Transcript AIDS defining illness

AIDS Defining and AIDS
Associated Malignancies
Objective: Think about concepts you don’t
think about in your every day evidence based
approach to the practice of medicine
without falling asleep
What are the AIDS Defining
Malignancies?
AIDS Associated Malignancies?
AIDS Defining Malignancies
• Kaposi’s sarcoma
• Non Hodgkin’s lymphoma
• Squamous cell carcinoma of the cervix/anus*
* AIDS associated malignancy
Variations on a Theme
• Oncogenic viral infection
– KS
– Lymphoma
– SCCa cervix/anus
• Proliferation of a benign cell
- KS
- Lymphoma
- SCCa cervix/anus
• Immune dysregulation
- Up regulation
- Down regulation
- Direct role of HIV
Variations on a Theme
• Oncogenic viral infection
– KS = KSHV
– Lymphoma = EBV and KSHV
– SCCa cervix/anus = HPV
• Proliferation of a benign cell
- KS = lymphatic endothelial cell
- Lymphoma = B lymphocyte
- SCCa cervix/anus = squamous epithelium
• Immune dysregulation
- Increased production of inflammatory cytokines
- Loss of cell mediated immunity to control viral infections
- Any direct role of HIV: Tat up regulation of virus gene
expression
How do viruses cause cancer?
What about cytokines
How does being CD4 T lymphopenic
make you susceptible to cancer?
Case 1
• A 28 year old man with early stage HIV
presented anxious and upset over the
development of disfiguring skin lesions.
Kaposi’s Sarcoma can range from disfiguring to …..
organ and limb threatening …
Kaposi’s Sarcoma
Don’t treat without meat…...
This is bacillary angiomatosis, an infection due to Bartonella sp.
It is treated with erythromycin
Kaposi’s Sarcoma
• Was among the initial features of AIDS
• Three epidemiologic subsets
– Endemic - seen in sub Saharan Africa
– Epidemic - associated with HIV infection
– Sporadic - aging men of Mediterranean descent
• Strong relationship with immune deficiency
– Transplant patients
– Recipients of immunosuppressive agents
– Aged individuals
• Long thought to have an infectious etiology
– HHV-8 or KSHV was discovered in 1994 by Moore and Chang
Kaposi Sarcoma Herpes Virus
Human Herpes Virus - 8
• How prevalent is KSHV in the US population?
• How prevalent is KSHV in HIV infected persons?
• What is the primary route of transmission of KSHV
• Does everyone with KSHV infection get KS?
Kaposi Sarcoma Herpes Virus
Human Herpes Virus - 8
• Prevalence of KSHV infection is 5% in USA.
• Prevalence of KSHV infections is 26% to 40% in HIV infected
persons.
• Shed in the SALIVA, the primary route of transmission
• KS develops in a minority of immune competent persons, but
50% of HIV infected persons.
• Present in ALL KS lesions from ALL types of KS
Two types of KSHV (HHV-8) Infection
• Latent seen in Kaposi’s sarcoma
– No virus replication
– Limited expression of virus genes
• Lytic seen primary effusion lymphoma
– Production of virus progeny
– Expression of many viral genes
Many of the KSHV genes operate to create
the perfect environment for malignancy
• Inhibition of cell cycle regulation
• Prevent apoptosis
• Modulate the immune system
• Promote angiogenesis
• Latent infection can be converted to lytic infection under
conditions of hypoxia.
Pathogenesis
• KSHV has tropism for lymphatic endothelial cells, B cells,
macrophages, and epithelial cells.
• In KS latent infection is more prevalent than lytic.
• Latent state KSHV genes codes for proteins that support KS
oncogenesis
– LANA-1 inhibits p53
– vCyclin (homolog of cyclin D2) that is resistant to CDK inhibitors
– vFLIP (homolog of FLIP) that inhibits apoptosis
Role of cytokines in pathogenesis
• Cytokines
– From HIV-infected macrophages and activated T cells
– IL-1, IL-2, PF4, IFN-g, TNF- a
– Cause proliferation of lymphatic endothelial cells
– Permissive environment for KSHV infection
Treatment
• First Line: protease inhibitor containing regimen
– 20% to 60% of patients may respond with HAART alone.
– Best responses: drug naïve, skin only, and CD4 increase >150
– CR is not necessarily protective against recurrence.
• Advanced KS in late stage AIDS often requires more Rx
– Enhanced immunity against KSHV is not enough
– VEGF inhibitors, liposomal adriamycin, conventional cytotoxic Rx
• Goal of treatment is palliation
Where has all the KS gone?
• There has been a dramatic decline in incidence with HAART
- Adjusted incidence pre HAART: 15.2/1000 person years
- Adjusted incidence post HAART: 4.9/1000 person years
• Immune reconstitution and better control of KSHV
• Anti angiogenesis effects of protease inhibitors
AIDS associated Lymphomas
AIDS associated Lymphomas
• Peripheral lymphomas
• ?
• ?
AIDS associated Lymphomas
• Peripheral lymphomas
• Primary effusion lymphomas
• Primary CNS
Epidemiology
• Rates may be under estimated 2° to hierarchy of
reporting.
• Incidence in AIDS is estimated from 4 to 16%.
• Risk of NHL in HIV is 100-200X risk of HIV neg.
– 80% of HIV lymphomas are high grade, 15% are low grade.
– Just the opposite for HIV negative persons
What viruses contribute to
lymphomagenesis?
• EBV
• KSHV
• HIV
Lymphomagenesis: virus
• HIV - not directly involved in malignant transformation.
• EBV - causes polyclonal B cell proliferation leading to
genetic instability increasing the chance of a
transforming mutation, such as myc translocation.
– Implicated in CNS and Primary Effusion Lymphomas
• KSHV - how could this virus possibly cause lymphoma?
– Implicated in primary effusion lymphoma and multicentric
Castleman’s disease
Lymphomagenesis
• Cytokines
– IL-6 and IL-10
• Loss of immune surveillance
– Loss of CD4 clones that control EBV infected B cells
– Loss of CD8 function (due to loss of CD4 help)
– Permits proliferation of EBV infected B lymphoblasts
– EBV infected lymphs can evade immune detection
Prognosis
• Most prognostic data comes from pre-HAART era
– CD4< 200 median survival = 4 months
– CD4 >200 median survival = 11 to 18 months
• Overall median survival in HAART era 24 months
• NCI AIDS Malignancy Branch peripheral lymphoma
patients receiving EPOCH ± R - at 53 months follow
up overall survival is 60%.
• Median survival for PEL 3 to 6 months.
• Median survival for primary CNS lymphoma
– Radiation alone - 4 months
– Chemotherapy 10 to 18 months
Antiviral therapy and Epidemiology
• Modern antiretroviral therapy does not prevent
lymphoma, but rather maintains CD4 counts at
levels that prevents development of the poor
prognosis lymphomas (immunoblastic and primary
CNS lymphoma).
Case 2
• A 37 year old man with long standing HIV
infection presents with mid epigastric pain,
hemoccult positive stools, and a microcytic
hypochromic anemia.
• Upper endoscopy revealed:
Peripheral Lymphoma Histology
• Burkitt’s and Burkitt’s-like
– Occurs in state of relative immune preservation
– Bone marrow and nodal sites predominate
– EBV is absent esp in sporadic Burkitt's
• Diffuse Large B cell Lymphoma; centroblastic
– Occurs in state of relative immune preservation
– GI and CNS sites predominate
– Good prognosis
• Diffuse Large B cell Lymphoma; immunoblastic
– Occurs in later stage HIV infection
– GI and CNS sites predominate
– Poor prognosis
Peripheral Lymphomas
• Extranodal involvement is common.
– CNS (leptomeninges) - 20 to 40% at presentation
– GI - 30% at presentation
– Orbit, skin, salivary glands, heart, lung, muscle,
bones, adrenals, rectum, gonads, placenta
• Stage
– Most present with stage III, IV or IE bulky disease
Treatment
• Induction of remission requires chemotherapy.
•All patients receive CNS prophylaxis
• Controversial Issues
– Dose intensity and regimen
– Infusional (EPOCH) vs. bolus (CHOP) therapy
– Concurrent use of HAART
– Use of rituximab WHY?
Case 3
• A 39 year old man, known to be HIV positive
presents with new onset ascites.
• Further examination and evaluation reveal
bilateral pleural effusions and pericardial
effusion.
• A pericardiocentesis reveals:
Primary Effusion Lymphoma
• Usually occurs in young, homosexual men with advanced HIV
• Epidemiology similar to that of KS
• Disease usually restricted to pericardium, pleura, peritoneal
cavity without contiguous tumor mass.
• Poor outcome (survival <5 mos).
• Tumor cell is B cell lineage:
– Kappa and lambda light chain mRNA
– Ig heavy chain with k light chain mRNA
– Uniformly express KSHV; frequently EBV
PEL Treatment
• Refractory to conventional chemotherapy
• Some short remissions with EPOCH
• Experimental therapies exploit KSHV pathophysiology
– KSHV codes for several kinases
– These kinases phosphorylate (activate) AZT and ganciclovir
– Theoretically, the drugs will be activated primarily in KSHV
infected B cells, killing primarily those cells.
AZT
Ganciclovir
Thymidine
Guanosine
AZT and GCV are phosphorylated and
then incorporated into a growing chain of
DNA. What do you think happens next?
B lymphoctye from person treated with AZT, GCV
AZT
AZT
AZT
AZT
AZT
GCV
GCV
GCV GCV
GCV
AZT AZT
ACTGACTGACTGACTGACT
TGACTGACTGACTGACTGA
cKINASE
Kinases triphosphorylate both AZT, GCV
AZT
AZT
AZT
AZT
AZT- (PO4)3
GCV
GCV
GCV GCV
GCV- (PO4)3
AZT AZT
ACTGACTGACTGACTGACT
TGACTGACTGACTGACTGA
cKINASE
KSHV infected B cell has additional kinase activity
AZT
AZT
AZT
AZT
AZT- (PO4)3
GCV
GCV
GCV GCV
GCV- (PO4)3
AZT AZT
ACTGACTGACTGACTGACT
TGACTGACTGACTGACTGA
cKINASE
v KINASE
What do you think happens to this cell?
AZT
AZT
AZT
AZT
AZT- (PO4)3
GCV
GCV- (PO4)3
GCV GCV- (PO4)3
GCV- (PO4)3
AZT AZT
ACTGACTGACTGACTGACT
TGACTGACTGACTGACTGA
KINASE
v KINASE
Theoretically, there is more cell kill in the
KSHV infected B cells because there is more
phosphorylation of the drugs.
Yes this therapy is toxic, but it targets
virus infected cells.
ACTGACTGACTGACTGACT
ACTGACTGACTGACTGACT
Case 4
• A 45 year old man with long standing HIV
infection presents with focal neurologic deficits.
• Imaging reveals:
Primary CNS
• Occurs in setting of severe immune suppression
• 20X decrease incidence with modern antivirals
• Multifocal (few large 3 to 5 cm lesions), developing at
perivascular cuffs
• Primarily immunoblastic histology
• Monoclonal B cell population, EBV+ ALWAYS
• PET +, thallium +, EBV PCR of CSF for dx vs. brain bx
– Nuc med scan + and PCR + has neg predictive value of 100%
Primary CNS Treatment
• Optimize antiretrovirals to restore or enhance EBV immunity.
• Radiation, 4000cGy, is standard approach
• Considerable morbidity associated with WB XRT
• Rubinstein (ASCO 2006): high dose methotrexate with leucovorin
rescue, temozolomide, and rituximab for induction, then high dose
ARA-C with etoposide infusion for consolidation.
– 52% complete remission rate
– Median progression free survival is 11.5 months
– Median overall survival has not been reached with 27.5 months follow up.
• Median survival pre HAART 4 months; HAART era 15 mos.
Case 5
• 48 year old man presents for follow up of rectal
bleeding, a sensation of rectal fullness, and some
pain with defecation.
• On exam he is found to have a numerous anal
condylomata and a firm 4cm mass just inside the
anal verge which is tender to palpation and slightly
ulcerated.
Squamous Cell Carcinoma
• SCCa of the anus is not AIDS defining, but is an AAM
– Relative risk is 6.8 in women, 37.9 in men
– About 130 to 160 fold increase over HIV- population
• SCCa of the cervix is and AIDS defining illness.
– Incidence still rising as of 1998
– RR is 3.2 in HIV infected women
– 20% of infected women without cervical disease developed SIL
within 3 yrs. (versus 5% of HIV neg women)
Role of HPV
• HIV + persons are 2-6X more likely to have HPV
infection than HIV- persons.
• HIV + persons are 7X more likely to have persistent
HPV infections compared to HIV-.
• HPV infection is poorly controlled in HIV+
– Cell mediated immune defects
– Humoral defects
• HPV16 or 18 is detected in most anal carcinomas
• HPV 16 is detected in nearly 50% of cervical cancers.
HPV Genome and Development of Malignancy
EARLY
GENES
E1
E2
E3
E4
E5
E6
E7
• HPV episomal (circular): E2 controls E6 and E7 gene
transcription.
• When episomal, HPV does no harm.
• By poorly understood mechanisms, HPV can become
linear and integrate into our DNA.
• The E2 gene is disrupted in this process.
HPV Genome and Development of Malignancy
Loss of transcriptional control
of E6 and E7 genes
EARLY
GENES
E1
E 2
E3
E4
E5
E6
E7
binds p53; loss
of suppressor
function
binds RB,
inactivating RB
gene product
• HPV integrates: E2 control is lost and E6 & E7 are over expressed.
• E6 and E7 gene products bind and inactivate p53 and RB
• p53 and RB are tumor suppressor genes.
• Tat up regulates E6 and E7 transcription further inhibiting tumor
suppression.
Clinical Features of Anal Carcinoma
• Most common location for anal cancer is at
transformation zone approximately 2 cm from the
anal verge.
• Rectal bleeding is the most common sign
• 30% have pain or sensation of a mass
• Often asymptomatic
Clinical Features of Cervical Cancer
• Presentation is usually at the junction of the primary
columnar epithelium of the endocervix and the
squamous epithelium of the ectocervix.
• Abnormal bleeding is most common sign
• High grade intraepithelial lesions may not bleed.
• Early disease is usually painless.
Treatment
• High grade squamous cell intraepithelial neoplasia
–
–
–
–
–
–
85% trichloroacetic acid
Liquid N2
Imiquimod (an immune response modifier)
Topical 5-FU
Podophyllotoxin
Surgical resection of the transformation zone
• These therapies do not eradicate the HPV infection and
recurrence of neoplasm is is common.
– Preventive vaccines prevent HPV-16 infx in HIV neg women.
– No evidence to suggest a therapeutic vaccine would work.
Treatment
• Invasive Disease
– HIV infected persons should be offered same
therapy used in HIV negative persons.
– Antiretroviral medications should be continued.
– Responses are comparable to HIV- patients, but
toxicity is much higher.
– Large prospective trials are sorely missing.
AAM - a unique opportunity
• Restore immune response to oncogenic viruses with
combination antiviral therapy
• Control cytokine dysregulation by controlling HIV
infection with combination antiretroviral therapy
• Specific therapy for oncogenic viruses
– Therapeutic vaccination
– Targeted therapies, i.e. directed at virus gene products, i.e.
bevacizumab
– Take advantage of viral proteins, i.e, KSHV, AZT, GCV
And the winner of January Mustache…….
Case 5
• 32 yo year old HIV infected man presents with several day
history of fevers, chills, orthostatic symptoms, extreme
fatigue, anorexia, and dyspnea at rest.
• T = 102 BP 90/40 P=120 RR 34/min O2 sat 92%
Acutely ill appearing man
• Diffuse lymphadenopathy, course rhonchi bilaterally,
decreased bowel sounds, mild diffuse abdominal
tenderness, scattered KS lesions on legs
• Labs: WBC 2.5, Hgb 7.6, Plt 43,000 Na 122, albumin 2.8,
CRP 9.43, LDH 254 (nl).
Castleman’s Disease
• Unicentric Castleman’s Disease
– Described by Benjamin Castleman in 1956.
– Isolated benign lymphoproliferative disorder of young adults
– Pathology is usually hyalin vascular type. (20% are plasma cell
variant)
– M=F, median age 35 yrs
– Large asymptomatic mediastinal or hilar nodes
– Cured with resection, radiation, rituximab
– May be associated with increased risk for B cell lymphoma
Castleman’s Disease
• Described in 1978
• Male predominance, median age 52, younger if HIV infected
• Present with waxing and waning symptoms over variable period of
time; may be difficult to dx if not considered.
• Symptoms: chills, wt loss, anorexia, fatigue, cough, abdominal pain
• Signs: Fever, generalized lymphadenopathy, hepatomegaly,
splenomegaly
• In HIV+ patients, 100% are associated with HHV-8
– Co-exists with Kaposi’s sarcoma
– Pathology: preserved architecture, proliferation of follicles, blood vessels and
plasma cells in the interfollicular areas, increased immunoblasts.
Plasma cell variant Castleman’s disease
Hyaline variant
Pathogenesis
• HHV-8 infection of B lymphocytes (mantle zone lymphs)
• Lytic infection (latent infx in KS)
• HHV-8 codes for vIL-6 which in turn stimulates VEGF
production.
• VEGF production stimulates human IL-6 from endothelial
cells
• IL-6 is responsible for the constitutional symptoms and
generalized adenopathy
• Most of the symptoms are thought related to IL-6 and is a
novel therapeutic target.
Treatment
• Combination chemotherapy
– Etoposide, vincristine, cladribine, chlorambucil, prednisone
– EPOCH-R and CHOP
• Rituximab alone
• High dose AZT and ganciclovir
• Interferon alpha (low dose escalating x 6 to 12 mos)
• Anti – IL-6 receptor
– Tocilizumab and atilzumab
• Cidofovir
… life threatening disease
Immune Reconstitution KS
Before HAART
After 2 months of HAART
Treatment
• When considering treatment other than HAART:
– Treat life threatening disease
– Treat limb or organ threatening disease
– Cosmetically significant lesions
• Complete remission does not protect against later
recurrence.