Jacob Lalezari

Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection

BACKGROUND Effective treatment for hepatitis C virus (HCV) genotype 1 infection in patients who have not had a sustained virologic response to prior interferon-based therapy represents an unmet medical need. METHODS We conducted a phase 3, randomized, open-label study involving patients infected with HCV genotype 1 who had not had a sustained virologic response after treatment with peginterferon and ribavirin, with or without a protease inhibitor. Patients were randomly assigned to receive the NS5A inhibitor ledipasvir and the nucleotide polymerase inhibitor sofosbuvir in a once-daily, fixed-dose combination tablet for 12 weeks, ledipasvir-sofosbuvir plus ribavirin for 12 weeks, ledipasvir-sofosbuvir for 24 weeks, or ledipasvir-sofosbuvir plus ribavirin for 24 weeks. The primary end point was a sustained virologic response at 12 weeks after the end of therapy. RESULTS Among the 440 patients who underwent randomization and were treated, 20% had cirrhosis and 79% had HCV genotype 1a infection. The rates of sustained virologic response were high in all treatment groups: 94% (95% confidence interval [CI], 87 to 97) in the group that received 12 weeks of ledipasvir-sofosbuvir; 96% (95% CI, 91 to 99) in the group that received 12 weeks of ledipasvir-sofosbuvir and ribavirin; 99% (95% CI, 95 to 100) in the group that received 24 weeks of ledipasvir-sofosbuvir; and 99% (95% CI, 95 to 100) in the group that received 24 weeks of ledipasvir-sofosbuvir and ribavirin. No patient discontinued treatment owing to an adverse event. The most common adverse events were fatigue, headache, and nausea. CONCLUSIONS Treatment with a once-daily, single-tablet regimen of ledipasvir and sofosbuvir resulted in high rates of sustained virologic response among patients with HCV genotype 1 infection who had not had a sustained virologic response to prior interferon-based treatment. (Funded by Gilead Sciences; ION-2 ClinicalTrials.gov number, NCT01768286.).

Maraviroc for Previously Treated Patients with R5 HIV-1 Infection

BACKGROUND CC chemokine receptor 5 antagonists are a new class of antiretroviral agents. METHODS We conducted two double-blind, placebo-controlled, phase 3 studies--Maraviroc versus Optimized Therapy in Viremic Antiretroviral Treatment-Experienced Patients (MOTIVATE) 1 and MOTIVATE 2--with patients who had R5 human immunodeficiency virus type 1 (HIV-1) only. They had been treated with or had resistance to three antiretroviral-drug classes and had HIV-1 RNA levels of more than 5000 copies per milliliter. The patients were randomly assigned to one of three antiretroviral regimens consisting of maraviroc once daily, maraviroc twice daily, or placebo, each of which included optimized background therapy (OBT) based on treatment history and drug-resistance testing. Safety and efficacy were assessed after 48 weeks. RESULTS A total of 1049 patients received the randomly assigned study drug; the mean baseline HIV-1 RNA level was 72,400 copies per milliliter, and the median CD4 cell count was 169 per cubic millimeter. At 48 weeks, in both studies, the mean change in HIV-1 RNA from baseline was greater with maraviroc than with placebo: -1.66 and -1.82 log(10) copies per milliliter with the once-daily and twice-daily regimens, respectively, versus -0.80 with placebo in MOTIVATE 1, and -1.72 and -1.87 log(10) copies per milliliter, respectively, versus -0.76 with placebo in MOTIVATE 2. More patients receiving maraviroc once or twice daily had HIV-1 RNA levels of less than 50 copies per milliliter (42% and 47%, respectively, vs. 16% in the placebo group in MOTIVATE 1; 45% in both maraviroc groups vs. 18% in MOTIVATE 2; P<0.001 for both comparisons in each study). The change from baseline in CD4 counts was also greater with maraviroc once or twice daily than with placebo (increases of 113 and 122 per cubic millimeter, respectively, vs. 54 in MOTIVATE 1; increases of 122 and 128 per cubic millimeter, respectively, vs. 69 in MOTIVATE 2; P<0.001 for both comparisons in each study). Frequencies of adverse events were similar among the groups. CONCLUSIONS Maraviroc, as compared with placebo, resulted in significantly greater suppression of HIV-1 and greater increases in CD4 cell counts at 48 weeks in previously treated patients with R5 HIV-1 who were receiving OBT. (ClinicalTrials.gov numbers, NCT00098306 and NCT00098722.)

ABT-450/r–Ombitasvir and Dasabuvir with or without Ribavirin for HCV

BACKGROUND The interferon-free regimen of ABT-450 with ritonavir (ABT-450/r), ombitasvir, and dasabuvir with or without ribavirin has shown efficacy in inducing a sustained virologic response in a phase 2 study involving patients with hepatitis C virus (HCV) genotype 1 infection. We conducted two phase 3 trials to examine the efficacy and safety of this regimen in previously untreated patients with HCV genotype 1 infection and no cirrhosis. METHODS We randomly assigned 419 patients with HCV genotype 1b infection (PEARL-III study) and 305 patients with genotype 1a infection (PEARL-IV study) to 12 weeks of ABT-450/r-ombitasvir (at a once-daily dose of 150 mg of ABT-450, 100 mg of ritonavir, and 25 mg of ombitasvir), dasabuvir (250 mg twice daily), and ribavirin administered according to body weight or to matching placebo for ribavirin. The primary efficacy end point was a sustained virologic response (an HCV RNA level of <25 IU per milliliter) 12 weeks after the end of treatment. RESULTS The study regimen resulted in high rates of sustained virologic response among patients with HCV genotype 1b infection (99.5% with ribavirin and 99.0% without ribavirin) and among those with genotype 1a infection (97.0% and 90.2%, respectively). Of patients with genotype 1b infection, 1 had virologic failure, and 2 did not have data available at post-treatment week 12. Among patients with genotype 1a infection, the rate of virologic failure was higher in the ribavirin-free group than in the ribavirin group (7.8% vs. 2.0%). In both studies, decreases in the hemoglobin level were significantly more common in patients receiving ribavirin. Two patients (0.3%) discontinued the study drugs owing to adverse events. The most common adverse events were fatigue, headache, and nausea. CONCLUSIONS Twelve weeks of treatment with ABT-450/r-ombitasvir and dasabuvir without ribavirin was associated with high rates of sustained virologic response among previously untreated patients with HCV genotype 1 infection. Rates of virologic failure were higher without ribavirin than with ribavirin among patients with genotype 1a infection but not among those with genotype 1b infection. (Funded by AbbVie; PEARL-III and PEARL-IV ClinicalTrials.gov numbers, NCT01767116 and NCT01833533.).

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

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. (Hepatology 2015;61:1127–1135)

Intravenous Cidofovir for Peripheral Cytomegalovirus Retinitis in Patients with AIDS: A Randomized, Controlled Trial

Cytomegalovirus (CMV) infection is a major cause of illness and death in patients with the acquired immunodeficiency syndrome (AIDS) and other immunocompromised states. About 20% to 40% of patients with AIDS develop CMV retinitis, gastrointestinal disease, or other systemic end-organ disease [1, 2]. Cytomegalovirus retinitis is the most common intraocular infection in patients with AIDS; if left untreated, it may lead to progressive destruction of retinal tissue and blindness [3-5]. Two systemic agents-ganciclovir and foscarnet-are available for the treatment of CMV retinitis. Both delay progression of CMV retinitis, but the median time to disease progression is approximately 7 weeks with either agent [6, 7]. Intravenous ganciclovir or foscarnet is given twice daily during induction therapy and daily during maintenance therapy. This usually necessitates placement of an indwelling catheter, and the morbidity associated with catheter-related complications is substantial [8]. The dose-limiting toxicity of ganciclovir is myelosuppression, a condition that often requires administration of colony-stimulating factors. Nephrotoxicity, anemia, seizures, and electrolyte disturbances have occurred with foscarnet [9]. A recently approved oral formulation of ganciclovir may reduce the need for catheter placement and is less myelosuppressive than intravenous ganciclovir; however, it is also less effective in delaying the time to progression and therefore may have limited usefulness in sight-threatening disease [10, 11]. Cidofovir (Vistide, Gilead Sciences, Inc., Foster City, California) is a nucleotide analogue of cytosine that has potent, prolonged in vitro and in vivo activity against several herpesviruses, including CMV, herpes simplex virus types 1 and 2, varicella-zoster virus, and Epstein-Barr virus [12-14]. Unlike acyclovir or ganciclovir, which require intracellular activation by viral-encoded enzymes, cidofovir is converted to cidofovir diphosphate (the active intracellular metabolite) by host cellular enzymes; thus, conversion is independent of viral infection. Consequently, cidofovir may remain effective against nucleoside-resistant strains of herpesviruses [15, 16]. The long intracellular half-life of the diphosphate (17 to 65 hours) may explain the prolonged antiviral effects of cidofovir [17, 18]. The major dose-limiting toxicity of cidofovir is dose- and schedule-dependent nephrotoxicity, characterized by degeneration and necrosis of renal proximal convoluted tubule cells. Concomitant administration of probenecid is thought to reduce nephrotoxicity by competing for uptake at the basolateral surface of the proximal tubule, thereby minimizing cidofovir uptake and concentration. Phase I and II studies of intravenous cidofovir in patients with human immunodeficiency virus (HIV) infection and asymptomatic CMV shedding in urine or semen showed a dose-dependent anti-CMV effect and dose-dependent nephrotoxicity [19, 20]. In these early trials, 4 of 12 patients who received cidofovir at anti-CMV doses ( 3 mg/kg of body weight) without receiving concomitant probenecid and hydration developed a serum creatinine level greater than 177 mol/L (2 mg/dL). None of 32 patients who received a greater cumulative dose of cidofovir along with concomitant probenecid and hydration developed a serum creatinine level greater than 177 mol/L. In addition, evidence of prolonged anti-CMV effect was seen for as long as several weeks after cidofovir infusion. On the basis of these results, intermittent treatment (once weekly for 2 weeks and once every 2 weeks thereafter) with concomitant oral probenecid and intravenous saline hydration was chosen for further study in patients with CMV retinitis. If efficacious, such a regimen would be more convenient than standard daily systemic therapies for CMV retinitis and would obviate the need for an indwelling catheter. Our study was a multicenter, randomized, controlled trial comparing immediate with deferred intravenous cidofovir treatment in patients with AIDS and previously untreated peripheral CMV retinitis. Patients randomly assigned to the deferred treatment group did not receive cidofovir until progression of CMV retinitis was documented by retinal photography. Methods Enrollment Patients who were 13 to 60 years of age and had HIV infection and newly diagnosed, previously untreated peripheral CMV retinitis (not immediately sight-threatening) were eligible. These patients were self-referred or were referred by their primary care physicians or ophthalmologists. The diagnosis of CMV retinitis was made by an experienced ophthalmologist on the basis of the presence of characteristic necrotic white, fluffy, or granular retinal opacities with or without associated hemorrhage. Lesions were defined as peripheral if they were located in retinal zones 2 or 3 (that is, at least 1500 m from the margin of the optic disc and 3000 m from the center of the fovea) [21]. Additional inclusion criteria were no previous therapy with ganciclovir, foscarnet, or other agents that have activity against CMV end-organ disease; serum creatinine level of 133 mol/L or less ( 1.5 mg/dL); proteinuria less than 1+; an absolute neutrophil count of at least 0.750 109/L ( 750 cells/mm3); a platelet count of at least 50 109/L ( 50 000 cells/mm3); a life expectancy of 3 months or longer; and a Karnofsky performance score of at least 60 [22]. Exclusion criteria were ocular media opacity that precluded adequate visualization of the retina for assessment of lesion changes, unrepaired retinal detachment, ongoing therapy with acyclovir or agents that have nephrotoxic potential, and a history of hypersensitivity to probenecid. We also excluded women who were pregnant or nursing. Concomitant antiretroviral therapy with approved or investigational agents and prophylaxis against opportunistic infections were encouraged. The protocol and informed consent documents were approved by the institutional review boards at each of the eight study centers, and patients provided signed, informed consent before randomization. Study Design and Treatment A biased-coin adaptive randomization scheme was used to enhance balance (within sites and across study patients) between the immediate and deferred treatment groups [23]. Patients in the immediate treatment group received cidofovir, 5 mg/kg once weekly for 2 weeks (induction), and then 5 mg/kg once every 2 weeks (maintenance). Cidofovir was administered by intravenous infusion in 100 mL of normal saline during a 1-hour period after intravenous hydration with 1 L of normal saline. All patients received concomitant oral probenecid on the day of cidofovir infusion only, administered as 2 g 3 hours before each cidofovir infusion, 1 g 2 hours after each infusion, and 1 g 8 hours after each infusion. Because the concomitant use of probenecid and zidovudine results in a 50% decrease in zidovudine clearance, patients were advised to decrease the zidovudine dose by 50% or to interrupt zidovudine treatment on the day of each cidofovir infusion [24]. Medical history, physical examination, and laboratory evaluation (including complete blood count, chemistry profile, and urinalysis) were done within 24 hours before each cidofovir infusion. In patients who developed mild to moderate nephrotoxicity (serum creatinine level 146 to 175 mol/L [1.7 to 1.9 mg/dL] or proteinuria of 1+, or both), the cidofovir dose was reduced to 3 mg/kg; in patients with proteinuria of at least 2+ or a serum creatinine level that had increased to at least 177 mol/L ( 2.0 mg/dL) or both, treatment was discontinued. Patients with symptoms that were temporally related to probenecid received treatment with antipyretic or antiemetic agents, antihistamines, or active probenecid desensitization, at the discretion of the investigator. Patients in the deferred treatment group were eligible to cross over to receive cidofovir after progression of CMV retinitis was documented. Urine and blood samples were collected at selected sites at baseline and at weeks 3, 11, and 23 for qualitative CMV culture (standard or shell vial method), as described elsewhere [19]. T-lymphocyte subsets were analyzed in all patients at study entry [25]. All patients were followed for determination of mortality rate even if study treatment had been discontinued. Ophthalmologic Evaluations Ophthalmologic evaluations, which included assessment of the best corrected visual acuity, dilated indirect ophthalmoscopy, bilateral full-field fundus photography, and intraocular pressure measurement, were done before randomization; during study weeks 1, 3, 5, 7, 11, 15, 19, and 23; and monthly thereafter until progression of CMV retinitis was documented. Visual acuity was assessed using charts from the Early Treatment for Diabetic Retinopathy Study (modified Bailey-Lovie chart). Bilateral, full-field retinal photography was done using a 50- to 60-degree wide-angle camera. Retinal photographs were read at an independent reading center by an ophthalmologist who was unaware of treatment assignment. The primary study end point-progression of CMV retinitis-was defined as either enlargement of a preexisting CMV lesion (the enlargement is identified by a lesion border that advances into the previously uninvolved retina and reaches or exceeds a threshold linear distance of 750 m in a direction perpendicular to the border position at baseline; the enlargement also involves a segment of border 750 m in width) or the occurrence in either eye of a new lesion at least 750 m in diameter. Statistical Analysis Study results were independently collected and analyzed by a contract research organization (Corning Besselaar, Inc., Princeton, New Jersey) according to a predetermined report and analysis plan. The funding source did not have veto power over publication of the results. All analyses were done using the SAS software package for Unix, version 6.09 (SAS Institute, Cary, North Carolina). The primary ef

Oral Ganciclovir for the Prevention of Cytomegalovirus Disease in Persons with AIDS

BACKGROUND In the advanced stages of the acquired immunodeficiency syndrome (AIDS), cytomegalovirus (CMV) disease, particularly vision-damaging retinitis due to CMV is common. We evaluated prophylactic treatment with orally administered ganciclovir as a way to prevent CMV disease. METHODS We conducted a prospective, randomized, double-blind, placebo-controlled study of CMV infected persons with AIDS with either CD4+ lymphocyte counts of < or = 50 per cubic millimeter or counts of < or = 100 per cubic millimeter in those with a history of an AIDS defining opportunistic infection. Patients were randomly assigned, in a 2:1 ratio, to receive either oral ganciclovir (1000 mg three times daily) or placebo. RESULTS The study was stopped after a median 367 days of follow-up. In an intention-to-treat analysis, the twelve month cumulative rates of confirmed CMV disease were 26 percent in the placebo group (n = 239) and 14 percent in the ganciclovir group (n = 486), representing an overall reduction in risk of 49 percent in the ganciclovir group (P < 0.001). The incidence of CMV retinitis after 12 months was 24 percent in the placebo group and 12 percent in the ganciclovir group (P < 0.0001). The prevalence of CMV-positive urine cultures at base line was 42 percent; after two months it was 43 percent in the placebo group and 10 percent in the ganciclovir group (P < 0.0001). The one year mortality rate was 26 percent in the placebo group and 21 percent in the ganciclovir group (P = 0.14). Therapy with granulocyte colony stimulating factor was more frequent in the ganciclovir group (24 percent) than in the placebo group (9 percent). CONCLUSIONS In persons with advanced AIDS, phophylactic oral ganciclovir significantly reduces the risk of CMV disease.

Safety and Immunogenicity of a Replication-Incompetent Adenovirus Type 5 HIV-1 Clade B gag/pol/nef Vaccine in Healthy Adults

BACKGROUND The safety and immunogenicity of the MRK adenovirus type 5 human immunodeficiency virus type 1 clade B gag/pol/nef vaccine, a replication-incompetent adenovirus type 5-vectored vaccine designed to elicit cell-mediated immunity against conserved human immunodeficiency virus proteins, was assessed in a phase 1 trial. METHODS Healthy adults not infected with human immunodeficiency virus were enrolled in a multicenter, dose-escalating, blind, placebo-controlled study to evaluate a 3-dose homologous prime-boost regimen of the trivalent MRK adenovirus type 5 human immunodeficiency virus type 1 vaccine containing from 3 x 10(6) to 1 x 10(11) viral particles per 1-mL dose administered on day 1, during week 4 and during week 26. Adverse events were recorded for 29 days after each intradeltoid injection. The primary immunogenicity end point was the proportion of study participants with a positive unfractionated Gag-, Pol-, or Nef-specific interferon-gamma enzyme-linked immunosorbent spot response measured 4 weeks after administration of the last dose. RESULTS Of 259 randomized individuals, 257 (99%) received > or = 1 dose of vaccine or placebo and were included in the safety analyses. Enzyme-linked immunosorbent spot results were available for 217 study participants (84%) at week 30. No serious vaccine-related adverse events occurred. No study participant discontinued participation because of vaccine-related adverse events. The frequency of injection-site reactions was dose dependent. Vaccine doses of > or = 3 x 10(9) viral particles elicited positive enzyme-linked immunosorbent spot responses to > or = 1 vaccine component in > 60% of recipients. High baseline antibody titers against adenovirus type 5 diminished enzyme-linked immunosorbent spot responses at all doses except the 3 x 10(10) viral particle dose. CONCLUSIONS The vaccine was generally well tolerated and induced cell-mediated immune responses against human immunodeficiency virus type 1 peptides in most healthy adults. Despite these findings, vaccination in a proof-of-concept trial with use of this vaccine was discontinued because of lack of efficacy.

Sofosbuvir and Ribavirin for Hepatitis C in Patients With HIV Coinfection

IMPORTANCE Treatment of hepatitis C virus (HCV) infection in patients also infected with human immunodeficiency virus (HIV) has been limited due to drug interactions with antiretroviral therapies (ARTs) and the need to use interferon. OBJECTIVE To determine the rates of HCV eradication (sustained virologic response [SVR]) and adverse events in patients with HCV-HIV coinfection receiving sofosbuvir and ribavirin treatment. DESIGN, SETTING, AND PARTICIPANTS Open-label, nonrandomized, uncontrolled phase 3 trial conducted at 34 treatment centers in the United States and Puerto Rico (August 2012-November 2013) evaluating treatment with sofosbuvir and ribavirin among patients with HCV genotypes 1, 2, or 3 and concurrent HIV. Patients were required to be receiving ART with HIV RNA values of 50 copies/mL or less and a CD4 T-cell count of more than 200 cells/μL or to have untreated HIV infection with a CD4 T-cell count of more than 500 cells/μL. Of the treatment-naive patients, 114 had HCV genotype 1 and 68 had HCV genotype 2 or 3, and 41 treatment experienced participants who had been treated with peginterferon-ribavirin had HCV genotype 2 or 3, for a total of 223 participants. INTERVENTIONS Treatment-naive patients with HCV genotype 2 or 3 received 400 mg of sofosbuvir and weight-based ribavirin for 12 weeks and treatment-naive patients with HCV genotype 1 and treatment-experienced patients with HCV genotype 2 or 3 received the same treatment for 24 weeks. MAIN OUTCOMES AND MEASURES The primary study outcome was the proportion of patients with SVR (serum HCV <25 copies/mL) 12 weeks (SVR12) after cessation of HCV therapy. RESULTS Among treatment-naive participants, 87 patients (76%) of 114 (95% CI, 67%-84%) with genotype 1, 23 patients (88%) of 26 with genotype 2 (95% CI, 70%-985), and 28 patients (67%) of 42 with genotype 3 (95% CI, 51%-80%) achieved SVR12. Among treatment-experienced participants, 22 patients (92%) of 24 with genotype 2 (95% CI, 73%-99%) and 16 patients (94%) of 17 (95% CI, 71%-100%) achieved SVR12. The most common adverse events were fatigue, insomnia, headache, and nausea. Seven patients (3%) discontinued HCV treatment due to adverse events. No adverse effect on HIV disease or its treatment was observed. CONCLUSIONS AND RELEVANCE In this open-label, nonrandomized, uncontrolled study, patients with HIV who were coinfected with HCV genotype 1, 2, or 3 who received the oral, interferon-free combination of sofosbuvir and ribavirin for 12 or 24 weeks had high rates of SVR12. Further studies of this oral regimen in diverse populations of coinfected patients are warranted. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01667731.

Phase 2 gene therapy trial of an anti-HIV ribozyme in autologous CD34+ cells

Gene transfer has potential as a once-only treatment that reduces viral load, preserves the immune system and avoids lifetime highly active antiretroviral therapy. This study, which is to our knowledge the first randomized, double-blind, placebo-controlled, phase 2 cell-delivered gene transfer clinical trial, was conducted in 74 HIV-1-infected adults who received a tat-vpr-specific anti-HIV ribozyme (OZ1) or placebo delivered in autologous CD34+ hematopoietic progenitor cells. There were no OZ1-related adverse events. There was no statistically significant difference in viral load between the OZ1 and placebo group at the primary end point (average at weeks 47 and 48), but time-weighted areas under the curve from weeks 40-48 and 40-100 were significantly lower in the OZ1 group. Throughout the 100 weeks, CD4+ lymphocyte counts were higher in the OZ1 group. This study indicates that cell-delivered gene transfer is safe and biologically active in individuals with HIV and can be developed as a conventional therapeutic product.

The Safety, Plasma Pharmacokinetics, and Antiviral Activity of Subcutaneous Enfuvirtide (T-20), a Peptide Inhibitor of gp41-Mediated Virus Fusion, in HIV-Infected Adults

Enfuvirtide (T-20) is a novel antiretroviral agent that blocks HIV-1 cell fusion. A 28-day randomized dose-comparison study was conducted to determine the safety, pharmacokinetics, and antiviral activity of enfuvirtide in 78 HIV-infected adults, most with extensive treatment experience. Patients received enfuvirtide, added to a failing regimen, either by continuous subcutaneous infusion (CSI: 12.5, 25, 50 or 100 mg/day) or by subcutaneous (SC) injection (50 or 100 mg twice daily). Dose-related decreases in viral load were observed, with a maximum mean reduction from baseline of 1.6 log(10) copies/ml (p< 0.001) seen in the 100 mg bid SC group. Most responses diminished by 28 days. Plasma pharmacokinetics and antiviral responses were more consistent for SC injection than for CSI because of technical difficulties experienced with CSI. Injection site reactions were common but generally mild. These results indicate that enfuvirtide is a promising new therapeutic agent for HIV-infected patients, including those with prior antiretroviral treatment.