Suppression of human and simian immunodeficiency virus replication with the CCR5-specific antibody Leronlimab in two species.

The CCR5-specific antibody Leronlimab is being investigated as a novel immunotherapy that can suppress HIV replication with minimal side effects. Here we studied the virological and immunological consequences of Leronlimab in chronically CCR5-tropic HIV-1 infected humans (n = 5) on suppressive antiretroviral therapy (ART) and in ART-naïve acutely CCR5-tropic SHIV infected rhesus macaques (n = 4). All five human participants transitioned from daily combination ART to self-administered weekly subcutaneous (SC) injections of 350 mg or 700 mg Leronlimab and to date all participants have sustained virologic suppression for over seven years. In all participants, Leronlimab fully occupied CCR5 receptors on peripheral blood CD4+ T cells and monocytes. In ART-naïve rhesus macaques acutely infected with CCR5-tropic SHIV, weekly SC injections of 50 mg/kg Leronlimab fully suppressed plasma viremia in half of the macaques. CCR5 receptor occupancy by Leronlimab occurred concomitant with rebound of CD4+ CCR5+ T-cells in peripheral blood, and full CCR5 receptor occupancy was found in multiple anatomical compartments. Our results demonstrate that weekly, self-administered Leronlimab was safe, well-tolerated, and efficacious for long-term virologic suppression and should be included in the arsenal of safe, easily administered, longer-acting antiretroviral treatments for people living with HIV-1. Trial Registration: ClinicalTrials.gov Identifiers: NCT02175680 and NCT02355184.

Safety and efficacy of vebicorvir administered with entecavir in treatment-naïve patients with chronic hepatitis B virus infection.

BACKGROUND & AIMS: Nucleos(t)ide reverse transcriptase inhibitors do not completely suppress HBV DNA in chronic HBV infection (cHBV). Vebicorvir (VBR) is an investigational core inhibitor that interferes with multiple aspects of HBV replication. This phase II trial evaluated the safety and efficacy of VBR in combination with entecavir (ETV) in treatment-naïve patients with cHBV. METHODS: HBeAg-positive, treatment-naïve patients without cirrhosis were randomised 1:1 in a double-blind manner to once-daily VBR 300 mg+ETV 0.5 mg or placebo (PBO)+ETV 0.5 mg for 24 weeks. The primary endpoint was change in mean log10 HBV DNA from Baseline to Week 12 and 24. RESULTS: All patients in both treatment groups (PBO+ETV: 12/12; VBR+ETV: 13/13) completed the study. At Week 12, VBR+ETV led to a greater mean (SD) reduction from Baseline in log10 IU/ml HBV DNA (-4.45 [1.03]) vs. PBO+ETV (-3.30 [1.18]; p = 0.0077). At Week 24, VBR+ETV led to a greater reduction from Baseline in log10 IU/ml HBV DNA (-5.33 [1.59]) vs. PBO+ETV (-4.20 [0.98]; p = 0.0084). Greater mean reductions in pregenomic RNA were observed at Week 12 and 24 in patients receiving VBR+ETV vs. PBO+ETV (p <0.0001 and p <0.0001). Changes in viral antigens were similar in both groups. No drug interaction between VBR and ETV was observed. Two patients experienced HBV DNA rebound during treatment, with no resistance breakthrough detected. The safety of VBR+ETV was similar to PBO+ETV. All treatment-emergent adverse events and laboratory abnormalities were Grade 1/2. There were no deaths, serious adverse events, or evidence of drug-induced liver injury. CONCLUSIONS: In this 24-week study, VBR+ETV provided additive antiviral activity over PBO+ETV in treatment-naïve patients with cHBV, with a favourable safety and tolerability profile. CLINICAL TRIAL NUMBER: NCT03577171 LAY SUMMARY: Hepatitis B is a long-lasting viral infection of the liver. Current treatments can suppress hepatitis B virus but do not offer the opportunity of cure, hence, new treatment approaches are required. Herein, we show that the combination of the novel core inhibitor vebicorvir with an existing antiviral (entecavir) in treatment-naïve patients chronically infected with hepatitis B virus demonstrated greater antiviral activity than entecavir alone. Additionally, vebicorvir was safe and well tolerated. Thus, further studies evaluating its potential role in the treatment of chronic hepatitis B are warranted.

Safety and efficacy of vebicorvir in virologically suppressed patients with chronic hepatitis B virus infection.

BACKGROUND & AIMS: HBV nucleos(t)ide reverse transcriptase inhibitors (NrtIs) do not completely suppress HBV replication. Previous reports indicate persistent viremia during NrtI treatment despite HBV DNA being undetectable. HBV core inhibitors may enhance viral suppression when combined with NrtIs. This phase II trial (NCT03576066) evaluated the efficacy and safety of the investigational core inhibitor, vebicorvir (VBR), in virologically- suppressed patients on NrtIs. METHODS: Non-cirrhotic, NrtI-suppressed patients with chronic HBV were randomised to VBR 300 mg once daily or matching placebo (PBO) for 24 weeks. Treatment was stratified by hepatitis B e antigen (HBeAg) status. The primary endpoint was change from Baseline in serum HBeAg or hepatitis B surface antigen (HBsAg) after 24 weeks. RESULTS: Of 73 patients enrolled, 47 were HBeAg positive and 26 were HBeAg negative. In HBeAg-positive and -negative patients, there were no differences in the change from Baseline at Week 24 for HBsAg or HBeAg. Using a novel, high-sensitivity assay to detect HBV DNA, a greater proportion of patients with detectable HBV DNA at Baseline achieved undetectable HBV DNA at Week 24 in the VBR+NrtI vs. PBO+NrtI group. In HBeAg-positive patients, a greater change from Baseline in HBV pregenomic (pg)RNA was observed at Week 24 with VBR+NrtI vs. PBO+NrtI. Treatment-emergent adverse events (TEAEs) in VBR+NrtI patients included upper respiratory tract infection, nausea, and pruritus. No serious adverse events, Grade 4 TEAEs, or deaths were reported. CONCLUSIONS: In this 24-week study, VBR+NrtI demonstrated a favourable safety and tolerability profile. While there were no significant changes in viral antigen levels, enhanced viral suppression was demonstrated by greater changes in DNA and pgRNA with the addition of VBR compared to NrtI alone. CLINICAL TRIALS NUMBER: NCT03576066. LAY SUMMARY: Core inhibitors represent a novel approach for the treatment of chronic hepatitis B virus (HBV) infection, with mechanisms of action distinct from existing treatments. In this study, vebicorvir added to existing therapy reduced HBV replication to a greater extent than existing treatment and was generally safe and well tolerated.

All-oral 12-week treatment with daclatasvir plus sofosbuvir in patients with hepatitis C virus genotype 3 infection: ALLY-3 phase III study.

UNLABELLED: Treatment options for patients with hepatitis C virus (HCV) genotype 3 infection are limited, with the currently approved all-oral regimens requiring 24-week treatment and the addition of ribavirin (RBV). This phase III study (ALLY-3; ClinicalTrials.gov: NCT02032901) evaluated the 12-week regimen of daclatasvir (DCV; pangenotypic nonstructural protein [NS]5A inhibitor) plus sofosbuvir (SOF; pangenotypic NS5B inhibitor) in patients infected with genotype 3. Patients were either treatment naïve (n = 101) or treatment experienced (n = 51) and received DCV 60 mg plus SOF 400 mg once-daily for 12 weeks. Coprimary endpoints were the proportions of treatment-naïve and treatment-experienced patients achieving a sustained virological response (SVR) at post-treatment week 12 (SVR12). SVR12 rates were 90% (91 of 101) and 86% (44 of 51) in treatment-naïve and treatment-experienced patients, respectively; no virological breakthrough was observed, and ≥99% of patients had a virological response (VR) at the end of treatment. SVR12 rates were higher in patients without cirrhosis (96%; 105 of 109) than in those with cirrhosis (63%; 20 of 32). Five of seven patients who previously failed treatment with an SOF-containing regimen and 2 of 2 who previously failed treatment with an alisporivir-containing regimen achieved SVR12. Baseline characteristics, including gender, age, HCV-RNA levels, and interleukin-28B genotype, did not impact virological outcome. DCV plus SOF was well tolerated; there were no adverse events (AEs) leading to discontinuation and only 1 serious AE on-treatment, which was unrelated to study medications. The few treatment-emergent grade 3/4 laboratory abnormalities that were observed were transient. CONCLUSION: A 12-week regimen of DCV plus SOF achieved SVR12 in 96% of patients with genotype 3 infection without cirrhosis and was well tolerated. Additional evaluation to optimize efficacy in genotype 3-infected patients with cirrhosis is underway.

On-treatment HCV RNA as a predictor of sustained virological response in HCV genotype 3-infected patients treated with daclatasvir and sofosbuvir.

BACKGROUND AND AIMS: Many currently available direct-acting antiviral (DAA) regimens are less effective against HCV genotype 3 than against other HCV genotypes. The all-oral, pangenotypic DAA combination of daclatasvir (NS5A inhibitor) + sofosbuvir (nucleotide NS5B inhibitor) was studied in genotype 3-infected treatment-naive and -experienced patients (ALLY-3) who achieved rates of sustained virological response at post-treatment Week 12 (SVR12) of 90 and 86% respectively. In this analysis, we assessed whether on-treatment responses to daclatasvir + sofosbuvir in genotype 3-infected patients could predict treatment outcome. METHODS: In ALLY-3, treatment-naive and -experienced patients, with or without cirrhosis, were treated with daclatasvir + sofosbuvir for 12 weeks. HCV RNA kinetics and categorical virological responses on treatment were assessed. The proportions of responders and nonresponders by study week, and time to first undetectable HCV RNA, were analysed for utility in predicting treatment outcome. RESULTS: Overall, HCV RNA levels declined rapidly during Week 1 of treatment in both treatment-naive and -experienced cohorts. Although patients with cirrhosis had a slower initial virological response as measured by the proportion of patients with HCV RNA below the lower limit of quantification at Week 1, responses converged thereafter. Positive and negative predictive values calculated for on-treatment responses were generally comparable with the overall SVR12 rate and were therefore limited indicators of outcome. SVR12 rates were not impacted by time to first undetectable HCV RNA. CONCLUSIONS: On-treatment responses are not useful predictors of ultimate virological response to the daclatasvir + sofosbuvir regimen.

Immunogenicity and Safety of 13-Valent Pneumococcal Conjugate Vaccine in HIV-Infected Adults Previously Vaccinated With Pneumococcal Polysaccharide Vaccine.

BACKGROUND: Persons with human immunodeficiency virus (HIV) infection are at increased risk of pneumococcal disease. We evaluated the safety and immunogenicity of 13-valent pneumococcal conjugate vaccine (PCV13) in this population. METHODS: HIV-infected persons ≥ 18 years of age who were previously vaccinated with ≥ 1 dose of 23-valent pneumococcal polysaccharide vaccine (PPSV23) and had CD4 cell counts ≥ 200 cells/mm(3) and HIV viral loads <50 000 copies/mL were enrolled in this 3-dose PCV13 open-label study. RESULTS: A total of 329 subjects received ≥ 1 dose, and 279 received 3 doses administered at 6-month intervals. Increases in anticapsular polysaccharide immunoglobulin G concentrations and opsonophagocytic antibody titers were demonstrated 1 month after each of the 3 doses of PCV13. Antibody levels were generally similar after each dose. The responses were similar whether subjects had previously received 1 or ≥ 2 doses of PPSV23. Pain at the injection-site was the most common local reaction. Severe injection site or systemic events were uncommon. CONCLUSIONS: Vaccination with PCV13 induces anticapsular immunoglobulin G and opsonophagocytic antibody responses in HIV-infected adults with prior PPSV23 vaccination and CD4 cell counts ≥ 200 cells/mm(3). The observations support the use of PCV13 in this population. CLINICAL TRIALS REGISTRATION: NCT00963235.

Bictegravir/emtricitabine/tenofovir alafenamide plus doravirine in highly treatment-experienced men with multidrug-resistant HIV.

OBJECTIVE: To evaluate the safety and efficacy of switching highly treatment-experienced people with HIV (HTE PWH) from rilpivirine/emtricitabine/tenofovir alafenamide (RPV/FTC/TAF) plus dolutegravir (DTG) to bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) plus doravirine (DOR). A pharmacokinetic (PK) analysis was conducted to assess the potential interaction between BIC and DOR. DESIGN AND METHODS: This open-label switch trial enrolled HTE PWH from a primary care private practice in the United States. Eligible participants were male, aged ≥45 years, with documented viral resistance to protease inhibitors, nucleoside reverse transcriptase inhibitors, and/or nonnucleoside reverse transcriptase inhibitors but no resistance to RPV or DOR, and no K65R or T69 insertion mutations. Virologic suppression (≤50 copies/ml) while on RPV/FTC/TAF plus DTG for ≥6 months was required prior to enrollment. The primary endpoint of the study was virologic suppression (<50 and <200 copies/ml) at 48 weeks. Secondary endpoints included safety, tolerability, changes in body mass index (BMI), and identification of PK parameters of BIC and DOR. RESULTS: Twenty males [median age: 65 years (range, 46-74), median time since HIV diagnosis: 37 years (range, 12-42)] completed the study. BIC/FTC/TAF plus DOR was well tolerated with no serious or treatment-related adverse events reported and no appreciable changes in BMI from baseline to Week 48. At Week 48, 100% of participants had <50 viral copies/ml. PK parameters for BIC and DOR ( n  = 10) were consistent with published data. CONCLUSIONS: Switching from RPV/FTC/TAF plus DTG to BIC/FTC/TAF plus DOR was well tolerated and efficacious in HTE men aged ≥45 years with HIV.

Anti-HIV-1 activity of weekly or biweekly treatment with subcutaneous PRO 140, a CCR5 monoclonal antibody.

BACKGROUND: PRO 140 is a humanized CCR5 monoclonal antibody that has demonstrated potent antiviral activity when it is administered intravenously to adults infected with CCR5-tropic (R5) human immunodeficiency virus type 1 (HIV-1). This study is the first to evaluate subcutaneous administration. METHODS: A randomized, double-blind, placebo-controlled study was conducted among 44 subjects with HIV-1 RNA levels of >5000 copies/mL, CD4(+) cell counts of >300 cells/microL, no receipt of antiretroviral therapy for >or=12 weeks, and only R5 HIV-1 detectable. Subjects received placebo, 162 mg of PRO 140, or 324 mg of PRO 140 weekly for 3 weeks or 324 mg of PRO 140 every other week for 2 doses by means of subcutaneous infusion. Subjects were monitored for 58 days for safety, antiviral effects, and PRO 140 serum concentrations. RESULTS: Subcutaneous PRO 140 demonstrated potent and prolonged antiretroviral activity. Mean log(10) reductions in HIV-1 RNA level were 0.23, 0.99 (P=.009), 1.37 (P<.001), and 1.65 (P<.001) for the placebo, 162 mg weekly, 324 mg biweekly, and 324 mg weekly dose groups, respectively. Viral loads remained suppressed between successive doses. Treatment was generally well tolerated. CONCLUSIONS: This trial demonstrates proof of concept for a monoclonal antibody administered subcutaneously in HIV-1 infected individuals. Subcutaneous PRO 140 offers the potential for significant dose-dependent HIV-1 RNA suppression and infrequent patient self-administration. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00642707 .

Case study of a critically ill person with COVID-19 on ECMO successfully treated with leronlimab.

The number of confirmed cases of infection with SARS-CoV-2, the virus causing Coronavirus disease 2019 (COVID-19), continues to increase and is associated with substantial morbidity and mortality in virtually every country in the world. Although in the long-term mass vaccinations remains the most promising approach to control the pandemic, evidence suggests that new variants of the virus have emerged that may be able to evade the immune responses triggered by current vaccines. Therefore despite the recent approval of a number of SARS-CoV-2 vaccines there remains considerable urgency for effective treatments for COVID-19. Severe-to-critical COVID-19 has been shown to be associated with a dysregulated host immune response to SARS-CoV-2 with elevated levels of C-C chemokine receptor type 5 (CCR5) ligands including chemokine C-C ligands 3, 4, 5, as well as interleukins 6 and 10. Leronlimab, a CCR5-specific humanised IgG4 monoclonal antibody originally developed for the treatment of HIV has been studied for the treatment of COVID-19. In the TEMPEST trial which compared leronlimab to placebo in subjects with mild-to-moderate COVID-19, a post hoc analysis showed that leronlimab led to improvements from baseline in National Early Warning Score 2 (NEWS2) at Day 14 in the sub-set of people with more severe disease. Data has also been released on a further ongoing, randomized, placebo-controlled phase 3 registrational trial of leronlimab in 394 people with severe-to-critical COVID-19. The results show that Day 28 mortality was reduced (P â€‹= â€‹0.0319) in the subset of participants receiving leronlimab plus other pre-specified commonly used COVID-19 treatments including dexamethasone administered as part of their standard of care (SOC) compared to participants receiving placebo plus other pre-specified commonly used COVID-19 treatments including dexamethasone as part of their SOC. Several cases have recently been reported demonstrated that treatment with leronlimab restores immune function and achieves clinical improvement in people with critical COVID-19. Here we report on a further case of a critically ill person who was treated with leronlimab. This person had been on extracorporeal membrane oxygenation (ECMO) for an extended period of time before receiving 4 doses of leronlimab. The male subject received his first dose of leronlimab on Day 79 of hospitalization he was weaned off ECMO by Day 84 and discharged from the ECMO intensive care unit on Day 91.

Disruption of CCR5 signaling to treat COVID-19-associated cytokine storm: Case series of four critically ill patients treated with leronlimab.

Coronavirus disease 2019 (COVID-19) is associated with considerable morbidity and mortality. The number of confirmed cases of infection with SARS-CoV-2, the virus causing COVID-19 continues to escalate with over 70 million confirmed cases and over 1.6 million confirmed deaths. Severe-to-critical COVID-19 is associated with a dysregulated host immune response to the virus, which is thought to lead to pathogenic immune dysregulation and end-organ damage. Presently few effective treatment options are available to treat COVID-19. Leronlimab is a humanized IgG4, kappa monoclonal antibody that blocks C-C chemokine receptor type 5 (CCR5). It has been shown that in patients with severe COVID-19 treatment with leronlimab reduces elevated plasma IL-6 and chemokine ligand 5 (CCL5), and normalized CD4/CD8 ratios. We administered leronlimab to 4 critically ill COVID-19 patients in intensive care. All 4 of these patients improved clinically as measured by vasopressor support, and discontinuation of hemodialysis and mechanical ventilation. Following administration of leronlimab there was a statistically significant decrease in IL-6 observed in patient A (p=0.034) from day 0-7 and patient D (p=0.027) from day 0-14. This corresponds to restoration of the immune function as measured by CD4+/CD8+ T cell ratio. Although two of the patients went on to survive the other two subsequently died of surgical complications after an initial recovery from SARS-CoV-2 infection.

Phase 2a study of the CCR5 monoclonal antibody PRO 140 administered intravenously to HIV-infected adults.

The anti-CCR5 antibody PRO 140 has shown potent and prolonged antiretroviral activity in subjects infected with CCR5-tropic (R5) HIV-1. Prior studies have examined single intravenous doses ranging up to 5 mg/kg of body weight or up to three subcutaneous doses ranging up to 324 mg. Here we report the results of a randomized, double-blind, placebo-controlled trial that examined the antiviral activity, tolerability, and pharmacokinetics of single 5-mg/kg and 10-mg/kg intravenous infusions of PRO 140 in 31 treated subjects. Eligibility criteria included HIV-1 RNA levels of >5,000 copies/ml, CD4(+) cell counts of >300/µl, no antiretroviral therapy for ≥12 weeks, and detection of only R5 HIV-1 in the original Trofile assay. Following poststudy testing with an enhanced-sensitivity Trofile assay, one subject treated with 10 mg/kg was reclassified as having dual/mixed-tropic virus at screening, and the data for that subject were censored from efficacy analyses. The mean maximum reduction of the HIV-1 RNA level from the baseline level was 1.8 log(10) units for both the 5-mg/kg and 10-mg/kg doses (P < 0.0001 relative to placebo). Viral loads reached their nadir at day 12 posttreatment and remained significantly (P < 0.01) reduced through day 29 for both PRO 140 dose groups. Treatment was generally well tolerated, with no dose-limiting toxicity being observed. Peak serum concentrations and overall exposures increased proportionally with dose. In summary, single 5-mg/kg and 10-mg/kg doses of PRO 140 exhibited potent, long-lived antiviral activity and were generally well tolerated. The findings further delineate the safety and antiviral properties of this novel, long-acting antiretroviral agent.

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.

BACKGROUND: Fostemsavir, a prodrug of the first-in-class attachment inhibitor, temsavir, is indicated for heavily treatment-experienced individuals with multidrug-resistant HIV-1. We previously reported superior efficacy of fostemsavir versus placebo in the randomised cohort of the BRIGHTE study after 8-day functional monotherapy (primary endpoint); here we report planned interim analyses through week 96. METHODS: BRIGHTE (NCT02362503) is an ongoing multicentre, two-cohort, phase 3 trial, done at 108 centres in 22 countries. We enrolled heavily treatment-experienced adults (≥18 years) failing antiretroviral therapy (HIV-1 RNA ≥400 copies per mL) into two cohorts: the randomised cohort, in which patients with one or two fully active antiretrovirals remaining received oral fostemsavir (600 mg twice a day) or placebo in combination with their failing regimen for 8 days, followed by fostemsavir plus optimised background therapy; or the non-randomised cohort, in which patients with no remaining antiretroviral options received oral fostemsavir (600 mg twice a day) plus optimised background therapy from day 1. Endpoints for the week 96 interim analyses included the proportions of participants with plasma HIV-1 RNA of less than 40 copies per mL, changes from baseline in CD4 cell counts, and the frequency of adverse events, adverse events leading to discontinuation, and deaths. The intention-to-treat exposed population and the safety population both included all participants who received at least one dose of study treatment. The response rates (proportion of participants with HIV-1 RNA <40 copies per mL) in the intention-to-treat exposed population were calculated via snapshot analysis at weeks 24, 48, and 96. FINDINGS: Between Feb 23, 2015, and Aug 11, 2016, 371 participants were enrolled and treated, of which 272 participants were in the randomised cohort and 99 in the non-randomised cohort. 320 (86%) of 371 reported a history of AIDS. In the randomised cohort, rates of virological suppression (HIV-1 RNA <40 copies per mL) increased from 53% (144 of 272) at week 24 to 60% (163 of 272) at week 96. Response rates in the non-randomised cohort were 37% (37 of 99) at week 24 and week 96. Mean increases in CD4 counts from baseline at week 96 were 205 cells per µL (SD 191) in the randomised cohort and 119 cells per µL (202) in the non-randomised cohort. Mean CD4/CD8 ratio increased from 0·20 at baseline to 0·44 at week 96 in the randomised cohort. Few adverse events led to discontinuation (26 [7%] of 371). 12 (4%) of 272 people in the randomised cohort and 17 (17%) of 99 in the non-randomised cohort died; the median baseline CD4 count for participants who died was 11 cells per µL. INTERPRETATION: In heavily treatment-experienced individuals with advanced HIV-1 disease and limited treatment options, fostemsavir-based antiretroviral regimens were generally well tolerated and showed a distinctive trend of increasing virological and immunological response rates through 96 weeks; these findings support fostemsavir as a treatment option for this vulnerable population. FUNDING: ViiV Healthcare.

Safety, tolerability, pharmacokinetics, and efficacy of an interleukin-2 agonist among HIV-infected patients receiving highly active antiretroviral therapy.

We sought to determine the safety, maximum tolerated dose, optimal dose, and preliminary dose efficacy of intermittent subcutaneously (s.c.) administered BAY 50-4798 among patients with HIV infection receiving highly active antiretroviral therapy (HAART) compared with patients receiving HAART alone. A phase I/II randomized, double-blind, dose-escalation study was conducted of the safety, tolerability, pharmacokinetics, and efficacy of s.c. BAY 50-4798 administered to HIV-infected patients already receiving stable HAART. There were no unexpected safety findings in a population of HIV-infected patients receiving HAART plus SC BAY 50-4798 as adjunctive therapy. BAY 50-4798 exhibited nearly dose-proportional pharmacokinetics, and accumulation was minimal during multiple-dose treatment. Limited efficacy data indicated that treatment with BAY 50-4798 caused at least a transient increase in CD4(+) T cell counts in some recipients, particularly at the early time points. In general, this effect appeared to increase with increasing dose. Bay 50-4798 was generally well tolerated across the dose range tested, but a lack of potent, sustained immunologic activity suggests that further optimization of dose and schedule will be necessary.

Enfuvirtide, an HIV-1 fusion inhibitor, for drug-resistant HIV infection in North and South America.

BACKGROUND: The T-20 vs. Optimized Regimen Only Study 1 (TORO 1) was a randomized, open-label, phase 3 study of enfuvirtide (T-20), a human immunodeficiency virus type 1 (HIV-1) fusion inhibitor. METHODS: Patients from 48 sites in the United States, Canada, Mexico, and Brazil with at least six months of previous treatment with agents in three classes of antiretroviral drugs, resistance to drugs in these classes, or both, and with at least 5000 copies of HIV-1 RNA per milliliter of plasma were randomly assigned in a 2:1 ratio to receive enfuvirtide plus an optimized background regimen of three to five antiretroviral drugs or such a regimen alone (control group). The primary efficacy end point was the change in the plasma HIV-1 RNA level from base line to week 24. RESULTS: A total of 501 patients underwent randomization, and 491 received at least one dose of study drug and had at least one measurement of plasma HIV-1 RNA after treatment began. The two groups were balanced in terms of the median base-line HIV-1 RNA level (5.2 log10 copies per milliliter in both groups), median CD4+ cell count (75.5 cells per cubic millimeter in the enfuvirtide group, and 87.0 cells per cubic millimeter in the control group), demographic characteristics, and previous antiretroviral therapy. At 24 weeks, the least-squares mean change from base line in the viral load (intention-to-treat, last observation carried forward) was a decrease of 1.696 log10 copies per milliliter in the enfuvirtide group, and a decrease of 0.764 log10 copies per milliliter in the control group (P<0.001). The mean increases in CD4+ cell count were 76 cells per cubic millimeter and 32 cells per cubic millimeter, respectively (P<0.001). Reactions at the site of the injections were reported by 98 percent of patients receiving enfuvirtide. There were more cases of pneumonia in the enfuvirtide group than in the control group. CONCLUSIONS: The addition of enfuvirtide to an optimized antiretroviral regimen provided significant antiretroviral and immunologic benefit through 24 weeks in patients who had previously received multiple antiretroviral drugs and had multidrug-resistant HIV-1 infection.

TORO: ninety-six-week virologic and immunologic response and safety evaluation of enfuvirtide with an optimized background of antiretrovirals.

The additional 48-week optional treatment extension of the T-20 versus Optimized Regimen Only (TORO) studies evaluated long-term safety and efficacy of enfuvirtide (ENF) through week 96 in patients receiving ENF plus optimized background (OB) and patients switching to ENF plus OB from OB alone. Patient randomization was 2:1 to ENF plus OB (n = 663) and OB (n = 334), of which 89.7% and 89.8% were male, 89.3% and 88.6% were Caucasian, and median age was 41 and 42 years, respectively. HIV risk factors were comparable between the ENF plus OB and OB groups with the major factors being 65.2% versus 66.2% homosexual contact, 17.8% versus 19.8% heterosexual contact, 4.1% versus 4.8% bisexual contact, respectively, and 6.9% injection drug use in both groups. OB patients were allowed to switch to ENF plus OB at virologic failure before week 48 and required to switch at week 48 to continue in the study (n = 230). Efficacy and safety assessments were conducted for each group. At week 96, 55% of ENF plus OB subjects completed the study and 26.5% achieved a viral load of less than 400 copies per milliliter (17.5% achieved less than 50 copies per milliliter). Viral load and CD4 mean change from baseline was -2.1 and -1.1 log(10) HIV-1-RNA copies per milliliter and +166 and +116 CD4 cells/mm(3) for ENF plus OB and switch patients, respectively. No new ENF-related safety issues emerged in weeks 48-96. Injection site reactions led to discontinuation in 7% and 10% of ENF plus OB and switch patients, respectively. In conclusion, these data demonstrate durable efficacy and safety of ENF over 96 weeks and that early use of ENF in combination with other agents for the treatment of antiretroviral-experienced HIV-infected subjects is beneficial.

Safety and efficacy of the HIV-1 attachment inhibitor prodrug fostemsavir in antiretroviral-experienced subjects: week 48 analysis of AI438011, a Phase IIb, randomized controlled trial.

BACKGROUND: Fostemsavir is a prodrug of temsavir, an attachment inhibitor that binds directly to HIV-1 gp120, blocking initial viral attachment and entry into host CD4+ T-cells. Efficacy, safety and dose-response data of fostemsavir in treatment-experienced, HIV-1-infected subjects, through week 48, are reported. METHODS: AI438011 is an ongoing Phase IIb, randomized, active-controlled trial (NCT01384734). Subjects were randomized 1:1:1:1:1 into five arms: fostemsavir (400 mg twice daily, 800 mg twice daily, 600 mg once daily or 1,200 mg once daily) and a reference arm (ritonavir-boosted atazanavir [ATV/r] 300/100 mg once daily), each with a backbone of raltegravir 400 mg twice daily plus tenofovir disoproxil fumarate 300 mg once daily. RESULTS: In total, 251 subjects were treated. Through week 48, the proportion of fostemsavir subjects with HIV-1 RNA <50 copies/ml was 61-82% and 77-95% (modified intent-to-treat [mITT] and observed analysis, respectively); 71% and 88% for ATV/r subjects (mITT and observed). Observed virological response rates were 74-100% versus 96% (fostemsavir versus ATV/r) in subjects with baseline viral load <100,000 copies/ml and 60-91% versus 71% when baseline viral load was ≥100,000 copies/ml. Across fostemsavir arms, median CD4+ T-cell count increases from baseline were 145-186 cells/µl and 142 cells/µl for the ATV/r arm. Fostemsavir doses were generally well tolerated and no fostemsavir-related adverse events led to discontinuation. CONCLUSIONS: Through week 48, fostemsavir continued to be well tolerated and showed similar efficacy to ATV/r. These results support the ongoing Phase III trial in heavily treatment-experienced adults with limited therapeutic options (≤2 classes of active antiretrovirals remaining). ClinicalTrials.gov identifier: NCT01384734.

Enfuvirtide for nurses: answering patient questions on activity, safety, and lifestyle impact.

The introduction of enfuvirtide, the first self-administered parenteral antiretroviral, has reinforced the HIV nurse's role in patient education, support, and motivation. Detailed background knowledge of the drug will assist nurses to provide answers to common questions and concerns raised during patient training. Three particular concerns often raised are curiosity about how enfuvirtide works, what side effects can be expected, and how these and the process of daily injection will affect the patient's daily routine. This brief review is designed to provide nurse-educators with clinical information on these three issues to help them better provide the answers patients will need to help them feel confident self-administering this new drug.

Safety and efficacy of the HIV-1 attachment inhibitor prodrug BMS-663068 in treatment-experienced individuals: 24 week results of AI438011, a phase 2b, randomised controlled trial.

BACKGROUND: BMS-663068 is an oral prodrug of BMS-626529, an attachment inhibitor that binds to HIV-1 gp120, blocking viral attachment to host CD4 cells. AI438011 is an ongoing trial investigating the efficacy, safety, and dose-response of BMS-663068 in treatment-experienced, HIV-1-infected patients. Herein we present the results of the primary analysis. METHODS: AI438011 is a phase 2b, randomised, active-controlled trial, at 53 hospitals and outpatient clinics across ten countries in North and South America, Europe, and Africa. Individuals with an HIV-1 RNA viral load of at least 1000 copies per mL and a BMS-626529 half-maximum inhibitory concentration lower than 100 nmol/L were randomly assigned (1:1:1:1:1) to receive either BMS-663068 at 400 mg twice daily, 800 mg twice daily, 600 mg once daily, or 1200 mg once daily or ritonavir-boosted atazanavir (300 mg of atazanavir and 100 mg of ritonavir once daily), each with 400 mg of raltegravir twice daily and 300 mg of tenofovir disoproxil fumarate once daily as a backbone. The sponsor, participants, and investigators were masked for BMS-663068 dose but not for allocation. Primary endpoints were the proportion of patients with an HIV-1 RNA viral load less than 50 copies per mL (response rate) at week 24 and the frequency of serious adverse events and adverse events leading to discontinuation, up to the week 24 analysis. The primary analyses included all patients who received at least one dose of study drug (modified intention-to-treat population). This study is registered at ClinicalTrials.gov, NCT01384734. FINDINGS: Between July 26, 2011, and July 16, 2012, 581 participants were assessed for eligibility. Of these, 254 patients were randomly assigned to receive either BMS-663068 (n=52 for the 400 mg twice daily group, n=50 for the 800 mg twice daily group, n=51 for the 600 mg once daily group, and n=50 for the 1200 mg once daily group) or ritonavir-boosted atazanavir (n=51). 200 patients received at least one dose of BMS-663068, and 51 patients received at least one dose of ritonavir-boosted atazanavir. At week 24, 40 (80%) of 50 patients in the BMS-663068 400 mg twice daily group, 34 (69%) of 49 patients in the 800 mg twice daily group, 39 (76%) of 51 patients in the 600 mg once daily group, and 36 (72%) of 50 patients in the 1200 mg once daily group had an HIV-1 RNA viral load less than 50 copies per mL, compared with 38 (75%) of 51 patients in the ritonavir-boosted atazanavir group. Serious adverse events were noted in 13 (7%) of 200 patients in the BMS-663068 groups and five (10%) of the 51 patients in the ritonavir-boosted atazanavir group. Four (2%) of the 200 patients in the BMS-663068 groups and two (4%) of the 51 patients in the ritonavir-boosted atazanavir group discontinued because of adverse events. No serious adverse events or adverse events leading to discontinuation were BMS-663068-related. Grade 2-4 adverse events related to study drug(s) occurred in 17 (9%) of 200 patients across the BMS-663068 groups and 14 (27%) of 51 patients in the ritonavir-boosted atazanavir group. For the BMS-663068 groups these events were mostly single instances with no dose relation and for the ritonavir-boosted atazanavir group these were mostly gastrointestinal or hepatobiliary disorders associated with hyperbilirubinaemia. INTERPRETATION: In a comparison with ritonavir-boosted atazanavir, efficacy and safety of BMS-663068 up to the week 24 analysis support continued development of BMS-663068, which is being assessed in a phase 3 trial in heavily treatment-experienced individuals. FUNDING: Bristol-Myers Squibb.

A phase II clinical study of the long-term safety and antiviral activity of enfuvirtide-based antiretroviral therapy.

OBJECTIVES: The primary objective was to determine the long-term safety of the subcutaneous self-administration of enfuvirtide. Secondary objectives included the determination of enfuvirtide pharmacokinetics and antiviral activity and the immunological response to the enfuvirtide-containing regimen. METHODS: A multicenter 48-week uncontrolled open-label rollover study was conducted on 71 HIV-infected adults recruited from previous enfuvirtide clinical trials. Patients with extensive previous use of protease and reverse transcriptase inhibitors received a twice-daily dose of 50 mg enfuvirtide subcutaneously (45 mg deliverable) combined with two or more antiretroviral drugs selected for each individual, guided by resistance testing and previous treatment history. RESULTS: The mean baseline plasma HIV-RNA level was 4.81 log(10) copies/ml and the mean CD4 cell count was 134.8 cells/microl. The majority (86.9%) of treatment-emergent adverse events were grade 2 or less in severity. Injection site reactions were common, but no patients discontinued treatment. A mean HIV-RNA change of -1.33 log(10) was achieved within 14 days of treatment initiation. At week 48, approximately one-third of all patients in the intent-to-treat population maintained significant suppression of plasma HIV RNA, with either less than 400 copies/ml or more than a 1.0 log(10) decline from baseline. The mean gain in absolute CD4 cell counts at 48 weeks was 84.9 cells/microl. Trough plasma concentrations of enfuvirtide were consistently higher than target concentrations. CONCLUSION: Self-administration of enfuvirtide is not associated with unexpected toxicities for up to one year, and combined with oral antiretroviral drugs was associated with a significant decrease in HIV RNA and an increase in CD4 cell counts.

Assessment of drug-drug interaction potential of enfuvirtide in human immunodeficiency virus type 1-infected patients.

INTRODUCTION: Enfuvirtide is the first drug to block human immunodeficiency virus type 1 (HIV-1) glycoprotein 41-mediated viral fusion to host cells. This study investigated whether enfuvirtide can influence the activities of cytochrome P450 (CYP) enzymes in HIV-1-infected patients. METHODS: An open-label, 1-sequence crossover study was conducted in 12 HIV-1-infected adults, by use of a 5-drug cocktail consisting of caffeine, chlorzoxazone, dapsone, debrisoquin (INN, debrisoquine), and mephenytoin to assess the activities of CYP1A2, CYP2E1, CYP3A4, CYP2D6, and CYP2C19, respectively. Dapsone was used to assess N-acetyltransferase activity. Patients received a single dose of the cocktail alone on day -15 and another together with enfuvirtide on day 6. Enfuvirtide (90 mg subcutaneously) was administered twice daily on days 1 to 7. Phenotypic index parameters were estimated and analyzed by ANOVA with factors subject and day (-15 and 6). RESULTS: The phenotypic index parameters, with and without enfuvirtide, for CYP3A4 (0.33 versus 0.34; 90% confidence interval [CI] for ratio of least squares means, 0.88-1.09), CYP2D6 (0.72 versus 0.71; 90% CI, 0.97-1.06), and N-acetyltransferase (0.35 versus 0.39; 90% CI, 0.82-0.98) were bioequivalent. The phenotypic index parameters, with and without enfuvirtide, for CYP1A2 (0.76 versus 0.81; 90% CI, 0.71-1.17), CYP2E1 (1.3 versus 1.2; 90% CI, 0.87-1.29), and CYP2C19 (93 versus 81.8; 90% CI, 0.98-1.28) were not bioequivalent but were not substantially different. CONCLUSIONS: Enfuvirtide had no clinically important effect on the metabolism of probe drugs mediated by CYP3A4, CYP2D6, or N-acetyltransferase and had little effect on the metabolism of drugs mediated by CYP1A2, CYP2E1, or CYP2C19. The potential for interactions between enfuvirtide and concomitantly administered drugs metabolized by the CYP enzymes tested in this study is low.