Table of contents
.
Introduction
- 1 million infected in US (1/3 unaware of diagnosis).
- Transmission:
- Spread through sexual content
- Contaminated blood (IVDU, occpational, tranfusion)
- Perinatally
- Risk Factors:
- MSM
- IDU sharing needles
- Immigrants from countries with high HIV prevalence (African)
- Sex and drugs (ETOH, ectasy, cocaine)
- Group Sex
- Traumatic intercourse (raping)
- Transfusions before 1985 (consider before 1991)
- Other STIs
- Prophylaxis:
- Pre-Exposure Prophylaxis: In 2012, FDA approved Emtricitabine/Tenofovir Disoproxil Fumarate for pre-exposure prophylaxis.
- Contraindicated for unknown or positive HIV status (causes resistance)
- Post-Exposure prophylaxis
- Standard for occupational exposure, and sometimes sexual.
- Pre-Exposure Prophylaxis: In 2012, FDA approved Emtricitabine/Tenofovir Disoproxil Fumarate for pre-exposure prophylaxis.
- Pathophysiology:
- HIV is a retrovirus infects CD4 cells (T-helper lymphocytes), replicate, integrade into genome.
- Descrution of CD4 cells leads to immunocompromised (90% of patients).
- HIV is a retrovirus infects CD4 cells (T-helper lymphocytes), replicate, integrade into genome.
Symp toms:
-
Acute Retroviral Syndrome (ARS) Chronic HIV Symptoms 96% - Fever
74% - Lymphadenopathy
70% - Pharyngitis + Rash
54% - Myalgia + Arthralgia
33% - Diarrhea / Headache
27% - Nausea/Vomiting
14% - HSM
12% - Wt loss , thrush, neuro symptoms
- Lymphadenopathy
- B-Sx: Fever, Night Sweats / Fatigue / Wt Loss
- Chronic diarrhea
- Skin: Seborrheic Dermatitis, Tinea, Onycomycosis
Oral aphthous ulcers, Oral hairy leukoplakia,
Gingivitis/periodontitis
- Neuro: Peripheral Neuropathy
- Blood: Anemia, Leukopenia, Thrombocytopenia
- Nephropathy
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
- Development of "indicator" opportunistic infections or malignancies
-
- Prior to progression patients can get common infections that don't quality as "opportunistic", but prolongued or severe:
Screening
- Center of Disease Control and Prevention in 2006 - widens testing, reduction of barriers of testing.
- All 13-64yo pts recommended to be tested at least once (unless prevalence < 0.1% in the region)
- Some guidelines expand to 75 years.
- Risk Factors: (Should undergo annual testing)
- IVDU and their sex partners
- Pts who exchange sex for money or drugs
- Sex partners of HIV infected ppl
- Men Sex with Men
- Patients who have had more than one sex partner since last HIV test
- Also Screen:
- Pregnant women, early in pregnancy.
- Now at-home rapid HIV test approved (uses swabs or oral fluid from upper/lower gums for antibodies)
- All results must be confirmed in office (due to window period), even if negative, repeat in 3 mo.
Diagnosis
-
Two stage serologic testing:
1. Initial: Enzyme ImmunoAssay (EIA)
(NEGATIVE EIA = enough to exclude HIV except in window period before seroconversion).
- If negative, repeat in 6-12w once seroconversion is established.
- If diagnosis during acute infection required: do quantitative PCR.
Use of viral load as a routine diagnostic test is discouraged. (poor during low viral load, and $$$).
2. Confirmatory: Western Blot Assay (Sn 99.5%, Sp 99.99%)
- Negative Western Blot = false positive EIA
- Indeterminate WB Assay = Presence of antibody bands to certain viral antigens
but insufficient to establish dx.(can happen during actute infection during low Ab levels)
- Repeated Indeterminate = Cross-reacting antibody (to another antigen).
- Quantitative RNA PCR (Viral Load) - Useful during Acute Retroviral Syndrome, but discouraged as a general diagnostic
test. (Poor test when viral load is low duing chronic infection).
- Rapid HIV tests now available in kits (EIA tests)
- Positive results require standard follow-up confirmatory testing.
- NEVER appropriate to tell the patient they have HIV based on EIA alone (without confirming with Western Blot).
- Indications For HIV testing: Symptoms, Opportunistic Infection, severe/recurrent infection (non-opportunistic), TB, HBV, HCV, other STI, hemophilia, high-risk behaviour, persons 13-64 (unless <0.1% prevalence) , known/suspected HIV exposure, sexual assault, patient request, all pregnant women, child born to mother HIV+, occupational exposure, Blood/semen/organ donor.
Evaluation
- Complete history (social, sexual), phyisical exam (signs/symptoms of opportunistic infections), counselling (prevention/transmissino).
- Lab Tests Indicated for new diagnosis:
- Repeat HIV ab if no documentation
- Viral resistance testing (NEW recommendtion) - guides ART
- Viral load (HIV RNA PCR), CD4 count - Determines stage of Infection
- Health Status: CBC+Diff, chemistry (incl, creatinine, fasting glucose), Liver (chemistry, enzymes), serum lipids,
- Co-Infection: TB skin test or IGRA, Pap test, Toxoplasma serology, Varicella/CMV serology for high risk.
- Co-Infection: Hep B/C, Syphilis serology +/- other STI
Treatment
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:
- Exclude MAC (clinically and negative blood cultures)
- (prophylaxis not effective in treatment, azithro resistance can emerge).
- 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 IGRATuberculosis 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
- NEW GUIDELINE --> INDICATED FOR ALL PATIENTS UNLESS THERE IS A CONTRAINDICATION
- 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
-
Pregnant Patients
- HIV testing appropriate for all pregnant women.
- 1 in 4 chance of acquiring HIV perinatally if ART not given.
- ART reduces transmission 25% to <2%.
- Can be transmitted through breast milk, mothers SHOULD NOT breastfeed infants, if alternative is available.
- Preferred ART:
- Zidovudine, lamivudine and lopinavir/ritonavir
- NOTE: Efavirenz is teratogenic, avoid in pregnancy!
- After delivery - same indications as non-pregnant adults.
- Zidovudine, lamivudine and lopinavir/ritonavir
Treatment Compliations
- Metabolic:
- 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.
-
- 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).
- Changes in body fat distribution -
- Mitochondrial toxicity - leading to lactic acidosis.
- Can be fatal.
- Decreased with replacement of stavudine, zidovudine, didanosine with lamivudine or emtricitabine and tenofovir.
- Osteopenia/ Osteoporosis - Due to HIV infection.
- DEXA scan only recommended in >50yo or other risk factors.
- CKD - HIV Associated Nephropathy
- Can be reversed with tx of HIV (if found early).
- May require transplant/dialysis.
- 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.
- Hyperlipidemia / Insulin Resistance
- 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.
- 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.
Opportunistic Infections
- Unlikely with CD4 >200 uL (threshold value used to define AIDs).
-
CD4 Count Treatment Oral Candidiasis CD4 < 200 - Risk Factors (inhaled corticosteroids, esophageal candidiasis)
Extension to esophageal candidiasis occurs often in AIDs).
- Diagnosis: inspection (whitish plaques on oral mucosa).
- Dysphagia or swallowing issues = esophageal candidiasis.
Oral Candidiasis:
Topical Agents: clotrimazole
nystatin.
Esophageal Candidiasis:
Need systemic agent
(fluconazole)
Crytococcal
Infection
(Cryptococcal
meningitis or lung
Infections)
Cryptococcal
Meningitis:
Typically
CD4 <100
(can do higher
counts)
- Starts in lung, rarely presents until disseminated
(meninges or skin)- Subacute/chronic presentation (headaches, changes in
MS, systemic sx - fever, nt sweats, wt loss).- Focal neuro deficits: cranial nerves common.
- Diagnosis: culture or cryptococcal antigen test in
CSF or serum.- Induction therapy with
Amphotericin B,
deoxycholate
OR lipid formulation of
AmpB combined with
flucytosine.
- Consolidation therapy:
fluconazole
- Monitor ICP!!! high
mortality, blindness.Pneumocystis
Jirovecii PneumoniaCD4 < 200 - Dyspnea, dry cough, fever.
- CXR - diffuse bilateral interstitial/alveolar infiltrates.
(classically middle-lung fields with cysts, but highly variable)- Diagnosis: Stains for organism in sputum or BAL fluid
Treatment: High dose
TMP/SMX
- Steroids if arterial
PaO2 <70mmHg on RA.
or A-a gradient >35mmHg
Toxoplasma
gondii
(Encephalitis)
CD4 < 100 - Protozoan (intracellular) transmitted with ingestion of
undercooked meat or exposure to cat feces.
- Encephalitis
- Symptoms: fever, headache, focal neuro deficits, seizure
- Contrast CT or MRI - multiple ring-enhancing lesions
MRI is modality of choice- high sensitivity (differentiates
toxo from other infections and CNS lymphoma).
Treatment: empiric
pyrimethamine +
sulfadiaizine
OR
pyrimethamine + clinda
OR
TMP/SMX
- Clinical + radiologic
response in 1-2w
Tuberculosis
- Likely to be extra-pulmonary
- Atypical CXR findings, (i.e. not upper lobes)
- Treatment is complicated
because interactions with
ART meds.
- Often involves rifabutin
instead of rifambin.
Mycobacterium
Avirum Complex
(MAC)
CD4 < 50 - Presents with fever, sweats, wt loss, lymphadenopathy,
hepatosplenomegaly, cytopenia.
- Mycobacterial blood cultures usually positive.
- Macrolide-based treatment
(Clarithromycin or
Azithromycin)
Cytomegalovirus
(CMV)
CD4 < 50 - GI involvement: esophageal and colonic ulcers
(can be anywhere in GI tract)- CNS involvement: encephalitis, polyradiculitis
- CMV Retinitis: most common presentation prior to ART
Now only in those patients not responding to ART
- Present with floaters, but eventually blindness.
- URGENT optho exam
- Ganciclovir, valganciclovir,
foscarnet
(esp for CMV retinitis).
Molluscum
contaginosum
- Caused by pox virus
- Dome shaped papules with central umbilication (face/neck)
- Resolve with ART Bacillary
angiomatosis
- Bartonella infection (most common presentation).
- Skin lesions (often confused with Kaposi sarcoma).
HHV-8
Kaposi sarcoma
- Red, purple, brown macules, papules plaques, nodules
on the skin or mucous membranes.
- Primarily in Men-Sex-With-Men group (rare in others)
Comments