What does resistance mean for our future treatment options? asks Robert Fieldhouse
During their lifetime, virtually everyone who takes antiretroviral therapy
will require treatment with more than one regimen. High levels of treatment
adherence are required to keep the virus under control, prevent emergence
of drug resistance and keep CD4 counts high.
When choosing therapy it is important to think long-term. While it is important
that you choose options you can live with; that you tolerate and take on a
day-to-day basis, it is also important to consider the long-term consequences
of any treatment in terms of side-effects and resistance. Development of drug
resistance can limit your future treatment options and it is never a bad thing
to think about how you would construct a new treatment should your current
therapy fail.
What causes first therapy to fail?
If your adherence is good (you are able to take at least 19 out of 20 doses
consistently), failure rates with current combinations are low. However therapy
is life-long and you are likely to need to think about a follow-up combination.
Resistance develops when there is a degree of viral replication, (the virus
being able to reproduce itself) despite the presence of antiretroviral therapy.
So if your viral load becomes detectable after being at very low levels on
treatment (below 50 copies) there is a chance your virus is becoming resistant
to one or more of the drugs you are taking. Usually, the more virus replicating
while you are taking treatment, the more mutations (changes in the virus)
will develop.
The most common cause of someone having detectable virus on treatment is poor
adherence; missing doses completely, or being late with them occasionally.
However, poor adherence is not the only reason for the emergence of drug resistance.
The way drugs are absorbed is influenced by whether you stick to dosing instructions.
Levels of drugs which need to be taken on an empty stomach will decline if
you take the drug with food and low drug levels contribute to the emergence
of drug resistance.
The way one person metabolises drugs (especially in the liver) can be very
different to how they are handled by someone else, and it is all determined
by your genes. Low drug levels due to your genetic make up could lead to drug
resistance.
Drug interactions also play a part. Take for example treatments for TB. Rifampicin
especially interacts with HIV protease inhibitors and the reduction in HIV
drug levels may allow the virus to become detectable again and promote gradual
evolution of drug resistance.
With reported increases in transmission of drug resistance among people newly
infected with HIV, it is particularly important to get a drug resistance test
when you are diagnosed. A resistance test is also important before you start
therapy to ensure you start on the most appropriate combination. These tests
are increasingly available in the UK and are recommended by the British HIV
Association in their current guidelines. If you are on failing antiretroviral
therapy, you should use resistance testing to guide your choice of subsequent
treatment.
Your doctor should discuss some of these issues with you at your appointment.
Your drug regimen should be individualised by you and your doctor to make
sure you are on the right treatment for you.
Genotype or phenotype resistance test?
There are two kinds of resistance test commonly used in the UK. One looks
for genetic changes in the make up of the virus (a genotypic test). Certain
changes mean that specific drugs will work less effectively. The other test
takes your HIV virus and applies different HIV drugs to see how susceptible
your virus is. If your virus requires increased levels of specific drugs,
it would suggest you have resistance to that drug and it is best to choose
another option. Genotypic changes or mutations are given a particular identifier
consisting of letters and numbers (for example M184V). Scientists use these
codes to describe how the genetic structure of the virus has changed.
How does resistance develop?
The HIV virus reproduces itself around 10 billion times each day. When it
makes new copies it makes mistakes so every day the new virus produced differs
slightly from previous virus. HIV’s genetic make up is in the form of
RNA: a structure of proteins and enzymes needed by the virus to infect cells
and produce new virus. When someone is not taking antiretroviral therapy,
resistant viruses are likely only to form a minority of your total virus population,
the rest is sensitive or ‘wild type.’ When you begin antiretroviral
therapy, the drug-sensitive virus declines to very low levels, but an environment
is created where the drug-resistant strains can, over time, become dominant.
The information we have about the way that drug resistance develops comes
from studies of drugs taken alone (monotherapy) as well as studies which test
drugs as part of triple combinations. When drugs are studied in triple combinations
it takes longer for resistance to develop to any of the components of the
regimen.
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This table seems complicated at first glance. But it tells you everything
you need to know about resistance to NRTIs. Vertically on the left we list
all the known resistance mutations to drugs from the nucleoside / nucleotide
analogue class.
Across the top you will see the most commonly prescribed drugs such as AZT
and 3TC. Let’s take the nucleoside analogue 3TC as an example. The table
shows you if 3TC fails and you develop a mutation known as M184V this means
you have high level resistance to both that drug and the closely related FTC.
However you will also see that having the M184V mutation is not all that bad
as it makes you more sensitive to AZT, d4T and tenofovir, but also means the
virus has low level resistance to ddI and abacavir.
Pick another mutation and see what implications it has for future treatment
options. 
Life after resistance?
Your choice of initial combination will affect your treatment decisions throughout
the rest of your life. If you start on NNRTI therapy such as efavirenz or
nevirapine and either of those drugs fail you are likely to be left with mutations
that mean other drugs in this class are unlikely to work. Two new NNRTIs are
in clinical trials at the moment and the hope is that they will be active
against virus that has developed resistance to efavirenz or nevirapine.
Starting therapy with a ritonavir-boosted protease inhibitor seems to provide
the most protection against the development of drug resistance, as resistance
to protease inhibitors develops slowly. But this needs to be balanced against
the potential long-term side effects of using drugs from the protease inhibitor
class such as increased risk of heart attack or lipodystrophy.
It is essential that treatment switches are guided by resistance testing,
which is becoming more widely available across the whole country and that
you make resistance an issue you discuss with your health care team.
Ultimately your first regimen needs to be one that is potent and that you
are likely to adhere to and can tolerate. But you should also think about
what you would switch to if this regimen fails.
To learn more about drug resistance take a look at www.clinicaloptions.com/hiv/.
On the homepage click on resistance in the clinical management series and
you will find a range of resources including charts explaining resistance
to protease inhibitors and NNRTIs, similar to the one we have reproduced here
detailing resistance to nukes. The site is free but you will need to register.
