HIV infection and AIDS

HIV/AIDS - History
 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.
Patient zero
Epidemiology of HIV
 59 million people have been infected
worldwide, with 20 million dead.
 About 35million people living with HIV in
2013. 95% in low and middle-income
countries
 64% of people with HIV are living in sub-
Saharan Africa
 though Sub-Saharan Africans only make up 10%
of world population
Transmission route
 Viral Transmission
 Sexual intercourse, exposure to
contaminated blood, or perinatal
transmission

 The cases due to sexual intercourse

transmission increasing

 Worldwide, 70-80% caused by vaginal sex,

perinatal transmision is 5-10%, and IV
drug use is 5-10%.
Transmission route
Human Immunodeficiency Virus
 An RNA retrovirus – subfamily Lentivirus
 HIV-1 and HIV-2
 Contains:
 2 copies of RNA
 Enzymes:
 Reverse Transcriptase
 Integrase
 Protease
 Two major envelope proteins:
 gp120
 gp41
Life Cycle of HIV virus
1. Interaction between viral envelope proteins and CD4
receptor and co-receptors leads to binding of the viral
envelope and host cytoplasmic membrane
2. Viral reverse transcriptase catalyses the conversion of viral
RNA into DNA
3. Proviral DNA enters the nucleus and becomes integrated
into chromosomal DNA of host cell (catalyzed by
integrase)
4. Expression of viral genes leads to production of viral RNA
and proteins.
5. Protease enzyme cleaves proteins into functional mature
products.
6. 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
 HIV tends to infect CD4+ T Cells, because CD4
receptor has high affinity for gp120 (HIV viral-
envelope protein)
 CD4+ T Cells initially die in acute phase due to
cytopathologic damage by virus.
 CD4+ T Cells then chronically die from:
 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
Human Immunodeficiency Virus –
Stages of Infection
 Acute HIV Infection
 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
 Include fever, lymphadenopathy, rash, pharyngitis, headache (aseptic
meningitis)
 HIV antibody will be negative at this point – need to check HIV viral load
or p24 antigen level!
 The asymptomatic stage (~10yrs)
 Patient has positive HIV antibody test
 Usually occurs 4 to 10 weeks after infection.
 The average rate of the CD4+ cell decline is ~50/uL per year
“Long-term non-progressors” tend to have little/no decrease in CD4 count
 Symptomatic disease--advanced HIV disease (AIDS)
CDC HIV infection stage 1-3
age<1 yr 1-5 yrs 6 yrs through
adult
stage cells/uL % cells/uL % cells/uL %
1 ≥1500 ≧34% ≥1000 ≥30 ≥500 ≥26
2 750- 26-33 500- 22-29 200- 14-25
1499 999 499
3 <750 <26 <500 <22 <200 <14
Based on the CD4 lymphocyte count, which takes precedence
over the CD4 percentage, and the percentage is considered if the
count is missing.

source: MMWR63, April 1 2014

HIV- Early Symptomatic Infection
 Includes:
 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
 Associated with EBV infection
 Does not rub off.
Bacillary Angiomatosis
 Caused by Bartonella species
Herpes Zoster
 “Shingles”
 Caused by Varicella
Acquired Immunodeficiency
Syndrome (AIDS)
 CD4 count < 200/mm3 (regardless of presence or absence of symptoms).
 Infection with HIV and one of the following conditions:
 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
Diagnosis of HIV
 HIV antibody ELISA – if positive, is always followed by a confirmatory
Western Blot
 Rapid HIV antibody test
 Sensitivity and Specificity 99%!
 Results in 5 to 40 minutes usually
 Used in:
 Occupational Exposure
 Pregnant women presenting in labor with no previous HIV testing
 Patients who are unlikely to return for results of HIV test
 HIV viral load
 First choice for diagnosing possible acute HIV
 HIV p24 Antigen
 Is the first antigen to be elevated in acute HIV
 Can be used for diagnosis of primary (acute) HIV
HIV – Initial Visit
 Labs
 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)
 Influenza
 Hepatitis B
 Hepatitis A and E
Don’t give live vaccines – no Varicella, no MMR if CD4 count < 200!
HIV - Opportunistic Infections
CD4 > 500/mm3 Acute HIV
Vaginal candidiasis
CD4 of 200-500/mm3 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
 Protozoa? Fungus?
 Used to be most common opportunistic infection, but much less common now that
prophylaxis used.
 Clinical Findings:
 Gradual onset
 Fever, chills, weight loss
 Cough, SOB
 Radiologic Findings Findings
 Diffuse interstitial infiltrates (on x-ray)
 Cysts
 Ground glass infiltrates (on CT scan)
 Pleural Effusions
 Pneumothorax
 Diagnosis:
 Positive immunofluorescent staining of sputum or bronchealveolar lavage.
 Often elevated LDH (LDH level correlates with severity); 1,3-beta-d-glucan
Pneumocystis jiroveci Pneumonia
Pneumocystis jiroveci Pneumonia
 Treatment:
 Typically worsen after two to three days of therapy,
presumably due to increased inflammation in response to
dying organisms
 Antibiotics:
 Bactrim (TMP-SMX, trimethoprim-sulfamethoxazole)
 Pentamadine
 Need to watch for hypoglycemia
 Steroids:
 Prednisone
 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
 Invasion of esophageal mucosa by Candida.
 Symptoms: Odynophagia, dysphagia
 Diagnosis: Clinical, EGD (esophagogastroduodenoscopy)
 Differential Diagnosis:
 Herpes Simplex Virus
 Cytomegalovirus
 HIV aphthous ulcer (treated with thalidomide!)
 Treatment: Fluconazole
Toxoplasmosis
 Toxoplasma gondii
 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:
 CNS infection:
 Ring-enhancing cerebral lesions
 Meningitis
 Chorioretinitis
 Pneumonitis
 Fever, dyspnea, cough
 Reticulonodular infiltrates
(appears similar to pneumocystis)
 Treatment: Pyremethamine
 Prophylaxis: Bactrim
Toxoplasmosis
Cryptococcosis
 Cryptococcus neoformans
 An encapsulated yeast
 Often found in soil containing droppings/guano of pigeons, canaries, parrots, turkeys.
 Infection usually occurs with CD4 counts less than 100.
 Frequently results in:
 Meningoencephalitis
 Lung nodules
 Skin findings
 Symptoms:
 Mental status changes
 Vision loss, hearing loss
 Diagnosis:
 Elevated serum cryptococcal antigen
 Lumbar Puncture
 Elevated opening pressure
 Elevated CSF cryptococcal antigen
 India Ink Stain showing encapsulated yeast
 Treatment:
 Serial lumbar punctures, ventriculostomy, VP shunt
 Amphotericin, fluconazole, flucytosine
Cryptococcosis
Mycobacterium avium intracellulare
 Usually occurs when in HIV people with CD4 count less than 50.
 Disease is usually disseminated.
 Symptoms:
 Fever
 Lymphadenopathy
 Night sweats
 Abdominal pain
 Diarrhea
 Weight loss
 Diagnosis:
 Positive blood culture
 Positive bone marrow biopsy
 Treatment:
 Rifabutin, clarithromycin, azithromycin
 Prophylaxis:
 Azithromycin – 1250 mg po Q week
 Start when CD4 count < 50!
HIV-Associated Malignancies
 Kaposi’s Sarcoma
 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).
 Found in 90% of cases
 Most common malignancy in HIV
 Clinical Findings:
 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
 AIDS defining malignancies:
 Non-Hodgkin’s Lymphoma
 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:
 Hodgkin’s Lymphoma
 Multiple myeloma
 Leukemia
 Lung Cancer
 Basal Cell Carcinoma of the skin
 Seminoma
Treatment of HIV
 Anti-retrovirals
 Infection prophylaxis
Antiretrovirals –
When to Start Therapy

Initiate the ART once

confirming the HIV infection
AIMS of ART
HAART
Why HAART
Who and When?
How
Antiretrovirals
 Nucleoside/Nucleotide Analogue Reverse Transcriptase Inhibitors
(NRTI’s)
 Block reverse transcriptase activity by incorporating themselves into the viral
DNA and acting as chain terminators in the synthesis of proviral DNA.
 Non-nucleoside Analogue Reverse Transcriptase Inhibitors (NNRTI’s)
 Bind directly and non-competitively with reverse transcriptase, blocking its
activity
 Protease Inhibitors
 Inhibit HIV-1 protease, resulting in release of structurally disorganized and
non-infectious viral particles.
 Fusion Inhibitors
 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)
 Include:
 Abacavir (ABC)
 Didanoside (ddI)
 Emtricitabine (FTC)
 Lamivudine (3TC)
 Stavudine (d4T)
 Tenofovir (TDF)
 Zalcitabine (ddC)
 Zidovudine (AZT, ZDV)
 Side Effects:
 Lactic Acidosis
 Hepatic Steatosis
 Peripheral neuropathy
 ***Hypersensitivity reaction with Abacavir
Non-nucleoside reverse transcriptase
inhibitors (NNRTI’s)
 Include:
 Nevirapine (NVP)
 Side effects:
 Rash (can cause Stevens Johnson)
 Hepatotoxicity in women with CD4 ≤ 250
 Efavirenz (EFV)
 Side Effects:
 CNS side effects: dizziness, insomnia, hallucinations
 Can cause fetal malformations, neural tube defects
 Dilavirdine (DLV)
 Side Effects
 Rash
 Increased transaminases
Protease Inhibitors
 Include:
 Amprenavir (APV)
 Atazanavir (ATV)
 Fosamprenavir (f-APV)
 Indinavir
 Lopinavir + Ritonavir (Kaletra)
 Nelfinavir
 Ritonavir
 VERY IMPORTANT – Is able to boost levels of other protease inhibitors!
 Saquinavir
 Side Effects
 Inhibit CYP450 system
 Hyperlipidemia
 Hyperglycemia
 GI upset
 Kidney stones -- Indinavir
Choosing Antiretroviral Regiment

 2NRTIs +INSTI/NNRTIs/PI plus PK

 Tenofovir, Emtricitabine and Lamivudine also
treat Hepatitis B!
HIV Prophylaxis
 When CD4 count < 200:
 Pneumocystis (PJP) prophylaxis
 Trimethroprim/Sulfamethoxazole (Bactrim) – one DS tab po QDay
If allergy, or unable to tolerate:
 Dapsone (need to check G6PD first!)
 Pentamadine (aerosolized)
 Atovaquone
 When CD4 count < 100
 Toxoplasma gondi prophylaxis:
 Trimethoprim/Sulfamethoxazole – one DS tab po QDay
 Dapsone (Qday) + pyramethamine (Q week) + leucovorin (Q week)
 When CD4 count < 50
 Mycobacterium avium intracellulare prophylaxis
 Azithromycin – 1200 mg po Qweek
Or
 Clarithromycin – 500 mg po q12h
Immune Reconstitution Inflammatory
Syndrome (IRIS)
 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.
 Most commonly:
 Cryptococcus
 Mycobacterium tuberculosis
 Mycobacterium avium intracellulare
 Toxoplamosis
 Patient should undergo testing for cryptococcus, toxoplasmosis, tuberculosis
(PPD) prior to starting therapy.
 Treatment:
 Treat infection!
 Continue antiretrovirals
 Administer steroids
 Hold antiretrovirals
Summary
 Predisposing factors: unprotected sexual
activity, injection drug use, contaminated
blood transfusion, perinatal exposure to an
infected mother
 Stages and OP based on CD4+ count
 Lab findings:
 Antiretroviral treatments and HAART
Reference
Question # 1
 A 27-year old HIV-positive male presents
with multiple purple pedunculated nodules on
his skin. 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
 The most likely diagnosis is:
(A.) Kaposi’s sarcoma
(B.) Pyogenic granulomas
(C.) Bacillary angiomatosis
(D.) Secondary syphilis
(E.) Cutaneous cryptococcosis
Question # 2
 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 # 2
 The likeliest diagnosis is:
(A) Hairy oral leukoplakia
(B) Oral candidiasis
(C) Aphthous stomatitis
(D) Acute necrotizing ulcerative gingivitis
Question # 3
 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 # 3
 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 # 3
 What is the most appropriate next step in
management?
(A.) Initiate therapy with pyramethamine-
sulfadiazine
(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.
Q 4:
 A 39-year-old man with HIV/AIDS presents
with 4 weeks of diarrhea, fever, and weight
loss. Which of the following tests makes the
diagnosis of cytomegalovirus (CMV) colitis?
 A.CMV IgG
 B.Colonoscopy with biopsy
 C.Stool CMV antigen
 D.Serum CMV polymerase chain reaction
(PCR)
Thank You!