HIV/AIDS 2008 Update

HIV/AIDS 2008 Update
By:David H. Spach, MD
Clinical Director, NWAETC
Professor of Medicine
Division of Infectious Diseases
University of Washington, Seattle

* HIV Epidemiology
* HIV Rapid Testing
* 2008 DHHS ARV Therapy Guidelines
* Antiretroviral Therapy: New Information in 2008
* New Scientific Discoveries
DHS/PP
Epidemiology*
Question
* In August 2008, the CDC reported their use of new epidemiologic methods that has led to significant revisions in the estimates of HIV incidence in the United States.

DHS/PP
In this recent report, which one of the following statements is TRUE regarding HIV infections in the United States in 2006?

* The number of estimated new infections in 2006 has been revised to a lower number (now 32,000 instead of 40,000)
* The rate (per 100,000 persons) of new infections in blacks was 7x whites
* Heterosexual sex has replaced male-to-male sex as the leading transmission category for new infections
* The number of new infections in women was greater than men
* “Based on extrapolations from these data, the estimated number of new infections for the United States in 2006 was 56,300.”
* “... the level of new HIV infections in the United States is higher than had previously been known, in fact approximately 40% higher than early estimates…”
Kevin Fenton, MD, PhD
Centers for Disease Control & Prevention.
HIV Rapid Testing*
Rapid HIV Tests
* In the June 18, 2008 issue of the MMWR, the NY City Department of Health and the CDC reported a problem with the OraQuick ADVANCE Rapid HIV-1/2 Antibody Test.

What was the reported problem with the OraQuick rapid HIV test?
* Contamination of test kits with mold
* Kits were shipped too close to the expiration date
* Failure of external Kit Controls to validate the assay
* Increased numbers of False-Positive results with oral fluid samples

Persons NOT Infected with HIV
OraQuick Rapid ORAL HIV Test
Confirmatory HIV Test (EIA/WB)
Preliminary
Positive
EIA
WB
Reactive
Oral Fluid
Oral
Possible Revised Approach: Rapid HIV Testing
OraQuick Rapid HIV Tests
Confirmatory HIV Test (EIA & WB)
Preliminary
Positive
Reactive
Oral
Oral Fluid
EXAMPLE: Specificity of HIV Antibody Test
Persons NOT Infected with HIV (N = 15)
EXAMPLE: Specificity of HIV Antibody Test
Antibody Test Result: Persons NOT Infected with HIV
EXAMPLE: Specificity of HIV Antibody Test
HIV Antibody Testing in Low Prevalence Setting
HIV Test Specificity
HIV Antibody Testing in Low Prevalence Setting
DHHS ARV Guidelines
Initiating Antiretroviral Therapy
* As a group, make a list of at least 5 recommendations regarding initiating antiretroviral therapy that are new/different in current 2008 guidelines when compared with guidelines that existed one year ago at this time (at that time October 2006 most recent updated version).
Initiating Antiretroviral Therapy
* NEW RECOMMENDATIONS
1. New CD4 threshold (350 cells/mm3 in 2008 instead of 200)
2. New indications for starting ARV (chronic HBV, HIVAN) in 2008
3. Less impact of HIV RNA level in 2008
4. Zidovudine-lamivudine removed from preferred list in 2008
5. Abacavir-lamivudine added to preferred list in 2008
6. Do HLA-B5701 testing if considering using abacavir
Initiating Antiretroviral Therapy January 2008 DHHS Guidelines
*Initiate Antiretroviral Therapy
Consider Antiretroviral Therapy
Construct Regimen by choosing one component from Column A and one component from Column B
Recent Concerns Regarding Abacavir
Antiretroviral Therapy New Information in 2008
Host Cellular Receptors
Extracellular Space
Intracellular Space
Entry Inhibitor: Maraviroc (Selzentry)
Host Cell Membrane
CD4 Receptor
Extracellular Space
Intracellular Space
R5 HIV
Maraviroc
CXCR4
CCR5
HIV Co-Receptor Tropism Assay Monogram Biosciences Trofile Assay
HIV-1 Tropism Assay
What is the major difference in the new ENHANCED Trofile assay when compared with the older Trofile assay?

* The new assay has a lower limit of detection of minor species (<1% compared with previous lower limit of 10%)
* Results can be obtained in 7 days with the new assay
* The new assay is accurate with very low HIV RNA levels (accurate down to 100 copies/ml)
* The new assay detects CCR5 mutants resistant to Maraviroc

HIV Co-Receptor Tropism Assay Monogram Biosciences ENHANCED Trofile Assay
Tenofovir + Lamivudine + Efavirenz (n = 38)
Eligibility
- HIV-infected
- Treatment Naive
- HIV RNA > 5,000 copies/ml
- CD4 count > 100 cells/mm3
- Randomized, double-blind
Tenofovir + Lamivudine +
Raltegravir* (n = 160)
Virologic Response: Week 24
INVESTIGATIONAL
* Background
- N = 368
- ARV-naīve
- HIV RNA > 5,000 copies/ml
- Randomized, double-blind
* Regimens (all include 2 NRTIs*)
- Efavirenz: 600 mg qd
- Rilpivirine: 25 mg qd
- Rilpivirine: 75 mg qd
- Rilpivirine: 150 mg qd
New Scientific Discoveries
A Cure for HIV?
* In July 2008, our patients starting coming in asking about the news reports regarding the newly discovered cure for HIV. The report that came out in July 2008 was related to HIV gp120 (envelope).

What new therapeutic strategy was discovered?

* A CD4 coating molecule that is an inhibitor of gp120-CD4 binding
* Use of Abzymes to destroy a critical region of gp120
* A new enzyme that cause gp120 to separate from gp41
* A new particle that destroys the human co-receptor CCR5 and thus prevents gp120-CCR5 binding

HIV: Basic Structure
DHS/PP
gp120
gp41
Envelope
HIV: Envelope
Abzymes
- Antibodies with enzymatic activity
- Can break down thousands of virus particles per molecule of abzyme

HIV: gp120
DHS/PP
HIV gp120: Abzyme Interaction .........

HIV/AIDS 2008 Update: Summary

* HIV Epidemiology
* HIV Rapid Testing
* 2008 DHHS ARV Therapy Guidelines
* Antiretroviral Therapy: New Information in 2008
* New Scientific Discoveries

HIV/AIDS 2008 Update.ppt

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Update on Infections

Update on Infections
By:Mark A. Lassoff, MD, MBA, MPH
September 18, 2007

Malacoplakia
* “malako” – soft, “plakos” – plaque
* Rare granulomatous disease
* Michaelis – Gutmann bodies: basophilic lamellar inclusion bodies
* Associated with other autoimmune diseases
o Sarcoidosis, Chedak-Higashi syndrome
* Incidence: 1 in 10,000
* Female: Male – 4:1
* Peak incidence is in patients ≥ 50 yrs old
* 75% of cases occur in GU system, most commonly in the bladder (2nd – kidney)
* Predilection for those with immunodeficiency, systemic dz, carcinoma or chronic UTI with coliform organisms (E Coli – up to 75%, Enterobacter, Klebsiella, Proteus and Pseudomonas)
* Etiology – unknown
o Theory: acquired immunodeficiency interfering with normal intracellular function of the monocyte’s phagolysosome. Residual undigested bacterial components become mineralized by Ca++ & Fe
o Cause appears to be related to imbalance in the intracellular cGMP/cAMP
* Dx made by biopsy
o Lesion: large histiocytes  von Hansemann cells and small intracytoplasmic calculospherules  Michaelis-Gutmann bodies
o Immunohistochemical staining for α1-antitrypsin useful for early and accurate differential dx
* Clinical findings
o Bladder
+ Irritability and hematuria
+ Mucosal plaques or nodules  fungating, firm, sessile masses
o Renal
+ Bilaterality in up to 50%; multifocal is more common
+ Fever, flank pain or mass on PE
+ Cause loss of function via direct invasion or obstruction
+ E Coli infxn in up to 93%
+ Bilateral dz  mortality rate approaches 100% w/i 6 mos of dx w/o intervention
+ IVP: unifocal – may displace calyces vs. multifocal – nephromegaly and poor renal fxn; multiple filling defects
* Management
o Lower tract:
+ Initial treatment with medications
# Bethanecol (↑ cGMP), Ascorbic acid (↓ cAMP)
# Fluoroquinolones (DOC)
# Others: Bactrim, Rifampin, Cipro
+ TUR prn for plaque removal
o Upper tract:
+ Unilateral renal dz: most often requires nephrectomy
o In immunodeficient pts and those with multifocal dz, surgical tx is essential to survival

Sexually Transmitted Infections
Syphilis
* Treponema pallidum (spirochete)
* Spread: infectious lesions, body fluids, in utero, blood transfusions
* Primary
o Single painless, indurated ulcer appearing 3 wks after inoculation (@ site of inoculation) and remains for 4 – 6 wks
o Often with bilateral, non-tender inguinal or regional lymphadenopathy
o Can heal w/o treatment; often goes unnoticed
o Presence of chancres increases risk of HIV acquisition 2-5x
* Latent
o Seroreactivity w/o clinical evidence of dz
o Early: within the last year
o Late latent vs. latent syphilis of unknown duration
* Secondary
o Begins 4 – 10 wks after the appearance of the ulcer but may present up to 24 mos after initial infection
o Mucocutaneous, constitutional and parenchymal signs and symptoms
+ Maculopapular rash (trunk and arms)
+ Generalized non-tender lymphadenopathy
+ Papular rash (may accompany first rash)
# Becomes necrotic and pustular
# Affects palms and soles
# Intertriginous areas: enlarge and erode  condyloma lata (infectious)
+ Less commonly: hepatitis and immune-complexed glomerulonephritis
* Tertiary
o One third of untreated pts
o Rare in industrialized countries, except for pts w/ HIV
o Cardiovascular, skeletal, CNS, skin
+ Aortitis, meningitis, uveitis, optic neuritis, general paresis, tabe dorsalis, gummas of skin/skeleton
* Screening
o Rapid Plasma Reagin (RPR) & Venereal Disease Research Laboratory (VDRL)
+ Correlate with disease activity
+ Become negative one year after treatment
o T. pallidum particle agglutination (TP-PA) or Fluorescent Treponemal Antibody Absorbed (FTA-ABS)
+ Antibody tests remain positive for life; do not correlate w/ active disease
o HIV can cause FN results by treponemal & non-treponemal methods
* Treatment
o Benzthiazide penicillin G (2.4 million units IM x 1)
o Jarisch – Herxheimer rxn
+ Headaches, myalgia, fever, tachycardia, increased resp rate within first 24 hrs after tx w/ PCN
+ Managed with bed rest and NSAIDs
o PCN allergy: Doxycycline (100mg BID x 14d)
o Latent: PCN IM weekly x 3 doses or doxycycline for a total of 4 wks
o Tertiary: Aqueous crystalline PCN G (IV q4h) x 10-14 d or PCN G procaine IM + probenecid (po QID) x 10-14 d
o Pregnancy: desensitization to PCN

Herpes Simplex Virus
* Genital herpes: HSV-2 (85-90%), HSV-1 (10-15%)
* Silent infection may account for >75% of transmission
* Primary
o Painful ulcers of genitalia or anus
+ Group of vesicles on an erythematous base that does not follow a neural distribution is pathognomonic
o Bilateral painful inguinal adenopathy
o Often associated with constitutional flu-like symptoms
o Urethral lesions may cause transient urinary retention in women
o Asx viral shedding can happen up to 3 mos after clinical presentation
* Recurrent episodes are usually less severe
* Severe dz and complications:
o Pneumonitis, disseminated infxn, hepatitis, meningitis, encephalitis
* Dx: viral culture with subtyping (gold standard)
o Not on clinical suspicion alone, classic presentation occurs in a small percentage of pts
o Can see abrasions, fissures or itching
o Subtyping is important for prognosis and counseling
+ HSV-2: ave of 4 recurrences in 1st yr vs. 1 for HSV-1
o Sensitivity: 30 – 95% depending on stage of lesion and whether it is primary or recurrence
* Treatment
o Oral acyclovir, valacyclovir and famciclovir
o Topical meds are not effective
o Recurrences: episodic or suppressive approach
+ Suppressive: decreases frequency/duration and viral shedding
Chancroid
* Haemophilus ducreyi
* Men: Women – 3:1
* Painful, non-indurated ulcer on penis or vulvovaginal area
o Friable base covered with a gray or yellow purulent exudate and a shaggy border
* Inguinal adenopathy is typically unilateral and tender with tendency to become suppurative and fistulize
* Dx: culture media not widely available so gram stain often helpful (short, fine, GN streptobacilli in short, parallel chains)
* Approximately 10% are co-infected w/ HSV or syphilis
* Treatment
o Single dose
+ Azithromycin 1gm po or Ceftriaxone 250mg IM
o Other tx: Cipro x 3d or Erythromycin x 7d

Lymphogranuloma Venereum
* Chlamydia trachomatis – L1, L2, L3
* Single, painless ulcer on the penis, anus or vulvovaginal area that goes unnoticed
* Painful unilateral suppurative inguinal adenopathy and constitutional symptoms that occur 2 – 6 wks after resolution of ulcer
* Significant tissue injury and scarring can occur leading to labial fenestration, urethral destruction, anorectal fistulas and elephantiasis of penis, scrotum or labia
* Dx: mainly clinical
o Complement fixation or indirect fluorescence antibody titers can confirm
* Tx: Doxycycline BID or erythromycin QID x 3 wks

Genital Warts
* Condylomata acuminata
* Human papillomavirus (HPV) – DNA virus
* Types 6 and 11 are most often responsible for visible external genital warts
o Cervix, vagina, urethra, anus, mucous membranes
* Types 16, 18, 31, 33, 35, 39, 45 and 51: associated with cervical dysplasia and neoplasm in women and squamous intraepithelial neoplasia in men
o >99% of cervical cancers and 84% of anal cancers are associated with HPV (16 & 18)
o Cervical cancer is considered an AIDS defining illness
* Most are subclinical and asx
* In women HPV may be associated with nonspecific symptoms such as vulvodynia or pruritis; malodorous vaginal discharge
* Dx: usually inspection or palpation
* Bx: not routinely needed
o Atypical, pigmented, indurated, fixed or ulcerated
o Lesions persist/worsen after tx; immunocompromised pts
* Treatment
o Depends on size, number, location, and patient and physician preference
o Observation (spontaneously resolve with time)
o Patient applied (less expensive)
+ Podofilox 0.5% solution or gel (3d on, 4d off, may repeat x 4)
+ Imiquod 5% cream (3/wk qhs for up to 16 wks)
# Needs to be washed off, can cause ulceration
o Provider applied
+ Cryotherapy with liquid nitrogen
+ Electrosurgery
+ Laser therapy (CO2)
+ Podophyllin resin (20 – 25%)
+ Trichloracetic acid (TCA) or bichloracetic acid (BCA)
+ Surgical excision
* Lesions around the meatus may herald presence of urethral or bladder condyloma
* Urethral or bladder lesions should be cystoscopically excised
* Intraurethral 5% FU cream 2/wk
* Vaccine containing 8 of the most common HPV types associated with cancer could potentially prevent 95% of cervical cancer
* Topical BCG: promising preliminary results

Sexually Transmitted Infections
Chlamydia
* Chlamydia trachomatis: most common bacterial STD in the US and worldwide
* Majority of men and women are asx
* 50% of men experience LUTS attributed to urethritis, epididymitis or prostatitis; may see clear or white urethral discharge
* 75% of women are asx and 40% of those untreated will have PID
* May be transmitted during vaginal birth
o Ocular, oropharyngeal, respiratory, urogenital or rectal infxn
Chlamydia
* Women should be screened annually until 25 yo or if risk factors such as new sexual partner are present
o Nucleic acid amplification test (NAAT) on endocervical swab or urine specimen
o Unamplified nucleic acid hybridization test, enzyme immunoassay or direct fluorescence antibody test
o Culture
* Treatment
o Azithromycin 1gm po x 1 or Doxy BID x 7d
o Refrain from sex until treatment completed or 7d after single dose therapy
o Re-culture recommended 3 wks later if treated with erythromycin, in pregnant women or if symptoms persist
o Re-screened 3 – 4 mos after tx as are high risk for re-infxn

Gonorrhea
* Neisseria gonorrhoeae (GN diplococcus)
* Men usually experience LUTS attributed to urethritis, epididymitis, proctitis or prostatitis w/ associated mucopurulent urethral discharge
* Women may have vaginal and pelvic discomfort, dysuria or abnormal vaginal discharge but are usually asx
* Same screening recs as for Chlamydia
* Treatment
o Ceftriaxone 125mg IM x 1
o Single dose oral regimen
+ Cipro, Levaquin, Ofloxacin (growing resistance to FQs)
o Simultaneous treatment for Chlamydia






Trichomoniasis

* Trichomonas vaginalis (flagellated protozoan)
* Increased incidence in developing countries and those with multiple sexual partners
* Can inhabit the vagina, urethra, Bartholin glands, Skene’s glands and prostate (not rectum/mouth)
* Men: usually asx but can produce short-term urethral discharge, dysuria and urgency
* Women: asx in 50%, otherwise can see sudden onset of frothy white or green, foul-smelling vaginal discharge, pruritis, and erythema
o Dyspareunia, suprapubic discomfort, urgency
Trichomoniasis
* Examination: frothy discharge and “strawberry vulva” or “strawberry cervix”
* Vaginal discharge has increased pH
* Motile protozoa on vaginal wet-mount smear or microscopic examination of urine
* Men: urethral cx or microscopic exam of urine
* Treatment
o Metronidazole 2gm po x 1 (ok in 2nd trimester)
+ GI side effects common
o Abstain from Etoh consumption
o Prolonged Metronidazole for failure

Vaginitides / Urethritides
* Ureaplasma urealyticum, Mycoplasma hominis, Mycoplasma genitalium
o Implicated in chronic prostatitis and urgency frequency symptoms in women and in up to 40% of NGU
o Tx: Azithromycin po x 1 or doxycycline x 2 wks
* Bacterial vaginosis
o Gardnerella vaginalis, anaerobic orgs, Mycoplasma and/or inhibition of normal vaginal flora
o 10% KOH with vag secretions  fishy odor secondary to release of amines
o Microscopic exam (3 of 4 necessary): (1) thin, white vag d/c (2) vag pH >4.5 (3) clue cells (4) pos whiff test
o Tx: Metro po BID x 7d, Clinda cream x 7d, Metro gel x 5d
* Candida albicans
o Thick, cheesy vaginal discharge usually associated with vulvar irritation and itching
+ Vaginal discomfort, burning, dyspareunia and external dysuria
o Dx: yeast or pseudohyphae on wet prep or gram stain
o Tx: single oral dose of fluconazole (150mg) or OTC antifungal vaginal creams, tablets or suppositories x 1-7 days (butoconazole, clotrimazole, miconazole and terconazole)
References

Update on Infections .ppt

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HUMAN PAPILLOMA VIRUS (HPV)

HUMAN PAPILLOMA VIRUS (HPV)
By: Nathalia Cruz

What is a Virus?
* Exceptionally simple living microbes.
* Contain a single type of nucleic acid (DNA or RNA) and a protein coat.
* Obligatory intracellular parasites.
* Range from 20 to 14.000 nm in length.
* It’s classification is based on type of nucleic acid, strategy for replication, and morphology

HUMAN PAPILLOMA VIRUS
* HPV is the virus that causes warts.
* More than 100 different kinds, 30-some of this cause genital HPV.
* Spread by sexual contact or from mother to baby.
* Genital warts appear 6 weeks to 8 months after contact with an HPV infected person.
* The most common sexually transmitted disease worldwide.
* Certain types of HPV are linked with cervical cancer.
* Divided into 2 subcategories: Genital Warts and Cervical Dysplasia.
* Most people do not know they have it.
* There are high risk and low risk types of it.

HISTORY
* The papillomaviruses are part of the PAPOVAVIRIDAE family of DNA tumor viruses.
* First discovered in the early 40’s.
* Gained notoriety in the early 80’s when it was discovered that some types of HPV caused cervical cancer.

MORPHOLOGY
* Papilloma virus genome is circular covalently closed double stranded DNA of about 8 kbp.
* All PV genes are coded in one of the 2 DNA strands utilizing the alternative splicing for the individual expression of each gene.
* Papillomavirus expression is characterized by a large array of mRNAs cells coding for different genes.
* 55 nm in diameter.

MECHANISM OF INFECTION
* All PV exhibit extreme specificity for infection on epithelial cells.
* The papillomavirus epitheliotrophy resides in the interaction of specific transmission factors with the viral regulatory region LCR.
* The infection normally results in hyperproliferation of the host cell and may lead to transformation and immortalization.

GENITAL WARTS
* Sometimes called condylomata acuminata.
* Are soft, moist or flesh colored, and appear in the genital area within weeks or months after infection.
* Sometimes appear in clusters and are either raised or flat, small or large.
* Women: appear in the vulva, cervix, vagina and anus.
* Men: Can appear on the scrotum or penis.

LIFE CYCLE (HPV-16)
* Starts with the infection of the host cell.
* The virus DNA is released within the nucleus
* Numerous cellular transcription factors interact with the non-coding viral regulatory region (LCR), starting transcription of the two hpv-16 transforming early genes (E6 and E7).
* The transforming proteins interact with the cellular antioncogenic regulator p53 disrupting the cell cycle.

HPV TYPES
* Numbered in order of discovery.
* 30 HPV types primarily infect the squamous epithelium of the lower anogenital tracts of both males and females.
* HPV types 6, 11, 42, 43, or 44 present as papillary condylomas, may also present as flat lesions that may or may not be visible to the unaided eye are part of the “low-risk” HPV types.
* Types 16, 18, 31, 33, 35, 45, 51, 52, and 56 are considered “high-risk” types because they have been found in cervical and other lower genital tract cancers.

HPV GENOMIC ORGANIZATION
* Three main regions (early, late and the long control region)
* (E) resides the transformation and immortalization potential.
* (L) Two capsid genes.
* (LCR) contains all the cis-regulatory elements.

HOW HPV CAUSES CANCER
* HPV DNA integrates into the host genome.
* The proteins E6 and E7 are produced from the resultant DNA.
* E6 binds and degrades p53 (a tumor suppressor gene).
* If the DNA is altered, the cell keeps replicating. The mutation rate of the cell increases.
* E7 binds and degrades retinoblastoma (another tumor suppressor gene).
* Retinoblastoma normally keeps the cell from growing too fast or responding to growth stimulators. This inhibitory factor is now lost.
* without these two mechanisms to slow down cell growth and prevent mutation. . .
* Malignant Transformation Occurs.

HPV TREATMENT
* Genital warts can be treated by a doctor and by different methods.
* Podofilox gel: A patient-applied treatment for external genital warts.
* Imiquimod cream: A patient-applied treatment.
* Chemical treatments (including trichloracetic acid and podophyllin), which must be applied by a trained health care provider to destroy warts.
* Cryotherapy: Uses liquid nitrogen to freeze off the warts.
* Laser therapy: Uses a laser beam or intense lights to destroy the warts.
* Electrosurgery: Uses and electric current to burn off the warts.
* Surgery: Can cut away the wart in one office visit .
* Interferon: an antiviral drug, which can be injected directly into warts.

CURE
* There is currently no cure for human papillomavirus.
* Once an individual is infected, he or she carries the virus for life even if genital warts are removed.
* The development of a vaccine against HPV is under way, but is still not available.
* If left untreated, some genital warts may regress on their own.

HUMAN PAPILLOMA VIRUS.ppt

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