Australian Federation of AIDS Organisations (AFAO)

Combination therapy means taking a combinationof antiretroviral drugs. Often, they’re just referred to as antivirals. There are currently six types or classes of these drugs, each of which work in different ways against HIV. It is now known that the most effective way to treat HIV is by combining different classes of drugs that attack the virus in different ways. In line with the current Australian and international treatment guidelines, widely supported by existing research, it is now standard practice to commence and maintain people on a combination of at least three drugs from two of these classes, or more.

The number of different drugs that you are on can be:

Monotherapy or one drug: this is generallyconsidered harmful as experience shows benefits may be short lived and resistance usually develops rapidly. Resistance to one drug may limit your future treatment options;
Two drugs: Usually two drugs is not considered sufficient when you first start treatments. Two drug combinations are usually only used because you have experienced severe side effects or sometimes as second line therapy after you have kept the virus suppressed for some time with your first treatment combination; and
Three or more drugs: This is considered thegeneral rule particularly when starting treatment.

Overwhelmingly, standard practice is three drugs in combination – widely supported by existing research and international guidelines. If your doctor suggests you start or remain on just one or two drugs, find out why. If you’re not satisfied with the explanation, or you think your doctor may not be up-to-date, seek a second opinion. “You’re doing OK so far on just one drug” (for example) might be one answer which suggests a second opinion may be useful.

The six classes of drugs are:

nucleoside reverse transcriptase inhibitors (or ‘nukes’ or NRTIs) - nucleoside analogues and nucleotide reverse transcriptase inhibitors (also known as ‘nukes’ or NRTIs);
non-nucleoside reverse transcriptase inhibitors(‘non-nukes’ or NNRTIs);
protease inhibitors;
fusion inhibitors;
integrase inhibitors; and
CCR5 entry inhibitors.

The most common combinations include two nucleoside reverse transcriptase inhibitors, in combination with either a non-nucleoside reverse transcriptase inhibitor or a protease inhibitor.

See also the section on Combination Therapy (PDF 55KB) in Taking Care of Yourself (AFAO 2nd edition 2003)

Resistance

Every time HIV reproduces itself there’s a high chance that it may ‘mutate’ slightly. A ‘mutation’ is a small alteration in the genetic makeup. These alterations may make the virus more resistant to an individual drug or potentially a class of drug. The more the virus is reproducing (i.e. the higher the viral load) the more chances there are of mutations occurring.

Three drug combinations are most frequently used because they stop most virus reproduction, and because the chances of a mutation becoming resistant to a number of drugs at the same time are very small. For example, if you are on one drug then the virus may only have to mutate in one place for resistance to occur. But if you are on three drugs then the virus has to mutate in three different places at the same time – and there is much less chance of this occurring.

If you miss doses regularly or stop taking the drugs for a few days, you give the virus a chance to mutate. And because small concentrations of one or more of the drugs you are on can still remain in your bloodstream, any mutations which are resistant to these drugs will multiply better and have more chances of then infecting new cells. So, each missed dose can mean slowly rising levels of resistant virus in your body. Missing doses regularly may allow the virus to escape the control of a drug.

If the virus does develop resistance, the treatments become much less effective and your choices of available drugs to use in the future may be limited. If this happens, HIV can keep multiplying in spite of the drugs, effectively behaving as untreated virus. This is why rises in viral load can mean you need to change treatments

A few tips to help stop the development of resistance:

Take the full dose of each drug as prescribed. This allows the drug always to be working at maximum capacity.
If you miss a dose, don’t double up on your next dose. You just risk more side effects but won’t have a better result against the virus.
Take all the drugs in your combination regularly. This means the drugs are always in your blood at levels that work effectively against the virus.
If you are having difficultiestaking a certain drug because of side effects or dose requirements, talk to your doctor about changing to a combination that suits you better and is easier to remember. It is better to change treatments than to stay on a combination which doesn’t suit.

The changing face of treatments strategies

Multiple combinations of HIV antiviral treatments, referred to as Highly Active Antiretroviral Treatments or HAART, first became shown to be highly effective in combating HIV in the mid 1990’s. Since that time there have been a number of different approaches to treating HIV infection. As our knowledge of how these drugs work and their side effects has grown over time, there are now a number of different strategies recommended:

These include:

individual tailoring of drug combinations to maximise viral suppression and minimize side effects
maximising future treatment options by getting the best combination of drugs used when initially starting treatments
undertaking resistance testing prior to the commencement of treatment to choose the drugs that will work the best for you
improving treatments adherence to minimise theopportunity of drug resistance from occurring in the future

When to start?

There is no set rule on when to start HIV treatments - if you feel generally lacking in energy, are suffering fevers, rashes or swollen glands you can consider HIV treatment at any CD4 count. However, you do not need to make any decisions straight away. The answer to the question of ‘when to start’ varies according to the stage of your HIV disease or if there are special reasons for starting.

a. For people with recent HIV infection – i.e. you had a recent seroconversion illness or you have had a recent positive HIV-test and had tested HIV negative in the previous 6 months.

A number of smaller studies have suggested that a short course (3 months) of treatment for people with recent HIV infection could help the body’s immune system make a more effective response against HIV infection, stabilising the CD4 count to delay CD4 cell decline and the need to take treatments in the future. Unfortunately there are no studies that strongly suggest any long-term benefit to early treatment.

There is also evidence that people with recent HIV infection have higher levels of the HIV virus in their semen, thereby increasing the likelihood of sexual transmission of HIV. By treating people in the first few weeks of HIV infection, this could help reduce the risk of HIV transmission to sexual partners. As there are no current guidelines for treatment of HIV for people with recent HIV infection, and treatment is not recommended outside of participation within a clinical trial, it is important that you speak with your doctor about the best options for you.

b. For people with chronic HIV infection who remain “well”

The current treatment guidelines (as of 2008) recommend treatment be offered whenever the CD4 cell count falls below 350. The pendulum is now swinging back towards earlier treatment of people who are well, and some experts would now recommend commencing treatment at CD4 counts about 350. The viral load is less important in determining when to start medication, but if the viral load is greater than 100,000 per ml, this might be another factor in starting treatment earlier rather than later. The goal of treatment is to prevent progression of HIV disease and the development of symptoms of HIV disease. Currently, no clear long term benefits have been established for the commencement of HIV treatment for people who are well (i.e. do not have symptoms of HIV infection) and have CD4 counts above 350, although a number of studies do suggest that there may be some benefit in starting with a CD4 count between 350 and 500.

c. For people with a history of an AIDS defining illness, a CD4 count below 200 or severe symptoms of HIV disease regardless of CD4 count

Treatment is recommended for any person with symptoms of HIV disease—including neurological HIV disease—or have experienced an AIDS defining illness (opportunistic infection) in the past. The goal of treatment is both improvement in health and the prevention of further damage to the immune system or reoccurrence of an AIDS defining illness.

d. For women who are pregnant.

Here the goal of HIV antiviral treatment is to reduce HIV viral load and therefore decrease the chances of vertical transmission from mother to baby.

Starting antiviral therapy is a serious commitment because it may mean taking treatments for the rest of your life. Taking treatments in the long term may affect your quality of life, particularly if you develop side effects or find daily pill taking burdensome.

On the other hand, many people feel an improvement in their health and energy levels after starting antiviral therapy.

Any treatment decision needs to be discussed fully with your doctor, taking into account not only viral load and CD4 counts but most importantly, your ability to integrate combination therapy into the way you live.

What combinations are best?

There are lots of possible combinations of HIV drugs. It’s not possible to describe them all here. Further, people will respond differently to the same combinations, for a variety of reasons. Just because something worked for a friend doesn’t mean it will work for you, and vice versa. There are many factors affecting individual responses to HIV and therapy.

Some drugs can’t be used in combination for scientific reasons (e.g. they compete with each other to get absorbed into the body), or they have the same side effec profile. Work with your doctor to choose the best drugs, considering some of the factors listed below:

What stage of disease are you at (viral load, CD4 counts, symptoms)?
What prior treatment, if any, have you had?
What other treatments are being taken now?
How easy will it be to take the particular combination?
What are the possible side effects?
Do you have a busy life and eat at different times every day?
Are there confidentiality issues around taking drugs regularly?
Do you travel a lot?

Australian HIV treatment guidelines are updated regularly and may contain recommendations about which drugs or combination of drugs to take in particular circumstances based on the latest evidence. These are available from AIDS Councils and PLWHA groups.

Adherence

Adherence (also referred to as compliance) means the extent to which you take the right dose of the drugs at the right time. Taking the right dose at the right time is important. Skipping doses can mean that the drug becomes ineffective against the virus and allows resistance to develop (see resistance page 16). Taking a drug on a full stomach when it’s meant to be taken before eating can make the drug less effective. Make sure you know how each drug should be taken to be as effective as possible against the virus.

There are plenty of ways to help you remember to take your drugs on time. You could experiment with some of these:

Take your drugs at the same time each day;
Have supplies of your drugs at places you know you’ll be (partner’s house; work, if relevant);
Take your drugs with you wherever you go;
When travelling, be aware of the different time zones you might be crossing and adjust your dosing times accordingly (this can be done by talking to your doctor before you leave);
Portable pill boxes, with a timer that you can set to beep each time you need to take a drug, are available from your local AIDS council or doctor;
Get a Dosette box — this is a box which lets you set out your pills for the week in labelled sections so you can easily see what you have taken and what you need to take next. These are available from chemists or AIDS councils;
Keep a calendar or diary in a prominent place at home and work which you can tick off each time you take your pills;
Establish a routine which associates pill taking with meals where appropriate;
Get an electronic diary and program it to remind you to take the drugs;
Prepare for holidays by getting a stock of drugs in advance; and
Find out from other people with HIV what they do to help remember their pills.

Monitoring and changing combinations

You may need to change your treatments for a number of reasons. If there are sudden unexplained changes to your viral load, it could mean that the virus has become resistant to one or more of the drugs in your combination. You may also need to change combinations if you are unable to meet the requirements for dosing schedules, or if you are finding the side effects intolerable, even if your viral load and CD4 levels are OK.

If you have been experiencing severe side effects due to a particular drug or class of drugs there may be other combinations that do not include this drug or classes of drugs that can be recommended. It is important that you speak with your doctor before stopping any of your HIV antiviral treatments. You will need to be monitored after each change in combination to see how the new combination is working. During these times, you will probably need more frequent viral load tests.

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Treatment breaks

At the turn of the century, combinations of three or more HIV antiviral drugs were shown to be highly effective in treating HIV disease. At the time it was hoped that after long periods on these drugs it may be possible to ‘eradicate’ HIV from the body. In 2008 it is now known this is not possible with the current treatments. For some people there are significant toxicities associated with using the current drugs for long periods. It is not surprising then that over the past few years one possible strategy examined to minimise long term side effects while attempting to maximize the length of antiviral benefit was the possibility of taking a break from your anti-HIV treatments. These breaks are commonly known as treatment breaks or structured treatment interruptions.

Recently, a large international trial was used to compare the people who continuously took their drugs and people who took treatment breaks. The study, initially designed to last nine years, was stopped after only two years due to the high number of people who took regular treatment breaks that developed AIDS-defining illnesses.

Except in very particular circumstances, as soon as you stop taking treatment HIV starts to reproduce again increasing viral load and CD4 cells decline. This is particularly so for people who have already had low CD4 counts, or have had an opportunistic illness in the past.

The results of this study clearly show that treatment breaks are associated with a rapid fall in CD4 counts, an increase in viral load, and illness, as well as the development of multiple drug resistance.

Sometimes, people stop treatments for just one or two days, e.g. during a party weekend. This is often referred to as a ‘drug holiday’. Stopping treatments for just one or two days could put you at real riskof developing resistance. There is some research to suggest that stopping drugs for short periods of time, or regularly missing some doses may be more risky in terms of resistance than stopping all at once for a longer time (e.g. a month). This is because different drugs remain active in your system for different periods of time between doses. You should not stop your drugs for these very short periods.

However, some people do feel the need to take longer, planned breaks from HIV drugs. This may be because of side effects, the desire to ‘have a rest’, or other factors like overseas travel. You should discuss this thoroughly with your doctor. Factors like viral load and CD4 counts are very important. If you have a very low CD4 count, stopping treatments could put you at risk of developing an opportunistic illness. You should consider whether you need prophylactic treatment during this time, particularly (but not only) if you have ever had an opportunistic infection.

If you do want to stop your drugs for whatever reason, devise a plan with your doctor, including:

whether you might need prophylactic treatment during this time;
how long a break;
at what point, if any (e.g. viral load, CD4 count) you would consider starting treatment again; and
how you feel about monitoring, blood tests, etc. during this period.

Some doctors feel that if a person is having major trouble with adherence and missing doses or taking their drugs erratically, it may be more sensible to stop all the drugs and work through these problems over time, before trying again.

Other issues

Salvage Therapy

Some people with HIV with significant immune impairment, or people who have taken a wide range of antiviral drugs over a period of many years may experience problems with their antiviral treatments because they are resistant to some classes of drugs. Treatment strategies for people who appear to have HIV that is resistant to many of the available treatments is often referred to as salvage therapy.

There are four different salvage therapy strategies that may be tried:

recycling drugs – that is, using drugs you have previously used in conjunction with resistance testing to determine which ones may work best;
‘mega-HAART’ regimens – using combinations of up to nine antiviral drugs – these regimens, of course, may pose serious side-effect problems;
‘treatment intensification’ – adding one or two drugs to an existing regimen; and
accessing new treatments that have not yet been approved for wide use via compassionate access, special access schemes or by participating in clinical trials. Your doctor or treatments officer can provide you with more information about accessing these types of drugs.

Sometimes none of these strategies may be suggested or you may choose not to try them because of the side effects or risks involved. Even if you are on a regimen to which you appear to be somewhat resistant, your doctor may recommend you continue on it as it still may provide protection and help to keep you healthy.

Other treatments

HIV causes different effects in different people. No two people with HIV have exactly the same experience of any side effects, illnesses or symptoms, though there are some common stories. At some times, you may need to take other drugs, like antibiotics, for specific infections or symptoms.

You will need to find out from your GP, pharmacist or specialist whether these interact with the antiviral treatments you are on.

There are some good resources around to help you understand the treatments you are on. See ourlinks page.

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Re-infection (super-infection) with HIV

Reinfection, or ‘superinfection’ as it is sometimes known, means someone contracting a new or secondary infection from a virus with which they havealready been infected. In some viral diseases such as measles or mumps, reinfection does not occur because the original infection creates immunity. In other viral infections such as colds and flu, reinfection occurs frequently, due to different strains of the virus.

While rare, we now know that reinfection with HIV happens through unsafe sex or injecting with other people with HIV. One study has shown it is most likely to occur within the first three years of HIV infection in people who have not previously taken HIV treatments or who have taken structured treatment interruptions. However, recently there was a documented case where reinfection occurred between two HIV positive gay men who had been in a long term relationship practicing unsafe sex and having a history of non-adherence to HIV treatments.

We do know that adherence to treatments may impact and provide protection against the possibility of re-infection occurring (e.g. it may be less likely to occur if both HIV positive partners are currently on treatments with a low or undetectable viral load). However, we do not know whether exposure to different viral strains during early infection provides protective immunity against later reinfection.

Studies among dually infected (more than one strain of HIV virus) people have shown that having more than one HIV strain or being reinfected is likely to lead to a poorer long-term prognosis and more rapid disease progression.

The rise of sexually transmissible infections (STIs) such as syphilis among HIV positive gay men can cause serious damage to the immune system and make HIV more difficult to treat. It may increase the chance of reinfection with an STI or with a different strain of HIV. It is important to test regularly for syphilis and other STIs such as herpes, and to seek early treatment to reduce the risk of further damage to your immune system or reinfection.

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Illicit and recreational drugs

There’s not a lot known about how HIV treatments interact with illicit or recreational drugs, though this is changing. Although it is not recommended or advised that recreational drugs be consumed, if you do take recreational drugs, there are some common cautions you could follow:

Avoid taking HIV drugs and other drugs at exactly the same time: wait at least a couple of hours between doses;
Ritonavir and possibly other protease inhibitors may cause dangerous, even fatal interactions with ecstasy, crystal/ice and other types of methamphetamines;
Drink plenty of water;
Start with a smaller amount of any illicit drug and monitor any unusual responses;
Seek emergency medical help if you experience dizziness, sudden drowsiness, blurred vision, heart palpitations, vomiting or any other severe or unexpected effect; and
Methamphetamines and ecstasy can often causeloss of appetite and even make eating difficult; which can be a problem for people who need to take treatments with food.

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Immune-based therapies

Most of the recent attention in HIV research has focused on treatments that attack HIV itself, or work against the virus in the body. However, there is a significant move towards looking at ways to prevent, treat or repair immune system damage caused by HIV. This makes sense, because it is not HIV itself, but the damage the virus does to the immune system, which puts people at risk of illness and death.

Approaches to managing or treating HIV immune system damage are called immune-based therapies or immune modulators. At this stage, there are no immune-based therapies licensed to treat HIV. However, a number of experimental treatments are being examined. Many people believe immune-based therapies will still need to be used in combination with antiviral drugs, but may mean that antiviral drugs need only be used infrequently or sporadically, rather than every day.

Interleukin-2 (IL-2) is the most advanced of the immune-based therapies. There are currently several clinical trials of this drug being conducted at sites all around the world, including a number of sites in Australia. IL-2 has previously been shown to increase the production of CD4 cells. The trial hopes to show that these cells function well and have a protective effect on the immune system.

Other immune-based therapy approaches include therapeutic vaccines, designed to stimulate the immune system’s ability to directly fight HIV. Ongoing research in this area continues, although the results to date have not been promising.

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