Capsid Inhibition with Lenacapavir in Multidrug-Resistant HIV-1 Infection.

BACKGROUND: Patients with multidrug-resistant human immunodeficiency virus type 1 (HIV-1) infection have limited treatment options. Lenacapavir is a first-in-class capsid inhibitor that showed substantial antiviral activity in a phase 1b study. METHODS: In this phase 3 trial, we enrolled patients with multidrug-resistant HIV-1 infection in two cohorts, according to the change in the plasma HIV-1 RNA level between the screening and cohort-selection visits. In cohort 1, patients were first randomly assigned in a 2:1 ratio to receive oral lenacapavir or placebo in addition to their failing therapy for 14 days; during the maintenance period, starting on day 15, patients in the lenacapavir group received subcutaneous lenacapavir once every 6 months, and those in the placebo group received oral lenacapavir, followed by subcutaneous lenacapavir; both groups also received optimized background therapy. In cohort 2, all the patients received open-label oral lenacapavir with optimized background therapy on days 1 through 14; subcutaneous lenacapavir was then administered once every 6 months starting on day 15. The primary end point was the percentage of patients in cohort 1 who had a decrease of at least 0.5 log10 copies per milliliter in the viral load by day 15; a key secondary end point was a viral load of less than 50 copies per milliliter at week 26. RESULTS: A total of 72 patients were enrolled, with 36 in each cohort. In cohort 1, a decrease of at least 0.5 log10 copies per milliliter in the viral load by day 15 was observed in 21 of 24 patients (88%) in the lenacapavir group and in 2 of 12 patients (17%) in the placebo group (absolute difference, 71 percentage points; 95% confidence interval, 35 to 90). At week 26, a viral load of less than 50 copies per milliliter was reported in 81% of the patients in cohort 1 and in 83% in cohort 2, with a least-squares mean increase in the CD4+ count of 75 and 104 cells per cubic millimeter, respectively. No serious adverse events related to lenacapavir were identified. In both cohorts, lenacapavir-related capsid substitutions that were associated with decreased susceptibility developed in 8 patients during the maintenance period (6 with M66I substitutions). CONCLUSIONS: In patients with multidrug-resistant HIV-1 infection, those who received lenacapavir had a greater reduction from baseline in viral load than those who received placebo. (Funded by Gilead Sciences; CAPELLA ClinicalTrials.gov number, NCT04150068.).

Long-acting cabotegravir and rilpivirine for HIV-1 suppression: switch to 2-monthly dosing after 5 years of daily oral therapy.

OBJECTIVES: Long-acting formulations of cabotegravir (CAB) and rilpivirine (RPV) have demonstrated efficacy in Phase 3 studies. POLAR (NCT03639311) assessed antiviral activity and safety of CAB+RPV long-acting administered every 2 months (Q2M) in adults living with HIV-1 who previously received daily oral CAB+RPV in LATTE (NCT01641809). DESIGN: A Phase 2b, multicenter, open-label, rollover study. METHODS: LATTE participants with plasma HIV-1 RNA less than 50 copies/ml who completed at least 300 weeks on study were eligible. Participants elected to switch to either CAB+RPV long-acting Q2M or daily oral dolutegravir/RPV for maintenance of virologic suppression. The primary endpoint was the proportion of participants with HIV-1 RNA greater than or equal to 50 copies/ml at Month 12 (M12) per the Food and Drug Administration Snapshot algorithm. The incidence of confirmed virologic failure (CVF, two consecutive HIV-1 RNA measurements greater than or equal to 200 copies/ml), as well as safety, laboratory, and patient-reported outcomes (HIV Treatment Satisfaction and preference questionnaires) were also assessed. RESULTS: Of 97 participants enrolled, 90 chose to receive CAB+RPV long-acting and seven chose dolutegravir/RPV. At M12, no participant had HIV-1 RNA greater than or equal to 50 copies/ml or met the CVF criterion in either treatment group. No new safety signals were identified. Total treatment satisfaction was high at Baseline and remained stable through M12 across both treatment groups. Overall, 88% (n = 77/88) of long-acting arm participants preferred CAB+RPV long-acting to oral CAB+RPV. CONCLUSION: CAB+RPV long-acting maintained virologic suppression in participants who had previously received daily oral CAB+RPV for at least 5 years in LATTE, with a favorable safety profile. Most participants preferred CAB+RPV long-acting to their prior oral CAB+RPV regimen at M12.

Efficacy, Safety, and Durability of Long-Acting Cabotegravir and Rilpivirine in Adults With Human Immunodeficiency Virus Type 1 Infection: 5-Year Results From the LATTE-2 Study.

BACKGROUND: In the Long-Acting Antiretroviral Treatment Enabling Trial 2 (LATTE-2) phase 2b study, long-acting (LA) injectable cabotegravir + rilpivirine dosed every 8 weeks (Q8W) or every 4 weeks (Q4W) demonstrated comparable efficacy with daily oral antiretroviral therapy (ART) through 96 weeks in ART-naive adults with human immunodeficiency virus type 1 (HIV-1). Here we report efficacy, tolerability, and safety of cabotegravir + rilpivirine LA over approximately 5 years. METHODS: After 20 weeks of oral cabotegravir + abacavir/lamivudine, participants were randomized to cabotegravir + rilpivirine LA Q8W or Q4W or continue oral ART through the 96-week maintenance period. In the extension period through week 256, participants continued their current LA regimen (randomized Q8W/Q4W groups) or switched from oral ART to Q8W or Q4W LA therapy (extension-switch groups). Endpoints assessed included proportion of participants with HIV-1 RNA <50 copies/mL (Snapshot algorithm) and adverse events (AEs). RESULTS: At week 256, 186 of 230 (81%) participants in randomized Q8W/Q4W groups and 41 of 44 (93%) participants in extension-switch groups had HIV-1 RNA <50 copies/mL. No protocol-defined virologic failures occurred after week 48. Injection wsite reactions infrequently resulted in discontinuation (4 [2%] and 1 [2%] participants in randomized Q8W/Q4W and extension-switch groups, respectively). Three participants in randomized Q8W/Q4W groups experienced drug-related serious AEs, including 1 fatal serious AE (Q4W group); none occurred in extension-switch groups. Of 25 participants with AEs leading to withdrawal, 20 were in the randomized Q4W group; no AE leading to withdrawal occurred in >1 participant. CONCLUSIONS: Cabotegravir + rilpivirine LA exhibited long-term efficacy and tolerability, demonstrating its durability as maintenance therapy for HIV-1 infection.Clinical Trials Registration. NCT02120352.

Long-Acting Injectable Cabotegravir + Rilpivirine for HIV Maintenance Therapy: Week 48 Pooled Analysis of Phase 3 ATLAS and FLAIR Trials.

BACKGROUND: Long-acting (LA) injectable regimens are a potential therapeutic option in people living with HIV-1. SETTING: ATLAS (NCT02951052) and FLAIR (NCT02938520) were 2 randomized, open-label, multicenter, multinational phase 3 studies. METHODS: Adult participants with virologic suppression (plasma HIV-1 RNA <50 copies/mL) were randomized (1:1) to continue with their current antiretroviral regimen (CAR) or switch to the long-acting (LA) regimen of cabotegravir (CAB) and rilpivirine (RPV). In the LA arm, participants initially received oral CAB + RPV once-daily for 4 weeks to assess individual safety and tolerability, before starting monthly injectable therapy. The primary endpoint of this combined analysis was antiviral efficacy at week 48 (FDA Snapshot algorithm: noninferiority margin of 4% for HIV-1 RNA ≥50 copies/mL). Safety, tolerability, and confirmed virologic failure (2 consecutive plasma HIV-1 RNA ≥200 copies/mL) were secondary endpoints. RESULTS: The pooled intention-to-treat exposed population included 591 participants in each arm [28% women (sex at birth), 19% aged ≥50 years]. Noninferiority criteria at week 48 were met for the primary (HIV-1 RNA ≥50 copies/mL) and key secondary (HIV-1 RNA <50 copies/mL) efficacy endpoints. Seven individuals in each arm (1.2%) developed confirmed virologic failure; 6/7 (LA) and 3/7 (CAR) had resistance-associated mutations. Most LA recipients (83%) experienced injection site reactions, which decreased in incidence over time. Injection site reactions led to the withdrawal of 6 (1%) participants. The serious adverse event rate was 4% in each arm. CONCLUSION: This combined analysis demonstrates monthly injections of CAB + RPV LA were noninferior to daily oral CAR for maintaining HIV-1 suppression.

Long-Acting Cabotegravir and Rilpivirine for Maintenance of HIV-1 Suppression.

BACKGROUND: Simplified regimens for the treatment of human immunodeficiency virus type 1 (HIV-1) infection may increase patient satisfaction and facilitate adherence. METHODS: In this phase 3, open-label, multicenter, noninferiority trial involving patients who had had plasma HIV-1 RNA levels of less than 50 copies per milliliter for at least 6 months while taking standard oral antiretroviral therapy, we randomly assigned participants (1:1) to either continue their oral therapy or switch to monthly intramuscular injections of long-acting cabotegravir, an HIV-1 integrase strand-transfer inhibitor, and long-acting rilpivirine, a nonnucleoside reverse-transcriptase inhibitor. The primary end point was the percentage of participants with an HIV-1 RNA level of 50 copies per milliliter or higher at week 48, determined with the use of the Food and Drug Administration snapshot algorithm. RESULTS: Treatment was initiated in 308 participants per group. At week 48, HIV-1 RNA levels of 50 copies per milliliter or higher were found in 5 participants (1.6%) receiving long-acting therapy and in 3 (1.0%) receiving oral therapy (adjusted difference, 0.6 percentage points; 95% confidence interval [CI], -1.2 to 2.5), a result that met the criterion for noninferiority for the primary end point (noninferiority margin, 6 percentage points). An HIV-1 RNA level of less than 50 copies per milliliter at week 48 was found in 92.5% of participants receiving long-acting therapy and in 95.5% of those receiving oral therapy (adjusted difference, -3.0 percentage points; 95% CI, -6.7 to 0.7), a result that met the criterion for noninferiority for this end point (noninferiority margin, -10 percentage points). Virologic failure was confirmed in 3 participants who received long-acting therapy and 4 participants who received oral therapy. Adverse events were more common in the long-acting-therapy group and included injection-site pain, which occurred in 231 recipients (75%) of long-acting therapy and was mild or moderate in most cases; 1% withdrew because of this event. Serious adverse events were reported in no more than 5% of participants in each group. CONCLUSIONS: Monthly injections of long-acting cabotegravir and rilpivirine were noninferior to standard oral therapy for maintaining HIV-1 suppression. Injection-related adverse events were common but only infrequently led to medication withdrawal. (Funded by ViiV Healthcare and Janssen; ATLAS ClinicalTrials.gov number, NCT02951052.).

Experiences with long acting injectable ART: A qualitative study among PLHIV participating in a Phase II study of cabotegravir + rilpivirine (LATTE-2) in the United States and Spain.

Challenges with adherence to daily oral antiretroviral therapy (ART) among people living with HIV (PLHIV) have stimulated development of injectable long-acting (LA) regimens. We conducted 39 in-depth interviews with participants and providers in a Phase IIb study (LATTE-2) evaluating an injectable LA regimen in the U.S. and Spain. Interviews exploring participant and provider attitudes and experiences with LA versus oral ART were audiotaped, transcribed and analyzed using thematic content analysis. Participants described the convenience of LA injections versus daily pills and emotional benefits such as minimized potential for HIV disclosure and eliminating the "daily reminder of living with HIV." Providers recognized benefits but cautioned that LA candidates still need to adhere to clinic visits for injections and raised questions around ongoing clinical management. LA was seen as preferable to daily oral ART among PLHIV. Further research is needed regarding appropriate candidates, including with women and "non-adherent" populations across settings.

Long-acting intramuscular cabotegravir and rilpivirine in adults with HIV-1 infection (LATTE-2): 96-week results of a randomised, open-label, phase 2b, non-inferiority trial.

BACKGROUND: Cabotegravir and rilpivirine are antiretroviral drugs in development as long-acting injectable formulations. The LATTE-2 study evaluated long-acting cabotegravir plus rilpivirine for maintenance of HIV-1 viral suppression through 96 weeks. METHODS: In this randomised, phase 2b, open-label study, treatment-naive adults infected with HIV-1 initially received oral cabotegravir 30 mg plus abacavir-lamivudine 600-300 mg once daily. The objective of this study was to select an intramuscular dosing regimen based on a comparison of the antiviral activity, tolerability, and safety of the two intramuscular dosing regimens relative to oral cabotegravir plus abacavir-lamivudine. After a 20-week induction period on oral cabotegravir plus abacavir-lamivudine, patients with viral suppression (plasma HIV-1 RNA <50 copies per mL) were randomly assigned (2:2:1) to intramuscular long-acting cabotegravir plus rilpivirine at 4-week intervals (long-acting cabotegravir 400 mg plus rilpivirine 600 mg; two 2 mL injections) or 8-week intervals (long-acting cabotegravir 600 mg plus rilpivirine 900 mg; two 3 mL injections) or continued oral cabotegravir plus abacavir-lamivudine. Randomisation was computer-generated with stratification by HIV-1 RNA (<50 copies per mL, yes or no) during the first 12 weeks of the induction period. The primary endpoints were the proportion of patients with viral suppression at week 32 (as defined by the US Food and Drug Administration snapshot algorithm), protocol-defined virological failures, and safety events through 96 weeks. All randomly assigned patients who received at least one dose of study drug during the maintenance period were included in the primary efficacy and safety analyses. The primary analysis used a Bayesian approach to evaluate the hypothesis that the proportion with viral suppression for each long-acting regimen is not worse than the oral regimen proportion by more than 10% (denoted comparable) according to a prespecified decision rule (ie, posterior probability for comparability >90%). Difference in proportions and associated 95% CIs were supportive to the primary analysis. The trial is registered at ClinicalTrials.gov, number NCT02120352. FINDINGS: Among 309 enrolled patients, 286 were randomly assigned to the maintenance period (115 to each of the 4-week and 8-week groups and 56 to the oral treatment group). This study is currently ongoing. At 32 weeks following randomisation, both long-acting regimens met primary criteria for comparability in viral suppression relative to the oral comparator group. Viral suppression was maintained at 32 weeks in 51 (91%) of 56 patients in the oral treatment group, 108 (94%) of 115 patients in the 4-week group (difference 2·8% [95% CI -5·8 to 11·5] vs oral treatment), and 109 (95%) of 115 patients in the 8-week group (difference 3·7% [-4·8 to 12·2] vs oral treatment). At week 96, viral suppression was maintained in 47 (84%) of 56 patients receiving oral treatment, 100 (87%) of 115 patients in the 4-week group, and 108 (94%) of 115 patients in the 8-week group. Three patients (1%) experienced protocol-defined virological failure (two in the 8-week group; one in the oral treatment group). Injection-site reactions were mild (3648 [84%] of 4360 injections) or moderate (673 [15%] of 4360 injections) in intensity and rarely resulted in discontinuation (two [<1%] of 230 patients); injection-site pain was reported most frequently. Serious adverse events during maintenance were reported in 22 (10%) of 230 patients in the intramuscular groups (4-week and 8-week groups) and seven (13%) of 56 patients in the oral treatment group; none were drug related. INTERPRETATION: The two-drug combination of all-injectable, long-acting cabotegravir plus rilpivirine every 4 weeks or every 8 weeks was as effective as daily three-drug oral therapy at maintaining HIV-1 viral suppression through 96 weeks and was well accepted and tolerated. FUNDING: ViiV Healthcare and Janssen R&D.

Dolutegravir versus placebo in subjects harbouring HIV-1 with integrase inhibitor resistance associated substitutions: 48-week results from VIKING-4, a randomized study.

BACKGROUND: The Phase III VIKING-3 study demonstrated that dolutegravir (DTG) 50 mg twice daily was efficacious in antiretroviral therapy (ART)-experienced subjects harbouring raltegravir- and/or elvitegravir-resistant HIV-1. VIKING-4 (ING116529) included a placebo-controlled 7-day monotherapy phase to demonstrate that short-term antiviral activity was attributable to DTG. METHODS: VIKING-4 is a Phase III randomized, double-blind study in therapy-experienced adults with integrase inhibitor (INI)-resistant virus randomized to DTG 50 mg twice daily or placebo while continuing their failing regimen (without raltegravir or elvitegravir) for 7 days (clinicaltrials.gov identifier NCT01568892). At day 8, all subjects switched to open-label DTG 50 mg twice daily and optimized background therapy including ≥1 fully active drug. The primary end point was change from baseline in plasma HIV-1 RNA at day 8. RESULTS: The study population (n=30) was highly ART-experienced with advanced HIV disease. Patients had extensive baseline resistance to all approved antiretroviral classes. Adjusted mean change in HIV-1 RNA at day 8 was -1.06 log10 copies/ml for the DTG arm and 0.10 log10 copies/ml for the placebo arm (treatment difference -1.16 log10 copies/ml [-1.52, -0.80]; P<0.001). Overall, 47% and 57% of subjects had plasma HIV-1 RNA <50 and <400 copies/ml at week 24, and 40% and 53% at week 48, respectively. No discontinuations due to drug-related adverse events occurred in the study. CONCLUSIONS: The observed day 8 antiviral activity in this highly treatment-experienced population with INI-resistant HIV-1 was attributable to DTG. Longer-term efficacy (after considering baseline ART resistance) and safety during the open-label phase were in-line with the results of the larger VIKING-3 study.

Atrial septal rupture, flail tricuspid valve, and complete heart block due to nonpenetrating chest trauma.

This is a report of a patient with an atrial septal defect with right-to-left shunting, flail tricuspid valve, and complete heart block secondary to blunt chest trauma after a motor vehicle accident. The patient surgically repaired with pericardial recreation of atrial septum, bioprosthetic tricuspid valve replacement, and pacemaker insertion. The patient had minimal problems during the hospital course and subsequently made a full postsurgical recovery.

T-1249 retains potent antiretroviral activity in patients who had experienced virological failure while on an enfuvirtide-containing treatment regimen.

BACKGROUND: T-1249 is a 39-amino acid synthetic peptide fusion inhibitor (FI) shown to preserve antiretroviral activity in vitro against human immunodeficiency virus (HIV) isolates that have decreased susceptibility to enfuvirtide (ENF). METHODS: A 10-day phase 1/2 study of the safety and antiretroviral activity of T-1249 was conducted in 53 HIV-1-infected adults with detectable viremia while on an ENF-containing treatment regimen. RESULTS: From FI-naive baseline levels, the geometric mean (GM) decrease in susceptibility to ENF was 116.3-fold, and the GM decrease in susceptibility to T-1249 was 2.0-fold. Patients continued to administer their failing treatment regimen but replaced ENF with T-1249 at a dose of 192 mg/day. T-1249 was generally well tolerated; injection site reactions, which were generally mild, were the most commonly reported adverse event (64% of patients). The median change from levels of HIV-1 RNA at baseline to levels on day 11 was -1.26 log(10) copies/mL (95% confidence interval, -1.40 to -1.09 log(10) copies/mL); on day 11, a decrease from baseline HIV-1 RNA levels of >/=1.0 log(10) copies/mL was seen in 73% of patients. Antiretroviral activity, as measured by levels of HIV-1 RNA, was not predicted by baseline susceptibility to T-1249 or to ENF; genotypic substitutions that emerged during T-1249 treatment were identified in virus from some patients. CONCLUSIONS: These results indicate that FIs constitute an expanding class of antiretroviral agents with the potential to be sequenced.

Pharmacodynamic effects of zidovudine 600 mg once/day versus 300 mg twice/day in therapy-naïve patients infected with human immunodeficiency virus.

STUDY OBJECTIVE: To compare the virologic activity of zidovudine monotherapy administered as 600 mg once/day versus 300 mg twice/day. DESIGN: Phase II, randomized (1:1), open-label study. SETTING: Thirteen medical centers in the United States. PATIENTS: Thirty-two antiretroviral-naive patients infected with human immunodeficiency virus (HIV). INTERVENTION: Patients were administered either zidovudine 600 mg every 24 hours (16 patients) or 300 mg every 12 hours (16 patients) for 13 days. MEASUREMENTS AND MAIN RESULTS: Plasma HIV-1 RNA concentration was measured daily. Study end points were between-group differences in change from baseline of log10-transformed HIV-1 RNA and in rates of viral load decline measured by the slope of HIV-1 RNA over time. At baseline, mean HIV-1 RNA was similar in the once/day and twice/day groups (4.33 and 4.40 log10 copies/ml, respectively). At day 14, a trend toward lower mean reduction in HIV-1 RNA from baseline was observed in the once/day group (-0.585, 95% confidence interval [CI] -0.728 to -0.442 log10 copies/ml) compared with the twice/day group (-0.849, 95% CI -1.067 to -0.630 log10 copies/ml, p=0.056). Viral load reduction also tended to be slower in the once/day group, as indicated by the smaller slope of viral load decline in the once/day group than in the twice/day group during days 1-14 (-0.045 vs -0.065 logic copies/ml/day, p=0.065). Both zidovudine regimens were similarly well tolerated. CONCLUSION: Zidovudine 600 mg once/day has antiviral activity, although less pronounced and more slowly achieved than that seen with zidovudine 300 mg twice/day. No differences were observed between the two treatment groups with respect to safety profile or tolerability

Twice-daily amprenavir 1200 mg versus amprenavir 600 mg/ritonavir 100 mg, in combination with at least 2 other antiretroviral drugs, in HIV-1-infected patients.

BACKGROUND: Low-dose ritonavir (RTV) boosts plasma amprenavir (APV) exposure. Little has been published on the efficacy, tolerability, and safety of APV 600 mg/RTV 100 mg (APV600/RTV) twice daily (BID) compared to APV 1200 mg BID (APV1200). METHODS: ESS40011 was a 24-week, multicenter, open-label, clinical trial in which antiretroviral therapy-naïve and -experienced HIV-1-infected adults were randomized 3:1 to receive either APV600/RTV BID or APV1200 BID, in combination with > or = 2 non-protease inhibitor antiretroviral drugs. Non-inferiority of the APV600/RTV regimen to the APV1200 regimen was established if the 95% lower confidence limit for the difference in proportion of patients achieving HIV-1 RNA <200 copies/mL at week 24 with APV 600/RTV minus APV1200 was > or =-0.12. Late in the conduct of the trial, patients not yet completing 24 weeks of therapy were given the option of continuing treatment for an additional 24-week period. RESULTS: 211 patients were randomized, 158 to APV600/RTV and 53 to APV1200. At week 24, APV600/RTV was similar to or better than APV1200 (HIV-1 RNA <200 copies/mL in 62% [73/118] vs 53% [20/38] of patients; intent-to-treat: observed analysis). In the APV600/RTV arm, significantly more patients achieved HIV-1 RNA <50 copies/mL (48% [57/118] vs 29% [11/38] with APV1200, P = 0.04), and greater mean reduction from baseline in HIV-1 RNA was observed (-2.21 vs -1.59 log10 copies/mL, P = 0.028). The two treatment arms were similar with respect to mean overall change from baseline in CD4+ count, frequency of drug-related grade 1-4 adverse events, and frequency of discontinuing treatment due to adverse events (most commonly nausea, diarrhea, vomiting or fatigue; 7% vs 8%), although a lower proportion of patients in the APV600/RTV arm experienced drug-related oral/perioral paresthesia (2% vs 8%). Eleven (73%) of 15 patients who had HIV-1 RNA <200 copies/mL at week 24 and chose to continue study treatment maintained this level of virologic suppression at follow-up 24 weeks later. CONCLUSIONS: APV600 RTV BID was similar to or better than APV1200 BID in virologic response. Virologic results in a small number of patients who continued treatment for 24 weeks post-study suggest that virologic suppression with APV600 RTV BID is durable.