The Whole is Greater than the Sum of the Parts, Combination Use as

CABENUVA in Treating HIV: Meta-Analysis from Clinical Datasets

Xuanji Cao

1,†

, Youkai Yang

2,†

and Yiyi Zhao

3,*,†

School of Chemistry, University of Nottingham, Nottingham, U.K.

Faculty of Engineering, China Pharmaceutical University, China Pharmaceutical University, Nanjing, China

WUT-AMU Institute, Wuhan University of Technology, Wuhan University of Technology, Wuhan, China

Keywords:

CABENUVA, HIV-1, Cabotegravir, Rilpivirine.

Abstract:

CABENUVA is a 2-drug co-packaged product for the treatment of HIV-1 infection in adults to replace current

antiretroviral therapy. The development of more effective and convenient medication can improve the lives

of HIV patients. This article mainly focuses on the drug profile, clinical trial and comparative analysis of

CABENUVA with other newly approved HIV-1 drugs. There have been several HIV-1 drugs approved since

2018, but the route of administration of them is still oral. The appearance of CABENUVA indicates the

possibility of introducing and developing injection HIV medications.

1 INTRODUCTION

1.1 Introduction of HIV-1

HIV is a type of retrovirus that infects cells of the

human immune system and causes the spread of

diseases in the human body by destroying the body's

T-lymphocytes, thereby blocking cellular and

humoral immune processes. That causes the immune

system to become paralyzed, thus creating the

environment for AIDS. Because HIV mutates so

rapidly, it is difficult to produce a specific vaccine.

The fact that is no effective treatment for the disease

made it a great threat to human health.

The Joint United Nations Programme on

HIV/AIDS estimates that in 2019, 38 million people

worldwide will be living with HIV, 1.7 million will

be newly infected and 690,000 will die from HIV

disease. Compared with their estimation in 2010, the

overall HIV incidence in 2019 has decreased by 23%

and mortality by 37%. However, age stratification

shows a 52% reduction in new infections among

children, and only a 13% reduction among adults.

With mortality declining but HIV incidence and

population continuing to grow, the total number of

people living with HIV in 2019 is 24% higher than in

2010. (De Cock, 2021)

†

These authors contributed equally

In the nearly 40 years since the discovery of HIV,

great progress has been made in developing effective

treatments. However, a vaccine that prevents HIV

infection remains elusive. Most licensed vaccines

protect through the induction of antibodies. In the

case of HIV, the antibodies induced by the vaccine

must be able to protect the human immune system

against the effects of the multiple variants of HIV that

are prevalent worldwide, known as broadly

neutralizing antibodies. Recent advances in the

identification and characterization of such antibodies,

as well as progress in the design of candidate

antibodies to stimulate cellular immunity and the

results of recent clinical trials, are driving efforts to

develop an HIV vaccine that can eradicate the virus

once and for all. (Koff, 2016)

However, the development of an HIV vaccine has

not been successful, the number of people living with

HIV is still huge and continues to grow, and the need

for HIV suppressant drugs gets stronger every day.

Antiretroviral therapy (ART), is the treatment of

HIV with a combination of several antiviral drugs.

Although ART is effective in suppressing the onset of

HIV, it is time-consuming and has serious side

effects. There is an urgent need to find new and easier

ways to cure HIV infection or suppress the onset of

AIDS.

440

Cao, X., Yang, Y. and Zhao, Y.

The Whole is Greater than the Sum of the Parts, Combination Use as CABENUVA in Treating HIV: Meta-Analysis from Clinical Datasets.

DOI: 10.5220/0012032200003633

In Proceedings of the 4th International Conference on Biotechnology and Biomedicine (ICBB 2022), pages 440-447

ISBN: 978-989-758-637-8

 2023 by SCITEPRESS – Science and Technology Publications, Lda. Under CC license (CC BY-NC-ND 4.0)

1.2 CABENUVA

CABENUVA is a 2-drug co-packaged product for the

treatment of human immunodeficiency virus type 1

(HIV-1) infection in adults to replace current

antiretroviral therapy in patients who are

virologically stable and suppressed. (Surve, 2020)

CABENUVA kept HIV-1 viral load at a suppressed

level.

CABENUVA is the world's first complete and

long-acting HIV treatment regimen, administered by

intramuscular injection (IM) once a month. The

approval of the drug marks a major milestone that will

revolutionize HIV treatment by shifting from oral

administration 365 days a day throughout the year to

monthly injections for only 12 days of treatment

throughout the year. CABENUVA (Cabotegravir and

Rilpivirine), developed by ViiV Healthcare is also the

latest drug currently approved by the FDA for the

treatment of AIDS, with approval scheduled on

January 20, 2021.

CABENUVA, an easier and more effective

treatment, is a huge improvement of the quality of life

for people with HIV. Simplified regimens for the

treatment of HIV-1 infection may increase patient

satisfaction and facilitate adherence. (Surve, 2020)

2 DRUG PROFILES

2.1 Highly Active Antiretroviral

Therapy

In 1996, the Chinese-American scientist D.Y. Ho

proposed the highly active antiretroviral therapy

(HAART), in which three or more antiretroviral drugs

are used in combination to treat AIDS. The HAART

combines protease inhibitors with a variety of

antiviral drugs, resulting in effective control of AIDS.

The application of this therapy reduces the drug

resistance caused by unitary medication, maximizes

the inhibition of viral replication, and restores some

or even all of the body's immune function.

Eventually, it slows the progression of the disease,

prolongs the patient's life ，and improves their quality

of life. CABENUVA (Cabotegravir and Rilpivirine)

also uses the principle of highly active antiretroviral

therapy to achieve better HIV suppression through a

combination of drugs.

2.2 Cabotegravir and Rilpivirine

The first part is a separate analysis of Cabotegravir

and Rilpivirine. The analysis illustrates Rilpivirine, a

long-term active, non-nucleoside reverse

transcriptase inhibitor; and Cabotegravir, a long-term

active HIV-1 integrase strand transfer inhibitor.

The target of Rilpivirine is NNRTIs, and the target

of Cabotegravir is HIV integrase. Rilpivirine

(TMC278) is a next-generation non-nucleoside

reverse transcriptase inhibitor (NNRTI) that

vigorously represses wild-type and NNRTI-resistant

HIV-1. activity. NNRTIs work by binding to and

blocking HIV reverse transcriptase, an HIV enzyme.

Cabotegravir (GSK744, GSK1265744) is an HIV

integrase inhibitor that is effective within a broad

range of HIV subtypes and inhibits the chain transfer

reaction catalyzed by HIV-1 integrase with an IC50

of 3 nM.

The following two figures (Figure1 and Figure2)

will show each chemical structure formula of two

important components of CABENUVA.

Figure 1: Chemical structure of Cabotegravir.

Figure 2: Chemical structure of Rilpivirine.

The Whole is Greater than the Sum of the Parts, Combination Use as CABENUVA in Treating HIV: Meta-Analysis from Clinical Datasets

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2.3 Pharmacokinetics and Treatment

Satisfaction

In terms of PHARMACOKINETICS, the research

team of the University of Nebraska’s Medical Center

confirmed that during therapy, Cabotegravir and

Rilpivirine concentrations in plasma were similar to

those reported during oral therapy (Figure 3). Both

drugs from the first trough at week 8 to the trough at

week 48 showed a cumulative accumulation of

approximately 2.3-fold, close to steady-state drug

concentrations. The geometric mean plasma

concentrations of Cabotegravir and Rilpivirine at

week 48 (2.84 micrograms per milliliter and 90.3

nanograms per milliliter, respectively) were each 17

and 7.5 times their respective protein-adjusted

concentrations, respectively, required for 90% viral

suppression, similar to the results obtained after

monthly dosing in the phase 2 study. (Swindells,

2020)

Figure 3: Plasma Concentration–Time Profiles.

As assessed by HIVTSQs: after 44 weeks,

participants in the long-term active treatment group

showed a substantial promotion in treatment

satisfaction compared to those in the oral treatment

group. The adjusted mean score for the long-term

active treatment group was 5.68 points (95% CI, 4.37

to 6.98) higher than that of the oral treatment group.

This difference met the threshold of a minimal

clinically important difference according to a

distribution-based approach. In a within-group

comparison conducted at week 48 in the long-term

active treatment group, 97% of participants who

responded to the questionnaire and 86% of

participants in the intention-to-treat exposed

population chose injectable therapy over daily oral

therapy as their preferred HIV treatment. (Swindells,

2020)

Eventually, Nebraska’s research team concluded

the comparative trial of long-term active

Cabotegravir and Rilpivirine with oral induction

therapy for HIV-1 infection. The conclusion is that

monthly injections were non-inferior to standard oral

therapy for maintaining HIV-1 suppression.

Injection-related adverse events were familiar but

infrequently led to medication withdrawal.

(Swindells, 2020)

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442

3 STUDY RESULTS

3.1

Pharmacology Property

CABENUVA was proved very effective to treat

single-cycle HIV-1 infections and HIV-1 mutants with

site-directed mutations (Elvitegravir-resistant

integrase mutants, raltegravir-resistant integrase

mutants, and raltegravir-resistant integrase mutants).

When using it for dolutegravir-resistant integrase

mutants and raltegravir-resistant integrase mutants,

the medication was less effective. The EC50 value was

shown below in Table.1.

Table 1: CABENUVA EC50 value of HIV mutants.

Mutants EC50 (nmol/L)

92UG029, NL4-3,

LAI, MJ4, 92UG001,

MVP5180-91

1.3-2.0

Y143C, T97A+Y143C 1.2

E92Q+N155H 5.9

E138K+G140S+Q148R 15

E92Q+Y143C 2.4

E92Q+NQ155H 12

G140A+Q148R 11

Participants were randomly allocated to IM

cabotegravir 800 mg after 14 days of receiving 30 mg

oral cabotegravir once a day, followed by three 200

mg SC doses, three 200 mg IM doses, or three One

400 mg IM doses every four weeks, or a second

cabotegravir 800 mg IM treatment after 12 weeks. At

month 3 (1200 mg) and month 4, those in the 200 and

400 mg IM cohorts received IM doses of long-acting

rilpivirine (900 or 600 mg). For all four regimens,

treatment-related plasma cabotegravir concentrations

(mean > 4 PA-IC90) were seen 3 days after injection

and lasted until the conclusion of the dosing interval.

The cabotegravir 800 and then 400 mg IM regimens

showed accumulation until the fourth month, whereas

the other regimens appeared to be stable after three

months.

The pharmacokinetic characteristics of the two

medications have low to moderate inter-subject

variability (cabotegravir AUC CV percent is 23-52

percent, and ripavirine AUC CV percent is 34-35

percent). At week 8, 4 weeks following the first IM

loading dosage (primary trough concentration), the

cumulative geometric mean (95 percent CI) plasma

concentrations for CAB (1.31 to 1.46) and RPV

(38.05 to 41.80) were 1.38 g/mL (1.31 to 1.46) and

39.88 ng/mL (38.05 to 41.80), respectively. The

geometric mean (95 percent confidence interval)

plasma concentration of CAB was 2.97 g/mL (2.85 to

3.10) at week 48, whereas the RPV was 86.42 ng/mL.

(82.87 to 90.14).

FLAIR (N = 566) and ATLAS (N = 618) trials

were conducted in HIV-1 infected adults to

demonstrate its non-inferior antiviral efficacy. The

distinction is that FLAIR enrolls ART-naive patients,

while ATLAS select ART-experienced patients who

were stable on an ARV regimen. (Clinical Review

Report)

The trials were divided into 3 stages. First of all,

the induction phase (FLAIR only) controls their

plasma HIV-1 RNA. Then in the maintenance phase,

the patients were randomly grouped in half to remain

on oral CART or switch to the CAB + RPV regimen.

Patients in the FLAIR studies continued their therapy

during the induction phase, whereas those in the

ATLAS trials continued to utilize their existing ARV

regimen. The latter group takes oral CAB + RPV (30

mg/25 mg, one tablet each) once a day for at least four

weeks, then injects the first dosage of CAB + RPV

(600 mg/900 mg) within two hours of the final oral

dose, then injects CAB + RPV (400 mg/600 mg)

every four weeks after that. Patients in the CAB +

RPV group continued their IM dose as normal

throughout the "extension phase," and those moving

from the CART group to CAB + RPV followed the

same treatment regimen.

Figure 4: Trial process.

HIV-1 immunotherapeutic vaccines, systemic

immunomodulators, acetaminophen (if acute viral

hepatitis is present), chronic use of systemic

glucocorticoids, HCV therapy, certain antibiotics,

consistent administration of medications that lower

the concentration of any study drug component, and

other exploratory agents, ARV drugs (not otherwise

specified), cytotoxic chemotherapy, or radiation

therapy were not allowed at any time during the study.

Over 90% of the patients in both trials were

continuing through or completed the maintenance

phase. However. 22% of patients in FLAIR and 12%

patients in ATLAS were considered screening

failures since lack of efficacy (5%), AE or withdraw

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from the trials (approximately 5% to 7% after

entering the long-term follow-up phase).

The results existed at week 48 as the virologic

responses became significant, which is the standard

time frame used in the HIV-1 trial and is consistent

with the shortest analysis duration recommended by

the FDA for virological endpoints. The trial is

ongoing and the planned duration is 120 to 148

weeks.

In FLAIR, virologic failure was reported in 2.1

percent and 2.5 percent of patients in the CAB + RPV

and CART groups, respectively, with HIV-1 RNA

levels of 50 copies/mL or above at week 48. In

CART, 1.6 percent of patients in the CAB + RPV

group and 1.0 percent in the CART group. In FLAIR,

CAB + RPV and CART scored 94 percent and 93

percent, respectively, while in ATLAS, CAB + RPV

and CART scored 93 percent and 95 percent,

respectively. At week 48, HIV-1 RNA was less than

50 copies/mL. In FLAIR and ATLAS, treatment

differences were 0.4 percent (95 percent CI, 3.7 to

4.5) and 3.0 percent, respectively. It shows that there

isn't much of a difference between CAB+RPV and

CART effectiveness. The 96-week results confirm the

48-week findings, indicating that long-acting

cabotegravir and rilpivirine are non-inferior to

maintaining a standard care regimen in individuals

with HIV-1 for viral suppression maintenance. These

findings suggest the long-acting cabotegravir and

rilpivirine as a treatment choice for virally suppressed

people with HIV-1 over a nearly 2-year period.

3.2 AE and Model Health-Related

Quality of Life

In both studies, the CAB + RPV group had higher

AEs than those in the CART group in the process of

the maintenance. In ATLAS and FLAIR, more than

90% of patients in the CAB + RPV group had at least

one AE across trials, whereas in ATLAS and FLAIR,

the overall prevalence of AEs in the CART group was

71 percent and 80 percent, respectively. Most of AEs

were classified as grade 1 or 2. The revealed higher

occurrence of AEs was due in part to a variety of ISRs

caused by the monthly IM injections. Another trial

suggests that the observed AE profile with CAB +

RPV LA treatment was identical to that in the CAR

arm, omitting ISRs, and is consistent with the

previously oral therapy. Despite the fact that ISRs are

widespread (they account for 25% of all injections),

the majority of them are moderate (99 percent grade

1 or 2). Throughout the trial, the overall incidence of

ISRs rapidly declined from 70% at week 4 to 16% at

week 48, and the length of ISRs was brief (median 3

days). These findings show that the initial high rate of

ISRs was due to the introduction of a novel treatment

administration method (IM injection), with a lower

rate over time as participants got more comfortable

with the injection process.

HRQoL can be a valuable data for us to evaluate

the patients’ prognosis. In that case, HIVTSQ, PIN,

ACCEPT, HAT-QoL, NRS, and SF-12 are used to

evaluate a variety of characteristics of HRQoL, such

as acceptance of an injectable regimen and issues that

may arise as a result of it. In ATLAS, the HIVTSQs

and PIN results were statistically significant in favor

of the CAB + RPV group, but this was not the case in

FLAIR (after adjusting for multiplicity). The other

measurements revealed that CAB + RPV had a

numerical advantage in terms of patients' HRQoL.

None of these analyses were multiplicity-adjusted,

except the total score of HIVTSQs and PIN, hence the

results should be regarded with care. (Clinical

Review Report)

4 PHARMACOECONOMIC

RESULT

Pharmacoeconomic research of CABENUVA has

been made by ViiV and CADTH using the Markov

cohort state transition model to discover its cost and

QALY to evaluate the value of this drug as a

treatment to HIV, especially comparing with oral

ART administration. The result was shown below in

Figure 5.

Figure 5: Annual Cost comparison between HIV treatments.

In comparison to combined oral ART, CAB+RPV

has lower overall costs and less total QALYs, as

indicated in the figure, indicating that it is not cost-

effective. The overall estimated cost of CAB + RPV

during the patient's lifetime is $647,491, whereas the

total estimated cost of oral contraceptives ART is

$646,865. The two comparisons generated similar life

years (CAB + RPV = 24.33; oral contraceptives ART

= 24.21) and QALY (18.05 and 17.96). The major

cause of the discrepancies in predicted QALYs was

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found by CADTH as adherence. The sponsor model

projected no drop in adherence among CAB + RPV

users, but increased adherence (measured as

treatment disruptions) in the oral ART method

(decline in adherence = 8.12 percent).

(Pharmacoeconomic Review Report, 2020)

Over and above what is already being done, there

is a need and potential for community pharmacists to

be used in major global health sectors. Pharmacists

may use their prescription knowledge to fill gaps in

care that fit with significant global health activities

and programs, from workforce development to drug

administration. It took decades for pharmacists in

high-income nations to move from product-centered

to patient-centered services with public health

consequences. It will take time for pharmacists in

low- and middle-income nations to make the

transition. These encouraging results highlight the

strategic necessity of enlisting the help of community

pharmacists in the Cabenuva administration. This

would be especially advantageous in many

communities where HIV services for extremely

vulnerable groups are endangered by anti-gay

legislation. Cabenuva administration at community

pharmacies provides feasible, discreet, and cost-

effective choices for patients and donor agencies

supporting ART programs in such scenarios. Finally,

authorities should ensure that pharmacists in their

communities have the resources they need to properly

support the administration of Cabenuva and other

potential public-health medications. The

aforementioned measures would complement the

many efforts being undertaken to achieve UNAIDS'

goal of ending the AIDS pandemic by 2030 by

attaining 95 percent diagnosis and 95 percent

antiretroviral treatment (ART) among all people

living with HIV (PLHIV). 95% on antiretroviral

therapy (ART) among diagnosed, and 95% virally

suppressed (VS) among treated. (Rasaq Kayode O,

2021)

The initiator created a queuing Markov state

transition model and a decision tree process hybrid

model. To represent the possibility of treatment

failure and/or interruption, the sponsor modelled

three ART lines and one remedial therapy line. The

cohort in this model migrated to the sponsor's health

condition, which was determined by the treatment

line, viral load, and CD4+ T cell count. Patients may

develop ADE, treatment-related AEs, or

cardiovascular illness in these conditions. The

transition between health condition in each monthly

cycle is determined by the cohort's viral status and

CD4+ T cell count, and the patient can reach the

absorptive state of death at any time throughout the

model cycle.

Consequently, due to the customized character of

HIV-1 therapy, particularly in terms of the timing and

reason for switching treatments, sponsors may have

overstated the cost reductions associated with CAB +

RPV. Cost reductions may or may not be obtained

depending on the setting in which CAB + RPV is

treated and if these expenses are shared by public

healthcare payers. Patients were enthusiastic about

the notion of a once-monthly injection, which is

supposed to minimize stigma by giving HIV-1

patients greater privacy and discretion. Furthermore,

patients thought that lowering pill load would

increase adherence and, as a result, viral suppression.

The experience of a patient on CAB + RPV, who

experienced less side effects and the capacity to be

more socially involved, was shared with one patient

group. (Aschenbrenner, 2021)

5 COMPARATIVE ANALYSIS

5.1 Route of Administration

Besides Cabenuva, there are other newly FDA-

approved HIV medications. Compared to other newly

approved HIV drugs, Cabenuva has its advantages as

well as its disadvantages, and the comparison will

depend on several aspects including MOA, route of

administration, indication. Although there is a large

amount of new HIV medications since the beginning

of this century. This article will mainly focus on the

comparison between Cabenuva and other new HIV

drugs since 2018.

Table 2. Route of administration and regimen of new medications

Name

Route of

Administration

Regimen Approved Time

Cabenuva Injection once a month January 22, 2021

Trogarzo Injection every 2 weeks March 6, 2018

Pifeltro Oral once daily August 30, 2018

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Dovato Oral once daily April 8, 2019

Biktarvy Oral once daily February 7, 2018

Symtuza Oral once daily July 17, 2018

Delstrigo Oral once daily August 30, 2018

Symfi Oral once daily March 22, 2018

Cimduo Oral once daily February 28, 2018

Table 2 shows the route of administration and

frequency of newly approved HIV drugs since 2018.

It can be concluded that the main route of

administration is oral, and the patients should take

medicine daily. Only Cabenuva and Trogarzo are

administered via injection and the regimen is once a

month and every 2 weeks, which reduces the impact

on patients’ daily life arising from taking medicines

daily. Compared to the regimen of Trogazo, injection

every 2 weeks, the regimen of Cabenuva is once a

month through injection after the patients take the

tablet for 28 days, which means only 12 days of

treatment is required for an entire year. (Villaluz,

2021)

5.2 Indication and MOA

Table 3 shows the indication and MOA of these new

medications. From Table 3, it can be concluded that

Trogarzo, Pifeltro and Cimduo should be used in

combination with other ARV. Dovato, Delstrigo and

Symfi can only be applied in the treatment of HIV-1

in adults. Only Cabenuva and Biktarvy are indicated

to be a complete regimen for all the patients.

Considering the indication, long-acting effect,

Cabenuva has its advantages to a large extent.

Cabenuva can be applied to a wide range of patients

and also can improve the lives of these patients.

(Villaluz, 2021)

Table 3. Indication and MOA of New Medications

Name Indication MOA

Cabenuva

Long-acting regimen with the all

HIV-1 patients

INSTI/NNRTI

Trogarzo In combination with other ARV Post-attachment Inhibitor

Pifeltro In combination with other ARV NNRTI

Dovato Treatment of HIV-1 in adults INSTI/NRTI

Biktarvy

Treatment of HIV-1 as a complete

regimen

INSTI/NRTI

Symtuza

Treatment of HIV-1 in adults and

pediatric patients

NNRTI/BOOSTER/NRTI

Delstrigo Treatment of HIV-1 in adults NNRTI/NRTI

Symfi Treatment of HIV-1 in adults NNRTI/NRTI

Cimduo In combination with other ARV NRTI

6 CONCLUSION

In conclusion, HIV is a dangerous disease that affects

patients, and the daily life of them can be improved

by accepting a wild range of treatments. Therefore,

the development of more effective and convenient

medication is important. Almost all the new HIV

drugs approved since 2018 are administered orally

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446

daily. However, there have been some drugs whose

route of administration is injection such as Trogazo

and Cabenuva. By reducing the frequency of

medicine dosage, the life quality of HIV patients can

be improved. Cabenuva, a newly approved HIV drug,

is the first complete, long-acting HIV treatment

regimen, administered by intramuscular injection

once a month. This drug can make changes to the life

of patients to a great extent compared to other HIV

medications. Moreover, the development of

Cabenuva indicates that it is possible to develop more

long-acting HIV drugs, which set a new development

trend not only focused on treatment efficiency but the

life quality of patients.

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