Cutting Edge Issues in HIV Clinical Management: No End to the Dynamism of HIV Medicine

from Infectious Disease Special Edition - Fall 2021

by McMahon Group

The Persistence of PrEP: Essential For Ending HIV

Cutting-Edge Issues In HIV Clinical Management:

No End to the Dynamism of HIV Medicine

BY RAJESH T. GANDHI, MD

The field of HIV medicine continues to be dynamic and innovative, even after 40 years since the first reports of AIDS. In 2021, we saw major advances, including the approval of the first injectable long-acting antiretroviral regimen, new insights into how to treat patients who have had virologic failure, a better understanding of HIV treatment during pregnancy, an appreciation for the interaction between HIV and COVID-19, and continued progress in our knowledge of comorbidities and coinfections.

Here, we review some of the highlights of the year in HIV clinical management from recent conferences.

Antiretroviral Therapy: The First Long-Acting HIV Regimen

In 2021, the FDA approved CAB/RPV, the first long-acting injectable regimen for the treatment of HIV. The approval of this dosage regimen of every 4 weeks was based on 2 phase 3 clinical rials—ATLAS and FLAIR—which demonstrated that monthly injections of CAB/RPV were able to maintain virologic suppression in people with HIV at rates similar to that of oral daily antiretroviral therapy (ART).1,2 In another advance, the ATLAS-2M trial demonstrated that CAB/RPV every 8 weeks was comparable with a dosage of every 4 weeks in terms of maintaining virologic suppression.3 At the 2021 Conference on Retroviruses and Opportunistic Infections, week 96 data from ATLAS-2M were presented: 91% of those receiving the regimen every 8 weeks and approximately 90% of those receiving it every 4 weeks had HIV RNA less than 50 copies/mL.4 These data support the recent filing with the FDA for a CAB/RPV dosage regimen of every 8 weeks; we eagerly await the FDA’s decision regarding this dosage interval.

What are the risk factors for virologic failure developing in people receiving CAB/RPV? In a separate analysis,

IDSE Review HIV Medication Abbreviation Key

3TC lamivudine ABC abacavir AZT zidovudine BIC bictegravir CAB/RPV cabotegravir and rilpivirine DTG dolutegravir DRV/r ritonavir-boosted darunavir EFV efavirenz FTC emtricitabine FTR fostemsavir TAF tenofovir alafenamide TDF tenofovir disoproxil fumarate

among 1,039 participants from the ATLAS, FLAIR, and ATLAS-2M clinical trials, only 13 (1.25%) had confirmed virologic failure.5 Risk factors for confirmed virologic failure included RPV resistance–associated mutations at baseline; lower RPV trough concentration at week 8; having HIV-1 subtype A1/A6; and higher body mass index. In participants who had none or only 1 of these risk factors, the rate of confirmed virologic failure was 0.4%.5 These findings support the FDA indication for CAB/RPV, which is to replace an oral regimen in patients who are virologically suppressed and have no history of treatment failure or known/suspected resistance to CAB or RPV.

What to Use in a Person Who Has Virologic Failure? A Surprising and Important Finding

Until recently, the most common first-line antiretroviral regimen in many parts of the world included an non-nucleoside reverse transcriptase inhibitor (NNRTI). What is the optimal regimen for a person who has virologic failure while receiving NNRTI-based therapy? In the NADIA trial,6 464 participants with virologic failure on TDF/3TC and an NNRTI were randomized in a 2x2 factorial design to receive DTG or DRV/r with either TDF/3TC or AZT with 3TC. Many participants in this study had advanced HIV infection: About 50% had a CD4 cell count of 200/mm3 or less, and 28% had HIV RNA of 100,000 copies/mL or higher. Nucleoside reverse transcriptase (NRTI) resistance mutations at baseline were common: 50% had K65R/N and 86% had M184V. Despite this high rate of NRTI resistance, the rates of virologic suppression on the new regimen were high: • About 90% of those randomized to received DTG and approximately 92% of those randomized to receive DRV/r achieved virologic suppression (HIV RNA <400 copies/mL). DTG resistance was detected in only 4 participants, and no participants developed DRV resistance. Even when there were no NRTIs predicted to be active in the regimen, the rate of virologic suppression was high. • About 92% of those randomized to receive

TDF/3TC and approximately 90% of those randomized to receive AZT/3TC achieved virologic suppression (HIV RNA <400 copies/mL).

The surprising and important conclusion from this study: In patients failing NNRTI-based therapy, DTG or DRV/r suppresses viremia even when NRTI resistance is present.

New Insights Into HIV Therapy During Pregnancy

One of the landmark studies on HIV therapy during pregnancy is the IMPAACT 2010 or VESTED trial. This phase 3 trial compared the safety and efficacy of the following 3 regimens in 643 treatment-naive women initiating ART during pregnancy (14-28 weeks of gestation): DTG plus FTC/TAF, DTG plus FTC/TDF, and EFV/FTC/ TDF. Most of the women in this study were in sub-Saharan Africa. At the time of enrollment, the median gestational age was about 22 weeks. At the time of delivery, the rate of virologic suppression was higher in women who received a DTG-based regimen than in those who received EFV/FTC/TDF (98% vs 91%, respectively).7 As expected, the time to virologic suppression was shorter in those who received DTG, an integrase inhibitor, compared with those who received EFV, an NNRTI. Adverse pregnancy outcomes occurred in 24% of those who received DTG plus 3TC/TAF, 33% of those who received DTG plus FTC/TDF, and 33% of those who received EFV/FTC/TDF. Neonatal mortality was lower in the group that received DTG plus FTC/TAF (1% of infants) compared with those who received EFV/FTC/TDF (5% of infants). A potential reason for the lower rate of adverse pregnancy outcomes in the group that received DTG plus FTC/TAF is that their average weight gain was closest to what is considered optimal during pregnancy.8 This hypothesis is plausible because both insufficient and excessive weight gain during pregnancy have been associated with adverse pregnancy outcomes.

This year also saw an update of the Department of Health and Human Services perinatal HIV guidelines.9 The main changes and some highlights include: • Based on new and reassuring data, DTG-based regimens are now considered one of the preferred choices throughout pregnancy and for those trying to conceive. • The preferred NRTI combinations during pregnancy are still TDF/FTC and ABC/3TC. However,

TAF/FTC is now considered an alternative NRTI combination because of data on its safety during pregnancy. • There are as yet insufficient data with BIC or with the new antiretroviral agent FTR to endorse their use during pregnancy.

COVID-19 and HIV

One of the most contentious topics of the year was whether people with HIV have worse COVID-19 outcomes than people without HIV.10

Early studies suggested there was no difference in outcomes, but recent investigations have come to the opposite conclusion. One example is an analysis of the National COVID Cohort Collaborative, which evaluated clinical outcomes in more than 500,000 adults with COVID-19.11 People with HIV were more likely to be hospitalized and require hospitalization than people without HIV, even after adjusting for other factors that portend poor outcomes. Similarly, a study from the World Health Organization12 reported that, after adjustment for age, sex, disease severity, and comorbidities, in-hospital mortality was 30% greater in people with HIV hospitalized with COVID-19 compared with people without HIV. Potential contributors10 to worse COVID-19 outcomes in people with HIV include immunodeficiency or an immune dysregulation legacy effect; comorbidities that increase the risk for clinical progression; and social determinants of health.13 These considerations, and others, highlight the importance of COVID19 prevention in people with HIV.

The most effective way to prevent COVID-19 among all people is, of course, vaccination. Do people with HIV have comparable immune responses to the COVID-19 vaccine as people without HIV? Two studies—one from the United Kingdom and the other from South Africa—reported that immune responses to the AstraZeneca COVID-19 vaccine were similar in those with and without HIV.14,15 However, the story may be different among people with HIV who are not on ART and who have low CD4 cell counts: In a case report, a person with uncontrolled HIV did not seroconvert after receiving 2 doses of a COVID-19 vaccine.16

Comorbidities and Coinfections

In recent years, it’s been recognized that certain antiretroviral medications—specifically integrase inhibitors and TAF—are associated with excess weight gain. For example, in a retrospective study called TRIO, in people with HIV who switched to an integrase inhibitor or to a new integrase inhibitor, weight gain was associated with female sex and changing from TDF to TAF.17 Whether changing from an integrase inhibitor to another drug, like DRV, or from TAF to TDF ameliorates weight gain is not certain, but is being evaluated in the AIDS Clinical Trials Group A5391 (Do-IT) study.18 Clinicians and their patients eagerly await the results of studies to inform us how to prevent or reverse weight gain among people with HIV.

Another advance from this year is the recognition that modern pangenotypic hepatitis C virus (HCV) medications make it possible to treat people with minimal monitoring. In the MINMON study, 399 participants with HCV received a 12-week course of sofosbuvir-velpatasvir; of note, there was no pretreatment genotyping and participants did not have any clinic visits or labs scheduled during the treatment course. The efficacy results were striking: Sustained virologic response occurred in 95% of participants.19

Conclusion

Even after 40 years since the first cases of AIDS were reported, there continues to be amazing progress in the care of people with HIV. We now have a variety of effective antiretroviral regimens including, for the first time, a long-acting monthly injectable regimen. We have new insights into how to achieve virologic suppres-

For people with sion in people who require second-line HIV and COVID-19, mortality was 30% therapy. We are learning more about the safety and efficacy of new regimens for treatment of HIV during higher than those pregnancy. We are making progress without HIV. in understanding the impact of HIV on COVID-19 outcomes and vaccines. Finally, we’re identifying new complications of ART, like weight gain, but also simplifying our care of coinfections, like HCV. All in all, this has been a banner year for advances in HIV medicine. I can’t wait to see what the future holds!

References

1. Swindells S, Andrade-Villanueva JF, Richmond GJ, et al. Long-acting cabotegravir and rilpivirine for maintenance of HIV-1 suppression. N Engl J Med. 2020;382(12):1112-1123. 2. Orkin C, Arasteh K, Górgolas Hernández-Mora M, et al. Longacting cabotegravir and rilpivirine after oral induction for HIV-1 infection. N Engl J Med. 2020;382(12):1124-1135. 3. Overton ET, Richmond G, Rizzardini G, et al. Long-acting cabotegravir and rilpivirine dosed every 2 months in adults with HIV-1 infection (ATLAS-2M), 48-week results: a randomised, multicentre, open-label, phase 3b, non-inferiority study. Lancet. 2021;396(10267):1994-2005. 4. Jaeger H, Overton ET, Richmond G, et al. Week 96 efficacy and safety of cabotegravir + rilpivirine every 2 months: ATLAS-2M. Presented virtually at: Conference on Retroviruses and Opportunistic Infections 2021; March 6-10, 2021. Abstract 401. http://www.croiwebcasts. org/y/2021?link=promo 5. Cutrell AG, Schapiro JM, Perno CF, et al. Exploring predictors of HIV-1 virologic failure to long-acting cabotegravir and rilpivirine: a multivariable analysis. AIDS. 2021;35(9):1333-1342. 6. Paton N, Musaazi J, Kityo CM, et al. Nucleosides and darunavir/dolutegravir in Africa (NADIA) trial: 48 weeks primary outcome. Presented virtually at: Conference on Retroviruses and Opportunistic Infections 2021; March 6-10, 2021. Abstract 94. http://www.croiwebcasts. org/y/2021?link=promo 7. Lockman S, Brummel SS, Ziemba L, et al. Efficacy and safety of dolutegravir with emtricitabine and tenofovir alafenamide fumarate or tenofovir disoproxil fumarate, and efavirenz, emtricitabine, and tenofovir disoproxil fumarate HIV antiretroviral therapy regimens started in pregnancy (IMPAACT 2010/VESTED): a multicentre, open-label, randomised, controlled, phase 3 trial. Lancet. 2021;397(10281):1276-1292. 8. Hoffman RM, Ziemba L, Brummel SS, et al. Antepartum weight gain and adverse pregnancy outcomes in IMPAACT 2010. Presented virtually at: Conference on Retroviruses and

Opportunistic Infections 2021; March 6-10, 2021. Abstract 176. http://www.croiwebcasts.org/y/2021?link=promo 9. HIV.gov. Recommendations for the use of antiretroviral drugs in pregnant women with HIV infection and interventions to reduce perinatal HIV transmission in the United States.

February 10, 2021. https://clinicalinfo.hiv.gov/en/guidelines/ perinatal/whats-new-guidelines 10. Triant VA, Gandhi RT. When epidemics collide: why people with human immunodeficiency virus may have worse coronavirus disease 2019 outcomes and implications for vaccination. Clin Infect Dis. 2021;72(12):e1030-e1034. 11. Sun J, Patel R, Madhira V, et al. COVID-19 hospitalization among people with HIV or solid organ transplant in the

US. Presented virtually at: Conference on Retroviruses and

Opportunistic Infections 2021; March 6-10, 2021. Abstract 103. http://www.croiwebcasts.org/y/2021?link=promo 12. Bertagnolio S, Thwin SS, Silva R, et al. Clinical characteristics and prognostic factors in people living with HIV hospitalized with COVID-19: findings from the WHO Global Clinical Platform. Presented virtually at: International AIDS Society 2021;

July 18-21, 2021. Track B, 2605. https://www.natap.org/2021/

IAS/IAS_49.htm 13. Meyerowitz EA, Kim AY, Ard KL, et al. Disproportionate burden of coronavirus disease 2019 among racial minorities and those in congregate settings among a large cohort of people with HIV. AIDS. 2020;34(12):1781-1787. 14. Frater J, Ewer KJ, Ogbe A, et al. Safety and immunogenicity of the ChAdOx1 nCoV-19 (AZD1222) vaccine against SARS-

CoV-2 in HIV infection: a single-arm substudy of a phase 2/3 clinical trial. Lancet HIV. 2021;8(8):e474-e485. 15. Madhi S, Koen A, Fairlie L, et al. ChAdOx1 nCoV-19 (AZD1222) vaccine in people living with and without HIV.

Preprint. Posted online March 17, 2021. Research Square. doi:10.21203/rs.3.rs-322470/v1 16. Touizer E, Alrubayyi A, Rees-Spear C, et al. Failure to seroconvert after two doses of BNT162b2 SARS-CoV-2 vaccine in a patient with uncontrolled HIV. Lancet HIV. 2021;8(6):e317-e318. 17. McComsey GA, Eron JJ, Santiago S, et al. Weight gain during treatment among 3,468 treatment-experienced adults with

HIV. Presented virtually at: Conference on Retroviruses and

Opportunistic Infections 2021; March 6-10, 2021. Abstract 671. http://www.croiwebcasts.org/y/2021?link=promo 18. ClinicalTrials.gov. Doravirine for persons with excessive weight gain on integrase inhibitors and tenofovir alafenamide. https://clinicaltrials.gov/ct2/show/NCT04636437 19. Solomon SS, Wagner-Cardoso S, Smeaton LM, et al. A simple and safe approach to HCV treatment: findings from the A5360 (Minmon) trial. Presented virtually at: Conference on Retroviruses and Opportunistic Infections 2021;

March 6-10, 2021. Abstract 135. http://www.croiwebcasts. org/y/2021?link=promo

Dr Gandhi reported having been on the scientific advisory boards for Gilead and Merck more than a year ago.

About the author

Rajesh T. Gandhi, MD, is a professor of medicine at Harvard Medical School, and the director of HIV Clinical Services and Education in the Division of Infectious Diseases, Massachusetts General Hospital, in Boston, Massachusetts. He is also the immediate past chair of the HIV Medicine Association.

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with CABENUVA, the first and only, once-monthly, long-acting, complete injectable treatment regimen for virologically suppressed adults living with HIV-1.1*

Michael, living with HIV.

CABENUVA is a DHHS

STRONGLY

RECOMMENDED (AI)† REGIMEN

for appropriate patients with HIV-12‡

CABENUVA is administered monthly as 2 intramuscular injections by a healthcare professional. Adherence to the dosing schedule is strongly recommended.1

‡Patients must have sustained viral suppression for 3 to 6 months (optimal duration is not defined), have good adherence and engagement in care, have no baseline resistance to cabotegravir or rilpivirine, have no prior virologic failures, have no active or occult HBV infection (unless receiving an oral HBV regimen), not be pregnant or plan on becoming pregnant, and not be receiving medications with significant drug interactions with oral or injectable cabotegravir or rilpivirine.2

INDICATION

CABENUVA is indicated as a complete regimen for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults to replace the current antiretroviral regimen in those who are virologically suppressed (HIV-1 RNA less than 50 copies per mL) on a stable antiretroviral regimen with no history of treatment failure and with no known or suspected resistance to either cabotegravir or rilpivirine.

IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS

• Do not use CABENUVA in patients with previous hypersensitivity reaction to cabotegravir or rilpivirine • Do not use CABENUVA in patients receiving carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine, systemic dexamethasone (>1 dose), and

St John’s wort

Please see additional Important Safety Information for CABENUVA throughout. Please see following pages for Brief Summary of full Prescribing Information for CABENUVA.

For virologically suppressed adults living with HIV-1*

ONCE-MONTHLY TREATMENT IS POSSIBLE WITH CABENUVA

First and only, once-monthly, complete treatment regimen for HIV-11†

Proven as effective as continuing a daily oral regimen1,3†

Preferred by 9 out of 10 patients in clinical trials3-5

In an exploratory endpoint in ATLAS and FLAIR Phase 3 clinical trials, patients completed a single-item question assessing their preference for CABENUVA vs their previous oral regimen.† At Week 48, 88% (523/591) of ITT-E population preferred CABENUVA vs 2% (9/591) who preferred their previous oral regimen†;59 patients did not respond to the question. These results are descriptive in nature and should not be used to infer clinical significance.

* HIV-1 RNA <50 copies/mL. 1 † Based on a pooled analysis from two Phase 3, international, randomized, non-inferiority trials (ATLAS and FLAIR) in virologically suppressed (HIV-1 RNA <50 copies/mL) adults ≥18 years with HIV-1. 1,3-5 In ATLAS, 616 treatment-experienced, virologically suppressed (for ≥6 months) patients on 2 NRTIs + an INSTI, NNRTI, or PI were randomized 1:1 to receive either CABENUVA (after a 4-week oral lead-in of daily cabotegravir 30 mg and rilpivirine 25 mg) or to remain on their current therapy.1,4 In FLAIR, patients without previous ARV exposure were given ABC/DTG/3TC (or DTG + 2 NRTIs if HLA-B*5701-positive) for 20 weeks to achieve suppression and then randomized 1:1 (N=566) to receive either CABENUVA (after a 4-week oral lead-in of daily cabotegravir 30 mg and rilpivirine 25 mg) or to remain on their current regimen.1,5 At baseline, in FLAIR and ATLAS, the median age was 34 and 40 years, respectively.1 In both studies, 7% had CD4+ cell count <350 cells/mm3 . 1 In ATLAS, baseline third-agents were 50% NNRTIs, 33% INSTIs, or 17% PIs.1 Patients were excluded if they were pregnant or breastfeeding, had moderate to severe hepatic impairment, or evidence of HBV infection at screening.4,5 Non-inferiority of CABENUVA would be shown if the upper bound of the 95% CI for the treatment difference was <6% for the individual studies or <4% for the pooled analysis.3-5 Primary endpoint was proportion of patients with HIV-1 RNA ≥50 copies/mL atWeek 48 via FDA Snapshot Algorithm.3 Proportion of patients with HIV-1 RNA ≥50 copies/mL atWeek 48 in pooled analysis was 2% for CABENUVA vs 2% for daily oral comparator (non-inferior treatment difference: 0.2% [95% CI: -1.4, 1.7]).1,3 3TC=lamivudine;ABC=abacavir;ARV=antiretroviral;CI=confidenceinterval;DTG=dolutegravir; FDA=FoodandDrugAdministration; HLA-B=human leukocyte antigen complex B; INSTI=integrase strand transfer inhibitor; ITT-E=intent-to-treat efficacy; NNRTI=non-nucleoside reverse transcriptase inhibitor; NRTI=nucleoside reverse transcriptase inhibitor; PI=protease inhibitor.

References: 1.CABENUVA [packageinsert].Research TrianglePark, NC:ViiV Healthcare;2021.2.Panel onAntiretroviral GuidelinesforAdults andAdolescents. Guidelinesforthe UseofAntiretroviral AgentsinAdultsandAdolescentswith HIV.Departmentof Healthand HumanServices. https://clinicalinfo.hiv.gov/sites/default/files/guidelines/documents/AdultandAdolescentGL.pdf.Accessed June30, 2021.3.Rizzardini G, Overton ET, OrkinC, etal. Long-actinginjectablecabotegravir + rilpivirinefor HIVmaintenancetherapy:Week 48pooledanalysisofphase3ATLASand FLAIRtrials.J Acquir Immune Defic Syndr.2020;85(4):498-506.4.SwindellsS, Andrade-Villanueva JF, Richmond GJ, etal. Long-actingcabotegravir andrilpivirineformaintenanceof HIV-1 suppression.N Engl J Med.2020;382(12):1112-1123.5. OrkinC, Arasteh K, Górgolas Hernández-MoraM, et al. Long-acting cabotegravir and rilpivirine after oral induction for HIV-1 infection. N Engl J Med. 2020;382(12):1124-1135.

WARNINGS AND PRECAUTIONS

Hypersensitivity Reactions:

• Hypersensitivity reactions, including cases of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), have been reported during postmarketing experience with rilpivirine-containing regimens. While some skin reactions were accompanied by constitutional symptoms such as fever, other skin reactions were associated with organ dysfunctions, including elevations in hepatic serum biochemistries •Serious or severe hypersensitivity reactions have been reported in association with other integrase inhibitors and could occur with CABENUVA •Discontinue CABENUVA immediately if signs or symptoms of hypersensitivity reactions develop. Clinical status, including liver transaminases, should be monitored and appropriate therapy initiated. Prescribe the oral lead-in prior to administration of CABENUVA to help identify patients who may be at risk of a hypersensitivity reaction

Post-Injection Reactions:

• Serious post-injection reactions (reported in less than 1% of subjects) were reported within minutes after the injection of rilpivirine, including dyspnea, agitation, abdominal cramping, flushing, sweating, oral numbness, and changes in blood pressure. These events may have been associated with inadvertent (partial) intravenous administration and began to resolve within a few minutes after the injection •Carefully follow the Instructions for Use when preparing and administering CABENUVA to avoid accidental intravenous administration. Observe patients briefly (approximately 10 minutes) after the injection. If a post-injection reaction occurs, monitor and treat as clinically indicated

Hepatotoxicity:

• Hepatotoxicity has been reported in patients receiving cabotegravir or rilpivirine with or without known pre-existing hepatic disease or identifiable risk factors •Patients with underlying liver disease or marked elevations in transaminases prior to treatment may be at increased risk for worsening or development of transaminase elevations •Monitoring of liver chemistries is recommended and treatment with CABENUVA should be discontinued if hepatotoxicity is suspected

Depressive Disorders:

•Depressive disorders (including depressed mood, depression, major depression, mood altered, mood swings, dysphoria, negative thoughts, suicidal ideation or attempt) have been reported with CABENUVA or the individual products •Promptly evaluate patients with depressive symptoms

Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions:

• The concomitant use of CABENUVA and other drugs may result in known or potentially significant drug interactions (see Contraindications and Drug Interactions) •Rilpivirine doses 3 and 12 times higher than the recommended oral dosage can prolong the QTc interval. CABENUVA should be used with caution in combination with drugs with a known risk of Torsade de Pointes

Long-Acting Properties and Potential Associated Risks with CABENUVA:

• Residual concentrations of cabotegravir and rilpivirine may remain in the systemic circulation of patients for prolonged periods (up to 12 months or longer). Select appropriate patients who agree to the required monthly injection dosing schedule because non-adherence to monthly injections or missed doses could lead to loss of virologic response and development of resistance • To minimize the potential risk of developing viral resistance, it is essential to initiate an alternative, fully suppressive antiretroviral regimen no later than 1 month after the final injection doses of CABENUVA. If virologic failure is suspected, switch the patient to an alternative regimen as soon as possible

ADVERSE REACTIONS

The most common adverse reactions (incidence ≥2%, all grades) with CABENUVA were injection site reactions, pyrexia, fatigue, headache, musculoskeletal pain, nausea, sleep disorders, dizziness, and rash.

DRUG INTERACTIONS

• Refer to the applicable full Prescribing Information for important drug interactions with CABENUVA, VOCABRIA, or EDURANT • Because CABENUVA is a complete regimen, coadministration with other antiretroviral medications for the treatment of HIV-1 infection is not recommended •Drugs that are strong inducers of UGT1A1 or 1A9 are expected to decrease the plasma concentrations of cabotegravir. Drugs that induce or inhibit CYP3A may affect the plasma concentrations of rilpivirine •CABENUVA should be used with caution in combination with drugs with a known risk of Torsade de Pointes

USE IN SPECIFIC POPULATIONS

•Pregnancy: There are insufficient human data on the use of CABENUVA during pregnancy to adequately assess a drug-associated risk for birth defects and miscarriage. Discuss the benefit-risk of using CABENUVA during pregnancy and conception and consider that cabotegravir and rilpivirine are detected in systemic circulation for up to 12 months or longer after discontinuing injections of CABENUVA. An Antiretroviral Pregnancy Registry has been established •Lactation: The CDC recommends that HIV-1−infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection. Breastfeeding is also not recommended due to the potential for developing viral resistance in HIV-positive infants, adverse reactions in a breastfed infant, and detectable cabotegravir and rilpivirine concentrations in systemic circulation for up to 12 months or longer after discontinuing injections of CABENUVA

Please see following pages for Brief Summary of full Prescribing Information for CABENUVA.

Visit CABENUVAhcp.com