently, lead to potential long-term
problems, including toxicity, drug-drug interactions, and
increasing costs. The other approved NNRTIs are well
absorbed and are available for oral use except for ETR,
RPV, and ESV. The low aqueous solubility for ETR and
Current Opinion in Pharmacology 2020, 54:179–187
Current Opinion in Pharmacology 2020, 54:179–187

182 Anti-infectives
Table 1

Summary of pharmacological features for clinically approved NNRTIs

NNRTI drugs# Approved Absorption Distribution Elimination Metabolism Common side effects
dosage regimens
F Cmax Tmax (h) t1/2 Vd t1/2 PPB CL
(mg/mL) (h) (L/h) (h) % (L/h)
Nevirapine (NVP, 200 mg once daily for 14 >90% 2 4 1.21 60% 45 60 1.5 Oxidation by 3A4,2B6 and Skin rash, fever,
Viramune) days, followed by mg/mL glucuronidation headache, nausea,
200 mg twice daily diarrhea
Delavirdine (DLV, DLV 400 mg (discontinued), 85% 7.22 mmol/L 1.17 0.8 1 98% 2.39 98 60.3 N-dealkylation and Moderate to severe rash,
Rescriptor) & thrice daily hydroxylation by 3A4,2D6 fatigue, headache and
nausea.
Efavirenz (EFV, 600 mg once daily 40 45% 4.1 mg/mL 5 3.8 99.5% 52 76 99.5 9.4 Oxidation by 3A4,2B6 and Vivid dreams, anxiety,
Sustiva) glucuronidation rash, nausea and
insomnia
Etravirine (ETR, 200 mg twice daily NA 0.40 mg/mL 4 6 99.9% 30 40 99.9 43.7 Oxidation by 3A4,2C9,2C19 Skin Rash and
Intelence) and glucuronidation hepatotoxicity
Rilpivirine (RPV, 25 mg once daily NA 0.15 mg/mL 4 NA 99.7% 34 55 99.7 11.8 Oxidation by 3A4,3A5 and Depression, difficulty
Edurant) glucuronidation sleeping, headache and
rash
Doravirine (DOR, 100 mg once daily 64% 0.96 mg/mL 1.5 60.5L 76% 12 21 76 3.73 Oxidation by 3A4 Nausea, headache,
Pifeltro) tiredness, abdominal
pain, diarrhea and
dizziness, or unusual
dreams
Elsulfavirine (ESV, 20 mg once daily NA 7.5 ng/mL 6.3 days 1.7 NA 7.4 days NA NA Hydrolysis Dizziness, headache,
Elpida)* sleep disorders, nausea
and diarrhea

# Single-dose data approved by US FDA * Approved in Russian MoH only.

CL: plasma clearance, Cmax: maximum plasma concentration, F: bioavailability, NA: not available, PPB: plasma protein binding, t1/2: elimination half life, Tmax: time to maximum plasma concentration,
Vd: apparent volume of distribution. Cytochrome subtypes : 2B6, 2C9, 2C19, 2D6, 3A4, 3A5.
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 Approved non-nucleoside transcriptase inhibitors and combination regimens Vanangamudi, Kurup and Namasivayam 183

Table 2

List of combination therapies approved as single-tablet regimen for the treatment of HIV-1 infection

NNRTI based drug combinations FDA Clinical indications Commonly reported side
approval date effects
600 mg efavirenz/200 mg July 12, Virologically suppressed for Dizziness, insomnia and skin
emtricitabine/300 mg tenofovir 2006 >3 months on their cART rash
disoproxil fumarate tablet (Atripla) regimen
600 mg efavirenz/300 mg March 22, For adult and pediatric Anxiety, irritability, loss of
lamivudine/300 mg tenofovir 2018 patients weighing at least 40 interest or pleasure,
disoproxil fumarate tablet (Symfi) February 7, 2018 kg irritability, stomach pain,
400 mg efavirenz/300 mg trouble concentrating and
lamivudine/300 mg tenofovir sleeping.
disoproxil fumarate tablet (Symfi Lo)
25 mg rilpivirine/200 mg Aug. 10, For naı̈ve patients and a viral Rash, depression, insomnia
emtricitabine/300 mg tenofovir 2011 load HIV-RNA level of 100 and headache.
disoproxil fumarate tablet 000 copies/mL.
(Complera)
25 mg rilpivirine/200 mg March 1, For naı̈ve adults and Headache, trouble sleeping
emtricitabine/25 mg tenofovir 2016 adolescents weighing >35 and depression
alafenamide tablet (Odefsey) kg with baseline viral loads
<100,000 copies/mL.
25 mg rilpivirine/50 mg dolutegravir November 21, 2017 Switch regimen for patients Headache, dizziness and
tablet (Juluca) with viral suppression under Somnolence
effective triple antiretroviral
combinations.
100 mg doravirine/300 mg August 30, 2018 For adult patients with no Dizziness, Nausea and
lamivudine/300 mg tenofovir prior antiretroviral treatment abnormal dreams
disoproxil fumarate tablet history
(Delstrigo)

RPV following oral administration has improved by incor-
porating a solid dispersion formulation technique
[29,33]. Combination regimens that included EFV or
RPV used to be preferred first-line standard of HIV care.
However, there has been a decline in their use due to
dose-limiting toxicities, resistant mutations, and severe
drug interactions [33,35,36].
Newer combination regimens
The NRTIs continue to be mainstays of cART regimens
based on demonstrated efficacy [32]. Among other anti-
retroviral agents included as core agents in combination
regimens, the chemokine receptor 5 (CCR5) antagonist,
maraviroc have been considered [37]. Maraviroc binds to
the CCR5 receptors on the cell surface and inhibits viral
binding and entry into the cell. However, it is not recom-
mended since it is only effective in CCR5-tropic patients
and suffers from high costs [7]. The PIs remain core
agents among combination regimens based on the super-
ior resistance profiles compared to NNRTIs. However,
the PIs and NRTIs share similar toxicities as the
NNRTIs. The PIs and NRTIs are associated with mito-
chondrial toxicities, pancreatitis, dyslipidemia, insulin
resistance, anemia, and renal dysfunction [7]. Thus,
cART regimens need to be optimized for minimizing
the long-term risk of comorbidities and drug-drug inter-
actions [33,36,37].
More recently, cART regimens have moved to incorpo-
rate newer drug classes such as integrase strand transfer
inhibitors (INSTIs) [38,33,6,7]. The integrase enzyme
catalyzes viral DNA integration into the host DNA, and
INSTIs prevent the integration of viral DNA into the
host DNA [39,40,41]. More recently, FDCs incorporate
INSTIs in place of NNRTIs. Biktarvy approved in
2018 includes FTC (NRTI), tenofovir alafenamide
(NtRTI) and bictegrevir (INSTI) [40]. Dovato approved
in 2019 includes an NRTI, lamivudine with INSTI,
dolutegrevir [41]. The latest NNRTI, DOR with fewer
adverse effects and drug interactions, was approved in
combination with FTC and TDF as the FDC, Delstrigo
in 2019 [42,46]. DOR, EFV, and RPV-based regimens, in
combination with NRTIs or NtRTIs, remain first-line
treatment options for patients where INSTI-based regi-
mens cannot be used [7].
Previous guidelines cautioned against two-drug NRTI
regimens concerning limited efficacy in comparison to
three-drug regimens [7]. Two drug regimens have also
been evaluated for PI/NNRTI regimens and demon-
strated positive results. Preliminary results for a regimen
of the boosted PI, darunavir/ritonavir with RPV appear
promising. However, the regimen is associated with an
increased risk of adverse effects and drug-drug interac-
tions based on the component PIs and NNRTIs. With the
advent of INSTI among the antiretroviral agent

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184 Anti-infectives

Figure 2

Nucleoside reverse transcriptase inhibitors (NRTIs)

Lamivudine (3TC) Tenofovir disoproxil fumarate (TDF)

1995 2001

Emtricitabine (FTC) Tenofovir alafenamide (TAF)

2003 2015

Integrase strand transfer inhibitors (INSTIs)

Raltegravir (RAL) Dolutegravir (DTG)

2007 2013

Bictegravir (BIC) Cabotegravir (CAB)

2018 Phase 3

Current Opinion in Pharmacology

Chemical structures of drugs approved by FDA or under investigation for NRTIs and INSTIs which are applied in combination with NNRTIs.

armamentarium, there is a renewed interest in developing
dual regimens that include INSTI as the backbone agent
[36,43]. The exclusion of an NRTI/NtRTI and PI could
reduce cumulative drug toxicities, minimize drug inter-
actions, and improve patient compliance. An NRTI-spar-
ing FDC, Juluca was approved in 2017 as a dual-regimen,
including an INSTI, dolutegrevir, and RPV
[44,45,46,47]. A two-drug regimen of INSTI, raltegravir,
and ETR was also clinically investigated [48]. Dual-
therapy with raltegravir and ETR had favorable efficacy
and tolerability outcomes. A co-formulation of cabotegre-
vir and RPV as a long-acting injectable demonstrated
acceptable safety and efficacy in clinical trials. However,
the FDA denied approval based on manufacturing and

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 Approved non-nucleoside transcriptase inhibitors and combination regimens Vanangamudi, Kurup and Namasivayam 185
controls [49]. A study of the combination of dolutegrevir
with DOR in healthy subjects demonstrated an accept-
able pharmacokinetic and safety profile with no interac-
tions. Thus, supporting the investigation of dolutegrevir
and DOR as an FDC for HIV-1 therapy [50]. The FDA
approval of Juluca is promising. It remains to be seen if
additional INSTI/NNRTI combinations will be success-
ful when evaluated clinically. Novel INSTI/NNRTI
combinations could be among future antiretroviral drug
approvals.
Research has focused on developing novel NNRTI for-
mulations for HIV-1 therapy as well as prophylaxis. A
long-acting nanoformulation of DOR combined with
islatrivir is being evaluated as a possible candidate for
pre-exposure prophylaxis [51,52]. A vaginal ring contain-
ing dapivirine is being evaluated for use as a monthly
vaginal ring [53,54]. The NNRTI, IQP-0528 is under
investigation with tenofovir for pre-exposure prophylaxis
to HIV [54,55]. The combination, DuoGel is a dual-
chamber microbicide gel for rectal and vaginal delivery.
Perspectives
- The NNRTI class of compounds target the allosteric
site of RT and cannot be used alone in therapy due to
the rapid development of resistance. As a result,
NNRTIs are used only as components of cART. Earlier
NNRTIs were associated with significant adverse
effects and drug interactions. Newer NNRTIs have
focused on optimizing synergistic effects with other
components of cART while minimizing the adverse
effects and drug interactions. The most recent NNRTI
to be approved, doravirine has shown fewer adverse
effects and drug interactions.
- Synergistic suppression of HIV-1, reduced adverse
effects, and improved resistance profiles are the main
goals of HIV combination therapy. There has been a
shift to include safer and fewer drugs as components of
cART to minimize adverse effects. Newer drugs that
target different stages of the viral life cycle are also
being investigated among newer cART regimens to
improve resistance profiles. Over the past decade, sev-
eral newer NNRTIs have been approved with more
acceptable pharmacokinetic and pharmacodynamic
profiles compared to their earlier counterparts.
- Novel cART regimens that include newer NNRTIs but
do not include PIs or NNRTIs have also been approved
for HIV. The PI/NRTI-based regimens have been
associated with significant toxicities and morbidities
due to overlapping adverse effects and drug interactions
with NNRTIs. This has negatively impacted patient
adherence and therapeutic outcomes. Newer PI/NRTI
sparing cART regimens demonstrate better toxicity
profiles.
- The INSTI class of antiretroviral agents has demon-
strated significant success and has challenged the posi-
tion and role of several older antiretroviral agents in
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practice. The FDC, Juluca, is a dual-regimen, including
an INSTI, dolutegrevir, and an NNRTI, rilpivirine.
Alternate INSTI/NNRTI regimens could be part of
future drug approvals and are currently being
investigated.
- Efforts are also being made to develop prophylactic
agents that minimize the spread of HIV-1 and have
minimal toxicities. The NNRTIs are being investi-
gated in combination with NRTIs as nanoformulations
or vaginal and rectal gels. Doravirine is a front runner
among NNRTIs being investigated for pre-exposure
prophylaxis.
Conflict of interest statement
Nothing declared.
CRediT authorship contribution statement
Murugesan Vanangamudi: Writing - original draft. Sonali
Kurup: Writing - original draft. Vigneshwaran Namasi-
vayam: Conceptualization, Writing - review & editing.
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have been highlighted as:
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