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Updates to the 2021 Guidelines for ARV Use in Adults and Adolescents With HIV
BY ASHLEY HOARE, MS; JESSICA HOARE, MS;
AND JULIA GARCIA-DIAZ, MD, MSC, FACP, FIDSA, CPI
There were almost 38,000 adults and adolescents diagnosed with HIV infection in the United States and dependent areas in 2018, a decrease compared with 2015.1 The highest rates of diagnoses were reported in the South, the Northeast, followed by the West (Figure). Although almost 80% of these new diagnoses were in men, the number of men diagnosed with HIV in the United States and dependent areas decreased by 10% between 2015 and 2019. Despite the decrease in new diagnoses, the prevalence of HIV in adults and adolescents in the United States increased to more than 1 million in 2019.2 Of those living with HIV, approximately 65% have achieved viral suppression of their HIV infection.3 Achieving viral suppression is the result of careful selection of and adherence to the appropriate treatment. Recent data from a number of ongoing clinical trials have led to several updates to the “Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents Living with HIV” that are important to consider when selecting the optimal treatment.4
Four regimens are currently in the category “recommended as initial regimens for most people with HIV” (Table 1).4 Three of these regimens include 1 integrase strand transfer inhibitor (INSTI) in combination with 2 nucleoside reverse transcriptase inhibitors (NRTIs). The fourth recommended regimen for initial treatment is a combination of 1 INSTI with 1 NRTI. Dolutegravirlamivudine (DTG/3TC; Dovato, ViiV Healthcare). However, DTG/3TC is only recommended for people who have already had genotypic testing for reverse transcriptase; it is not recommended for those with HIV RNA greater than 500,000 copies/mL, nor for patients with hepatitis B virus
IDSE Review Table 1. Recommended as Initial Regimens for Most People With HIV
Brand Name Generic Name Abbreviation
Biktarvy
Triumeq
Tivicay + Emtriva/Epivir + Vemlidy/Viread Bictegravir 50 mg/emtricitabine 200 mg/ tenofovir alafenamide 25 mg BIC/TAF/FTC
Dolutegravir 50 mg/abacavir 600 mg/ lamivudine 300 mg
Dolutegravir 50 mg + emtricitabine 200 mg/lamivudine 300 mg + tenofovir alafenamide 25 mg/tenofovir disoproxil fumarate DTG/ABC/3TC
DTG + TAF/TDF + FTC/3TC 1 integrase strand transfer inhibitor (INSTI) + 2 nucleoside reverse transcriptase inhibitors (NRTIs)
Dovato Dolutegravir 50 mg/lamivudine 300 mg DTG/3TC 1 INSTI with 1 NRTI
Adapted from reference 3.
(HBV) coinfection.4 The aforementioned regimens are considered effective with high tolerability, favorable toxicity profiles, and virologic efficacy in addition to ease of use.
Since the 2018 guidelines update, regimens based on raltegravir (RAL; Isentress and Isentress HD, Merck) have been removed from the “recommended initial regimens for most people with HIV”’ category and placed in the “recommended initial regimen in certain clinical situations” category. The regimens listed in this category may be more favorable for patients presenting with different clinical situations that would make the typical starting regimens less ideal. Raltegravir-based regimens may be preferred in the setting of chronic kidney disease, specifically when abacavir (ABC), tenofovir alafenamide, and tenofovir disoproxil fumarate cannot be used due to HBV coinfection. In the setting of hyperlipidemia, RAL may be a preferred treatment option because it has fewer effects on lipid levels. This regimen also may be considered in patients with high cardiac risk to avoid worsening hyperlipidemia. In addition, RAL does not require food intake to increase absorption, and can be considered for patients who find higher caloric intake challenging. Despite its usefulness in these specific patient populations, RALbased regimens are no longer recommended for most people living with HIV. This is partially due to RAL no longer being required as an alternative to DTG.4 Raltegravir was initially preferred over DTG because of preliminary results from the initial analysis of the Tsepamo study, conducted in Botswana. These results showed a prevalence of neural tube defects (NTDs) in 0.94% in those with DTG exposure during conception compared with 0.12% in those with non-DTG antiretroviral treatment (ART) exposure.5 The Tsepamo study looks at birth outcomes to evaluate the prevalence of NTDs associated with antiretroviral (ARV) exposure at conception. Further analysis, as of April 2020, showed a significantly reduced prevalence of 0.19% with DTG exposure compared with 0.11% in those with nonDTG ART at conception. Furthermore, the difference in prevalence between the 2 groups was not considered statistically significant.5 Due to the significant decrease in actual prevalence of NTDs associated with DTG exposure, the Panel on Antiretroviral Guidelines for Adults and Adolescents now considers DTG-based regimens appropriate for women of childbearing potential. In conjunction to no longer being needed as an alternative for DTG in women of childbearing potential, RAL also has a higher pill burden when compared with bictegravir (BIC) or DTG regimens, is not part of a single-tablet regimen, and has a lower barrier to resistance than the other INSTI-based regimens.3
Dolutegravir in Women of Childbearing Potential
Because DTG has multiple advantages, the panel considers it as a “preferred ARV.” Dolutegravir is administered as a single, once-daily dose and has favorable tolerability, increasing the likelihood of patient adherence. Furthermore, studies such as DolPHIN1 have shown an association between DTG-containing regimens and rapid viral load suppression. In women of childbearing potential attempting to conceive, this is favorable, as it reduces changes of perinatal HIV transmission while maintaining maternal health.6In the randomized DolPHIN1 study, the safety and pharmacokinetics of DTG was compared
with standard-of-care drugs (nevirapine) in pregnant women with untreated HIV. Suppression of HIV RNA to less than 50 copies/mL occurred twice as fast with DTG compared with the nevirapine standard-of-care treatment.6 The guidelines now recommend that DTG can be prescribed in most people with HIV, if providers fully discuss the risks and benefits of this treatment option with women of childbearing potential. On the contrary, data regarding BIC-based regimens in pregnant women remain insufficient and still should not be used in this population.4
Cabotegravir (CAB), an INSTI, was approved as an oral tablet in combination with rilpivirine (RPV), a nonNRTI, for treatment of patients living with HIV-1.4,7,8 In June 2021, the treatment guidelines for optimizing ART in the setting of virologic suppression were updated to include the long-acting injectable combination of CAB and RPV (CAB LA + RPV LA; Cabenuva, ViiV Healthcare) as an option for patients.3 This update was the result of several successful clinical trials, such as FLAIR (First Long-Acting Injectable Regimen Trial) and ATLAS (Antiretroviral Therapy as Long-Acting Suppression Trial). This and other recently approved antiretroviral therapies are highlighted in Table 2.
FLAIR looked at the use of CAB LA plus RPV LA in more than 600 adults with HIV-1 who were treatment-naive. Patients with HIV-1 levels of at least 1,000 copies/mL and any CD4+ count were enrolled from centers around the world. They received 20 weeks of daily induction therapy with DTG/ABC/3TC before being randomly selected for a treatment group. If their viral loads were suppressed, they were randomly selected for either the maintenance arm, which was the continuation of oral standard-of-care therapy, or CAB LA plus RPV LA.9
As lead-in therapy, participants in the experimental arm received 4 weeks of daily oral CAB (30 mg) and RPV (25 mg). At week 4, they received injections of 600 mg of CAB and 900 mg of RPV. This was followed by an injectable 400 mg of CAB and 600 mg of RPV 21 to 28 days after the first and second injections, and 28 to 35 days later for each subsequent injection. At 48 weeks, the long-acting injectable regimen was noninferior to the oral maintenance arm. Injection site reactions were very common among participants in the long-acting injectable arm, occurring at least once in 86% of the participants. Most were injection site reactions that were mild or moderate and resolved within a week. The incidence of injection site reactions also decreased after the first injection. In the long-acting injectable arm, the most common other drug-related adverse events were headache, fatigue, and pyrexia.9 While the updates to the treatment guidelines were based on the 48-week data, the recently analyzed 124week data also were favorable. At 124 weeks, 80.2% of participants receiving CAB LA plus RPV LA had maintained virologic suppression. Less than 5% of participants had a virologic nonresponse. Virologic data for the other 15% of participants are not yet available.10
The CAB LA plus RPV LA regimen also was investigated in patients with HIV-1 who had already achieved viral suppression on oral ARV medication. ATLAS enrolled adult participants with HIV-1 RNA levels less
West (n=7,229) Urban: 88% Suburban: 9% Rural: 3%
Midwest (n=4,904) Urban: 78% Suburban: 15% Rural: 7%
Northeast (n=5,495)
Urban: 92% Suburban: 6% Rural: 2%
Figure. HIV diagnoses by region in 2018. Based on reference 1.
South (n=19,369) Urban: 76% Suburban: 15% Rural: 9% IDSE
than 50 copies/mL and had completed 6 months of oral ART; patients who received DTG/ABC/3TC were excluded from participating. Participants who met eligibility criteria were randomly selected to either the standard-of-care maintenance arm, continuation of oral ART, or the CAB LA plus RPV LA arm.11
Similar to FLAIR, the participants were given four weeks of lead-in therapy: 30 mg of CAB and 25 mg of RPV. Once the lead-in was complete at 4 weeks, they received injections of 600 mg of CAB and 900 mg of RPV. They then received injections of 400 mg of CAB and 600 mg of RPV every 4 weeks. At 48 weeks, CAB LA plus RPV LA met the primary end point and was noninferior to the comparator arm. Those in the CAB LA plus RPV LA arm had viral loads of 59 copies/mL or less compared with 1% of those in the oral maintenance arm. Those in the long-acting injectable arm reported injection site reactions, headache, pyrexia,
Table 2. Recently Approved Drugs for Adults With HIV
Drug Class Generic Name Brand Name Indication FDA Approval Date
Post-Attachment Inhibitors
Post-attachment inhibitors block CD4 receptors on the surface of certain immune cells that HIV needs to enter the cells Ibalizumab-uiyk Trogarzo Approved for HIV patients who are heavily treatmentexperienced and whose HIV cannot be successfully treated with other currently available therapies to be used in combination with other ARVs March 6, 2018
Attachment Inhibitors
Attachment inhibitors bind to glycoprotein 120 on the outer surface of HIV, preventing HIV from entering CD4 cells Fostemsavir Rukobia Approved for HIV patients who have tried multiple HIV medications and whose HIV infection cannot be successfully treated with other therapies because of resistance, intolerance, or safety considerations to be used in combination with other ARVs July 2, 2020
New Integrase Inhibitors
Cabotegravir-rilpivirine injectable formulation
Cabotegravir tablet formulation Cabenuva Injectable approved as a complete regimen for the treatment of HIV-1 in adults to replace a current ART in those who are virologically suppressed on a stable ART with no history of treatment failure and with no known/ suspected resistance to either cabotegravir or rilpivirine
Vocabria This tablet should be taken in combination with oral rilpivirine (Edurant) for 1 mo prior to starting treatment with Cabenuva to ensure the medications are well tolerated before switching to the extended-release injectable formulation Jan 21, 2021
Jan 21, 2021
Preexposure Prophylaxis
Cabotegravir tablet formulation
Cabotegravir extendedrelease injectable suspension
ART, antiretroviral treatment; ARVs, antiretrovirals Vocabria Note that these formulations were approved for preexposure prophylaxis and not treatment Dec 20, 2021
Apretude Dec 20, 2021
and fatigue. The injection site reactions were mostly mild or moderate and resolved within 3 days.11
After ATLAS and FLAIR established the noninferiority of an injectable regimen of CAB and RPV, different injection time lines were considered. From 2017 to 2018, participants from the ATLAS trial enrolled into the ATLAS-2M trial, a phase 3b, multicenter study. More than 1,000 eligible participants were randomly selected to receive either CAB LA plus RPV LA every 4 or every 8 weeks. There were no significant differences in safety or efficacy between the every-4-week injection arm and the every-8-week injection arm.12 65 FLAIR, ATLAS, and ATLAS-2M also collected surveys on participant satisfaction with their regimen.9,11,13 The large majority of participants from FLAIR and ATLAS greatly favored the CAB LA plus RPV LA regimen over continued daily oral therapy.9,11 Surveys from ATLAS2M considered a variety of participant satisfaction–specific questions including treatment satisfaction, reason for transitioning to a long-acting injectable regimen, and acceptability of injections. Similar to findings from FLAIR and ATLAS, participants reported greatly favoring the treatment schedule for the long-acting injectable regimen compared with their previous daily oral therapy regimens. Participants also reported favoring the every-8-week regimen over the every-4-week regimen.13
To maintain viral suppression, patients living with HIV-1 usually rely on oral ART medication that must be taken every day. This regimen can be time-consuming and disheartening for patients. Long-acting injectable ARVs are emerging as an effective alternative for maintaining viral suppression for these patients.11 The guideline update recommends that providers consider this option for patients who have already achieved 3 to 6 months of virologic suppression on an oral regimen and are capable and committed to make the necessary visits for the injections.4
Fostemsavir (FTR; Rukobia, ViiV Healthcare) was approved in 2020, and is a therapy option that providers can consider for patients with multidrug-resistant (MDR) HIV in the setting of a failing ARV regimen due to resistance, intolerance, or safety concerns. Fostemsavir, which is given with other ARVs, is an attachment inhibitor that binds to glycoprotein 120 on the HIV envelope, preventing it from binding to the host CD4 cell surface.14 BRIGHTE, an ongoing phase 3, randomized trial, is analyzing the efficacy of FTR in heavily ART-experienced participants with MDR HIV in virologic failure.15 Participants were split into 2 cohorts. The first cohort included 272 participants who were randomized in a 3:1 ratio to receive either 600 mg of FTR twice daily or placebo. In conjunction with the cohort’s regimen failure for 8 days and following day 8, the placebo group began FTR treatment while all participants initiated optimized background therapy. The nonrandomized cohort included 99 participants who were placed on FTR with optimized background therapy from the start.1 HIV RNA levels decreased by 0.79 log10 copies/ mL in the FTR group compared with a decline of 0.17 log10 copies/mL in the placebo Only 65% of group. In addition, HIV RNA was reduced to less than 40 copies/mL in 54% of the randomized cohort those living with and 38% in the nonrandomized cohort.15 After 96 weeks, virologic HIV in the US response increased to 60% in the randomized cohort and remained achieved viral unchanged in the nonrandomized cohort.16 Only 7% of participants suppression. discontinued treatment secondary to adverse events.16 The phase 2b randomized trial, Al438011, found that viral response rates among 251 treatment-experienced participants randomized in a 1:1:1:1:1 ratio across 4 different dosing regimens of FTR (400 mg twice daily, 800 mg twice daily, 600 mg once daily, and 1,200 mg once daily) and a control group receiving ritonavir-boosted atazanavir once daily remained similar through 48 weeks.17 Both groups also had similar tolerability and adverse events.16
Ibalizumab-uiyk
Ibalizumab-uiyk (IBA; Trogarzo, Theratechnologies), a CD4 post-attachment inhibitor, is also considered a safe, effective treatment option in MDR patients with HIV. In a phase 3 single-arm clinical trial, 40 MDR HIV participants who experienced virologic failure on their current ARV regimen were given IBA infusions every 2 weeks in addition to optimized baseline therapy.18 After 25 weeks of treatment, 27 participants continued through 96 weeks of IBA infusion. At week 25, the median viral load reduction of patients continuing long-term treatment was 2.5 log10 copies/mL. By week 96, the median viral load reduction was 2.8 log10 copies/mL. Of the 27 patients who continued 96 weeks on study, 64% had HIV RNA less than 50 copies/mL at week 25. By week 96, 14 of those 16 patients maintained viral suppression. No new safety concerns were noted through the 96 weeks, and efficacy was maintained throughout the study.19 Updated guidelines recommend providers consider IBA injections with other ARVs in heavily treatment-experienced patients whose HIV cannot be treated appropriately with other available therapy options. While IBA
offers a safe, effective, and lasting treatment option for those with MDR HIV, the drug is only administered via IV infusion compared with the oral regimen of FTR.
Looking to the Future
A wide array of treatment options are available for patients living with HIV. The standard regimens recommended for most patients with HIV continue to be daily oral ART. DTG, a preferred ARV, remains a promising treatment option for women with HIV who are of childbearing potential to reduce the risk for perinatal transmission. CAB LA plus RPV LA regimens offer a promising alternative to daily oral therapy for people living with HIV who are able to commit to the monthly injection visits. In individuals with MDR HIV, the FTR oral regimen and IBA infusion offer safe, effective treatment that reduces viral loads.
References
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2. CDC. Diagnoses of HIV infection in the United States and dependent areas 2019. HIV Surveillance Report. 2019;32. Published May 2021. Accessed March 14, 2022. https://www.cdc. gov/hiv/library/reports/hiv-surveillance/vol-32/index.html
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March 14, 2022. https://www.cdc.gov/hiv/library/reports/hivsurveillance/vol-26-no-2/index.html
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Botswana. Presented at: 2020 International AIDS Conference;
July 6-10, 2020. Abstract OAXLB0102.
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7. National Institutes of Health. Cabotegravir - patient.
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8. National Institutes of Health. Rilpivirine - patient. Accessed
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13. Chounta V, Overton ET, Mills A, et al. Patient-reported outcomes through 1 year of an HIV-1 clinical trial evaluating long-acting cabotegravir and rilpivirine administered every 4 or 8 weeks (ATLAS-2M). Patient. 2021;14(6):849-862.
14. Lalezari JP, Latiff GH, Brinson C, et al. Safety and efficacy of the HIV-1 attachment inhibitor prodrug BMS-663068 in treatment-experienced individuals: 24 week results of
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16. Lataillade M, Lalezari JP, Kozal M, et al. Safety and efficacy of the HIV-1 attachment inhibitor prodrug fostemsavir in heavily treatment-experienced individuals: week 96 results of the phase 3 BRIGHTE study. Lancet HIV. 2020;7(11):e740-e751.
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J Acquir Immune Defic Syndr. 2018;77(3):299-307.
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19. Emu B, Lalezari J, Kumar P, et al. Ibalizumab: 96 week data and efficacy in patients resistant to common antiretrovirals [CROI Abstract 485]. Top Antivir Med. 2019;27(suppl 1):179s.
About the authors
Ashley Hoare, MS, is a clinical research coordinator, Ochsner Clinic Foundation, New Orleans, Louisiana.
Jessica Hoare, MS, is a clinical research coordinator, Ochsner Clinical Foundation, New Orleans, Louisiana.
Julia Garcia-Diaz, MD, MSc, FACP,
FIDSA, CPI, is the director of clinical infectious diseases research, the director of medical student research, and an associate professor at the University of Queensland, Ochsner Clinical School, in Brisbane, Australia; a clinical assistant professor at Tulane University School of Medicine, Ochsner Clinical School, in Brisbane, Australia; and a clinical assistant professor at Tulane University School of Medicine, Oschner Medical Center, in New Orleans, Louisiana.
