4
Imminently Fatal or Severely Disabling HIV-Associated Conditions

Even in the era of potent antiretroviral therapy, patients with HIV infection continue to develop very aggressive, generally untreatable conditions that are imminently fatal or severely disabling. Although much less common than in the early epidemic, these conditions resemble the AIDS-defining infections or cancers that were considered appropriate for disability allowance in the previous HIV Infection Listings. This chapter identifies and describes these conditions and discusses how the committee believes they should be addressed in the HIV Infection Listings.

IMMINENTLY FATAL OR SEVERELY DISABLING CONDITIONS

Although the treatment of HIV infection has improved greatly since the beginning of the epidemic with the development of combination antiretroviral therapy, some rare but very aggressive conditions occur that can rapidly lead to death or severe disability (see Box 4-1). These HIV-associated conditions are generally untreatable even with combination antiretroviral therapy, resulting in limited recovery. The average length of survival for people afflicted with these conditions ranges from 3 to 24 months. The probability that claimants with these conditions will die or be seriously disabled within a year is so high that the committee believes they deserve immediate disability. As opposed to allowances made based on low CD4 counts as discussed in Chapter 3, allowances resulting from these aggressive conditions would be permanent on verification of the condition and would not require reevaluation.



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4 Imminently Fatal or Severely Disabling HIV-Associated Conditions Even in the era of potent antiretroviral therapy, patients with HIV infection continue to develop very aggressive, generally untreatable condi- tions that are imminently fatal or severely disabling. Although much less common than in the early epidemic, these conditions resemble the AIDS- defining infections or cancers that were considered appropriate for disabil- ity allowance in the previous HIV Infection Listings. This chapter identifies and describes these conditions and discusses how the committee believes they should be addressed in the HIV Infection Listings. IMMINENTLY FATAL OR SEVERELY DISABLING CONDITIONS Although the treatment of HIV infection has improved greatly since the beginning of the epidemic with the development of combination antiretro- viral therapy, some rare but very aggressive conditions occur that can rap- idly lead to death or severe disability (see Box 4-1). These HIV-associated conditions are generally untreatable even with combination antiretroviral therapy, resulting in limited recovery. The average length of survival for people afflicted with these conditions ranges from 3 to 24 months. The probability that claimants with these conditions will die or be seriously disabled within a year is so high that the committee believes they deserve immediate disability. As opposed to allowances made based on low CD4 counts as discussed in Chapter 3, allowances resulting from these aggressive conditions would be permanent on verification of the condition and would not require reevaluation. 

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4 HIV AND DISABILITY BOX 4-1 Immediately Fatal or Severely Disabling Conditions Documented presence of one of the following conditions ought to be considered a permanent disability: • HIV-associated dementia; • Multicentric Castleman’s disease; • Kaposi’s sarcoma involving the pulmonary parenchyma; • Primary central nervous system lymphomas; • Primary effusion lymphoma; or • Progressive multifocal leukoencephalopathy. HIV-Associated Dementia HIV-associated dementia (also known as AIDS dementia complex, HIV dementia, or HIV encephalopathy) is part of the spectrum of HIV- associated neurocognitive disorders (HANDs), discussed in Chapter 5. It refers to severe impairment (measured as performance greater than two standard deviations below normal) in at least two cognitive domains that extremely limits everyday functioning (Antinori et al., 2007). The main features are disabling cognitive impairment accompanied by motor dysfunc- tion, speech problems, and behavioral change. This results in an inability to carry out more than the most basic activities of daily living independently (e.g., eating, bathing, dressing) and an inability to work. Before the introduction of combination antiretroviral therapy, the mean survival of patients with HIV-associated dementia was 3 to 6 months; marginal improvement lasting over several months may be gained through use of combination antiretroviral therapy (Tozzi et al., 2007). Incidence of HAND in developed countries has declined ten-fold as a result of combi- nation antiretroviral therapy (Bhaskaran et al., 2008; Kaul, 2009). HIV- associated dementia by definition qualifies as a severely disabling condition and is observed in 5 percent or fewer of HIV-infected persons (Heaton et al., 2009). HIV-associated dementia typically occurs after years of HIV infection and is associated with low CD4 levels and high plasma viral loads. Diagno- sis can be made by a clinician based on a mental status evaluation assessing the domains of cognitive functioning. Although HIV encephalopathy is currently considered under sublistings 14.08G and 114.08G, the term is no longer widely used in the treatment of adults infected with HIV. HIV-associated dementia is characterized by

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 IMMINENTLY FATAL OR SEVERELY DISABLING CONDITIONS cognitive or motor dysfunction that limits ability to perform daily functions and therefore should be considered a severely disabling condition in Part A of the HIV Infection Listing. Multicentric Castleman’s Disease Multicentric Castleman’s disease (MCD) resembles advanced-stage non- Hodgkin’s lymphoma, with diffuse nodal involvement and “B” symptoms, although the proliferative tissue is histologically inflammatory, but benign. MCD can affect the liver and spleen. It has been associated with high levels of the marker of immune activation interleukin-6. Like Kaposi’s sarcoma, multicentric Castleman’s disease is associated with infection by the human herpesvirus-8 (HHV-8). Unlike Kaposi’s, how- ever, widespread availability of combination antiretroviral therapy has not led to decreased prevalence of this disease. The prognosis for multicentric Castleman’s disease is poor, with an overall mortality rate of 44 percent (Mylona et al., 2008). However, advances in therapy have led to longer survival; a recent study of 21 patients found a 2-year survival rate of 95 per- cent with rituximab (Bower et al., 2007). Malignancies have been reported in 32 percent of patients (Bowne et al., 1999; Newlon et al., 2007). The disease occurs more frequently in men and in people ages 30 through 50. Although MCD is uncommon in pediatric populations, children may have better outcomes than adults (Newlon et al., 2007; Parez et al., 1999). Diagnosing multicentric Castleman’s disease has many uncertainties be- cause it exhibits nonspecific characteristics and can mimic other neoplasms. Definitive diagnosis can be made by surgical resection and histopathologic findings showing B-cell proliferation. While the Epstein-Barr virus (EBV) is not consistently associated with MCD, HHV-8 infection is nearly uni- versal. Combined chemotherapy is recommended for patients with good health status; however, those with poor health status should be considered for treatment with steroids and single-agent chemotherapy. Rituximab and antiretroviral therapy both may be effective (Stebbing et al., 2008; Sullivan et al., 2008). Multicentric Castleman’s disease is not specifically indicated in the cur- rent Listing of Impairments. However, given its severity in those infected with HIV, the disease should be considered in the HIV Infection Listings. Kaposi’s Sarcoma Involving the Pulmonary Parenchyma Kaposi’s sarcoma is a fatal condition when it manifests in the lungs, where it tends to grow as sheets of tumor tissue in the peribronchial and perivascular axial interstitial spaces. Chest radiographs typically show a patchy infiltrating process. The disease is commonly multifocal and pleural

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 HIV AND DISABILITY effusions are common. These are typically hemorrhagic, but cytologically benign. The most common symptoms are progressive dyspnea, nonproduc- tive cough, and fever. Even with the use of combination antiretroviral therapy, survival for pulmonary Kaposi’s sarcoma has been shown to be 4 to 19 months (Hannon et al., 1998; Holkova et al., 2001; Palmieri et al., 2006). Approximately 20 percent of deaths related to pulmonary Kaposi’s sarcoma are due to com- plications of the disease, such as upper airway obstruction or parenchymal destruction (Gasparetto et al., 2009; Restrepo et al., 2006). Pulmonary Kaposi’s sarcoma is diagnosed through a combination of tests (clinical, radiographic, and laboratory) and specifically by bron- choscopy and transbronchial biopsy (Aboulafia, 2000; Gasparetto et al., 2009). Kaposi’s sarcoma in the pulmonary parenchyma is currently considered as part of sublistings 14.08E2b and 114.08E2b. The committee concludes that due to the aggressive and fatal nature of pulmonary Kaposi’s sarcoma, it needs to be retained in the HIV Infection Listings and should be consid- ered a permanent disability. Primary Central Nervous System Lymphomas Primary central nervous system lymphomas are aggressive B-cell, non- Hodgkin’s lymphomas arising within the central nervous system (CNS). Although uncommon, they are associated with advanced stages of HIV- induced immunodeficiency. The peripheral CD4 count is in the 0 to 50 cells/mm3 range. EBV infection is almost invariably demonstrated in the CNS. Prognosis is extremely poor even with the initiation of combination antiretroviral therapy. This therapy has resulted in decreased incidence and increased median survival for HIV-infected patients with primary CNS lymphomas (Bower et al., 2006). With antiretroviral therapy, 2-year survival increased to 29 percent (Biggar et al., 2005) with a median survival of 8 to 18 months (Diamond et al., 2006; Hoffmann et al., 2001). Magnetic resonance imaging (MRI) or contrast-enhanced computed tomography (CT) usually show multiple lesions in almost any location, but usually deep in the white matter of the brain in the periventricular region. Unlike lymphomas listed in 13.05 and 113.05, these lymphomas spe- cifically impair people living with advanced stages of immunodeficiency. Therefore they should be considered under the HIV Infection Listings and should be provided permanent disability because of the severity of the disease.

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 IMMINENTLY FATAL OR SEVERELY DISABLING CONDITIONS Primary Effusion Lymphoma Primary effusion lymphoma (PEL, also called body cavity lymphoma) is a rare, aggressive type of B-cell, non-Hodgkin’s lymphoma arising within body cavities (e.g., pleural space, pericardium, peritoneum). The median survival for PEL is around 6 months. Prognosis is poor, even with combi- nation chemotherapy. Death in patients with PEL is frequently associated with opportunistic infection, HIV-related complication, and progression of lymphoma (Chen et al., 2009). Primary effusion lymphoma accounts for 1 to 5 percent of AIDS-related lymphomas (Navarro and Kaplan, 2006). PEL is associated with evidence of HHV-8 and EBV infection, although the involvement of these infections in its pathogenesis remains poorly un- derstood. Patients with primary effusion lymphoma usually also have low CD4 counts. PEL is diagnosed by pathological analysis of the involved tis- sue and biopsies of body cavity-lining tissue (Chen et al., 2009). Primary effusion lymphoma is a fatal condition. It is not specifically considered in the Malignant Neoplastic Diseases section of the Listing of Impairments (13.00 and 113.00) and is appropriate for inclusion in the HIV Infection Listings. Progressive Multifocal Leukoencephalopathy Progressive multifocal leukoencephalopathy (PML) is a rare disorder caused by polyomavirus JC. Asymptomatic primary infection in the CNS from polyomavirus JC occurs in childhood; antibodies can be found in 86 percent of all adults, where it is latent in the kidneys and lymphoid organs (Weber et al., 1997). In individuals with compromised immune systems, the virus reactivates, spreads to the brain, and has damaging inflammatory effects. PML occurs more frequently in people with AIDS than in others with compromised immune systems, perhaps because of how HIV affects brain tissue or interacts with polyomavirus JC (Berger, 2003). The most prominent symptoms, which evolve over several days to several weeks, are clumsiness; progressive weakness; and visual, speech, and sometimes personality changes (NINDS, 2010). Untreated, PML results in death over a period of weeks to months. Nearly 5 percent of HIV-infected people develop PML prior to combination antiretroviral therapy (NINDS, 2010). Since the advent of potent antiretro- viral therapy, the median survival of patients with PML has increased to 16 to 26 months (Berenguer et al., 2003; Falcó et al., 2008); 40 to 50 percent of patients survive PML (Antinori et al., 2003; De Luca et al., 2000), al- though most with significant neurologic sequelae. PML continues to occur in HIV-1-infected patients despite combination antiretroviral therapy. These

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 HIV AND DISABILITY patients may have a shorter median survival compared with patients who do not receive treatment (Wyen et al., 2004). Diagnosis of PML includes brain biopsy, MRI with consistent white- matter lesions, and confirmation of the presence of polyomavirus JC (NINDS, 2010). There is no specific treatment for PML. Therapy with cytosine arabinoside, interferon-alfa, and cidofovir has not shown any benefit in the treatment of PML compared to antiretroviral therapy alone (De Luca et al., 2008). PML is considered under the current 14.08D sublisting. Because of its aggressive nature in HIV-infected patients, it should be included in the HIV Infection Listings as a condition that warrants permanent disability. PLACE IN THE DETERMINATION PROCESS The rare conditions described above are generally untreatable and are fatal or extremely disabling. Because of the gravity of these conditions, the committee believes these claimants need to be considered separately from other HIV infection claimants. To expedite their claims, these claimants ought to receive permanent disability on confirmation of diagnosis. Supple- mental Security Income applicants may qualify for presumptive disability on presentation at the Social Security Administration (SSA) field offices, which allows for immediate payment of benefits for up to 6 months as the claim goes through the five-step disability determination process. It is worth noting that in 2007, SSA launched a program called “com- passionate allowances” as a way of quickly identifying conditions that should be deemed permanently disabling and providing these claimants with disability benefits. Compassionate allowance cases require minimal objective medical evidence to determine the claimant disabled and eligible to receive benefits. Notably, PML is also one of less than 100 conditions identified by SSA as so serious that claimants receive a compassionate allowance. Compassionate allowance cases progress through Steps 1 and 2 and either meet or equal the listings in Step 3 (see Figure 1-1). It is important to note that conditions identified as compassionate allowances are typically found in the Listing of Impairments under the appropriate body system. If the condition cannot be verified, the claim will proceed through Steps 4 and 5 of the determination process. The committee believes the conditions identified in this chapter are so severe that SSA may want to consider them as compassionate allowance conditions. RECOMMENDATION 2. SSA should make disability determination allowances permanent for imminently fatal and/or severely disabling

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 IMMINENTLY FATAL OR SEVERELY DISABLING CONDITIONS HIV-associated conditions. These conditions may be appropriate as compassionate allowances. These include the following: • HIV-associated dementia; • Multicentric Castleman’s disease; • Kaposi’s sarcoma involving the pulmonary parenchyma; • Primary central nervous system lymphomas; • Primary effusion lymphoma; and • Progressive multifocal leukoencephalopathy. REFERENCES Aboulafia, D. M. 2000. The epidemiologic, pathologic, and clinical features of AIDS-associated pulmonary Kaposi’s sarcoma. Chest 117(4):1128–1145. Antinori, A., A. Cingolani, and P. Lorenzini. 2003. Clinical epidemiology and survival of progressive multifocal leukoencephalopathy in the era of highly active antiretroviral therapy: Data from the Italian registry investigative neuro AIDS (IRINA). Journal for Neuroirology 9(Suppl):1–25. Antinori, A., G. Arendt, J. T. Becker, B. J. Brew, D. A. Byrd, M. Cherner, D. B. Clifford, P. Cinque, L. G. Epstein, K. Goodkin, M. Gisslen, I. Grant, R. K. Heaton, J. Joseph, K. Marder, C. M. Marra, J. C. McArthur, M. Nunn, R. W. Price, L. Pulliam, K. R. Robertson, N. Sacktor, V. Valcour, and V. E. Wojna. 2007. Updated research nosology for HIV-associated neurocognitive disorders. Neurology 69(18):1789–1799. Berenguer, J., P. Miralles, J. Arrizabalaga, E. Ribera, F. Dronda, J. Baraia-Etxaburu, P. Domingo, M. Márquez, Francisco J. Rodriguez-Arrondo, F. Laguna, R. Rubio, J. L. Rodrigo, J. Mallolas, and V. de Miguel. 2003. Clinical course and prognostic factors of progressive multifocal leukoencephalopathy in patients treated with highly active anti- retroviral therapy. Clinical Infectious Diseases 36(8):1047–1052. Berger, J. R. 2003. Progressive multifocal leukoencephalopathy in acquired immunodeficiency syndrome: Explaining the high incidence and disproportionate frequency of the ill- ness relative to other immunosuppresive conditions. Journal of Neuroirology 9(Suppl 1):38–41. Bhaskaran, K., C. Mussini, A. Antinori, A. S. Walker, M. Dorrucci, C. Sabin, A. Phillips, and K. Porter. 2008. Changes in the incidence and predictors of human immunodeficiency virus-associated dementia in the era of highly active antiretroviral therapy. Annals of Neurology 63(2):213–221. Biggar, R. J., E. A. Engels, S. Ly, A. Kahn, M. J. Schymura, J. Sackoff, P. Virgo, and R. M. Pfeiffer. 2005. Survival after cancer diagnosis in persons with AIDS. Journal of Acquired Immune Deficiency Syndromes 39(3):293–299. Bower, M., T. Powles, M. Nelson, S. Mandalia, B. Gazzard, and J. Stebbing. 2006. Highly active antiretroviral therapy and human immunodeficiency virus-associated primary ce- rebral lymphoma. Journal of the National Cancer Institute 98(15):1088–1091. Bower, M., T. Powles, S. Williams, T. N. Davis, M. Atkins, S. Montoto, C. Orkin, A. Webb, M. Fisher, M. Nelson, B. Gazzard, J. Stebbing, and P. Kelleher. 2007. Brief communica- tion: Rituximab in HIV-associated multicentric Castleman disease. Annals of Internal Medicine 147(12):836–839. Bowne, W. G., J. J. Lewis, and D. A. Filippa. 1999. The management of unicentric and mul- ticentric Castleman’s disease: A report of 16 cases and a review of the literature. Cancer 85(3):706–717.

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0 HIV AND DISABILITY Chen, S. Y., W. J. Moss, S. S. Pipkin, and W. McFarland. 2009. A novel use of AIDS surveil- lance data to assess the impact of initial treatment regimen on survival. International Journal of STD & AIDS 20(5):330–335. De Luca, A., M. L. Giancola, A. Ammassari, S. Grisetti, M. G. Paglia, M. Gentile, A. Cingolani, R. Murri, G. Liuzzi, A. D’Arminio Monforte, and A. Antinori. 2000. The effect of potent antiretroviral therapy and JC virus load in cerebrospinal fluid on clinical outcome of patients with AIDS-associated progressive multifocal leukoencephalopathy. Journal of Infectious Diseases 182(4):1077–1083. De Luca, A., A. Ammassari, P. Pezzotti, P. Cinque, J. Gasnault, J. Berenguer, S. Di Giambenedetto, A. Cingolani, Y. Taoufik, P. Miralles, C. M. Marra, and A. Antinori for Gesida 9/99, IRINA, ACTG 363 study groups. 2008. Cidofovir in addition to anti- retroviral treatment is not effective for AIDS-associated progressive multifocal leukoen- cephalopathy: A multicohort analysis. AIDS 22(14):1759–1767. Diamond, C., T. H. Taylor, T. Im, M. Miradi, M. Wallace, and H. Anton-Culver. 2006. Highly active antiretroviral therapy is associated with improved survival among patients with AIDS-related primary central nervous system non-Hodgkin’s lymphoma. Current HIV Research 4(3):375–378. Falcó, V., M. Olmo, S. V. del Saz, A. Guelar, J. R. Santos, M. Gutiérrez, D. Colomer, E. Deig, G. Mateo, M. Montero, E. Pedrol, D. Podzamczer, P. Domingo, and J. M. Llibre. 2008. Influence of HAART on the clinical course of HIV-1-infected patients with progressive multifocal leukoencephalopathy: Results of an observational multicenter study. Journal of Acquired Immune Deficiency Syndromes 49(1):26–31. Gasparetto, T. D., E. Marchori, S. Lourenco, G. Zanetti, A. Domingues Vianna, A. A. Santos, and L. F. Nobre. 2009. Pulmonary involvement in Kaposi sarcoma: Correlation between imaging and pathology. Orphanet Journal of Rare Diseases 4(18). Hannon, F. B., P. J. Easterbrook, S. Padley, F. Boag, R. Goodall, and R. H. Phillips. 1998. Bronchopulmonary Kaposi’s sarcoma in 106 HIV-1 infected patients. International Jour- nal of STD & AIDS 9(9):518–525. Heaton, R. K., D. Franklin, D. Clifford, S. P. Woods, M. R. Mindt, O. Vigil, M. Taylor, T. Marcotte, J. H. Atkinson, and I. Grant. 2009. HIV-associated neurocognitie impairment (NCI) remains prealent in the era of combination antiretroiral therapy (cART): The CHARTER Study. Paper presented at 16th Conference on Retroviruses and Opportunis- tic Infections, Montreal, Canada, February 8–11. Hoffmann, C., S. Tabrizian, E. Wolf, C. Eggers, A. Stoehr, A. Plettenberg, T. Buhk, H.-J. Stellbrink, H.-A. Horst, H. Jäger, and T. Rosenkranz. 2001. Survival of AIDS patients with primary central nervous system lymphoma is dramatically improved by HAART- induced immune recovery. AIDS 15(16):2119–2127. Holkova, B., K. Takeshita, D. M. Cheng, M. Volm, C. Wasserheit, R. Demopoulos, and A. Chanan-Khan. 2001. Effect of highly active antiretroviral therapy on survival in patients with AIDS-associated pulmonary Kaposi’s sarcoma treated with chemotherapy. Journal of Clinical Oncology 19(18):3848–3851. Kaul, M. 2009. HIV-1 associated dementia: Update on pathological mechanisms and thera- peutic approaches. Current Opinion in Neurology 22(3):315–320. Mylona, E. E., I. G. Baraboutis, L. J. Lekakis, O. Georgiou, V. Papastamopoulos, and A. Skoutelis. 2008. Multicentric Castleman’s disease in HIV infection: A systematic review of the literature. AIDS Reiews 10(1):25–35. Navarro, W. H., and L. D. Kaplan. 2006. AIDS-related lymphoproliferative disease. Blood 107(1):13–20. Newlon, J. L., M. Couch, and J. Brennan. 2007. Castelman’s disease: Three case reports and a review of the literature. Ear, Nose & Throat Journal 86(7):414–418.

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