PI Perspective #23

November 1997     View PDF     En español

Immune Based Therapy Update

Several important studies of immune based therapies are ongoing and others are enrolling.

Thymus CT Scan
Project Inform previously reported on a thymus study at the Gladstone Institute in San Francisco. The thymus is an important organ in the development of new T-cells (CD4+ and CD8+ cells are T-cells) - it is unknown if immune reconstitution can occur without a thymus in severely immune compromised people. The study data show that people with CD4+ cell counts between 300 and 500 are more likely to have detectable thymic mass than people with CD4+ counts of either less than 300 or greater than 500. The detection of thymic mass among people with CD4+ cell counts ranging 300 to 500 was independent of age. In contrast, all HIV-negative volunteers over the age of 40 had no detectable thymic mass. These results are surprising, contradicting conventional wisdom that HIV targets and alters the thymus early in the course of HIV disease. Currently the therapeutic implications of these findings remain unclear.

For the time being, these results support using highly active antiretroviral therapy (HAART) well before progression to AIDS, while people still have CD4+ counts at least as high as the 300–500 range. Particularly among people with CD4+ counts between 300 and 500, thymus activity may increase to compensate for the progressive loss of immune cells. The thymus may start working overtime producing new cells as existing cells are destroyed by the virus. It is unclear if people who have undetectable thymus mass will regenerate thymic material when CD4+ cells rise as a result of HAART. Until this is understood, thymus transplantation in people with advanced HIV disease remains an important avenue of research.

Thymus Transplantation
Two studies are looking at the safety of thymus transplantation in people with HIV. Despite failed transplants in the early 1980s, researchers are encouraged by new technology to preserve the tissue for transplantation. Transplantation in children and adults with Di George’s syndrome, in which children are born without a thymus, appears to have been successful, adding more optimism for applying the technique to HIV.

One study was funded by PI in collaboration with the Foundation for AIDS and Immune Research (FAIR). In this study, conducted through the University of Vermont, 8 HIV-positive volunteers with CD4+ counts below 200 have undergone the procedure, which involves implanting thymus tissue where the stomach muscles join. An additional plug of material is implanted in the arm so it can be easily accessed for biopsies to test whether the graft succeeded. After the procedure, volunteers are given an agent called anti-thymocyte globulin (ATG), to clear out any cells which might remain from the thymus donor. Side effects from ATG may include fevers, rigors and hives. Hives may persist for a few weeks. The side effects, which diminish over time, associated with the surgery are similar to those seen with any stomach surgery, like a hernia operation, and include muscle soreness, tenderness and gastrointestinal distress.

When the data was presented, 3 of the 8 volunteers had had biopsies of the material in their arms. Biopsies are being performed 8+ months after surgery. Researchers hope the results will show whether the tissue placed between the stomach muscles is viable and healthy. Two of the three biopsies found healthy tissue. In both volunteers with viable biopsies, there appeared to be increases in both CD4+ and CD8+ cells, as well as evidence of increases in ‘naïve’ cells, suggesting that some of these cells may have developed through the thymus tissue. Because all volunteers were encouraged to begin aggressive antiviral regimens before transplantation and most included a protease inhibitor in their regimens for the first time, it is unknown if thymus transplantation, or HAART, contributed more to increases in cell counts. Only further research will answer this question. At the least, the research proved that the transplantation is relatively safe and viable thymus material may be maintained in some people.

The second study, which includes 16 people with CD4+ cell counts between 200 and 500, is taking place at Duke University. Eight will receive AZT + 3TC + ritonavir (Norvir) and 8 will receive the same anti-HIV therapy regimen and thymus transplantation. This study should clarify the relative contribution of transplantation vs. antivirals in improving immune parameters, including CD4+ and CD8+ cell counts and percentages of naïve cells. Thus far, four transplants have been completed and a total of 8 volunteers are being followed. All 8 have experienced decreases in HIV RNA levels to below the limit of quantification. All that can be concluded at this time is that the transplant does not appear to have negative effects on HIV RNA levels or cell counts. Preliminary data were presented about 2 months after the transplants; too early to see differences between the study groups. The effects of thymus transplantation in Di George patients take at least 6 months to be apparent, indicating that it will be some months before differences may emerge between the groups. Moreover, the study is very small and unlikely to yield data about the effectiveness of thymus transplantation. Rather, differences between the two groups and data on safety and feasibility of the procedure will inform the decision to move forward with more research.

Chinese Herbs Study Seeking Volunteers!
The Community Consortium in San Francisco is seeking volunteers for a study evaluating a Chinese herbal formula, Marrow Plus, for treating HIV-related mild-to-moderate anemia. Anemia, a low red blood cell (RBC) count, is common in people with HIV and can be a side effect of many drugs. Standard treatment of mild to moderate anemia is either no treatment, or the use of an injected growth factor called Epogen. A number of the ingredients in the Chinese herbal formula are commonly used in China to treat low red and white blood cell counts.

Volunteers will receive either the herbal formula or an inactive formula for 12 weeks. The study is open to men and women above the age of 17 who have mild or moderate anemia, defined as a hemoglobin count between 9–12 g/dl (or between 9–11 g/dl for women). As part of the study, 20 participants can choose to receive Traditional Chinese Medicine (TCM) diagnoses at entry and at 12 weeks to help researchers understand how well TCM diagnoses correlates to clinical laboratory findings.

Volunteers will be reimbursed for participating and will receive the herbal formula free for a maximum of 12 weeks after the study ends, regardless of whether they received the formula or placebo during the study. For information call 415-502-0658.

CD8+ Cell Study Needs Volunteers!
A CD8+ cell therapy study at the Harvard Center for Blood Research needs volunteers with CD4+ cell counts greater than 400. Participants will receive AZT + 3TC + indinavir (Crixivan), or the combination with cell therapy. The cells are called HIV-specific Cytotoxic Lymphocytes (CTLs), primarily CD8+ cells. They seek and destroy HIV-infected cells. The CTLs will be collected and “educated” to recognize the individuals’ major HIV strains. Volunteers in the cell therapy group will receive 2 infusions of HIV-specific CTL (5 billion cells per infusion); one after participating in the study for 3 months and the second 3 months later. The second infusion will be given with a 5-day cycle of interleukin-2 (IL-2) delivered by subcutaneous (under the skin) injection. IL-2 may help support the cell’s activity against HIV. For details on participating, call Susan Crockett at 617-278-3464.

HIV-specific CTLs may be very important in controlling HIV immediately after initial infection. Some studies suggest that people with initial strong and persistent HIV-specific cell responses are more likely to be long-term non-progressors. Other studies, however, suggest that even though there is an increase in CD8+ cell number in people with HIV, these cells never control HIV well. Thus, capitalizing on what is known about the immune system’s response to HIV and how it controls the virus, HIV-specific CTL therapy may provide the immune system with additional support by training the CD8+ cells to better control the virus.

Two previous studies, done before protease inhibitors became available, used smaller numbers of cells per infusion and no IL-2. Preliminary results from these studies show that there are no side effects associated with cell infusion, either during or following the infusion. Participants experienced increases in CD4+ cells and decreases in HIV RNA levels, but these changes were not sustained over time. Tests showed an increase in HIV-specific CTL activity which was sustained for up to 8 months, however. Side effects seen with IL-2 include fevers, rash and flu-like symptoms, and can be managed with the use of ibuprofen and antihistamines. For information on IL-2 and managing its side effects, call the Project Inform's National HIV/AIDS Treatment Hotline at 800-822-7422 for the new IL-2 Fact Sheet.

Educating Cells
A study at Stanford University is attempting to educate cells outside the body to recognize HIV. The study involves HIV-negative and positive family members. Cells are removed from HIV-negative volunteers and educated in a test tube environment to recognize HIV. Once they have been trained to be HIV-specific, they are infused into the HIV-positive family member. Preliminary data from the first 5 volunteers suggest that the procedure is safe, with no measurable side effects during or after the infusion of the HIV-specific cells. An increase in HIV-specific cell activity was seen in volunteers with CD4+ counts greater than 400, suggesting that the more intact the immune system the better the benefit of this approach. The study is enrolling people with CD4+ counts of greater than 300, who have willing HIV-negative family members with suitable cell types. While seemingly “high tech”, most such studies are relatively easy to participate in. Both having the cells drawn, and having them infused, is similar to giving blood, and takes just a few hours.

IL-12 Study Enrolling!
A study to find the best dose for IL-12 is enrolling across the country. The first phase is open to people with CD4+ cell counts of less than 50. Later phases will be open to people with counts between 300 and 500. IL-12 may enhance macrophage function. These cells fight many of the infections associated with HIV-disease, particularly Mycobacterium avium Complex (MAC). Thus, IL-12 may be useful in preventing these infections. It may also be important in enhancing other types of immune function. IL-12 or a placebo will be given by an injection under the skin twice weekly for 4 weeks. Volunteers will be allowed to use anti-HIV therapy and will be required to be on preventative therapy for PCP. The goal is to find an optimal dose for use in larger trials, and volunteers will receive IL-12 doses of 30, 100 or 300ng/kg (nanograms per kilogram of body weight), or placebo. The 30ng/kg dose group has fully enrolled and new volunteers will receive the 100 ng/kg or 300ng/kg dose, or placebo. For study locations, call 800-TRIALS-A and ask for information about ACTG 325.

WF-10 Studies
WF-10, a product of Oxie-Chemie (Germany), has shown interesting immunologic properties in a small study at San Francisco General Hospital. Earlier studies of the drug, which lacked adequate controls, suggested the drug may enhance protection against infections in people with advanced HIV disease. In this study, WF-10 appeared to provide a significant and substantial enhancement of macrophage function and activity, which might lead to better response against opportunistic infections. It also appeared to do this without stimulating T-cell activation or increasing viral load, two concerns which the FDA had raised earlier. Although how the drug does this is somewhat uncertain, these results suggest it may be a potent yet very selective activator of macrophages. If a planned additional study shows clinical benefit to this activity, WF-10 may find its place among immune-based therapies. It is sold in Germany and other countries to hasten healing of wounds.

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