Management of the adverse effects of antiretroviral therapy and medication adherence.

A commonly cited cause of poor adherence to highly active antiretroviral therapy (HAART) is adverse drug reactions. Short-term adverse effects are potential threats to successful introduction and maintenance of HAART. The long-term toxicities of HAART are still emerging and being defined, as evidenced by the recently described metabolic disorders (i.e., the syndrome of maldistribution, hyperlipemia, glucose intolerance and insulin resistance). With 14 licensed agents in 2000, other agents in common use, and numerous combinations of >/=3 drugs, awareness and recognition of adverse effects are increasingly important for clinicians and patients. The common adverse drug reactions encountered with HAART, including new agents and their impact on patient adherence, are reviewed. Current strategies to anticipate and mitigate adverse effects are summarized.

[1]  R. Dubner,et al.  Efficacy of desipramine in painful diabetic neuropathy: a placebo-controlled trial , 1991, Pain.

[2]  S. Steinberg,et al.  2',3'-didehydro-3'-deoxythymidine (d4T) in patients with AIDS or AIDS-related complex: a phase I trial. , 1993, The Journal of infectious diseases.

[3]  C. Flexner HIV-protease inhibitors. , 1998, The New England journal of medicine.

[4]  Jianping Ding,et al.  Locations of anti-AIDS drug binding sites and resistance mutations in the three-dimensional structure of HIV-1 reverse transcriptase. Implications for mechanisms of drug inhibition and resistance. , 1994, Journal of molecular biology.

[5]  E. Casalino,et al.  Fatal case of 2',3'-dideoxyinosine-associated pancreatitis , 1990, The Lancet.

[6]  J. Condra Virological and clinical implications of resistance to HIV-1 protease inhibitors. , 1998, Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy.

[7]  J. J. Henning,et al.  Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents, January 28, 2000 , 1998, HIV clinical trials.

[8]  G. Skowron Biologic effects and safety of stavudine: overview of phase I and II clinical trials. , 1995, The Journal of infectious diseases.

[9]  K. Koeplinger,et al.  Microsomal metabolism of delavirdine: evidence for mechanism-based inactivation of human cytochrome P450 3A. , 1998, The Journal of pharmacology and experimental therapeutics.

[10]  C. Manthous,et al.  Nevirapine-induced hepatitis treated with corticosteroids? , 1998, AIDS.

[11]  R. Brian Haynes,et al.  Compliance in Health Care , 1979 .

[12]  D. Cooper,et al.  Current clinical experience with nevirapine for HIV infection. , 1996, Advances in experimental medicine and biology.

[13]  M. Tagliati,et al.  Nucleoside analogue-associated peripheral neuropathy in human immunodeficiency virus infection. , 1995, Journal of acquired immune deficiency syndromes and human retrovirology : official publication of the International Retrovirology Association.

[14]  V. Calvez,et al.  Stavudine Resistance: An Update on Susceptibility following Prolonged Therapy , 1999, Antiviral therapy.

[15]  M. Dalakas,et al.  Mitochondrial toxicity of antiviral drugs , 1995, Nature Medicine.

[16]  B Clotet,et al.  Antiretroviral drug resistance testing in adults with HIV infection: implications for clinical management. International AIDS Society--USA Panel. , 1998, JAMA.

[17]  C. Tsai,et al.  Comparison of mitochondrial morphology, mitochondrial DNA content, and cell viability in cultured cells treated with three anti-human immunodeficiency virus dideoxynucleosides , 1994, Antimicrobial Agents and Chemotherapy.

[18]  T. Brown,et al.  HIV risk behavioral surveillance: a methodology for monitoring behavioral trends. , 1998, AIDS.

[19]  R. Tubiana,et al.  Evaluation of safety and efficacy of 3TC (lamivudine) in patients with asymptomatic or mildly symptomatic human immunodeficiency virus infection: a phase I/II study. , 1995, The Journal of infectious diseases.

[20]  J. Lennox,et al.  Benign symmetric lipomatosis associated with protease inhibitors , 1997, The Lancet.

[21]  E. De Clercq,et al.  Inhibitory effect of 9-(2-phosphonylmethoxyethyl)-adenine (PMEA) on human and duck hepatitis B virus infection. , 1993, Antiviral research.

[22]  J. Cherrington,et al.  The safety and efficacy of adefovir dipivoxil, a novel anti-human immunodeficiency virus (HIV) therapy, in HIV-infected adults: a randomized, double-blind, placebo-controlled trial. , 1997, The Journal of infectious diseases.

[23]  J. Montaner,et al.  A randomized, double-blind trial comparing combinations of nevirapine, didanosine, and zidovudine for HIV-infected patients: the INCAS Trial. Italy, The Netherlands, Canada and Australia Study. , 1998, JAMA.

[24]  J. Montaner,et al.  A pilot study of hydroxyurea among patients with advanced human immunodeficiency virus (HIV) disease receiving chronic didanosine therapy: Canadian HIV trials network protocol 080. , 1997, The Journal of infectious diseases.

[25]  J. Schapiro,et al.  Drug-resistance genotyping in HIV-1 therapy: the VIRAD APT randomi sed controlled trial , 1999, The Lancet.

[26]  R. Walensky,et al.  Anaphylaxis after rechallenge with abacavir. , 1999, AIDS.

[27]  K. Kreuzer,et al.  Pathogenesis and pathophysiology of anemia in HIV infection , 1997, Annals of Hematology.

[28]  M A Fischl,et al.  The toxicity of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. A double-blind, placebo-controlled trial. , 1987, The New England journal of medicine.

[29]  S. Hammer,et al.  Zidovudine: Five Years Later , 1992, Annals of Internal Medicine.

[30]  S W Lagakos,et al.  Zidovudine in Asymptomatic Human Immunodeficiency Virus Infection , 1990 .

[31]  D. Venzon,et al.  Five-year follow-up of a phase I study of didanosine in patients with advanced human immunodeficiency virus infection. , 1995, The Journal of infectious diseases.

[32]  Robert S. Pinals,et al.  A double‐blind, placebo‐controlled trial , 1986 .

[33]  N. Leung,et al.  A one-year trial of lamivudine for chronic hepatitis B. Asia Hepatitis Lamivudine Study Group. , 1998, The New England journal of medicine.

[34]  D. Fish,et al.  Dosage adjustment of antiretroviral agents in patients with organ dysfunction. , 1998, American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists.

[35]  F. Wit,et al.  Randomised trial of addition of lamivudine or lamivudine plus loviride to zidovudine-containing regimens for patients with HIV-1 infection: the CAESAR trial , 1997 .

[36]  A. Beydoun,et al.  Gabapentin for the Symptomatic Treatment of Painful Neuropathy in Patients With Diabetes Mellitus: a Randomized Controlled Trial , 1999 .

[37]  M. S. Chen,et al.  Human DNA polymerases alpha and beta are able to incorporate anti-HIV deoxynucleotides into DNA. , 1992, The Journal of biological chemistry.

[38]  J. Revuz,et al.  Nevirapine‐induced overlap Stevens–Johnson syndrome/toxic epidermal necrolysis , 1999, The British journal of dermatology.

[39]  K. Henry,et al.  Severe premature coronary artery disease with protease inhibitors , 1998, The Lancet.

[40]  J. Smeitink,et al.  Adverse effects of reverse transcriptase inhibitors: mitochondrial toxicity as common pathway , 1998, AIDS.

[41]  J. Shapiro,et al.  Zidovudine-induced fatal lactic acidosis and hepatic failure in patients with acquired immunodeficiency syndrome: report of two patients and review of the literature. , 1997, Critical care medicine.

[42]  M A Fischl,et al.  The efficacy of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. A double-blind, placebo-controlled trial. , 1987, The New England journal of medicine.

[43]  I. Pike,et al.  The didanosine Expanded Access Program: safety analysis. , 1993, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[44]  A. Telenti,et al.  HIV treatment failure: testing for HIV resistance in clinical practice. , 1998, Science.

[45]  C. Fichtenbaum,et al.  Risk factors for dideoxynucleoside-induced toxic neuropathy in patients with the human immunodeficiency virus infection. , 1995, Journal of acquired immune deficiency syndromes and human retrovirology : official publication of the International Retrovirology Association.

[46]  J. Neaton,et al.  A comparative trial of didanosine or zalcitabine after treatment with zidovudine in patients with human immunodeficiency virus infection. The Terry Beirn Community Programs for Clinical Research on AIDS. , 1994, The New England journal of medicine.

[47]  Daniel Snower,et al.  Changing etiology of macrocytosis. Zidovudine as a frequent causative factor. , 1993, American journal of clinical pathology.

[48]  A. Sampson,et al.  Recombinant Human Erythropoietin in the Treatment of Anemia Associated with Human Immunodeficiency Virus (HIV) Infection and Zidovudine Therapy: Overview of Four Clinical Trials , 1992 .

[49]  R. Reves,et al.  The case for conservative management of early HIV disease. , 1998, JAMA.

[50]  M. Feinberg,et al.  Report of the NIH Panel to Define Principles of Therapy of HIV Infection and Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents. Vol. 47/No. RR-5. , 1998 .

[51]  B. Gazzard,et al.  Marked hypertriglyceridaemia associated with ritonavir therapy. , 1998, AIDS.

[52]  C. Kemper,et al.  Mexiletine for HIV-infected patients with painful peripheral neuropathy: a double-blind, placebo-controlled, crossover treatment trial. , 1998, Journal of acquired immune deficiency syndromes and human retrovirology : official publication of the International Retrovirology Association.

[53]  A. Carr HIV protease inhibitor-related lipodystrophy syndrome. , 2000, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[54]  Douglas D. Richman,et al.  The safety and efficacy of zidovudine (AZT) in the treatment of subjects with mildly symptomatic human immunodeficiency virus type 1 (HIV) infection a double-blind, placebo-controlled trial , 1990 .

[55]  A. Fauci,et al.  HIV/AIDS in 1998--gaining the upper hand? , 1998, JAMA.

[56]  M. Sadler,et al.  Peripheral Neuropathy with Nucleoside Antiretrovirals , 1998, Drug safety.

[57]  P. Furth,et al.  Nail pigmentation changes associated with azidothymidine (zidovudine). , 1987, Annals of internal medicine.

[58]  K. Baughman,et al.  Cardiomyopathy Associated with Antiretroviral Therapy in Patients with HIV Infection: A Report of Six Cases , 1992, Annals of Internal Medicine.

[59]  J. Holden-Wiltse,et al.  ACTG 260: a Randomized, Phase I-II, Dose-Ranging Trial of the Anti-Human Immunodeficiency Virus Activity of Delavirdine Monotherapy , 1999, Antimicrobial Agents and Chemotherapy.

[60]  R. Sherer Adherence and antiretroviral therapy in injection drug users. , 1998, JAMA.

[61]  A. Cross,et al.  Stavudine in patients with AIDS and AIDS-related complex: AIDS clinical trials group 089. , 1995, The Journal of infectious diseases.

[62]  J. Montaner,et al.  Drug Evaluations Anti-infectives: Nevirapine: A review of its development, pharmacological profile and potential for clinical use , 1996 .

[63]  M. Munshi,et al.  Hyperosmolar Nonketotic Diabetic Syndrome Following Treatment of Human Immunodeficiency Virus Infection With Didanosine , 1994, Diabetes Care.

[64]  M. Fischl,et al.  Zalcitabine Compared with Zidovudine in Patients with Advanced HIV-1 Infection Who Received Previous Zidovudine Therapy , 1993, Annals of Internal Medicine.

[65]  O. Kirk,et al.  Combination therapy containing ritonavir plus saquinavir has superior short-term antiretroviral efficacy: a randomized trial. , 1999, AIDS.

[66]  J. Chaput,et al.  Pharmacokinetics of zidovudine in patients with liver cirrhosis , 1990, Clinical pharmacology and therapeutics.

[67]  Morris Schambelan,et al.  “Buffalo hump” in men with HIV-1 infection , 1998, The Lancet.

[68]  Gallant Je,et al.  Adherence to antiretroviral regimens in HIV-infected patients: results of a survey among physicians and patients. , 1998, Journal of the International Association of Physicians in AIDS Care.

[69]  B. Klaus,et al.  Assessing and enhancing compliance with antiretroviral therapy. , 1997, The Nurse practitioner.

[70]  M. Cappell,et al.  Pancreatic disease in AIDS--a review. , 1993, Journal of clinical gastroenterology.

[71]  Mardge H. Cohen,et al.  Marked declines in human immunodeficiency virus-related mortality in Chicago in women, African Americans, Hispanics, young adults, and injection drug users, from 1995 through 1997. , 2000, Archives of internal medicine.

[72]  A. Cross,et al.  Clinical Efficacy of Monotherapy with Stavudine Compared with Zidovudine in HIV-Infected, Zidovudine-Experienced Patients , 1997, Annals of Internal Medicine.

[73]  A. Sukthankar,et al.  Stavudine induced macrocytosis. , 1997, Genitourinary medicine.

[74]  J. Metcalf,et al.  Randomized, controlled phase I/II, trial of combination therapy with delavirdine (U-90152S) and conventional nucleosides in human immunodeficiency virus type 1-infected patients , 1996, Antimicrobial agents and chemotherapy.

[75]  B. Walker,et al.  Treat HIV-1 infection like other infections--treat it. , 1998, JAMA.

[76]  D. Cooper,et al.  A controlled trial of nevirapine plus zidovudine versus zidovudine alone in p24 antigenaemic HIV‐infected patients , 1996, AIDS.

[77]  Feher,et al.  Marked hypertriglyceridaemia associated with ritonavir therapy [letter] , 1998 .

[78]  S. Broder,et al.  Dermatologic complications associated with administration of 2',3'-dideoxycytidine in patients with human immunodeficiency virus infection. , 1989, Journal of the American Academy of Dermatology.

[79]  J. Cameron,et al.  Effects of (-)-2'-deoxy-3'-thiacytidine (3TC) 5'-triphosphate on human immunodeficiency virus reverse transcriptase and mammalian DNA polymerases alpha, beta, and gamma , 1992, Antimicrobial Agents and Chemotherapy.

[80]  C. Greco,et al.  Prognosis in AZT myopathy , 1991, Neurology.

[81]  R. Chaisson,et al.  Hepatomegaly and steatosis in HIV-infected patients receiving nucleoside analog antiretroviral therapy. , 1995, The American journal of gastroenterology.

[82]  D. Kelsell,et al.  Evidence for a single genetic locus in Clouston's hidrotic ectodermal dysplasia , 1999, The British journal of dermatology.

[83]  G. Baldwin,et al.  Combined therapy with recombinant granulocyte colony-stimulating factor and erythropoietin decreases hematologic toxicity from zidovudine. , 1991, Blood.

[84]  D. Kuritzkes,et al.  Treatment with Lamivudine, Zidovudine, or Both in HIV-Positive Patients with 200 to 500 CD4+ Cells per Cubic Millimeter , 1995 .

[85]  S. Penzak,et al.  Depression in patients with HIV infection. , 2000, American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists.

[86]  D. Ho,et al.  Toward HIV eradication or remission: the tasks ahead. , 1998, Science.

[87]  T. Merigan,et al.  Safety and tolerance of dideoxycytidine as a single agent: Results of early-phase studies in patients with acquired immunodeficiency syndrome (AIDS) or advanced AIDS-related complex , 1990 .

[88]  J. Palmisano,et al.  Lactic acidosis associated with stavudine administration: a report of five cases. , 2000, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[89]  Kilby Jm,et al.  Severe hyperglycemia in an HIV clinic: preexisting versus drug-associated diabetes mellitus. , 1998 .