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Starting, Monitoring & Switching HIV Treatment

An HIV-positive South African woman holding her ARV drugs

The success of antiretroviral treatment for someone living with HIV depends on:

• Starting treatment at the right time
• Choosing the right combination of antiretroviral drugs
• Monitoring the effectiveness of the treatment.

Starting HIV treatment

In order to decide whether or not a person living with HIV should start treatment, clinical tests will determine the stage of HIV infection and their readiness for antiretroviral drug (ARV) treatment.
The average person is recommended to start treatment when their CD4 count drops below 500 cells/mm³. This is in line with the most recent World Health Organisation (WHO) Treatment Guidelines which increased the eligibility from under 350 to under 500 cells/mm³. 1
People who have a CD4 cell count higher than 350 cells/mm³ are typically healthy and do not show any symptoms. Health professionals are concerned that people in this situation will feel complacent about adhering to taking treatment for a virus that is not yet making them ill.
However, many people report the desire to stay healthy, and to reduce the chance of HIV transmission to others as the main reasons why they are keen to start antiretroviral treatment early. A rural HIV clinic in Uganda found that between 95 and 98 percent of their patients with a CD4 cell count above 350 cells/mm³ achieved excellent adherence and viral suppression within 48 months. 2
Starting treatment early significantly reduces the likelihood of onwards HIV transmission - known as ' treatment as prevention'. It also delays the onset of AIDS-related illnesses, and morbidity and mortality in general. These findings were a result of the HPTN 052 study (completed in 2011), which showed that early initiation of treatment has both health and prevention benefits. 3
The WHO 2013 guidelines also have recommendations for if there are complications. They say ARV treatment should be initiated immediately regardless of CD4 count for patients who are: pregnant or breastfeeding, have active tuberculosis (TB), have severe and chronic HBV liver disease, are HIV-positive in a serodiscordant relationship, or a child under 5 years of age. 4
The WHO guidelines have also been summarised and adapted to resource-rich areas. 5

The CD4 test

Usually, the CD4 test is used to determine when a person should start HIV treatment.
HIV attacks a type of immune system cell called the T-helper cell. The T-helper cell plays an essential part in the immune system by helping to co-ordinate all the other cells to fight illnesses. HIV damages and destroys T-helper cells. A major reduction in the number of T-helper cells can have a serious effect on the immune system.

CD4 testing at Saint Francis hospital in Katete, Zambia

A CD4 test measures the number of T-helper cells (in a cubic millimetre of blood) which is known as a CD4 count. Someone who is not infected with HIV normally has between 500 and 1200 cells/mm³. In a person infected with HIV, the CD4 count often declines over a number of years.
HIV treatment is now recommended when the CD4 test shows fewer than 500 cells/mm³, as stated in the World Health Organization (WHO) 2013 guidelines. 6 This will vastly increase the number of people eligible for treatment by 9.2 million, forming a challenge for resource-limited countries. 7 As of 2011, most but not all resource-limited countries had been administering ART to patients with a CD4 count of 350 cells/mm³ or less. However some are only able to start treatment at less than 200 cells/mm³, which was what the WHO's 2006 guidelines recommended. (See Universal access to AIDS treatment for more information).
Some countries may have treatment guidelines which differ from WHO recommendations. For example, although USA treatment guidelines state that treatment should be initiated for all patients with a CD4 count <350 cells/mm³ they had also been recommending treatment for patients with a CD4 count between 350 and 500 cells/mm³ before WHO did.

WHO clinical staging

However the resources needed to measure the CD4 count are not available everywhere, in which case, a recommendation is made based on the person’s clinical stage. This describes the different stages of HIV disease based on clinical symptoms. WHO recommend not starting treatment until the advanced stages of HIV infection because it is an important decision with long-term consequences. The decision also depends on the person; children and pregnant women have different guidelines. See our Treatment for Children page, and our HIV and Pregnancy page.
Where a patient is showing signs of stage 1 and 2 they should not start treatment. However, if they are showing signs of WHO clinical stages 3 or 4 they should start treatment. Clinical stages 3 and 4 are identified by the emergence of certain opportunistic infections (such as PCP) and cancers, which a healthy immune system would normally fight off.
Read more about the Stages of HIV Infection.

Basic clinical assessment

Before a person starts treatment, a basic clinical assessment should also be carried out. This assessment determines, for example, existing medical conditions (such as hepatitis, TB, pregnancy, injecting drug use and major psychiatric illness), whether or not the individual is currently taking medications (including traditional and herbal HIV medications), their weight measurement, and a patient's readiness for therapy. Treatment should only be started once the person is ready. A lot of commitment is needed, since following a drug regime can be quite demanding and in most circumstances, the treatment will have to be taken every day for life.
Once it is decided that treatment should be started, doctors will give advice about the various HIV drugs and combinations available and which might be most suitable.

Choosing the best combination of antiretroviral drugs

There are a number of issues which need to be considered when choosing a combination of antiretroviral drugs. The first combination of drugs that a person takes is called first-line therapy. In order for HIV treatment to be effective, patients should take a combination of three drugs.
Antiretroviral drugs attack the ability of HIV to infect healthy cells in five different ways and are therefore divided into five different classes. The WHO 2013 guidelines recommend an antiretroviral combination that consists of two drugs from the Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTIs) class and one drug from the Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) class. 8

Transmitted HIV drug resistance

If possible, a test should be carried out to make sure that a person doesn’t have a strain of HIV that is already resistant to a certain class of drug. If a person’s strain of HIV is resistant to a class of drug, taking that type of drug may be ineffective or at worse, harmful as it may lead to failure of the treatment to work effectively. This type of drug resistance is known as ‘transmitted drug resistance’ because it has been passed from one person to another.

• Acquired drug resistance

Acquired HIV drug resistance refers to when HIV mutates after it has become established in  the body into a form that can no longer be treated with the current course of antiretroviral drugs. This can be as a result of poor adherence, interruptions in treatment, and the use of ineffective drugs or faulty drug combinations. 9
Around 1 in 10 people living with HIV in Europe and America are infected with a type of HIV that is already resistant to at least one class of antiretroviral drug before treatment is started. 10 It is thought that the number of Europeans infected with a drug-resistant strain of HIV has risen by 35 percent since 2003. 11

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 and thereby lead to treatment failure.
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.
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. 12 Symptoms can range from lightheadedness to an abnormal heartbeat with the possibility that more severe side effects will develop such as ventricular fibrillation. 13 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. 14 Women living with HIV taking oral contraceptives and/or hormone replacement therapy need to talk to their doctor about possible drug interactions.
Herbal and complementary treatments: Garlic capsules, for example, stop saquinavir - a protease inhibitor - from working properly. 15
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. 16
Recreational drugs: Minimal research has been carried out on the relationship between recreational drugs (such as ecstasy, cocaine and amphetamines) and antiretroviral drugs, as many recreational drugs are illegal. However, as most recreational drugs and antiretroviral drugs are broken down in the liver, they may interact and result in serious clinical consequences. Laboratory experiments and case studies have found that the interaction between some recreational drugs and some antiretrovirals results in increased toxicity which increases the risk of potentially fatal side effects such as respiratory depression. However, this has not been determined for all recreational and antiretroviral drugs. The safest action is not to mix these drugs with antiretroviral drugs at all.
HIV infected injecting drug users who are taking opioid substitution therapy (such as methadone or bureprenorphine) may be at increased risk of intensified side effects. 17 Another risk is that certain antiretrovirals reduce the concentration of the drug substitution therapy leading to withdrawal symptoms. 18 However, the effects vary considerably depending on the opioid substitution agent and the antiretroviral drugs taken. 19 20
The University of Liverpool maintains an up-to-date chart of drug interactions.

Number of pills

An HIV-positive man sitting at home before taking his antiretroviral drugs

Some combinations - especially those involving a protease inhibitor - require swallowing many pills throughout the day, which some people find hard to do. The size of the pills can also be an issue. WHO now recommends taking an FDC (fixed dose combination), which combines two or more drugs in a single tablet or capsule. This eases the treatment regimen and makes treatment adherence more likely.

Food restrictions

There are a few drugs, particularly protease inhibitors, which have to be taken with food to improve absorption rates. If taken on an empty stomach, some drugs can be extremely painful to take. In areas where there is no regular access to food therefore, taking these drugs may be unfeasible. However, some other drugs have to be taken on an empty stomach.

Storage requirements

Storage can be an issue as some HIV drugs have to be kept below a certain temperature to last long term. The older version of ritonavir, for example, must be refrigerated.

Monitoring HIV treatment

Once a person starts HIV treatment, it is essential that they adhere to their treatment. The patient will need to be monitored by a doctor to make sure that the treatment is working for them.

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. 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.

Viral load monitoring

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. Therefore, the aim of antiretroviral treatment is to keep the viral load as low as possible. Treatment monitoring is now recommended to be based on viral load, rather than CD4 count, because it provides greater accuracy of test results. 21
The current WHO treatment guidelines recommend that a viral load test is carried out at 6 months after treatment begins, at 12 months, and then every year. If the treatment is working effectively the viral load will drop to an undetectable level – below 50 copies/ml. 22 Ideally this will happen within 24 weeks of starting treatment, but for some it can take 3 to 6 months. On the other hand, some people never reach undetectable in which case alternative regimens can be started if necessary.
Viral load testing is costly and rather complicated, resulting in its limited use in many resource-poor areas. Some solutions to the cost and logistical issues have been put forward:

• Dried blood spot testing – tests dried samples of blood for any trace of HIV. Dried blood is easier to transport to laboratories than fresh blood samples, which is of importance in rural areas with limited infrastructure.
• Pooled samples – mixes a blood sample from five different people and tests its viral load; this reduces the need for five different tests which overcomes some of the cost barriers to scaling-up viral load testing. If the combined average viral load is less than 1000 copies/ml then all patients have a low viral load; above 1000 copies/ml means treatment is failing for at least one patient. In this case all will need individual viral load tests to confirm the person/people with a higher viral load.
• Follow the viral load cascade – follow up viral load tests with appropriate treatment and care, re-tests, and second-line therapy if necessary. This reduces the number of patients lost along the care continuum, and prevents the need for unnecessary re-testing. 23 24

Video of HIV STATUS? Undetectable

Structured Treatment Interruptions (STIs)

A Structured Treatment Interruption (STI) or 'drug holiday' is when someone stops taking antiretroviral treatment temporarily. 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 risk of HIV disease progression. 25 26

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.
Read more about side effects.

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. 27
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. 28

Switching treatment

First-line ART

First-line ART is the combination of drugs given to a HIV-positive person who has not taken antiretroviral drugs (ARVs) before. The first-line regimen typically consists of two NRTIs and one NNRTI.
Some people on ART will develop a 'failure of therapy'. This means first-line ART is no longer effective as the HIV strain has become resistant to the course of drugs. This can occur as a result of drug resistance, poor adherence, poor drug absorption or a weak drug combination.​ Increased viral load or a HIV-related illness are signs of treatment failure.
Where viral load testing is available, some healthcare professionals recommend switching to second-line ART as soon as the viral load starts to rise, although this could reduce the number of treatment options more quickly. Others recommend monitoring the trend of the viral load before making the decision to change. However, this approach may increase the risk of developing resistance to certain drugs, which can limit future treatment options.
Where viral load testing is not available, the WHO staging system - which determines the stage of HIV infection based on clinical symptoms - may be used instead.
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

Second-line ART

Second-line ART uses two NRTIs and one protease inhibitor (PI) drug together. Second-line ART is stronger than first-line ART but requires someone to take more ARVs, adjust their diet, and may have more side-effects. If second-line ART fails, third-line ART may have to be used.

Third-line ART

Third-line ART uses drugs such as etravirine (ETV), darunavir (DRV) and raltegravir (RAL). However, the costs are significantly higher than those for both first and second-line ART, which may reduce access in resource-poor countries.​ 29

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, 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.

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.

Avoiding and detecting 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.

Salvage treatment

Salvage therapy is the term often used to describe the treatment for those who are resistant to drugs in the three original 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 introduction of two additional classes of drugs since 2003 (fusion or entry inhibitors and integrase inhibitors) has meant that there are more alternative combinations for those who were running out of treatment options.

HIV transmission and antiretroviral drugs

Although antiretroviral drugs suppress HIV they do not eliminate the risk of HIV transmission completely, even when the viral load is undetectable. Antiretroviral treatment cannot make HIV disappear from the blood completely.
Read our treatment as prevention page as to find out more about the effect of antiretroviral treatment on reducing the risk of HIV prevention.
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 with a different strain 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.