First Things First (assess the following)

• Human immune deficiency virus (HIV) infection leads to the disease acquired immune deficiency syndrome (AIDS). An HIV-positive test does not mean the person has AIDS.
• AIDS is defined by a CD4+ T-cell count of < 200/mm3 or the presence of an AIDS indicator condition (opportunistic infections or malignancies defined by the CDC; see www.CDC.gov for complete listing).
• Determine the stage of HIV infection.
  • Incubation period: The patient becomes infected and develops HIV antibodies, but is asymptomatic. An HIV test result that detects antibodies can be falsely negative during this time period, which lasts 2-4 weeks.
  • Acute infection: Seroconversion with production of HIV antibodies; flu-like symptoms and swollen glands develop. Symptoms last for about 1 month.
  • Latency period: variable symptom-free periods up to 20 years
• For immune reconstitution inflammatory syndrome (IRIS)
  • Diagnosis of AIDS
  • Treatment with HAART medications
  • Symptoms consistent with an infectious or inflammatory condition that appeared while on antiretroviral therapy
  • Symptoms that cannot be explained by a newly acquired infection or by the expected clinical course of the disease or side effects of therapy

History and Physical (assess for the following)

• Symptoms
  • Dry or productive cough
  • Dyspnea on exertion
  • Dysphagia
  • Unintentional weight loss
  • Recurrent fevers and night sweats
  • Diarrhea
  • Neurological symptoms including memory loss
• Signs
  • Oral ulcers
  • Oral candidiasis
  • Purple skin lesions
  • Lymphadenopathy
  • Lung consolidation
  • Mental status changes
  • Visual changes
  • Hypotension

Diagnostic Tests

HIV/AIDS/IRIS

• HIV
  • ELISA (enzyme-linked immunosorbent assay) to detect HIV-1 antibodies. Positive test results lead to duplicate ELISA testing.
  • Western blot is the confirmatory test. If it is indeterminate, the patient may be infected and have an incomplete antibody response or is uninfected and has a nonspecific response. A repeat test should be performed 1 month later.
  • Viral RNA nucleic acid testing
• For underlying infection
  • CXR
  • Blood cultures
  • Sputum DFA and cultures
  • Bronchoscopy
  • EGD
  • Liver function tests
  • Cerebral MRI or CT
  • CBC
  • Cortical level
  • Aldosterone level

Abnormalities commonly seen in patients with HIV on HAART therapy

• Macrocytosis
  • A normal finding with zidovudine, stavudine, or tenofovir therapy, provided there are no hypersegmented polymorphonuclear leukocytes

• Hyperbilirubinemia
  • Mild indirect hyperbilirubinemia in patients on atazanavir or indinavir
• Hyperuricemia
  • Hyperuricemia in patients taking didanosine

• CPK
  • Elevations of creatinine phosphokinase in patients taking zidovudine or tenofovir, but may reflect clinical myositis
• Hyponatremia
  • Hyponatremia is relatively common and well tolerated in advanced HIV infection, but frank adrenal insufficiency or isolated hypoaldosteronism may require specific diagnosis and management.

General Management Principles

• No cure
• HAART (highly active antiretroviral therapy) recommended if CD+4 ≤350: three-drug regimens consisting of 2 classes of antiretroviral agents
  • NARTIs (nucleoside analogue reverse transcriptase inhibitors) plus either
    
    • Protease inhibitor
    • NNRTI (non-nucleoside reverse transcriptase inhibitor)
  • Entry inhibitors: used in resistant cases
• Life expectancy is increased up to 30 years if HIV treatment is started before AIDS develops. Without HAART therapy, AIDS development from HIV occurs at a median of 10 years and the median survival time is estimated to be < 1 year.
• Non-adherence to HAART regimens: due to dosing frequency, quantity of pills and side effects
• Side effects:
  • Lipodystrophy
  • Hyperlipidemia
  • Insulin resistance
  • Rapid coronary artery disease development
• Bone marrow transplant in leukemia patients with a compatible donor possessing the CCR5-Δ32 mutation, which offers resistance to HIV

Prevention

• HIV
  • Universal precaution application by medical personnel to treat each patient as if s/he is HIV infected by using proper barrier techniques: latex gloves, aseptic techniques and proper sharps disposal
  • Post-exposure prophylaxis
    • Flush mucous membranes with water.
    • Wash skin wounds with soap and water.
    • Start medications within 72 hours after known exposure to reduce risk of seroconversion
      • Zidovudine, 600 mg per day in divided doses + lamivudine 150 mg bid (or Combivir™, one tablet bid )
      • Lamivudine 150 mg bid + stavudine 40 mg bid
    • Repeat HIV antibody testing at 6 weeks, 3 months and 6 months
  • Vaccines (not available yet)

Opportunistic infections in patients with AIDS

• Pneumocystis CD4+ < 200:
  • Trimethoprim-sulfamethoxazole Bactrim-DS
  • Aerosolized pentamidine
  • Dapsone
• Toxoplasma gondii CD4+ < 100:
  • Bactrim-DS
  • Dapsone-pyrimethamine
• Mycobacterium avium intracellulare (MAC) CD4+ < 50:
  • Clarithromycin
  • Rifabutin
• Streptococcus pneumoniae CD4+ >200:
  • Polysaccharide pneumococcal vaccine
• Cytomegalovirus CD4+ < 50 and CMV+:
  • Ganciclovir

Specific Treatment

Most commonly seen for respiratory failure

• Non-opportunistic pathogens (Streptococcus pneumoniae, Haemophilus influenzae, Pseudomonas, Staphylococcus aureus)
  • Symptoms of bacterial pneumonia
    • Pleuritic chest pain
    • Productive cough
    • Rigors
  • Signs
    • Fever
    • Tachypnea
    • Tachycardia
    • Rales
  • Laboratory and diagnostic studies
    • Preserved CD4+ counts
    • CXR lobar consolidation
    • Blood cultures
    • WBC count
    • Sputum Gram stain and cultures

• Opportunistic pathogens (Pneumocystis jiroveci [formerly carinii])
  • Symptoms
    • Progressive dyspnea
    • Nonproductive cough
    • High fevers
  • Signs
    • Hypoxemia
    • Crackles
  • Laboratory and diagnostic studies
    • CD+4 < 200 cells/ul
    • Elevated LDH >500 mg/dl
    • CXR typically shows diffuse symmetrical interstitial infiltrates; cysts in the upper lobes are common as is pneumothorax.
    • Chest CT shows ground glass attenuation.
    • Gallium scans show increased pulmonary uptake.
    • Bronchoalveolar lavage for direct immunofluorescent staining is needed for definitive diagnosis.
  • Treatment for 21 days with:
    • Trimethoprim-sulfamethoxazole
    • Primaquine and clindamycin
    • Pentamidine
    • Atovaquone
    • Trimetrexate with leucovorin rescue therapy
  • If associated with room air PaO2 < 70 mm Hg, steroids should be started.
    • Days 1-5: Prednisone 40 mg bid
    • Days 6-10: Prednisone 40 mg daily
    • Days 11-21: Prednisone 20 mg daily
    • IV methylprednisolone at 75% of the prescribed prednisone dose may be used.
  • Severe hypoxemia leading to ventilator support requirement has poor prognosis, with 60% mortality.
  • Stop or start HAART therapy due to synergistic toxicities and possibility for immune reconstitution syndrome.
    • Mycobacterium tuberculosis 
    • Cytomegalovirus
    • Aspergillus 
    • Endemic fungi

End-stage liver disease

• Hepatitis C is a major cause of mortality.
• Eight-fold increase in HCV infection compared with non-HIV-infected individuals
• Co-infection of HCV and HIV results in four-fold increased risk of cirrhosis development than those with HCV alone. Management of co-infection with HIV and HCV involves two separate combination drug regimens with interactions and overlapping toxicities, administered for at least 6 and often 12 months. Such therapy requires close supervision by experienced personnel and may, in fact, exacerbate liver dysfunction in cases of decompensated cirrhosis.

Sepsis from Salmonella or chemotherapy-related

Life-threatening complications of HAART drug toxicity

• Direct effects
  
  • NRTIs may cause severe lactic acidosis with lactic acid levels >5 mmol/uL.
    • Severe lactic acidosis mandates that anti-retroviral therapy be stopped immediately until the cause is identified (sepsis, toxicity) and empiric antibiotics started.
    • Continuation of partial anti-retroviral therapy may lead to resistance.
  • NRTIs can cause severe pancreatitis.
    • 1.5% of patients treated with abacavir develop hypersensitivity reactions within a few weeks, and re-exposure to this agent often leads to life-threatening anaphylaxis.
• Indirect effects: immune reconstitution syndrome (IRS)
  • Inhibits viral replication
  • Increased number of T cells (both memory and naïve)
  • Increased IL-2 receptor expression
  • Enhanced lymphoproliferative responses
  • Leads to exacerbation of underlying opportunistic infections, and syndrome should be considered in any patient with worsening symptoms who has recently been started on HAART

Acute renal failure

Acute coronary syndrome(s)

Gastrointestinal bleeding

• CMV colitis
  • Symptoms
    • Weight loss
    • Anorexia
    • Abdominal pain
• Signs
  • Fever
  • Severe diarrhea
  • Abdominal perforation
  • Gastrointestinal hemorrhage

Meningitis

• Cryptococcus neoformans
  • Symptoms
    • Headache
    • Mental status changes
  • Signs
    • Fever
    • Photophobia
  • Laboratory and diagnostic studies
    • CD4+ cell count < 50 cells/ul
    • CSF cryptococcal antigen
    • Positive blood cultures
  • Treatment for 2 weeks with amphotericin B + flucytosine; 8 weeks fluconazole

Encephalitis

• Toxoplasma gondii
  • Symptoms
    • Headache
    • Confusion
    • Fever
  • Signs
    • Focal neurologic defects
    • Seizures
    • Mental status changes
  • Laboratory and diagnostic studies
    • CD4+ cell count < 50 cells/ul
    • CT/MRI show contrast-enhancing lesions
    • Anti-Toxoplasma IgG antibodies
    • Brain biopsy to detect organism with hematoxylin and eosin stains if empiric therapy fails
  • Treatment for 6 weeks with
    • Pyrimethamine + sulfadiazine + leucovorin
    • Pyrimethamine + clindamycin + leucovorin
    • Anticonvulsants for seizures only during acute therapy

Retinitis

• CMV
  • Symptoms: unilateral visual disturbance
  • Signs
    • Peripheral field defects
    • Central field defects
  • Laboratory and diagnostic studies
    • CD4+ cell count < 50 cells/ul
    • Retinal changes on ophthalmologic exam
  • Treatment for 4 weeks with:
    • Valganciclovir
    • Ganciclovir
    • Foscarnet

Malignancy

Ongoing Assessment

• Follow balance between:
  • HAART continuation during ICU stay
  • HAART discontinuation during ICU stay
• Reduction in doses due to drug interactions in the ICU can lead to resistance for future HAART therapy.
  • Discussion of code status

Complications

• Related to specific drug therapies
  • HAART—see above
  • Trimethoprim-sulfamethoxazole
    • Hyperkalemia
    • Stevens-Johnson syndrome
    • Thrombocytopenia
    • Azotemia
  • Dapsone: methemoglobinemia
  • Primaquine: hemolysis
  • Pentamidine
    • Hyperglycemia
    • Pancreatitis
  • Atovaquone
    • Headache
    • Nausea
    • Transaminase elevation
    • Diarrhea
  • Trimetrexate
    • Bone marrow suppression
    • Hepatitis
• Drug interactions with HAART
  • Azoles
  • Benzodiazepines
  • Calcium channel blockers
• HAART in the ICU
  • Antiretrovirals are available only in oral tablet form, which makes the pharmacokinetics unpredictable.
  • Antiretrovirals are metabolized by the p450 cytochrome enzyme system, which alters the metabolism of many drugs.
  • A few days of suboptimal therapy can lead to irreversible drug resistance.

Authors

• Larry Lindenbaum, MD, and Sylvia Y. Dolinski, MD