**4. Agents and strategies inhibiting retroviral replication**

#### **4.1. Using the HAART for a functional cure**

**2. Why should we look beyond the HAART?**

210 Trends in Basic and Therapeutic Options in HIV Infection - Towards a Functional Cure

susceptible ones and render the HAART inactive.

techniques and cellular transplants.

eliminate HIV [6].

and/or strategies to supplement, if not to supplant the HAART [5].

**3. Novel agents and strategies currently being tried against HIV**

The major problem faced with HAART is that it only controls the infection and never eliminates it. When used continually on a lifelong basis, the HAART provides an infected individual with a significant improvement of clinical condition, enhancement of the quality of life and drastic reduction of circulating viral load. Nevertheless, treatment cessation at any point results in a rebound viremia, stripping off all the benefits that the patient had enjoyed during therapy. This could be stated as the inherent flaw in HAART, which exerts its inhibitory effect only against the actively replicating viruses in circulation and has little or no effect in destroying the quiescent viruses hidden in the latent cellular and anatomical reservoirs. Due to several reasons, this proviral reservoir gets activated at a later date proceeding to active viral replica‐

tion and viremia, which can occur unchecked upon discontinuation of HAART [1-4].

Another worrisome aspect of HIV is its ability to undergo rapid genetic evolution as a consequence of its voracious mutating capacity. For a virus with such a feature, lifelong therapy with anti-retroviral drugs can be deleterious by itself, as the constant drug pressure eventually selects the resistant mutant viral populations. Such mutant viruses, resistant to the currently used anti-retroviral drugs have already emerged and are being disseminated in various countries across the globe. There is a possibility that these strains may replace the drug

Lifelong HAART also faces the practical constraint of continuous patient adherence to the prescribed regimen and also its discontinuation due to adverse drug effects. Optimistic predictions of worldwide HIV control using HAART would be just a mirage if the impending failure of the HAART in the future is not foreseen from the present. In the light of these issues, any attempt to curtail the HIV pandemic warrants the need for novel anti-retroviral agents

All of the therapeutic strategies which are either currently available or under experimental research, involve attacking HIV at any one of the different phases in its infection course. (Figure-1) All these strategies use one or more of the following principles including adminis‐ tration of active chemical compounds, nanotechnology, DNA manipulation, RNA based

Apart from these therapeutic strategies which directly impede the viral activity, several immune based therapies are also being developed which intend to enhance the ability of the immune system to overcome HIV on its own. These strategies also act at one or more points in the natural course of HIV infection allowing the immune system to suppress and possibly

The HAART and the other anti-retroviral agents halt the natural course of HIV infection at the phase of active viral replication. This section elucidates the newer concepts that propose to maximize the utility of the existing anti-retroviral agents and also sheds light on novel compounds and targets which could be exploited for use against HIV.

The scope of the HAART to achieve a 'functional cure' is being studied extensively. Functional cure is said to be achieved when the infected individual treated aggressively with HAART early in the course of infection, does not develop rebound viremia on cessation of therapy for several months [7]. This concept had stemmed from the story of the Mississippi baby, where a mother seropositive for HIV-1 gave birth to an infant who was also found to be infected. Anti-retroviral therapy was initiated to the baby at 30 hours of birth and was continued till 18 months of age after which the therapy was discontinued. Surprisingly at 30 months of age, the child was tested negative for plasma HIV-1 RNA, proviral DNA in peripheral-blood mono‐ nuclear cells and serum HIV-1 antibodies [8].

In an attempt to replicate the observations of the Mississippi baby, the VISCONTI study conducted in France has effectively achieved a functional cure in a cohort of 14 adults who currently are free of viremia even after several years of interruption of anti-retroviral therapy [9]. Likewise, functional cure has been reported in an elderly German patient who had deliberately interrupted treatment after five years and has controlled rebound viremia for nine years after the cessation of treatment [10].

The reason hypothesized behind functional cure is that, early aggressive treatment prevents the build-up of large latent reservoirs and also reduces the viral load low enough that the immune system clears off the residual infection without continued use of antiretroviral drugs [11]. The drawback of this concept is that it necessitates the stoppage of the anti-retroviral drugs that have helped in the control of viremia. It is not known whether this might result in a functional cure or cause a rebound viremia. As it would be unethical to stop treatment in an individual with good viremic control without knowing the correlates of protection, well designed clinical trials must be conducted prior to implementation of this concept, to obtain answers to questions of uncertainty such as; what is the time period within which the treatment should be initiated following infection to favour functional cure? How long should the treatment be given? When is the ideal time for the interruption of treatment? What are the host factors involved in protection?

By the time the functional cure concept offered some hope, the occurrence of rebound viremia in the Mississippi baby smashed all the excitement [12]. It might only be a matter of time before we know whether the other patients claimed to be functionally cured, progress to viremia or remain "cured". Nevertheless, the Mississippi baby and the other studies have hinted that control of viremia is possible on treatment cessation. Further studies are required to find how to prolong this drug-free control of viremia.
