Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The HIV fusion inhibitor enfuvirtide (ENF/Fuzeon) targets the env gp41 transmembrane domain. Mutations in gp41 are associated with ENF resistance. We developed a prototype assay to genotype a 676-bp region spanning the heptad repeat domains (HR1 and HR2) of HIV-1 gp41. Plasma samples were collected from 126 HIV-1-infected blood donors in Cameroon, Brazil, Uganda, South Africa, Thailand, and Argentina. Based on analysis of gag p24, pol integrase, and env gp41 genes, the panel was composed of subtypes A/A2 (18), B (11), C (14), D (10), F/F2 (9), G (7), CRF01_AE (9), CRF02_AG (33), and recombinant strains (15). Genotyping was successful for 119 of the 126 samples (94.4%). Although numerous amino acid polymorphisms were detected in some samples, none had primary mutations associated with ENF resistance. The gp41 HIV-1 research reagents developed by Celera are useful tools for genotyping analysis of the gp41 region in diverse HIV-1 strains.
 ...
PMID:Analysis of HIV type 1 gp41 sequences in diverse HIV type 1 strains. 1816 19

Enfuvirtide (T20) is the first and only HIV-1 fusion inhibitor approved for clinical use, but it can easily induce drug resistance limiting its practical application. A novel anti-HIV peptide, termed sifuvirtide, was designed based on the three-dimensional structure of the HIV-1 gp41 fusogenic core conformation. Here we report its in vitro anti-HIV potency, its mechanism of action, as well as the results from Phase Ia clinical studies. We demonstrated that sifuvirtide inhibited HIV-1-mediated cell-cell fusion in a dose-dependent manner and exhibited high potency against infections by a wide range of primary and laboratory-adapted HIV-1 isolates from multiple genotypes with R5 or X4 phenotypes. Notably, sifuvirtide was also highly effective against T20-resistant strains. Unlike T20, sifuvirtide could efficiently block six-helix bundle formation in a dominant negative fashion. These results suggest that sifuvirtide has a different mechanism of action from that of T20. Phase Ia clinical studies of sifuvirtide (FS0101) in 60 healthy individuals demonstrated good safety, tolerability, and pharmacokinetic profiles. A single dose regimen (5, 10, 20, 30, and 40 mg) by subcutaneous injection once daily at abdominal sites was well tolerated without serious adverse events. Pharmacokinetic studies of single and multiple administration of sifuvirtide showed that its decay half-lives were 20.0 +/- 8.6 h and 26.0 +/- 7.9 h, respectively. In summary, sifuvirtide has potential to become an ideal fusion inhibitor for treatment of HIV/AIDS patients, including those with HIV-1 strains resistant to T20.
 ...
PMID:Design and evaluation of sifuvirtide, a novel HIV-1 fusion inhibitor. 1830 20

Human immunodeficiency virus type 1 (HIV-1) entry is an attractive target for therapeutic intervention. Two drugs that inhibit this process have been approved: the fusion inhibitor T20 (enfuvirtide [Fuzeon]) and, more recently, the CCR5 blocker maraviroc (Selzentry). T1249 is a second-generation fusion inhibitor with improved antiviral potency compared to the first-generation peptide T20. We selected T1249-resistant HIV-1 variants in vitro by serial virus passage in the presence of increasing T1249 doses after passage with wild-type and T20-resistant variants. Sequence analysis revealed the acquisition of substitutions within the HR1 region of the gp41 ectodomain. The virus acquired mutations of residue V38 to either E or R in 10 of 19 cultures. Both E and R at position 38 were confirmed to cause resistance to T1249, as well as cross-resistance to T20 and C34, but not to the third-generation fusion inhibitor T2635. We also observed substitutions at residues 79 and 90 (Q79E and K90E), which provide modest resistance to T1249 and, interestingly, T2635. Thus, the gp41 amino acid position implicated in T20 resistance (V38 replaced by A, G, or W) is also responsible for T1249 resistance (V38 replaced by E, R, or K). These results indicate that T20 and T1249 exhibit very similar inhibition modes that call for similar but not identical resistance mutations. All T1249-resistant viruses with changes at position 38 are cross resistant to T20, but not vice versa. Furthermore, substitutions at position 38 do not provide resistance to the third-generation inhibitor T2635, while substitution at positions 79 and 90 do, suggesting different resistance mechanisms.
 ...
PMID:Selection of T1249-resistant human immunodeficiency virus type 1 variants. 1843 91

Enfuvirtide (ENF) administration by needle/syringe is commonly associated with injection site reactions (ISRs). This study assessed ISRs and participant preference between a needle-free injection device (NFID) and a 27-gauge 1/2-inch needle/syringe (NS). A total of 349 participants with human immunodeficiency virus infection, who had difficulty tolerating long-term administration of ENF by NS, underwent randomization (2:1) to ENF administered twice daily by NFID for 8 weeks, or by NS for 4 weeks followed by NFID for 4 weeks. The objectives of the study were to compare ISRs associated with ENF injection using NFID or NS based on a composite endpoint, ISR incidence/severity, overall ISR scores, and discontinuations. In the NFID group, ISRs improved as the percentage of participants meeting the composite endpoint decreased from baseline (40.1%) to week 4 (25.4%) and remained stable at week 8 (21.2%). In the NS --> NFID group, the percentage meeting the composite endpoint worsened from baseline (36.5%) to week 4 (45.1%), but improved at week 8 (26.1%) after switching. Between-participant comparison showed a statistically significant greater improvement from baseline to week 4 in overall ISR score in the NFID group compared to the NS group. Within-participant comparison of the NS --> NFID group showed a significantly greater decrease in overall ISR score from baseline to week 8. In responses to a questionnaire, 87.2% of the participants surveyed preferred the NFID delivery system over NS. NFID is an alternative injection method that may reduce the incidence and severity of treatment-limiting ISRs associated with ENF administration.
 ...
PMID:An open-label safety study of enfuvirtide injection with a needle-free injection device or needle/syringe: the Biojector 2000 Open-label Safety Study (BOSS). 1850 25

Enfuvirtide has been a cornerstone of salvage therapy for multidrug-resistant HIV. Raltegravir provides another novel class option, with the advantages of easier administration and improved tolerability. Thirty-five adults electively replaced enfuvirtide with raltegravir while the rest of their regimen was unchanged. All maintained virologic suppression after a median of 7 months except one who experienced a transiently detectable viral load after 5 months. The new regimen was well tolerated with no apparent new drug-related adverse clinical or laboratory events.
 ...
PMID:Outcomes of multidrug-resistant patients switched from enfuvirtide to raltegravir within a virologically suppressive regimen. 1852 70

It has been roughly 25 years since the threat posed by human immunodeficiency virus type 1 (HIV-1) became widely known. The cumulative death toll from HIV/AIDS is now greater than 25 million. There are approximately 33 million people living worldwide with this disease, of whom about 68% (22.5 million) live in sub-Saharan Africa (http://www.avert.org/worldstats.htm). A number of antiretroviral (ARV) drugs have been approved for treatment of HIV/AIDS. Inhibitors of HIV reverse transcriptase (RTIs) include the nucleoside/nucleotide drugs zidovudine, lamivudine, abacavir, didanosine, stavudine, emtricitabine and tenofovir disoproxil fumarate. Non-nucleoside RTIs include nevirapine, efavirenz and etravirine. Inhibitors of HIV protease (PIs) include saquinavir, ritonavir, lopinavir, nelfinavir, indinavir, fosamprenavir and atazanavir. Enfuvirtide inhibits the HIV fusion protein. The CCR5 chemokine antagonist maraviroc and the integrase inhibitor raltegravir were very recently approved by the US FDA. Fixed-dose combinations (FDCs) have been formulated to increase tolerability, convenience and compliance. First-line drug combinations are offered to treatment-naive patients, while second-line drugs are reserved for those who no longer respond adequately to first-line therapy. In developing countries a modest but increasing fraction of those infected have access to ARVs. The Clinton HIV/AIDS Initiative estimates that 2.4 million of the nearly 8 million individuals needing treatment in developing nations have access to some drugs. First-line FDCs used in resource-poor settings are largely combinations of two nucleoside RTIs and a non-nucleoside RTI or PI. The effectiveness of these combinations decreases over time, requiring a switch to combinations that retain potency in the presence of viral resistance. Increasing access to second-line FDCs and new developments in first-line ARV therapy are cost challenges. In high-income countries the cost of ARV therapy is largely irrelevant, except for "advanced salvage" drugs such as enfuvirtide. In resource-poor settings cost is a huge factor that limits drug access, resulting in high rates of new infection and subsequent mortality. IP coverage, where granted, can keep access prices for essential ARVs higher than would otherwise be the case. Large, innovator companies have made drugs available at prices very close to the cost of manufacturing for "lowest income" countries. Generic providers in India and elsewhere provide the largest supply of drugs for the developing world. The recent issuance of Voluntary and Compulsory Licenses (VLs, CLs) through the World Trade Organization's TRIP (Treaty Respecting Intellectual Property) provisions arguably contribute to bringing down access prices. The utilization of improved science, pooled purchasing and intelligent procurement practices all definitely contribute to access. This work surveys the production processes for several critical ARVs. These are discussed in terms of scale up, raw material/intermediates and active pharmaceutical ingredient (API) costs. In some cases new routes to APIs or critical intermediates are needed. Based on potential new chemistries, there are significant opportunities to reduce cost for a number of critical ARVs.
 ...
PMID:A survey of the syntheses of active pharmaceutical ingredients for antiretroviral drug combinations critical to access in emerging nations. 1857 Dec 46

The peptidic anti-HIV drug T20 (Fuzeon) and its analog C34 share a common heptad repeat (HR) sequence, but they have different functional domains, i.e., pocket- and lipid-binding domains (PBD and LBD, respectively). We hypothesize that novel anti-HIV peptides may be designed by using artificial sequences containing multiple copies of HR motifs plus zero, one or two functional domains. Surprisingly, we found that the peptides containing only the non-natural HR sequences could significantly inhibit HIV-1 infection, while addition of PBD and/or LBD to the peptides resulted in significant improvement of anti-HIV-1 activity. These results suggest that these artificial HR sequences, which may serve as structural domains, could be used as templates for the design of novel antiviral peptides against HIV and other viruses with class I fusion proteins.
 ...
PMID:Novel anti-HIV peptides containing multiple copies of artificially designed heptad repeat motifs. 1868 48

Enfuvirtide is the first fusion inhibitor approved for use in HIV treatment and is a useful therapeutic option for highly treatment experienced individuals. Passive reporting has associated increased neuropathy rates with enfuvirtide use in some early studies but not others. The aim of this study was to describe any functional or clinical changes consistent with neuropathy among enfuvirtide users. A prospective cohort study of patients commencing or continuing enfuvirtide at a state HIV referral service, including clinical and sensory threshold monitoring, was conducted. A total of 14 patients were studied. All had advanced HIV disease and 13 (93%) had symptoms and/or signs consistent with neuropathy at baseline. Patients who entered the study on enfuvirtide-based therapy remained neurologically stable throughout follow-up. Eleven patients were assessed preand postenfuvirtide. No evidence was found for any clear effect of enfuvirtide on neuropathic symptoms, neuropathic signs, or sensory thresholds at a cohort level (p > 0.3 for all, Wilcoxon signed rank test). However, three (21%) patients experienced worsening of existing neuropathy symptoms (transient in two cases) and two (14%) patients' symptoms improved with enfuvirtide commencement. Breakthrough HIV viremia was associated with worsening symptoms in two patients at 5 and 18 months of enfuvirtide use. This study found no clear effect on peripheral nerves from enfuvirtide. Although limited by a small sample size, this study involved patients who would have been particularly vulnerable to a neurotoxin, with advanced HIV disease and a high rate of baseline neurological abnormalities. We observed no clear evidence of neurotoxicity from enfuvirtide in this population.
 ...
PMID:A report on the effect of commencing enfuvirtide on peripheral neuropathy. 1872 2

It has been over 25 years since the first diagnosis of what would be known as AIDS. Although great strides in anti-HIV therapeutics have been made, there is still a great need for antiretrovirals that are effective against drug-resistant HIV. Enfuvirtide (ENF) is the first of a new class of fusion inhibitors to be approved by the US Food and Drug Administration for use in combination with other antiretroviral agents among HIV-1 infected patients with previous treatment experience. The inclusion of enfuvirtide in an optimized antiretroviral background regimen for the treatment of HIV-1 infected (treatment-experienced) patients followed the success of two critical clinical trials (TORO: T20 vs Optimized Regimen Only I and II). Even though injection-site reactions persisted in these trials, improved virological and immunological responses were observed among patients. Challenges associated with ENF treatment include the high cost of the drug, injection-site reactions, determining the optimal time to initiate treatment, and the potential for the selection of drug resistant mutants and viral evolution. ENF is a promising novel treatment for HIV infected individuals whose choices for effective treatment are limited by previous treatment and resistance. Understanding the implications of viral fitness and evolution in the presence of ENF treatment is crucial in determining effective and safe treatment regimens, particularly among treatment-experienced patients.
 ...
PMID:Enfuvirtide antiretroviral therapy in HIV-1 infection. 1872 46

Enfuvirtide (Fuzeon) is the first self-injectable antiretroviral (ARV) therapy approved for the treatment of HIV. This study was undertaken to explore the perceptions of injectable ARVs among physicians and treatment-experienced HIV-infected patients and identify potential motivators or barriers to the initiation of injectable ARV therapies. This empirical study was conducted based on qualitative field research conducted in multiple centres in five European countries and the US. A purposive sampling strategy was employed and structured interviews carried out with physicians and patients. Discussion guides for these interviews focused on attitudinal responses to a range of key areas. For physicians, these areas included HIV treatment, treatment-experienced patients and their relationships with them and injectable therapy usage, while for patients - some of whom were receiving enfuvirtide therapy - the focus included relationships with their physicians and attitudes towards injectable ARV therapy. Sixty-eight physicians and 43 patients were interviewed. Qualitative analysis of the interview responses revealed a number of recurring themes among physician and patient perceptions of HIV and its treatment. Physicians tended to view injectable ARVs as a last resort, with only limited suitability among treatment-experienced patients and a low level of patient acceptability. In contrast, patients generally perceived the potential value of effective injectable ARV therapy, if recommended to them by their physicians, indicating that its benefits could outweigh the drawbacks associated with its administration. This study identified some potential disconnects between physician and patient perceptions of injectable therapy. Our findings emphasize the need for patients to discuss their treatment goals with their physicians so that they can work together to find the regimen that is most likely to achieve these goals.
 ...
PMID:Initiation of therapy with a subcutaneously administered antiretroviral in treatment-experienced HIV-infected patients: understanding physician and patient perspectives. 1882 12


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>