Across Europe, more and more HIV is becoming resistant to the drugs that treat it. But you can still win against resistant virus, says Anna Poppa - it’s a matter of the weapons you choose
 illustration: john Clarkson |
Earlier this year, Europe-wide surveillance found that one in 10 HIV positive Europeans were carrying HIV resistant to at least one drug, even before they’d started on any HIV treatments. The figure for newly infected North Americans last year was nearly one in eight. And in the UK itself, the rate has been reported to be higher still: about one in six of all new infections.
Though the risk appears greater in some communities than others - essentially those who have benefited from the greatest access to HIV treatments - the overall picture is pretty clear. For those who become HIV positive today, the risk of picking up HIV that is drug-resistant is growing. For a small but increasing number, HIV infection may involve virus resistant to several classes of drugs rather than just one.
It is also becoming increasingly clear that you can catch HIV more than once,
in so-called superinfection. This means the rise in drug-resistant virus is
a concern for everyone with HIV, not just the newly infected. There have been
cases where people responding successfully to treatment suddenly started to
fail, apparently because they’d acquired a second, drug-resistant strain.
The implication of contracting drug-resistant HIV is that your treatment options could be narrowed significantly. Treating drug-resistant HIV can be very complicated, and tends to result in earlier treatment failure.
However, HIV pharmacies boast an increasingly broad array of antiretroviral agents, and this means that losing a few of the available choices, though significant, rarely means these days that you’ve run out of options.
Drug resistance in HIV is a normal consequence of viral reproduction. In its ‘natural’ habitat - that is, inside the body, and without the presence of antiretroviral drugs to contend with - HIV is one busy bug, creating billions of offspring on a daily basis.
While copying its genes, HIV periodically makes errors, so that the ordering
of its genetic code sometimes contains variations. When this happens, the result
is that the new HIV that is created will be structurally different to its ‘parent’.
Viruses containing these changes are called mutants. The effect of the mutation varies. Most in fact produce HIV that is crippled and completely unviable. Others may be weaker than their parents; a few are stronger.
But importantly, some mutants are resistant to HIV drugs, and these are the ones that can cause problems once it’s time to start treatment.
Successful HIV treatment should slow down HIV reproduction sufficiently to reduce the production of resistant virus to virtually zero. But if treatment is only partially effective in preventing HIV from reproducing - which happens if you miss doses, or take a combination that isn’t very powerful - it forces the overall HIV population inside the body to become dominated by resistant mutants. They gain a foothold, and sow further generations of HIV that the treatments will be unable to control.
This loss of control over the virus is shown by a rising viral load, and signals the need to change your HIV treatment combination. This is where you can run into problems selecting new drugs if you have resistant HIV. Virus resistant to one drug is often resistant to other drugs in the same class. Testing your HIV for drug resistance at this point can help you avoid drugs that won’t work well for you.
Viruses are simple things compared to bigger life forms, more like little machines than living beings. Scientists have pretty well mapped out each component of the HIV machine.
Imagine being able to inspect HIV’s machinery up close. In particular look at its genetic material: a long chain of linked molecules which together contains the full specifications for building new virus.
Mutant viruses carry different building blocks. The shape of the virus has changed so it, and its successors, will function differently. Each of the building blocks has a number, attached to a symbol for the type of building block you’d usually expect to see at each numbered place. The ‘blocks’ are chosen from around 20 different varieties of the kind of chemicals called amino acids.
If, for instance, a mutation occurs at place 184 in one of the genes so that a ‘brick’ called methionine is substituted with another one called valine, then the resulting virus will be resistant to the drug 3TC (lamivudine). This mutant is termed M184V, because methionine (M) has been changed to valine (V) at position 184.
This same system of letters and numbers is used to describe all HIV mutants, and therefore all drug-resistant viruses.
Drug resistance is not an absolute concept, however. It’s more useful to think of it as a spectrum of higher and lower susceptibilities to specific treatments. Not all drug-resistant mutants are created equal. Some may make one treatment useless, another may just convey a ‘bit’ or resistance, meaning the drug will still work, but only if you have a higher level of it in your body. Some mutations even cancel out the effect of others - the M184V mutation, for instance, makes you completely resistant to 3TC but can improve susceptibility to AZT. So it’s the pattern of overall mutants which someone might be harbouring that really matters, and this pattern emerges according to the way individual drugs are combined.
This can get really complicated. If you take abacavir together with either AZT or d4T, and your combo fails, you will develop a kind of resistance that also conveys resistance to AZT and d4T. But if you take it with other drugs, you will tend to develop resistance to 3TC plus possibly ddI, and maybe also to tenofovir, depending on what kind of mutant you get!
Resistance to the currently used non-nucleoside drugs (NNRTIs - efavirenz, nevirapine, delavirdine) is difficult to manage. All that needs to happen for HIV to become completely resistant to all the current NNRTIs is to develop one of the two mutations called K103N or Y181C. Each emerges easily if a treatment combination containing an NNRTI starts to fail. New NNRTIs will be available in the not-too-distant future designed to be effective against resistant virus.
Resistance to protease inhibitors (PIs) is even more complex. Some mutations may make you very resistant to one or more drugs, but with PI resistance it’s the number of mutations you have that generally matters. If you only have one or two, some PIs will still work, particularly if they are ‘boosted’ like lopinavir/ritonavir (Kaletra®).
Resistance emerges where drug levels in your bloodstream are below those required to suppress your HIV. So some newer HIV drugs are designed to reach high concentrations in the blood without causing intolerable side effects, such as Kaletra. These have become useful in fighting resistance. For people who haven’t taken a PI before, the high levels of lopinavir, boosted by the ritonavir, are able to guard against the emergence of PI resistance.
And those who have used PIs before often still find lopinavir/ritonavir useful because the raised drug levels allow the drug to remain effective despite some reduction in susceptibility. The high levels of the drug ‘vault’ over the resistance barrier erected by the virus.
Boosting blood levels of a PI with a small amount of ritonavir, so that the higher levels counter resistance, is becoming standard practice with PIs, particularly if you are PI-experienced. Boehringer Ingelheim’s experimental PI, tipranavir, has also proven effective in people with some PI resistance when taken boosted, as has atazanavir, the new PI from Bristol-Myers Squibb.
The development of new drug classes is another important goal in managing
resistant HIV. T-20 (Fuzeon), which prevents HIV from fusing with and entering
human cells, has been used exclusively, so far, in people with highly drug-resistant
HIV and few remaining treatment choices as a result. T-20 certainly works in
these people who are able to place it into a combination of other treatments
that have some activity against HIV.
T-20’s developers Roche/Trimeris already have a ‘daughter-drug’ in development, T-1249, which has proven effective against HIV which is resistant to T-20.
This slugging match between HIV and biotechnologists is unlikely ever to be over, so long as drugs are used to treat HIV. But these developments give us more grounds for optimism.
Anna Poppa is a freelance writer. annapoppa@tiscali.co.uk
