Study on NNRTIs Treatment for HIV-1 by Comparison of RPV and

EFV

Yichen Yan

Shanghai Weiyu High School, China

Keywords: AIDS, Treatment, RPV and EEV.

Abstract: AIDS （acquired immune deficiency）is a disease caused by progressive failure of immune system, allowing

cancer and opportunistic infection to survive. Without any therapy being taken, people who get HIV/AIDS

could only survive 9-11 years. AIDS are not only difficult to detect, Aids also spreads easily through several

ways. It could spread through the contact of blood, pre-ejaculate, semen, vaginal fluid and other body humor.

A simple contact with patient’s humor could cause the infection to happen. From the first-time researchers

discovered AIDS IN 1981, there are more than 32 million people died because of AIDS. The severity of the

disease could be seen in these large infection numbers. Until now, researchers had not found any useful

method to cure the disease. What researchers could do is only to try to make the patient live longer. This essay

is aimed on the comparison of two drugs (Rilpivirine and Efavirenz) which could help the Aids patient to live

longer and find out why the second generation rilpivirine (RPV) will be better than the first generation

Efavirenz (EFV). CCS concept: Professional topics, Life and medical sciences, Architectures.

1 INTRODUCTION

The first sample of AIDS was discovered by CDC in

1981 and published on the Morbidity and Mortality

weekly report. Then, after having some research, this

disease soon been named as AIDS. After then, AIDS

soon spread to every continent in the world and

become one of the most difficult disease to be cured.

The reason makes the disease spread so fast is

because Aids could spread easily by the contact of

humor of human body, including blood, semen and

vaginal fluid. It normally spread through sexually and

condomless contact with AIDS patient. On the other

way, a mother who have AIDS could also bring the

disease through pregnancy and the process during the

birth. These two particular ways to spread help us to

limit the ages people who are easily get AIDS, which

is 18-45. This is because normally people at this age

would have most of sex life in their whole life time

and most of mother will be pregnancy in this period.

The large year period which people could easily

get AIDS makes the disease spread quickly in the

world. By the spreading of disease, it causes huge

effects on society and makes people realize the

severity of the disease. In 2018, 37.9 million people

were living with HIV and it resulted in 770,000

deaths.

Between the time that AIDS was identified

(in the early 1980s) and 2018, the

Figure 1. The global percentage of infecting HIV.

disease caused an estimated 32 million deaths

worldwide. As the graph shown here, most of the

countries have an infected rate more than 0.1%-0.5%,

even there is country has a rate of 15%-34%. The

graph could certainly prove that the speed it spread

and the large numbers of infections.

Large base numbers of patients show similar

symptoms after getting infected. Most of the patient

firstly get Flu in the early stage of AIDS and at the

later stage those patients will get fever, large lymph

nodes and weight loss.

264

Yan, Y.

Study on NNRTIs Treatment for HIV-1 by Comparison of RPV and EFV.

DOI: 10.5220/0011281100003438

In Proceedings of the 1st International Conference on Health Big Data and Intelligent Healthcare (ICHIH 2022), pages 264-271

ISBN: 978-989-758-596-8

AIDS has had a large impact on society, both as an

illness and as a source of discrimination. The disease

also has large economic impacts. This is because

particularly in China and some other country who may

still have a conservatism concepts to sexual life will

show extreme discrimination and stereotypes to the

people who get AIDS and considered them as

dissipated people. However, those people who get

AIDS could be infected by unconsciously contact with

the infected people. These stereotypes cause large

difficulties to the infected people in the society. On the

economically part, it also creates large burdens for the

patients to buy the particular drugs and take the

treatments. Because there are no drugs could

completely cure the AIDS, so the treatment will last a

long period, leading to a severe economic burden to

the family or individual.

2 TREATMENT

Currently, the most effective way to inhibit the AIDS

is to use antiviral treatment. These antiviral treatments

include NNRTIs (non-nucleoside reverse transcriptase

inhibitor). However, the first time we discover

NNRTIs and other drugs which could be used as a

treatment could be retrospect to decades before,

including the two drugs, RPV and EFV. In the

summer of 1981, the acquired immunodeficiency

syndrome was first discovered by people. Two years

later the etiological link to AIDS, the human

immunodeficiency virus (HIV) was identified. Since

the identification of HIV, the development of effective

antiretroviral drugs and the scientific achievements in

HIV research has been vital. The first

NNRTI(nevirapine) was discovered by researchers

at Boehringer Ingelheim . In 1996, it was approved by

FDA. In the next two years two other NNRTIs were

approved by the FDA, delavirdine and EFV in 1997

and 1998 respectively. These three drugs are the first

generation NNRTIs treatment. The yearning to get for

NNRTIs with better resistance profile led to the

development of the next generation of NNRTIs.

Janssens Foundation and Tibotec’s

researchers discovered the first drug in this

class, etravirine. It was approved in 2008 by FDA. The

second drug in this class, RPV, was also discovered by

Tibotec and was approved by the FDA in 2011.

2.1 Nomenclature

rilpivirine: 4-{[4-({4-[(E)-2-cyanovinyl]-2,6-

dimethylphenyl} amino) pyrimidin-2-yl] amino}

benzonitrile

Efavirenz: (4S)-6-Chloro-4-(2-

cyclopropylethynyl)-4-(trifluoromethyl)-2,4-

dihydro-1H-3,1-benzoxazin-2-one

ure 2. The structure of Ril

ivirine

ure.3 The structure of Efavirenz

2.2 Chemical Properties

Table 1 the basic properties of RPV and EFV.

Molar mass formula Half life

RPV 366.428 g·mol

−1

hours

EFV 315.68 g·mol

−1

ClF

40–55

hours

Study on NNRTIs Treatment for HIV-1 by Comparison of RPV and EFV

265

3 THE PHARMACOLOGY

3.1 Introduction of RT: The Targets of

NNRTIs

RT is one of the most important enzymes for HIV to

spread in the host cell. During uncoating, the single-

stranded RNA genomes within the core or capsid of

the virus are released into the cytoplasm. HIV now

uses the enzyme

reverse transcriptase

to replicate the

RNA genome. Normal transcription in nature is when

the DNA genome is transcribed into mRNA which is

then translated into protein. In HIV reverse

transcription, RNA is reverse-transcribed into DNA.

3.2 The Targets of NNRTIs and the

Function Affected by NNRTIs

NNRTIs could inhibit the polymerization of HIV RT,

which is an essential viral enzyme in the process to

produce double-stranded viral DNA genomes from

the single strand viral DNA genome. RT is a

heterodimer of p66 and p51. P66 is formed like

people’s right hand. It contains the thumb, fingers,

palm and connections subdomains. Although the

exact mechanisms of NNRTI action is not clear yet, it

is commonly agreed that the using of NNRTIs to the

drug-binding pocket of HIV-1 RT would lead to a

reposition of the template-primer, therefore guarding

against the dNTP binding to form a competent RT-

DNA-dNTP complex. Moreover, non-competitive

NNRTIs allosterically target a hydrophobic pocket.

What needs to notice is that NNRTIs is only useful to

the HIV type 1 but not HIV type 2. This is because

HIV-2 RT possesses isoleucine at codon181 and

leucine at 188. Both of the amino acids there could

prevent the NNRTIs binding to the pocket. (Figure.

4).

Figure. 4: The binding process.

E.g. This is a graph showing the comparison

between the original hinge motion and the hinge

motion after using the NNRTIs (Ivetac, McCammon

2009). The thumb is colored in blue and the fingers is

colored in red. The hinge motion is the process that

thumb and fingers close and become a straight line.

However, as the graph has shown, the NNRTIs acts

like a wedge in the center of the thumb and fingers.

This “wedge effect” prevent the full closure of the

hinge motion. Then, the NNRTIs inhibits the RT to

replicate one single strand of DNA into double helix

structures.

3.3 Mode of Delivery

Depending on the different function of different

medicines and the different doses, each particular

medicine requires a different way to deliver them.

3.3.1 The Mode of Delivery of RPV

Traditionally, RPV is delivered orally by patients

with 25mg once-daily(Williams, Crauwels, Basstanie

2015, Sanford 2012). Rilpivirine should always be

taken with a meal to make sure that there is adequate

exposure. However, there are several recent studies

which are researching the effects of RPV-LA (Long

acting RPV). This type of RPV is focusing on the

different mode of delivery of RPV. Currently, the

RPV-LA pharmacokinetic data showed that

therapeutic concentrations of RPV can be maintained

for at least 28 days after intramuscular administration

of doses between 600 and 1200 mg (Ferretti, Boffito

2018), with high RPV levels achieved in rectal tissue

and in vulvovaginal secretions. With regards to HIV

prevention, a study in HIV negative women showed

that RPV-LA is generally safe and well tolerated and

accepted in this group (Cohen, Molina, Cahn, Clotet,

Fourie, Grinsztejn, Boven 2012). What makes the

new type of the mode of delivery attracting is that it

could overcome the adherence issues and relieve the

pill burden of patients. It is more patient-friendly than

orally available RPV tablets.

3.3.2 The Mode of Delivery of EFV

EFV is delivered orally by the patient once-daily. The

recommended dosage once-daily should be 600mg

(Ivetac, McCammon 2009), taken on an empty

stomach, and favorable at bedtime, to diminish

possible neuropsychiatric side effects. Efavirenz is

contraindicated in pregnancy (category D) because it

can cause fetal harm in the first three months.

However, a recent study conducted by Kamboj,

S., Sethi, S., & Rana, V. in 2018 gives a new idea in

ICHIH 2022 - International Conference on Health Big Data and Intelligent Healthcare

266

the mode of delivery in order to raise the

bioavailability of the EFV. The new deliver mode was

described as EFV1. It turns to a lipid base delivered

mode (Kamboj, Sethi, Rana 2018, Varshosaz,

Taymouri, Jahanian-Najafabadi, Alizadeh 2018)).

This particular mode focused on QbD-driven

systematic development of EFV loaded isotropic

mixture (IM). It contains long chain triglycerides that

have an ability to abolish unstable absorption and

obliterating the food associated variabilities which

could possibly enhances oral bioavailability.

3.3.3 Comparison of Different Modes of

Delivery

With all the existed data and clinical trials have

shown, the orally available RPV has a high

bioavailability than the orally available EFV for the

problems of different structures of the medicines.

However, researchers find that RPV-LA does not

significantly enhance the bioavailability of the RPV,

while the EFV1 (isotropic mixture) shows that it

could overcome the food associated effects and the

erratic absorption of the drug. EFV seems to have a

great potential on overcoming the existed problems

and becoming more bioavailable for patients.

3.4 Result

3.4.1 Pharmacokinetics of EFV

Efavirenz, a benzoxazinone compound, has 40%-

45% (Figure 2) oral bioavailability. After a single

dose of EFV orally administered to volunteers who

are not infected, its maximum plasma concentration

(Cmax) is 4.1 μg/mL by 5 hours. Efavirenz is suitable

for a once-daily regimen because the plasma half-life

(t1/2) of single-dose EFV (52 to 76 hours) is similar

to that of multiple-dose EFV (40 to 55 hours)

(Adkins, Noble, 1998) 90% of efavirenz is

metabolized in the liver by the cytochrome P450 3A4

and 2B6. About 14 to 34% of a radiolabeled dose of

efavirenz 400mg was excreted in the urine in the form

of metabolites and 16 to 61% was excreted in the

faeces as unchanged drug. Less than 1% of an

administered dose of efavirenz is excreted unchanged

in the urine.

Table 2: The properties and experimental data of different kinds of NNRTIS.

This is a snap shot taken from Current and

emerging non-nucleoside reverse transcriptase

inhibitors (NNRTIs) for HIV-1 treatment. (Wang, Y.,

De Clercq, E., & Li, G. (2019). Current and emerging

non-nucleoside reverse transcriptase inhibitors

(NNRTIs) for HIV-1 treatment. Expert Opinion on

Drug Metabolism & Toxicology.)

3.4.2 The Pharmacokinetics of RPV

RPV is a diarylpyrimidine compound with a high oral

bioavailability. After the oral administration, the

maximum plasma concentration (Cmax) of RPV is

generally achieved within 4 hours (Tmax). RPV has a

long half-life (t1/2=34-55h)(Wang, Clercq, Li, 2019;

Garvey, Winston, 2009), which is suitable for its

once-daily dosing. Since RPV is primarily

metabolized by CYP 3A4 and 3A5, administration

with other drugs that induce or inhibit CYP3A could

be influential to the concentration of RPV. RPV can

effectively inhibit HIV-1 wild-type strains (EC50:

0.51 nM). Moreover, the EC50(half maximal

effective concentration) values of RPV are generally

lower than that of NVP, EFV, and ETR in the

inhibition of HIV-1 group M isolates.

Study on NNRTIs Treatment for HIV-1 by Comparison of RPV and EFV

267

3.4.3 Comparison of RPV and EFV on the

Efficacy, Safety and Tolerability

Seemingly, EFV has a longer half life than RPV. It

means that the time of EFV to be metabolize half is

longer than RPV. However, the terminal half life of

RPV is 55h and it shows non-inferior efficacy than

EFV. For comparison of oral bioavailability of EFV

and RPV, it is only described as high oral availability

but does not give exact values. What the data presents

is only the bioavailability of EFV which is 40-45%. It

is not an effective number. Therefore, by researching

on a designed trial to test the efficacy, safety and

tolerability, it tells that 346 patients were randomly

assigned to take RPV and 344 to take EFV and take

at least one dose of study drug. The virological

failures of RPV was 13% versus 6% of EFV (11%vs

4% respectively by ITT-TLOVR). Rash, dizziness,

and nightmares, even thoughts to suicide were more

commonly appeared with EFV (Jackson, McGowan

2015). (This experiment is carried by Jean-Michel

Molina, Pedro Cahn, Beatriz Grinsztejn, Adriano

Lazzarin, Anthony Mills, Michael Saag, Khuanchai

Supparatpinyo, Sharon Walmsley, Herta Crauwels,

Laurence T Rimsky, Simon Vanveggel, Katia Boven,

ECHO study group). According to the results given in

the experiment, it shows that although RPV has a

higher rate of virological failure, it is safer and has a

higher tolerability than EFV. No doubt the virological

failure could affects the therapy taken by patients, but

the safety issues and the side effects should definitely

be more vital than the progression of the therapy.

3.5 Conclusion

For comparison, there are several differences could

help researchers to decide why the second generatioN

RPV is better than the first generation EFV. On the

side of the mode of delivery, RPV seems to be more

convenient. It does not need extra time to take the

pills and to notice when people have empty stomach.

To determine if people have an empty stomach will

be much difficult to determine whether people have

food in their stomach. Therefore, on the mode of

delivery, RPV is more convenient than EFV. On the

pharmacokinetics side, RPV has a similar

bioavailability as EFV does. However, considering

the safety issue, EFV has more side effects than RPV.

RPV is much safer than EFV. With the similar

efficacy, RPV will definitely becomes the more

popular one. Therefore, RPV could be the second

generation of HIV treatment of NNRTIs.

4 CHEMICAL SYNTHESIS

4.1 Chemical Synthesis of the RPV

Figure.5: The chemical synthesis method of RPV(Mordant, Schmitt, Pasquier, Demestre, Queguiner, Masungi, Guillemont

2007).

Compound 5(RPV) was synthesized in two

procedures from derivative 12. After heating (150 C)

the chloropyrimidine 12 and researchers use 3,5-

dimethyl-4-hydroxybenzaldehyde with sodium

hydride in a 1:1 ratio mixture of NMP dioxane to

displace the chlorine on the pyrimidine

(Namasivayam, Vanangamudi, Kramer, Kurup, Zhan,

Liu, Byrareddy 2018, Mordant, Schmitt, Pasquier,

Demestre, Queguiner, Masungi, Guillemont 2007). A

Wittig reaction on 5a then happened to form the RPV.

A Wittig reaction usually happened on the aldehyde.

There is an aldehyde on 5a and with same charge, it

could be replaced with a carbon connected to the

cyanide. Then, RPV is synthesized.

4.2 Chemical Synthesis of EFV

The synthesis of EFV starts with 4-chloroaniline (43).

In order to introduce the trifluoroacetyl group into the

chlorine, the amino group is protected as tert-butyl

carbamate, followed by reaction with n-

butyllithium/ethyl trifluoroacetate. The tert-butyl

carbamate was deprotected with HClCH3COOH in 45

to obtain 46, which was crystallized and purified at

5°C and separated with a yield of 87%. For further

ICHIH 2022 - International Conference on Health Big Data and Intelligent Healthcare

268

reactions, 46 forms need to be neutralized.

Therefore, it can be stirred with NaOAc in MTBE to

get 47. The p-methoxybenzylation reaction is carried

out by p-methoxybenzyl alcohol, which is a cheap and

less toxic alternative previously reported for 103,

forming 48 (90% yield). Enantioselective

alkynylation of compound 48 with 49 enantiomer 48

in the THF-toluene-hexane mixture at -50°C in the

presence of ligand 50, the yield was 51%, The body

excess (ee) is 98.5%. Cyclization of 51 by COCl 2

/TEA with a yield of 95%, and then deprotection of p-

methoxybenzyl by cerium ammonium nitrate to obtain

EFV (53) with a yield of 76%. However, p-

methoxybenzyl deprotection and cerium ammonium

nitrate are by-products such as p-

methoxybenzaldehyde and some cerium salts.

Therefore, another method was studied, in which 51

reacted with DDQ in toluene to obtain 54a/54b, and

then reacted with NaOH-MeOH to obtain amino

alcohol 55 (yield 94%). The by-product p-

methoxybenzaldehyde was It is converted into p-

methoxybenzyl alcohol by reduction with NaBH4.

Phosgene can achieve a ring closure of 55 and obtain

EFV (53) with a yield of 95% (purity> 99.5%,

enantiomeric excess or ee greater than 99.5% after ee-

heptane crystallisation), and try to convert it by methyl

carbamate After 55-ring closed recrystallization, only

EFV was obtained with a yield of 83%. Using p-

nitrophenyl carbamate, the yield reached 94%.

The synthesis of EFV starts with 4-chloroaniline

(43). In order to introduce the trifluoroacetyl group

into the chlorine, the amino group is protected as tert-

butyl carbamate, followed by reaction with n-

butyllithium/ethyl trifluoroacetate. The tert-butyl

carbamate was deprotected with HClCH3COOH in 45

to obtain 46, which was crystallized and purified at

5°C and separated with a yield of 87%. For further

reactions, 46 forms need to be neutralized. Therefore,

it can be stirred with NaOAc in MTBE to get 47. The

p-methoxybenzylation reaction is carried out by p-

methoxybenzyl alcohol, which is a cheap and less

toxic alternative previously reported for 103, forming

48 (90% yield). Enantioselective alkynylation of

compound 48 with 49 enantiomer 48 in the THF-

toluene-hexane mixture at -50°C in the presence of

ligand 50, the yield was 51%, The body excess (ee) is

98.5%. Cyclization of 51 by COCl 2 /TEA with a

yield of 95%, and then deprotection of p-

methoxybenzyl by cerium ammonium nitrate to obtain

EFV (53) with a yield of 76%. However, p-

methoxybenzyl deprotection and cerium ammonium

nitrate are by-products such as p-

methoxybenzaldehyde and some cerium salts.

Therefore, another method was studied, in which 51

reacted with DDQ in toluene to obtain 54a/54b, and

then reacted with NaOH-MeOH to obtain amino

alcohol 55 (yield 94%). The by-product p-

methoxybenzaldehyde was It is converted into p-

methoxybenzyl alcohol by reduction with NaBH4.

Phosgene can achieve a ring closure of 55 and obtain

EFV (53) with a yield of 95% (purity> 99.5%,

enantiomeric excess or ee greater than 99.5% after ee-

heptane crystallisation), and try to convert it by methyl

carbamate After 55-ring closed recrystallization, only

EFV was obtained with a yield of 83%. Using p-

nitrophenyl carbamate, the yield reached 94%.

Figure.6 The synthesis method of EFV (Namasivayam, Vanangamudi, Kramer, Kurup, Zhan, Liu, Byrareddy 2018)

Study on NNRTIs Treatment for HIV-1 by Comparison of RPV and EFV

269

Resource delivered from:

RPV

Invented RPV

The main building blocks 77 and 83 (Scheme 13)

are the main parts in the reaction.

117, 146-149 is the basic compound synthesis

requirements of RPV. 77 is prepared from thiouracil

(74), which can be purchased in bulk. Thiouracil (74)

used MeI/NaOH to form75% yield at 60°C with a

yield of 90%, then react with 68 at 150°C to obtain 76

with a yield of 70%. Then by using POCl3 to carry

out the halogenation reaction of 76 to obtain 80%

yield of 77

117,146−149 Compound 83 (another key

intermediate) is prepared from 3,5-4-bromo-2,6-

dimethylaniline in four steps

(78). Use N,N-dimethylformamide dimethylacetal to

protect the amino group in 78 to form dimethyl (79).

It forms 80, then react with n-butyl lithium to Give

81. Compound 81 carries the Wadsworth-Emmons

Reaction. Protection of dimethylformamide with

(diethoxyphosphino)acetonitrile followed by ZnCl2

gave the 83 compound. 77 and 83 are reacted together

at 150°C to obtain RPV

5 DRUG ECONOMICS

5.1 Cost of RPV and EFV

According to the research to different pharmacies, the

research shows that no matter how great the discount

the pharmacies are giving, all of the RPV is more than

1000 dollars for 30 tablets per month. Comparatively,

EFV has a price among $981–1,177, which is slightly

cheaper than RPV.

5.2 Potential

Edurant (Brand name of RPV), received a thumbs up

back in 2011 and has achieved annual sales growth

ever since. In 2017, the drug raked in $714 million,

an increase of 25% from the year prior. However,

according to the resources available, the Atripla

(efavirenz, emtricitabine, and tenofovir) has a sale

of $3.470 billion in 2014. Atripla has a higher sale

than RPV. However, RPV has a greater sale

increasing speed than atripla. Atripla even have lower

sales in 2014 than 2013. In the long term, RPV has

more potential than Atripla.

6 CONCLUSIONS

By collecting the data of RPV and EFV, we compared

and analyzed the two drugs from three dimensions:

pharmacology, chemical composition and price.

Based on the comparison of actual data, we finally

come to the conclusion that EFV is better in

application. I hope our work can play a reference role

in the medical application of life-prolonging drugs for

AIDS patients.

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