Incidence and risk factors for liver enzymes elevations in highly treatment-experienced patients switching from enfuvirtide to raltegravir: a sub-study of the ANRS-138 EASIER trial.

BACKGROUND: In the ANRS EASIER trial where treatment-experienced patients switched from enfuvirtide (ENF) to raltegravir (RAL), a high incidence of transaminase elevation was reported in the RAL arm. METHODS: We compared the incidence of emergent liver enzyme elevations (LEE) of grade 2 or more among patients randomized to the maintenance ENF arm or the switch RAL arm up to W24. We also assessed the overall incidence of LEE over the 48-week duration of the trial and baseline risk factors for grade 2 or more alanine aminotransferase (ALT) elevation using univariate and multivariate analyses. RESULTS: During the first 24 weeks, 6/84 (7.1 %) and 2/85 patients (2.4 %) presented with ALT elevation of grade 2 or more in the RAL and ENF arms, respectively (p = 0.21). Grade 2 or more γGT and ALP elevations were seen in 18 and 11 % (p = 0.35), and 5 and 1 % (p = 0.14) of patients in the RAL and ENF arms, respectively. The 48-week incidence of grade 2 or more LEE was 11.6 per 100-pts-years for ALT, 24.5 per 100-pts-years for γ-GT and 4.5 per 100-pts-years for ALP, respectively. In the multivariate analysis, tipranavir/ritonavir use (OR 3.66; 95 % CI [1.20-11.1], p = 0.022) and elevated ALT at baseline (OR 10.3; 95 % CI [2.67-39.6], p < 10(-3)) were significantly associated with a grade 2 or more ALT elevation during follow-up. CONCLUSION: The incidence of LEE was relatively high in these highly treatment-experienced patients switching to a RAL-based regimen. Both tipranavir/ritonavir use and high baseline ALT levels were associated with an increased risk of ALT. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00454337.

Pharmaceutical amyloidosis associated with subcutaneous insulin and enfuvirtide administration.

Protein and peptide drugs administered subcutaneously, such as insulin can be amyloidogenic and result in localized amyloid deposits at the sites of medication injections. These iatrogenic amyloidoses typically present as a localized subcutaneous nodule or skin reaction at the site of administration, and often pose diagnostic challenges. We have analyzed the amyloid proteome in 52 cases of insulin and enfuvirtide associated amyloidosis using laser microdissection/tandem mass spectrometry. We show that the deposits are composed of the drug, as well as other amyloid precursor proteins such as apolipoproteins A-I, A-IV, E and serum amyloid protein. Mass spectrometry-based amyloid sub-typing allows for accurate amyloid diagnosis with resultant therapeutic and prognostic implications. This insight into the amyloid proteome in drug-induced amyloidosis may help further understand pathogenesis of amyloid fibril formation.

Enfuvirtide and cutaneous injection-site reactions.

Enfuvirtide belongs to a newer class of antiretroviral (ARV) agents called fusion inhibitors for the treatment of human immunodeficiency virus type 1 (HIV-1) infection. Enfuvirtide blocks attachment, binding, and entry of the viral capsid into the host CD4+ cell. Administration is only available subcutaneously in a twice-daily regimen particularly for those patients who have previously failed more than one ARV regimen. Common side effects of enfuvirtide administration include fatigue, insomnia, nausea, and diarrhea; however, injection-site reactions are the most common side effect and present in nearly all individuals undergoing treatment. The spectrum of cutaneous manifestations ranges from little to no reaction to cysts, nodules, induration, or sclerodermalike lesions. These reactions are mostly variants of iatrogenically induced hypersensitivity and are self-limited.

Relapse of intravenous drug use triggered by enfuvirtide, a parenteral antiretroviral medication.

Fuzeon® (enfuvirtide; Hoffmann-LaRoche, Nutley, NJ) is a parenteral medication prescribed to antiretroviral-experienced HIV patients. Clinicians are frequently concerned when prescribing enfuvirtide to former drug addicts because of the risk of triggering relapse, however, no previous report has described this adverse event. We describe two HIV-infected patients, previously abstinent from injection drug use, who experienced relapse or near-relapse situations after starting treatment with enfuvirtide. Along with the concerns related to adherence and to injection site reactions, clinicians who prescribe enfuvirtide should consider and discuss the risk of triggering relapse among former or recovering drug addicts.

Enfuvirtide injection site reactions: a clinical and histopathological appraisal.

BACKGROUND/OBJECTIVES: Enfuvirtide was the first of a new class of antiretroviral agents termed 'fusion inhibitors' used for the treatment of HIV-1 infection. Enfuvirtide is administered subcutaneously and injection site reactions (ISR) are commonplace (98%). The aim of this study was to analyse in detail the histopathological changes associated with striking ISR seen in four patients. METHODS: Biopsies were obtained at various times post-injection and were reviewed histologically. The changes in epidermal, dermal and subcutaneous connective tissue and the presence and nature of the inflammatory cellular infiltrate were noted. An immunohistochemical assessment was undertaken. RESULTS: All biopsy specimens demonstrated striking changes in the dermal connective tissue. Alteration in collagen was the most prominent feature and resembled a morphoea/scleroderma-like process. These changes persisted well beyond cessation of enfuvirtide (>1 year). The relative populations of dermal dendritic cells (DDC) (types 1 (Factor XIIIa) and 2 (CD34+)) were analysed and a reciprocal relationship between DDC subpopulations was observed akin to that observed in other sclerosing and fibrosing conditions. CONCLUSION: This study details histopathological changes associated with enfuvirtide ISR. We postulate that changes in DDC populations may contribute to the pathogenesis of the sclerotic process observed with enfuvirtide ISR.

The effects of enfuvirtide therapy on body composition and metabolic parameters over 48 weeks in the TORO body imaging substudy.

OBJECTIVE: The aim of the study was to compare the metabolic and morphological effects of enfuvirtide plus an optimized background (OB) regimen vs. OB alone (control group) in treatment-experienced patients in the T-20 vs. Optimized Regimen Only (TORO) studies. METHODS: Body composition and metabolic changes were investigated in patients over 48 weeks, based on fasting chemistries, body weight, and other anthropometric measurements. Dual-energy X-ray absorptiometry (DEXA) and computed tomography (CT) scans were performed in a patient subgroup (n=155) at baseline and at weeks 24 and 48. RESULTS: At week 48, mean changes from baseline were similar between treatment groups for glucose, insulin, C-peptide, total cholesterol, low-density lipoprotein (LDL) cholesterol, very low density lipoprotein (VLDL) cholesterol, high-density lipoprotein (HDL) cholesterol and triglyceride levels. The enfuvirtide group experienced a significant increase in body weight [mean change from baseline +0.99 kg; 95% confidence interval (CI) +0.54, +1.44] and, in those who had body scans, there was a significant increase in truncal fat (by DEXA: median change +419.4 g; 95% CI+71.3, +767.5) and total fat [visceral adipose tissue (VAT)+subcutaneous adipose tissue (SAT) by single-slice abdominal CT scan: median change +25.5 cm(2) ; 95% CI+8.9, +42.0] over 48 weeks; significant increases in these parameters were not seen in the control group. There was no significant change in truncal:peripheral fat ratio in either the enfuvirtide or the control group. CONCLUSION: The addition of enfuvirtide to an OB regimen does not appear to have unfavourable effects on fat distribution or metabolic parameters.

A 48-week pilot study switching suppressed patients to darunavir/ritonavir and etravirine from enfuvirtide, protease inhibitor(s), and non-nucleoside reverse transcriptase inhibitor(s).

Treatment options for HIV-infected patients can be limited due to viral drug resistance to antiretroviral agents. Enfuvirtide (ENF) is an injectable entry/fusion inhibitor that is effective in achieving viral suppression when used in combination with protease inhibitors (PIs) in patients with pre-existing resistance. However, ENF treatment is associated with injection site reactions and dosing fatigue. This multicenter, open-label, Phase IIIb, 48-week pilot study assessed safety, tolerability, and effectiveness of the PI darunavir (DRV), boosted with ritonavir (DRV/r), and the non-nucleoside reverse transcriptase inhibitor (NNRTI) etravirine (ETR), when substituted for ENF/PI (±NNRTI)-based therapy. Ten virologically suppressed (HIV RNA less than 50 copies/ml) men who were intolerant to ENF were enrolled. Median (range) CD4+ count was 301 (187-663) cells/mm(3). Two patients discontinued the study; all remaining patients maintained a viral load of less than 50 copies/ml at Week 48. Viral load increased to greater than 50 copies/ml in two patients, but was eventually re-suppressed without the need for changes in treatment. Median (range) increase (last observation carried forward) in CD4+ count from baseline to Week 48 was 64 (-53-100) cells/mm(3). Two grade 3 adverse events (AEs), nausea and weight loss, and one serious AE, acute cholecystitis, were reported; each AE resolved without treatment interruption. Most common AEs related to study drug were fatigue, rash, headache, and diarrhea. Decreases in triglycerides, low-density lipoprotein, and high-density lipoprotein, were observed. This study suggests that a DRV/r- and ETR-based regimen can be substituted for an ENF-based regimen while maintaining virologic suppression.

Interaction between enfuvirtide, an injectable fusion inhibitor, and niacin in an HIV-infected patient.

OBJECTIVE: To report a potential drug-drug interaction between enfuvirtide, an injectable HIV fusion inhibitor, and niacin in an HIV-infected man with dilated cardiomyopathy. CASE SUMMARY: A 47-year-old HIV-infected man with dilated cardiomyopathy and prolonged QT syndrome with an automatic implantable cardiovascular defibrillator device was prescribed subcutaneous enfuvirtide 90 mg twice daily as part of his antiretroviral regimen and oral extended-release niacin 500 mg/day for a high-density lipoprotein level of 8 mg/dL. After 1 week of concomitant therapy, the patient began experiencing extreme redness, edema, and swelling at the injection site that corresponded with the flushing sensation due to niacin. This interfered with his daily activities, leading to self-discontinuation of both agents. As the patient had tolerated enfuvirtide therapy prior to the addition of niacin, we reinitiated enfuvirtide with close follow-up, and the patient has been maintained on this agent since then without consequence. Based on the Horn Drug Interaction Probability Scale, a probable interaction occurred between enfurvirtide and niacin. DISCUSSION: We hypothesize that a drug-drug interaction occurs between enfuvirtide and niacin related to prostaglandin synthesis and mobilization of inflammatory cells, specifically Langerhans cells. A theoretical mechanism for this interaction is that the Langerhans cells in the epidermis function improperly due to the presence of HIV and the attachment of enfuvirtide. When these cells are exposed to nicotinic acid, an exaggerated immune response is produced that may lead to pain, redness, and swelling at the injection site. Prostaglandins, cytokines, and other inflammatory molecules may all have a role in this interaction. CONCLUSIONS: Caution should be used when coadministering enfuvirtide and niacin to HIV-infected patients.

Enfuvirtide: from basic investigations to current clinical use.

IMPORTANCE OF THE FIELD: Drug resistance is a major challenge in the treatment of HIV infection. Enfuvirtide is the first entry inhibitor to have been approved for clinical use. AREAS COVERED IN THIS REVIEW: Relevant information through searches of MEDLINE (1998 to June 2010) and meeting abstracts of major HIV/AIDS conferences (2003 - June 2010) using the search terms 'enfuvirtide', 'T-20' and 'fusion inhibitor'. WHAT THE READER WILL GAIN: Enfuvirtide blocks HIV fusion to host cells. It works against the different HIV-1 variants but is not active against HIV-2. The recommended dosage of enfuvirtide is 90 mg b.i.d. subcutaneously. The two large Phase III pivotal clinical trials TORO 1 and 2 showed that enfuvirtide is an effective therapeutic option as rescue therapy in combination with other active antiretroviral drugs. Resistance to enfuvirtide is conferred by mutations in the HR1 region of gp41. Single and double mutations have been shown to result in high-level resistance to enfuvirtide. Postmarketing studies have been helpful to define more precisely the place of enfuvirtide in the sequence of antiretroviral therapy. TAKE HOME MESSAGE: The emergence of new compounds and new classes of drugs, highly active against multiresistant virus but more convenient to administer than enfuvirtide, will probably prevent the extensive use of enfuvirtide. This drug remains attractive in some subgroups of patients because of its excellent systemic tolerance and the lack of interactions with the major cytochrome P450 isoenzymes.

Short communication: evaluation of the effect of enfuvirtide in 11 HIV-1 vertically infected pediatric patients outside clinical trials.

The effect of enfuvirtide (ENF) in 11 HIV-1 heavily antiretroviral-experienced children and adolescents enrolled in the HIV-1 Paediatric Spanish cohort was further investigated. Patients who received ENF with novel drugs (etravirine, darunavir, and/or tipranavir) reached and maintained undetectable plasma HIV-1 RNA levels and showed immunological recovery within the first 3 months of therapy that was maintained during the follow-up. Viremia was not fully suppressed in patients who did not combine ENF with novel drugs but interestingly, immunological benefit was observed in half of these patients. Therefore, ENF showed a greater and more stable efficacy when administrated with novel drugs.

Does enfuvirtide increase the risk of bacterial pneumonia in patients receiving combination antiretroviral therapy?

BACKGROUND: Pooled analysis of the TORO comparative clinical trial data sets showed a significantly higher incidence rate (IR) of bacterial pneumonia (BP) among patients treated with enfuvirtide-containing combination antiretroviral therapy (ENF-cART) than in those treated with other cART regimens. OBJECTIVES: To examine the possible impact of ENF-cART on the risk of BP. METHODS: From the French Hospital Database on HIV, we selected two groups of patients among cART-treated patients who were prescribed a new cART regimen during the period 2001-2006, when their CD4 counts were <350 cells/mm(3). The ENF-cART and cART groups consisted of 1220 and 9374 patients, respectively. Poisson regression models were used to quantify the relationship between ENF-cART therapy and the risk of BP. RESULTS: At baseline the median CD4 counts were 100 and 211 cells/mm(3) and the median plasma viral load (pVL) values were 60 276 and 2702 copies/mL in the ENF-cART and cART groups, respectively. The respective BP IRs were 0.65 [95% confidence interval (CI) 0.25-1.06] and 0.31 (95% CI 0.25-0.38) cases per 100 person-years. After adjustment for age, the HIV transmission group, the time period, co-trimoxazole prophylaxis, and stratified CD4 cell counts and pVL values, we found that the BP risk ratio was not increased by enfuvirtide treatment (relative rate 1.39; 95% CI 0.46-4.13). In contrast, lower CD4 cell counts and higher pVL values were significantly associated with a higher risk of BP. CONCLUSIONS: ENF-cART is not associated with a significantly higher risk of BP than other cART regimens, although the value of the adjusted risk and the upper limit of the CI do not allow us to exclude a small increased risk.

Fuzeon-induced collagenophagic granuloma: a peculiar granulomatous injection site reaction to Fuzeon--a case report and review of literature.

Enfuvirtide (ENF, T-20, or Fuzeon [Hoffman-La Roche Inc, Nutley, NJ, and Trimeris, Inc, Durham, NC]) is an HIV-1 fusion inhibitor and is the only injectable antiretroviral drug available. Injection site reactions (ISRs) are the most frequently reported adverse events, occurring in about 98% of patients. A granuloma annulare-like granulomatous ISR has been reported. We report a granulomatous ISR that is different from granuloma annulare and granuloma annulare-like reaction because it is rich in multinucleated giant cells engulfing altered collagen. We call this type of ISR a collagenophagic granuloma. Most previous reports-with the exception of 1 report-about ISRs with ENF treatment have used punch biopsies, which lack the depth to analyze the reticular dermis and subcutaneous tissue and, therefore, may have missed ISRs, which look like granuloma annulare, and the collagenophagic granulomatous reaction.

Switch from enfuvirtide to raltegravir in virologically suppressed multidrug-resistant HIV-1-infected patients: a randomized open-label trial.

BACKGROUND: Among patients with multidrug-resistant human immunodeficiency virus type 1 (HIV-1) infection, salvage regimens including enfuvirtide have demonstrated sustained efficacy. Because of reluctance to use subcutaneous injections, raltegravir may be an alternative to replace enfuvirtide within a suppressive regimen. We conducted a prospective, randomized, open-label trial to compare the antiviral efficacy and safety of a switch to raltegravir with the efficacy and safety of continuing enfuvirtide. METHODS: A total of 170 patients with multidrug-resistant HIV-1 infection and plasma HIV-1 RNA levels <400 copies/mL who were receiving enfuvirtide-based regimens were randomized 1:1 to maintain enfuvirtide or to switch to raltegravir. The primary efficacy end point was the cumulative proportion of patients with virologic failure, defined as a confirmed plasma HIV-1 RNA level >or=400 copies/mL, over 24 weeks. The secondary end points mainly involved safety. RESULTS: The switch to raltegravir was non-inferior to the maintenance of enfuvirtide, with virologic failure rates of 1.2% in both treatment arms in the intention-to-treat analysis (beta = 0.01%; 95% confidence interval, -6.7 to 6.8) and 1.2% and 0%, respectively, in the on-treatment analysis (beta = 1.22%; 95% confidence interval, -5.6 to 8.1). At week 24, 88%-89% of patients in both arms had plasma HIV-1 RNA levels <50 copies/mL. No significant CD4 cell count changes occurred in either arm. Grade 3-4 adverse events and laboratory abnormalities were uncommon and were not different between the treatment arms. CONCLUSION: A switch to raltegravir was safe, well tolerated, and virologically non-inferior to the maintenance of enfuvirtide in patients infected with multidrug-resistant HIV-1 infection who were receiving suppressive antiretroviral therapy. CLINICAL TRIALS REGISTRATION: NCT00454337

The fusion inhibitor enfuvirtide in recent antiretroviral strategies.

PURPOSE OF REVIEW: The purpose of this review is to discuss recent pharmacological, virological, and clinical data that concern enfuvirtide usage in different antiretroviral combinations. RECENT FINDINGS: Randomized, recent trials in multidrug-experienced patients suggest that antiretroviral combinations with enfuvirtide have excellent virological responses with new antiretroviral compounds, including darunavir, etravirine, raltegravir, vicriviroc, and maraviroc. Trials confirm long-term safety, in spite of moderate injection-site reactions or pain, and lack of significant interactions. Preliminary data suggest that switching from enfuvirtide to raltegravir is effective and using enfuvirtide in prophylaxis of mother-to-child transmission is well tolerated. To administer enfuvirtide in an intensification strategy in antiretroviral-naïve or experienced populations may accelerate virological decline. SUMMARY: Dosage adaptations to renal insufficiency are not necessary with enfuvirtide. Spinal fluid concentrations and ombilic cord passage are negligible. Durability of virological responses with enfuvirtide in combinations has been confirmed, in spite of injection-site reactions and twice daily subcutaneous administration. Enfuvirtide should be used with at least one other fully active drug in optimized background therapy in multidrug-experienced populations, a possible exception being with entry inhibitors, which may further benefit from the addition of a third active drug. Data concerning enfuvirtide in antiretroviral combinations show accelerated viral load decline, and the possibility of switching from enfuvirtide to raltegravir without modification of optimized background therapy.

Risk factors for gastrointestinal adverse events in HIV treated and untreated patients.

Advanced immunosuppression from HIV infection can lead to gastrointestinal symptoms such as diarrhea, nausea, vomiting, dysphagia, weight loss, and abdominal pain. There is a complex, combined effect of HIV infection plus antiretroviral treatment on the incidence of gastrointestinal symptoms, and, for some trials, the majority of gastrointestinal adverse events may not be related to antiretroviral treatment. Antiretroviral treatment can lead to improvements in gastrointestinal symptoms for patients with advanced immunosuppression. This was observed in the TORO trials of enfuvirtide and the DUET trials of etravirine, which were conducted in highly treatment experienced patients with low baseline CD4 counts. While antiretroviral treatment can improve immune function, leading to fewer gastrointestinal symptoms, this could be counter-balanced by adverse gastrointestinal toxicity profiles from certain antiretrovirals. Ritonavir-boosted protease inhibitors show a range of gastrointestinal side effects; there are differences in tolerability within this class of antiretrovirals, influenced both by the dose of ritonavir used and the choice of boosted protease inhibitor. Overall, lopinavir/ritonavir and fosamprenavir/ritonavir tend to show the highest rates of drug-related grade 2-4 diarrhea, compared with atazanavir/ritonavir, darunavir/ritonavir, or saquinavir/ritonavir. Of the nucleoside analogs, zidovudine leads to a well-characterized problem of nausea. Issues relating to gastrointestinal complications are often subjective, reliant upon patient reporting and perception, along with clinician interaction and intervention. In trial publications, many different systems are used to present gastrointestinal adverse events. Most are based on the US Division of AIDS Grading Scale, ranging from grade 1 (mild) to grade 4 (life-threatening). Clinical trials most commonly report grade 2-4 gastrointestinal adverse events, which are at least possibly related to study medication. In future, it is important for clinical trials to report gastrointestinal adverse events in a consistent way. The percentage of patients with drug-related grade 2-4 events should be reported. In addition, the percentage with any grade 2-4 gastrointestinal adverse event should be included, since there could be subjectivity in the assessment of drug relatedness in open-label clinical trials. The percentage of patients who use medications to lessen the symptoms of diarrhea and other gastrointestinal adverse events should also be reported.