HIV Update

Educational Objectives

The goal of this program is to improve the management of HIV-associated conditions and side effects of highly active antiretroviral therapy (HAART). After hearing and assimilating this program, the clinician will be better able to:

1.   Review the significance of the CD4 count in determining the stage of HIV infection and in monitoring therapy.

2.   Describe the metabolic complications associated with the use of HAART.

3.   Recognize and manage immune reconstitution inflammatory syndrome.

4.   Discuss how HAART increases the risk for cardiovascular and cerebrovascular disease.

5.   Recognize and treat complications associated with specific drugs used in HAART.

Faculty Disclosure

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the plan­ning committee to disclose relevant financial relationships within the past 12 months that might create any personal con­flicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, the faculty and planning committee reported nothing to disclose.

Acknowledgments

Dr. Chin was recorded at High Risk Emergency Medicine, held May 21-23, 2009, in San Francisco, CA, and sponsored by the Emergency Department at San Francisco General Hospital and Department of Emergency Medicine, University of Cali­fornia, San Francisco, School of Medicine. Dr. Venkat was recorded at the Pennsylvania Chapter of the American College of Emergency Physicians (PaACEP) Scientific Assembly 2009: Advances, Controversies and Technology, held April 13-16, 2009, in Pittsburgh, PA, and sponsored by PaACEP. The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation in the production of this program.

HIV Emergencies

Rachel L. Chin, MD, Professor of Clinical Emergency Medicine, University of California, San Francisco, School of Medicine, and San Francisco General Hospital

CD4 count: stage of HIV infection  —  changes management; defined by CD4 count; early in disease, >500 cells/μL (immunocompetent); if 200 to 500 cells/μL, intermediate; <200 cells/μL, late; <50 cells/μL, very late; viral load (VL)  —important for monitoring therapy; checked every 3 mo; if increased, signifies that medication ineffective due to nonadherence, drug-drug interactions, malabsorption of medications, or point mutation in HIV chain; if CD4 count <200 cells/μL and patient not on Pneumocystis jerovici pneumonia (PCP) prophylaxis, all upper respiratory infections require close follow-up; if CD4 count >200 cells/μL and patient on prophylaxis, immediate follow-up not necessary

Pneumocystis jerovici (previously carinii) pneumonia (PCP): treated with trimethoprim-sulfamethoxazole (TMP-SMZ); clinical presentation  —  late; symptoms include fever, dyspnea on exertion, dry cough (classic), and fatigue; duration not acute (2-4 wk); signs not specific; laboratory tests  —  only possible clue serum lactate dehydrogenase (LDH) level; if >350 mg/dL, consider PCP; chest x-ray  —  presentation often bilateral and symmetric; pattern often interstitial and granular (ground glass appearance); may see consolidation; cysts occur in £20% of patients and best seen in high-resolution computed tomography (CT); normal findings in £20% of patients and pneumothorax in £30%; treatment  —  TMP-SMZ superior to all other medications; if patient on primaquine or dapsone, glucose-6-phosphate dehyrogenase (G6PD) deficiency or methemoglobinemia possible; treat for 21 days followed by prophy­laxis; if partial pressure of O₂ <70 mm Hg, start steroids

Bacterial pneumonia: in HIV-positive individuals, 100 times more common than in general population, regardless of CD4 count (possible in patient with CD4 count ³ 700 cells/μL); symptoms  —fever, shortness of breath, chest pain, productive cough with purulent sputum; duration acute (3-5 days); rales and rhonchi evident on physical examina­tion (PE); laboratory tests  —  elevated white blood cell (WBC) count; positive blood culture

Cryptococcal meningitis: Cryptococcus neoformans most common fungus responsible for infection in AIDS pa­tients; clinical presentation  —  if CD4 count <100 cells/μL, symptoms often include fever and headache; occasion­ally, fever absent or patient may have nagging headache for 1 mo; usual meningeal signs often absent; CT and magnetic resonance imaging (MRI) often negative; diagnosis  —  if available, order serum cryptococcal antigen test; if positive, perform lumbar puncture (LP) to determine whether also positive in cerebrospinal fluid (CSF); if serum negative, testing of CSF unnecessary (will also be negative); treatment  —  amphotericin B with flucytosine for 2 wk, then oral fluconazole for long-term suppressive therapy; must manage increased intracranial pressure (ICP); high opening ICP correlates with mortality; reduce opening ICP to <25 mm Hg before removing spinal needle; in­creased ICP due to gelatinous structure of C neoformans; perform daily LPs to drain CSF in admitted patients

Cerebral toxoplasmosis: most common cause of focal brain lesions in patients with AIDS; clinical presentation late; CD4 count <200 cells/μL; symptoms include fever, headache, altered mental status, or focal findings; seizures seen in £50% of patients; toxin titers usually positive; reliability of CD4 counts  — if patient not on therapy, any count >3 mo old not reliable; diagnosis  —  CT or MRI showing multiple ring-enhancing lesions; presence of single lesion may indicate lymphoma, but treat for toxoplasmosis for 2 wk and refer to oncologist if unresolved; treatment  —  pyrimethamine, sulfadiazine, and folinic acid; clinical and radiologic improvement expected within 2 wk

Ocular emergencies: cytomegalovirus (CMV) retinitis  —  most common vision-threatening condition in patients with AIDS; clinical presentation often very late; CD4 count <50 cells/μL; complaints range from subtle (floaters) to se­rious; any ocular complaint in patient with CD4 count <50 cells/μL worrisome; treatment  —valganciclovir, foscar­net, and cidofovir; prophylaxis necessary

HIV prophylaxis and treatment: if patient started on highly active antiretroviral therapy (HAART) and CD4 count increases to >200 cells/μL for 6 mo, may stop all prophylaxis for PCP; also true for disseminated Mycobacterium avium complex and CMV retinitis; prophylaxis recommended for herpes simplex virus (HSV) types 1 and 2 only, because outbreaks upregulate HIV viral production and threaten viral suppression; HAART  —  combination of ³3 drugs; now standard of care; therapies available include nucleoside reverse transcriptase inhibitors (NRTIs), nucle­otide RTIs, non-NRTIs (NNRTIs), protease inhibitors (PIs), and fusion inhibitors

Mitochondrial toxicity: lactic acidosis with or without fatty liver; symptoms sudden or gradual; nonspecific (eg, nausea, vomiting, fatigue); laboratory tests  —  elevated liver function tests (LFTs) and serum lactate >5 mg/dL; monitor every 3 mo; if LFTs increase, serum lactate level determined (consider in patient on NRTI); mortality 80% if serum lactate >10 mg/dL; other emergencies related to HIV therapy  —  pancreatitis; lactic acidosis; life-threaten­ing rashes (with NNRTIs); drug interactions

Nucleoside reverse transcriptase inhibitors (NRTIs): didanosine (ddI), stavudine (d4T), and dideoxycytidine (ddC) can cause pancreatitis and neuropathy; azathioprine (AZT) causes myopathy; lactic acidosis with or without fatty liver seen with NRTIs, most commonly with d4T; lipodystrophy syndrome  —thinning of arms, face, and legs and fat accumulation in abdomen; truncal obesity associated with PIs (“crix belly” due to crixivan); fat visceral, not subcutaneous

Metabolic complications: impairment of glucose metabolism seen with PIs (insulin resistance and impaired glucose tolerance, with development of frank diabetes); lipid metabolism also abnormal, with increased triglycerides, total cholesterol, and low-density lipoproteins (LDL), and undetectable high-density lipoproteins (HDL); diabetes, hy­perlipidemia, and visceral fat all contribute to cardiovascular and cerebrovascular disease; early case series show patients at premature risk for cardiovascular problems; Kaiser Permanente study  —  found coronary artery disease (CAD) and myocardial infarctions (MIs) significantly higher among HIV-positive patients 35 to 64 yr of age, com­pared to HIV-negative patients; Data Collection on Adverse Events of Anti-HIV drugs (D:A:D) Study  —  found small increase in cardiovascular disease associated with duration of combination therapy; the longer the duration of therapy, the higher the incidence of MIs per 1000 patients per year; Strategies for Management of Antiretroviral Therapy (SMART) study  —  participants with CD4 counts >350 cells/μL in 2 arms (continuous treatment vs no treat­ment until CD4 count <250 cells/μL, then treatment resumed); uncontrolled HIV replication increased risk for car­diovascular disease; study terminated early; 1.5-fold increase in non-HIV-related severe complications; HIV-related complications also increased; therefore, interruption of treatment deemed unacceptable; elevated inflammatory markers seen in patients on intermittent therapy; increased risk due to infection itself, HAART, or both

Drug interactions: some statins (eg, simvastatin) prescribed to offset PI’s effect on lipid metabolism may cause death due to rhabdomyolysis (cytochrome P₄₅₀ system inhibited); rashes  —associated with NNRTIs; seen in £37% of patients in clinical trials; maculopapular rash seen within 4 to 6 wk; sometimes severe, as in toxic epidermolysis or Stevens-Johnson syndrome; 8% of patients on nevirapine required admission to burn unit; atazanavir  —  new PI; nonlife-threatening jaundice due to elevated indirect bilirubin seen in 8% of patients; not associated with lactic aci­dosis seen with NRTIs

Immune reconstitution syndrome (IRS): HAART allows partial recovery of immune system (eg, increase in T cells); can lead to strong immune response to previously subclinical opportunistic infections (eg, blindness caused by extreme inflammatory response to CMV retinitis)

Rapid HIV testing: National Clinicians Consultation Center or nccu.ucsf.edu/statelaws website for HIV testing laws and resources in each state; 4 tests with turnaround time of 20 min approved by Food and Drug Administration

ED Management of the HIV Patient in
the Antiretroviral Era

Arvind Venkat, MD, Assistant Professor of Emergency Medicine, Drexel University College of Medicine, Al­legheny General Hospital, Pittsburgh, PA

HAART-related lactic acidosis: caused by all NRTIs, but most commonly ddI and d4T; related to mitochondrial tox­icity; symptoms nonspecific; treatment supportive; time to recovery £28 wk

Drug interactions: most involve PIs and relate to inhibition of cytochrome P₄₅₀ system and resultant increase in med­ication levels; increased levels of antiarrhythmics, anticonvulsants, benzodiazepines, statins, and warfarin com­monly seen in patients on PIs, with resulting complications due to toxicity

Immune reconstitution inflammatory syndrome: unique consequence of HAART initiation; pathophysiology  —  rapid reconstitution of immune function, leading to exacerbation of dormant opportunistic pathogens or clinically apparent illness of HIV viremia; autoimmune-type symptoms seen (eg, sarcoidosis-like symptoms, autoimmune thyroiditis); risk factors include being naive to antiretroviral therapy at HAART initiation, recent opportunistic in­fection, or rapid decrease in VL; most commonly presents within 8 wk of initiation of HAART; no specific diag­nostic test; clinical diagnosis based on history and PE; treatment symptomatic, although steroid use explicitly contraindicated if reconstitution of opportunistic pathogen possible, particularly those without specific treatment (eg, JC virus); not necessary to discontinue HAART

Cardiovascular complications: CAD and peripheral vascular disease increasingly common in patients on HAART; consider even in young patients with HIV; in one study, HAART associated with 26% increase in relative risk (RR) for MI, compared to HIV patients not on HAART; another study found RR for MI per year of PI use increases 1.6; each additional year of PI use increases RR of developing MI; increased RR for MI of 1.75 in HIV patients; due to aging of population and side effects of PIs, ie, hyperlipidemia, hyperglycemia, and truncal obesity (all risk factors for CAD)

HAART-related pneumonias: in HAART era, Streptococcus pneumoniae most prevalent cause of pneumonia in HIV-positive population; in pre-HAART era, PCP most common infection in HIV patients; also at increased risk for chronic obstructive pulmonary disease (regardless of smoking status) and pulmonary hypertension; according to CDC and Department of Health and Human Services (HHS) guidelines, if patient’s CD4 count >200 cells/μL for 3 mo and on ART, possible to stop PCP prophylaxis; current literature suggests that patients with well-managed HIV infection should not be treated in same manner as general emergency department population with pneumonia; pneumonia severity index used to risk-stratify patients for admission

HIV nephropathy: due to primary HIV nephropathy and renal toxicity caused by HAART; blacks disproportionately affected; presentation insidious, without secondary signs of renal disease; tenofovir and indinavir associated with renal toxicity; PIs (particularly indinavir) associated with urolithiasis; radiolucent crystals form nidus for stone for­mation; appear radiopaque on noncontrast CT; lower risk for urolithiasis with atazanavir

Neurologic complications: in pre-HAART era, toxoplasmosis, space-occupying lesions, and lymphoma considered; HIV itself significant independent risk factor for cerebrovascular disease, with RR for ischemic stroke 9.1 (12.7 for intracerebral hemorrhage); independent of side effects of HAART; tipranavir has blackbox warning for intracere­bral hemorrhage; HIV associated with peripheral neuropathies ranging from neuropathic pain to ascending paraly­sis (Guillain-Barré-type syndrome)

Hepatobiliary disease: most worrisome complication in HAART era coinfection with hepatitis B virus (HBV) and hepatitis C virus (HCV); felt that HIV causes acceleration to cirrhosis in coinfected patients; difficulty seen in man­aging patients with both diseases on ART; often shorter time to AIDS-defining illnesses; all ART, especially nevi­rapine, associated with liver toxicity; in patient with isolated increase in serum transaminases, differential diagnosis includes hepatitis A virus, HBV, or HCV infection, adverse effects of ART, ethanol or substance abuse, opportunis­tic infections, and IRS; isolated indirect hyperbilirubinemia benign side effect of atazanavir and indinavir, but re­quires monitoring to determine whether change in dosage necessary; direct hyperbilirubinemia and elevated alkaline phosphatase greater cause for concern and may indicate cholangiopathy secondary to Cryptosporidium parvum; frank liver failure with elevated international normalized ratio and synthetic dysfunction nearly always due to HBV, HCV, nevirapine toxicity, or cholangiopathy

Malignancies: with HAART, incidence of Kaposi’s sarcoma decreased, but incidence of Hodgkin’s lymphoma, lung cancer, and anal cancer have increased; unclear whether due to aging or adverse effect of long-term HAART; no change in incidence of human papillomavirus (HPV) infection in HIV population, despite HAART; HIV patients who present with anal condylomata or HPV-related illness require urgent follow-up for malignancy screening

Psychiatric illness: depression and demoralization extremely common in HIV patients and significant factors in compliance; AIDS mania more common in pre-HAART era (late-stage finding associated with AIDS dementia); efavirenz  —NNRTI; one of most common first-line HAART agents; common early side effects include nightmares and irritability; psychosis not uncommon side effect (requires discontinuation of drug); most psychiatric side ef­fects resolve within 4 wk of discontinuation

Musculoskeletal disease: osteoporosis and osteonecrosis commonly seen with HAART; previously believed to be side effect of ART, but now considered side effect of long-term HIV illness itself with increased longevity; lumbo­sacral spine most commonly affected; hip fractures not uncommon in, eg, 45-yr-old HIV patient

Dermatologic disease: most common clinical ailment in HIV patients; significant factor in compliance; bacterial fol­liculitis, drug reactions, scabies, seborrheic dermatitis, and warts most common; abacavir hypersensitivity  —  associated with fever and hypotension; elevated creatine kinase with “shock liver” picture and lymphopenia; treat­ment supportive, but admission to hospital necessary; laboratory test available for specific HLA serotype associated with abacavir toxicity

Suggested Reading

Côté HC et al: Changes in mitochondrial DNA as a marker of nucleoside toxicity in HIV-infected patients. N Engl J Med 346:811, 2002; d'Arminio Monforte A et al: Decreasing incidence of CNS AIDS-defining events associated with antiretroviral therapy. Neu­rology 54:1856, 2000; Martin DF et al: Valganciclovir Study Group. A controlled trial of valganciclovir as induction therapy for cy­tomegalovirus retinitis. N Engl J Med 346:1119, 2002; Erratum in N Engl J Med 347:862, 2002;  Monier PL et al: Metabolic complications associated with the use of highly active antiretroviral therapy in HIV-1-infected adults. Am J Med Sci 328:48, 2004; Morse CG et al: Metabolic and skeletal complications of HIV infection: the price of success. JAMA 296:844, 2006; Paramsothy P et al: The effect of highly active antiretroviral therapy on human papillomavirus clearance and cervical cytology. Obstet Gynecol 113:26, 2009; Strategies for Management of Antiretroviral Therapy (SMART) Study Group et al: CD4+ count-guided inter­ruption of antiretroviral treatment. N Engl J Med 355:2283, 2006; Tremont-Lukats IW et al: The immune inflammatory reconstitu­tion syndrome and central nervous system toxoplasmosis. Ann Intern Med 150:656, 2009; Weber R et al: Liver-related deaths in persons infected with the human immunodeficiency virus: the D:A:D study. Arch Intern Med 166:1632, 2006; Whitcup SM: Cyto­megalovirus retinitis in the era of highly active antiretroviral therapy. JAMA 283:653, 2000; Wolff AJ et al: Pulmonary manifesta­tions of HIV infection in the era of highly active antiretroviral therapy. Chest 120:1888, 2001.

Internet Resources

www.aidsmeds.com 
www.hivinsite.com 
www.epocrates.com 
www.EDHIVtestguide.org

www.nccu.ucsf.edu/statelaws