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Reports of KS in Aging SF Patients
 
 
  there are 4 articles below...
 
"cluster of cases of persistent HIV-associated Kaposi's sarcoma in patients with HIV viral suppression and good immune-system function
(as measured by the viral load and CD4 cell count) is important for three reasons....high number of aging patients who are infected with both HIV and human herpesvirus 8....raises questions about the immune system's integrity and ability to control certain viruses in patients with long-standing HIV-infection (from Jules: which may relate to why patients who take treatment interruptions experience diseases associated with the return of viral replication)....This phenomenon may increase in frequency as the HIV-infected population ages, and we recommend that physicians monitor this group carefully.....
 
....this cluster reflects the likelihood that even when HIV is ostensibly under good control, the immune system is still impaired, possibly due to HIV infection itself or to additional effects of aging.....Clinicians should continue to perform careful skin exams on all patients and should be aware of the manifestations of mild KS, particularly as their patients become older......need for studies to identify clinically relevant correlates that can distinguish between patients whose Kaposi's sarcoma responds to antiretroviral therapy and those who do not have such a response. These factors may include age, duration of HIV infection, human herpesvirus 8 viral load, and patterns of viral gene expression within tumors....
 
from Dr Susan Krown, Memoral Sloan Kettering, NYC: "Our data suggest that persistent Kaposi's sarcoma despite apparently effective antiretroviral therapy is not a rare, isolated, or recent phenomenon, as suggested by Maurer and colleagues in their letter to the editor (Sept. 27 issue).1 On the contrary, our findings indicate that since the introduction of effective antiretroviral therapy, many patients with AIDS-associated Kaposi's sarcoma have CD4 counts above the level typically associated with susceptibility to opportunistic diseases. Furthermore, although effective HIV suppression has been correlated with regression of Kaposi's sarcoma after antiretroviral therapy,2 a substantial proportion of our patients had undetectable HIV viral loads."
 
from SF Chronicle Oct 12 2007:
 
"The big question," Dr Toby Mauer (Chief of Dermatology at SF General Hosp) added, is that if the HHV-8 virus can't be controlled, does that mean other things won't be controlled in these patients, as their immune system ages? That's why we are following this very closely."
 
Dr. Marcus Conant was a dermatologist catering to a gay clientele in the early 1980s when the first cases of deadly Kaposi's sarcoma began to appear. Since then, he built one of the largest private AIDS practices in the nation. After the arrival of effective AIDS drugs, KS cases plummeted, but he has seen about a dozen of these mild cases among patients who have their HIV under control. None has developed the fulminant Kaposi's sarcoma that killed so many during the 1980s and early 1990s.
 
"I believe some other virus, or infection, is stimulating HHV-8 to replicate," he said.
 
An eyewitness to the epidemic since its earliest days, Conant is not alarmed by the new Kaposi's sarcoma cases. "This is nothing like what we saw 25 years ago," he said.
 
....Our findings also suggest that patients in King County diagnosed with KS in the HAART era had an increased prevalence of mental illness and substance use relative to both pre-HAART-era KS patients and HAART-era non-KS AIDS patients. It is difficult to explain the higher prevalence of mental illness and substance use among contemporary KS patients. (see study below near end of this report)"
 
An Unusual Cluster of HIV-Associated Kaposi Sarcoma?
 
A recent report from San Francisco described nine patients with long-standing HIV infection who developed KS despite good immune function.
 
HIV-associated Kaposi sarcoma (KS) typically occurs in patients who have low CD4 counts (<150 cells/mm3) and high viral loads (>10,000 copies/mL). In most patients, KS lesions regress within the first year of antiretroviral therapy (ART), as immune function improves and viral load declines. However, investigators in San Francisco recently reported an unusual cluster of nine patients who developed HIV-associated KS despite good immune function.
 
At the time of KS diagnosis, patients were aged 41 to 74 (median, 51) and had been infected with HIV for 4 to 25 years (median, 18 years). None had a history of opportunistic infections. All were receiving maximal ART and had sustained CD4 counts >300 cells/mm3 and undetectable viral loads for at least 2 years. Seven of the patients were receiving regimens that contained PIs, which had previously been proposed to be beneficial in treating KS because of their antiangiogenic and antitumorigenic effects. All nine patients had relatively mild skin disease with no visceral involvement. The authors hypothesized that these unusual cases of HIV-associated KS may be more common in San Francisco than elsewhere because of the large population of aging people there who are coinfected with HIV and human herpesvirus 8 (HHV8; a known cause of KS).
 
Comment: The clinical picture in this report closely resembles classic KS (originally described by Moritz Kaposi in 1872), an indolent neoplasm that is seen predominantly in elderly men of Mediterranean or Jewish descent and often involves the lower extremities (Semin Oncol 1987; 14:7). Whether any of the nine patients described in the present report had a history of KS or recent HHV8 infection would be interesting to know. Regardless, this cluster reflects the likelihood that even when HIV is ostensibly under good control, the immune system is still impaired, possibly due to HIV infection itself or to additional effects of aging. Fortunately, mild skin lesions can be treated relatively easily with local measures rather than with systemic chemotherapy, but patients with KS might eventually require more-specific treatment for their underlying HHV8 infection. Clinicians should continue to perform careful skin exams on all patients and should be aware of the manifestations of mild KS, particularly as their patients become older.
 
- Joan Goldberg, MD
 
Dr. Goldberg is Medical Director of the HIV Program at Harvard Vanguard Medical Associates in Boston and a member of the Hematology/Oncology Department there.
 
Published in AIDS Clinical Care October 29, 2007
 
Citation(s):
Maurer T et al. HIV-associated Kaposi's sarcoma with a high CD4 count and a low viral load. N Engl J Med 2007 Sep 27; 357:1352.
 

HIV-Associated Kaposi's Sarcoma with a High CD4 Count and a Low Viral Load
 
NEJM Sept 2007
 
To the Editor: Kaposi's sarcoma associated with HIV infection has been decreasing in incidence and severity since the introduction of antiretroviral therapy.1 These reductions have been attributed to improved immune function directly related to such therapy. Patients with Kaposi's sarcoma typically have a low CD4 cell count (<150 cells per cubic millimeter) and a high viral load (>10,000 copies per milliliter).1,2 In the majority of patients, the regression of Kaposi's sarcoma lesions has been reported to occur within 8 months after the initiation of antiretroviral therapy, paralleling the increase in the CD4 cell count and decrease in the viral load that mark successful therapy.3 Likewise, progression of Kaposi's sarcoma has been associated with a high viral load, a low CD4 cell count, and concomitant opportunistic infections.2,3
 
We report on a cluster of unusual cases of cutaneous, unremitting HIV-associated Kaposi's sarcoma occurring in nine patients with sustained CD4 cell counts of more than 300 cells per cubic millimeter and suppression of the viral load to a value below 300 copies per milliliter for at least 2 years. These patients presented between November 2004 and January 2006. All were receiving antiretroviral regimens containing at least one protease inhibitor or non-nucleoside reverse-transcriptase inhibitor. The median age was 51 years (range, 41 to 74), the median time since the onset of HIV infection was 18 years (range, 4 to 25), and the median duration of antiretroviral therapy was 7 years (range, <1 to 19). The median nadir CD4 cell count was 340 (range, 90 to 455). None of the patients had a history of opportunistic infections. The patients have had a relatively indolent course of Kaposi's sarcoma, with no eruptive cutaneous lesions, visceral involvement, or other AIDS-defining illnesses.
 
This cluster of cases of persistent HIV-associated Kaposi's sarcoma in patients with HIV viral suppression and good immune-system function (as measured by the viral load and CD4 cell count) is important for three reasons. First, although there have been sporadic reports of similar patients,4 it is possible that we are seeing a greater number in San Francisco because of the high number of aging patients who are infected with both HIV and human herpesvirus 8. This hypothesis raises questions about the immune system's integrity and ability to control certain viruses in patients with long-standing HIV infection.5 Second, it has been postulated that drug regimens containing protease inhibitors are preferable in the treatment of Kaposi's sarcoma because of their antitumorigenic and antiangiogenic effects. In our series, seven patients have been receiving protease inhibitors without improvement in their Kaposi's sarcoma. Finally, these patients present a clinical and prognostic conundrum in that they are receiving maximal antiretroviral therapy yet have persistent Kaposi's sarcoma. This phenomenon may increase in frequency as the HIV-infected population ages, and we recommend that physicians monitor this group carefully.
 
Toby Maurer, M.D.
Maya Ponte, Ph.D.
Kieron Leslie, M.D.
University of California at San Francisco
San Francisco, CA 94110
maurert@derm.ucsf.edu
 
References
 
1. Gallafent JH, Buskin SE, De Turk PB, Aboulafia DM. Profile of patients with Kaposi's sarcoma in the era of highly active antiretroviral therapy. J Clin Oncol 2005;23:1253-1260. [Free Full Text]
2. Stebbing J, Sanitt A, Nelson M, Powles T, Gazzard B, Bower M. A prognostic index for AIDS-associated Kaposi's sarcoma in the era of highly active antiretroviral therapy. Lancet 2006;367:1495-1502. [CrossRef][ISI][Medline]
3. Cattelan AM, Calabro ML, Gasperini P, et al. Acquired immunodeficiency syndrome-related Kaposi's sarcoma regression after highly active antiretroviral therapy: biologic correlates of clinical outcome. J Natl Cancer Inst Monogr 2001;28:44-49. [Free Full Text]
4. Chan J, Kravcik S, Angel JB. Development of Kaposi's sarcoma despite sustained suppression of HIV plasma viremia. J Acquir Immune Defic Syndr 1999;22:209-210. [ISI][Medline]
5. Guihot A, Dupin N, Marcelin AG, et al. Low T cell responses to human herpesvirus 8 in patients with AIDS-related and classic Kaposi sarcoma. J Infect Dis 2006;194:1078-1088. [CrossRef][ISI][Medline]
 

More on HIV-Associated Kaposi's Sarcoma
 
To the Editor: The AIDS Malignancy Consortium, a multicenter cooperative group funded by the National Cancer Institute, has enrolled 442 patients who have human immunodeficiency virus (HIV) infection and measurable Kaposi's sarcoma in a series of therapeutic trials since 1996 (Table 1).
 

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Our data suggest that persistent Kaposi's sarcoma despite apparently effective antiretroviral therapy is not a rare, isolated, or recent phenomenon, as suggested by Maurer and colleagues in their letter to the editor (Sept. 27 issue).1 On the contrary, our findings indicate that since the introduction of effective antiretroviral therapy, many patients with AIDS-associated Kaposi's sarcoma have CD4 counts above the level typically associated with susceptibility to opportunistic diseases. Furthermore, although effective HIV suppression has been correlated with regression of Kaposi's sarcoma after antiretroviral therapy,2 a substantial proportion of our patients had undetectable HIV viral loads.
 
These findings raise important questions about the mechanisms that control the progression of human herpesvirus 8 and Kaposi's sarcoma. They also suggest a need for studies to identify clinically relevant correlates that can distinguish between patients whose Kaposi's sarcoma responds to antiretroviral therapy and those who do not have such a response. These factors may include age, duration of HIV infection, human herpesvirus 8 viral load, and patterns of viral gene expression within tumors.
 
Susan E. Krown, M.D.
Memorial Sloan-Kettering Cancer Center
New York, NY 10065
krowns@mskc.org
 
Jeannette Y. Lee, Ph.D.
University of Alabama at Birmingham
Birmingham, AL 35294-3300
 
Dirk P. Dittmer, Ph.D.
University of North Carolina at Chapel Hill
Chapel Hill, NC 27599-7290
 
for the AIDS Malignancy Consortium
 
References
 
1. Maurer T, Ponte M, Leslie K. HIV-associated Kaposi's sarcoma with a high CD4 count and a low viral load. N Engl J Med 2007;357:1352-1353. [Free Full Text]
2. Martinez V, Caumes E, Gambotti L, et al. Remission from Kaposi's sarcoma on HAART is associated with suppression of HIV replication and is independent of protease inhibitor therapy. Br J Cancer 2006;94:1000-1006. [CrossRef][ISI][Medline]
 
-------------------
 
The authors reply: With respect to the comments of Krown and colleagues: we note with interest the number of patients with a CD4 count of 300 per cubic millimeter or more and an undetectable HIV viral load who were enrolled in their therapeutic trials. We have not claimed that what we are observing in San Francisco is an isolated phenomenon and, on the contrary, have suspected it to be more widespread. However, Kaposi's sarcoma remains a striking rarity in published studies1,2,3,4,5 and is not a well-described phenomenon in clinical practice.
 
It is difficult to compare directly the subjects in the trials by Krown et al. with our patients, since the correspondents have not provided data regarding the duration of the CD4 counts and viral loads, the duration of HIV infection, the CD4 nadirs of the subjects, the temporal relationship with the presentation of Kaposi's sarcoma lesions, and the response to antiretroviral treatment. Our patients have persistent Kaposi's sarcoma despite sustained high CD4 counts and undetectable viral loads for more than 2 years. The median CD4 nadir in our group is 340 per cubic millimeter, with a median duration of HIV infection of 18 years. We encourage Krown et al. and others to publish their data more fully.
 
Toby Maurer, M.D.
Maya Ponte, M.D., Ph.D.
Kieron Leslie, M.B., B.S., M.R.C.P.
University of California at San Francisco
San Francisco, CA 94110
maurert@derm.ucsf.edu
 
References
 
1. Stebbing J, Sanitt A, Nelson M, Powles T, Gazzard B, Bower M. A prognostic index for AIDS-associated Kaposi's sarcoma in the era of highly active antiretroviral therapy. Lancet 2006;367:1495-1502. [CrossRef][ISI][Medline]
 
2. Ledergerber B, Egger M, Erard V, et al. AIDS-related opportunistic illnesses occurring after initiation of potent antiretroviral therapy: the Swiss HIV Cohort Study. JAMA 1999;282:2220-2226. [Free Full Text]
 
3. Mocroft A, Kirk O, Clumeck N, et al. The changing pattern of Kaposi sarcoma in patients with HIV, 1994-2003: the EuroSIDA Study. Cancer 2004;100:2644-2654. [CrossRef][ISI][Medline]
 
4. Martinez V, Caumes E, Gambotti L, et al. Remission from Kaposi's sarcoma on HAART is associated with suppression of HIV replication and is independent of protease inhibitor therapy. Br J Cancer 2006;94:1000-1006. [CrossRef][ISI][Medline]
 
5. Nasti G, Talamini R, Antinori A, et al. AIDS-related Kaposi's sarcoma: evaluation of potential new prognostic factors and assessment of the AIDS Clinical Trial Group Staging System in the Haart Era -- the Italian Cooperative Group on AIDS and Tumors and the Italian Cohort of Patients Nave from Antiretrovirals. J Clin Oncol 2003;21:2876-2882. [Free Full Text]
 

Profile of Patients With Kaposi's Sarcoma in the Era of Highly Active Antiretroviral Therapy
 
Journal of Clinical Oncology, Vol 23, No 6 (February 20), 2005: pp. 1253-1260
 
James H. Gallafent, Susan E. Buskin, Peter B. De Turk, David M. Aboulafia
 
From the University of Washington, School of Medicine and Department of Epidemiology; Public Health-Seattle and King County, HIV/AIDS Epidemiology Program; and Virginia Mason Medical Center, Division of Hematology/Oncology, Seattle, WA
 
ABSTRACT
 
PURPOSE: Since the advent of highly active antiretroviral therapy (HAART), the incidence of Kaposi's sarcoma (KS) among AIDS patients has declined both nationwide and in King County, Washington. We sought to compare clinical parameters of patients diagnosed with KS in the pre-HAART (1990 to 1996) and HAART (1997 to 2002) eras.
 
METHODS: We used patient data abstracted from the Adult/Adolescent Spectrum of HIV-Related Diseases study of Public Health-Seattle and King County.
 
RESULTS: Patients diagnosed with KS in the HAART era (n = 40) were significantly more likely (P < .05) than pre-HAART-era KS patients (n = 366) to be diagnosed with alcohol problems (43% v 18%), noninjection drug use (45% v 18%), injection drug use (25% v 10%), psychosis (25% v 13%), and hypertension (13% v 2%). Although median CD4+ count and HIV-1 viral load at the time of KS diagnosis were not significantly different between the two groups, significantly fewer (P < .01) HAART-era KS patients developed opportunistic illnesses (OIs) during their follow-up. The risk of dying among KS patients diagnosed in the HAART era is significantly lower (P < .01) than for KS patients diagnosed in the pre-HAART era (hazard ratio, 0.24).
 
CONCLUSION: Although HAART-era KS patients in King County were as likely to have a depleted CD4+ cell count and high HIV-1 viral loads at the time of KS diagnosis as pre-HAART KS patients, they survived longer and fewer of them were diagnosed with other OIs. They also had an increased prevalence of substance abuse and mental illness, contributing to a dynamic and changing KS clinical profile.
 
INTRODUCTION
 
Persons with AIDS have a risk for Kaposi's sarcoma (KS) that is 100,000-fold greater than that in the general population.1 This markedly increased risk is multifactorial. HIV-infected individuals, especially men who have sex with men (MSM), have a high prevalence of coinfection with KS-associated herpesvirus (KSHV; also known as human herpesvirus 8)2; the virus is etiopathologically linked to KS.3 KSHV coinfection, as identified by either KSHV antibodies or viremia, is associated with an elevated KS risk.3,4 In addition, measures of HIV-related immune suppression and viral replication, as reflected by low CD4+ T-lymphocyte cell count, high circulating HIV-1 viral load, and high levels of circulating neopterin and beta2-microglobulin, strongly predict KS.5,6
 
On a microscopic level, KS lesions are rife with activated endothelial cells, spindle cells, infiltrating leukocytes, and angiogenic activity.7 Clinically, patients may present with multicentric mucocutaneous plaques and nodules. Less frequently, KS may involve the viscera. Treatment with highly active antiretroviral therapy (HAART) has led to reduced morbidity in patients infected with HIV and partial or complete regression of AIDS-associated KS in many patients.8,9 In the United States,10-12 including King County, Washington,13 the incidence of KS has declined dramatically since the introduction of HAART.
 
The rapidly changing landscape of HIV medical care has resulted in a change in the natural history of KS. Nonetheless, KS remains the most common HIV-related neoplasm10,12 and one of the most common opportunistic illnesses.14 In this study we sought to compare the clinical characteristics of KS patients in the HAART era with pre-HAART-era KS patients and with patients with AIDS who have never been diagnosed with KS.
 
DISCUSSION
 
In King County, Washington, it appears that KS patients in the HAART era possess subtle clinical differences compared with their pre-HAART predecessors and their AIDS contemporaries who have not developed KS. Patients with KS were less likely to be MSM and increasingly more likely to use injection drugs, originate from non-US countries, and represent nonwhite patients. Although KS patients in the HAART era were as likely to have a depleted CD4+ cell count at the time of diagnosis as were pre-HAART KS patients, fewer of them were diagnosed with other OIs. The clinical benefits of immune reconstitution and reduction of HIV-1 viral loads after initiation of HAART are well documented.8,9 Doubtless, prophylactic antimicrobial therapy also played a role in decreased OI incidence.
 
Our findings also suggest that patients in King County diagnosed with KS in the HAART era had an increased prevalence of mental illness and substance use relative to both pre-HAART-era KS patients and HAART-era non-KS AIDS patients. It is difficult to explain the higher prevalence of mental illness and substance use among contemporary KS patients. Fortunately, these conditions do not seem to represent an absolute barrier to accessing health care, given that 95% of HAART-era KS patients received a prescription for HAART at some point during their time of follow-up.
 
We speculate that HAART-era KS patients, perhaps associated with their higher prevalence of mental illness, substance use, and racial minority status, might have delayed accessing HIV-directed health care until their disease progressed to a more outwardly obvious and symptomatically evident condition. This seemed to be true for the 58% of HAART-era KS patients who were not prescribed HAART at any time before their KS diagnosis. This delay in treatment put them at risk for developing OIs-even in this modern era of HIV care. Late diagnosis of HIV, including HIV diagnosed at the same time as KS or another opportunistic illness, however, likely also contributed to the lack of HIV care before a KS diagnosis.
 
It is noteworthy that 42% of HAART-era KS patients received a prescription for HAART before their KS diagnosis but nonetheless developed KS. One reason this occurred may have been poor adherence to whatever antiretroviral regimen they were prescribed. Evaluating the impact of substance use and mental illness on patient adherence is complicated. Additional analyses are needed.
 
Another factor that could help explain why some study patients in the HAART era developed KS despite receiving HAART lies in the possibility that they may have acquired multidrug-resistant HIV and are thus less likely to reap the full benefits associated with such therapy. Although HAART is helpful in restoring the immune system and dramatically reducing HIV-1 viral loads, it does not ensure that KS will not develop. KS may occur in rare patients with CD4+ T-lymphocyte counts more than 200 cells/L and nondetectable HIV-1 viral loads.20,21
 
Recently, Nasti et al22 compared clinical data on 211 individuals with AIDS-related KS from two well-described Italian cohorts of patients with HIV. Fifty-one patients were already taking HAART at the time of KS diagnosis; 160 patients were naive to HAART at KS diagnosis and initiated such therapy after diagnosis. HAART-naive patients had a median CD4+ count of 61 cells/L, which is similar to the median CD4+ counts of 53 and 40 cells/L found, respectively, among pre-HAART- and HAART-era KS patients in our study. In contrast, Italian patients who received HAART before their KS diagnosis demonstrated a significantly higher median CD4+ count of 129 cells/L. Similarly, those who received HAART before their KS diagnosis were more likely to have suppressed HIV-1 viremia than their HAART-naive counterparts or pre-HAART- or HAART-era KS patients in our study. HAART-era KS patients in our study include both HAART-naive patients and patients who have been prescribed HAART before their KS diagnosis. The finding that their CD4+ cell count and HIV-1 viral load at the time of KS diagnosis more closely matches those of the HAART-naive patients in the Nasti et al22 study emphasizes our belief that there are delays in accessing or adhering to appropriate HIV-directed health care in King County.
 
Nasti et al22 found that improved immune function and virologic status had a significant effect in the presentation of KS at the time of diagnosis. Patients who had received HAART before diagnosis of KS presented with a less aggressive and more localized disease than those who were HAART naive. Although they found no difference in 3-year survival rates between the HAART-naive patients and the groups of patients previously treated with HAART, their results suggest that improving patients' access and adherence to HIV-directed care before a diagnosis of KS can have a positive impact in reducing KS-associated morbidity.
 
We have not yet addressed the long-term impact that HAART prescriptions have had on CD4+ cell counts and HIV-1 viral loads, which is important to consider in seeking to gain a fuller clinical profile of modern KS patients and how they respond to therapy. This represents a limitation to this study-the extent to which CD4+ cell counts and HIV-1 viral loads are recorded in ASD is highly variable from patient to patient, and the timing of these tests does not necessarily correlate closely with other significant events (eg, date of AIDS diagnosis, date of KS diagnosis, and so on). Other limitations to this study include those inherent to a medical record review project such as the ASD study (limitations of ASD have been documented previously10) and the use of pre-existing data from a project not designed explicitly to explore trends in KS. For example, the dosage of drugs and the reasons for prescription are not recorded. In addition, although ASD encompasses a large and diverse portion of the HIV-positive population in Seattle and King County, it does not represent the entire population of HIV-infected persons in the area. Compared with HIV/AIDS Surveillance reports in King County, ASD captures an estimated 31% of HIV and AIDS patients in the Seattle and King County area.23,24 Similarly, it is not known what percent of all HIV-associated KS patients ASD captures and if there are any biases introduced by limiting our sampling of KS patients to those followed by ASD.
 
The high prevalence of smoking among HAART-era KS patients in King County is disconcerting. We have shown that HIV-infected patients in King County who developed KS lived almost twice as long before they were diagnosed with AIDS. Mortality among AIDS patients with OIs has also dramatically declined in King County during the HAART era.15 Thus, with KS patients living longer and with a large fraction of them smoking, tobacco-related health problems, such as emphysema, lung cancer, and cardiovascular disease, may become more prevalent.
 
Although the incidence of KS has declined dramatically since the advent of HAART, KS remains an important disease among the AIDS population. In Seattle and King County, a large portion of HAART-era KS patients represent a marginalized sector of society whose problems with mental illness and substance abuse may interfere with their ability to access HIV-directed health care. It may also be that the higher prevalence of mental illness and substance use among HAART-era KS patients contributed to poor antiretroviral drug adherence. The increased prevalence of mental illness and drug use among HAART-era KS patients will likely continue to present a challenge in securing long-term quality care for this group. Consequently, even in the era of HAART, KS patients continue to be afflicted with other OIs. Often, it is the OI that leads the patients to seek HIV treatment. The decline in KS diagnosis, the significantly increased time between HIV infection and development of KS, and improved survival following a diagnosis of KS, nonetheless, are testaments to advancements in HIV care.
 
 
 
 
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