Table of Contents
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Abstract
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Case Presentations
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Introduction
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Selected Abbreviations
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Critical Appraisal of the Literature
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Epidemiology And Pathophysiology
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Prehospital Care
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Emergency Department Evaluation
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History
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Physical Examination
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Diagnostic Testing
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Laboratory Testing
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Medication Side Effects
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Highly Active Antiretroviral Therapy
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Nucleoside Reverse Transcriptase Inhibitors And Nucleotide Reverse Transcriptase Inhibitors
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Nonnucleoside Reverse Transcriptase Inhibitors
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Protease Inhibitors
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Integrase Inhibitors
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Fusion Inhibitors
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System-Based Disease And Medication Effects
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Cardiovascular Disease
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Pulmonary Disease
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Renal Disease
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Neurologic Disease
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Gastrointestinal And Hepatobiliary Disease
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Hematologic Disease
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Endocrine Disease
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Musculoskeletal Disease
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Psychiatric Disease
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Dermatologic Disease
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Special Circumstances
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Summary
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Key Points
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Case Conclusions
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Acknowledgement
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Clinical Pathway For Management Of Weakness In HIV-Infected Patients
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Tables and Figures
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Table 1. Major Adverse Effects Of Antiretroviral Medications
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Figure 1. Chest X-Ray Of Pneumocystis jiroveci Pneumonia
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References
Abstract
The care of the HIV-infected patient in the emergency department has changed since the development of highly active antiretroviral therapy. This therapy has resulted in longer life expectancies and increased quality of life for HIV-infected patients, and in cases of treatment compliance and success, virtual elimination of AIDS-associated opportunistic infections. As a result, the emergency clinician is now more often confronted with adverse events related to medication and the diseases associated with aging and chronic disease. This issue focuses on the differences in evaluation of HIV patients on long-term therapy and patients with medication noncompliance and low CD4 counts, as well as recognition of life-threatening and rare opportunistic infections. Disease processes related to the effect of longstanding HIV infection, even with good control, on many organ systems are addressed.
Case Presentations
You arrive for your ED shift and are presented with 3 HIV-infected patients with various chief complaints. The first patient is a 28-year-old man with 1 day of right flank pain, nausea, vomiting, and hematuria. He had a kidney stone a year ago with identical pain, and a point-of-care ultrasound shows asymmetric hydronephrosis; however, a nonenhanced CT scan demonstrates hydronephrosis and hydroureter without a stone. You wonder if the CT eliminates an impacted stone or if there is another explanation.
The second patient is a 42-year-old HIV-infected woman complaining of as many as 3 episodes a day of diarrhea for the past 3 weeks. She denies pain, melena, rectal bleeding, and fevers. Her laboratory test results are unremarkable. You wonder if additional testing is needed and whether sending her home is appropriate.
The third patient presents because her family has noticed that she has been acting increasingly “sad.” She denies any suicidal or homicidal ideation, but does corroborate that since initiation of an SSRI antidepressant drug 6 months ago, she has not noticed any improvement in her mood. In the absence of suicidal ideation, you wonder if she can be sent home.
You are reminded that caring for the HIV-infected patient is not so simple, and you realize quickly that you are dealing with 3 very different presentations related to the same disease and must prioritize where to begin.
Introduction
The human immunodeficiency virus (HIV) causes a progressive failure of the immune system, ultimately leading to acquired immunodeficiency syndrome (AIDS) in the absence of treatment. Although under different nomenclature, AIDS was first described in the early 1980s when clusters of patients developed opportunistic infections (OIs) not seen in patients with intact immune systems. HIV has spread to every country in the world, creating a global pandemic. In 2012, there were 35.3 million people living with HIV worldwide and 2.3 million new diagnoses that year.1
The development of highly active antiretroviral therapy (HAART) in 1996 dramatically increased life expectancy for HIV-infected patients. Due to the effectiveness of HAART, by the early 2000s, life expectancy of HIV-infected patients in developed countries was equivalent to that of comparable persons who were not HIV-infected.2,3
Current guidelines from the United States Department of Health and Human Services recommend the treatment of all HIV-infected patients with antiretroviral medications (ARVs).4 These current recommendations are based on evidence that ARVs reduce the risk of disease progression in all patients with CD4 T lymphocyte (CD4) count < 350 cells/mm3, CD4 count 350 to 500 cells/mm3, and CD4 count > 500 cells/mm3. This recommendation is a change from prior guidelines, which recommended therapy only for patients with lower CD4 counts. The guidelines are also based on evidence that treatment decreases the risk of transmission, and that patients with undetectable HIV viral loads are at exceedingly low risk for transmitting the virus to others.5
In addition to improving life expectancy, HAART has also changed the epidemiology of conditions affecting HIV-infected patients. In the beginning of the epidemic, HIV patients generally presented with infectious complications of their advanced disease. These included OIs such as Pneumocystis jiroveci pneumonia and Kaposi sarcoma. Now, patients more commonly present with complications unrelated to OIs, including cardiovascular, hepatic, and kidney disease, as well as HIV-related malignancies and adverse effects from medication.5,6 The spectrum of presenting complaints is associated with patient compliance with treatment. OIs are still seen in patients with undiagnosed infection presenting with advanced disease and those with financial, social, or other barriers to medication compliance.
This changing epidemiology of HIV complications poses a particular challenge for emergency clinicians, who should be familiar with these presentations as well as the presentation of OIs. This issue of Emergency Medicine Practice reviews the emergency complications of long-term HIV infection, especially noninfectious conditions and complications common in the HAART-adherent HIV patient.
Selected Abbreviations
AIDS: Acquired immunodeficiency syndrome
ARV: Antiretroviral
AZT/ZDV: Zidovudine
HAART: Highly active antiretroviral therapy
HIV: Human immunodeficiency virus
NNRTI: Nonnucleoside reverse transcriptase inhibitor
NRTI: Nucleoside reverse transcriptase inhibitor
NtRTI: Nucleotide reverse transcriptase inhibitor
OI: Opportunistic infection
PEP: Postexposure prophylaxis
PI: Protease inhibitor
Critical Appraisal Of The Literature
PubMed and the Cochrane Database of Systematic Reviews were searched for English-language articles related to the management of HIV/AIDS. Attention was focused on articles relevant to the emergency clinician, those published after 1996 (to coincide with the advent of HAART), and on articles that discussed the effects of chronic HIV infection and HAART adverse events. Search terms included HIV, AIDS, combination antiretroviral therapy, highly active antiretroviral therapy, and immune reconstitution inflammatory syndrome. Because of the large number of articles retrieved in these searches, the initial focus was on review articles with cross-referencing primary literature cited in the bibliographies. Relevant guidelines by the World Health Organization, the United States Department of Health and Human Services, and the American College of Emergency Physicians were also reviewed.
Now, nearly 20 years after the advent of HAART, considerable literature exists on the subject of HIV both in terms of the OIs patients experience and the chronic effects of longstanding illness and treatment. This literature provides strong evidence to support the practice recommendations made in this article.
Tables and Figures
References
Evidence-based medicine requires a critical appraisal of the literature based upon study methodology and number of subjects. Not all references are equally robust. The findings of a large, prospective, randomized, and blinded trial should carry more weight than a case report.
To help the reader judge the strength of each reference, pertinent information about the study are included in bold type following the reference, where available. In addition, the most informative references cited in this paper, as determined by the authors, are noted by an asterisk (*) next to the number of the reference.
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UNAIDS. UNAIDS fact sheet. Accessed November 8, 2014. (United Nations publication)
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* Nakagawa F, May M, Phillips A. Life expectancy living with HIV: recent estimates and future implications. Curr Opin Infect Dis. 2013;26(1):17-25. (Systematic review)
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Lima VD, Hogg RS, Harrigan PR, et al. Continued improvement in survival among HIV-infected individuals with newer forms of highly active antiretroviral therapy. AIDS. 2007;21(6):685-692. (Prospective; 2000 patients)
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Panel on Antiretroviral Guidelines for Adults and Adolescents. Department of Health and Human Services. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Accessed August 5, 2015. (Government report)
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Rodger A, Bruun T, Cambiano V, et al. HIV transmission risk through condomless sex if HIV+ partner on suppressive ART: PARTNER Study. Paper presented at: 21st Conference on Retroviruses and Opportunistic Infections, Abstract 153LB. March 3-6, 2014. (Prospective; 30,000 cases)
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* Palella FJ Jr, Baker RK, Moorman AC, et al. Mortality in the highly active antiretroviral therapy era: changing causes of death and disease in the HIV outpatient study. J Acquir Immune Defic Syndr. 2006;43(1):27-34. (Prospective; 7000 patients)
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Hall HI, An Q, Tang T, et al. Prevalence of diagnosed and undiagnosed HIV infection – United States, 2008-2012. MMWR. 2015;64(24):657-662. (CDC report)
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* Mohareb AM, Rothman RE, Hsieh YH. Emergency department (ED) utilization by HIV-infected ED patients in the United States in 2009 and 2010 - a national estimation. HIV Med. 2013;14(10):605-613. (Observational; 1.1 milliion patients)
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Shapiro NI, Karras DJ, Leech SH, et al. Absolute lymphocyte count as a predictor of CD4 count. Ann Emerg Med. 1998;32(3 Pt 1):323-328. (Retrospective; 322 patients)
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Napoli AM, Fischer CM, Pines JM, et al. Absolute lymphocyte count in the emergency department predicts a low CD4 count in admitted HIV-positive patients. Acad Emerg Med. 2011;18(5):565. (Retrospective; 866 patients)
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Hammer SM, Squires KE, Hughes MD, et al. A controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less. AIDS Clinical Trials Group 320 Study Team. N Engl J Med. 1997;337(11):725- 733. (Prospective randomized controlled; 1056 patients)
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Moore RD, Chaisson RE. Natural history of HIV infection in the era of combination antiretroviral therapy. AIDS. 1999;13(14):1933-1942. (Retrospective; 1000 patients)
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Gulick RM, Mellors JW, Havlir D, et al. Treatment with indinavir, zidovudine, and lamivudine in adults with human immunodeficiency virus infection and prior antiretroviral therapy. N Engl J Med. 1997;337(11):734-739. (Prospective randomized double-blind; 97 patients)
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PubChem. Compound summary for zidovudine. Accessed November 18, 2014. (Website)
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Martin MA, Hoffman JM, Freimuth RR, et al. Clinical pharmacogenetics implementation consortium guidelines for HLA-B genotype and abacavir dosing: 2014 update. Clin Pharmacol Ther. 2014;95(5):499-500. (Clinical guideline)
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Mallal S, Nolan D, Witt C, et al. Association between presence of HLA-B*5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir. Lancet. 2002;359(9308):727-732. (Observational; 200 patients)
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Worm SW, Sabin C, Weber R, et al. Risk of myocardial infarction in patients with HIV infection exposed to specific individual antiretroviral drugs from the 3 major drug classes: the data collection on adverse events of anti-HIV drugs (D:A:D) study. J Infect Dis. 2010;201(3):318-330. (Observational; 580 patients)
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Gupta SK, Anderson AM, Ebrahimi R, et al. Fanconi syndrome accompanied by renal function decline with tenofovir disoproxil fumarate: a prospective, case-control study of predictors and resolution in HIV-infected patients. PLoS One. 2014;9(3):e92717. (Prospective case-control; 56 patients)
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Jiang B, Hebert VY, Zavecz JH, et al. Antiretrovirals induce direct endothelial dysfunction in vivo. J Acquir Immune Defic Syndr. 2006;42(4):391-395. (Animal study)
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Cespedes MS, Aberg JA. Neuropsychiatric complications of antiretroviral therapy. Drug Saf. 2006;29(10):865-874. (Systematic review)
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Stern JO, Robinson PA, Love J, et al. A comprehensive hepatic safety analysis of nevirapine in different populations of HIV infected patients. J Acquir Immune Defic Syndr. 2003;34 Suppl 1:S21-S33. (Prospective; 3000 patients)
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Fantry LE. Protease inhibitor-associated diabetes mellitus: a potential cause of morbidity and mortality. J Acquir Immune Defic Syndr. 2003;32(3):243-244. (Editorial)
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* Venkat A, Piontkowsky DM, Cooney RR, et al. Care of the HIV-positive patient in the emergency department in the era of highly active antiretroviral therapy. Ann Emerg Med. 2008;52(3):274-285. (Systematic review)
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Triant VA, Lee H, Hadigan C, et al. Increased acute myocardial infarction rates and cardiovascular risk factors among patients with human immunodeficiency virus disease. J Clin Endocrinol Metab. 2007;92(7):2506-2512. (Prospective observational; 4000 patients)
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Giannarelli C, Klein RS, Badimon JJ. Cardiovascular implications of HIV-induced dyslipidemia. Atherosclerosis. 2011;219(2):384-389. (Systematic review)
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O’Cleirigh C, Valentine SE, Pinkston M, et al. The unique challenges facing HIV-positive patients who smoke cigarettes: HIV viremia, ART adherence, engagement in HIV care, and concurrent substance use. AIDS Behav. 2015;19(1):178-185. (Cross-sectional; 300 patients)
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Friis-Moller N, Reiss P, Sabin CA, et al. Class of antiretroviral drugs and the risk of myocardial infarction. N Engl J Med. 2007;356(17):1723-1735. (Prospective observational; 23,437 patients)
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Smith RL, Ripps CS, Lewis ML. Elevated lactate dehydrogenase values in patients with Pneumocystis carinii pneumonia. Chest. 1988;93(5):987-992. (Case control; 7 patients)
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Benito N, Moreno A, Miro JM, et al. Pulmonary infections in HIV-infected patients: an update in the 21st century. Eur Respir J. 2012;39(3):730-745. (Review)
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Fine MJ, Auble TE, Yealy DM, et al. A prediction rule to identify low-risk patients with community-acquired pneumonia. N Engl J Med. 1997;336(4):243-250. (Retrospective; 14,000 patients)
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Hull MW, Phillips P, Montaner JS. Changing global epidemiology of pulmonary manifestations of HIV/AIDS. Chest. 2008;134(6):1287-1298. (Review)
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Crothers K, Butt AA, Gibert CL, et al. Increased COPD among HIV-positive compared to HIV-negative veterans. Chest. 2006;130(5):1326-1333. (Prospective observational; 1000 patients)
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Rasmussen LD, Dybdal M, Gerstoft J, et al. HIV and risk of venous thromboembolism: a Danish nationwide population-based cohort study. HIV Med. 2011;12(4):202-210. (Retrospective; 4000 patients)
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Heaton RK, Clifford DB, Franklin DR Jr, et al. HIV-associated neurocognitive disorders persist in the era of potent antiretroviral therapy: CHARTER Study. Neurology. 2010;75(23):2087-2096. (Observational; 1555 patients)
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Heaton RK, Franklin DR Jr, Deutsch R, et al. Neurocognitive change in the era of HIV combination antiretroviral therapy: the longitudinal CHARTER study. Clin Infect Dis. 2015;60(3):473-480. (Cross-sectional observational; 1500 patients)
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Ortiz G, Koch S, Romano JG, et al. Mechanisms of ischemic stroke in HIV-infected patients. Neurology. 2007;68(16):1257- 1261. (Retrospective; 80 patients)
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* Knox TA, Spiegelman D, Skinner SC, et al. Diarrhea and abnormalities of gastrointestinal function in a cohort of men and women with HIV infection. Am J Gastroenterol. 2000;95(12):3482-3489. (Cross-sectional; 600 patients)
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Collini PJ, Kuijper E, Dockrell DH. Clostridium difficile infection in patients with HIV/AIDS. Curr HIV/AIDS Rep. 2013;10(5):273-282. (Review)
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Puoti M, Airoldi M, Bruno R, et al. Hepatitis B virus co-infection in human immunodeficiency virus-infected subjects. AIDS Rev. 2002;4(1):27-35. (Systematic review)
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Staples CT Jr, Rimland D, Dudas D. Hepatitis C in the HIV (human immunodeficiency virus) Atlanta V.A. (Veterans Affairs Medical Center) Cohort Study (HAVACS): the effect of coinfection on survival. Clin Infect Dis. 1999;29(1):150-154. (Prospective observational; 300 patients)
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den Brinker M, Wit FW, Wertheim-van Dillen PM, et al. Hepatitis B and C virus co-infection and the risk for hepatotoxicity of highly active antiretroviral therapy in HIV-1 infection. AIDS. 2000;14(18):2895-2902. (Retrospective; 400 patients)
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Sullivan PS, Dworkin MS, Jones JL, et al. Epidemiology of thrombosis in HIV-infected individuals. The Adult/Adolescent Spectrum of HIV Disease Project. AIDS. 2000;14(3):321- 324. (Longitudinal observational; 42,000 patients)
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Saif MW, Bona R, Greenberg B. AIDS and thrombosis: retrospective study of 131 HIV-infected patients. AIDS Patient Care STDS. 2001;15(6):311-320. (Retrospective; 100 patients)
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Becker S, Fusco G, Fusco J, et al. HIV-associated thrombotic microangiopathy in the era of highly active antiretroviral therapy: an observational study. Clin Infect Dis. 2004;39 Suppl 5:S267-S275. (Prospective observational; 6000 patients)
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Heath KV, Hogg RS, Chan KJ, et al. Lipodystrophy-associated morphological, cholesterol and triglyceride abnormalities in a population-based HIV/AIDS treatment database. AIDS. 2001;15(2):231-239. (Prospective observational; 1000 patients)
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Mallal SA, John M, Moore CB, et al. Contribution of nucleoside analogue reverse transcriptase inhibitors to subcutaneous fat wasting in patients with HIV infection. AIDS. 2000;14(10):1309-1316. (Prospective; 277 patients)
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Crum NF, Ganesan A, Johns ST, et al. Graves disease: an increasingly recognized immune reconstitution syndrome. AIDS. 2006;20(3):466-469. (Correspondence)
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Hadigan C, Kattakuzhy S. Diabetes mellitus type 2 and abnormal glucose metabolism in the setting of human immunodeficiency virus. Endocrinol Metab Clin N Am. 2014;43(3):685-696. (Review)
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Takhar SS, Hendey GW. Orthopedic illnesses in patients with HIV. Emerg Med Clin North Am. 2010;28(2):335-342. (Review)
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Marquez J, Restrepo CS, Candia L, et al. Human immunodeficiency virus-associated rheumatic disorders in the HAART era. J Rheumatol. 2004;31(4):741-746. (Prospective; 75 patients)
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Martins CR. Cutaneous drug reactions associated with newer antiretroviral agents. J Drugs Dermatol. 2006;5(10):976- 982. (Review)
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Maurer T, Rodrigues LK, Ameli N, et al. The effect of highly active antiretroviral therapy on dermatologic disease in a longitudinal study of HIV type 1-infected women. Clin Infect Dis. 2004;38(4):579-584. (Cross-sectional; 800 patients)
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Centers for Disease Control and Prevention. PEP. Available at: http://www.cdc.gov/hiv/basics/pep.html. Accessed July 30, 2015. (CDC website)
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Thomas R, Galanakis C, Vezina S, et al. Adherence to post-exposure prophylaxis (PEP) and incidence of HIV seroconversion in a major North American cohort. PLoS ONE. 2015; 11;10(11):e0142534. (Prospective; 3547 patients)