New approaches in the treatment of HIV infection

Introduction
There have been recent major advances in the management of HIV disease. These advances have been triggered by two key developments: sensitive assays using the polymerase chain reaction (PCR) and the availability of potent antiviral drugs.

PCR assays: high levels of ongoing viral replication
Sensitive HIV PCR assays can determine the amount of circulating virus in infected patients. The discovery of high levels of constantly replicating virus has changed our view of HIV disease. Originally, it was thought that there was a long period of clinical and virological latency when very little was happening in an asymptomatic, but infected, patient. We thought that the virus would at some stage (6-10 years later) reactivate and cause profound immune deficiency. With our ability to measure the amount of replicating virus that spills over into the blood, we now know that there is no latent period in HIV disease (Fig. 1).

The unfortunate truth is that up to 10 billion viruses are produced daily from recently infected CD4+ T-lymphocytes. These viruses are cleared very rapidly by the immune system, but, unfortunately, only after new cells are infected, and so the cycle continues. This constant battle between the virus and the immune system slowly erodes an individual's functional immune surveillance. Eventually, AIDS-defining opportunistic infections develop. It is surprising, given the high levels of viral replication, that it takes so long before the immune system erodes to the point where clinical disease appears. The rate at which an individual progresses down the path of worsening immunodeficiency depends upon the amount of virus produced. The more virus, the faster the disease progresses.

Antiretroviral drugs: combination approach required
Fortunately, this increased understanding of the disease process coincides with the accelerated approval of several potent antiretroviral drugs. Single drugs are not powerful enough, but the use of up to 3 drugs in combination can control the high levels of viral replication in some patients.¹

The currently available antiretroviral drugs fall into 3 main classes (Table 1). The first of these are the nucleoside analogues which inhibit reverse transcriptase. These drugs mimic the nucleic acid building blocks required for the production of double-stranded viral DNA. Unfortunately for the virus, they lack the chemical structures required for connection to

subsequent nucleotides and are, hence, referred to as chain terminators (Fig. 2). The second class of drugs are the non-nucleoside reverse transcriptase inhibitors. They are chemically diverse drugs capable of binding to the active site of the viral reverse transcriptase enzyme. By blocking this enzyme, they prevent the production of viral DNA from viral RNA (Fig. 2). The third group of drugs are the protease inhibitors. They bind to the viral protease enzyme which is essential for cleaving long chains of protein into their functional elements. By blocking this enzyme, the virus is unable to mature into fully infectious virions.

While the choice of therapeutic drugs to use in a combination regimen is complicated (Table 2), the underlying tenets are quite simple. Therapy aims to suppress viral replication as efficiently as possible and hence prevent the insidious erosion of immune surveillance.

Clinical trials are providing us with further insight into the clinical and virological benefit of combination therapies. Triple therapy is superior to dual therapy in terms of improving CD4 lymphocyte counts and suppressing viral replication as highlighted by one of these studies.³

Treatment failure
Unfortunately, not everybody can totally suppress viral replication by taking antiretroviral drugs. Resistance can also develop rapidly.

HIV, being a RNA virus, is incapable of repairing randomly-occurring mistakes or mutations in replicating itself. The daily progeny contain numerous variations from the parent form. This results in huge swarms of viral populations, some of which contain mutations which confer resistance to antiviral drugs.

The virus's genetic infidelity allows it to escape the replicative control imposed by antiviral drugs. The clinical implications are that incomplete suppression of ongoing viral replication

will encourage the emergence of drug-resistant virus.⁴ More importantly, because these mutant sub-populations will persist once a drug has been rendered ineffective, then the patient will probably never respond successfully to that drug again. With the high rates of replication that have been shown, it will usually only take two weeks for the viral population to return to its pre-treatment equilibrium if there is no ongoing suppressive activity.

Factors that result in therapeutic failure are:

• severe infection (as indicated by high plasma levels of HIV and low CD4 counts)
• use of incompletely suppressive treatment regimens
• non-compliance
• inadequate dose, due either to non-compliance, poor bioavailability or drug interactions that induce the metabolism of particular drugs.

The general practitioner has an important role in increasing the chances that therapy will succeed (see box overleaf).