February 8, 2006
With the major stories from the 13th Conference on Retroviruses and Opportunistic Infections (CROI) including heightened concern about the safety of treatment interruptions1 and data supporting the earlier use of potent antiretroviral therapy (ART),2,3 it is clear that the use of ART will be expanded in the future.
However, long-term ART use brings with it several drawbacks, including numerous toxicities, the development of drug-resistant variants, as well as the expense of the therapies. One approach that has often been considered to lesson the need for long-term, continuous ART involves administering some form of immune-based therapy that enhances a patient's ability to safely maintain adequate immune function, but without ART. One basic problem with the field of immune-based therapy, however, is the general lack of correlation between any particular laboratory assay of immune function and the control of HIV replication to a clinically relevant extent during either natural infection or after a treatment interruption.
Immune Control of HIV Infection
Bruce Walker presented an overview on the immunologic control of HIV infection.4 A major theme from his presentation was the importance of HIV-specific CD8+ T cells for the control of HIV infection in conjunction with a favorable genetic background (i.e., specific human leukocyte antigen [HLA] alleles) and some level of residual help from CD4+ T cells.
In the setting of chronic infection, CD4+ T-cell function is often severely attenuated. When coupled with the fact that most HIV-infected individuals do not have a favorable genetic profile, most individuals hence fail to control viremia over the long term. The importance of CD8+ T-cell function, in tandem with a favorable HLA profile, was further highlighted by David Watkins who, using a macaque model, identified a sub-group of monkeys -- so-called elite controllers -- that was able to spontaneously control the replication of a pathogenic SIV strain.5
To his surprise, the control of SIV replication was found to be highly dependent on CD8+ T cells. Drs. Walker and Watkins both underscored the importance of studying elite controllers in both humans and animal models, and they also emphasized the need to combine the evaluation of both the genetic and immune responses of the host to key viral epitopes. A better understanding of which viral epitopes trigger an optimized immune response may lead to improved therapeutic vaccines, which could attenuate the course of HIV infection over time (see a related study by Mesesan et al6 who modeled the impact of a partially effective HIV vaccine on the HIV epidemic in South Africa). Combining new genetic knowledge with a better understanding of immunology based on carefully performed studies may lead to more effective HIV vaccines.
Immune-Based Therapies for HIV Infection
In any case, the 13th CROI meeting had only a modest number of papers addressing immune-based therapies for HIV infection.
Adoptive immunotherapy involves isolating an individual's white blood cells and then re-infusing them after treatment with a growth factor or other intervention designed to enhance the immune control of a particular condition. Wendy Bernstein and colleagues described a study wherein eight trial participants with a CD4+ cell count greater than 250 cells/mm3 received an infusion of a median of 43 x 109 autologous CD4+ cells via serial infusions over the course of one year.7 The cells were co-stimulated with anti-CD3 and anti-CD28, which causes polyclonal proliferation of CD4+ cells and down-regulation of CCR5 expression (which theoretically could make the cells more resistant to HIV infection). The investigators hypothesized that the re-infused cells would support immune homeostasis in the absence of ART.
The median baseline CD4+ cell count and percentage were 442 cells/mm3 and 25%. At the end of the observation period -- after a median follow-up of 3.3 years -- the median levels were 778 cells/mm3 and 35%, respectively. The infusions were generally well tolerated, and no AIDS-related events occurred in the study cohort.
A major confounding issue in this study had to do with the fact that ART could also result in increased CD4+ cell counts, and no gene marker was used to allow for the identification and quantification of the expanded, infused CD4+ T cells versus the patient's natural CD4+ T cells. This small study is interesting from the immune pathogenesis standpoint but does not provide convincing evidence for expanded use of this invasive and expensive procedure outside of the research setting.
Interest remains high regarding the potential clinical role of interleukin-2 (IL-2) as an adjunctive therapy with highly active antiretroviral therapy (HAART) for the treatment of HIV infection, especially for patients with low CD4+ cell counts despite HAART.
Manel Crespo and colleagues from Barcelona reported the results of a study involving 19 patients with a median nadir CD4+ cell count of 36 cells/mm3 and a median baseline CD4+ cell count of 99 cells/mm3.8 Sixteen of 19 patients completed six cycles of IL-2 at 4.5 x 106 IU given subcutaneously for five successive days every four weeks.
At the end of IL-2 treatment, the median CD4+ cell count increased to 147 cells/mm3, which then further increased to 180 cells/mm3 at 18 months after IL-2 administration. Moreover, the increase in CD4+ cell count was associated with a decrease in immune activation markers.
The small size of the study and the lack of a control group make interpretation of the results difficult. Results from two large, randomized trials evaluating the clinical benefit of IL-2 therapy in combination with HAART are expected within several years (i.e., the SILCAAT study for patients with a CD4+ cell count below 350 cells/mm3 and the ESPRIT study for patients with a CD4+ cell count above 350 cells/mm3) and will better address the efficacy of IL-2 adjunctive therapy.
Another agent that has been looked at in previous studies and has been shown to improve thymic output and immune recovery is growth hormone.9,10 Results of another small study presented at CROI evaluated the effect of growth hormone administered subcutaneously at 4 mg/day on CD4+ and CD8+ cell counts and function in 12 patients on effective HAART.11
Over a 48-week period, HIV-RNA levels and CD4+ and CD8+ cell counts remained stable. A modest dose-dependent reversal of CD4+ and CD8+ lymphocyte dysfunction was observed. The authors hypothesized that growth hormone may enable the induction of effective HIV-specific CD4+ T cells and the expansion of HIV-specific CD8+ T cells. One of the authors suggested that growth hormone plus another immune intervention (e.g., a therapeutic vaccine) might result in more complete HIV-specific immune reconstitution during ART.
However, growth hormone administered in this manner is extremely expensive and causes significant side effects in some patients (e.g., insulin resistance and bone pain). It remains unclear whether the enhanced immune response associated with growth hormone actually has any clinical benefit.
Therapeutic Vaccines for HIV Infection
Sabine Kinloch and colleagues presented the one-year, follow-up results of the QUEST Study.12 In this study of therapeutic vaccination, 66 patients with primary HIV infection were treated with HAART + placebo, HAART + ALVAC-HIV vCP1452, or HAART + ALVAC-HIV vCP1452 + Remune. The primary endpoint was the proportion of individuals with an HIV-RNA level below 1,000 copies/mL.
By 48 weeks, 22% of patients in the HAART-only arm and 14% in the two vaccine arms had an HIV-RNA level below 1,000 copies/mL, thus indicating no benefit in viral suppression with vaccination.
This study was well designed and focused on a patient population -- that is, those with primary infection -- for which the hope of enhancing immune control of HIV replication is highest. However, the results were disappointing and substantiate the growing body of evidence showing the ineffectiveness of current HIV vaccines.
With antiretroviral therapy still holding center stage, the current role of immune-based therapy in HIV therapeutics remains meek. That status is partly attributable to the complexity of the immune response and host genetics. It doesn't help that clearly useful laboratory markers for immune control of HIV replication are still lacking. That shortcoming is highlighted in the well done QUEST Study, where there was an absence of any correlation between the immunogenicity of therapeutic vaccination and the subsequent level of HIV viremia. The current status of HIV vaccine research aimed at promoting cytotoxic T-cell immunity was nicely summarized in an oral presentation at CROI by Larry Corey of the HIV Vaccine Trials Network.13 However, despite the absence of currently effective forms of immune-based therapy, steady advances in immunology and genetics seem likely to yield clues on how to better design immune-based therapy in the years ahead.
|Please note: Knowledge about HIV changes rapidly. Note the date of this summary's publication, and before treating patients or employing any therapies described in these materials, verify all information independently. If you are a patient, please consult a doctor or other medical professional before acting on any of the information presented in this summary. For a complete listing of our most recent conference coverage, click here.|