Summary

The management of established HIV infection has changed dramatically over the past few years. Antiviral therapy is no longer only aimed at those patients with severe immunodeficiency. It actually achieves better results earlier in the course of the illness. Antiretroviral drugs should only be used in combination. They are suitable for patients with HIV infection who have symptoms of immunodeficiency, a CD4 count of 10 000 copies/mL) indicating rapid disease progression.Factors such as potency, toxicity, cross-resistance profiles and dose regimen need to be individualised when deciding the best combination.

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.

Fig. 1

Natural history of HIV disease*

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* adapted from

– Longini IM, Clark WS, Gardner LI, Brundage JF. The dynamics of CD4+ T-lymphocyte decline in HIV-infected individuals: a Markov modeling approach. J Acquir Immune Defic Syndr 1991;4:1141-7.

– Piatak M, Saag MS, Yang LC, Clark SJ, Kappes JC, Luk KC, et al. High levels of HIV-1 in plasma during all stages of infection determined by competitive PCR. Science 1993;259:1749-54.


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

Table 1

Daily dosing of available antiretroviral agents

Drug Abbreviation Usual daily adult dosing

Nucleoside analogue reverse transcriptase inhibitors

lamivudine 3TC 150 mg twice daily
stavudine d4T 40 mg twice daily
zalcitabine ddC 0.75 mg 3 times daily
didanosine ddI 2 x 100 mg twice daily
zidovudine ZDV (AZT) 2 x 100 mg 3 times daily or 300 mg twice daily

Non-nucleoside reverse transcriptase inhibitors

nevirapine NVP 200 mg twice daily
delavirdine DLV 4 x 100 mg 3 times daily
Protease inhibitors
indinavir IDV 2 x 400 mg 3 times daily
saquinavir SQV 3 x 200 mg 3 times daily
nelfinavir NFV 3 x 250 mg 3 times daily
ritonavir RTV 6 x 100 mg twice daily

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

Fig. 2

Mechanism of action: reverse transcriptase inhibitors

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Table 2*

Effective antiretroviral combinations

Column A Column B Column C
zidovudine + lamivudine indinavir nevirapine
zidovudine + didanosine nelfinavir delavirdine
zidovudine + zalcitabine ritonavir saquinavir
stavudine + lamivudine ritonavir + saquinavir
stavudine + didanosine

Therapy should comprise a combination of drugs from Column A together with one from Column B.

Some experts feel that, for patients with lower baseline viral loads, a combination of drugs from Column A plus Column C may also be appropriate.

Patients with previous exposure to a combination listed in Column A should be placed on an alternative combination to which the virus has not previously been exposed, together with a drug from Column B or Column C.

* adapted from Reference2.

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).

Important points in practice

  • Inappropriate use of an antiretroviral may encourage drug resistance and render the drug ineffective in the future.
  • To avoid resistance, reinforcing the need for compliance is critical.
  • Beware drug interactions (most commonly seen with the protease inhibitors and their propensity to stimulate or inhibit hepatic metabolism of other drugs).

References

  1. Carpenter CC, Fischl MA, Hammer SM, Hirsch MS, Jacobsen DM, Katzenstein DA, et al. Antiretroviral therapy for HIV infection in 1997. Updated recommendations of the International AIDS Society - USA panel. JAMA 1997;277:1962-9.
  2. NIH guidelines for the use of antiretroviral agents in HIV-infected adults and adolescents. June 1997. http://www.cdcnac.org
  3. Gulick RM, Mellors JW, Havlir D, Eron JJ, Gonzalez C, McMahon D, et al. Treatment with indinavir, zidovudine and lamivudine in adults with human immunodeficiency virus infection and prior antiretroviral therapy. N Engl J Med 1997;337:734-9.
  4. Feinberg M. Hidden dangers of incompletely suppressive antiretroviral therapy. Lancet 1997;349:1408-9.