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Query: UMLS:C0001175 (AIDS)
 120,706 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
AIDS 2008 Jun 19
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.
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PMID:A survey of the syntheses of active pharmaceutical ingredients for antiretroviral drug combinations critical to access in emerging nations. 1857 Dec 46

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.
AIDS Res Hum Retroviruses 2008 Aug
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.
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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.
AIDS Care 2008 Oct
PMID:Initiation of therapy with a subcutaneously administered antiretroviral in treatment-experienced HIV-infected patients: understanding physician and patient perspectives. 1882 12

T20 (generic name: Enfuvirtide, brand name: Fuzeon) is the only FDA-approved HIV fusion inhibitor that is being used for treatment of HIV/AIDS patients who have failed to respond to current antiretroviral drugs. However, it rapidly induces drug resistance in vitro and in vivo. On the basis of the structural and functional information of anti-HIV peptides from a previous study, we designed an HIV fusion inhibitor named CP32M, a 32-mer synthetic peptide that is highly effective in inhibiting infection by a wide range of primary HIV-1 isolates from multiple genotypes with R5- or dual-tropic (R5X4) phenotype, including a group O virus (BCF02) that is resistant to T20 and C34 (another anti-HIV peptide). Strikingly, CP32M is exceptionally potent (at low picomolar level) against infection by a panel of HIV-1 mutants highly resistant to T20 and C34. These findings suggest that CP32M can be further developed as an antiviral therapeutic against multidrug resistant HIV-1.
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PMID:Potent HIV fusion inhibitors against Enfuvirtide-resistant HIV-1 strains. 1885 75

Enfuvirtide and sifuvirtide, the first- and next-generation HIV-fusion inhibitors, contain different functional domains and have distinct target sites. Here, we found that a combination of enfuvirtide and sifuvirtide resulted in potent synergism in inhibiting HIV-1-mediated cell-cell fusion and infection by X4 and R5 as well as enfuvirtide-resistant HIV-1 strains. These findings suggest that application of enfuvirtide and sifuvirtide in combination may improve their efficacy and resistant profile, leading to a reduction of the dosage and frequency of drug use.
AIDS 2009 Mar 13
PMID:Synergistic efficacy of combination of enfuvirtide and sifuvirtide, the first- and next-generation HIV-fusion inhibitors. 1924 16

Enfuvirtide is beneficial in patients with limited treatment options. We report this case to highlight the possibility of a delayed hypersensitivity reaction as an important potential side-effect of enfuvirtide treatment. A highly antiretroviral treatment-experienced man was commenced on a new regimen containing enfuvirtide. Prophylaxis for Pneumocystis jirovecii pneumonia was started using trimethoprim/sulphamethoxazole (TMP-STX) simultaneously. Ten days later, he developed a maculopapular rash on the chest and abdomen without any systemic features. Both enfuvirtide and TMP-STX were discontinued. Re-introduction of enfuvirtide occurred in a hospital setting. Before re-challenge, haemodynamic observations were stable. The rash re-appeared involving the whole body 5 hours post-dose and was associated with fever (temperature 38.4), nausea and a presyncopal episode. Hypersensitivity to this drug occurred immediately post-dose in phase III trials. Enfuvirtide is a useful drug in those with reduced drug options. The possibility of delayed hypersensitivity has not been reported previously.
Int J STD AIDS 2009 Apr
PMID:A delayed hypersensitivity reaction to enfuvirtide after rechallenge. 1930 81

T20 (generic name, enfuvirtide; brand name, Fuzeon) is a first-generation human immunodeficiency virus (HIV) fusion inhibitor approved for salvage therapy of HIV-infected patients refractory to current antiretroviral drugs. However, its clinical use is limited because of rapid emergence of T20-resistant viruses in T20-treated patients. Therefore, T1249 and T1144 are being developed as the second- and third-generation HIV fusion inhibitors, respectively, with improved efficacy and drug resistance profiles. Here, we found that combinations of T20 with T1249 and/or T1144 resulted in exceptionally potent synergism (combination index, <0.01) against HIV-1-mediated membrane fusion by 2 to 3 orders of magnitude in dose reduction. Highly potent synergistic antiviral efficacy was also achieved against infection by laboratory-adapted and primary HIV-1 strains, including T20-resistant variants. The mechanism underlying the synergistic effect could be attributed to the fact that T20, T1249, and T1144 all contain different functional domains and have different primary binding sites in gp41. As such, they may work cooperatively to inhibit gp41 six-helix bundle core formation, thereby suppressing virus-cell fusion. Therefore, these findings strongly imply that, rather than replacing T20, combining it with HIV fusion inhibitors of different generations might produce synergistic activity against both T20-sensitive and -resistant HIV-1 strains, suggesting a new therapeutic strategy for the treatment of HIV-1 infection/AIDS.
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PMID:Combinations of the first and next generations of human immunodeficiency virus (HIV) fusion inhibitors exhibit a highly potent synergistic effect against enfuvirtide- sensitive and -resistant HIV type 1 strains. 1949 96

There are now 26 antiretroviral drugs and 6 fixed-dose combinations, including reverse transcriptase inhibitors, protease inhibitors, integrase inhibitors and fusion (or entry) inhibitors, approved by the US Food and Drug Administration for clinical use. Although they are clinically effective when used in combination, none of the existing drugs are considered ideal because of toxic side effects and the ascendance of inducing drug-resistant mutants. Development of new antiviral agents is essential. In the past decades, there has been great progress in understanding the structure of HIV type-1 (HIV-1) gp41 and the mechanism of HIV-1 entry into host cells. This opened up a promising avenue for rationally designed agents to interfere with this process. A number of fusion inhibitors have been developed to block HIV-1 replication. Enfuvirtide (T20) was one of those approved for clinical use. This signalled a new era in AIDS therapeutics. It is a synthetic polypeptide with potent inhibitory activity against HIV-1 infection. However, it is sensitive to proteolytic digestion and resistant virus strains are easily induced with multiple clinical use. One of the directions in designing new fusion inhibitors is to overcome these shortages. In the past years, large numbers of promising fusion inhibitory peptides have emerged. The antiviral activities are more potent or they can act differently from that of T20. Some of these new compounds have great potential to be further developed as therapeutic agents. This article reviewed some recent developments of these peptides and the possible role in anti-HIV-1 therapy.
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PMID:Current peptide HIV type-1 fusion inhibitors. 1979 28


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