FAST FACTS AND CONCEPTS #213

PROGNOSIS IN HIV AND AIDS

Steven Oppenheim MD

Introduction The prognosis of patients with HIV/AIDS (Human Immunodeficiency Virus infection/Acquired Immune Deficiency Syndrome) has improved dramatically since 1996 for those who have access to appropriate treatment. Due to the success of combination antiretroviral therapy (cART) since 1996 as well as improvements in the prevention and treatment HIV complications, over 80% of patients are now alive 10 years after sero-conversion,. Deaths from opportunistic infections (OI) have declined while mortality from other co-morbidities has become more common (e.g. hepatitis B and C infection, renal failure, non-HIV-related cancers, cardiovascular disease, suicide, and complications of substance abuse). In fact, patients with CD4 counts >200 cells/mm3 are more likely to die from non-HIV-related illnesses than they are from complications of AIDS, at least over a time-frame of one decade. This Fast Fact discusses prognostication in patients who are suffering life-threatening complications related to HIV infection using data where cART was available. Fast Fact #214 will discuss prognosis specifically for malignancies arising in the setting of HIV infection.

Prognostic Principles

· Numerous factors affect prognosis such as age, remaining antiviral treatment options, opportunistic infections’ response to therapy, the development of untreatable complications, functional status, nutritional status, CD4 cell count, and HIV viral load.

· In the pre-cART era median survival for people with a CD4 count <>

· Due to the rapidly changing field of HIV medicine, close collaboration with the patient’s HIV provider is mandatory. While the following data are the best available they remain incomplete, may become outdated as therapies evolve, and should be applied to individual patients cautiously.

· Survival for all the HIV associated complications discussed in this Fast Fact has improved due to the use of cART.

Common causes of death in patients with HIV/AIDS with available survival data

· Disseminated mycobacterium avium complex infection: median survival is ~10 months with optimal therapy.

· Pneumocystis pneumonia: survival for all patients presenting is 80-90%. Short-term ICU survival is 75% in patients on cART and 37% not on cART.

· Disseminated cytomegalovirus infection (including retinitis): the largest prospective cohort study demonstrated a median survival of 35 months for all patients on cART compared with 8 months for those not using cART. Six month survival is 61-73% for patients not taking or not responding to cART, but 98% for patients with low CD4 counts who initiate and respond well to cART (CD4 count increases to over 50 cells/mm3).

· Toxoplasma encephalitis: 77-90% of patients are alive after 12 months if on cART, and most who die do so within 6 months of diagnosis. Persistence of altered mental status after initiation of therapy is a strong predictor of early death.

· Progressive multifocal leukoencephalopathy: median survival is ~11 months on cART, 4 months without cART. If cART is started after PML is diagnosed 1 year survival is 58% vs. 24% for those who develop PML already cART.

· AIDS Dementia complex: is caused by HIV and results in progressive cognitive, motor, and behavioral decline. The median survival is 40-81 months from the time of diagnosis; shorter if the CD4 cell count remains <200>5,000 copies/ml.

· AIDS wasting syndrome: is defined by the involuntary loss of >10% body weight along with fever not associated with an OI or neoplasm, and either chronic diarrhea or weakness. Patients with very low lean body mass index (mass in kilograms/height in meters squared) – less than 14.5kg/m2 – have a median survival of ~16 months. These data are from the mid-1990s and it is unclear if the prognosis has changed in the last decade. With unintentional weight loss which does not meet the syndrome definition (loss of 5-10% body weight) there is still a four-fold increased risk of death over 6 months.

References

1. Antinori A, Cingolani A, Lorenzini P, et al. 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). J Neurovirol. 2003; 9(suppl 1):47-53.

2. Antinori A, Larussa D, Cingolani A et al. Prevalence, associated factors and prognostic determinants of AIDS-related Toxoplasmic encephalitis in the era of advanced highly active antiretroviral therapy. Clin Infect Dis. 2004; 39:1681-1691.

3. Bhaskaran K, Hamouda O, Sannes M, et al. Changes in the Risk of Death After HIV Seroconversion Compared With Mortality in the General Population. JAMA. 2008; 300(1):51-59.

4. Clifford DB, Yiannoutsos C, Glicksman M, et al. HAART improves prognosis in HIV-associated progressive multifocal leykoencephalopathy. Neurology. 1999; 52:623-625.

5. Coakley E, Samore M, Gillis J, et. Al. The values of quantitative serum HIV-1 RNA levels and CD4 cell counts of <50 x 10 6 cells/L. AIDS. 2000; 14:1147-1153.

6. D’Avignon LC, Schofield CM, Hospenthal DR. Pneumocystis Pneumonia. Semin Respir Crit Care Med. 2008; 29(2):132-40.

7. Dore GJ, MvDonald A, Yueming L, et al. Marked improvement in survival following AIDS dementia complex in the era of highly active antiretroviral therapy. AIDS. 2003; 17:1539-1545.

8. Dworkin MS, Wan PC, Hanson DL, Jones JL. Progressive Multifocal leukoencephalopathy: Improved survival of human immunodeficiency virus-infected patients in the protease-inhibitor era. J Infect Dis. 1999; 180:621-625.

9. Gasnault J, Taoufik Y, Goujard C et al. Prolonged survival without neurological improvement in patients with AIDS-related progressive multifocal leukoencephalopathy on potent combined antiretroviral therapy. J Neurovirol. 1999; 13:1426-1428.

10. Hoffmann C, Ernst M, Wolf E, et al. Evolving characteristics of toxoplasmosis in patients infected with human immunodeficiency virus-1: clinical course and Toxoplasma gondii-specific immune responses. Clin Microbiol Infect. 2007; 13:510-515.

11. Karakousis PC, Moore RD, Chaisson RE. Mycobacterium avium complex in patients with HIV infection in the era of highly active antiretroviral therapy. Lancet Infectious Diseases. 2004; 4:557-565.

12. Kempen JH, Jabs DA, Wilson LA, et al. Mortality risk for patients with cytomegalovirus retinitis and acquired immune deficiency syndrome. Clin Infect Dis. 2003; 37:1365-1373.

13. Krentz HB, Kliewer G and Gill MJ. Changing mortality rates and causes of death for HIV-infected individuals living in Southern Alberta, Canada from 1998 to 2003. HIV Medicine. 2005; 6:99-106.

14. MacArthur RD, et.al. Comparison of prognostic significance of latest CD4 cell count and HIV RNA levels in patients with advanced HIV infection on highly active antiretroviral therapy. HIV Clin Trials. 2005; 6:127-135.

15. Melchior JC, Niyongabo T, Henzel D, Durack-Bown J, Boulier A. Malnutrition and wasting, immunodepression, and chronic inflammation as independent predictors of survival in HIV-infected patients. Nutrition. 1999; 15:865-869.

16. Mikaelsson L, Jacobson G, Andersson R. Pneumocystis pneumonia: a retrospective study 1991-2001 in Gothenburg, Sweden. J Infect. 2006; 53:260-265.

17. Moore RD, CHaisson RE. Natural history of opportunistic disease in an HIV infected urban clinical cohort. Ann Intern Med. 1996; 124:633-642.

18. Morris A, Wachter RM, Luce J, Turner J and Huang L. Improved survival with highly active antiretroviral therapy in HIV-infected patients with severe Pneumocystis carinii pneumonia. AIDS. 2003; 17:73-80.

19. Selwyn PA, Forstein M. Overcoming the False Dichotomy of Curative vs Palliative for Late-Stage HIV/AIDS “Let me live the way I want to live, until I can’t”: JAMA. 2003; 290:806-814.

20. Shen JM, Blank A, Selwyn PA: Predictors of Mortality for Patients with Advanced Disease in an HIV Palliative Care Program: J AIDS. 2005; 40:445-447.

21. Shetty SM, Vanston VJ, Alexander C. The Hospice and Palliative Medicine Approach to Caring for Patients with HIV/AIDS. UNIPAC-7, 3^rd Ed. American Academy of Hospice and Palliative Medicine. 2008.

22. Tang AM, Forrester J, Spieglman D, et al. Weight loss and survival in HIV-positive patients in the era of highly active antiretroviral therapy. JAIDS. 2002; 31:230-236.

23. Tozzi V, Balestra P, Serraino D, et al. Neurocognitive impairment and survival in a cohort of HIV-infected patients treated with HAART. AIDS Res Human Retrov. 2005; 21:706-713.

24. The Antiretroviral Therapy (ART) Cohort Collaboration. Prognosis of HIV-1-infected patients up to 5 years after initiation of HAART: collaborative analysis of prospective studies. AIDS. 2007; 21:1185-1197.

25. The CASCADE Collaboration. Effective Therapy has altered the spectrum of cause-specific mortality following HIV-seroconversion. AIDS. 2006; 20: 741-749.

26. Welch K, Morse A, et al. The clinical profile of end-stage AIDS in the era of highly active antiretroviral therapy. AIDS Pt Care and STDs. 2002; 16:75-81.

Author Affiliation: San Diego Hospice at the Institute for Palliative Care, San Diego, California.

#212: Phantom Limb Pain

FAST FACTS AND CONCEPTS #212

PHANTOM LIMB PAIN

Kavitha Ramchandran MD and Joshua Hauser MD

Background Phantom limb pain (PLP) can be a painful and debilitating consequence of limb amputation from any cause including trauma, cancer, and vascular diseases. This Fast Fact will review the evaluation and management of PLP.

Definition and Characteristics PLP describes pain which patients perceive as coming from an amputated limb as if it were still contiguous with the body. It is distinct from pain at the actual site of the amputation (‘stump pain’). Patients usually experience PLP as occurring in the distal part of the phantom limb and can describe it as feeling ‘burning,’ ‘tingling,’ ‘sharp,’ and ‘cramping.’ Uncomfortable perceptions of limb distortion (such as retraction into the stump) are also reported. PLP is most commonly seen after limb amputation, but similar syndromes can occur with the removal of other body parts including breasts, testicles, eyes, and tongue.

Epidemiology PLP occurs in 50-80% of patients after amputation, but is severe in 5-10% of cases. Risk factors for developing PLP include: tumor-related amputations, chronic limb pain prior to amputation, and significant pain the day of amputation. Despite this, meticulous peri-operative analgesia with epidural anesthesia has not been clearly shown to prevent PLP.

Pathophysiology Both central and peripheral mechanisms are believed to mediate PLP and are incompletely understood. Amputation can lead to reorganization of the somatosensory cortex with ‘remapping’ of the location of amputated limb into the mouth and chin areas. For these patients stimulation of the mouth or ipsilateral face can cause sensations, including pain, that seem be originating from the phantom limb. Central sensitization from preexisting chronic limb pain as well as ectopic discharges from the stump neuroma are also implicated.

Therapy While both drug and non-drug therapies have been investigated, treatment of phantom limb pain remains poorly studied and is largely empiric. Due to the complex nature of PLP and its therapies, a multi-disciplinary approach to treatment is mandatory including pain specialists, physiatrists, physical and occupational therapists, and psychologists.

· Drug treatment: Most clinicians approach PLP as a neuropathic pain syndrome. A few small controlled trials have shown positive results with gabapentin, ketamine, and opioids, but not with tricyclic antidepressants. Despite this, there is insufficient evidence to judge the superiority or inferiority of any drug therapy for PLP, and most clinicians empirically use the full range of adjuvant analgesics along with opioid therapy if needed in its management.

· Non-drug treatments: Non-pharmacologic therapies have also been investigated. These include myoelectrical prostheses, transelectrical nerve stimulation, and mirror therapy. In small studies, the regular use of a myoelectric prosthesis (a prosthesis with electrodes embedded in the socket which stimulate nerves in the stump), has been demonstrated to alter cortical re-organization and reduce pain. For those patients for whom a myoelectric prosthesis is not possible, transelectrical nerve stimulation (a TENS unit) to the stump can have a similar affect. A newly investigated approach is mirror therapy. Mirror therapy involves the placement of mirrors to create the illusion of an intact limb (patients visually perceive that they have an intact limb where their stump is). Patients are taught to move both the real and the illusory limb with the hypothesis that this increases control of the brain over the phantom limb and leads to a decrease in PLP. In one small controlled study 100% of patients who underwent mirror therapy had a decrease in pain.

References

1. Devor M and Seltzer Z. Pathophysiology of damaged nerves in relation to chronic pain. In: Wall PD and Melzack RA, Editors. Textbook of Pain (4th Ed). Churchill-Livingstone, New York (1999), pp. 128–164.

2. Bone M, Critchley P, Buggy D. Gabapentin in postamputation phantom limb pain: A randomized, double-blind, placebo-controlled, cross-over study. Reg Anesth Pain Med. 2002; 27:481-486.

3. Robinson LR, Czerniecki JM, Ehde DM, et al. Trial of amitriptyline for relief of pain in amputees: results of a randomized controlled study. Arch Phys Med Rehabil. 2004; 85:1-6.

4. Flor H. Phantom limb pain: characteristics, causes, treatment. Lancet Neurol. 2002; 1:182-189.

5. Dworkin RH et al. Pharmacologic management of neuropathic pain: evidenced-based recommendations. Pain 2007. 132:237-251.

6. Chan BL, Witt R. Mirror therapy for phantom limb pain. N Engl J Med. 2007; 357:2206-7.

Author Affiliations Northwestern University Feinberg School of Medicine Palliative Care and Home Hospice Program.