Kaposi Sarcoma Inflammatory Cytokine Syndrome Presenting as Infection: A Case Report.

Kaposi sarcoma inflammatory cytokine syndrome is a rare and fatal malignancy that is challenging to treat. The syndrome appears in individuals who are both human immunodeficiency virus and human herpesvirus 8 positive. The diagnosis of disease is challenging because its presentation mimics sepsis and it has a high mortality rate. A bone marrow biopsy is necessary for definitive diagnosis. This case report discusses a 40-year-old human immunodeficiency virus infection-positive African American male who presented to the emergency department with a chief complaint of left hallux pain in January 2018 after a trip to a nail salon in December 2017. Radiographic and magnetic resonance images suggested osteomyelitis of the distal phalanx, and Gram stain of bone showed gram-negative rods. The patient was started on antibiotic therapy for presumed osteomyelitis. As the patient's status deteriorated, a partial hallux amputation was then performed. Intraoperative specimens were negative for bacterial involvement, but pathology was positive for Kaposi sarcoma. During a 7-month progression, the patient's hematologic and overall status continued to decline. Despite diagnostic and treatment guidelines being followed, the patient died from this illness in July 2018. This case is interesting because of the atypical presentation of Kaposi sarcoma and highlights the rapid progression of the disease.

Daclatasvir plus Sofosbuvir for HCV in Patients Coinfected with HIV-1.

BACKGROUND: The combination of daclatasvir, a hepatitis C virus (HCV) NS5A inhibitor, and the NS5B inhibitor sofosbuvir has shown efficacy in patients with HCV monoinfection. Data are lacking on the efficacy and safety of this combination in patients coinfected with human immunodeficiency virus type 1 (HIV-1). METHODS: This was an open-label study involving 151 patients who had not received HCV treatment and 52 previously treated patients, all of whom were coinfected with HIV-1. Previously untreated patients were randomly assigned in a 2:1 ratio to receive either 12 weeks or 8 weeks of daclatasvir at a standard dose of 60 mg daily (with dose adjustment for concomitant antiretroviral medications) plus 400 mg of sofosbuvir daily. Previously treated patients were assigned to undergo 12 weeks of therapy at the same doses. The primary end point was a sustained virologic response at week 12 after the end of therapy among previously untreated patients with HCV genotype 1 who were treated for 12 weeks. RESULTS: Patients had HCV genotypes 1 through 4 (83% with genotype 1), and 14% had compensated cirrhosis; 98% were receiving antiretroviral therapy. Among patients with genotype 1, a sustained virologic response was reported in 96.4% (95% confidence interval [CI], 89.8 to 99.2) who were treated for 12 weeks and in 75.6% (95% CI, 59.7 to 87.6) who were treated for 8 weeks among previously untreated patients and in 97.7% (95% CI, 88.0 to 99.9) who were treated for 12 weeks among previously treated patients. Rates of sustained virologic response across all genotypes were 97.0% (95% CI, 91.6 to 99.4), 76.0% (95% CI, 61.8 to 86.9), and 98.1% (95% CI, 89.7 to 100), respectively. The most common adverse events were fatigue, nausea, and headache. There were no study-drug discontinuations because of adverse events. HIV-1 suppression was not compromised. CONCLUSIONS: Among previously untreated HIV-HCV coinfected patients receiving daclatasvir plus sofosbuvir for HCV infection, the rate of sustained virologic response across all genotypes was 97.0% after 12 weeks of treatment and 76.0% after 8 weeks. (Funded by Bristol-Myers Squibb; ALLY-2 ClinicalTrials.gov number, NCT02032888.).

Efficacy, safety, and tolerability of switching to long-acting cabotegravir plus rilpivirine versus continuing fixed-dose bictegravir, emtricitabine, and tenofovir alafenamide in virologically suppressed adults with HIV, 12-month results (SOLAR): a randomised, open-label, phase 3b, non-inferiority trial.

BACKGROUND: Cabotegravir plus rilpivirine is the only approved complete long-acting regimen for the maintenance of HIV-1 virological suppression dosed every 2 months. The SOLAR study aimed to compare long-acting cabotegravir plus rilpivirine every 2 months with continued once-daily bictegravir, emtricitabine, and tenofovir alafenamide for the maintenance of HIV-1 virological suppression in adults living with HIV. METHODS: SOLAR is a randomised, open-label, multicentre, phase 3b, non-inferiority study. The study was done in 118 centres across 14 countries. Participants with HIV-1 RNA less than 50 copies per mL were randomly assigned (2:1), stratified by sex at birth and BMI, to either long-acting cabotegravir (600 mg) plus rilpivirine (900 mg) dosed intramuscularly every 2 months or to continue daily oral bictegravir (50 mg), emtricitabine (200 mg), and tenofovir alafenamide (25 mg). Participants randomly assigned to long-acting therapy had a choice to receive cabotegravir (30 mg) plus rilpivirine (25 mg) once daily as an optional oral lead-in for approximately 1 month. The primary efficacy endpoint was the proportion of participants with virological non-response (HIV-1 RNA ≥50 copies per mL; the US Food and Drug Administration snapshot algorithm, 4% non-inferiority margin; modified intention-to-treat exposed population) at month 11 (long-acting start with injections group) and month 12 (long-acting with oral lead-in group and bictegravir, emtricitabine, and tenofovir alafenamide group). The study is registered with ClinicalTrials.gov, NCT04542070, and is ongoing. FINDINGS: 837 participants were screened between Nov 9, 2020, and May 31, 2021, and 687 were randomly assigned to switch treatment or continue existing treatment. Of 670 participants (modified intention-to-treat exposed population), 447 (67%) switched to long-acting therapy (274 [61%] of 447 start with injections; 173 [39%] of 447 with oral lead-in) and 223 (33%) continued bictegravir, emtricitabine, and tenofovir alafenamide. Baseline characteristics were similar; median age was 37 years (range 18-74), 118 (18%) of 670 were female sex at birth, 207 (31%) of 670 were non-White, and median BMI was 25·9 kg/m2 (IQR 23·3-29·5). At month 11-12, long-acting cabotegravir plus rilpivirine showed non-inferior efficacy versus bictegravir, emtricitabine, and tenofovir alafenamide (HIV-1 RNA ≥50 copies per mL, five [1%] of 447 vs one [<1%] of 223), with an adjusted treatment difference of 0·7 (95% CI -0·7 to 2·0). Excluding injection site reactions, adverse events and serious adverse events were similar between groups. No treatment-related deaths occurred. More long-acting group participants had adverse events leading to withdrawal (25 [6%] of 454 vs two [1%] of 227). Injection site reactions were reported by 316 (70%) of 454 long-acting participants; most (98%) were grade 1 or 2. INTERPRETATION: These data support the use of long-acting cabotegravir plus rilpivirine dosed every 2 months as a complete antiretroviral regimen that has similar efficacy to a commonly used integrase strand transfer inhibitor-based first-line regimen, while addressing unmet psychosocial issues associated with daily oral treatment. FUNDING: ViiV Healthcare.

Clinical experience in adults and children treated with intravenous peramivir for 2009 influenza A (H1N1) under an Emergency IND program in the United States.

BACKGROUND: Peramivir, an investigational intravenous neuraminidase inhibitor in Phase 3 trials for hospitalized patients, was made available during the 2009 H1N1 influenza pandemic under the Emergency Investigational New Drug (eIND) regulations. We describe the clinical characteristics and outcomes of all patients for whom peramivir was requested under the eIND. METHODS: After obtaining eIND approval from the Food and Drug Administration and local institutional review board approval, clinicians caring for hospitalized patients with influenza administered intravenous peramivir and collected information on demographic characteristics, clinical characteristics, and outcomes. RESULTS: From April through October 2009, peramivir was requested for 42 patients and administered to 20 adults and 11 children. At hospitalization, all patients had rapidly progressing, radiographically confirmed viral pneumonia with respiratory failure, and all but 1 patient required mechanical ventilation. In most patients, including 1 person with documented oseltamivir-resistant infection, the illness had progressed despite oseltamivir treatment. Peramivir was administered for 1-14 days (median duration, 10 days). The 14-day, 28-day, and 56-day survival rates were 76.7%, 66.7%, and 59.0%, respectively. Peramivir was generally well tolerated. CONCLUSIONS: Intravenous peramivir was well tolerated and was associated with recovery in most patients hospitalized with severe 2009 H1N1 influenza viral pneumonia and treated under an eIND.

Efavirenz-Induced Vanishing Bile Duct Syndrome: A Case Report.

BACKGROUND: Efavirenz (Sustiva®) is used for the treatment of human immunodeficiency virus (HIV) type 1 infection. Hepatoxicity is a known potential adverse drug event with efavirenz; however, to our knowledge, vanishing bile duct syndrome (VBDS), a type of liver injury, has not been reported with this therapy. CASE PRESENTATION: We report the case of a 48-year-old male with HIV and VBDS secondary to antiretroviral therapy. The patient was started on efavirenz, emtricitabine, and tenofovir disoproxil fumarate (Atripla®). Four weeks later, the patient presented with complaints of poor appetite, nausea with emesis, dark urine, and malaise. Labs obtained supported the diagnosis of acute hepatitis, and a liver biopsy confirmed a diagnosis of VBDS. The Naranjo adverse drug reaction probability scale showed that it was probable (score of 7) that the VBDS was related to drug therapy. Efavirenz was assessed to be the most likely cause of VBDS, end-stage liver disease, and the eventual need for liver transplantation. CONCLUSION: To our knowledge, this is the first reported case of probable efavirenz-induced VBDS in a patient living with HIV. Recognition and awareness of this adverse drug reaction by clinicians for quick diagnosis, discontinuation of therapy, and management are important in patients receiving this regimen.

Doravirine dose selection and 96-week safety and efficacy versus efavirenz in antiretroviral therapy-naive adults with HIV-1 infection in a Phase IIb trial.

BACKGROUND: The safety and efficacy of doravirine were compared with that of efavirenz as initial treatment of adults living with HIV-1 infection (NCT01632345). METHODS: A Phase IIb double-blind trial with participants stratified by screening HIV-1 RNA (≤ or >100,000 copies/ml) and randomized 1:1:1:1:1 to receive once-daily doravirine (25, 50, 100 or 200 mg) or efavirenz 600 mg (Part I) for up to 96 weeks, with open-label tenofovir disoproxil fumarate 300 mg/emtricitabine 200 mg (TDF/FTC). After dose selection at week 24, doravirine 100 mg was provided to participants receiving the other doses of doravirine and additional participants were randomized 1:1 to receive once-daily doravirine 100 mg or efavirenz 600 mg for 96 weeks with TDF/FTC (Part II). Primary outcomes were the proportion of participants with HIV-1 RNA <40 copies/ml at week 24, and central nervous system (CNS) adverse events (AEs) by weeks 8 and 24 (Parts I+II combined). RESULTS: 210 and 132 participants were randomized in Parts I and II, respectively, and 216 (108 on doravirine 100 mg, 108 on efavirenz) were evaluable for Parts I+II combined. At week 24, the proportion of participants with HIV-1 RNA <40 copies/ml was 72.9% for doravirine 100 mg and 73.1% for efavirenz (difference -0.5 [95% CI -12.3, 11.2]). In addition, CNS AEs were reported by 26.9% and 47.2% of doravirine and efavirenz recipients, respectively (difference -20.4 [95% CI -32.6, -7.5]; P=0.002). CONCLUSIONS: Doravirine 100 mg with TDF/FTC demonstrated similar antiretroviral activity and superior CNS safety compared with efavirenz 600 mg with TDF/FTC.

Coformulated bictegravir, emtricitabine, tenofovir alafenamide after initial treatment with bictegravir or dolutegravir and emtricitabine/tenofovir alafenamide.

: A phase 2, randomized, active-controlled study of initial antiretroviral therapy with bictegravir or dolutegravir in combination with emtricitabine and tenofovir alafenamide showed excellent efficacy. After 60 weeks of blinded treatment, participants switched to a single-tablet regimen of bictegravir, emtricitabine, and tenofovir alafenamide. Switching maintained viral suppression in all participants who remained on the study through 12 weeks in the open-label phase, and was safe and well tolerated.

Outpatient treatment of osteomyelitis with telavancin.

Telavancin is a lipoglycopeptide antibiotic with bactericidal activity against Gram-positive pathogens including Staphylococcus aureus, the most frequent cause of osteomyelitis. Treatment is often challenging due to needs for surgical intervention along with prolonged administration of intravenous antimicrobials, frequently in an outpatient setting. This was a retrospective analysis of the efficacy and safety of telavancin for treatment of osteomyelitis provided as outpatient parenteral antimicrobial therapy (OPAT) in physician office infusion centres. Medical records of 60 patients receiving telavancin for osteomyelitis in 22 physician office infusion centres from 2010 to 2011 and 2013 to 2015 were reviewed. Of these, 60% were treated without hospitalisation, 37% had orthopaedic hardware and 56% had concurrent infections. Staphylococcus aureus was the most common pathogen (78%), primarily methicillin-resistant. The median duration of telavancin treatment in the outpatient setting was 21 days (range 3-105 days). Telavancin was used as first-line therapy in 32% of cases, following prior antibiotic failure in 47% and due to intolerance to previous agents in 22%, predominantly daptomycin or vancomycin. The telavancin dose was 10 mg/kg/day, adjusted for renal function in 25% of patients. The majority of patients self-administered telavancin at home via an elastomeric infusion pump. Overall clinical success was 73%. No significant differences in outcomes were observed with the presence of hardware, concurrent infection, concomitant therapies or type of osteomyelitis. Telavancin-associated adverse events occurred in 57%, with discontinuation in three patients (5%). These data demonstrate the effective and safe OPAT use of telavancin, providing an alternative for successful treatment of patients with osteomyelitis.

Response by gender of HIV-1-infected subjects treated with abacavir/lamivudine plus atazanavir, with or without ritonavir, for 144 weeks.

PURPOSE: The 144-week results of the open-label, multicenter Atazanavir/Ritonavir Induction with Epzicom Study (ARIES) were stratified by gender to compare treatment responses. METHODS: A total of 369 HIV-infected, antiretroviral-naïve subjects receiving once-daily abacavir/lamivudine + atazanavir/ritonavir (ATV/r) whose HIV-1 RNA was <50 copies/mL by week 30 were randomized 1:1 at week 36 to maintain or discontinue ritonavir for 108 subsequent weeks. Between- and within-treatment gender-related efficacy and safety differences were analyzed. RESULTS: Subjects were 85% male; 64% white; and had a mean age of 39 years, baseline median HIV-1 RNA of 114,815 copies/mL, and median CD4+ cell count of 198 cells/mm3. Gender (ATV [n=189]: 29 females/160 males; ATV/r [n=180]: 25 females/155 males) and most other demographics were similar between groups; more females than males were black (65% vs 25%) and fewer females had baseline HIV-1 RNA ≥100,000 copies/mL (41% vs 58%). At week 144, no significant differences between genders were observed in proportion maintaining HIV-1 RNA <50 copies/mL (ATV, 79% vs 77%; ATV/r, 60% vs 75%) or <400 copies/mL (ATV, 83% vs 84%; ATV/r, 68% vs 82%) (intent-to-treat-exposed: time to loss of virologic response analysis); median CD4+ change from baseline (ATV, +365 vs +300 cells/mm3; ATV/r, +344 vs +301 cells/mm3); proportion with treatment-related grade 2-4 adverse events (baseline to week 144: ATV, 41% vs 31%; ATV/r, 36% vs 43%; weeks 36 to 144: ATV, 14% vs 13%; ATV/r, 24% vs 23%); or proportion developing fasting lipid changes. Female and male virologic failure rates (ATV, 0 vs 5; ATV/r, 2 vs 4) and proportions completing the study were similar during the extension phase. Primary withdrawal reasons were loss to follow-up and pregnancy for females and loss to follow-up and other for males. CONCLUSION: Over 144 weeks, no significant gender differences were observed in efficacy, safety, or fasting lipid changes with abacavir/lamivudine +ATV or abacavir/lamivudine +ATV/r.

Bictegravir versus dolutegravir, each with emtricitabine and tenofovir alafenamide, for initial treatment of HIV-1 infection: a randomised, double-blind, phase 2 trial.

BACKGROUND: All recent treatment guidelines recommend integrase strand transfer inhibitors (INSTIs) as components of initial HIV therapy. Bictegravir, a novel, once-daily, unboosted INSTI, showed potent activity in a 10 day monotherapy study and has a high in-vitro resistance barrier. On the basis of these results, we did a phase 2 trial comparing bictegravir with dolutegravir. METHODS: In this randomised, double-blind, phase 2 trial, we recruited previously untreated adults (aged ≥18 years) with HIV-1 infections from 22 outpatient centres in the USA. Eligible patients had HIV-1 RNA concentrations of at least 1000 copies per mL, CD4 counts of at least 200 cells per µL, estimated glomerular filtration rates of at least 70 mL per min, and HIV-1 genotypes showing sensitivity to emtricitabine and tenofovir. We excluded patients if they were hepatitis B-co-infected or hepatitis C-co-infected, had new AIDS-defining conditions within 30 days of screening, or were pregnant. We randomly allocated participants (2:1) to receive oral once-daily 75 mg bictegravir or 50 mg dolutegravir with matching placebo plus the fixed-dose combination of 200 mg emtricitabine and 25 mg tenofovir alafenamide for 48 weeks. We randomly allocated participants via an interactive web system, stratified by HIV-1 RNA concentration. Investigators, patients, study staff giving treatment, collecting data, and assessing outcomes, and the funder were masked to treatment group. The primary outcome was the proportion of participants with plasma HIV-1 RNA concentrations of less than 50 copies per mL at week 24 according to the US Food and Drug Administration-defined snapshot algorithm. We included all participants receiving one dose of study drug in analyses. This trial is registered with ClinicalTrials.gov, number NCT02397694. FINDINGS: Between March 23, 2015, and May 21, 2015, we screened 125 patients, randomly allocating and giving study drug to 98 (65 received bictegravir plus emtricitabine and tenofovir alafenamide and 33 received dolutegravir plus emtricitabine and tenofovir alafenamide). At week 24, 63 (96·9%) of 65 in the bictegravir group had HIV-1 RNA loads of less than 50 copies per mL compared with 31 (93·9%) of 33 in the dolutegravir group (weighted difference 2·9%, 95% CI -8·5 to 14·2; p=0·50). Treatment-emergent adverse events were reported by 55 (85%) of 65 participants in the bictegravir plus emtricitabine and tenofovir alafenamide group versus 22 (67%) of 33 in the dolutegravir plus emtricitabine and tenofovir alafenamide group. The most common adverse events were diarrhoea (eight [12%] of 65 vs four [12%] of 33) and nausea (five [8%] of 65 vs four [12%] of 33). One participant taking bictegravir plus emtricitabine and tenofovir alafenamide discontinued because of a drug-related adverse event (urticaria) after week 24. No treatment-related serious adverse events or deaths occurred. INTERPRETATION: Bictegravir plus emtricitabine and tenofovir alafenamide and dolutegravir plus emtricitabine and tenofovir alafenamide both showed high efficacy up to 24 weeks. Both treatments were well tolerated. Administration of bictegravir, a novel, potent, once-daily INSTI designed to improve on existing INSTI options with the backbone of emtricitabine and tenofovir alafenamide, might provide an advantage to patients. FUNDING: Gilead Sciences.

Pilot study of once-daily simplification therapy with abacavir/lamivudine/zidovudine and efavirenz for treatment of HIV-1 infection.

OBJECTIVE: The purpose of this pilot study was to explore the efficacy and safety of the abacavir/lamivudine/zidovudine fixed-dose combination tablet administered as two tablets once daily (qd) versus one tablet twice daily (bid) in combination with efavirenz (EFV). METHOD: This was a prospective, randomized, open-label, multicenter study with a 24-week treatment period in 7 outpatient HIV clinics in the United States. Patients currently receiving an initial regimen of abacavir/lamivudine/zidovudine bid plus EFV qd for at least 6 months with HIV-1 RNA <50 copies/mL for at least 3 months and a screening CD4+ cell count > or = 200 cells/mm3 were eligible. Thirty-six patients enrolled, and 35 (97%) completed the study. Participants were randomized to switch to 2 tablets of abacavir/lamivudine/zidovudine qd plus EFV qd (QD arm) or continue current treatment (BID arm) for 24 weeks. RESULTS: Efficacy, safety, and adherence were evaluated. Median baseline CD4+ cell count was 521 cells/mm3. At week 24, HIV-1 RNA <50 copies/mL was achieved for 94% of participants in the QD arm and 89% in the BID arm by intent-to-treat, missing = failure analysis (95% confidence interval for difference: > or = 0.29 to +0.18, p = 1.000). At week 24, median CD4+ cell count change from baseline was +26 cells/mm3 for the QD arm and -39 cells/mm3 for BID arm. One patient randomized to the QD arm met virologic failure criteria (confirmed HIV-1 RNA >120 copies/mL) at week 20 and viral genotype showed M184V. After failure, this patient revealed he never took EFV throughout the entire study after randomization, effectively receiving only abacavir/lamivudine/zidovudine qd alone. Median adherence was slightly higher in the QD arm, although both arms had broad variability and overlapping interquartile ranges. Adverse events were infrequent and occurred with similar frequency between arms; treatment-related adverse events were abdominal pain, flatulence, nausea, headache, and abnormal dreams (1 patient [3%] for each adverse event). No patients withdrew due to adverse events, and no abacavir hypersensitivity reactions were reported. CONCLUSION: In this pilot study of patients suppressed on abacavir/lamivudine/zidovudine bid plus EFV, 94% of participants switching to abacavir/lamivudine/zidovudine qd plus EFV maintained virologic suppression, compared to 89% of participants continuing abacavir/lamivudine/zidovudine bid plus EFV.

Forty-eight-week efficacy and safety and early CNS tolerability of doravirine (MK-1439), a novel NNRTI, with TDF/FTC in ART-naive HIV-positive patients.

INTRODUCTION: Doravirine (DOR) is an investigational NNRTI (aka MK-1439) that retains activity against common NNRTI-resistant mutants. We have previously reported the Part 1 results from a two-part, randomized, double-blind, Phase IIb study in ART-naïve HIV-1-positive patients (1). At doses of 25, 50, 100 and 200 mg qd, DOR plus open-label tenofovir/emtricitabine (TDF/FTC) demonstrated potent antiretroviral activity comparable to EFV 600 mg qhs plus TDF/FTC and was generally well tolerated at week 24. DOR 100 mg was selected for use in patients continuing in Part 1 and those newly enrolled in Part 2. METHODS: Patients receiving DOR 25, 50 or 200 mg in Part 1 were switched to 100 mg after dose selection. In Part 2, 132 additional patients were randomized 1:1 to DOR 100 mg qd or EFV 600 mg qhs (each with TDF/FTC). We present week 48 efficacy and safety results for all patients in Part 1, and early (week 8) CNS tolerability only for patients randomized to DOR 100 mg or to EFV in Parts 1 and 2 combined. The primary safety endpoint is the % of patients with pre-specified CNS events (all causality) by week 8 for DOR 100 mg qd vs EFV (Parts 1 + 2 combined). RESULTS: Part 1 week 48 efficacy and safety results are shown below. CONCLUSIONS: In ART-naïve, HIV-1-positive patients also receiving TDF/FTC, DOR 100 mg qd demonstrated potent antiretroviral activity and immunological effect at week 48 and was generally safe and well tolerated. Patients who received DOR 100 mg qd had significantly fewer treatment-emergent CNS AEs by week 8 than those who received EFV.

Cryptogenic organizing pneumonia during adjuvant chemotherapy with oxaliplatin, 5-fluorouracil, and leucovorin (FOLFOX) for colon cancer.

Lung disease associated with FOLFOX (oxaliplatin/5-fluorouracil/leucovorin) chemotherapy is uncommon. We describe a case of cryptogenic organizing pneumonia (COP) occurring in a 78-year-old woman after receiving 2 cycles of modified FOLFOX6 as adjuvant chemotherapy for treatment of resected nonmetastatic colon cancer. This patient presented with respiratory symptoms including cough with scant clear sputum and wheezing on day 10 of the second cycle of mFOLFOX6. Despite therapy with systemic antibiotics and supplemental oxygen, she had a steady and relentless progression of her respiratory symptoms and status, with chest radiographs revealing progressive bilateral pulmonary infiltrates. Further chest radiograph evaluation demonstrated findings consistent with COP. Antibiotics were discontinued and methylprednisolone sodium succinate initiated as the mainstay of management for COP. The patient required a higher dose of methylprednisolone sodium succinate than typical for initial response with doses up to 3 mg/kg per d leading to prompt improvement in her respiratory symptoms and function and declining need for supplemental oxygen therapy. Chest radiographs also showed improvement. The Naranjo adverse drug reaction probability scale indicated a probable relationship (score of 5) between the patient's COP and the FOLFOX chemotherapy. Clinicians should be aware of the potential for this uncommon, yet severe adverse reaction associated with the FOLFOX chemotherapy.