HIV-infected patients

The most recent advance in treating HIV infections has been to simultaneously attack the virus on a second front using a protease inhibitor. Recall from Section 27.10 that proteases are enzymes that catalyze the hydrolysis of proteins at specific points. When HIV uses a cell s DNA to synthesize its own proteins, the initial product is a long polypeptide that contains several different proteins joined together. To be useful, the individual proteins must be separated from the aggregate by protease-catalyzed hydrolysis of peptide bonds. Protease inhibitors prevent this hydrolysis and, in combination with reverse transcriptase inhibitors, slow the reproduction of HIV. Dramatic reductions in the viral load in HIV-infected patients have been achieved with this approach. 

Kaposi sarcoma (KS) - an angiogenic-inflammatory neoplasm - is the most prevalent cancer in HIV-infected patients and its appearance is preceded by infection with human Heipesvitus-8 (HHV-8). Although chemotherapy has become the treatment of choice approved by the FDA, there are also good response rates in patients treated with IFN-a. Fortunately, today highly active antiretroviral therapy (HAART) has dramatically decreased the incidence of KS in AIDS patients. 

The first study to demonstrate the activity of enfuvirtide in HIV-infected patients (Kilby et al. 1998) showed that patients receiving the maximum 100 mg intravenous dose had maximum median declines in HIV-1 RNA of -1.96 logjo copies/mL through 14 days. Several additional studies (Kilby et al. 2002 Lalezari et al. 2003a, b) further demonstrated the safety and efficacy of enfuvirtide and led to the selection of twice-daily subcutaneous injections of a 90 mg nominal dose for testing in the TORO (T-20 vs. optimized regimen only) pivotal clinical trials. 

Poveda E, Rodes B, Lebel-Binay S, Faudon JL, Jimenez V, Soriano V (2005) Dynamics of enfuvir-tide resistance in HIV-infected patients during and after long-term enfuvirtide salvage therapy. J Clin Virol 34 295-301... 

Several trials have evaluated the antiviral efQcacy of standard IFN-a in HIV-infected patients also receiving zidovudine, in comparison with zidovudine alone. 

Brockmeyer NH, Poflhoff A, Bader A, Hochdorfer B, Schlottmann R, Rasokat H, Altmeyer P, Kreuter A (2006) Treatment of condylomata acuminata with pegylated interferon alfa-2b in HIV-infected patients. Eur J Med Res 11 27-32... 

Macpherson JL, Boyd MP, Amdt AJ, Todd AV, Fanning GC, Ely JA, Elliott F, Knop A, Raponi M, Murray J, Gerlach W, Sun LQ, Penny R, Symonds GP, Carr A, Cooper DA (2005) Long-term survival and concomitant gene expression of ribozyme-transduced CD4 + T-lymphocytes in HIV-infected patients, J Gene Med 7 552-564... 

Flori and le Vaillant (2004) studied the temporal relationship between the uptake of the more aggressive antiretroviral therapy and the use and cost of hospital treatment for HIV-infected patients in France from 1995 to 2000 from a hospital perspective. The authors found that during this period the proportion of patients on ARV treatment increased from 69.5% to 97%, with a large rise in the use of polytherapy. This increase was most notable for patients with CD4 cell counts above 500. ART expenditures per patient increased between the study years by 220%, reaching US 1,886 in 2000. Unlike that, inpatient hospitalization fell by 60% and average length of stay declined. Thus hospital costs (excluding ART) decreased to US 2,137 in 2000. 

Bozette et al. (2001) examined expenditures for the care of adult HIV-infected patients since the introduction of highly active antiretroviral therapy. They interviewed a representative random sample of 2,864 patients in early 1996 and followed them for up to 36 months. They estimated the average expenditure per patient per month on the basis of self-reported information. According to their calculations, the mean expenditure was US 1,792 per patient per month at base hne in early 1996, but it decbned to US 1,359 for survivors in 1997, since the increases in pharmaceutical expenditures were smaller than the reductions in hospital costs. After adjustments for the interview date, clinical status, and deaths, the estimated annual expenditure declined from US 20,300 per patient (1996) to US 18,300 (1998). 

Yazdanpanah et al. (2002) calculated the resource use and cost for different stages of HIV infection in France based on a clinical database of HIV-infected patients between 1994 and 1998. The total costs attributable to bed-day and day-care inpatient care included the mean cost of each inpatient day times the length of stay, as well as total number of laboratory tests, dosage and quantity of medications, and total number of procedures. The total cost attributable to outpatient care included the mean physician and nurse fees per visit, as well as total number of laboratory tests and total number of procedures. In the absence of an AIDS-deflning event, the average total cost of care ranged from US 797 per person-month in the highest CD4 stratum to US 1,261 per person-month in the lowest CD4 stratum. 

Stoll et al. (2002b) examined provider costs in a German monocentric cohort of HIV-infected patients after the introduction of HA ART. According to their findings, mean provider costs per capita decreased from US 31,812 in 1997 to US 21,926 in 2001. The costs of HA ART per capita decreased significantly from US 15,739 in 1997 to US 14,336 in 2001. Also quite impressive was the continuous decrease of expenditures for additional drug therapy (-43.3%) and hospitalization (-52.1%), respectively. However, the costs caused by HAART increased from 49.5% of all provider costs in 1997 to 65.4% in 2001. 

Beside their calculation of direct costs, Stoll et al. (2002a) also examined indirect costs in a German sample of HIV-infected patients after the introduction of HAART. To emphasize the implications of different approaches of indirect costs, the authors determined both costs based on the human capital approach and costs calculated on the friction cost approach. They concluded that indirect costs based on the friction approach per patient in 1997 (US 2,421) add up to only one-tenth of the amount derived from the human capital approach (US 24,639). 

Borleffs JC, Jager JC, Marinus JJ (1990) Hospitalcost for patient with HIV infection in a university hospital in The Netherlands, Health Pohcy 16 43-54 Bozette S, Joyce G, McCaffrey DE et al (2001) Expenditures for the care of HIV-infected patients in the era of highly active antiretroviral therapy, N Engl J Med 344 817-823 Breidert C (2006) Estimation of wilhngness-to-pay theory, measurement, application, Deutscher Universitats-Verlag, Wiesbaden... 

Moatti JP, Spire B, Kazatchkine M (2004) Drug resistance and adherence to HIV/AIDS antiretroviral treatment against a double standard between the north and the south, AIDS I8 S55-S6I Moore RD, Chaisson RE (1997) Costs to Medicaid of advancing immunosuppression in an urban HIV-infected patient population in Maryland, J Acquir Immune Defic Syndr Hum Retrovirol 16 223-231... 

Mizuno T, Kawanokuchi J, Numata K, Suzumura A (2003) Production and neuroprotective functions of fractalkine in the central nervous system. Brain Res 979(l-2) 65-70 Monteiro de Almeida S, Letendre S, Zimmerman J, Kolakowski S, Lazzaretto D, McCutchan JA, Ellis R (2006) Relationship of CSF leukocytosis to compartmentalized changes in MCP-1/ CCL2 in the CSF of HIV-infected patients undergoing interruption of antiretroviral therapy. J Neuroimmunol 179(1-2) 180-185... 

In advanced AIDS, MM is usually associated with opportunistic infections such as CMV (Said et al. 1991 RouUet et al. 1994 Kolson and Gonzalez-Scarano 2001) or is secondary to lymphoma (Fuller et al. 1993). Despite a role for other herpes viruses in AIDS-associated myelitis, no substantive evidence has been published in support of a role for other vimses in the development of HIV-associated MM, including herpes simplex 1 or 2, varicella zoster, or Epstein Barr vims (Kolson and Gonzalez-Scarano 2001). MM can occur secondary to hepatitis B and C viruses, which are common co-infections of HIV-infected patients, particularly when there is an associated cryoglobulinemia (Taillan et al. 1993 Caniatti et al. 1996). Rarely... 

The clinical presentation of MM in HIV-infected patients is similar to that in other patients with vasculitic neuropathy (Hoke and Comblath 2004). It is characterized by symptoms and signs of sensory involvement, with numbness and tingling in the distribution of one peripheral nerve trunk. Sequential involvement of other noncontiguous peripheral or cranial nerves progresses over days to weeks. The initial multifocal and random neurologic features may evolve to symmetrical neuropathy (Ferrari et al. 2006). 

Makela and colleagues described the occurrence of a probable recurrent GBS six weeks after initiation of HAART and after a striking increase in CD4 cell count in an HfV-infected individual (Makela et al. 2002). Piliero and colleagues described an HIV-infected patient with AIDS who developed GBS, 26 days after initiation of a 6-drug HAART regimen, which had led to an impressive immune reconstitution (a rise in CD4 cell count from 31 to 602 cells/pL) (Piliero et al. 2003). Puthanakit and colleagues identified a child who developed GBS, 3 weeks after initiation of efavirenz-based HAART in a cohort of HIV-infected Thai children (Puthanakit et al. 2006). 

Epidermal nerve fiber analysis by immunocytochemical techniques using the panaxonal marker protein gene product 9.5 (PGP 9.5) allows the study of epidermal innervation by small fiber C and A5 nerve fibers (McCarthy et al. 1995 Holland et al. 1997). Studies of skin biopsies of HIV infected patients with DSP or ATN showed reduction in the number of epidermal fibers in distal areas of the lower extremities with an inverse correlation between neuropathic pain intensity and epidermal nerve fiber density (Polydefkis et al. 2002) (Fig. 4.3). There were also fewer epidermal fibers in HIV seropositive patients without clinical evidence of neuropathy, suggesting that HIV infection may be associated with the loss of cutaneous innervation even before the onset of sensory symptomatology (McCarthy et al. 1995). 

Currently, treatment of DSP and ATN is similar to many other neuropathies that have predominantly painful sensory involvement (Mendell and Sahenk 2003 Gonzalez-Duarte et al. 2007). It is purely symptomatic as there are no proven regenerative therapies to reverse the underlying process. An 8-month prospective pilot study reported an improvement in subjective quantitative sensory testing (QST) in HIV-infected patients who responded to HAART (Martin et al. 2000). The patients who did not respond to HAART did not show any improvements in QST. It is possible that suppression of viral load will slow the progression of DSP. Some studies have found a correlation between viral load and incidence (Childs et al. 1999), or severity (Simpson et al. 2002) of sensory neuropathy. Others, however, did not find any correlation between plasma viral loads and incidence of DSP or ATN (Brew et al. 2003). 

A rabbit model of 2, 3 -dideoxycytidine neurotoxicity. Lab Invest 66(l) 63-74 Apostolski S, McAlarney T et al (1993) The gpl20 glycoprotein of human immunodeficiency virus type 1 binds to sensory ganghon neurons. Ann Neurol 34(6) 855-863 Araujo AP, Nascimento OJ et al (2000) Distal sensory polyneuropathy in a cohort of HIV-infected children over five years of age. Pediatrics 106(3) E35 Authier FJ, Gheradi RK (2003) Peripheral neuropathies in HIV-infected patients in the era of HAART. Brain Pathol 13(2) 223-228... 

Cornblath DR, Hoke A (2006) Recent advances in HIV neuropathy. Curr Opin Neurol 19(5) 446-450 Cornblath DR, McArthur JC (1988) Predominantly sensory neuropathy in patients with AIDS and AIDS-related complex. Neurology 38(5) 794-796 Cornblath DR, McArthur JC et al (1987) Inflammatory demyeUnating peripheral neuropathies associated with human T-cell lymphotropic virus type III infection. Ann Neurol 21(l) 32-40 Corral I, Quereda C et al (1997) Acute poly radiculopathies in HIV-infected patients. J Neurol 244(8) 499-504... 

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