Agents Used in Antiretroviral Therapy
Clinical Care Options | September 2021

 

Philip Grant, MD

Assistant Professor

Division of Infectious Diseases

Stanford University

Stanford, California


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In this educational module, Philip Grant, MD, reviews the development and clinical application of antiretroviral agents and classes. Highlights of the content on integrase strand transfer inhibitors are provided below. Click through to the full module to learn about other agents.


Integrase Strand Transfer Inhibitors


INSTIs act to inhibit HIV-associated DNA strand transfer, a process catalyzed by the HIV integrase enzyme. With their high efficacy and improved tolerability, current US and European guidelines favor INSTIs for first-line therapy in combination with NRTIs. Raltegravir was the first INSTI approved by the FDA. Elvitegravir was approved in 2012 as part of the single-tablet regimen cobicistat/elvitegravir/emtricitabine/tenofovir DF for use in treatment-naive patients, in 2014 as a single agent and in 2015 as part of the single-tablet regimen cobicistat/elvitegravir/emtricitabine/tenofovir alafenamide for use in treatment-naive patients and as a switch regimen in patients with virologic suppression on their current regimen. Dolutegravir was approved in August 2013 for use in both treatment-naive and treatment-experienced patients, including INSTI-experienced patients. In 2018, another INSTI, bictegravir, was approved by the FDA as part of the coformulated regimen bictegravir/emtricitabine/tenofovir AF for treatment-naive patients and for patients who have been virologically suppressed on another complete antiretroviral regimen for 3 months or longer.


In 2021, injectable cabotegravir plus injectable rilpivirine was approved for the treatment of HIV infection in adults to replace the current antiretroviral regimen in patients who are virologically suppressed (HIV-1 RNA <50 copies/mL) on a stable antiretroviral regimen with no history of treatment failure and with no known or suspected resistance to either cabotegravir or rilpivirine.65


Dolutegravir. Dolutegravir was approved in August 2013 and is indicated in combination with other antiretroviral agents for the treatment of HIV infection in adults and children aged at least 4 weeks and weighing ≥3 kg.66 It is coformulated as part of 3 complete regimens for the treatment of HIV infection, abacavir/dolutegravir/lamivudine, dolutegravir/rilpivirine, and dolutegravir/lamivudine. Abacavir/dolutegravir/lamivudine is indicated for both treatment-naive and treatment-experienced patients,67 dolutegravir/rilpivirine is indicated as a switch regimen for patients with virologic suppression (HIV-1 RNA <50 copies/mL) on a stable antiretroviral regimen for 6 months or longer with no history of treatment failure and no known resistance to dolutegravir or rilpivirine,68 and dolutegravir/lamivudine is indicated for adults with no antiretroviral treatment history or with undetectable HIV-1 RNA on their current antiretroviral regimen and no history of treatment failure and no known substitutions associated with resistance to dolutegravir or lamivudine.69


Dolutegravir was approved as a result of efficacy demonstrated in treatment-naive patients in the phase III studies: SPRING-2 vs raltegravir,29 SINGLE vs efavirenz,30 and FLAMINGO (open label) vs darunavir/ritonavir.73 The SAILING study vs raltegravir in treatment-experienced, INSTI-naive patients74 and the VIKING-3 trial in treatment-experienced patients with current or previous failure of an INSTI-containing regimen5 provided additional evidence of this drug’s efficacy. dolutegravir is generally dosed as 50 mg once daily in both treatment-naive and treatment-experienced adult patients. The exception to this occurs in INSTI-experienced patients with INSTI-associated resistance or clinically suspected INSTI-associated resistance and in patients receiving certain concomitant medications; these individuals should receive dolutegravir 50 mg twice daily. The dose of dolutegravir does not generally need to be adjusted in renal or hepatic dysfunction but has not been studied in end-stage renal disease or Child-Pugh class C hepatic dysfunction.


Raffi and colleagues29 reported the primary efficacy analysis of the SPRING-2 trial that compared dolutegravir with raltegravir, both with 2 NRTIs. At Week 48, once-daily dolutegravir was found to be noninferior to twice-daily raltegravir with 88% vs 85% of patients, respectively, with HIV-1 RNA levels <50 copies/mL by FDA snapshot analysis. Both arms were associated with a CD4+ cell count increase of 230 cells/mm3. There were no significant differences between arms in HIV-1 RNA <50 copies/mL at Week 48 according to baseline HIV-1 RNA level or NRTI backbone. The rate of protocol-defined virologic failure was not significantly different between dolutegravir vs raltegravir (5% vs 7%, respectively). No integrase or NRTI resistance was identified among patients in the dolutegravir arm. Integrase and NRTI resistance was seen in the raltegravir arm but was uncommon, identified in 1 and 4 patients, respectively. Few AEs leading to discontinuation were seen in either arm. Week 96 results confirmed noninferiority of dolutegravir to raltegravir with 81% of patients in the dolutegravir arm and 76% of patients in the raltegravir arm group having HIV-1 RNA <50 copies/mL.75 No study drug–related serious AEs occurred between Week 48 and Week 96. At virologic failure, no additional resistance to INSTIs or NRTIs was detected after Week 48 or in any patient receiving dolutegravir.


Dolutegravir as a part of the 1-pill once-daily coformulation abacavir/dolutegravir/lamivudine was approved as a single-tablet regimen by the FDA in 2014 following results from the phase III SINGLE trial comparing dolutegravir plus abacavir/lamivudine to efavirenz/emtricitabine/tenofovir DF.30,67 In this trial, the dolutegravir regimen was found to be superior to efavirenz at Week 48, which was the first time any ART combination had been found to be statistically superior to efavirenz in a randomized comparative clinical trial of first-line therapy at the primary endpoint of the study. At Week 48, 88% of patients receiving dolutegravir vs 81% of those receiving the efavirenz regimen had HIV-1 RNA levels <50 copies/mL by the FDA snapshot analysis (difference in response: +7.4%; 95% CI: +2.5% to +12.3%; P = .003). The difference was driven primarily by discontinuations for AEs: more patients in the efavirenz arm vs the dolutegravir arm discontinued therapy for AEs (10% vs 2%, respectively). The AEs seen with efavirenz were primarily neuropsychiatric events and rash. The rate of protocol-defined virologic failure was 4% in each arm. At Week 96, the trial switched to an open-label phase. At Week 144, the dolutegravir regimen remained superior to efavirenz at reducing HIV-1 RNA levels to <50 copies/mL with 71% of patients compared with 63% achieving virologic success, respectively (difference in response: +8.3%; 95% CI: +2% to +14.6%; P = .01).76 No treatment-emergent integrase or NRTI resistance mutations were identified among patients with protocol-defined virologic failure in the dolutegravir arm, but NNRTI and NRTI resistance were identified in 6 and 1 patients, respectively, among patients in efavirenz arm. A CD4+ cell count increase of 267 cells/mm3 was seen with dolutegravir vs 208 cells/mm3 with efavirenz at Week 48, and by Week 144, these increases reached 378 cells/mm3 vs 332 cells/mm3, respectively.30,76


In both trials of treatment-naive patients, dolutegravir was associated with a small increase in creatinine resulting from the anticipated inhibition of creatinine secretion of dolutegravir without affecting glomerular filtration rate. No patients withdrew because of renal events.29-30


The open-label FLAMINGO study randomized 484 treatment-naive individuals to dolutegravir vs darunavir/ritonavir, each with investigator-selected NRTIs.73 At 48 weeks, a greater proportion of patients receiving dolutegravir vs darunavir/ritonavir met the study’s primary endpoint, HIV-1 RNA levels <50 copies/mL by the FDA snapshot analysis: 90% vs 83%, respectively (adjusted treatment difference: 7.1%; 95% CI: +0.9% to +13.2%; P = .025). This difference between the 2 regimens was explained by reduced rates of discontinuation for AEs (1% in the dolutegravir arm vs 4% in the darunavir/ritonavir arm) or for other reasons (2% vs 5%, respectively). Increases in low density lipoprotein cholesterol were significantly smaller in the dolutegravir arm, although small increases in serum creatinine were observed in this group. Overall, however, laboratory abnormalities were uncommon. Serious AEs were reported in 11% of dolutegravir recipients and 5% of darunavir/ritonavir recipients. At Week 96, the dolutegravir regimen remained superior to darunavir/ritonavir with 80% of patients vs 68% achieving HIV-1 RNA <50 copies/mL (difference in response +12.4%; 95% CI: +4.7 to +20.2; P = .002).77 Smaller changes in lipid levels with the dolutegravir regimen also continued through Week 96.


In addition, dolutegravir is now included as part of a recommended first-line, NRTI-limiting regimen, paired with lamivudine in the DHHS and EACS guidelines.10-11 This recommendation was based largely on the promising results from the parallel, double-blind, randomized phase III GEMINI-1 and GEMINI-2 trials. These studies compared initial ART with dolutegravir plus lamivudine vs dolutegravir plus emtricitabine/tenofovir DF and demonstrated noninferiority of the 2-drug regimen after 48 weeks by a Snapshot analysis of the intention-to-treat–exposed population.78 In a pooled analysis of both trials, 91% of patients treated with the 2-drug regimen vs 93% of patients treated with the 3-drug regimen had HIV-1 RNA <50 copies/mL (primary endpoint) at Week 48 (adjusted difference -1.7%; 95% CI: -4.4% to 1.1%), meeting the prespecified -10% noninferiority margin. Virologic efficacy was generally consistent across patient subgroups stratified by baseline HIV-1 RNA level and CD4+ cell count. However, among patients in the dolutegravir plus lamivudine arm, the rate of virologic suppression at Week 48 by Snapshot analysis was numerically lower, at 79% (50/63), for the subgroup of patients with baseline CD4+ cell counts ≤200 cells/mm3 vs 93% (605/653) among those with baseline CD4+ cell counts >200 cells/mm3. The rates of confirmed virologic withdrawal through Week 48 were low (≤1%) in both treatment arms, and no treatment-emergent INSTI or NRTI resistance associated mutations were detected among patients with confirmed virologic withdrawal in either arm. Although the overall AE profiles were similar between treatment arms, there were significant differences in the magnitude of change from baseline to Week 48 for renal and bone biomarkers (P <.001 for all renal and bone markers assessed), with the differences indicating a more favorable renal and bone profile for dolutegravir plus lamivudine vs dolutegravir plus emtricitabine/tenofovir DF. The results of the 96-week analysis showed that the 2-drug dolutegravir plus lamivudine regimen had high efficacy rates compared with the 3-drug regimen of dolutegravir plus emtricitabine/tenofovir DF with no treatment-emergent resistance detected. In a pooled analysis, 86% (616/716) of patients receiving dolutegravir plus lamivudine had HIV-1 RNA <50 copies/mL vs 90% (642/717) of patients receiving dolutegravir plus emtricitabine/tenofovir DF (adjusted difference: -3.4%; 95% CI: -6.7% to 0%). In addition, 11 patients (1.5%) receiving dolutegravir plus lamivudine and 7 patients (1.0%) receiving the 3-drug regimen met protocol-defined virologic withdrawal criteria. Treatment with dolutegravir plus lamivudine was associated with significantly lower rate of drug-related AEs and more favorable changes in renal and bone biomarkers vs the 3-drug regimen.79


As a result of these trials, several dolutegravir-based regimens are recommended as first-line therapy in HIV guidelines. The DHHS guidelines10 include abacavir/dolutegravir/lamivudine (in patients who are HLA-B*5701 negative), dolutegravir plus (emtricitabine or lamivudine) plus (tenofovir AF or tenofovir DF), and dolutegravir/lamivudine (except for individuals with baseline HIV-1 RNA >500,000 copies/mL, HBV coinfection, or in whom ART is to be started before the results of HIV genotypic resistance testing for reverse transcriptase or HBV testing are available) as recommended first-line therapies. The IAS-USA guidelines12 include dolutegravir plus emtricitabine/tenofovir AF, dolutegravir plus emtricitabine/tenofovir DF, dolutegravir plus lamivudine/tenofovir DF, and dolutegravir/lamivudine (except for individuals being treated for an active opportunistic infection, with baseline HIV-1 RNA >500,000 copies/mL, with HBV coinfection, with baseline CD4+ cell count <200 cells/mm3, or in whom ART is to be started before the results of HIV genotypic resistance testing for reverse transcriptase or HBV testing are available) as recommended first-line therapies. Finally, the EACS11 guideline panel includes abacavir/dolutegravir/lamivudine (in patients who are HLA-B*5701 negative), dolutegravir plus emtricitabine/tenofovir AF, dolutegravir plus emtricitabine/tenofovir DF, dolutegravir plus lamivudine/tenofovir DF and dolutegravir/lamivudine (except for individuals with baseline HIV-1 RNA >500,000 copies/mL or HBV coinfection) as recommended first-line therapies.


Dolutegravir/lamivudine is also approved as a switch option for suppressed patients in the United States and in Europe based on the results of the TANGO study. The TANGO study compared the safety and efficacy of switching to dolutegravir/lamivudine vs continued tenofovir AF–based 3-drug or 4-drug ART in 741 virologically suppressed adults.80 Nearly 80% of participants were receiving elvitegravir/cobicistat-based ART at baseline. The study showed comparable virologic efficacy between study arms at Week 48. Indeed, only 0.3% and 0.5% of patients in the switch and continuation arms, respectively, had virologic failure at Week 48 according to an FDA Snapshot analysis (treatment difference, adjusted for baseline third agent class: -0.3%; 95% CI: -1.2% to 0.7%). In addition, 93.2% and 93.0% of patients in the switch and continuation arms maintained HIV-1 RNA ≤50 copies/mL at Week 48, respectively (treatment difference, adjusted for baseline third agent class: 0.2%; 95% CI: -3.4% to 3.9%). Virologic outcomes were consistent across a variety of patient subgroups, including age, race, sex, baseline third agent, and baseline CD4+ cell count. Finally, there was no confirmed virologic withdrawal or development of resistance in the Dolutegravir/lamivudine arm, and the safety of Dolutegravir/lamivudine was consistent with previous reports of each agent when used separately.


In the phase III SAILING study, Cahn and colleagues74 evaluated the efficacy of dolutegravir 50 mg once daily vs raltegravir 400 mg twice daily plus optimized background regimen comprising ≤2 agents, 1 of which was fully active, in 715 treatment-experienced, INSTI-naive patients. At Week 48, 71% of participants in the dolutegravir group achieved HIV-1 RNA level <50 copies/mL vs 64% of participants in the raltegravir group, a statistically significant difference demonstrating the superior efficacy of dolutegravir vs raltegravir in this population (P = .03). Additional analysis also showed that among patients with virologic failure, significantly fewer participants in the dolutegravir group developed integrase resistance versus those in the raltegravir group.


The open-label phase III SWORD 1 and 2 studies investigated the continuation of a fully suppressive 3-drug regimen with a switch to the 2-drug regimen of dolutegravir paired with rilpivirine in 1028 patients with virologic suppression for 6 months or longer.81 After 100 weeks of follow-up, the 2-drug regimen maintained virologic suppression in 89% of patients and was well tolerated with no emergent integrase resistance mutations in the small number of patients with confirmed virologic failure. More participants receiving the 2-drug regimen reported AEs leading to withdrawal than did participants remaining on 3-drug ART (3% vs 1%). As a result of these studies, an NRTI-sparing coformulation of dolutegravir/ rilpivirine was approved by the FDA as a switch regimen for virologically suppressed patients (HIV-1 RNA <50 copies per mL) on a stable antiretroviral regimen for 6 months or longer with no history of treatment failure and no known resistance to dolutegravir or rilpivirine.68


The 24-week report on all patients randomized in the phase III VIKING-3 trial (N = 183) showed that dolutegravir given twice daily maintained activity in a heavily pretreated HIV-infected population harboring raltegravir- or elvitegravir-resistant virus.5 Virologic suppression rates were 78% in patients with no primary integrase mutations (n = 60), 64% in those with primary integrase mutations (n = 123), 58% with a Q148 change plus 1 secondary mutation (n = 36), and 24% with Q148 plus 2 or more secondary mutations (n = 21). Multivariate analysis identified that mutations at Q148 plus 2 or more secondary integrase mutations and a higher baseline fold change in dolutegravir susceptibility were highly associated with lack of virologic suppression with dolutegravir. Virologic response rates were 76% for patients with ≤4-fold change in susceptibility to dolutegravir at baseline, 54% in those with a fold change between 4 and 10, and 27% in those with a fold change >10. Background regimen susceptibility score was not associated with virologic response.


Several mutations are required in HIV integrase to confer high-level resistance to dolutegravir. Cross-resistance studies with raltegravir- and elvitegravir-resistant viruses indicate that Q148H/R and G140S in combination with mutations L74I/M, E92Q, T97A, E138A/K, G140A, or N155H are associated with 5-fold to 20-fold reduced dolutegravir susceptibility and reduced virologic suppression in patients.8


Dolutegravir is metabolized primarily via UGT1A1-mediated glucuronidation. dolutegravir has several important drug–drug interactions with other medications including some antiepileptic agents and antiretroviral agents (ie, etravirine , fosamprenavir, nevirapine, efavirenz, and tipranavir). Also, dolutegravir should be administered at least 2 hours before or 6 hours after the dose of an agent that contains polyvalent cations (eg, aluminum, calcium, iron, magnesium, selenium, zinc).


Initial results from an ongoing National Institutes of Health–funded birth surveillance study in Botswana, Tsepamo, reported an increased risk of neural tube defects (NTD) in infants whose mothers became pregnant while receiving dolutegravir-based ART (0.9% of 426 births).70 However, an updated analysis including 3591 women revealed that the NTD prevalence among infants born to women receiving dolutegravir are much more comparable to the prevalence for infants exposed to non-dolutegravir ART during conception (0.19% vs 0.11%, respectively),71 and thus, the current recommendation from the US DHHS Panel on Treatment of Pregnant Women with HIV Infection and Prevention of Perinatal Transmission and the IAS-USA is that dolutegravir is a preferred antiretroviral drug in women who are trying to conceive and throughout pregnancy, in combination with the appropriate counseling and informed decision-making.12,72 However, the EACS guidelines still specify that dolutegravir is not recommended for women trying to conceive and during the first 8 weeks of pregnancy.11


Raltegravir. Raltegravir is indicated in combination with other antiretroviral agents for the treatment of HIV infection in adult patients and pediatric patients weighing ≥2 kg.93 It was initially approved by the FDA in 2007 for use in treatment-experienced patients as a result of the BENCHMRK trials94; as a result of the STARTMRK trial,95 the FDA extended the indication to treatment-naive adult patients. Raltegravir is given orally at a dose of 400 mg twice daily (for treatment-naive or treatment-experienced patients) or 1200 mg once daily (for treatment-naive patients only, using 2 tablets of a 600-mg formulation approved in 2017) and is well tolerated. The ONCEMRK trial investigated a once-daily dose of a reformulated version of raltegravir 1200 mg, given as two 600-mg tablets and demonstrated that this once-daily strategy was noninferior to raltegravir 400 mg twice daily at 48 weeks (both in combination with emtricitabine/tenofovir DF).96 Dose adjustment is not required with kidney or liver dysfunction. Previously, the QDMRK trial investigating the use of once-daily raltegravir 800 mg in treatment-naive patients found that once-daily 800-mg dosing was not noninferior to twice-daily 400-mg dosing.97


The STARTMRK trial demonstrated the noninferiority of raltegravir to efavirenz when both were combined with emtricitabine/tenofovir DF at Weeks 48 and 96.95,98 In extended follow-up of the STARTMRK trial, the raltegravir regimen was superior to the efavirenz regimen based on better virologic and immunologic outcomes after 240 weeks.99 The ACTG 5257 study compared raltegravir with atazanavir/ritonavir or darunavir/ritonavir, each paired with emtricitabine/tenofovir DF, and found a lower rate of the combined outcome of virologic/tolerability failure at Week 96 in those randomized to raltegravir vs atazanavir/ritonavir and vs darunavir/ritonavir.100 The differences were primarily driven by lower rates of drug discontinuation in those randomized to raltegravir.


The EACS guidelines list raltegravir plus emtricitabine/tenofovir DF, emtricitabine/tenofovir AF, or lamivudine/tenofovir DF as recommended regimens for first-line therapy.11 In addition, raltegravir is a recommended INSTI for use in pregnant women in combination with other antiretroviral agents by the DHHS and the IAS-USA panel.10,12 raltegravir, in combination with darunavir and ritonavir10-12 or cobicistat/darunavir,11 is also listed as an NRTI-sparing regimen in the guidelines.


Raltegravir is well tolerated by most patients. There have been reports of renal failure with rhabdomyolysis and cerebellar ataxia associated with use of this agent,101-103 but it is not clear whether these events were causally related to raltegravir. Raltegravir is metabolized primarily by glucuronidation, specifically by the enzyme uridine diphosphate glucuronosyltransferase 1A1. Although rifampin is a strong inducer of uridine diphosphate glucuronosyltransferase 1A1, a small clinical study (N = 155) suggested that rifampin and raltegravir (at either a 400-mg twice-daily or 800-mg once-daily dose) can be safely coadministered.104 However, this was a small study with approximately 50 patients in each arm, and it is not appropriate to make clinical recommendations based on its results. Relatively few other drug–drug interactions have been documented with raltegravir.


Raltegravir resistance occurs from one third and one half of patients with virologic failure on raltegravir-based regimens (4 out of 8 patients at Week 48 and 4 out of 12 patients at Week 96 in STARTMRK) and is associated with mutations in the integrase gene that take 1 of at least 3 distinct genetic pathways. These are defined by the presence of 2 or more mutations including a signature mutation at Q148H/K/R, N155H, or Y143R/H/C plus 1 or more addi­tional minor mutations in the Q148H/K/R path­way. These include L74M + E138A, E138K, or G140S. The most common mutational pattern in this pathway is Q148H + G140S, which also confers the greatest loss of drug susceptibility.


Mutations de­scribed in the N155H pathway include this major mutation plus either L74M, E92Q, T97A, E92Q, T97A, Y143H, G163K/R, V151I, or D232N.105 Patients who remain on raltegravir-based therapy while experiencing virologic failure typically experience ongoing evolution of resistance mutations, with more mutations and greater loss of susceptibility accumulating with longer time on the failing regimen.106


Raltegravir-resistant viral variants are also cross-resistant to elvitegravir. However, many raltegravir-resistant variants retain susceptibility to dolutegravir administered at a dose of 50 mg twice daily (the dose for INSTI-experienced patients), although the degree of susceptibility varies by the mutational pattern.4 Of note, the development of INSTI resistance is generally uncommon in patients receiving a first-line INSTI-based regimen.


Bictegravir. The coformulated regimen bictegravir/emtricitabine/tenofovir AF was approved in 2018 as a complete regimen for the treatment of HIV infection in adults who have no antiretroviral treatment history or as a switch regimen in those who are virologically suppressed (HIV-1 RNA <50 copies/mL) on a stable antiretroviral regimen for 3 months or longer with no history of treatment failure and no known substitutions associated with resistance to the individual components.59 This regimen is recommended as a first-line regimen by the DHHS, the IAS-USA, and the EACS.10-12 Bictegravir/emtricitabine/tenofovir AF is not recommended for patients with estimated creatinine clearance <30 mL/min or in patients with severe hepatic impairment.


The approval of this regimen was based on results of the phase III GS-1490 trial in which coformulated bictegravir/emtricitabine/tenofovir AF was found to be noninferior to dolutegravir plus emtricitabine/tenofovir AF at the 48-week analysis primary endpoint.107 In this trial, HIV-infected treatment-naive adults with HIV-1 RNA ≥500 copies/mL and estimated glomerular filtration rate ≥30 mL/min were randomly assigned to receive fixed-dose combination bictegravir/emtricitabine/tenofovir AF (n = 320) or dolutegravir plus emtricitabine/tenofovir AF (n = 325) once daily for 144 weeks. The primary endpoint was the proportion of participants with plasma HIV-1 RNA <50 copies/mL at Week 48 by the FDA snapshot algorithm, with a prespecified noninferiority margin of -12%. At Week 48, 286 (89%) of those in the bictegravir arm and 302 (93%) of those in the dolutegravir arm achieved HIV-1 RNA <50 copies/mL (difference -3·5%; 95% CI: -7.9% to 1.0%; P = .12), demonstrating noninferiority of the bictegravir regimen to the dolutegravir regimen. No treatment-emergent resistance to any study drug was observed. Incidence and severity of AEs were similar between groups, and only 5 patients (2%) in the bictegravir group and 1 patient (<1%) in the dolutegravir group discontinued treatment due to AEs. Study drug–related AEs were significantly less common in the bictegravir group than in the dolutegravir group (57 [18%] vs 83 [26%], respectively; P = .022).


The phase III GS-1489 trial compared the 2 coformulated regimens bictegravir/emtricitabine/tenofovir AF and abacavir/dolutegravir/lamivudine for initial ART.108 In this trial, 629 HIV-infected, HLA-B*5701–negative, treatment-naive adults with HIV-1 RNA ≥500 copies/mL and estimated glomerular filtration rate ≥50 mL/min were randomly assigned to receive the oral fixed-dose combination bictegravir/emtricitabine/tenofovir AF (n = 314) or oral fixed-dose Abacavir/dolutegravir/lamivudine(n = 315) once daily for 144 weeks. (In this study, patients with chronic HBV infection were excluded; they were eligible for GS-1490.) At Week 48, 92.4% of patients in the bictegravir arm vs 93.0% of those in the dolutegravir arm achieved HIV-1 RNA <50 copies/mL (difference: 0.6%; 95% CI: -4.8% to 3.6%), demonstrating noninferiority of the coformulated bictegravir regimen to the coformulated dolutegravir regimen. Similar to GS-1490, few patients discontinued treatment for AEs related to the study drugs: 0 patients receiving bictegravir/emtricitabine/tenofovir AF vs 4 (1.3%) patients receiving abacavir/dolutegravir/lamivudine. Nausea (all grades) was more common with use of Abacavir/dolutegravir/lamivudine(P <.001). No treatment-emergent resistance to any study drug was observed. Treatment assignment had no significant impact on change in renal markers, bone mineral density at spine or hip, or lipid levels at Week 48.


The phase III GS-1878 study evaluated the efficacy and safety of switching virologically suppressed HIV-infected adult patients from a multitablet regimen containing a boosted PI to fixed-dose bictegravir/emtricitabine/tenofovir AF in patients with no previous experience with INSTIs.109 In this ongoing study, the switch to bictegravir/emtricitabine/tenofovir AF was found to be noninferior to continuing a boosted PI–containing regimen and demonstrated no treatment-emergent resistance at 48 weeks. In total, 577 virologically suppressed adults (HIV-1 RNA <50 copies/mL for ≥6 months) receiving boosted atazanavir or darunavir plus abacavir/lamivudine or emtricitabine/tenofovir DF were randomized 1:1 to continue their PI-based regimen (n = 287) or to switch to open-label coformulated bictegravir/emtricitabine/tenofovir AF once daily (n = 290). At the 48-week analysis primary endpoint, switching to bictegravir/emtricitabine/tenofovir AF was noninferior to continuing on a boosted PI–based regimen, with 2% of patients in each group having HIV-­1 RNA ≥50 copies/mL (difference: 0; 95% CI: ­-2.5% to 2.5%; P = 1.00)? the proportion of patients with HIV-1 RNA <50 copies/mL at Week 48 (secondary endpoint) was 92% in the bictegravir arm vs 89% in the boosted PI continuation arm (difference: 3.2%; 95% CI: -1.6% to 8.2%). No patients in the bictegravir/emtricitabine/tenofovir AF arm developed treatment-emergent resistance and 1 participant receiving darunavir/ritonavir plus abacavir/lamivudine in the boosted PI continuation arm developed a treatment-emergent NRTI mutation associated with abacavir resistance. No renal AEs leading to discontinuation or cases of proximal renal tubulopathy were reported with bictegravir/emtricitabine/tenofovir AF. The incidence of grade 3/4 AEs was 4% (n = 13) for the bictegravir/emtricitabine/tenofovir AF arm vs 6% (n = 18) for the boosted PI continuation arm; the incidence of grade 3/4 laboratory abnormalities was 16% (n = 45) for the bictegravir arm vs 29% (n = 83) in the boosted PI continuation arm. Lipid parameters significantly improved with the switch to bictegravir/emtricitabine/tenofovir AF vs continued baseline PI-based ART.


In another double-blind, active-controlled phase III noninferiority trial, Study 380-4030, adults receiving dolutegravir plus emtricitabine/tenofovir DF or emtricitabine/tenofovir AF who had experienced viral suppression (HIV-1 RNA <50 copies/mL) for at least 3-6 months (3 months if no known NRTI resistance mutations, 6 months with known/suspected NRTI resistance) and who had no known INSTI resistance and no previous virologic failure on an INSTI-based regimen were randomized 1:1 to switch to bictegravir/emtricitabine/tenofovir AF (n = 284) or to continue/switch to dolutegravir plus emtricitabine/tenofovir AF (n = 281).110 The primary endpoint was the proportion of patients with HIV-1 RNA ≥50 copies/mL at Week 48 by FDA Snapshot analysis, with a noninferiority margin of 4%. This trial permitted enrolled patients to have documented or suspected NRTI, NNRTI, or PI resistance, and patients were stratified by known/suspected NRTI resistance at baseline (K65R or ≥3 thymidine analogue mutations vs other NRTI resistance associated mutations vs none). At Week 48, 1 patient in the bictegravir/emtricitabine/tenofovir AF switch arm and 3 patients continuing dolutegravir-based treatment met the primary endpoint of HIV-1 RNA ≥50 copies/mL (difference -0.7%; 95% CI: -2.8% to +1.0%), demonstrating noninferiority. No patient with preexisting NRTI resistance experienced HIV-1 RNA ≥50 copies/mL, and there were no significant differences between treatment arms in AEs, fasting lipid values, or weight change. Among patients with virologic rebound, no treatment-emergent resistance was detected through Week 48.


Finally, the BRAAVE study was a randomized, open-label, active-controlled phase II study that evaluated a switch from a baseline regimen (2 NRTIs + third agent) to bictegravir/emtricitabine/tenofovir AF in 495 virologically suppressed Black patients with HIV. Investigators showed that the switch was noninferior to remaining on the participant’s baseline regimen at Week 24 (primary efficacy endpoint).111 In addition, the majority of patients (≥95%) with baseline NRTI resistance remained suppressed at Week 24 in both study arms.


Cabotegravir. In 2021, injectable cabotegravir plus injectable rilpivirine was approved for the treatment of HIV infection in adults to replace the current antiretroviral regimen in those who are virologically suppressed (HIV-1 RNA <50 copies/mL) on a stable antiretroviral regimen with no history of treatment failure and with no known or suspected resistance to either cabotegravir or rilpivirine.65


The approval of this regimen was based on 2 phase III studies, ATLAS and FLAIR. In ATLAS, 616 patients on stable ART with HIV-1 RNA <50 copies/mL for ≥6 months with no previous virologic failure were randomized to switch to monthly intramuscular injections of cabotegravir plus rilpivirine (following a short lead-in with oral formulations of both drugs) or continued baseline ART.112 The primary endpoint was HIV-1 RNA ≥50 copies/mL at Week 48 by FDA Snapshot analysis. Approximately 50% of patients were receiving baseline NNRTI-based ART, 33% were receiving baseline INSTI-based ART, and 17% of patients were receiving baseline PI-based ART. At Week 48, rates of virologic nonresponse were similar between study arms: 1.6% vs 1.0% in switch patients vs nonswitch patients, respectively (treatment difference: 0.6%; 95% CI: -1.2% to 2.5%). The key secondary endpoint, HIV-1 RNA <50 copies/mL, was achieved in 92.5% and 95.5% of patients in the switch vs nonswitch arms, respectively (treatment difference: -3.0%; 95% CI: -6.7% to 0.7%). Nearly all of the drug-related AEs in the cabotegravir plus rilpivirine arm were grade 1/2 in severity (95%), and similarly, almost all of the injection-site reactions in the cabotegravir plus rilpivirine arm were grade 1/2 (99%). Of importance, patient satisfaction was higher in the cabotegravir plus rilpivirine arm vs the continued baseline ART arm at both Weeks 24 and 44 (P <.001).


In FLAIR, 629 ART-naive patients with HIV-1 RNA ≥1000 copies/mL who were hepatitis B surface antigen negative and had no NNRTI resistance associated mutations received Abacavir/dolutegravir/lamivudine for 20 weeks and then were randomized to either monthly intramuscular injections of cabotegravir plus rilpivirine (following a short lead-in with oral formulations of both drugs) or to continue abacavir/dolutegravir/lamivudine.113 The primary endpoint was HIV-1 RNA ≥50 copies/mL at Week 48 by FDA Snapshot analysis. At Week 48, rates of virologic nonresponse were similar between study arms: 2.1% vs 2.5% in switch patients vs nonswitch patients, respectively (treatment difference: -0.4%; 95% CI: -2.8% to 2.1%). The key secondary endpoint, HIV-1 RNA <50 copies/mL, was achieved in 93.6% and 93.3% of patients in the switch vs nonswitch arms, respectively (treatment difference: 0.4%; 95% CI: -3.7% to 4.5%). Confirmed virologic failure was observed in 3 patients in each study arm; although no resistance mutations were observed in the 3 cases of virologic failure in the abacavir/dolutegravir/lamivudine arm, NNRTI and INSTI resistance associated mutations were observed in all cases of cabotegravir plus rilpivirine failure. Similar to the ATLAS study, most drug-related AEs and injection-site reactions were grade 1/2 (94% and 99%, respectively), and patient satisfaction was higher in the cabotegravir plus rilpivirine arm vs the continued abacavir/dolutegravir/lamivudine arm at Week 48 (P <.001).


The randomized, open-label phase IIIb ATLAS-2M study investigated whether cabotegravir plus rilpivirine long-acting maintenance therapy administered intramuscularly every 8 weeks was noninferior to administration every 4 weeks in adults from both the ATLAS study and outside of the ATLAS study who were virologically suppressed on their current ART regimen.114 Study results showed that cabotegravir plus rilpivirine every 8 weeks was noninferior to dosing every 4 weeks according to the primary endpoint of HIV-1 RNA ≥50 copies/mL (2% vs 1%, respectively), with an adjusted treatment difference of 0.8% (95% CI: -0.6% to 2.2%). In addition, the key secondary endpoint, HIV-1 RNA <50 copies/mL, was achieved in 94% and 93% of patients in the every 8 weeks vs every 4 weeks groups, respectively (treatment difference: 0.8%; 95% CI: -2.1% to 3.7%). Confirmed virologic failure was observed in 2% and 1% of patients in the every 8 weeks and every 4 weeks groups, respectively. In the every 8 weeks group, 63% (5/8) of patients with virologic failure had archived NNRTI resistance -associated mutations to rilpivirine at baseline. The safety profile was similar between the 2 dosing groups. Results remained consistent in the 96-week analysis with 2.1% and 1.1% of patients in the every 8 weeks vs every 4 weeks groups, respectively, having HIV-1 RNA <50 copies/mL (treatment difference: 1.0%; 95% CI: -0.6% to 2.5%) and 91% and 90% of patients in the every 8 weeks vs every 4 weeks groups, respectively, achieving HIV-1 RNA <50 copies/mL (treatment difference: 0.8%; 95% CI: -2.8% to 4.3%).115 No new safety signals were discovered between Weeks 48 and 96.