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Press room ... 2001 archiveSelected Highlights from the 8th Conference
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| Time Period | '94
– '95 |
'96
– '97 |
After
'98 |
|---|---|---|---|
| Number of deaths | 799 |
610 |
271 |
| % with AIDS defining illness at death | 93% |
88.7% |
73.4% |
| Median Age at time of death | 37.4 |
38.5 |
41.7 |
| Median CD4+ cell count at time of death | 14 |
18 |
84 |
Of note there are significantly fewer deaths over the time periods described. The percentage of people dying subsequent to an AIDS defining illness dropped from 93% before '95 to about 73% after '98. In addition to being dramatic decreases in the overall numbers of deaths, there has also been a change in what people are dying of. The following chart provides a look at causes of death for select years including 1995, when single agent and two-drug therapy was standard, 1996, the first year that protease inhibitors were more widely available but use of triple-drug therapy was still fairly limited, 1997, when three-drug therapy was becoming more common and 1999 and 2000 combined, to give a more current picture:
| Cause of Death | 1995 (number / %) |
1996 |
1997 |
1999
& 2000 |
|---|---|---|---|---|
| Unknown | 116 (22%) |
76 (19%) |
31 (16%) |
33 (29%) |
| Opportunistic Infection | 121 (23%) |
106 (26%) |
28 (14%) |
9 (8%) |
| Kaposi's Sarcoma | 28 (5%) |
24 (6%) |
9 (5%) |
2 (2%) |
| Lymphoma | 32 (6%) |
36 (9%) |
28 (14%) |
12 (11%) |
| Dementia | 28 (5%) |
12 (3%) |
4 (2%) |
0 (0%) |
| Wasting | 51 (10%) |
38 (9%) |
13 (7%) |
2 (2%) |
| Bacterial | 56 (11%) |
39 (10%) |
22 (11%) |
7 (6%) |
| Suicide | 7 (1%) |
4 (1%) |
6 (3%) |
3 (3%) |
| Other | 86 (16%) |
76 (19%) |
58 (29%) |
45 (40%) |
The above chart provides a dramatic shift in the picture of AIDS deaths from '95 onward. Of note, there has been an increase in "other" causes of death, from conditions that are not AIDS defining illnesses. Researchers observe that in 1994 only 19% of people died of liver problems (hepatitis, liver cancer and liver failure) whereas in the combined years 1999/2000 all of the "other" deaths were due to liver problems. This might suggest that hepatitis is becoming an increasing cause of death as people are living longer, as is supported by observation in U.S. studies. It also might suggest that the triple-drug anti-HIV therapy regimens are toxic to the liver, which has also been observed.
Consistent with previous observations, the overall number of people developing and dying of AIDS-related cancers, including lymphoma and Kaposi's Sarcoma has declined dramatically overtime, but not to the same degree that other opportunistic infections have. The end result is that while AIDS-related cancers appear to be on the decline in terms of absolute numbers, deaths from these conditions contribute a greater proportion to overall deaths per year than previously. This does not mean that incidence rates of AIDS-related cancers are on the rise, to the contrary they are declining but not to the same degree as other opportunistic infections.
In addition to looking at numbers and percentages of people dying, the European group examined factors that were associated with dying prior to developing an AIDS diagnosis. They found that injection drug use was strongly correlated with the risk of dying without ever having had an AIDS diagnosis. The use of triple-drug therapy decreases, significantly the risk of dying pre-AIDS.
Anti-HIV Therapy: Does Age Make A Difference?
It has long been shown that older people, over the age of fifty, progress more rapidly to AIDS after HIV infection than younger people. Interestingly, people over the age of 50 are more likely to be diagnosed with HIV because they are experiencing an AIDS-defining condition than are younger people. Moreover, diagnosis of HIV is likely to be delayed in older people because of a failure to recognize the risk for HIV infection as a possibility. People over the age of 50 comprise about 10% of all AIDS cases in North America and Canada, yet results from research on the impact of aging on HIV disease has been slow in coming.
Whether or not older people who initiate potent anti-HIV therapy benefit as much as younger people from therapy has not been well researched. In fact, older people have been excluded from many studies of anti-HIV therapies. A group in Canada sought to shed light on this issue by taking a look at the experiences of older and younger patients in their clinic. They defined an older person as someone over the age of 55 and a younger person as someone younger than 40. They then examined the records of the 90 older people living with HIV in their clinic of 1,200 and found 90 younger people who had similar lowest pre-therapy CD4+ cell counts, highest pre-therapy viral levels and time since initial infection with HIV and compared the experiences of the two groups.
Risk factors for HIV infection previously differed between younger and older people. In the past a large number of older people diagnosed with HIV sited contaminated blood products (HIV exposure via a blood transfusion prior to the time of blood screening for HIV) as their risk factor associated with HIV infection. Exposure to HIV through a blood transfusion may well alter the course of HIV infection in an individual, given the large amount of virus a person might be exposed to during this type of infection. This is no longer the case, however, as blood products undergo far more rigorous screening in the United States and Canada. Risk factors associated with HIV infection are now fairly similar among older and younger people.
When comparing the experiences of the older and younger people, investigators found that patterns of anti-HIV therapy use were similar with 62% of older people and 67% of younger people currently receiving triple-drug therapy including a protease inhibitor. Responses to therapy will nearly identical in the two groups by all measures, including increases in CD4+ cell count, decreases in viral load, duration of viral suppression from therapy and proportion of people achieving viral levels below the limit of detection. Moreover, the rates of AIDS defining events were also similar between the two groups, with 21% of the older group and 24% of the younger group ever having had an opportunistic infection.
These findings are very encouraging, suggesting that possibly previous data showing an increased risk of HIV disease progression in the elderly may have been due to factors associated with the route of infection (e.g. blood transfusion). They are also encouraging in showing that elderly people with HIV appear to benefit from anti-HIV therapy in the same way and to the same degree as younger people, particularly with regard to the impact of therapy on viral levels and CD4+ cell counts. It is hoped that more information on immunology, aging and HIV will be forthcoming as a number of centers are funded to conduct research in this important area. The finding of this Canadian group hopefully provide an optimistic first glimpse into what we'll be hearing more about in the future.
Kidney Dysfunction in African Americans
HIV-associated Nephropathy (HIVAN) is a kidney dysfunction almost exclusively seen in African American's living with HIV. It is unknown why there is a racial bias for this condition but it is an increasing problem and currently represents the third leading cause of death associated with kidney failure among African American adults. Little is known about its cause and far less is known about how to treat the condition. Several years ago the AIDS Clinical Trials Group attempted to conduct a study of prednisone for treating HIVAN but the study was stopped due to lack of enrollment in the study. At many sites, prednisone, an immune suppressive steroid, is considered standard of care for treating HIVAN, even though there are no studies documenting its benefits. Anecdote and observation have lead physicians to adopt the use of prednisone therapy for treating HIVAN, as people with the condition appear to improve following therapy.
At the Chicago conference a New York group presented information on an African American man presenting with HIVAN in conjunction with a severe flu-like syndrome signifying recent exposure and infection with HIV. Treatment with potent anti-HIV therapies resulted in remarkable improvements in HIVAN, as noted improvements in laboratory markers of kidney function and improvements in kidney biopsy results. Despite treatment with anti-HIV therapy, cells in the kidney showed persistent evidence of HIV infection. More research is needed to understand the role of the kidney as a reservoir for HIV infection and to improve treatments for HIVAN.
People diagnosed with HIVAN should be aware of a kidney and liver transplant study currently underway at the University of California, San Francisco (UCSF). Currently UCSF is one of the few transplant centers willing to perform transplantations on people living with HIV. The group at UCSF, lead by Michelle Rolland and Peter Stock, are coordinating the development of a nation-wide multi-center transplant study, which will hopefully provide organ transplantation to people with HIV in need across the country. Activism is needed to encourage transplant centers to get involved in this study so that people with HIV throughout the country have better access to organ transplantation in their local area. Increased research and improved therapies for HIVAN are desperately needed. For people with HIVAN experiencing kidney failure, however, organ transplantation, accessible where people live, is a critical and needed option.
While giving attention to the increased risk that African American's have to HIVAN, it's probably equally important to highlight that racial differences persist in many conditions and diseases. For example, for reasons equally not well understood, African Americans appear to be at greatly decreased risk for the AIDS-related cancer, Non-Hodgkin's Lymphoma (NHL). Differences in HIV disease do not only exist across racial lines. Women, for example, very rarely develop Kaposi's Sarcoma, an AIDS-related cancer observed primarily in men. Understanding why these differences exist and persist may hold important clues to new directions for research and therapies and hopefully, one day, cures.
Complementary and Alternative Medicine (CAM)
There has been increasing interest and attention being given to issues regarding complementary and alternative medicines (CAMs). A study conducted at the University Hospitals of Cleveland sought to identify factors associated with use of CAMs and characterize the type of CAMs people living with HIV are commonly using. A total of 324 people with HIV visiting an inner city care clinic were interviewed with regard to their use of CAMs and overall 82% reported use of some type of CAM at some point, about 54% reported using CAMs at the time of interview. Of note, nearly 60% of people noted that they'd told their doctor of the complementary therapies they were using but this information was only present in their medical charts only about 13% of the time. This represents a major breakdown in communication between people living with HIV and their doctors. Many CAMs can cause side effects or have potentially serious interactions with medications used to treat HIV and related infections. Unless information about CAMs are recorded in medical charts serious interactions may be missed. It is critical for people to tell their doctors about alternative therapies they are using and it is equally important for doctors to record this information in medical records.
Men were more likely than women to use complementary and alternative medicine (56% vs. 43%). White people were more likely than African Americans to use CAMs (62% vs. 44%). The most commonly used CAMs included non pharmacologic therapies (massage, reiki and acupuncture), which are all unlikely to interact negatively with HIV treatments, herbs, vitamins, supplements and teas. The most commonly used herbs included Echinacea, ginseng, gingko, St. John's Wort, goldenseal, garlic, saw palmetto, Chinese herbs, milk thistle and yohimbe. Of these some have been shown to have interactions with HIV drugs, specifically St. John's Wort and garlic. For more information on decision-making and the use of herb and vitamins, call the Project Inform Hotline.
Immune-Based Therapies
Thalidomide
Thalidomide is a controversial therapy currently approved for treating a condition associated with leprosy called ENL. Thalidomide has been researched for its value in treating HIV infection, tuberculosis in people with HIV, HIV-associated skin conditions, HIV-associated wasting syndrome and HIV-related mouth ulcers. The most compelling data to date in the setting of HIV are those showing benefit for treating mouth ulcers.
Thalidomide is famous for causing birth defects if used during the first trimester of pregnancy. Until recently it was never approved for use in the United States, but was used regularly and routinely many years ago in other countries. It was even prescribed to pregnant women to manage morning sickness and at one time could be found in many over-the-counter products including cold medicines. The tragic result of this product being so widely used and available without proper testing is a generation of children born with severe disfigurement. The majority of babies exposed to thalidomide during their mother's first trimester of pregnancy died in early childhood. Those who have survived into adulthood suffer numerous health complications and challenges due to social stigma and disfigured and malformed arms and legs.
There are several products on the market today that can cause equal and greater complications if used during first trimester pregnancy. Not the least of these products is an acne medication called Accutane. The difference between the current products and thalidomide is that thalidomide was available over-the-counter and information about its possible effects on a developing child and warnings to women who are pregnant or trying to get pregnant did not accompany its use.
While the history of this drug is not one to be overlooked, many studies have shown that thalidomide may provide some benefits for select indications. One test-tube study presented at the recent Chicago conference suggests that thalidomide might boost anti-HIV and anti-CMV specific CD8+ cell responses. CD8+ cells from people infected with both HIV and CMV were looked at before and after exposure to thalidomide. Adding thalidomide to the cultures appeared to enhance the ability of the cells to function. Two of the volunteers who gave blood for the study were given thalidomide and their cells were looked at before and after thalidomide therapy. After twenty-one days of therapy their HIV and CMV specific CD8+ cell numbers appeared to be significantly increased.
It must be noted that this was a very small study and the majority of the work was done only in test tubes. Only two volunteers were actually given thalidomide and looked at before and after treatment. A large study of thalidomide was previously conducted by the AIDS Clinical Trials Group. This study showed no measurable impact of thalidomide on HIV levels. It's possible, however, that new versions of thalidomide might selectively enhance HIV specific immune responses to a greater and more measurable degree than the version of thalidomide that has been tested in larger studies. Companies developing thalidomide derivatives are focusing resources on developing versions of the drug that do not cause birth defects. As it turns out these new versions might also more potently enhance specific immune responses. One of these new compounds was also evaluated in the test tube studies and showed some promise. Re-evaluation of thalidomide and perhaps more importantly suitable thalidomide-like drugs that don't cause birth defects would be warranted based on preliminary findings from this study.
A larger study of thalidomide was also presented at the recent Chicago conference, which included 36 people with CD4+ cell counts between 200 and 500, on stable anti-HIV therapy who received various doses of thalidomide, or placebo, for eight weeks. Doses of thalidomide ranged from 50mg to 150mg, once daily. In this study thalidomide did not appear to have effects on either viral load of CD4+ cell counts. In a large AIDS Clinical Trials Group study (ACTG 251), thalidomide was associated with slight increases in viral load. This was not observed in this smaller study, perhaps due to the generally better health of the volunteers in this study and the fact that they were very well controlled on anti-HIV therapy. HIV-specific immune responses were not measured in this study so it remains unknown if thalidomide enhances these responses as suggested by the test tube studies described previously.
Mycophenolate Mofetil (MMF, CellCept)
MMF is an immune suppressive therapy used commonly to prevent the body from rejecting organ transplants. The success of the immune system is largely due to its ability to recognize the difference between self and other. For example, your immune system recognizes your liver as self, and therefore doesn't attack and try to destroy it. In the setting of organ transplantation, however, there are two concerns. One is that a person's immune system will reject the organ, turn against it and destroy it. The other concern is that immune cells in the transplanted organ will attack the person who received the new organ (called graft vs. host disease or GVHD). In order to prevent rejection of a newly transplanted organ and prevent GVHD, life-long immune suppressive therapies are typically given to transplant recipients. MMF is one such immune suppressive therapy.
Interest in MMF as a therapy for HIV arose when it was discovered that MMF suppresses chemicals inside of cells that HIV needs in order to reproduce. MMF is believed to have some anti-HIV affect in the same way that hydroxyurea (Hydrea, HU) works, by suppressing cellular factors. Also, like hydroxyurea, MMF is believed to work better in partnership with an anti-HIV drug. In the case of hydroxyurea, that partner is ddI; in the case of MMF that partner is abacavir (Ziagen). It has been speculated that while these types of therapies may be useful because they inhibit cellular factors that HIV requires in order to reproduce, they may also have benefits because of the way that they modulate the immune system. Specifically, by suppressing the immune system MMF might reduce activation and cell death associated with HIV replication and disease progression. One group examined the impact of MMF on activation and cell death rates in people previously treated with anti-HIV therapy who were highly resistant to therapies and had persistent viral load.
Seven volunteers received 250mg of MMF, twice daily, in addition to an anti-HIV regimen of abacavir (Ziagen), ddI (didanosine, Videx), amprenavir (Agenerase) and ritonavir (Norvir) over the course of this sixteen-week study. Also, those participants not shown to be resistant to efavirenz (Sustiva) were also given this anti-HIV drug. At study entry the group had a median CD4+ cell count of about 28, and folks had experienced viral failure while taking ten or more anti-HIV therapies. Four of the seven volunteers demonstrated decreased rates of cell death (apoptosis) and cell activation despite increases in HIV levels. Among those experiencing decreases in cell death and activation there was a doubling of CD4+ cell counts, despite failure of anti-HIV therapies to control viral load. Increases in CD4+ cell counts were not observed in people who did not experience decreases in cell death rates, and these individuals were least likely to be adherent to the MMF-containing third-line therapy. These preliminary findings from this very small study suggest that MMF warrants further study not only for its direct anti-HIV affect but also for its potential benefits as an immune modulator.
Blood Transfusion
Red blood cell transfusion is standard treatment for severe anemia in people living with HIV. Anemia, low red blood cell counts, can be caused by HIV and it can also be a side effect of some anti-HIV therapies. Red blood cells carry oxygen throughout the body. Common early symptoms of anemia include fatigue, low energy and shortness of breath. Anemia can be monitored by tracking red blood cell counts on routine laboratory work. Many physicians will take a wait and see approach to mild-to-moderate anemia. For mild-to-moderate anemia that is related specifically to AZT (zidovudine, Retrovir) use, a therapy called erythropoetin-alpha (EPO) is approved and sometimes used as a treatment. For treating severe anemia, transfusion is the only approved and recommended treatment. EPO is not useful for treating severe anemia.
When giving a blood transfusion it is sometimes standard to leukoreduce, to remove any white cells that may be in the mix that might attack the recipient, a condition called GVHD as described in the previous discussion on MMF. Transfusion-associated GVHD (TA GVHD) has not been reported as a problem among people living with HIV. To examine this further a group at the National Institutes of Health's Heart Lung and Blood Institute conducted a study including 93 women living with HIV who received blood transfusions, with white cells removed or not, from male blood donors. By giving women men's blood researchers were able to look for the men's cells in the women's blood at various time points after the transfusion. Of the 47 women who received blood transfusions that were not leukoreduced, that still had some white cells in the mix, only five had detectable white cells from the male donor in their blood one to two weeks after the transfusion. None had detectable male white cells after one month. None of those who received the red blood cells that were treated to remove white cells had evidence of men's white blood cells in their body. Researchers conclude that people living with HIV are probably not at risk for TA GVHD and radiation to prevent TA GVHD is not warranted, generally, for people with HIV receiving red cell transfusions.
Cell Transfer Study in Twins
If I'm losing my CD4+ T cells and I have an identical twin, can't I replenish my CD4+ cells with some of theirs? Not everyone, obviously, has an identical twin, but studies of cell transfer in twins will provide insights into whether or not cell transfer is feasible or worthwhile to pursue in the general population. The reason researchers want to start these studies including identical twins is because the risk of a person's immune cells seeking out and destroying the newly transfused cells is far less if there is an identical match in cell type. A number of years ago the National Institutes of Health started a registry of twins where one twin is living with HIV and the other is HIV-negative. Twins who sign up for the registry are offered the ability to participate in novel studies. One such study was presented at the recent conference in Chicago.
In this study HIV-negative twins gave cells that were grown outside their body and modified with gene therapy. Half of the cells were modified with a gene that simply marked them, the other half were modified with the marker gene as well as genes that have anti-HIV activity. After the cells were modified, they were infused into the HIV-positive twin. The study sought to determine if the cells containing the anti-HIV genes survived longer than the cells that contained only the marker. Ten twin sets participated in this study.
The researchers concluded that the process was relatively safe, with side effects primarily limited to transfusion-related toxicities that included fevers and chills. One of the volunteers developed B Cell Lymphoma three years after his last transfusion and it was not thought to be related to the procedure. Others had elevations in the laboratory marker, bilirubin and a few others experienced thrombocytopenia (low platelets) throughout the course of the study.
After the first 12 weeks following infusion, cells that were modified with anti-HIV genes appeared to have a survival advantage one to three times greater than the cells that were only marked. This suggests that the anti-HIV gene may be providing some protection to those transfused cells. Overall there were no dramatic increases in CD4+ cell counts or decreases in viral load, however. In one volunteer who has subsequently stopped potent anti-HIV therapy there appears to be a forty to one hundred fold preferential survival advantage for the cells with the protective genes compared to the marked cells. In this individual there was a transient increase in CD4+ cell counts after the infusion of cells and viral load has been stable despite stopping anti-HIV therapy. In all ten HIV-positive volunteers, cells modified with the anti-HIV gene are detectable in their blood 3 months to one year after their last infusion. These data support moving forward, cautiously, with anti-HIV gene therapy experiments.
Gene Therapy in Stem Cells
In addition to gene therapy experiments that involve cell transfusions of genetically modified cells from HIV-negative cell donors, investigators are moving forward with experiments that modify a person's own cells. A stem cell can be likened to the mother of all cells. A single stem cell can divide and change to repopulate the entire spectrum of immune cells. Researchers are interested in isolating stem cells, modifying them with anti-HIV genes, in hopes that they will repopulate the body with a variety of different cell types resistant to HIV infection. This is the goal of stem cell therapy, but the field is in its infancy.
A study conducted at the University of California, San Francisco, removed and modified stem cells from people living with HIV with three different anti-HIV genes, called antisense genes to TAT and TAR. Five volunteers participated in this study. Their stem cells were "mobilized" to move out of their bone marrow and into the blood for collection using a therapy called G-CSF (filgrastim, Neupogen). Cells modified with the genes were reinfused into patients. These cells were detected in the blood of the study participants four and five months after the infusion. In one instance, modified cells have been detected one year after the infusion. In most studies of stem cell therapy, people receive immune suppressive therapy to "make room" for the new cells in their body. In this study, no immune suppressive therapy was used. No information was presented on whether or not the presence of the modified cells were associated with increases in CD4+ cell counts or decreases in viral levels. It is likely the procedure had not effect on these parameters, however. Small and incremental steps in this field are to be expected. The first step is to see if cells can be modified and if they thrive, the second step is to find out a way to really make them work.
AIDS-Related Cancers
Kaposi's Sarcoma Herpes Virus (HSHV, also known as HHV8)
Kaposi's Sarcoma (KS) is among the most common AIDS-related cancers. A few years ago a virus was identified, KSHV, also called HHV8, that is believed to cause KS. Since that time much work has been done to identify the prevalence of KSHV infection and to try to understand risk factors associated with the development of KS. KS is more often seen in men than women in the United States and Western Europe. In Africa it is found in both men and women and some studies suggest that the virus causing KS can be transmitted from mother-to-child. In general, KS is rarely seen in people without HIV infection, though a few cases have been noted in the United States in HIV-negative men. It is not uncommon in older men of Mediterranean descent, some Africans and a specific group of Jewish people who are not living with HIV. Of note, KS is rarely seen in women in the United States, but when it is observed in women it appears to develop later in the course of HIV disease, is more aggressive and less responsive to therapy than KS in men. The reason for the gender difference in KS in the United States is not known.
A French group looked at the prevalence of HIV-1, HIV-2 and KSHV in Djibouti, where KS is common. In order to assess the risk of heterosexual transmission of KSHV, researchers evaluated presence of these three viruses in female sex workers in bars and hotels, women who were not sex workers and men blood donors (total 207 women, 75 men). Not surprisingly, the women sex workers were more likely to be infected with HIV than the women who were not sex workers and the male blood donors. Male blood donors, however, were more likely to be infected by KSHV than women sex workers and had similar rates of KSHV (29%) as women who were not sex workers. This suggests that for reasons not wholly understood KSHV transmission is not increased by the same factors that increase risk for HIV transmission.
Another study looked at predictors of KSHV infection in a group of pregnant women in Zambia, another area where KS is common. The study included a total of 1,843 mother/infant pairs. The goal was to determine the prevalence of KSHV, factors associated with infection and predictors associated with risk for infection. About 40% of the mother/infant pairs were infected with KSHV, 31% with HIV and 14% were co-infected with both viruses. The study concluded that the presences of genital warts or a history of sexual abuse increased the risk of KSHV infection. It should be noted, however, that hundreds of participants with no genital warts and no history of sexual abuse were infected with KSHV.
It appears that the use of iron supplements decreased the risk of KSHV infection. This warrants further study. It is unclear if the use of iron supplements simply indicates health promoting behavior or lifestyles that delineates women with decreased likelihood of KSHV exposure, or if iron supplements actually have a protective affect. Of the participants with KSHV, 362 did not receive iron supplements and 370 did. While the percentages of people receiving supplements was lower in the group with KSHV, iron supplementation, if at all protective, was not wholly protective. This study sheds little light on factors associated with KSHV infection. A previous study has shown that infants born to KSHV+ women were more likely to be infected with KSHV and only children born to women who were KSHV+ developed KS.
AIDS-related Cancers and Potent Anti-HIV Therapy
Three presentations at the Chicago conference examined the impact of potent anti-HIV therapy on AIDS-related cancers. One study looked at the immune response to KSHV, the virus that causes Kaposi's Sarcoma, following initiation of anti-HIV therapy. Another looked at the effects of anti-HIV therapy on KS disease progression as well as immune response to KSHV. The third examined the effect of anti-HIV therapy on survival in people with KS or non-hodgkins lymphoma (NHL), another common AIDS-related cancer.
The first study included nineteen people with HIV, six who were KSHV+ with no KS, six who were KSHV+ with KS and seven with neither KSHV or KS. In the first group, significant increases in cellular immune responses to KSHV were observed in all six people coincident to immune reconstitution following the initiation of anti-HIV therapy. In the second group, only two people showed evidence of cellular immune responses to KSHV. In the third group, no cellular immune responses to KSHV were noted. The team showed that as HIV levels decreased, cellular responses to KSHV demonstrated a corresponding increase. Work is now ongoing to assess cellular responses as control of KS over the course of one year of anti-HIV therapy.
In the second study, twenty-one people with KS and fifteen people without KS were evaluated before and after starting anti-HIV therapy. About half of those studied showed complete or partial KS remission, seven went on to use chemotherapy for KS treatment, three demonstrated KS progression and one died of KS in the lungs. KSHV levels were significantly higher in people with KS than those without KS. Among those who had partial or complete KS remission over the 36 weeks of follow up, 100% achieved optimal suppression of HIV. Of those who experienced KS progression and/or initiated chemotherapy, only 45% achieved optimal suppression of HIV. KSHV levels appeared to decline as HIV levels decreased. This study confirms other findings that anti-HIV therapy appears to decreases KSHV levels by unknown mechanisms, believed to be associated with immune restoration.
Lastly, the third study examined outcomes in 387 men with either KS or Non-Hodgkin's lymphoma (NHL) who had participated in the Multicenter AIDS Cohort Study (MACS). Thirteen of 100 men with NHL and 43 of 287 men with KS had been treated with potent anti-HIV therapy. Comparing survival rates between men who initiated anti-HIV therapy and those who did not, investigators found that the use of anti-HIV therapy reduced the risk of death associated with KS by 81% and reduced the risk of NHL-related death by 83%. The survival advantage conferred with the use of anti-HIV therapy was independent of other factors including CD4+ cell count at time of cancer diagnosis and years since diagnosis.
The group speculated as to why people receiving anti-HIV therapy faired so much better than those who did not. They proposed that immune restoration following the use of anti-HIV therapy may restore or enhance responses to KSHV and/or Epstein Barr virus (EBV), the viruses believed to cause KS and NHL respectively. They further speculate that the decrease in immune activation associated with the use of anti-HIV therapy may decrease the rate that cancerous NHL cells reproduce. They note that overall improvements in health associated with the use of anti-HIV therapy allow people receiving treatment for NHL to better tolerate chemotherapy. Finally, anti-HIV therapy may have some direct or indirect anti-KSHV or anti-EBV effects.
Researchers conclude that the use of anti-HIV therapy can prolong life in people with KS and NHL, even when therapy is initiated after initial diagnosis with these cancers. Based on these data, investigators strongly recommend that people with KS or NHL receive anti-HIV therapy, if they are not already taking it.
Primary Central Nervous System Lymphoma (PCNSL) and Anti-HIV Therapy
Before the advent of potent anti-HIV therapy, time from diagnosis to death following PCNSL was one month without therapy and three month if therapy with cranial radiation was applied. PCNSL is believed to be caused by Epstein Barr Virus (EBV) in the central nervous system. It is never seen in people with CD4+ cell counts above 200 and rarely seen in people with counts above 50. A German group sought to identify PCNSL cases, brain biopsy proven, throughout four centers in Germany. Twenty nine cases were identified, six of whom had received potent anti-HIV therapy.
Of those who did not receive potent anti-HIV therapy or cranial radiation (CR) survival after PCNSL was 33 days. Of those who did not receive anti-HIV therapy but did receive CR survival was 132 days. In the group receiving potent anti-HIV therapy, all elected CR and survival was 1093 days. Among the six people initiating potent anti-HIV therapy, two did not sustain increases in CD4+ cell counts to above 200 nor optimal viral suppression. These two individuals died 55 and 253 days following PCNSL diagnosis respectively. Of the four people who achieved immune recovery and viral suppression, two died about 3 years following PCNSL diagnosis of conditions not related to PCNSL. Of the two who are still alive, one has been alive for over five years following his initial PCNSL diagnosis. The longest survivor to date coincidently had the most profound immune response to therapy, with CD4+ cell counts rising from 3 before initiating anti-HIV therapy to nearly 700. This level of immune recovery has been sustained.
Immunology
Predictors of Disease Progression
A large study conducted by the Community Program for Clinical Research on AIDS (CPCRA) compared two protease inhibitors, nelfinavir (Viracept) and ritonavir (Norvir), in combination with other anti-HIV therapies in people with CD4+ cell counts below 200. The study included 775 volunteers, 47% were white, 43% were African American, 10 % Latino/a and 17% were women. The mean CD4+ cell count at study entry was 58, viral levels were over 100,000 copies/ml and about half of the participants had previously been diagnosed with an AIDS-defining illness. In the reported analysis, investigators sought to examine factors that may be predictive of a risk for HIV disease progression and/or death. In the study 183 people experienced a new AIDS defining illness and/or died. A total of 108 volunteers died during the median 37 months of follow up.
The CPCRA team concluded that for people with advanced HIV disease who are taking potent anti-HIV therapy, CD4+ cell count is a better predictor for the risk of disease progression than is viral load. This is not wholly surprising. HIV attacks the immune system, but ultimately it is the immune system that combats infections and cancers that can cause disease and death. No matter how well anti-HIV therapies are working, if the immune system is not recovering or being maintained, it cannot act to preserve and enhance health.
Also not surprising, the investigators note that pre-therapy CD4+ cell counts and viral load were not as predictive as these values after therapy, overtime, in predicting risk of HIV disease progression, among people who initiate therapy when CD4+ cell counts are below 200. How well an individual responds to therapy and their trends overtime give a better picture of immune health and activity of the virus than do number prior to starting therapy. How well a person responds to therapy, however, may well be related to when they initiate anti-HIV therapy and this might be more evident in studies that include people with CD4+ cell counts above 200. The CPCRA study only included people with CD4+ cell counts below 200.
Finally, the CPCRA study showed that people with CD4+ cell counts below 100 were at greatly increased risk for HIV disease progression and death, regardless of HIV RNA levels. It further showed that among people with CD4+ cell counts above 200 there is little risk of HIV disease progression and/or death. Of note, of the AIDS defining events reported among people with higher CD4+ cell counts a large number were due to HIV-associated cancers, specifically lymphoma and Kaposi's Sarcoma.
An independent group from the University of Alabama at Birmingham (UAB), presented information from an observational study of 759 people who initiated three-drug anti-HIV therapy since 1996 who were receiving care at the UAB HIV clinic. The UAB group sought to identify factors associated with long-term survival after the initiation of potent anti-HIV therapy. They found that people who began three-drug anti-HIV therapy while CD4+ cell counts were above 200 faired significantly better than those who started therapy when counts were below 200. Of those initiating therapy when CD4+ cell counts were above 200, 85% were alive four years after starting therapy. Of those starting therapy at lower counts, only 65% were alive four years later.
The UAB group found that lower CD4+ cell count or an opportunistic infection prior to starting potent three-drug anti-HIV therapy were associated with increased risk of death. A second group at the University of British Columbia in Vancouver, Canada, confirmed the observations of the UAB group. Other factors that were looked at that were not associated with an increased risk of death included race, age, gender, viral load, prior use of single or two-drug anti-HIV therapy, use of protease inhibitor as part of a three-drug regimen and the number of different three-drug regimens used after starting potent therapy.
Together, the CPCRA and the UAB studies show that CD4+ cell count is an important measure of immune health and changes in this measurement should play a major role in therapy decision-making. The CPCRA study shows that risk of HIV disease progression and death increases as CD4+ cell counts decline, regardless of the viral levels, in people with counts below 200 who are taking anti-HIV therapy. The UAB study also shows that CD4+ cell counts are critically important in therapy decision-making, showing that those who started potent anti-HIV therapy when counts were above 200 faired much better than those who started therapy when counts fell below 200.
These results do not suggest that viral load isn't a useful measure of the effectiveness of therapy. Using viral load to evaluate the effectiveness of anti-HIV therapy is an important and useful tool. Viral load can tell an individual important information about the activity of an anti-HIV regimen and it can also provide clues as to how long a regimen might work for.
The goal of anti-HIV therapy is to decrease the amount of virus in the body and viral load measurements provide a tool to see how well therapy is doing this. The overall goal of managing HIV disease, however, is to preserve and enhance immune health such that the immune system is successfully combating and eliminating serious infections before they can cause life-threatening diseases. In almost all studies of anti-HIV therapy, decreases in viral load are associated with increases in CD4+ cell counts.
The CPCRA and UAB studies tell us that when the immune system is seriously compromised, when counts are below 200, despite the use of anti-HIV therapy, risk of life-threatening infections and death increases as measures of immune health decline. These studies also tell us that anti-HIV therapy is better able to preserve and enhance immune function, decreasing the risk of serious life-threatening disease, if it is started before serious immune damage has already taken place and counts are above 200.
The Impact of Pregnancy & Menopause on CD4+ Cell Counts in HIV+ Women
The European Women's Study includes 382 women who were included in this study. Investigators evaluated the impact of menopause and pregnancy on CD4+ cell counts in this group that included 34 women who became pregnant during the study and nine women who reached menopause during the follow-up period of the study. A total of 17 women entered the study postmenopausal. Researchers note that postmenopausal women had a slightly lower CD4+ cell count after seroconversion than pre-menopausal women. Whether this is due to hormones, in general, or older age is unclear. In general, pregnant women have lower CD4+ cell counts than women who are not pregnant. During pregnancy CD4+ cell counts decline temporarily, but return to pre-pregnancy levels after the child is born. Pregnancy does not appear to affect the overall rate of CD4+ cell count decline. These results suggest that hormones do impact CD4+ cell count, though they do not seem to have an overall negative impact on HIV disease progression rates, particularly with regard to pregnancy.
Co-Receptors for HIV Infection
A few years ago there were breakthrough discoveries regarding the role of certain proteins found on cells, called chemokine receptors, that help to facilitate HIV's ability to infect cells. (For more information call the Project Inform hotline and ask for information on Co-receptors and HIV infection.) At the time of the initial discovery, it was found that two receptors found on cells, CCR5 and CXCR4 (also called fusin) were critical for HIV to latch on to in order to get into a cell. It was also found that some people had alterations in these structures on their cells, rendering them less able to be infected by HIV and/or less susceptible to HIV disease progression. At the time of the initial discovery, a flurry of work was initiated to better understand the role of alterations in these proteins that might help explain why some people do not progress to symptoms of AIDS despite long-term HIV infection.
As with most progress in science, the picture has become more confusing overtime as the field seeks to gain clarity. This is not unexpected. Initially alterations in a key protein, called the CCR5 receptor, were almost solely observed in Caucasians (white people) and were associated with resistance to HIV infection and/or slower progression of HIV disease. It was then noted that some people who had an alteration in this receptor became infected, almost preferentially, with a more aggressive strain of HIV that relied less on the CCR5 receptor and more on the CXCR4 receptor. These people progressed to symptoms of disease very rapidly. Since that time other chemokine receptors have been identified, such as CCR2, that also contribute to HIV infection of cells. More work has been done examining alterations in these receptors that may confer some protection against HIV infection and/or disease progression among groups.
In order to evaluate relationships of these proteins, or receptors, to disease progression, one group evaluated 202 African women from Rwanda who became infected with HIV soon after enrollment at a GYN clinic in 1986. These women have been followed in the clinic for over 11 years. Researchers found that alterations in CCR5 and CCR2 occurred in similar rates in the black African women as those observed among white people and that in this group of women the alterations were similarly correlated to decreased risk of HIV disease progression.
These new findings are encouraging as companies working in the field of new anti-HIV therapies have been focusing attention on developing approaches that might block the ability of HIV to bind to the protein and gain entry into a cell. Showing that alteration in the protein do appear to be consistent and correlated to decreased disease progression in those living with HIV not only across races, but also across different strains of the virus found in Africa as opposed to the United States and Western Europe is important and encouraging. This means that if these therapies prove useful in test tube studies and advance to human studies, they will be broadly applicable across populations throughout the world.
Blocking the Receptors
Two experimental therapies currently under study that may block CCR5 and CXCR4 include AMD3100 and NNY (n-nonanoyl) -RANTES. AMD3100 has been shown, in test tube and animal studies, to block CXCR4-dependent HIV from infecting cells. NNY-RANTES has been similarly shown to block CCR5-dependent HIV. Results from a small study in mice of these two agents combined showed that the combination did better than either alone in preventing HIV infection of cells, completely blocking CCR5-dependent HIV infection and preventing the emergence of the more aggressive CXCR4-dependent variety of HIV. This animal study suggests that using a combination approach might be the key to success for this area of drug development. It's always possible that blocking with these two types of agents will result in an evolution of HIV such that HIV that is CCR2-dependent will emerge as the dominant virus. Because use of these types of therapies may force changes in predominant virus and how HIV infects cells it's important that the field move forward with caution.
Another approach being researched is a part of pertussis toxin, called PTX-B. In test tubes PTX-B blocked the ability of CCR5-dependent virus to infect cells as well as blocked the ability of CXCR4-dependent HIV to reproduce within cells. Of interest is a mutation of pertussis toxin, called PT-9K/129G, which is commonly used in vaccines to prevent pertussis infection, had similar anti-HIV properties in test tube experiments. The use of pertussis toxin as a possible new strategy for treating HIV infection is not new. Many years ago a researcher at the University of Wisconsin at Madison proposed that pertussis toxin may also make cells traffic through the body and away from the lymph nodes, which represents the major site where infection of new cells occur. Dr. Pauza, who is now at the Institute of Human Virology, working with Dr. Bob Gallo's group, had proposed that by using pertussis toxin, or similar agents to clear the lymph nodes, more appropriate immune responses might be generated capable of controlling HIV infection. These new findings, from an Italian group, showing a direct anti-HIV affect of PTX-B against CCR5-dependent HIV further supports study of this approach.
Co-receptors and Cervical Cells
Two groups of HIV-negative women, one group using oral contraceptives the other not, were evaluated to look at cervical cells for markers of activation and co-receptor expression. Researchers note that a high level of activation and co-receptor expression in cervical cells appears to be normal, yet noted that CCR5 expression on cervical cells was significantly higher among women using oral contraceptives. While the ramifications of this observation are not wholly clear, one might speculate that the use of oral contraceptives might increase the risk of HIV infection if an exposure occurs, as these researchers did. Before jumping to conclusions and discouraging the use of oral contraceptives, clinicians should be aware that upregulation of receptors in other experimental models have been correlated with an increase in chemokine expression and an overall decrease in the ability of cells to support HIV replication. A poster presentation at this conference, examining the use of IL-2 therapy on chemokine and receptor expression, shows just this. At best more research is needed to understand if the use of oral contraceptives increase or decrease the susceptibility of HIV infection in the context of HIV exposure. At worst physicians will jump to premature conclusions and perhaps discourage women from using a contraceptive option based on incomplete information.
Low Platelets (Thrombocytopenia)
Thrombocytopenia, low platelet counts, occurs in as many as 40% of people living with HIV, across the spectrum of HIV disease, though it remains unclear why this happens. Sometimes this condition is called idiopathic thrombocytopenia purpura, or ITP for short. Platelets are produced largely by the liver and are important in wound healing and blood clotting. People with low platelet counts are likely to bruise easily, may bleed more if cut (and this can be quite serious) and are likely to feel fatigued. In some people with HIV who have developed thrombocytopenia it's been observed that an immune response (antibodies) to platelets has developed, suggesting that the immune system is turning against and destroying the platelets. This isn't observed in all people with HIV-associated thrombocytopenia, however. In the days before triple-drug therapy, a high dose of AZT (1200mg/day) was prescribed that sometimes corrected the problem of low platelets. Sometimes immune globulin preparations, called IVIG, can be useful in treating low platelets. It has been shown that effective triple-drug anti-HIV therapy, at routine doses, results in dramatic increases in platelet counts. The fact that anti-HIV therapy, and the lowering of HIV levels, increases platelet counts suggests that HIV itself may be doing something to interfere with platelet production, function and/or contribute to the destruction of platelets.
One group sought to examine the impact of HIV infection of a cell type called macrophages on platelets. Macrophages are believed to be the first cell type typically targeted by HIV after initial infection. These cells are scavengers and gobble up foreign organisms. They will sometimes kill an organism outright in this process, other times they'll digest it and show components of the organism to a CD4+ cell in order to initiate specific immune responses. For example, when a macrophage shows a CD4+ T cell a digested part of HIV, this may lead to the development of HIV-specific CD4+ and CD8+ cell responses, cells that seek out and destroy HIV infected cells (find a brief discussion of HIV specific cells later in this article under the section titled Natural Killer Cells).
In order to assess the impact of HIV infection of macrophages on platelets, the group examined alterations in chemicals produced by the macrophage after infection by HIV in a test tube. HIV infection apparently induced the macrophages to produce more of a chemical called macrophage-derived chemokine (MDC). Ironically, this chemical may be important in blocking HIV infection of cells with the CXCR4 receptor by binding with the receptor shown to be important for HIV infection of cells. This chemical, MDC, also appears to alter the function of platelets. This small test tube study provides a possible explanation for HIV-associated thrombocytopenia that warrants further exploration.
A different group looked at the role of another chemokine, called stromal-derived factor-1 (SDF-1), which is also a CXCR4-related chemokine. SDF-1 appears to alter the way that some cells move through the body. One cell in particular, a megakaryocyte, is particularly affected and this cell is important for platelet release. Another group recently found that only people with a CXCR4 strain of HIV had HIV-associated thrombocytopenia. No one with only the CCR5-dependent HIV had thrombocytopenia.
These findings, taken together, suggest that HIV may affect platelets in a variety of ways. Anti-HIV therapy may be a useful tool for treating HIV-associated thrombocytopenia. Strategies that interfere with CXCR4 interaction with HIV may also have a unique role in preventing and/or treating low platelets. As new therapies are researched and developed that seek to interfere with co-receptor binding, their impact on thrombocytopenia should also be evaluated.
Interestingly, when comparing people with HIV-associated thrombocytopenia to people without HIV who have thrombocytopenia, researchers find distinct differences. Of note, people who are HIV-negative show a dramatic decrease in platelet survival time, suggesting that in general this condition is caused by destruction of platelets. In people living with HIV, on the other hand, platelet survival time does not appear to be decreased, suggesting that the condition is caused by interference in production or release of new platelets. Thus, treatments of thrombocytopenia in people with HIV may well need to be approached differently.
Activist involvement in learning about the somewhat more complex area of immunology and raising issues with companies developing new anti-HIV agents and immune-based approaches are important to see research relevant to community needs pursued. This is one area where activist involvement is needed and unfortunately, sparse. Thrombocytopenia is a large problem for people living with HIV, impacting many people ranging the spectrum of CD4+ cell counts and adequate research into this important area is sorely lacking.
Dendritic Cells
In general there are two types of dendritic cells, DC1 and DC2. DC1s preferentially stimulate T-helper 1 (TH-1) type responses, which are cellular immune responses (e.g. cells that seek out and destroy virally infected cells). DC2's stimulate T-helper 2 (TH-2) type responses, which are humoral, or antibody responses. A number of groups have looked at the impact of HIV-infection on dendritic cells. Both absolute number and the percentage of DC1 and DC2s are decreased in the setting of HIV infection compared to what is observed in HIV-negative people. There appears to be no significant differences in DC decreases in people across different stages on HIV infection. These defects seem to persist, especially in the setting of chronic established infections, despite anti-HIV therapy. This may explain the inability of people who, despite control of HIV replication, do not regain anti-HIV specific immune responses. DCs are critical to the initiation of functional anti-HIV cellular responses.
Another team evaluated the impact of potent anti-HIV therapy on restoring DC numbers. This group, unlike the previous one, did show a greater decrease in DC numbers in people with HIV with higher viral levels. In order to assess the ability of anti-HIV therapy on DC numbers, five people with chronic established HIV infection and three people with very recent infection with HIV had DC numbers looked at before and after the initiation of anti-HIV therapy. Those people with recent HIV infection had a more severe depletion of DC's prior to initiating therapy, but following therapy had DC numbers return to levels observed in healthy HIV-negative people. Those volunteers with established infection showed DC depletion that did improve following anti-HIV therapy, but not near levels observed in healthy uninfected people. This study suggests that depletion of DCs can be somewhat corrected by therapy. DC1s decrease progressively as viral load increases, whereas DC2s are lost at much lower viral levels. DC2s produce an immune chemical called interferon-alpha, which has antiviral effects. The loss of DC's may thus impact the ability to control HIV in many ways and other strategies, beside anti-HIV therapy are warranted to try to improve DC numbers, percentages and function. One such approach might be a therapy called Flt-3 Ligand, which is being evaluated in several test tube studies and will hopefully, one day, be tested in people living with HIV.
Natural Killer Cells
While much attention is given to the role of CD4+ and CD8+ cell counts and percentages in the management of HIV infection, there are many other cells of the immune system that are affected by HIV. Over the course of the next year it's likely that research in the field of immunology will have an increased focus on the role of something call innate immunity. HIV-specific CD4+ and CD8+ cells, which have been the topic of much discussion over the past few years, particularly with regard to therapeutic immunization and Structured Treatment Interruption (STI) strategies, are part of the acquired immunity. Simplistically, innate immunity is something that we're born with and acquired immunity is something that our immune systems learn over time as we become exposed to organisms and our bodies learn how to respond and deal with them. There is an interplay, a synergy, between innate and acquired immunity. The first line of immune defense against many if not most new infections and diseases is likely innate immunity, as acquired immunity takes some time to develop. Moreover, parts of the innate immune responses help to facilitate the development of acquired immunity. At the recent Chicago conference there were a number of interesting presentations looking at innate immune responses in the setting of HIV infection.
While HIV-specific CD4+ and CD8+ cells are important in promoting the killing of HIV infected cells, natural killer cells (NK cells) are less specific but are also critical in the control of cells infected with HIV and other organisms. Consider the immune system to be something of an army of peacekeepers. HIV-specific CD8+ cells, with the help of HIV-specific CD4+ cells, might be likened to hired guns that are given a dossier on a specific enemy target and told to kill only that target HIV infected cells. NK cells, on the other hand, are a bit more like thugs, who kill at random anything that they perceive as the enemy. Natural killer cells destroy HIV infected cells, but they also destroy cells that they perceive as being infected with any virus or foreign organism. They are not highly specific in that they don't simply seek out and destroy, specifically, HIV infected cells.
It has been long demonstrated that NK cell numbers and function are impacted by HIV infection. Function of the cells is observed to be particularly impaired among people with symptoms associated with HIV disease. One group sought to study the impact of anti-HIV therapy on NK cells and found that potent anti-HIV therapy results in a normalization of NK cell function. This group compared NK cell function in HIV-negative people to NK cell function in HIV-positive people successfully treated with potent anti-HIV therapy (sustaining HIV levels to below 50 copies/ml for at least one year), people initiating anti-HIV therapy for the first time and people who had not been treated with anti-HIV therapy. Researchers saw a normalization of NK cell function occurring within eight weeks of initiating triple-drug anti-HIV therapy and this normalization was sustained over 48 weeks of observation. The researchers note that this restoration in NK function may help to contribute to explanations of restored immunity following the initiating of anti-HIV therapy and further study of the role of NK cells in both early and established infection is warranted.
HIV Specific Cellular Responses: More Commentary than Clarity
A number of groups have been examining the presence and function of HIV specific immune responses over the course of HIV infection, with and without the use of anti-HIV therapy. Largely it can be said that this area is largely unfocused and results are conflicting and confusing. Some groups assert that HIV-specific cellular responses are lost early in the course of HIV infection, within days to weeks after initial infection with HIV. Many agree with this perspective. One group has shown that initiating anti-HIV therapy very early on, within days to weeks of initial HIV infection, and applying a Structured Treatment Interruption (STI) approach, preserves and possibly even enhances HIV-specific cellular responses. Other groups, however, have not found this to be the case. Still other groups have shown that initiating anti-HIV therapy in people with advanced HIV infection can result in a return of measurable and robust HIV specific immune responses. Other groups contend that HIV specific immune cells are never lost, but rather they are always detectable but not functional. This area of research is awash in contradiction and disagreement.
Despite a great deal of disagreement and conflicting data, there are some areas in this arena that nearly everyone agrees upon. HIV-specific cellular immune responses are very likely critical in the immune system's ability to control HIV replication and disease. HIV-specific CD8+ cells are likely highly dependent on the function and support of HIV-specific CD4+ cells. While it's not wholly clear if HIV-specific cellular responses are lost early after infection, it is clear that whether the cells are there or not they do not appear to be functioning optimally and controlling HIV. Efforts to understand the defect in HIV-specific immune responses and the development of therapies to correct that defect are critical toward advancing the field of HIV therapeutics.
Differences observed that are resulting in conflicting data are a product of different techniques used to measure the presence and function of HIV-specific cellular responses. The field of immunology, in general, lacks consensus on the best way to measure HIV-specific cellular responses and functions. Each test being applied has different strengths and weaknesses and none have produced results that are validated and correlated with HIV disease progression and/or improvements in health as a result of proven therapies. For example, while the field is hedging toward embracing the early loss of HIV-specific cellular responses as dogma, several groups presented data showing a persistent and robust response across the spectrum of HIV infection. One group used numerous tests to look for the presence and function of these responses in lymph tissue, which is likely the site that these responses are initiated and have the most impact. This group surprised itself by finding robust HIV-specific cellular responses in the lymph tissue and puzzled at why, despite no deficiency in either number or function of these cells in the lymph tissue, there is not control of HIV replication. Other groups contend that the cells are there, but they're simply not functioning. One group, in Seattle, published last year that the cells were there, but dying very quickly (in about three days). Still other groups claim that they're not there at all.
One of the biggest mistakes that HIV research could make right now is to too easily and quickly latch on to one particular view or interpretation of results from studies of HIV-specific cellular responses. The jury is simply not out with regard to the extent of the defect in HIV-specific cellular responses nor what to do about them. This is an area of research that would greatly benefit from both an infusion of funds as well as fresh perspectives. If there were ever an area of AIDS research that might be advanced by a Manhattan Project-style approach to problem solving, this would be one. There are a discrete number of technologies on the table for evaluation and a number of datasets to evaluate and tap into for further research. Bringing together a group of researchers, laying the data on the table, and providing mechanisms to address the conflicts in current data and support to conduct studies to bring clarity to this field could be done if there was a scientific and community will to make it so.
The Thymus, Is It Working? The thymus is an organ that resides behind the breastplate and in adults it is about the size of a closed fist. The cells of the body come from the bone marrow and where a cell matures will determine its function. B-cells mature in the bone marrow whereas T-cells (including CD4+ and CD8+ T cells) mature in the thymus. An outstanding question in understanding HIV disease is a full explanation of how and why CD4+ cells are depleted throughout the course of HIV infection. It's well established that HIV infects CD4+ cells and that a good number of cells die to infection and destruction by the virus. This does not wholly explain the depletion of CD4+ cells in the body overtime, however, and for years researchers have been studying other causes for the loss of these important cells. Many have speculated that the decline in CD4+ cell counts are not solely a result of HIV infection and destruction, but contend that there is a simultaneous defect in the production of new cells. In other words, the sink is draining and there's no new water coming in. Similar to discussions about HIV-specific cellular responses, this area of study is rife with conflicting information.
A group in New York looked at the rate of CD4+ cell destruction in the blood and developed a mathematical model to determine whether or not there was a defect in thymic output of new cells following the initiating of potent anti-HIV therapy. According to their mathematical model, their findings do not suggest a defect in the thymus' ability to produce new immune cells. Another group, based in Texas, used a new technology called TREC, which stands for T-cell Receptor Excision Circles. TREC levels in a cell indicate that the cell has very recently come from the thymus. According to their findings, TREC levels were significantly decreased almost immediately following HIV infection and the decrease in TREC levels were correlated with an increase in the activation and destruction of immune cells. Following the initiation of potent anti-HIV therapy they have observed both an increase in TREC as well as a decrease in cell destruction, suggesting that HIV is interfering with thymic output of new cells and that by controlling HIV this interference is corrected to some degree.
CD8+ Cells: Are They Infectable by HIV? For years conventional wisdom held out that CD8+ cells were not infectable by HIV. When examining the blood of people living with HIV, CD8+ cells could not be harvested that were productively infected with the virus. Given that CD8+ cell counts increased while CD4+ cell counts decreased provided further fodder for this long-held view. A few years ago researchers showed that CD8+ cells can become infected by HIV and after infection they are destroyed almost instantly. Another group presented data at the recent Chicago conference showing that when CD8+ cells are stimulated they can and do express CD4+ markers, providing HIV a mechanism for infecting the cell. The research team showed that a subgroup of activated CD8+ cells, expressing CD4+, CCR5 and CXCR4, can be infected by the virus. These cells seem to be uniquely susceptible to the more virulent CXCR4-dependent HIV. This might help to explain the decline in CD8+ cell counts that appear in more advanced stage disease, which is associated with increased levels of activation markers on CD8+ cells.
A group from Canada also presented data from experiments seeking to identify exactly how HIV infects CD8+ cells and what HIV infection of CD8+ cells does to the function of these cells. They showed that HIV may infect CD8+ cells through either a CD4+ or CD8+ dependent pathway, demonstrating that blocking either CD4+ or CD8+ resulted in blocking HIV infection of the cells. They further showed, similar to the previous group, that CD8+ cells are uniquely susceptible to infection by CXCR4-dependent HIV. However, they observed that CCR5-dependent HIV could also infect CD8+ cells. This group showed that memory CD8+ cells were more susceptible to infection than naïve cells. In other words, CD8+ cells that were mature and capable of mounting immediate and robust responses were most susceptible to HIV infection. CD8+ cells that were infected with HIV appeared to have altered function.
Neurology
IRINA
A large study in Italy evaluated neurologic manifestations of HIV disease before and after the use of potent anti-HIV therapy. Neurologic refers to the central nervous system and brain. HIV-related diseases known to impact the nervous system and brain function include toxoplasmosis, HIV encephalopathy (HIVe, swelling of the brain), cryptococcosis, and progressive multifocal leukoencephalopathy (PML), among others. The study, called IRINA, showed that when neurologic conditions occur while on therapy, they typically happen within the first six months after starting potent anti-HIV therapy. Those most likely to occur in this six-month window include PML, HIVe and cytomegalovirus (CMV) and tuberculosis (mTB) with neurologic involvement.
Toxoplasmosis is the most common neurologic condition associated with HIV-disease. People with HIV are encouraged to be tested for antibodies to toxoplasmosis after learning of their HIV status to identify if they are at risk for this condition. Those who don't have antibodies to toxoplasmosis are encouraged to learn about how they can prevent the infection. Those who do have toxoplasmosis antibodies are encouraged to talk to their doctor about preventive therapies if their CD4+ cell counts fall below 200. When comparing the incidence of toxoplasmosis in people treated with anti-HIV therapy and those not treated, it's noted that anti-HIV therapy significantly reduces the risk of toxoplasmosis, though it remains the most common neurologic condition. The risk of HIVe is also significantly decreased with the use of anti-HIV therapies.
The study team also evaluated the risk of neurologic conditions associated with CD4+ cell counts and viral load. For the most part, neurologic manifestations are unlikely to occur when CD4+ cell counts are above 200. The one most likely to occur when CD4+ cell counts are above 200 is not-determined leukoencephalopathy (NDL). The risk of cryptococcosis rises significantly among people who have had a previous AIDS-defining illness. Neurologic conditions more common to occur when HIV levels are above 500 include PML, HIVe and cryptococcosis.
Peripheral Neuropathy
Peripheral neuropathy (PN) is characterized by pain and tingling in the hands, feet and/or legs. It can feel like a numbness or dull throbbing pain in the extremities, or it can include very spiking pain. HIV disease itself can cause peripheral neuropathy, perhaps by inflammation causing nerve damage. Some therapies to treat HIV and opportunistic infections can also cause PN. A few anti-HIV drugs, specifically the nucleoside analog reverse transcriptase inhibitors (NARTIs) ddI (didanosine, Videx), ddC (zalcitabine, Hivid) and d4T (stavudine, Zerit) are associated with a risk of peripheral neuropathy, with upwards of 10% of people taking the therapies developing PN.
There are unique differences between PN caused by these anti-HIV drugs and PN caused by HIV, perhaps the most relevant being the course of action with regard to managing the condition. An Australian research team sought to identify laboratory markers that may be helpful in diagnosing PN associated with the use of the nucleoside drugs as opposed to PN associated with HIV infection itself.
Currently, PN related to NARTI therapy is typically associated with taking NARTI therapy for several months and PN improves when NARTI therapy is stopped. Treatment of NARTI-associated with PN usually involves stopping the NARTI therapy suspected of causing PN and/or switching to another NARTI. After therapy there is persistent pain for a time that may even worsen slightly before improving. The absolute cause of NARTI-associated PN is unknown, but is thought to be due to mitochondrial toxicity, and there may be a window of opportunity to withdraw therapy before the nerve damage is irreversible.
HIV-associated PN is typically not associated with beginning a therapy. Treatment is largely palliative, which is simply pain management approaches. Some studies suggest that the initiation of potent anti-HIV therapy may improve some symptoms of HIV-associated PN. As with NARTI-associated PN, there may be a window of opportunity to alter the course of therapy after which time the damage may be irreversible.
The Australian team sought to determine if elevations in serum lactate levels, an indication of mitochondrial toxicity associated with the use of certain NARTI's was related to the development or diagnosis of NARTI-related PN. (For more information on Mitochondrial Toxicity, call the Project Inform Hotline.) Indeed, preliminary findings show that people with NARTI-related PN are more likely to have elevated serum lactate levels (3.2) compared to people on NARTI's who don't have PN (1.7) despite the use of NARTIs and those with HIV-related PN (1.8). This was particularly true for people with PN taking d4T, who represented the majority of study participants. The study included people who had only complained of PN symptoms for four weeks or less. Preliminary evaluation of people who have had symptoms for a longer period of time suggest serum lactate levels may be less correlative and thus less useful in helping to distinguish NARTI-associated PN from HIV-associated PN.
Progressive Multifocal Leukoencephalopathy (PML)
PML is a progressive disorder caused by a virus, called the JC Virus, which affects the brain. While the vast majority of people are infected with the JC Virus, it only rarely causes disease. It's unknown why some people who carry the JC Virus develop PML, which is most commonly seen in people with low CD4+ cell counts, below 200, who are living with HIV. Prior to the wide scale use of potent anti-HIV therapy, the median time from diagnosis to death after a diagnosis of PML was four to six months, according to observations in Spain. Other studies have suggested this time was shorter, in the range of one to three months. A Spanish group conducted a study to examine the impact of the availability of potent anti-HIV therapy on survival after a PML diagnosis. Sure enough, after potent therapies became available, survival after a PML diagnosis has improved significantly, with a current mean survival of four years following diagnosis.
Factors associated with prolonged survival include CD4+ cell counts above 100. Those with counts above 100 have a survival rate of 4.5+ years, whereas those with counts below 100 have a survival rate of 3.4 years. Those who initiate anti-HIV therapy sooner (within 1 week) after PML diagnosis faired slightly better than those who waited. Moreover, among those starting anti-HIV therapy, there was a 44% cure rate whereas 53% experienced stable or worsening disease. A "cure" for PML is defined as resolution of PML lesions in the brain, but rarely do people see dramatic improvements of symptoms associated with PML, though certainly some improvements have been observed. The researchers are still analyzing the information gathered to determine if people who have better anti-HIV and CD4+ cell count responses to anti-HIV therapy fare better than those who do not.
Cidofovir for Treating PML Twenty-four people with PML were enrolled in a study of cidofovir (Vistide). People were given cidofovir 5mg/kg intravenously (in the vein) at study entry and one week later, after which time doses were adjusted to accommodate for side effects and given every two weeks until week 23. Twelve volunteers died of PML during the course of the study. Five discontinued therapy due to side effects. Only two people showed improvements during the course of the study. Overall, no improvements were observed in the group after two months. Of those who did show improvements in neurologic evaluations after two months, all had undetectable HIV levels associated with anti-HIV therapy. This study suggests that the benefits of cidofovir for treating PML are not well established and benefits observed in this study may well be associated with the use of potent anti-HIV therapy.
Topotecan for Treating PML Topotecan is a drug that has been shown to have activity against the virus that causes PML, the JC Virus. Eleven people with PML participated in this study and received 0.3mg/m2 topotecan by continuous intravenous infusion for twenty-one days, every twenty eight days. Doses were escalated if well tolerated throughout a twenty-one day course of therapy. All volunteers must have been on stable anti-HIV therapy for three weeks prior to entering the study. Three of the eleven volunteers showed signs of improvement. These three individuals appeared to have better neurologic scores at the beginning of study. One of these individuals improved despite not controlling HIV levels with anti-HIV therapies. While these results are not overwhelmingly positive, further research is warranted to determine if topotecan has a role in treating PML.
Topical Aspirin/Diethyl Ether (ASA/DE) for Treating Peripheral Neuropathy
A small study evaluated the use of topical ASA/DE in people with HIV-associated peripheral neuropathy (PN) included 43 volunteers who received ASA/DE or placebo for two weeks, no therapy for three days and then switched to therapy or placebo for another two weeks. Thirty-one of the 43 volunteers completed the study. Researchers note that eight of the twelve who did not complete the study had significant improvement during the first two weeks of study but symptoms worsened when they were switched to placebo in the second phase of the study, and thus they dropped out. Investigators conclude that ASA/DE was useful in managing PN associated with HIV infection. This approach warrants further study.
Organ Transplantation
As people are living longer due to the use of potent anti-HIV therapies, there appears to be an increase in the percentage of people with HIV dying of non-AIDS conditions, including organ failure. Liver disease associated with hepatitis C can lead to liver failure. The six-year survival rate of people with cirrhotic liver disease ranges from 21% to 54% depending on the severity of the disease. Liver transplantation is virtually the only option for people with severe liver disease. HIV-related kidney diseases, specifically HIV-associated Nephropathy (HIVAN), is of major concern to African Americans and represents the third leading cause of end stage kidney failure in African American adults. Other causes of organ failure may include side effects of therapies to treat HIV and associated conditions. In cases of frank organ failure, organ transplantation is the only viable option. For people with kidney dysfunction, dialysis may provide a short- or even long-term solution for some people. For people with HIV experiencing organ failure, transplantation needs to be made an option.
Current guidelines put forward by transplant surgeons contraindicate organ transplantation in people living with HIV. While groups that allocate organs will include people with HIV on waiting lists for organs, most surgeons will not transplant an organ into an HIV-positive person and transplant surgeons who advise insurance companies advise that insurers and federal third party payers not pay for these transplants. These policies were put in place during an era when little was known about HIV disease and potent anti-HIV therapies were not available.
In recent years community activists and researchers have been working together to move the organ transplant field to reassess this issue and reconsider organ transplantation for people with HIV in need. Given that shortages of organs is a real issue, showing that organ transplantation benefits people living with HIV and prolongs life is key to moving the field to allow people with HIV to receive organ transplants. Previous information suggests that people with HIV undergoing organ transplants may have a poorer outcome (11% reduced survival) than people who are not infected with HIV. Whether this hold true today, when people with HIV are living longer and experiencing fewer opportunistic infections due to the availability and use of potent anti-HIV therapy needs to be examined. Moreover, as people with HIV are living longer, more and more people with HIV are dying of organ failure, particularly associated with complication of hepatitis. As a result a group in Pittsburgh has agreed to perform a number of these transplants and a group at the University of California, San Francisco (UCSF) is spearheading efforts to develop a nationwide study to make available and evaluate organ transplantation in people with HIV. Some individuals, on a case-by-case basis, have had success in convincing institutions to perform organ transplants for them, despite their HIV status.
At the Chicago conference, a great deal of information was presented on the issue of organ transplantation. A group from Spain presented information on 20 people with HIV experiencing end stage liver disease (ESLD) being seen in their clinic. Of the 20 people with ESLD, 17 were associated with hepatitis C (five also had complications due to alcoholism and 2 were also infected with hepatitis B) and two were associated with hepatitis B. Control of HIV with therapies was difficult and complicated because of a frequent need to stop therapies due to their effects on the liver. The overall survival time from the onset of ESLD was about 22 months. For people with lower CD4+ cell counts and more advanced stage liver disease, survival was only four months. These data highlight the need to have inclusion criteria for organ transplant studies that are realistic based on the actual condition of people in need. For example, studies that require volunteers to have undetectable viral load at the time of transplantation, as is the case with the proposed study in the United States, may not be feasible due to a frequent need to interrupt therapies in people with liver disease.
A group in the United Kingdom (UK) examined eight people with HIV who underwent liver transplantation at King's College Hospital in London. Five of the transplant recipients were experiencing ESLD, four associated with hepatitis C and one with hepatitis B. Three were experiencing liver failure, two associated with hepatitis B, one associated with hepatitis non-A non-B. Of the four transplant recipients who had ESLD associated with hepatitis C, all died following transplantation (at 3, 6, 15 and 25 months). CD4+ cell counts in this group ranged from 160 to greater than 500. Of the two individuals with viral load measures available, both had well suppressed HIV levels, one below 400 copies/ml and the other at 965. Of the four transplant recipients who are alive, CD4+ cell counts at time of transplantation ranged from 124 to 293, none had well controlled HIV levels at time of transplantation with measures ranging from 25,000 to 197,000 copies/ml. Currently these individuals have been alive 1, 5, 15 and 35 months following transplantation respectively. Of the four people alive today, three have reported CD4+ and viral load measurements (the fourth, alive one month post transplant, did not have measures available at time of data presentation). In all cases, CD4+ cell counts rose and in all cases HIV levels are well controlled, two to below 50 copies/ml and one to 64 copies/ml. The observations from the UK group suggest that the cause of liver disease, and the subsequent ability to control that disease with medications following transplantation, may be more important than immunologic and virologic characteristics in predicting who might best respond to liver transplantation. These findings might support re-evaluating inclusion criteria for the proposed U.S. study, allowing people with measurable viral load in the study if liver disease is associated with hepatitis B as opposed to hepatitis C. More work is needed to determine who with hepatitis C might best thrive following liver transplantation.
Finally the team at UCSF presented preliminary data from their pilot study for liver and kidney transplants in people with HIV. This is the study that is the basis for a larger, multicenter study that is being developed. While part of the same study, inclusion criteria for people in need of liver and kidney transplants are slightly different. For kidney transplants, people must have a CD4+ cell count greater than 200, whereas for liver transplants CD4+ cell counts must be above 100. In both groups, volunteers must have undetectable viral load for three months prior to transplantation. Kidney transplant recipients must show no signs of serious liver damage (cirrhosis) associated with hepatitis C infection. Volunteers may not have had previous opportunistic infections (with the exception of treatment sensitive candidiaisis) or cancers.
To date six individuals, one Latino, three African Americans and two white people, have received transplants under this study, one liver and five kidney. Thus far all six volunteers are alive today, 40 to 315 days afte