Continuing HIV treatment

ARV treatment should stop a person from becoming ill for many years. For many people the therapy works without any major problems. However, sometimes there can be difficulties related to drug resistance, drug interactions, side effects and adherence.
This page provides information about the issues that a person may face when continuing their antiretroviral treatment.
The following information continues from the pages introduction to HIV & AIDS treatment and starting HIV & AIDS treatment.

Monitoring treatment success

The viral load test

Once ARV treatment has been started, it is important to track how well it is working. This is the purpose of the viral load test.

Viral load refers to the amount of HIV in the blood. If the viral load is high, T-helper cells tend to be destroyed more quickly. The aim of antiretroviral treatment is to keep the viral load as low as possible.
In places where it is available, a viral load test is carried out shortly after antiretroviral treatment is started. If the treatment is working effectively, the viral load will drop to the undetectable level – below 50 copies/ml. Ideally this will happen within 24 weeks of starting treatment, but for some it can take 3 to 6 months. Some people never reach undetectable.
Viral load tests are then carried out every few months. As some viral load tests can produce slightly different results on the same sample of blood, the results are monitored over a period of time. An increase in viral load may be followed by a fall in CD4 count and a greater risk of developing opportunistic infections.
If viral load is increasing it is important to determine whether the treatment is failing due to drug resistance, poor adherence or drug interactions.

Other assessments after starting treatment

Once therapy has begun, there should be additional clinical and laboratory monitoring, including:

• Assessment for signs/symptoms of potential drug toxicities
• Adherence counselling and assessment of adherence
• Assessment of response to therapy and signs of treatment failure
• Weight measurement
• CD4 testing at least every six months (if available)
• Haemoglobin monitoring for patients on AZT

In resource-poor communities it is recommended that this monitoring should take place 2, 4, 8, 12 and 24 weeks after treatment begins and then every six months once the patient has stabilised on therapy.

Drug resistance

Antiretroviral drugs slow the replication of HIV in the body. However the drugs cannot stop the replication completely, so some HIV is able to survive despite ongoing HIV treatment.
When HIV replicates it often makes slight mistakes, so each new generation of HIV differs slightly from the one before. These tiny differences in the structure of HIV are called mutations. Some of the mutations occur in the parts of HIV that are targeted by antiretroviral drugs. So although there is some HIV that continues to be attacked by the drugs, there are other strains of HIV that are less likely to be affected. This HIV is called drug resistant HIV, and it is able to replicate unaffected by the drugs.
When someone has drug resistant HIV (commonly referred to as drug resistance), the amount of HIV in the blood rises and the risk of the person becoming ill increases. Drug resistance is one of the main reasons why antiretroviral treatment fails. If resistance develops, usually the drug regimen needs to be changed.

Avoiding and detecting resistance

Taking medication exactly as prescribed is a very important part of avoiding resistance.

There are certain things that can be done to reduce the risk of developing drug resistant HIV. Ensuring that the drug combination is strong to begin with will lessen the risk of resistance developing. This usually means taking a combination of 3 or 4 drugs.
Taking medication exactly as prescribed is a very important part of avoiding resistance. Missing doses or not taking them on time lowers the amount of antiretroviral chemicals in the body, which means the virus is not properly suppressed. The virus is then able to replicate faster, increasing the chance of it becoming resistant.
Regular viral load testing is also important as the results can indicate whether a drug resistant strain of HIV is developing. If the drug combination is working, the viral load should be undetectable. An increasing viral load can be a sign of growing drug resistance.

Cross-resistance

Resistance to some ARVs can limit future treatment options. If HIV is resistant to one drug, it will sometimes be resistant to similar drugs in the same group. This is called cross-resistance and it means that some antiretroviral drugs will not work even if they have not been used before.

Drug interactions

Interactions between certain antiretroviral drugs and other drugs, both pharmaceutical and recreational, can alter the effectiveness of antiretroviral therapy. Interactions may lower the amount of antiretroviral drugs absorbed, allowing low level HIV replication to occur, which may increase the risk of drug resistance.
ARVs may interact with the following types of drugs:
Other antiretrovirals. An ongoing study has found that Invirase (saquinavir) when combined with Norvir (ritonavir) may cause an abnormal heart rhythm by affecting the heart's electrical signals.¹ Symptoms can range from lightheadedness to an abnormal heartbeat with the possibility that more severe side effects will develop such as ventricular fibrillation.² This has been found from preliminary data and a review of these findings are ongoing.
Other pharmaceutical drugs. Some other pharmaceutical drugs may cause side effects or decrease the effectiveness of some antiretroviral drugs. For example, it is not recommended that protease inhibitors be taken with drugs such as Cafergot and Migranal, which are used to treat migraine headaches.³
Herbal and complementary treatments. Garlic capsules, for example, stop saquinavir - a protease inhibitor - from working properly.
Drugs for treating opportunistic infections. For example the tuberculosis treatment rifabutin should usually not be used with the protease inhibitor saquinavir or the NNRTI delavirdine.⁴
Recreational drugs. Interactions between recreational drugs and antiretroviral drugs can be dangerous because of the potentiation (boosting) effects that antiretrovirals have on recreational drugs. Minimal research has been carried out in this area and little is known about how the body processes recreational drugs. The safest action is not to mix these drugs with antiretrovirals at all.
Drug interactions are often a concern amongst older people living with HIV, as there is a higher chance they will be taking other medications for age-related illnesses.
It is advised that those taking antiretroviral treatment seek advice from their doctor to avoid any drug interactions.
The University of Liverpool maintains an up-to-date chart of drug interactions.

Immune Reconstitution Inflammatory Syndrome (IRIS)

IRIS is an illness that occurs for a small number of patients soon after treatment is started. It is caused by an excessive response by the recovering immune system to opportunistic infections that were already present, but were previously dormant and not producing symptoms. Although the symptoms of IRIS are often mild, occasionally they can be life threatening. Generally those who have a severely damaged immune system before starting antiretroviral treatment are more at risk of developing IRIS.
IRIS does not indicate that treatment is failing. Usually the best response to IRIS is to continue treatment; the symptoms normally disappear within a few weeks. In cases involving severe opportunistic infections, such as cryptococcal meningitis or tuberculosis, it may be necessary to stop antiretroviral therapy whilst the infection is treated.

Side effects

Side effects occur when the drugs affect the body in ways other than those intended. Most of the antiretroviral drugs have known side effects, but this does not mean that everyone who takes the drugs will experience them. Some people only experience mild side effects and find them easily manageable. But for some the side effects occur so strongly that they have to consider alternative drugs.

The side effects often get better after a person has been on treatment for a while, as the body starts to adjust to the antiretroviral drugs.

Side effects are often referred to by the grade of the effect, and the grades range from mild to moderate to severe to life-threatening. For example, it is considered a mild side effect if a person has 2-3 vomiting episodes a day. Life-threatening side effects such as extreme limitations in daily activity and hospitalisation are rare, but are still threats to some.⁵
The side effects often get better after a person has been on treatment for a while, as the body starts to adjust to the antiretroviral drugs. Doctors can usually prescribe some treatment to help with the most common side effects such as nausea and diarrhoea.
Some people use alternative therapies and medications with combination therapy to ease the side effects. For example, ginger for some may ease nausea.⁶ Sometimes the side effects do not diminish over time; in some instances one or more of the drugs in the combination can be changed to reduce the side effects.

Adherence

The term adherence means taking the drugs exactly as described. This includes taking all of the medication at the right time and exactly as the directions state.  It also means ensuring that there will be no interactions with other drugs being taken.
Anything below 95 percent adherence has been associated with increases in viral load and drug resistance.⁷ Therefore adherence to antiretroviral treatment is extremely important. This means missing no more than one dose a month, if taking antiretroviral drug treatment once a day.
Often experiencing side effects makes adherence difficult. As adherence is such a vital part of treatment, it is important to monitor closely the impact that side effects may have on adherence. A patient should inform their doctor if side effects are affecting adherence or if it is difficult to stick to a drug regimen.

Changing HIV treatment

Side effects and treatment failure are the two main reasons why antiretroviral treatment may need to be changed.

Side effects

Sometimes side effects can be so strong, intolerable or even life-threatening that the treatment must be changed. In such cases it is normally safe to change only the offending drug(s). Antiretroviral drug side effects has more information.

Treatment failure

A change of treatment is needed when the antiretrovirals fail to slow down the replication of the virus in the body. This can occur as a result of drug resistance, poor adherence, poor drug absorption or a weak combination of drugs. Increased viral load or an HIV-related illness may be signs of failing antiretroviral treatment.
There are different opinions about when to change treatment if viral load is increasing.  Some doctors recommend changing as soon as the viral load starts to rise, although this could mean running out of treatment options more quickly. Others recommend monitoring the trend of the viral load before making a decision to change. This latter approach may increase the risk of developing resistance to certain drugs, which can limit future treatment options.
The changes made to the drug regimen will depend on the drugs already being used, the CD4 count and the patient’s general health.
If viral load testing is not available it can be difficult to identify treatment failure. The World Health Organisation (WHO) has developed a staging system for HIV disease based on clinical symptoms, which may be used to guide medical decision making. More information about the four stages of HIV disease can be found in the different stages of HIV infection.
WHO guidelines state that treatment failure may be signified by a new or recurrent Stage IV condition occurring after at least six months of therapy.⁸ Conditions occurring before this time often represent immune reconstitution syndrome. The onset or recurrence of certain Stage III conditions such as pulmonary TB and severe bacterial infections after at least six months of treatment may also indicate treatment failure. Some Stage IV conditions, such as lymph node TB, may not be indicators of treatment failure.
Combined with clinical judgement, the following table can guide the decision of whether to switch treatment.

Treatment failure criteria	WHO Stage I	WHO Stage II	WHO Stage III	WHO Stage IV
Clinical (CD4 testing unavailable)	Do not switch	Do not switch	Consider switching	Switch
CD4 failure (viral load testing unavailable)	Do not switch repeat CD4 test in three months	Do not switch repeat CD4 test in three months	Consider switching	Switch
CD4 failure and viral load failure	Consider switching	Consider switching	Switch	Switch

In 2008 a study concluded that these guidelines only effectively detected treatment failure in a minority of patients.⁹ The majority of those identified as having treatment failure by clinical criteria or CD4, in fact had adequate viral load suppression and therefore did not need to change treatment. However without viral load testing, these guidelines are the most helpful way of recognising treatment failure.

Salvage therapy

Salvage therapy is the term often used to describe the treatment for those who are resistant to drugs in the three main drug classes. In this situation it may be difficult to find a drug regimen that suppresses the viral load to undetectable.
Many people start their salvage therapy with a much higher viral load than when they started previous HIV treatments. This puts more pressure on the new combination to work. Each combination used lessens the chance of maintaining a low viral load because of the possibility of developing resistance to the drugs. The choice of new treatment should always depend on what caused the previous one to fail.
The recent introduction of new classes of drugs has meant that there are more alternative combinations for those who were running out of treatment options.

Structured Treatment Interruptions (STIs)

A Structured Treatment Interruption (STI) is when someone stops taking antiretroviral treatment temporarily. Sometimes people have to stop treatment due to severe side effects, ineffectiveness of the drugs or psychological issues. Taking an STI does not mean skipping or stopping medication randomly, but taking a break from the drug regimen with a planned timescale and close monitoring from a doctor.
UK and American treatment guidelines do not recommend taking planned treatment breaks unless under clinical trial settings. Studies have shown that some types of STI have been associated with an increased short-term risk of HIV disease progression.¹⁰

HIV transmission and antiretroviral drugs

Although antiretroviral drugs suppress HIV, they have not been proven to stop transmission, even when the viral load is undetectable. Unprotected sex between two HIV positive people is not a risk-free activity; there are many different strains of HIV and it is possible to become infected more than once, which can complicate treatment. Those taking antiretroviral drugs should take as much care to minimise the risk of HIV transmission as they did before starting the treatment.

References:

1. FDA (2010, 23rd February) 'Ongoing safety review of Invirase (saquinavir) and possible association with abnormal heart rhythms'
2. FDA (2010, 23rd February) 'FDA announces possible safety concern for HIV drug combination'
3. www.hiv-druginteractions.org ‘Drug interaction charts’.
4. CDC (2008) ‘Managing drug interactions in the treatment of HIV-related tuberculosis’. Accessed 9th July 2008.
5. Calmy. A. et al (2007, 7th July) ‘Clinical update: adverse effects of antiretroviral therapy’, The Lancet 370(9581).
6. Ernst, E & Pittler, M.H (2000) ‘Efficacy of ginger for nausea and vomiting: a systematic review of randomised clinical trials’. British Journal of Anaesthesia, Mar; 84(3):367-71.
7. BHIVA guidelines (2001) ‘1.0 The role of adherence in HIV disease’.
8. World Health Organisation (August 2006) 'Antiretroviral therapy for HIV infection in adults and adolescents in resource-limited settings: towards universal access - Recommendations for a public health approach'.
9. Mee, P. et al (2008) 'Evaluation of the WHO criteria for antiretroviral treatment failure among adults in South Africa'. AIDS, Vol. 22, No. 15, p.1971-1977.
10. El-Sadr, W & Neaton, J (2006) ‘Episodic CD4-guided use of ART is inferior to continuos therapy: results of the SMART study’. CROI 2006 Abstract #106LB, February 2006.