HIV

Acute Retroviral Syndrome

• Seen in 90% of infected pts, most undiagnosed. 
• Described as acute symptomatic illness can start days to 2-4w post-exposure.  Accurate Dx not always established.
• Symptoms last 2-3w, anywhere from simple febrile illness to full-blown mononucleosis-type syndrome.
  • See above.
  • Generally fever, arthralgias, myalgias, headache, rash, pharyngitis, oral and/or genital ulcers.
  • Infection resolves after a few weeks, and is followed by asymptomatic period. 
• During this phase:
  • Lack of immune response, viral levels very high, VERY INFECTIOUS.
  • Symptoms resolve spontaneously.
  • This is also called the "window period", where seroconversion has not yet happened.
  • Results of HIV antibody testing negative, but viral specific test such as PCR are positive at high levels = establishes dx.
  • Benefit of beginning of antiretroviral therapy (ART) not proved, but theoretical.

Chronic HIV Infection

• Period of years of symptomatic infection occurs --> depletion of CD4 T-lymphocytes progresses.
• AIDs
  • Prior to progression patients can get common infections that don't quality as "opportunistic", but prolongued or severe:
    • Recurrent or refractory vaginal candidiasis.
    • Severe oral/genital HSV infection.
    • Herpes zoster infection
    • Pneumococcal pneumonia
  • Diagnosis of AIDS:

    • Diagnosis of AIDS:   Development of "indicator" opportunistic infections or malignancies OR CD4 count drops to < 200 / uL

Prevention of Complications

• All patients with HIV should get following vaccines: (as indicated for general public)
  • Pneumococcal polysaccharide
  • Hep B vaccine (3 doses) if not immune
  • Annual Influenza
  • Tetanus, Diptheria, Acellular pretussus
  • HepA
  • HPV
  • Meningicoccal
• AVOID Live Virus Vaccines:
  • MMR
  • Varicella  (studies ongoing for HIV+ and high CD4 counts).
• All HIV patients need:

1. Exclude MAC (clinically and negative blood cultures)

• (prophylaxis not effective in treatment, azithro resistance can emerge).

2. Tuberculin skin test or IGRA

• Check TB Skin Test (>5cm = positive) or positive IGRA  = INH 300mg/day x9mo.

Opportunistic Prophylaxis:

• Indication	Opportunistic Infection	Preferred Drug
  CD4 < 200/uL	Pneumocystis jirovecii Candidiasis (oral/esopageal)	TMP/SMX double-strength OD or 3x/week
  CD4 < 100/uL	Toxoplasmosis (but need positive serology) Cryptococcus (meningitis risk) Histoplasma (Not in Canada)	TMP/SMX, double strenght OD
  CD4 < 50	Mycobacterium avium complex (MAC) CMV	Azithromycin 1200 mg/week  (Cover MAC)
  TST > 5mm or positive IGRA	Tuberculosis	INH 300 mg/d for 9 months

Anti-Retroviral Therapy

• Treatment transformed from uniformly fatal infection into a manageable chronic disease.
• New Guidelines: Treat all irregardless of CD4 count.  (used to be 350/uL then 500/uL, viral loads etc.)
• Highly Active Anti-Retroviral Therapy (HAART)
• • Term used initlaly to differentiate  more aggressive multiple drug therapy (from single/double that was standard).
  • But now HAART = ART now. (now standard of care).
• Baseline resistance testing is standard of care, to guide choice of agents and in treatment failure(suboptimal control of viral load)
  • Need >500 copies/mL of blood for resistance testing.
  • Do not need to stop ART to do repeat resistance testing (need selective pressure).
• When to initiate treatment?
  • NEW GUIDELINE --> INDICATED FOR ALL PATIENTS UNLESS THERE IS A CONTRAINDICATION
    • Early Treatment Benefit demonstrated, start as early as possible!
    • Previous indications:
      • History of AIDS-definine opportunistic infection
      • Symptomatic HIV or HIV nephropathy
      • CD4 count <500/uL
      • Active co-infection with HepB/C
      • Pregnancy to prevent perinatal transmission
• Newest drug regimens are published at www.aidsinfo.nih.gov
• Objective: fully suppress viral replication to prevent development of drug resistance. --> to make viral load = undetectable.
  • Must discuss adherence!!! (difficult!!)
• Treatment Regimens:
  • At least 3 drugs from at least 2 different classes.
  • Current drug regimen (2014):
    • Two NARTI (Tenofovir, Emtricitabine) + NNRTI (Efaverenz) = once daily combination pill.
    • Combination pill improves adherence and effectiveness.
    • Caution = neural tube defects in pregnancy (avoid in women high risk of pregnancy).  Substitude Efaverenz with integrase inhibitor (Raltegravir) or protease inhibitor (Atazanavir or Duranavir).
      • Protease inhibitors given with small dose of ritonavir (boosts drug levels of protease inhibitors, rather than anti-retroviral itself - inhibits CYP450, improves drug levels, effectiveness, tolerability of others.). 
• UNDER CONSTRUCTION

  • Category	Drug	Notes
    NARTI (Nucleoside analog reverse transcriptase inhibitor aka NARTIs)	Stavudine	- Causes changes in fat distribution. - Can cause mitochondrial toxicity--> fatal lactic acidosis - Not used as often anymore.
    	Zidovudine - Pregnancy
    	Didanosine	- lactic acidosis (can be fatal)
    	Lamivudine - Pregnancy	- newer
    	Emtricitabine - Common	- newer
    	Tenofovir - Common	- Rare Fanconi syndrome.
    	Abacavir
    NNRTI (Nonnucleoside RTI's)	Efavirenz - Common	Neural tube defects in pregnancy, AVOID
    	Etravirine
    	Nevirapine
    	Rilpivirine
    Protease Inhibitors	Atazanavir Duranavir Fosamprenavir Indinavir Lopinavir - Pregnancy Nelfinavir Ritonavir - Pregnancy Saquinavir Tipranavir	Atazanavir - avoid PPI's. ALL protease inhibitors - avoid lovastatin and simvastatin   (HIV on ART = pravastatin is statin of choice).
    Entry Inhibitors	Enfuvirtide Maraviroc
    Integrase Inhibitor	Raltegravir

Treatment Compliations

1. Metabolic:
   1. Hyperlipidemia / Insulin Resistance

      • Lab Value	HIV Infection	ART
        Total Cholesterol	Decrease	Increases
        LDL	Decrease	Increases
        HDL	Decrease	Remains decreased
        Triglycerides	Increase	Remains increased

      • Protease inhibitors are especially associated with hyperlipidemia.
      • Atorvastatin is effective in decreasing hyperlipidemia, however it interacts with protease inhibitor Ritonavir.
        • Start at LOWER doses
      • Insulin resistance develops or worsens in HIV infection.
      • Must measure Fasting Lipids, glucose, HbA1c with every initiation or change in ART.  And needs periodic followup.
   2. Body fat redistribution, lipid dystrophy
      • Changes in body fat distribution -
        • Truncal and visceral fat accumulation.
        • Loss of sucutaneous fat in face and extremities.
      • Decrease fat mobilization by avoiding thymidine analogue reverse transcriptase inhibitors (stavudine, zidovudine).
   3. Mitochondrial toxicity - leading to lactic acidosis.
      • Can be fatal.
      • Decreased with replacement of stavudine, zidovudine, didanosine with lamivudine or emtricitabine and tenofovir.
   4. Osteopenia/ Osteoporosis - Due to HIV infection.
      • DEXA scan only recommended in >50yo  or other risk factors.
   5. CKD - HIV Associated Nephropathy
      • Can be reversed with tx of HIV (if found early).
      • May require transplant/dialysis.
   6. Liver Disease - High prevalence of co-infection with HepB/C
      • Can have regimens against both HIV and HepB.
      • Concurrent HIV / HepC infection --> high risk of progression to liver disease.
2. Cardiovascular Disease
   • Due to HIV infection as well as ART.
   • SMART studyrandomized pts w/ CD4 > 350/uL to continue ART vs. CD4-cell count guided treatment interruptions.  Pts in treatment interruptions arm had more infections, more cardiovascular disease, and death. (Early termination).
     • Demonstrated that increase in CVD caused by metabolic s/e of treatment is more than offset by risk reduction of what it would be with uncontrolled HIV infection.
     • This increased risk is thought to be due to ongoing inflammation --> increases risk of atherosclerosis.
   • Focus on modifiable CV risk factors: smoking, hyperlipemia, HTN, DMII.
3. Immune Reconstitution Inflammatory Syndrome (IRIS)
   • With initiation of ART, viral load falls sharply, CD4 counts increase quickly, and immune response is improved.
   • Presence of opportunistic infection that hasn't been previously recognized.
     • Most commonly MAC, TB, or disseminated fungemia.
   • Reconstituted immune system reacts drastically to the high burdens of antigens --> IRIS.
   • This occurs few weeks to few months after ART is initiated.
   • Treatment:
     • CONTINUE treatment.
     • Corticosteroids to moderate excessive inflammation.