AIDS Treatment Update, No. 44, August 1996
Edward King

A drug-resistant HIV strain is one that is less susceptible to the effects of one or more anti-HIV drugs because of its genetic make-up. HIV reproduction is an error-prone process; every time a new generation of viruses is produced from an infected cell, random changes occur in their structure. Some of these changes may make the new viruses potentially more vulnerable to the effects of anti-HIV drugs, while other changes make some viruses less susceptible, or resistant.

If the individual is taking anti-HIV drugs, new viruses that are relatively resistant to the drugs' effects will be the most likely to survive in the body, through 'survival of the fittest'. As this process is repeated from generation to generation, the resistant viruses have an evolutionary advantage and so may gradually become the dominant strain. This process is called 'selection' of resistance.

Why drugs fail

Several American researchers argued that it is now clear why many anti-HIV drug regimens have only limited or short-term effects. Whenever HIV is still able to reproduce in the body of someone who is taking anti-HIV drugs, the selection process means that it is extremely likely that resistant strains will eventually emerge. Combination therapy regimens tend to delay the onset of resistance, because new viruses that are resistant to the effects of one of the drugs may still be wiped out by the other drug(s).

From this perspective, any anti-HIV drug regimen is likely to fail if it only partially suppresses viral replication, which may be because the drugs are too weak or because the individual doesn't take the full dose regularly. However, the closer a drug regimen gets to suppressing HIV replication completely, the fewer new viruses with random, possibly resistance-inducing variations will be produced. This means that the emergence of drug resistance may theoretically be avoided for as long as the drugs continue to suppress viral replication. If in turn viral replication remains suppressed for as long as resistance is avoided, it is conceivable that once almost complete suppression of replication has been achieved, it may be maintained indefinitely.

New evidence

Several triple-drug combination therapy studies presented at the conference provided evidence to support this theory. For example, the development of the drug nevirapine (see AIDS Treatment Update issue 43) was almost abandoned a few years ago because treated people developed HIV strains that were highly resistant to nevirapine within weeks of starting treatment. However, in a trial in which nevirapine was combined with AZT and ddI, the combined effects of the drugs produced such a strong anti-HIV effect that 70% of recipients had viral load that was too low to measure (below 200 copies/ml) during treatment. Remarkably, in these people no nevirapine-resistant strains have developed despite over a year of exposure to the drug, suggesting that controlling replication can indeed delay resistance. By contrast resistance did develop in the majority of people who only took nevirapine plus AZT (Mo.B.294).

Likewise, people taking 3TC tend to develop 3TC-resistant strains within weeks (although as described in AIDS Treatment Update issue 24/25, this may not be entirely a bad thing as such strains may be more vulnerable to AZT). But in people who achieved viral load below the level of detection during treatment with triple combinations containing 3TC, no 3TC-resistant strains have developed.

Early optimism about protease inhibitors was also clouded by the rapid emergence of resistant strains in trials in which people received the drugs on their own, or at doses now known to be too low. But in more recent studies in which protease inhibitors were given as part of triple combinations, the development of resistance has been much reduced (Th.B.932).

Treatment implications

This perspective lends weight to the view that anti-HIV treatment should ideally consist of as strong an initial regimen as possible. Taking treatments that only partially suppress HIV replication may be effective in the short or even medium-term, but in the long-term resistance is likely to develop. According to viral load expert Dr John Mellors, "if you let the virus replicate it will become resistant".

The new virological data also give support to the theory that the earlier treatment is started, the more effective it is likely to be. Recently infected people will have undergone fewer generations of viral replication, so are less likely already to harbour HIV strains that will be resistant to drug treatment. "Treatment of people with the best prognosis may paradoxically produce the greatest effects," said Dr Mellors, by permanently tipping the balance between HIV and the immune system in favour of the immune system. However, this window of opportunity may be narrow; other researchers suggest that it takes only about three months for every possible HIV mutant to have evolved.

There are also implications for people who experience disease progression or worrying laboratory tests such as falling CD4 count or rising viral load while taking anti-HIV drugs. Dr Margaret Fischl argued that the common practice of "adding or changing a single new drug in a failing regimen is likely to select for drug resistance", because the impact of that one new drug will be insufficient to block replication. Likewise, Dr Joep Lange contended that a protease inhibitor should never simply be added to an existing regimen of nucleoside analogues such as AZT, ddI and ddC. Instead, he and a growing number of clinicians argue that any treatment change should always consist of at least two new drugs. Those drugs should be chosen to minimise the risk that the HIV in the body will already be cross-resistant; for example, HIV that has developed resistance to indinavir is always also resistant to ritonavir.

This is the reason why doctors place so much stress on the importance of sticking rigidly to the suggested dose and regularity when taking anti-HIV drugs. Taking too little drug (by missing or reducing doses) could allow drug levels in the blood to fall to sub-optimal levels, allowing viral replication to occur and thus greatly increasing the risk of the emergence of resistance. All the major protease inhibitor manufacturers have reported that when people who initially responded very well to protease inhibitor regimen later start to experience disease progression, the commonest reason appears to be poor compliance. This is emerging as a major issue, particularly since people taking multi-drug combinations are asked to take many tablets according to a strict schedule.

Log changes in viral load refer to logarithmic changes. For readers who thought they had safely left logarithms behind them at school, here's a simple guide.

- A one log change is a ten-fold change. An example of a one log fall might be 40,000 copies to 4,000 copies. Put another way, this is a 90% fall.

- A two log fall might be 40,000 copies to 400 copies. This is a 99% or hundred-fold fall.

- A three log fall might be 40,000 copies to 40 copies. This is a 99.9% or thousand-fold fall.

So for each log fall, cross off one zero from the number you start with to get some idea of the magnitude of the change.

Fractions of logs are harder to remember, because they don't correspond to round-number percentages. For example, a 0.5 log fall in viral load is a 66.6% or two-thirds fall in viral load. A 1.5 log fall is approximately a 96% reduction.

The higher the baseline viral load, the greater the log change that will be required to bring it down to undetectable levels. Undetectable levels vary on different viral load tests, or assays, with the highest limit being around 500 copies. The lowest limit is around 20 copies. Wherever we report on undetectable viral load, we make clear the cut-off point for the test used in that particular study.

Undetectable viral load does not necessarily mean the virus has disappeared, but it does mean that any virus activity in the blood is so limited, the test used cannot detect it.

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