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This page is intended as a basic introduction to the use of antiretroviral drugs for the treatment of HIV/AIDS in adults and adolescents in resource-limited settings. For more detailed information, and for information regarding treatment for specific groups such as pregnant women, children, and people with TB, other documents should also be consulted, and in particular the 2006 guidelines published by the World Health Organisation.¹ This page should not be used as a guide to treatment for an individual, when a physician or similar health care professional should be consulted.

What is HIV antiretroviral drug treatment?

It is the main type of treatment for HIV or AIDS. It is not a cure, but it can stop people from becoming ill for many years. The treatment consists of drugs that have to be taken every day for the rest of someone's life.

HIV is a virus and when it is in a cell in the body it produces new copies of itself. With these new copies, HIV can go and infect other previously healthy cells. So HIV can quickly spread through the billions of cells in the body, if it is not stopped from replicating or producing new copies of itself. Antiretroviral treatment for HIV infection consists of drugs which work by slowing down the replication of HIV in the body.

The drugs are often referred as:

• antiretrovirals
• anti-HIV drugs
• HIV antiviral drugs
• ARVs.

Do you take more than one drug at the time?

You need to take at least two and preferably three drugs at the same time. The reason for this is that if you only take one drug, it will just be a short time before the drug will stop working. This is referred to as becoming "resistant" to the drug. If you take several drugs together, and if the drugs are from more than one group, then it generally takes longer before the HIV in your body becomes resistant.

How do you decide which drugs to take?

The decision about which drugs to take, and indeed which drugs should be made available in a particular country or area, depends on a number of different factors. These include the availability and price of drugs, the numbers of pills, the side-effects of the drugs, the laboratory monitoring requirements and whether there are co-blister packs or fixed dose combinations available.

What are co-blister packs & fixed dose combinations (FDCs)?

A co-blister pack is when two or more pills, capsules or tablets are packaged together in one unit of use of a plastic or aluminium blister pack. In contrast, a fixed dose combination (FDC) is when two or more drugs are combined together in one pill, capsule or tablet.

FDCs reduce the number of pills or tablets to be taken. Also the person taking the pills cannot leave out one of their drugs by not taking some of the pills. This improves the ability of people to take the drugs correctly (known as adherence) and it limits the emergence of resistance. Co-blister packs help people to take the pills at the correct time by packaging them together, but the drugs can still be separated, and co-blister packs do not reduce the number of pills or tablets to be taken.

Using standard regimens

The World Health Organisation (WHO) recommends that when antiretroviral treatment is being provided to a large number of people in a country with limited resources, it is best to take a standardised approach.

WHO recommends that one particular combination of drugs should be chosen to be provided for most people when they start treatment. This is sometimes called the "first line regimen". Additional drugs should be available for people who need to substitute one drug for another because of toxicity, or for use in special situations.

For those people who later need to change from this first choice of drugs because it has stopped working, a different set of drugs should be selected for "second line regimens". If someone needs to change again from the second line regimen then they should then be referred to a specialist physician for individualised care.

What drug combinations are recommended by WHO for a first line regimen?

HIV treatment usually involves three drugs taken together. WHO recommends that in most cases a first line regimen should consist of two drugs from the nucleoside/nucleotide (NRTI) group and one drug from the non-nucleoside (NNRTI) group. Drugs from the protease inhibitor (PI) group are generally less suitable for starting treatment in resource-limited settings for a number of reasons including cost, the number of pills which need to be taken, and the particular side effects that occur with the protease drugs.

The preferred first line regimen consists of AZT or TDF (NRTI class) combined with 3TC or FTC (NRTI class) combined with EFV or NVP (NNRTI class). Alternatively, AZT or TDF can be replaced by either d4T or ABC.

A combination of three NRTIs may be considered in situations where NNRTI options provide additional complications. In this case the preferred combination is AZT+3TC+ABC or AZT+3TC+TDF (where FTC may be substituted for 3TC).

First drug	Second drug	Third drug
Preferred	AZT or TDF	3TC or FTC	EFV or NVP
Alternative	d4T or ABC	3TC or FTC	EFV or NVP
Triple NRTI	AZT	3TC or FTC	ABC or TDF

Because d4T is associated with lactic acidosis (build up of acid in the body), lipoatrophy (fat loss) and peripheral neuropathy (damage to the nervous system), WHO recommends moving away from the use of this drug. However, WHO also recognises that, because d4T is cheaper than alternatives and is widely available in FDCs, it may remain the most accessible option for people in urgent need of treatment in resource-limited settings in the short to medium term. A survey of twenty-three developing countries in early 2006 found that more than two-thirds of patients were receiving d4T as part of first line therapy.²

AZT is also associated with lactic acidiosis and lipoatrophy, but to a lesser extent than d4T. AZT can also cause severe anaemia (low levels of red blood cells) and neutropenia (low levels of one type of white blood cell), so haemoglobin monitoring is recommended before and during treatment with AZT, especially in areas where malaria is common.

Some experts recommend that TDF should be used in pregnant women only after careful consideration of other alternatives.

EFV should be avoided in patients with a history of severe psychiatric illness, when there is a potential for pregnancy (unless effective contraception can be assured) and during the first trimester of pregnancy. NVP should be used with caution in women with CD4 counts between 250 and 350 cells per cubic millimetre.

• AZT is also called zidovudine or ZDV
• TDF is also called tenofovir
• d4T is also called stavudine
• ABC is also called abacavir
• 3TC is also called lamivudine
• FTC is also called emtricitabine
• EFV is also called efavirenz
• NVP is also called nevirapine

How available are co-blister packs & FDCs?

The antiretroviral drugs used in more developed countries are manufactured by a number of different companies. There have been difficulties with these companies working sufficiently together to produce, in one tablet or pill, drugs made by different companies.

In addition, some of these drugs, the protease inhibitors in particular, cannot easily be combined with other drugs, as the dose needed can vary from person to person, and is generally too large to go in one capsule. Similarly, there are chemical reasons why ddI (an NRTI) in particular cannot easily be combined with other drugs.

As of mid-2006, the following co-blister packs and FDCs were available for use in first- and second-line regimens. This list includes generic formulations.

Combination	Co-blister pack?	FDC?
AZT+3TC+EFV	Yes	No
AZT+3TC+ABC	Yes	Yes
AZT+3TC+NVP	Yes	Yes
d4T+3TC+NVP	No	Yes
TDF+FTC+EFV	No	Yes
ABC+3TC	No	Yes
AZT+3TC	No	Yes
d4T+3TC	No	Yes
LPV/r*	No	Yes
TDF+FTC	No	Yes

What are generic drugs? Are they safe?

A generic drug is a non-branded copy of a branded drug, and is supposed to be an identical, or 'bio-equivalent' copy. It is allowed to be produced and marketed after the brand name drug's patent has expired, or in circumstances where the drug patent does not apply, or has been waived by the patent-holder.

If the generic drug is a bio-equivalent copy, then it is as safe as the branded drug.

AVERT.org has more about generic drugs and the issues surrounding their use.

When do you start treatment?

WHO recommends that before anyone starts treatment in a resource-limited setting, a basic clinical assessment should be carried out. This should include determination of existing medical conditions (such as hepatitis, TB, pregnancy, injecting drug use and major psychiatric illness), assessment of current medications (including traditional and herbal medications), weight measurement and assessment of patient readiness for therapy. If AZT is being considered then a haemoglobin measurement should be taken, and a pregnancy test should be taken if EFV is being considered.

WHO has a method of describing the different stages of HIV disease based on clinical symptoms. This is known as the WHO staging system for HIV disease, and further details are given at the end of this page.

WHO recommends that all people who have WHO Stage IV disease should start treatment. But making a decision about whether other people should start depends on what laboratory tests are available, and in particular whether the person's CD4 cell count is known.

What is a CD4 cell count?

A CD4 test measures the number of CD4 or T-helper cells in a person's blood. The more CD4 cells there are per millilitre, the stronger is the immune system. The stronger the immune system, the better the body can fight illnesses.

So when should people start if they don't have a CD4 test result?

As has been previously stated, if a person has WHO Stage IV disease, then WHO recommends that they start treatment. They should also start if they have Stage III disease. If no CD4 test is available then the person should not start therapy if they have Stage I or Stage II disease.

If a CD4 test result is available, when should people start treatment?

Someone who has WHO Stage IV disease should start whatever the result of their CD4 test. And they should also start if they have Stage I or Stage II disease and a CD4 count below 200.

If the person has Stage III disease, then whether they should start depends on their clinical symptoms, and whether they have a CD4 cell count below 350. Initiation of treatment is recommended for all HIV-infected pregnant women who have CD4 counts below 350 and have reached Stage III. It is also recommended for all HIV-infected people who have CD4 counts below 350 and have pulmonary TB or severe bacterial infection.

WHO clinical staging	CD4 testing unavailable	CD4 testing available
1	Do not treat	Treat if CD4 count is below 200
2	Do not treat
3	Treat	Consider treating if CD4 count is below 350 start treating before CD4 count falls below 200
4	Treat	Treat irrespective of CD4 count

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

At the minimum, 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.

Changing antiretroviral therapy

There are two main reasons why antiretroviral treatment needs to be changed.

Side effects

Firstly, the drug combinations often cause side-effects. A side-effect is when a drug affects the body in ways other than those that are intended. Some people only experience mild side-effects and find them easily manageable. But for some people the side-effects are so severe that they have to consider alternative drugs.

If it is possible to identify the drug that is causing the side-effects then it is usually best to replace it with another drug that does not have the same side-effects. For example, AZT may be replaced by TDF, ABC or d4T if the side-effect is anaemia, and EFZ may be replaced by NVP, TDF or ABC if the side-effect is central nervous system toxicity. Given the limited number of treatment options in resource-limited settings, it is important to try to use single drug substitutions where possible instead of early switching to a completely new regimen.

Treatment failure

The second reason for changing treatment is treatment failure. This is when the drugs have failed to work and are not slowing down the replication of HIV in the body.

What is the definition of treatment failure?

The WHO definition of treatment failure depends on whether CD4 testing and viral load testing are available.

If viral load testing is available then treatment failure has occurred if viral load exceeds 10,000 copies after at least six months of therapy, if adherence is thought to have been sufficient.

If CD4 testing is available then treatment failure has occurred if, after at least six months of therapy, the CD4 count has fallen to the pre-therapy level (or below), or if the count has fallen by more than 50% whilst the person has been on therapy, or if the count remains persistently below 100, unless some other infection can account for this decrease.

If neither type of testing is available then treatment failure may be signified by a new or recurrent Stage IV condition occurring after at least six months of therapy. Conditions occurring before this time often represent immune reconstitution syndrome, which is not a sign of treatment failure. 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

Changing to a second line therapy

If treatment failure has occurred then WHO recommends that the entire drug combination should be changed. The new second line regimen will ideally include at least three new drugs, with at least one from a new class, in order to increase the likelihood of treatment success and minimize the risk of cross resistance.

Sometimes HIV becomes resistant to more than one drug. This is called "cross resistance". It is important to consider cross resistance when changing treatment, so that the new drugs are not among those to which HIV is already resistant. For example, cross resistance exists between d4T and AZT, so if treatment failure has occurred when taking d4T then the second line regimen should not include AZT (and vice versa).

So what are suitable second line regimens?

Standard second line regimens contain two NRTI drugs combined with a ritonavir-boosted protease inhibitor, abbreviated as PI/r. The first choice is usually ritonavir-boosted lopinavir (LPV/r) because this is available in a form that does not require refrigeration.

If the first line regimen consisted of three NRTIs then the second line regimen should include an NNRTI and a PI/r, and may optionally include ddI as well.

The table below shows recommenations for switching regimens.

First line regimen			Second line regimen
Standard	First drug	Second drug	Third drug	First drug	Second drug	Third drug
	AZT or d4T	3TC or FTC	NVP or EFV	ddI or TDF	ABC	PI/r
				TDF	3TC*	PI/r
	TDF	3TC or FTC	NVP or TDF	ddI	ABC or 3TC*	PI/r
	ABC	3TC or FTC	NVP or TDF	ddI or TDF	3TC*	PI/r
Triple NRTI	First drug	Second drug	Third drug	First drug	Second drug	Third drug
	AZT or d4T	3TC or FTC	TDF or ABC	EFV or NVP	optional ddI	PI/r

* AZT may be administered as well as 3TC in an attempt to prevent or delay further drug resistance

What is meant by adherence?

The term adherence means taking the drugs exactly as prescribed. It also means taking the drugs on time and following any dietary restrictions.

What makes adherence work?

There are a number of different things that can help to improve adherence. Firstly, there is a need for education, which is needed before the patient starts taking the medication. The person needs to know basic information about HIV and its effects; the benefits and side effects of antiretroviral medications; how the medications should be taken (including consideration of how the treatment will be fitted into the person's lifestyle) and the importance of not missing any doses.

There is also a need for ongoing support to ensure that adherence is maintained. This should involve adherence assessments at every visit to the treatment centre, reinforcement of adherence principles by treatment supporters, and the continuous involvement of relatives, friends and/or community support personnel.

Other things that can be done to help with adherence include minimising the number of pills in the regimen, minimising the frequency of dosing, minimising dietary restrictions, and providing the medication free of charge to those who can least afford to pay.

There can be additional issues and difficulties involved with ensuring good adherence among certain groups of people, such as pregnant women.

WHO clinical staging of HIV disease in adults and adolescents

In resource-poor communities, medical facilities are sometimes poorly equipped, and it is not possible to use CD4 and viral load test results to determine the right time to begin treatment. The World Health Organization has therefore developed a staging system for HIV disease based on clinical symptoms.

Clinical Stage I:

• Asymptomatic
• Persistent generalized lymphadenopathy

Clinical Stage II:

• Moderate unexplained* weight loss (under 10% of presumed or measured body weight)**
• Recurrent respiratory tract infections (sinusitis, tonsillitis, otitis media, pharyngitis)
• Herpes zoster
• Angular chelitis
• Recurrent oral ulceration
• Papular pruritic eruptions
• Seborrhoeic dermatitis
• Fungal nail infections

Clinical Stage III:

• Unexplained* severe weight loss (over 10% of presumed or measured body weight)**
• Unexplained* chronic diarrhoea for longer than one month
• Unexplained* persistent fever (intermittent or constant for longer than one month)
• Persistent oral candidiasis
• Oral hairy leukoplakia
• Pulmonary tuberculosis
• Severe bacterial infections (e.g. pneumonia, empyema, pyomyositis, bone or joint infection, meningitis, bacteraemia)
• Acute necrotizing ulcerative stomatitis, gingivitis or periodontitis
• Unexplained* anaemia (below 8 g/dl), neutropenia (below 0.5 billion/l) and/or chronic thrombocytopenia (below 50 billion/l)

Clinical Stage IV:***

• HIV wasting syndrome
• Pneumocystis pneumonia
• Recurrent severe bacterial pneumonia
• Chronic herpes simplex infection (orolabial, genital or anorectal of more than one month’s duration or visceral at any site)
• Oesophageal candidiasis (or candidiasis of trachea, bronchi or lungs)
• Extrapulmonary tuberculosis
• Kaposi sarcoma
• Cytomegalovirus infection (retinitis or infection of other organs)
• Central nervous system toxoplasmosis
• HIV encephalopathy
• Extrapulmonary cryptococcosis including meningitis
• Disseminated non-tuberculous mycobacteria infection
• Progressive multifocal leukoencephalopathy
• Chronic cryptosporidiosis
• Chronic isosporiasis
• Disseminated mycosis (extrapulmonary histoplasmosis, coccidiomycosis)
• Recurrent septicaemia (including non-typhoidal Salmonella)
• Lymphoma (cerebral or B cell non-Hodgkin)
• Invasive cervical carcinoma
• Atypical disseminated leishmaniasis
• Symptomatic HIV-associated nephropathy or HIV-associated cardiomyopathy

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AVERT.org has more about:

• HIV/AIDS treatment
• HIV/AIDS treatment and care in resource poor communities (a general introduction)
• HIV/AIDS related opportunistic infections
• AIDS treatment access