2008 Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents : Part 4

1. 2008 Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents : Part 4 CDC NIH HIVMA/IDSA 1

2. Human Herpesvirus-8 Disease 2

3. HHV-8: Epidemiology Seroprevalence General population: 1-5% MSM: 20%–77% sub-Saharan Africa: 30%–80% Associated with KS (i.e., classic, endemic, transplant related, and AIDS related) Primary effusion lymphoma (PEL) Multicentric Castleman disease (MCD) 3

4. HHV-8: Epidemiology HHV-8 viremia associated with a nine-fold increased risk for KS compared with HHV-8 seropositive men without HHV-8 viremia HHV-8 viremia almost always accompanies symptomatic episodes of MCD KS and PEL most frequently among HIV-infected persons with CD4+ counts of <200 cells/µL although they can occur at any CD4+ count Episodes of MCD may present at any CD4+ count. 4

5. HHV-8: Epidemiology Ganciclovir, foscarnet, and cidofovir use inhibit the replication of HHV-8 in vitro Patients receiving ganciclovir or foscarnet (but not acyclovir) have a reduced rate for developing KS Incidence of KS has declined dramatically after the introduction of PI drugs and highly active ART 5

6. KSHV Genome 6 Schematic representation of KSHV genome showing some of the genes involved in the pathogenesis of KSHV-related neoplasias. The differential transcriptional pattern found in KS, MCD, and PEL in a signigicant number of cells is shown. Transcripts in brackets refer to occasional lytic (virus replicating) cells in KS lesions. KS—Kaposi's sarcoma; KSHV—Kaposi's sarcoma-associated herpesvirus; MCD—multicentric Castleman's disease; PEL—primary effusion lymphoma.Schematic representation of KSHV genome showing some of the genes involved in the pathogenesis of KSHV-related neoplasias. The differential transcriptional pattern found in KS, MCD, and PEL in a signigicant number of cells is shown. Transcripts in brackets refer to occasional lytic (virus replicating) cells in KS lesions. KS—Kaposi's sarcoma; KSHV—Kaposi's sarcoma-associated herpesvirus; MCD—multicentric Castleman's disease; PEL—primary effusion lymphoma.

7. HHV-8: Clinical Manifestations Most with chronic infection are asymptomatic Primary infection syndrome consisting of fever, rash, lymphadenopathy, bone marrow failure, and occasional rapid progression to KS MCD presents with generalized adenopathy and fever and may progress to multi-organ failure KS mucocutaneous lymph node visceral (occasionally without the presence of skin lesions ) 7

8. HHV-8: Clinical Manifestations Asymptomatic HHV-8 infection is often associated with HHV-8 shedding in the saliva and occasional shedding in genital secretions these may result in HHV-8 transmission to uninfected partners 8

9. HHV-8: Diagnosis Routine screening for HHV-8 by PCR or serologic testing for HHV-8 antibody is not indicated Quantifying HHV-8 in the peripheral blood by PCR is helpful in the diagnosis and management of persons with MCD 9

10. KSHV and LANA in MCD 10 Expression of KSHV proteins in primary effusion lymphoma (PEL) and multicentric Castleman's disease (MCD) is shown. A, KSHV latency-associated nuclear antigen (LANA) is expressed in almost all PEL cells. Inset depicts the speckled nuclear localization of LANA. B, A few tumor cells from a peritoneal biopsy with invasive PEL are immunopositive for viral IL-6. C, Lymph node biopsy from a plasma cell variant of KSHV-associated MCD displays hyalinization of germinal centers, targetoid mantle zone, and increased vascularity. D, Only a subpopulation of mantle zone lymphocytes from an MCD lymph node biopsy stains positive for KSHV LANA with a nuclear staining pattern Expression of KSHV proteins in primary effusion lymphoma (PEL) and multicentric Castleman's disease (MCD) is shown. A, KSHV latency-associated nuclear antigen (LANA) is expressed in almost all PEL cells. Inset depicts the speckled nuclear localization of LANA. B, A few tumor cells from a peritoneal biopsy with invasive PEL are immunopositive for viral IL-6. C, Lymph node biopsy from a plasma cell variant of KSHV-associated MCD displays hyalinization of germinal centers, targetoid mantle zone, and increased vascularity. D, Only a subpopulation of mantle zone lymphocytes from an MCD lymph node biopsy stains positive for KSHV LANA with a nuclear staining pattern

11. Multicentric Castleman Disease 11 Lymph node biopsy from a plasma cell variant of KSHV-associated MCD displays hyalinization of germinal centers, targetoid mantle zone, and increased vascularity.Lymph node biopsy from a plasma cell variant of KSHV-associated MCD displays hyalinization of germinal centers, targetoid mantle zone, and increased vascularity.

12. Kaposi’s Sarcoma 12 E, Extensive cutaneous epidemic/AIDS KS that is cosmetically disfiguring in an East African patient. F, Extensive oral mucosal epidemic/AIDS KS in an East African patient. Oral lesions are also common and frequently involve the gingivae.E, Extensive cutaneous epidemic/AIDS KS that is cosmetically disfiguring in an East African patient. F, Extensive oral mucosal epidemic/AIDS KS in an East African patient. Oral lesions are also common and frequently involve the gingivae.

13. Kaposi’s Sarcoma 13

14. Pulmonary Kaposi’s Sarcoma 14 Chemotherapy response. Patients with symptomatic visceral Kaposi's sarcoma (KS) may benefit significantly from chemotherapy. A, Chest radiograph from a patient with extensive pulmonary KS before chemotherapy. B, After chemotherapy, the patient shows marked improvement of bilateral pulmonary lesions. Chemotherapy response. Patients with symptomatic visceral Kaposi's sarcoma (KS) may benefit significantly from chemotherapy. A, Chest radiograph from a patient with extensive pulmonary KS before chemotherapy. B, After chemotherapy, the patient shows marked improvement of bilateral pulmonary lesions.

15. HHV-8: Preventing Disease Despite observational evidence supporting a role for anti-HHV-8 therapy in preventing the development of KS, the toxicity of current anti-HHV-8 therapy outweighs the potential benefits of administration 15

16. HHV-8: Treating Disease KS regression has been documented after ganciclovir or foscarnet therapy although one small study indicated cidofovir was ineffective The use of IV ganciclovir or oral valganciclovir is, however, recommended in the treatment of MCD and may be useful adjunctive therapy in the treatment of PEL 16

17. HHV-8: Treating Disease Highly active ART that suppresses HIV replication should be administered to all HIV-infected persons with KS, PEL, or MCD Chemotherapy, in combination with ART, should be considered for patients with PEL or visceral/extensive cutaneous KS Rituximab also appears to be an effective alternative to antiviral therapy in the treatment of MCD 17

18. HHV-8 IRIS Fatal IRIS has been reported in persons initiating ART with pre-existing KS and MCD The frequency of HHV-8-associated IRIS is not known but suppression of HIV replication and immune reconstitution are key components of therapy and initiation of ART should not be delayed. 18

19. HHV-8: Pregnancy Routine screening for HHV-8 by PCR or serology is not indicated for pregnant women Perinatal transmission of HHV-8 may infrequently occur cases of KS developing in the infant shortly after birth higher risk of transmission with higher maternal HHV-8 antibody titer substantially higher rate of HHV-8 seropositivity among children born to HHV-8 antibody-positive compared with HHV-8 antibody-negative women increased mortality through 24 months among HIV-infected infants born to HHV-8-seropositive compared with HHV-8-seronegative mothers 19

20. Progressive Multifocal Leukoencephalopathy (JC Virus) 20

21. PML: Epidemiology Caused by the polyoma virus JC virus (JCV) and characterized by focal demyelination 85% of adults are seropositive for JCV Primary JCV infection usually occurs in childhood – asymptomatic Chronic asymptomatic carrier frequent virus detection in urine (30%) and tonsils (40%) of immunologically normal adults PML associated with immunosuppression natalizumab , rituximab HIV 21

22. PML: Epidemiology Incidence of PML has decreased substantially in HAART era PML may still appear in with CD4 > 200 as well as in those on ART PML may develop in the setting of initiating ART and immune reconstitution The overall probability of survival at 6 months was 61.5% in HAART era 1 22

23. PML: Clinical Manifestations Focal neurological deficits, usually with insidious onset and steady progression Any region of the CNS may be involved but more favored are the occipital lobes (with hemianopia) frontal and parietal lobes (hemiparesis and hemisensory deficits) cerebellar peduncles and deep white matter (dysmetria and ataxia) 23

24. PML: Clinical Manifestations The time course of this evolving demyelination, with clinical progression over several weeks, often provides a clue to diagnosis cerebral toxoplasmosis and primary CNS lymphoma characteristically progress more rapidly over hours or just a few days cerebral infarcts begin even more abruptly Headache and fever are not part of the disease Seizures in 20% 24

25. PML: Prognostic Factors CD4 at presentation OR (death) 2.71 if CD4<100 (reference:>=100) Contrast enhancement at presentation (favorable) Radiological improvement at 6 months on ART1 OR 14.0 (2.2-87.2), p = 0.003 25

26. Survival with PML 26

27. PML: Diagnosis Combination of clinical and neuroimaging findings steady progression of focal neurological deficits MRI almost always confirms distinct white matter lesions hyperintense (white) on T2-weighted and FLAIR sequences hypointense (dark) on T1-weighted sequences usually no mass effect or displacement of normal structures Contrast enhancement unusual unless IRIS PCR to identify JCV DNA in CSF (+ in 70-90%) Brain biopsy (rarely necessary) 27

28. PML 28 Progressive multifocal leukoencephalopathy (PML). This unenhanced CT of an HIV-infected boy aged 9 years with PML shows hypodensity of the periventricular white matter in both frontal regions. No mass effect occurs on adjacent structures. Mild dilatation of the lateral ventricles because of brain atrophy is seen. PML is uncommon in children. It is the only disease caused by the JC virus and occurs most frequently as a devastating neurologic syndrome with insidious onset and progression over weeks or months.Progressive multifocal leukoencephalopathy (PML). This unenhanced CT of an HIV-infected boy aged 9 years with PML shows hypodensity of the periventricular white matter in both frontal regions. No mass effect occurs on adjacent structures. Mild dilatation of the lateral ventricles because of brain atrophy is seen. PML is uncommon in children. It is the only disease caused by the JC virus and occurs most frequently as a devastating neurologic syndrome with insidious onset and progression over weeks or months.

29. Inflammatory PML: IRIS Reported to present within the first weeks to months after initiating ART Atypical features that include mass effect of the PML lesions with surrounding edema and sometimes striking contrast enhancement on MRI Likelihood of detecting JCV in CSF may be reduced in these patients compared to “classical” PML 29

30. Inflammatory PML: IRIS The cellular immune response against JCV, mediated by CD8+ T-lymphocytes, is key in the containment of PML progression and has been associated with a favorable clinical outcome However, an “excessive” response related to IRIS may be lethal as a consequence of the inflammatory reaction or, rarely, brain swelling and herniation 30

31. Figure 1. (A and B) Initial brain nuclear MR (NMR), July 2004. Axial fluid-attenuated inversion recover (FLAIR) fast spin echo (FSE) (repetition time [TR]/echo time [TE] = 8,000/120 milliseconds, inversion time [TI] = 2,200 milliseconds) image (A) shows high signal intensity lesion in the white matter of the right frontal and parietal lobes and left centrum semiovale without mass effect. No enhancement was present on contrast enhanced T1-weighted (500/15 milliseconds) image (B). (C through E) Follow-up brain NMR, October 2004 (1 month after initiation of highly active antiretroviral therapy). Axial FLAIR FSE (TR/TE = 8,000/120 milliseconds, TI = 2,200 milliseconds) image (C) shows progression of white matter abnormalities with mass effect and compression of the right ventricle. On T1-weighted (500/15 milliseconds) images (D and E), diffuse enhancement of white matter abnormalities is present. (F and G) Subsequent brain MRI, January 2005 (3 months after immune reconstitution inflammatory syndrome). Axial FLAIR FSE (TR/TE = 8,000/120 milliseconds, TI = 2,200 milliseconds) image (F) shows white matter abnormalities without mass effect; no enhancement is observed in coronal T1-weighted (500/15 milliseconds) image (G).Figure 1. (A and B) Initial brain nuclear MR (NMR), July 2004. Axial fluid-attenuated inversion recover (FLAIR) fast spin echo (FSE) (repetition time [TR]/echo time [TE] = 8,000/120 milliseconds, inversion time [TI] = 2,200 milliseconds) image (A) shows high signal intensity lesion in the white matter of the right frontal and parietal lobes and left centrum semiovale without mass effect. No enhancement was present on contrast enhanced T1-weighted (500/15 milliseconds) image (B). (C through E) Follow-up brain NMR, October 2004 (1 month after initiation of highly active antiretroviral therapy). Axial FLAIR FSE (TR/TE = 8,000/120 milliseconds, TI = 2,200 milliseconds) image (C) shows progression of white matter abnormalities with mass effect and compression of the right ventricle. On T1-weighted (500/15 milliseconds) images (D and E), diffuse enhancement of white matter abnormalities is present. (F and G) Subsequent brain MRI, January 2005 (3 months after immune reconstitution inflammatory syndrome). Axial FLAIR FSE (TR/TE = 8,000/120 milliseconds, TI = 2,200 milliseconds) image (F) shows white matter abnormalities without mass effect; no enhancement is observed in coronal T1-weighted (500/15 milliseconds) image (G).

32. Figure 2. (A) "Ground glass" viral inclusion in oligodendrocyte with inflammatory cells (arrow). Hematoxylin–eosin (HE); x400. (B) Inflammatory cells around vessel wall and within the brain parenchyma (arrows). HE; x400. (C) In situ hybridization to JC virus. The arrow shows oligodendrocyte nuclei. Original magnification, x1,000. Positive reaction for JC.Figure 2. (A) "Ground glass" viral inclusion in oligodendrocyte with inflammatory cells (arrow). Hematoxylin–eosin (HE); x400. (B) Inflammatory cells around vessel wall and within the brain parenchyma (arrows). HE; x400. (C) In situ hybridization to JC virus. The arrow shows oligodendrocyte nuclei. Original magnification, x1,000. Positive reaction for JC.

33. PML: Treatment ART should be started immediately ART should be changed to an effective regimen if already on ART Effectiveness of an ART-intensification strategy in patients with undetectable plasma HIV requires further study More than half of patients with PML experience a remission after initiating effective ART 33

34. PML: Treatment Not recommended cytarabine cidofovir interferon-alpha topotecan Serotonergic 5HT2a receptor antagonists (e.g. mirtazapine) not justified for routine use 5HT2a receptor can serve as the cellular receptor for JCV in a glial cell culture system 34

35. IRIS PML: Treatment No evidence supporting the routine use of corticosteroids in HIV-related PML without an inflammatory response on neuroimaging In those with progressing clinical deficits and neuoroimaging features suggesting inflammatory disease (edema, swelling, and contrast enhancement), corticosteroid treatment is justified Although some have suggested stopping ART in the face of PML-IRIS, this is likely counterproductive in the longer run and is not recommended 35

36. PML: Treatment Failure Working definition continued clinical worsening and continued detection of CSF JCV at 3 months Optimize ART Experimental options 36