Are Immunosuppressive Drugs a Useful Adjuvant to Treatment of HIV with Antiretrovirals?

The use of HAART has produced significantly positive results in reducing the morbidity and mortality of HIV infection. Still, the prospects of long-term treatment have been diminished by the serious adverse side effects of antiretroviral drugs and by the development of multi-drug resistance to these agents.

Various approaches have been considered and studied to circumvent these pitfalls, including structured treatment interruptions (STI) and the use of immune therapies and therapeutic vaccines.

In the current article, Spanish researchers at the University of Barcelona, Spain report on the employment of immunosuppressive drugs as adjuvant therapy.

The investigators point out that HIV infection is characterized by a strong and continuous state of immune activation, as evidenced by the elevation of  activated CD8+ T cells and the increased turnover of B and T lymphocytes, natural killer cells, and high levels of pro-inflammatory cytokines (e.g. interleukin-7 and tumor necrosis factor-alfa.

Further, say the researchers, “this continual process leads to the spread of HIV infection and to the exhaustion of the immune system.” They subscribe to the rationale that the use of immunosuppressive drugs could favorably alter this state of hyper immune activation.

Potential agents studied to date to accomplish this include corticosteroids, hydroxyurea (HU), mycophenelate mofetil (MMF), thalidomide and ciclosporin A.
The use of ciclosporin A and probably other immunosuppressive drugs reduces the number of activated CD4 cells that support massive virus production, and may prevent sequestration of CD4 T cells into lymphoid tissue, which is the place of antigen presentation and productive HIV infection.

However, it is not  known whether—by establishing a new immunological set-point that may affect the rate of disease progression—these approaches will clinically benefit long-term infection.

In the chronic stage of infection, the tructured treatment interruption (STI) strategy allows for control of viral replication in 20% of patients. However, the use of HU and MMF showed the significant improvement in viral dynamics after HAART interruption mainly because of cytostatic and immune properties that did not have a deleterious effect on HIV-specific responses.

This approach could also have an indirect impact on the latent reservoir pool, strikingly diminishing the pool of activated T cells. It was demonstrated that MMF reduced the isolation of the virus from the T cell peripheral pool and also from lymphoid tissue, decreasing the release rate of virus from reservoirs. Studies focusing on the correct measure of viral load in reservoirs are needed.

Optimal candidates, exact drug, dosage, duration of therapy and the optimum time to initiate it within the natural course of infection are questions that need to be answered in the context of large clinical trials.

The authors conclude, “Although no major drug toxicity was reported in trials using different drugs, the long-term safety in terms of opportunistic infections and development of lymphoproliferative diseases are a major concern.”

“The strategy for using drugs that interfere with the HIV life-cycle, acting on the target cells of HIV rather than on viral enzymes, offers the advantage of avoiding the development of antiretroviral drug-resistant HIV mutants.”

“Caution is required when combining HAART and cytostatic drugs in HIV infection until the impact and long-term safety of this approach have been further investigated in larger clinical trials.”

03/12/04

Reference
E Fumero and others. Immunosuppressive drugs as an adjuvant to HIV treatment. Journal of Antimicrobial Chemotherapy 53: 415-417. February 12, 2004.