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HIV
Shelly Ritter, M.D.
ARGY Resident
HIV/AIDS - History
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Cases of Pneumocystis carinii (now jarovecii)
pneumonia and Kaposi’s sarcoma first noticed in
homosexual males in 1981.
The responsible retrovirus was discovered in 1983.
Serologic testing was started in 1985.
Anti-retroviral therapy was first started in 1987.
Combination anti-retroviral therapy (Highly Active
Antiretroviral Therapy – HAART) in 1996.
Epidemiology of HIV
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59 million people have been infected
worldwide, with 20 million dead.
About 405,926 people living with HIV in U.S.
in 2003.
64% of people with HIV are living in subSaharan Africa
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though Sub-Saharan Africans only make up 10%
of world population
Human Immunodeficiency Virus
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An RNA retrovirus – subfamily Lentivirus
Contains:
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2 copies of RNA
Enzymes:
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Reverse Transcriptase
Integrase
Protease
Two major envelope proteins:
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gp120
gp41
Life Cycle of HIV virus
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Interaction between viral envelope proteins and CD4
receptor and co-receptors leads to binding of the viral
envelope and host cytoplasmic membrane
Viral reverse transcriptase catalyses the conversion of viral
RNA into DNA
Proviral DNA enters the nucleus and becomes integrated
into chromosomal DNA of host cell (catalyzed by integrase)
Expression of viral genes leads to production of viral RNA
and proteins.
Protease enzyme cleaves proteins into functional mature
products.
Viral proteins and viral RNA are assembled at the cell
surface into the new viral particles and leave the host
through budding.
Human Immunodeficiency Virus –
Lifecycle in Host Cell
Human Immunodeficiency Virus – Life
Cycle in Host Cell
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HIV tends to infect CD4+ T Cells, because CD4
receptor has high affinity for gp120 (HIV viralenvelope protein)
CD4+ T Cells initially die in acute phase due to
cytopathologic damage by virus.
CD4+ T Cells then chronically die from:
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Chronic activation of T cells
Inhibition of thymic output of T cells
Suppression of the bone marrow
Destruction of lymph-node architecture
Low-level ongoing infection of memory CD4+ T cells
Diagnosis of HIV
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HIV antibody ELISA – if positive, is always followed by a confirmatory
Western Blot
Rapid HIV antibody test
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Sensitivity and Specificity 99%!
Results in 5 to 40 minutes usually
Used in:
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HIV viral load
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Occupational Exposure
Pregnant women presenting in labor with no previous HIV testing
Patients who are unlikely to return for results of HIV test
First choice for diagnosing possible acute HIV
HIV p24 Antigen
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Is the first antigen to be elevated in acute HIV
Can be used for diagnosis of primary (acute) HIV
Human Immunodeficiency Virus –
Stages of Infection
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Viral Transmission
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Sexual intercourse, exposure to contaminated blood, or perinatal transmission
In U.S., 50% of cases due to male-to-male transmission.
Worldwide, 70-80% caused by vaginal sex, perinatal transmision is 5-10%, and IV drug use is 510%.
Acute HIV Infection
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A transient, symptomatic period shortly following infection with HIV virus, associated with a high
HIV-viral load and robust immune response.
Occurs in 40-90% of new HIV infections.
Symptoms usually develop in days to weeks after initial infection
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Patient has positive HIV antibody test
Usually occurs 4 to 10 weeks after infection.
Chronic/Latent HIV disease
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HIV antibody will be negative at this point – need to check HIV viral load or p24 antigen level!
Seroconversion
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Include fever, lymphadenopathy, rash, pharyngitis, headache (aseptic meningitis)
Viral load tends to increase slowly, CD4 count decreases slowly
“Chronic non-progressors” tend to have little/no decrease in CD4 count
Early Symptomatic HIV Infection
AIDS
HIV- Early Symptomatic Infection
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Includes:
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Thrush
Persistent vaginal candidiasis
Fever
Diarrhea
Oral Hairy Leukoplakia
Herpes Zoster
Bacillary Angiomatosis
Cervical dysplasia/carcinoma in situ
Peripheral neuropathy
Pelvic inflammatory Disease
Thrush
If plaques wiped off with gauze, erythematous, often bleeding mucosa will be
revealed.
Oral Hairy Leukoplakia
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Associated with EBV infection
Does not rub off.
Bacillary Angiomatosis
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Caused by Bartonella species
Herpes Zoster
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“Shingles”
Caused by Varicella
Acquired Immunodeficiency
Syndrome (AIDS)
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CD4 count < 200/mm3 (regardless of presence or absence of symptoms).
Infection with HIV and one of the following conditions:
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Recurrent bacterial pneumonia
Invasive cervical cancer
Candidiasis of esophagus, trachea, bronchi, or lungs
Coccidiodomycosis, extrapulmonary
Cryptococcosis, extrapulmonary
Cryptosporidiosis with diarrhea > 1 month
Cytomegalovirus of any organ other than lymph nodes, liver, spleen
Herpes simplex with mucocutaneous ulcer >1 month, or bronchitis, pneumonitis or esophagitis
Histoplasmosis, extrapulmonary
HIV-associated dementia
HIV-associated wasting (involuntary weight loss of >10%, with diarrhea for > 30 days)
Kaposi’s sarcoma in patient under age 60
Lymphoma of brain in patient under age 60.
Non-Hodgkins Lymphoma
Disseminated Mycobacterium avium or Mycobaterium kansasii
Disseminated Mycobacterium tuberculosis
Pulmonary tuberculosis
Nocardiosis
Pneumocytis jiroveci pneumonia
Progressive Multifocal Leukencephalopathy
Salmonella septicemia
Strongyloides, extraintestinal
Toxoplasmosis of internal organ.
HIV Disease Progression
HIV – Initial Visit
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Labs
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CD4 Count
HIV Antibody Test
HIV Viral Load (need to check this when concerned about Primary HIV!)
HIV Resistance Testing – for selected patient
Hepatitis virus screening (check viral loads)
Tuberculin skin testing
Pap smear
PPD (positive if >/ = 5mm)
Sexually transmitted disease (especially RPR)
Toxoplasma serologic test
CMV serologic test (optional)
Chest radiograph (optional)
Vaccinations
Pneumococcal Vaccine (repeat after 5 years)
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Influenza
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Hepatitis B
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Hepatitis A
Don’t give live vaccines – no Varicella, no MMR if CD4 count < 200!
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HIV - Opportunistic Infections
CD4 > 500/mm3
CD4 of 200-500/mm3
Acute HIV
Vaginal candidiasis
Bacterial pneumonias
Pulmonary tuberculosis
Oral thrush (candidiasis)
Oral hairy leukoplakia
Herpes Zoster
Kaposi’s sarcoma
CD4 < 200
Candida esophagitis
Toxoplasmosis
Cryptococcosis
Pneumocystis jiroveci pneumonia
CD4 < 50
Disseminated Mycobacterium avium complex
Pneumocystis jiroveci Pneumonia
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Protozoa? Fungus?
Used to be most common opportunistic infection, but much less common now that
prophylaxis used.
Clinical Findings:
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Radiologic Findings Findings
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Gradual onset
Fever, chills, weight loss
Cough, SOB
Diffuse interstitial infiltrates (on x-ray)
Cysts
Ground glass infiltrates (on CT scan)
Pleural Effusions
Pneumothorax
Diagnosis:
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Positive immunofluorescent staining of sputum or bronchealveolar lavage.
Often elevated LDH (LDH level correlates with severity)
Pneumocystis jiroveci Pneumonia
Pneumocystis jiroveci Pneumonia
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Treatment:
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Typically worsen after two to three days of therapy,
presumably due to increased inflammation in response to
dying organisms
Antibiotics:
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Bactrim
Pentamadine
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Need to watch for hypoglycemia
Steroids:
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Prednisone
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If partial pressure of oxygen (PaO2) is 70 or less
OR
If alveolar/arterial (A-a) gradient is 35 mm Hg or more.
Esophageal Candidiasis
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Invasion of esophageal mucosa by Candida.
Symptoms: Odynophagia, dysphagia
Diagnosis: Clinical, EGD
Differential Diagnosis:
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Herpes Simplex Virus
Cytomegalovirus
HIV aphthous ulcer (treated with thalidomide!)
Treatment: Fluconazole
Toxoplasmosis
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Toxoplasma gondii
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Intracellular protozoan parasite
Felines are the only animals in which it can complete its reproductive cycle.
Usually in AIDS patients with CD 4 count < 100/mm3
Clinical Manifestations:
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CNS infection:
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Pneumonitis
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Ring-enhancing cerebral lesions
Meningitis
Chorioretinitis
Fever, dyspnea, cough
Reticulonodular infiltrates
(appears similar to pneumocystis)
Treatment: Pyremethamine
Prophylaxis: Bactrim
Toxoplasmosis
Cryptococcosis
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Cryptococcus neoformans
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Infection usually occurs with CD4 counts less than 100.
Frequently results in:
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Meningoencephalitis
Lung nodules
Skin findings
Symptoms:
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An encapsulated yeast
Often found in soil containing droppings/guano of pigeons, canaries, parrots, turkeys.
Mental status changes
Vision loss, hearing loss
Diagnosis:
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Elevated serum cryptococcal antigen
Lumbar Puncture
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Elevated opening pressure
Elevated CSF cryptococcal antigen
India Ink Stain showing encapsulated yeast
Treatment:
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Serial lumbar punctures, ventriculostomy, VP shunt
Amphotericin, fluconazole, flucytosine
Cryptococcosis
Mycobacterium avium intracellulare
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Usually occurs when in HIV people with CD4 count less than 50.
Disease is usually disseminated.
Symptoms:
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Diagnosis:
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Positive blood culture
Positive bone marrow biopsy
Treatment:
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Fever
Lymphadenopathy
Night sweats
Abdominal pain
Diarrhea
Weight loss
Rifabutin, clarithromycin, azithromycin
Prophylaxis:
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Azithromycin – 1250 mg po Q week
Start when CD4 count < 50!
HIV-Associated Malignancies
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Kaposi’s Sarcoma
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Due to excessive proliferation of spindle cells thought to have an endothelial
cell origin.
Associated with Human Herpesvirus-8 (HHV-8), which is also known as
Kaposi’s Sarcoma Virus (KSV).
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Most common malignancy in HIV
Clinical Findings:
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Found in 90% of cases
Skin: Deep purple/red lesions; Can appear anywhere on skin (sometimes on soles
of feet, causing pain with walking)
Gastrointestinal: Nausea, vomiting, abdominal pain, odynophagia, dysphagia,
bowel obstruction,
Pulmonary: cough, dyspnea, shortness of breath, chest pain
Diagnosis: Biopsy
Treatment: Antiretrovirals, Local therapy (radiation, topicals), Systemic
Chemotherapy
Kaposi’s Sarcoma
HIV-Associated Malignancy
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AIDS defining malignancies:
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Non-Hodgkin’s Lymphoma
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Usually B Cell lymphomas
Includes primary CNS lymphoma and body cavity
lymphoma (primary effusion lymphoma
Often associated with Epstein Barr Virus (EBV)
Treatment: Anti-retrovirals, chemotherapy, steroids (for CNS)
Kaposi’s Sarcoma (Human herpesvirus- 8 – HHH-8)
Cervical/Anal Cancer (Human papillomavirus - HPV)
Non-AIDS defining malignancies:
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Hodgkin’s Lymphoma
Multiple myeloma
Leukemia
Lung Cancer
Basal Cell Carcinoma of the skin
Seminoma
Treatment of HIV
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Anti-retrovirals
Infection prophylaxis
Antiretrovirals –
When to Start Therapy
Symptomatic HIV Disease
Antiretroviral therapy
recommended
Asymptomatic HIV Disease
CD4 count ≤ 200
Antiretroviral therapy
recommended
CD4 count > 200 but <350 Antiretroviral therapy should be
considered and individual decision
(if viral load > 100,000)
CD4 count ≥ 350
Antiretroviral therapy generally not
recommended
Human Immunodeficiency Virus –
Lifecycle in Host Cell
Antiretrovirals
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Nucleoside/Nucleotide Analogue Reverse Transcriptase Inhibitors
(NRTI’s)
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Non-nucleoside Analogue Reverse Transcriptase Inhibitors (NNRTI’s)
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Bind directly and non-competitively with reverse transcriptase, blocking its
activity
Protease Inhibitors
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Block reverse transcriptase activity by incorporating themselves into the viral
DNA and acting as chain terminators in the synthesis of proviral DNA.
Inhibit HIV-1 protease, resulting in release of structurally disorganized and
non-infectious viral particles.
Fusion Inhibitors
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Inhibit fusion of initial virus with CD4 cell
Only member is Enfuvirtide (T20)
Only used in salvage therapy
Nucleoside/Nucleotide Reverse
Transcriptase Inhibitors (NRTI’s)
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Include:
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Abacavir (ABC)
Didanoside (ddI)
Emtricitabine (FTC)
Lamivudine (3TC)
Stavudine (d4T)
Tenofovir (TDF)
Zalcitabine (ddC)
Zidovudine (AZT, ZDV)
Side Effects:
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Lactic Acidosis
Hepatic Steatosis
Peripheral neuropathy
***Hypersensitivity reaction with Abacavir
Non-nucleoside reverse transcriptase
inhibitors (NNRTI’s)
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Include:
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Nevirapine (NVP)
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Side effects:
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Efavirenz (EFV)
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Side Effects:
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Rash (can cause Stevens Johnson)
Hepatotoxicity in women with CD4 ≤ 250
CNS side effects: dizziness, insomnia, hallucinations
Can cause fetal malformations, neural tube defects
Dilavirdine (DLV)
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Side Effects
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Rash
Increased transaminases
Protease Inhibitors
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Include:
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Amprenavir (APV)
Atazanavir (ATV)
Fosamprenavir (f-APV)
Indinavir
Lopinavir + Ritonavir (Kaletra)
Nelfinavir
Ritonavir
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VERY IMPORTANT – Is able to boost levels of other protease inhibitors!
Saquinavir
Side Effects
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Inhibit CYP450 system
Hyperlipidemia
Hyperglycemia
GI upset
Kidney stones -- Indinavir
Choosing Antiretroviral Regiment
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Need Protease Inhibitor or NNRTI
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2 – NRTI’s
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Most popular initial regimens:
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Efavirenz + (lamivudine or emtricitabine) + (zidovudine or tenofovir)
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Lopinavir/Ritonavir + (lamivudine or emtricitabine) + zidovudine
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Tenofovir, Emtricitabine and Lamivudine also treat Hepatitis B!
HIV Prophylaxis
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When CD4 count < 200:
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Pneumocystis (PJP) prophylaxis
Trimethroprim/Sulfamethoxazole (Bactrim) – one DS tab po QDay
If allergy, or unable to tolerate:
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When CD4 count < 100
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Toxoplasma gondi prophylaxis:
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Dapsone (need to check G6PD first!)
Pentamadine (aerosolized)
Atovaquone
Trimethoprim/Sulfamethoxazole – one DS tab po QDay
Dapsone (Qday) + pyramethamine (Q week) + leucovorin (Q week)
When CD4 count < 50
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Mycobacterium avium intracellulare prophylaxis
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Azithromycin – 1200 mg po Qweek
Or
Clarithromycin – 500 mg po q12h
Immune Reconstitution Inflammatory
Syndrome (IRIS)
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Following the initiation of antiretroviral therapy, patient may have exaggerated
immune response to underlying opportunistic pathogens.
Most patients develop symptoms one week to a few months of the initiation of
antiretrovirals.
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Most commonly:
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Cryptococcus
Mycobacterium tuberculosis
Mycobacterium avium intracellulare
Toxoplamosis
Patient should undergo testing for cryptococcus, toxoplasmosis, tuberculosis
(PPD) prior to starting therapy.
Treatment:
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Treat infection!
Continue antiretrovirals
Administer steroids
Hold antiretrovirals
Question # 1
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A 27-year old HIV-positive male presents
with multiple purple pedunculated nodules on
his sin. He says that these lesions have spread
rapidly and have a tendency to bleed. In the
previous 2 weeks, he has had intermittent
fevers and general malaise.
Question # 1
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The most likely diagnosis is:
(A.) Kaposi’s sarcoma
(B.) Pyogenic granulomas
(C.) Bacillary angiomatosis
(D.) Secondary syphilis
(E.) Cutaneous cryptococcosis
Question # 2
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A 36-year old male with a history of HIV infection
for the past 5 years comes to your office for a second
opinion about starting antiretroviral therapy. He had
varicella zoster infection 1 year ago, and recently
noticed some white plaques on the inside of his
cheeks. The only medications he is taking are
vitamins. Physical examination reveals diffuse
adenopathy, which appears unchanged from previous
examinations.
Question # 2
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Labs:
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Hct: 36%
Leukocyte count: 2.2
Platelet count: 125
CD4 cell count: 345
HIV RNA level: 5,000 copies/mL
Question # 2
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Which is the most appropriate recommended
antiretroviral therapy?
(A) No therapy
(B) Zidovudine
(C) Zidovudine in combination with didanosine and
zalcitabine or lamivudine
(D) Efavirenz in combination with lamivudine and
zidovudine.
Question # 3
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An 32-year old man is seen for an initial visit
after the diagnosis of HIV infection. The
patient believes his infection was sexually
acquired. He works at a nursing home, and
two years ago had a positive tuberculin skin
test, for which he received 1 year of isoniazid
therapy. His physical examination is
unremarkable.
Question #3
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In addition to a CD4 count, viral load testing,
and a blood chemistry profile, what additional
clinical and laboratory testing should be
ordered?
(A) Rapid plasma reagin
(B) HIV-1 p24 antigen
(C) Hepatitis C antibody
(D) Tuberculin skin testing
(E) Beta-2 microglobulin
Question # 4
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A 23-year old HIV-infected woman comes to your
office because she has noticed painless white lesions
in her mouth when brushing her teeth. She is taking
no medications. Her last CD4 count 2 months earlier
was 520/microliter. On physical examination, she
has patches of white, linear, frondlike lesions along
both lateral surfaces of the buccal mucosa; the
lesions do not scrape off with a tongue blade.
Scraping from the surface of the buccal mucosa
reveal a few yeast forms in a microscopic wet mount
prepared with potassium hydrochloride.
Question # 4
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The likeliest diagnosis is:
(A) Hairy oral leukoplakia
(B) Oral candidiasis
(C) Aphthous stomatitis
(D) Acute necrotizing ulcerative gingivitis
Question # 5
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A 34-year old HIV-seropositive man with a
CD4 count of 89 comes to your office with a
2-week history of progressive headache and
subjective fever. Current medications include
dapsone, 200 mg po QDay; Zidovudine,
Didanosine, and Nevirapine. A serologic test
for antibodies to Toxoplasma gondii obtained
2 years ago was positive (titer 1:32)
Question # 5
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Physical examination is remarkable for mild
weakness in his left arm and temperature of
39°C; A contrast-enhanced CT scan shows
multiple enhancing lesions in the right
cerebral hemisphere.
Question # 5
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What is the most appropriate next step in
management?
(A.) Initiate therapy with pyramethaminesulfadiazine
(B.) Obtain an MRI
(C.) Consult a neurosurgeon for brain biopsy
(D.) Obtain a PET scan
(E.) Repeat the serologic test for toxoplasmosis to
assess the change in titer.
Question # 6
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A 28-year old married woman states at the
end of a visit for mild knee pain that she
would like an HIV test. Brief review of her
HIV risk factors confirms that neither she nor
her husband uses drugs. She was last sexually
active with a man other than her husband in
college. She has had no extramarital
relationships and believes her husband also is
monogamous.
Question #6
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The best response to this patient’s request is to:
(A) Explain that the expense of the HIV test is
unjustified given her negligible risk.
(B) Order a CD4 cell count as a proxy for HIV
testing.
(C) Order quantitation of viral RNA by polymerase
chain reaction (PCR) as a more precise assessment
of HIV status.
(D) Order an HIV antibody test by enzyme-linked
immunosorbent assay (ELISA) with a confirmatory
Western blot.