Austin J HIV/AIDS Res. 2016; 3(1): 1022.
Possible Drug-Induced Severe Hypertriglyceridemia in a Patient Co-Infected with Human Immunodeficiency Virus and Hepatitis C Virus
Riello III RJ¹ and Salvo MC²*
1Department of Pharmacy Services, Yale-New Haven Hospital, USA
²Department of Pharmacy Practice, University of Connecticut School of Pharmacy, USA
*Corresponding author: Salvo MC, Department of Pharmacy Practice, University of Connecticut School of Pharmacy, 69 North Eagleville Road Unit 3092, Storrs, CT 06269-3092, USA
Received: February 24, 2016; Accepted: March 03, 2016; Published: March 07, 2016
Lipid-related disturbances are commonly associated with Protease Inhibitor (PI) use; however, PI-sparing Human Immunodeficiency Virus (HIV) regimens are less frequently associated with increased lipids. A 53 year-old African American female, co-infected with Hepatitis C Virus (HCV) and HIV, maintained on a PI-sparing antiretroviral therapy, experienced a significant elevation in triglycerides following the initiation of HCV treatment with peginterferon Alfa-2a 180 mcg subcutaneously weekly, ribavirin 600 mg orally twice daily, and telaprevir 1125 mg orally three times daily. Two weeks after the start of treatment, a lipid panel was drawn with results: triglycerides (1678 mg/dL), high density lipoprotein-cholesterol (27 mg/dL), total cholesterol (257 mg/dL), and low density lipoprotein-cholesterol (not calculated). Fenofibrate 48mg orally daily was initiated 1 week later. After 7 weeks of fibrate therapy, the triglycerides remained elevated (1690 mg/dL). Marked triglyceride reduction (344 mg/dL) was achieved within 4 weeks of rosuvastatin 10 mg orally daily initiation.
Based on the Naranjo score of 4, it is possible that the patient’s hypertriglyceridemia was drug-induced by peginterferon Alfa-2a. Statin selection is an important component of dyslipidemia management in co-infected HIV and HCV patients with baseline lipid abnormalities.
Keywords: Hepatitis C virus; HIV; Peginterferon Alfa-2a; Severe hypertriglyceridemia
HIV: Human Immunodeficiency Virus; HCV: Hepatitis C Virus; PI: Protease Inhibitor; NNRTI: Non-Nucleoside Reverse Transcriptase Inhibitor; ART: Antiretroviral Therapy; CD4: Cluster of Differentiation 4; RNA: Ribonucleic Acid; IU: International Units; PO: By mouth; LDL-C: Low Density Lipoprotein-Cholesterol; HDL-C: High Density Lipoprotein-Cholesterol (HDL-C); CYP3A4: Cytochrome P450 3A4; AUC: Area Under The Curve; Cmin: Minimum Drug Concentration
Of the people living with human immunodeficiency virus (HIV) in the United States, 25% are co-infected with hepatitis C virus (HCV) . Treatment options suppress HIV and clear HCV infection. However, antiviral medications are not free of adverse effects or potential drug interactions. For example, marked triglyceride elevations are a frequently reported adverse effect associated with protease inhibitor (PI) use for HIV management, but uncommon with PI-sparing regimens [2-6].
Documented cases of dyslipidemia in patients co-infected with HCV Genotype 1a and HIV, who are receiving a PI-sparing regimen, are rare; particularly, given that reports indicate HCV may promote favorable lipid profiles and reduce rates of dyslipidemia [7,8]. We report a case of severe hypertriglyceridemia in a co-infected HCV and HIV patient on a concomitant PI-sparing, non-nucleoside reverse transcriptase inhibitor (NNRTI) based antiretroviral therapy (ART) regimen and HCV treatment.
A primary care provider requested a pharmacist consult for a hypertriglyceridemia therapy recommendation following 10 weeks of HCV treatment in a 53 year-old, 66 kg African American female. The patient’s medical history was significant for HCV Genotype 1a, diabetes mellitus type 2 (A1c of 5.8%, drawn 9 months prior to the start of HCV treatment), controlled hypertension, HIV (CD4 T cell count of 433 cells/uL and HIV RNA viral load of < 20 copies/mL, both drawn at the start of HCV treatment), and hypertriglyceridemia (triglycerides 430 mg/dL, drawn 9 months prior to the start of HCV treatment).There was no documentation of symptoms that may be associated with elevated triglycerides.
Table 1 contains the patient’s medications at the time of pharmacy consultation. To confirm adherence, the pharmacist called the patient’s community pharmacy to assess fill dates; compliance was deemed appropriate. No use of complementary and alternative medicine was noted, and the patient had no recorded drug allergies. Social history reported denial of current tobacco, alcohol, or illicit drug use, and the patient was employed as a residential assistant. Family history was not available. Adult vaccines, including influenza and Hepatitis A, were up-to-date.
Dose, Route of Administration, and Frequency
600 mg/200 mg/300 mg 1 tablet POdaily
375 mg 3 tablets PO three times a day
180 mcg/0.5 mL subcutaneous solution, 180 mcg subcutaneously weekly
Weeks 1 to 6 of treatment: 200 mg 3 capsules PO twice a day
Weeks 7 to 12 of treatment: 200 mg 1 capsule PO twice a day
Week 13+ of treatment: 200 mg 2 capsules PO twice a day
48 mg 1 tablet PO daily
1 tablet PO daily
50,000 units 1 capsule PO weekly
PO = by mouth
Table 1: Patient’s drug therapy at the time of pharmacist consult.
Lipid panel results, prior to and following HCV treatment initiation, are in Table 2. Other relevant laboratory results (drawn 4 weeks following initiation of HCV treatment) include: HCV RNA viral load of 249 IU/mL, aspartate aminotransferase of 48 IU/L (normal range 10-35 IU/L), and the following which are within normal limits: alanine aminotransferase of 28 IU/L, albumin of 4.1 g/ dL, albumin: globulin ratio of 1.2, prothrombin time of 10.4 sec, and international normalized ratio of 1.0. The complete metabolic panel results were within normal limits. Creatinine clearance of 76 mL/min (serum creatinine of 0.75 mg/dL and ideal body weight of 55.3 kg) was calculated using the Cockcroft-Gault equation.
Date of Result
Total Cholesterol (mg/dL)
21months prior to starting HCV treatment
Unable to calculate
9 months prior to startingHCV treatment
Unable to calculate
2 weeks after startingHCV treatment
(1 week prior to starting fenofibrate)
Unable to calculate
6 weeks after starting HCV treatment
(3 weeks after starting fenofibrate)
Unable to calculate
10 weeks after starting HCV treatment
(7 weeks after starting fenofibrate)
Unable to calculate
HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol.
Table 2: Lipid panel results.
The patient started HCV treatment for Genotype 1a with peginterferon Alfa-2a 180 mcg subcutaneously weekly, ribavirin 600 mg PO twice daily, and telaprevir 1125 mg PO three times daily (education provided on fat consumption with use). At that time, treatment with telaprevir followed guideline recommendations. Telaprevir frequency was increased due to reduced concentrations when used concurrently with efavirenz [9,10]. HIV antiretroviral treatment (efavirenz/emtricitabine/tenofovir 600 mg/200 mg/300 mg PO daily) remained unchanged for nearly four years, and the patient’s HIV was classified as stable.
Approximately 2 weeks after the initiation of HCV treatment, a lipid panel was drawn, indicating a triglyceride level of 1678 mg/ dL (Table 2). One week after the receipt of the results, the patient started fenofibrate 48 mg PO daily, as prescribed by her physician. Following 7 weeks of fenofibrate therapy, a lipid panel was drawn with the following results: triglycerides of 1690 mg/dL, low density lipoprotein-cholesterol (LDL-C) could not be calculated, high density lipoprotein-cholesterol (HDL-C) of 28 mg/dL, and total cholesterol of 254 mg/dL. At this time, the pharmacist was consulted for a hypertriglyceridemia therapy recommendation. Following review of the collected information, the pharmacist recommended and the physician initiated rosuvastatin 10 mg PO daily and continued fenofibrate 48mg PO daily. In alignment with evidence-based guidelines, a statin was recommended rather than fibrate optimization given comorbid cholesterol elevations that fenofibrate would not have appreciably affected . Atorvastatin and simvastatin were avoided due to metabolism through cytochrome P450 3A4 (CYP3A4), which telaprevir strongly inhibits. Additionally, efavirenz significantly reduces exposure to atorvastatin and pravastatin; therefore, rosuvastatin remained the only potent statin option available [9-12].
After 4 weeks of rosuvastatin treatment, a lipid panel was drawn with the following results: triglycerides of 344 mg/dL, LDL-C of 14 mg/dL, HDL-C of 29 mg/dL, and total cholesterol of 112 mg/dL. Additionally, during this time, telaprevir was discontinued after 12 consecutive weeks of use, and ribivirin and interferon therapy were continued as recommended.
This case report details severely elevated triglycerides in a co-infected HIV and HCV patient following the initiation of peginterferon Alfa-2a, ribavirin, and telaprevir for HCV treatment. Despite not using a PI-based ART regimen for HIV management, hypertriglyceridemia was present in this patient prior to the start of HCV treatment, likely due to side effect profiles of the HIV medications. Efavirenz, a NNRTI, can cause triglycerides > 750 mg/ dL in 6% to 11% of those treated . Emtricitabine may also increase triglycerides, but to a lesser extent [13,14]. Tenofovir, unlike other antiviral agents, may have favorable effects on lipid profiles [15,16]. Noteworthy is 4% of those treated with combination therapy of efavirenz, emtricitabine and tenofovir, such as this patient, experience triglycerides > 750 mg/dL .
Ribavirin and peginterferon Alfa-2ainhibit HCV RNA replication and induce innate antiviral immune response, respectively [17,18]. Ribavirin is a nucleoside analogue not known to cause lipid abnormalities. However, in combination with peginterferon Alfa-2a, a recombinant pegylated alpha interferon, adverse reactions including elevated triglycerides (= 400 mg/dL) and severe hypertriglyceridemia (>1000 mg/dL) have occurred in up to 36% and 7% of co-infected HCV and HIV patients, respectively .
While this patient had elevated triglycerides prior to starting HCV treatment, use of peginterferon Alfa-2a, ribavirin, and telaprevir caused triglycerides to significantly increase within 2 weeks of therapy initiation. Interferon in various formulations, with and without ribavirin, has been found to cause elevated triglycerides early on during treatment of HCV infected patients [19-21]. Triglycerides typically decline before returning to normal limits following interferon dose reduction or discontinuation of therapy [19-21]. Unlike prior studies, this case report describes severe triglyceride elevation in a co-infected HIV and HCV patient who was receiving a newer formulation of interferon, peginterferon Alfa-2a, along with ribavirin, and an increased dose of telaprevir. The increased telaprevir dose of 1125 mg three times daily was indicated due the decrease in telaprevir’s area under the curve (AUC) and minimum drug concentration (Cmin) by 26% and 47%, respectively, caused with co-administration of efavirenz [10,22,23]. A pharmacokinetic interaction between telaprevir and efavirenz could also have contributed to elevated triglyceride levels. Telaprevir inhibits CYP450 3A4, which may increase efavirenz exposure and the possibility of efavirenz-related adverse effects, including further triglyceride elevation. Telaprevir has not been shown to independently cause hypertriglyceridemia, but triglyceride elevations are a notable class effect of protease inhibitors . Additionally, it is reasonable to consider that the dietary requirements of telaprevir consumption with fatty meals may increase total cholesterol, LDL, and potentially triglycerides .
Employing the Naranjo adverse drug reaction probability scale to evaluate this case (Table 3) yielded a score of 4, indicating a possible drug-induced adverse effect . Lipid values, drawn 4 weeks following the initiation of rosuvastatin and just over 2 weeks following the discontinuation of telaprevir, indicate greatly reduced triglycerides. While telaprevir therapy was discontinued at week 12, peginterferon Alfa-2a and ribavirin were continued . Previous studies support recovery to baseline triglycerides after 12-24 weeks of interferon treatment [20,21]. However, considering the magnitude of triglyceride elevation and insensitivity to initial fenofibrate lipidlowering effect, we believe this patient’s hypertriglyceridemia would have persisted beyond week 12 without statin initiation.
Do Not Know
Are there previous conclusive reports on this reaction?
Did the adverse event appear after the suspected drug was administered?
Did the adverse reaction improve when the drug was discontinued or a specific antagonist was administered?
Did the adverse reaction reappear when the drug was re-administered?
Are there alternative causes (other than the drug) that could on their own have caused the reaction?
Did the reaction reappear when a placebo was given?
Was the drug detected in blood (or other fluids) in concentrations known to be toxic?
Was the reaction more severe when the dose was increased or less severe when the dose was decreased?
Did the patient have a similar reaction to the same or similar drugs in any previous exposure?
Was the adverse event confirmed by any objective evidence?
Table 3: Naranjo adverse drug reaction probability scale.
While ribavirin remains part of the recommended treatment regimens for multiple HCV genotypes, it is important to also recognize that guidelines continue to recommend treatment with peginterferon for genotypes 3, 4, 5, and 6. However, with the approval of new oral HCV therapies, telaprevir is no longer recommended for HCV treatment . Considering treatment guidelines, the findings of this case report underscore the importance of advancing HCV treatment for both improved efficacy and safety, particularly regarding drug interactions with antiretrovirals and metabolic adverse effects such as hypertriglyceridemia.
The cause of severe hypertriglyceridemia in this case may be due to a combination of factors: peginterferon-induced hypertriglyceridemia, pharmacokinetic interaction between telaprevir and efavirenz resulting in increased risk of efavirenzinduced triglyceride elevation, and increased fatty meal consumption with telaprevir administration. Marked triglyceride reduction was achieved within 4 weeks following the initiation of rosuvastatin in a patient co-infected with HCV and HIV, who experienced a significant hypertriglyceridemia following the initiation of HCV treatment with peginterferon Alfa-2a, ribavirin, and telaprevir. Statin initiation in patients with baseline hypertriglyceridemia may be warranted for HIV co-infected patients initiating a hepatitis C treatment regimen including peginterferon. Clinician evaluation of the risk and benefit of antilipidemic therapy initiation must be considered in the context of patient specific characteristics. If therapy is not initiated, periodic lipid panel monitoring is warranted.
- Centers for Disease Control and Prevention. HIV and Viral Hepatitis.
- Echevarria KL, Hardin TC, Smith JA. Hyperlipidemia associated with protease inhibitor therapy. Ann Pharmacother. 1999; 33: 859-863.
- Carling RS, Hextall R, DeSilva PA, Barth JH. Severe hypertriglyceridaemia associated with human immunodeficiency virus and highly active antiretroviral therapy. Ann Clin Biochem. 2002; 39: 409-413.
- Bonnet F, Bonarek M, De Witte S, Beylot J, Morlat P. Efavirenz-associated severe hyperlipidemia. Clin Infect Dis. 2002; 35: 776-777.
- Imarhiagbe FA, Kubeyinje EP. Hypertriglyceridemia in antiretroviral therapy. Med Gen Med. 2005; 7: 65.
- Bain AM, White EA, Rutherford WS, Rahman AP, Busti AJ. A multimodal, evidence-based approach to achieve lipid targets in the treatment of antiretroviral-associated dyslipidemia: case report and review of the literature. Pharmacotherapy. 2008; 28: 932-938.
- Patroni A, Torti C, Tomasoni L, Quiros Roldan E, Bertelli D, Puoti M et al. Effect of highly active antiretroviral therapy (HAART) and hepatitis C co-infection on hyperlipidemia in HIV-infected patients: a retrospective longitudinal study. HIV Clin Trials. 2002; 3: 451-461.
- Bedimo R, Ghurani R, Nsuami M, Turner D, Kvanli MB, Brown G, Margolis D. Lipid abnormalities in HIV/hepatitis C virus-coinfected patients. HIV Med. 2006; 7: 530-536.
- Incivek (telaprevir) package insert. Cambridge, MA: Vertex Pharmaceuticals Incorporated 2013.
- Garg V, Chandorkar G, Yang Y, Adda N, McNair L, Alves K, Smith F. The effect of CYP3A inhibitors and inducers on the pharmacokinetics of telaprevir in healthy volunteers. Br J Clin Pharmacol. 2013; 75: 431-439.
- Dube MP, Stein JH, Aberg JA, et al. Guidelines for the evaluation and management of dyslipidemia in human immunodeficiency virus (HIV)-infected adults receiving antiretroviral therapy: recommendations of the HIV Medical Association of the Infectious Disease Society of America and the Adult AIDS Clinical Trials Group. Clin Infect Dis. 2003; 37: 613–627.
- Gerber JG, Rosenkranz SL, Fichtenbaum CJ, Vega JM, Yang A, Alston BL, Brobst SW. Effect of efavirenz on the pharmacokinetics of simvastatin, atorvastatin, and pravastatin: results of AIDS Clinical Trials Group 5108 Study. J Acquir Immune Defic Syndr. 2005; 39: 307-312.
- Sustiva (efavirenz) package insert. Princeton, NJ: Bristol-Myers Squibb Company. 2013.
- Emtriva (emtricitabine) package insert. Foster City, CA: Gilead Sciences. 2012.
- Viread (tenofovir) package insert. Foster City, CA: Gilead Sciences. 2013.
- Tungsiripat M, Kitch D, Glesby MJ, Gupta SK, Mellors JW, Moran L, Jones L. A pilot study to determine the impact on dyslipidemia of adding tenofovir to stable background antiretroviral therapy: ACTG 5206. AIDS. 2010; 24: 1781-1784.
- Rebetol (ribavirin) package insert. Whitehouse Station, NJ: Merck & Co., Inc.; 2013.
- Pegasys (Peginterferon alfa-2a) package insert. San Francisco, CA: Genetech USA, Inc. 2013.
- Naeem M, Bacon BR, Mistry B, Britton RS, Di Bisceglie AM. Changes in serum lipoprotein profile during interferon therapy in chronic hepatitis C. Am J Gastroenterol. 2001; 96: 2468-2472.
- Fernández-Miranda C, Castellano G, Guijarro C, Fernández I, Schöebel N, Larumbe S, Gómez-Izquierdo T. Lipoprotein changes in patients with chronic hepatitis C treated with interferon-alpha. Am J Gastroenterol. 1998; 93: 1901-1904.
- Shinohara E, Yamashita S, Kihara S, et al. Interferon alpha induces disorder of lipid metabolism by lowering postheparin lipases and cholesteryl ester transfer protein activities in patients with chronic hepatitis C. Hepatology. 1997; 25: 1502-1506.
- Sulkowski MS, Sherman KE, Dieterich DT, Bsharat M, Mahnke L, Rockstroh JK, Gharakhanian S. Combination therapy with telaprevir for chronic hepatitis C virus genotype 1 infection in patients with HIV: a randomized trial. Ann Intern Med. 2013; 159: 86-96.
- Centers for Disease Control and Prevention, the National Institutes of Health, and the HIV Medicine Association of the Infectious Disease Society of America. Guidelines for the prevention and treatment of opportunistic infections in HIV-infected adults and adolescents.
- Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, Janecek E. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981; 30: 239-245.
- American Association for the Study of Liver Diseases/ Infectious Diseases Society of America/ International Antiviral Society-USA (AASLD/IDSA/IAS-USA). Recommendations for testing, managing, and treating hepatitis C.
Citation: Riello III RJ and Salvo MC. Possible Drug-Induced Severe Hypertriglyceridemia in a Patient Co-Infected with Human Immunodeficiency Virus and Hepatitis C Virus. Austin J HIV/AIDS Res. 2016; 3(1): 1022. ISSN : 2380-0755