Has a time to talk about cure of AIDS arrived?

Dr Matin Ahmad Khan

Abstract

Has a time to talk about cure of AIDS arrived?

Background :Cure can have different meanings in the context of epidemiology , clinical care and programmatic evaluation as in RNTCP(Revised National TB Control Program).It could range from ‘remission( cancer model) to ‘eradication’ (Infectious diseases model ) Antiretroviral drugs have reached the limit of their effectiveness. The cost of providing universal access has become unsustainable, and accumulating evidence underscores the detrimental effects of persistent HIV infection even while plasma viral load is low and CD4 cell count is high .There could be host of factors attributed for this scenario ---- life long treatment involving the cost of therapy and requiring a very high level of adherence unpleasant side effects , including risk for CVD and cancer increasing with age , ultimately HAART failing, leading to resistance, and absence of a therapeutic/preventive vaccine in near future. Naturally ever than before, much need has been felt for the quest for a ‘cure’. Achieving either a functional cure (long-term control of HIV in the absence of HAART) or a sterilizing cure (elimination of all HIV-infected cells) remains a major challenge Two men—both dubbed "the Berlin Patient # 1 & # 2"— who will be remembered as ‘harbingers ‘ in the discovery for a cure have changed the course of history , particularly with the publication of the Berlin patient # 2 case report (2009) with AML BMT from a donor who carried a 32 base pair deletion in the CCR5 gene , has infused new hope in researchers for at least a ’functional cure ‘ . Ultrasensitive tests reveal very low levels of plasma HIV RNA (as little as 1 copy/mL) in most people with "undetectable" viral load. Replication-competent HIV can still be isolated from resting CD4 T-cells from people with the longest duration of HAART use—now around 15 years—and viral rebound almost always occurs soon after treatment interruption.HIV can persist inspite of continuing ART as it hides in reservoirs , some of them becoming latent ones , that are not sensitive to current therapies . The most significant barrier to cure is the establishment of a latent or 'silent' infection in resting CD4+ T cells and the persistence of HIV in a latent form in different cellular and anatomical reservoirs Mathematical modeling suggests that it would require 70 years ot treatment with HAART to eradicate latent reservoirs.. Researchers are exploring many approaches for eradicating HIV or achieving a functional cure,which are --- Starting ART very early before viral reservoirs are fully established , Intensifying antiretroviral therapy to stop residual HIV replication Activating resting T-cells to purge or flush out latent virus , Maintaining latency to keep proviral DNA permanently silenced , Eliminating or disabling HIV-containing resting cells , Protecting uninfected cells against viral entry , Strengthening the immune system's response to HIV.

Aim & Objectives: This presentation focuses on the key scientific and clinical variables that we need to understand in order to significantly expand the breadth and scope of the various approaches aimed at finding a cure for HIV. In addition we will focus on limitations of long term HIV Therapy , obstacles coming in finding a ‘cure’ and explores for eradicating HIV or achieving a ‘functional cure ‘.

Methods/Study Design : Data Source : The scientific literature, and eligible materials were surveyed related to ‘cure/eradication of AIDS Data Selection: Building on this conceptual framework, the related observational studies and modeliling works,who met the selection criteria of being related to ‘ cure of AIDS’ Data Extraction : Reports were screened and information from eligible studies was abstracted independently and synthesized. Design : A descriptive study on the issues of ‘cure from AIDS’ comprising several randomized and non randomized studies

Results/Findings, : Several randomized clinical trials have demonstrated that treatment intensification with additional antiretrovirals has little impact on latent reservoirs. Some potential other approaches that may reduce the latent reservoir include very early initiation of HAART and the use of agents that could reverse latent infection. Drugs such as histone deacetylase inhibitors, currently usedand licensed for the treatment of some cancers; methylation inhibitors; cytokines such as IL-7 or activators of nuclear factor kappa B (NF-κB) such as prostratin, show promising activity in reversing latency in vitro when used either alone or in combination. Alternate strategies include using gene therapy to modify expression of CCR5 and therefore make cells resistant to HIV. One multicenter, open-label, non-randomized trial , called ‘New Era study’ to evaluate treatment with multi-drug class (MDC) HAART and its impact on the decay rate of latently infected CD4+ T cells has been going on in Germany with primary objective of reducing proviral DNA in PBMC (peripheral blood mononuclear cells)and achieving HIV eradication.The ‘EraMune trials are evaluating whether an intensified ART regimen with either Interleukin-7 or a therapeutic vaccine can eliminate HIV from the body.Another investigational approach to curing HIV is modifying CD4 T-cells to make them resistant to HIV entry, by removing CCR5 by a zinc finger nuclease.

Study Limitations; There are multiple barriers to the eradication of HIV infection and despite some recent significant advances in in-vitro models of latency, better animal models and the identification of several compounds that can reverse latency in vitro, there is still a need for more research.

Conclusion: In summary, research to date on HIV eradication and the likely more achievable goal of a functional cure has spotlighted several promising proofs of concept, but none of these approaches are ready for widespread clinical application.. It is likely that multiple combined approaches will be needed to eradicate HIV given that HIV can persist in diverse cell populations in patients on HAART. A well funded multidisciplinary approach that includes basic virologists, immunologists, clinicians, pharmacologists and the infected community will be needed if we are ever going to meet this challenge.

Author(s):

Dr Matin Ahmad Khan

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