What are HIV and AIDS?

The main treatment for HIV at this time uses 3 or more drugs that help block viruses from reproducing (making more viruses). Anti-HIV drugs are often called anti-retroviral drugs (or ARVs) because HIV is a type of retrovirus.

Combinations of anti-HIV drugs that are very good at stopping HIV growth are sometimes called highly active anti-retroviral therapy (HAART). Stopping or slowing the growth of HIV with these drugs helps improve the quality and length of the person's life.

The best anti-HIV treatment combination varies with the person, disease stage, whether the person's infection is resistant to any the drugs, and other factors. With effective treatment using 3 or more drugs, people live longer and the disease progresses more slowly. Still, no combination of drugs available at this time can actually get rid of all the HIV in your body. But the more the drugs cut down on the amount of virus in your body, the better they are at keeping you from getting sick.

When is anti-retroviral treatment started?

Anti-retroviral (anti-HIV) treatment should be started after you and your doctor discuss the pros and cons of the drugs you are thinking about taking. The best time to start is not completely clear, because HIV is an infection that usually progresses slowly, and anti-HIV drugs are known to have some fairly serious side effects over time. But in recent years, doctors have found that there are usually better outcomes if the anti-HIV drugs are started before the immune system has been seriously damaged.

Disease progression: Most doctors agree that anti-HIV treatment should begin when:

• The HIV infection is causing serious symptoms (major infections, cancers, physical weakening, or AIDS), regardless of T helper cell count and viral load.
• The T helper cell (CD4) level is below 350, even if there are no symptoms.

Some people have faster drops in their T helper cell counts over time. These people may need to see the doctor more often to closely watch their counts so that anti-HIV drugs can be started before they get too low. This is especially important as the counts are dropping down near the danger zone, in which the person is at higher risk for serious HIV-related conditions. Many doctors start their patients on HIV drugs when their count goes below 500, or even before.

There may be other reasons to either start or delay treatment, and these should be discussed with your doctor. For example, the potential side effects of treatment may make some people want to delay it for as long as possible. Others may want to be treated before their T helper cell counts drop to help preserve immune function and further reduce the risk of AIDS-related conditions.

Pregnancy: One very good reason to take anti-HIV drugs is pregnancy. If the woman isn't already taking anti-HIV drugs, they are best started when she is between 12 and 28 weeks of pregnancy. Taken every day all the way through delivery, the drugs can be used to reduce the baby's risk of getting HIV from the mother. The mother's viral load is watched carefully during pregnancy and kept as low as possible. This requires an HIV expert working with her, along with her obstetrician, to help reduce the risk of her baby getting HIV during her pregnancy and delivery. After the baby is born, the mother may stop the HIV treatment drugs, depending on her case. The baby is treated with anti-HIV drugs for a few weeks after birth. The mother is advised not to breast-feed, since she can still pass on the infection to her child in this way.

Kidney disease due to HIV (HIV nephropathy): Experts recommend that anyone who already has kidney problems caused by HIV take anti-HIV drugs to prevent further loss of kidney function. Treatment with anti-HIV drugs also improves survival for those with this kind of kidney disease.

During treatment for hepatitis B infection: People with the hepatitis B virus (HBV) are often given lamivudine or emtricitabine for the HBV. These 2 drugs actually started out as anti-HIV drugs, and are still used for treating HIV (see section, "Anti-retroviral drugs used to treat HIV and AIDS" below). Doctors later learned that they were good for treating hepatitis B as well, so now the drugs are used for both infections. But if one of these drugs is given to treat HBV in a person who also has HIV, the HIV in the person's body can become resistant to the drug (see "Drug resistance" section below). Any resistance to anti-HIV drugs makes HIV much harder to treat. Because of this, anyone with HIV who is going to get one of these HBV drugs should get a full set of HIV treatment drugs at the same time to reduce the risk of HIV drug resistance.

Primary HIV infection: For those few people whose infection is found within a few days or weeks after exposure (during primary HIV), doctors are still studying the effects of HIV on the body. They are also looking at whether treatment might prevent immune system damage and whether the benefits of treatment outweigh the risks. Some doctors offer treatment at this stage of HIV infection. Whether or not you wish to be treated, you might want to think about entering a clinical trial (see the "Clinical trials" section in the "Cancers and cancer treatment in HIV infection" section). Some clinical trials just observe people at this stage of infection, while others look at the effects of treatment.

Other problems: Some people with certain other illnesses may be treated when their T helper cell counts are normal. In some cases, those at high risk of certain diseases might do better with earlier treatment. And people whose T helper cell counts are dropping very quickly may be started on anti-HIV drugs sooner.

Anti-retroviral drugs used to treat HIV and AIDS

More than 20 drugs have been approved to treat HIV infections and AIDS. They fall roughly into 6 classes.

Nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs) work by blocking the enzyme reverse transcriptase, which helps the virus make DNA from its RNA. Drugs in this class include:

• Zidovudine (ZDV, AZT, Retrovir^®)
• Abacavir (Ziagen^®)
• Didanosine (Videx^®)
• Emtricitabine (Emtriva^®)
• Lamivudine (Epivir^®)
• Stavudine (Zerit^®)
• Tenofovir (Viread^®)
• Zalcitabine (Hivid^®)

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) work somewhat like the ones listed above, but they act on a different part of the reverse transcriptase molecule. There are 4 drugs in this class:

• Nevirapine (Viramune^®)
• Delavirdine (Rescriptor^®)
• Efavirenz (Sustiva^®)
• Etravirine (Intelence^®)
• Rilpivirine (Edurant^®)

Protease inhibitors (PIs) work against an enzyme called protease that HIV produces in the late stages of its reproduction. The job of protease is to cut a large viral protein into usable sections as the newly-created viruses move out of the cells. When this protein is blocked by a protease inhibitor, the virus cannot be assembled properly. Protease inhibitors include:

• Atazanavir (Reyataz^®)
• Indinavir (Crixivan^®)
• Nelfinavir (Viracept^®)
• Ritonavir (Norvir^®)
• Saquinavir (Fortovase^®)
• Lopinavir (combined with ritonavir and called Kaletra^® -- see information below on boosting)
• Fosamprenavir (Lexiva^®)
• Tipranavir (Aptivus^®)
• Darunavir (Prezista^®, which must be taken with ritonavir -- see boosting information, below)

Boosting anti-HIV drug effects: Ritonavir has a special use as a protease-inhibitor booster. Ritonavir was first approved as an HIV treatment, and is still used in standard doses as part of 3-drug combination treatments for HIV. But doctors noticed that, along with helping stop the virus, ritonavir kept certain other protease inhibitors and some other drugs in the body longer.

Ritonavir is now also used in small doses along with other protease inhibitors to take advantage of this effect. This practice is called "boosting" a protease inhibitor, because it helps keep the drug levels in the body higher and often allows the drug to be given less often.

When ritonavir is used just for its booster effect, it is given in doses that are not high enough to affect the virus. Doctors give just enough to affect the level of the other drug. That means it is not being used as an anti-HIV drug, but only to help one of the other drugs last longer.

No matter what dose you take, it is important to know that any amount of ritonavir can raise the levels of many other drugs, not just HIV treatment drugs. This can be very dangerous depending on the drugs you are taking. Before starting any new drug, anyone who takes ritonavir must always find out whether the new drug interacts with it. It can cause serious harm if it raises the level of certain drugs to toxic amounts in the body. And if you are stopping ritonavir, you should check to see if you need your doses of other drugs changed.

Entry and fusion inhibitors work by blocking the virus from entering the host cell. One of the approved drugs, enfuvirtide (Fuzeon^®) is called a fusion inhibitor, and must be given by injection. The newer drug in this group is called maraviroc (Selzentry^®). It helps to keep HIV out of individual CD4 cells by blocking the protein CCR5. This drug can only be used in patients with a strain of HIV that uses the protein CCR5 as its "door" into the CD4 cell. Before starting this drug, a person must be tested to be sure that the strain of HIV they have is a type this drug can block.

Integrase inhibitors work by keeping the virus from putting its DNA into the host cell. This keeps the virus from being able to take over the cell to make more viruses. The only drug in this class so far is raltegravir (Isentress^®).

Combination drugs are fixed-dose combinations of the above drugs that help to reduce the number of pills a person has to take. Some examples include:

• Combivir^® - zidovudine and lamivudine
• Trizivir^® - zidovudine, lamivudine, and abacavir
• Epzicom^® - abacavir and lamivudine
• Truvada^® - tenofovir and emtricitabine
• Atripla^® - efavirenz, emtricitabine, and tenofovir

Atripla is the first combination formula of a full 3-drug regimen that comes in a single pill to be taken once a day. Although not everyone can take this combination, for those who can, it is a major improvement over taking several pills 3 or 4 times a day.

Choosing anti-HIV drugs for treatment

Since more than one drug is used to treat HIV, and they all have their own schedules and side effects, doctors look at each person to figure out which drug combinations might work best. Factors such as drug resistance, other illnesses the person has, potential for drug interactions, and the risk of serious side effects must be weighed. Patients must learn about drug scheduling, which drugs can be taken together, and any food restrictions before they commit to a set of anti-HIV drugs. There are special factors to think about with each drug. This is a good time for patients to be involved with helping their doctors choose the drugs that will work best for them.

Taking anti-HIV drugs exactly as prescribed can be hard for many people. Some drugs are taken 3 times a day, others once a day. Some don't work if they are taken with food, and others work better if they are taken with a meal. This can be confusing and hard to keep up with. It may take some time for a person to be ready for this commitment.

If you are not able to keep to a strict schedule, tell your doctor. You may be able to work out an easier set of drugs. Many doctors now try to start with combinations of drugs that can be taken once or twice a day. But drug resistance testing may show that your options for treatment drugs that will work on your virus are limited, and there may be other drugs that won't work for different reasons.

Is treatment working?

The success of any anti-HIV drug regimen is measured by checking the viral load a few weeks after the drugs are started, and then checking the viral load and T helper cell count every 3 to 4 months as the drugs are taken. The T cell count normally goes higher as the viral load goes down.

The goal of treatment is to get the viral load down so that the lab test cannot find any trace of virus in the blood (this is called an undetectable level). Different tests have different cutoffs for detection, so results may differ slightly between labs.

It is important to know that an undetectable virus load does not mean that there is no HIV in the person's blood, only that the test was not able to detect it. Undetectable virus levels do not mean that the person cannot infect others with HIV. Even with undetectable virus levels, safer sex and other precautions are needed to avoid passing the virus on to others.

If the viral load cannot be kept down to undetectable levels with the first drug combination, others are usually tried. If no combination gets the viral load down to undetectable levels, doctors usually keep trying until they find a drug combination that will help keep it as low as possible. In such difficult cases, this may mean using 4 or more anti-HIV drugs together. Or your doctor may recommend a clinical trial.

Many of the anti-HIV drugs available today are not given as first-line treatments – they are used only if the preferred drugs have failed. Because researchers are still comparing treatments and new drugs are still being tested, the drugs and combinations used for HIV treatment keep changing as more research is done.

HIV treatment issues

Drug resistance: Treating HIV infection is hard, in part because the virus can change its outer proteins and become drug resistant. This means that the virus starts to grow even when the anti-HIV drugs are in your body. This is one reason that anti-HIV drugs are never used one at a time – if HIV can grow even a little bit while a drug is in your system, those viruses often become more and more resistant to that drug. It usually takes the full effect of 3 drugs to stop HIV growth, so all of the anti-HIV drugs must be taken on time in order to work properly. HIV can quickly become resistant to even the most potent anti-HIV drugs if they are not taken as prescribed.

Even when drugs are taken exactly as prescribed, people can develop drug-resistant virus after years on the drugs. If the virus load starts to climb while a person is taking anti-HIV drugs correctly, a drug resistance test is usually done to learn which drug or drugs the virus is resistant to. Since many of the HIV drugs in each group are a lot alike, resistance to one drug may mean resistance to more drugs in the same class. This limits the number of drug combinations that a person might expect to use after one or more combinations fail.

If the first drug combination fails, or if you cannot take it, it often becomes harder to find a second or third combination that works well. After a few drugs have failed, it may take combinations of 4 or 5 drugs to try and keep the virus from growing.

Some people have HIV that has already become resistant to nearly all the drugs that are available. A person with drug-resistant virus can still transmit that virus to others. This means that an increasing number of people who get HIV find that they already have drug-resistant virus, even before they have taken any drugs to treat HIV.

Drug interactions: Another challenge with anti-HIV drugs, especially the protease inhibitors, is that they can interact with other drugs in the body. This means that one or more drugs might not work, or that one might build up to toxic levels in the body. For example, some anti-HIV drugs interact with certain antibiotics, cholesterol-lowering drugs, anti-seizure drugs, birth control pills, erectile drugs, or even other anti-HIV drugs. Each time a new drug is prescribed, your doctor and pharmacist should review all your drugs and supplements to be sure that no harmful interactions are likely. This can complicate treatment of many conditions.

As noted above, ritonavir interacts with many other drugs in ways that can be dangerous. Some treatment regimens exploit this property of ritonavir by using less frequent doses of other protease inhibitors to get the same effect. In cases like this, doses can be often be adjusted, but there are a few drugs that are simply not safe to use with some HIV drugs. This is one of the reasons it is important to keep a list of all your drugs, along with the dose and how often you take them, with you at all times. It also means that if you are taking one of these interacting drugs and stop taking it, you may need to have other drug doses adjusted back to the usual levels.

Side effects: Like all drugs, anti-HIV drugs can have side effects. Short-term side effects show up within a day or a few weeks, depending on the drug. They can range from nausea, vomiting, diarrhea, headaches, and rashes, to severe allergic reactions. Most of these effects only happen to a few people who take the drugs. Luckily, no one has every possible side effect of any drug.

As part of caring for patients on HIV drugs, doctors see the patients and check labs often. They watch for signs of diabetes, high cholesterol, high triglycerides, heart disease, fat redistribution, liver damage, low blood counts, and other effects that may appear or worsen the longer the drugs are given. Because many of the anti-HIV drugs are still fairly new, some of the long-term side effects are still being found. For example, doctors are noticing that some people taking these drugs are more likely to have thinner bones, but it is unclear how much is due to HIV infection and how much to the drugs.

Some drugs may cause certain side effects that may go on even after the drug that caused them is stopped. In rare cases, side effects may be serious enough that the person may need time in the hospital, and there have even been a few deaths.

Each drug carries some risk for certain side effects, which needs to be discussed with your doctor before you start. Ask your doctor or nurse what you can do to reduce your risk of side effects. Find out which side effects need to be reported right away and what to do if you should have these problems after office hours or on weekends. Some side effects and problems are typical of each drug class:

The NRTIs can cause acidosis of the blood, which is a serious chemical imbalance, in a few people. Acidosis can make you feel very weak and short of breath. It is rare, but if you have these kinds of symptoms, go to an emergency room right away. A blood test can show if you have acidosis. NRTIs can cause fatty changes in the liver, usually after 6 months or more. They can also cause lipodystrophy, in which body fat builds up on the chest and belly and is lost from the arms and legs. These drugs can lower blood counts and can cause fatigue, nausea, anemia, headaches, and other symptoms in some people. AZT causes the most problems with blood counts, although only in some patients.

Abacavir is also known for causing a type of allergic reaction that can damage organs in certain people. Now, doctors can test for this reaction before this drug is even started. Most people find out which side effects (if any) they will have after they start taking the drug.

The NNRTIs can cause rashes and allergic reactions, and may interact with some other drugs. They can also lead to liver damage, which is usually found through blood tests but is rarely a serious problem. The NNRTIs can also affect mood, thinking, and sleep patterns. One drug in this class, efavirenz, can cause birth defects if it is taken by pregnant women.

The PIs can also cause body fat to redistribute in the body (lipodystrophy). Over the long term, they can raise blood levels of cholesterol and triglycerides and increase risk of heart attacks or strokes. They can raise blood sugar and even cause diabetes in some people. Cholesterol and blood sugar levels are checked while a patient is on these drugs, and some people may require treatment if there are problems. You may be able to reduce the risk of heart problems by avoiding tobacco, eating healthy, and staying active. The PIs also can interact with other drugs.

Entry inhibitors can cause serious rashes and allergic reactions with fevers, chills, trouble breathing, and faintness or dizziness. Maraviroc can cause liver damage in some people, with symptoms like jaundice (yellowing of the skin or eyes). Because enfuvirtide is injected, people can get irritations or infections at the injection site.

Integrase inhibitors can cause milder symptoms such as nausea, headache, fever, and diarrhea. A few people develop a serious problem that shows up with muscle pain, weakness, and dark colored urine. This must be treated right away.

Cost: Combination treatment can be costly (often more than $17,000 per person per year for the drugs alone, not counting labs and doctor visits). Contact your health plan, and talk with your doctor about what you can afford or what insurance will pay.

Guiding principles of treatment

In 1997, the Office of AIDS Research of the National Institutes of Health (NIH) brought together a panel of experts to discuss the advances in basic HIV research, treatment research, and testing in order to give the best information to doctors and patients. The final report presented the following principles that have guided treatment for more than a decade. They are summarized here because they offer important information about HIV and its treatment:

• HIV infection is always harmful, and true long-term survival without serious loss of immune function is unusual. When HIV continues to reproduce, it damages the immune system and leads to AIDS.
• Regular viral load tests and T helper cell counts are required to find out when to start or change anti-HIV therapy and to find out if the effects of infection are likely to get worse.
• The time to start HIV treatment should be based on viral load and T helper cell count as well as other factors, which vary with each patient.
• The goal of treatment is to keep HIV from growing, so that it stays below levels that can be detected by viral load tests.
• The anti-HIV drugs used in combination must be carefully chosen and given together.
• Each anti-HIV drug in the combination should always be used according to the schedules and dosages that work best.
• Any change in a person's anti-HIV treatment reduces future treatment options.
• Women should receive effective anti-HIV therapy even when pregnant.
• The principles of anti-HIV therapy presented above apply to both HIV-infected children and adults, although the treatment of HIV-positive children involves unique considerations.
• People with acute (primary) HIV infection may also be helped by combination anti-HIV therapy to decrease the virus load to undetectable levels.
• All people infected with HIV, even those with viral loads below detectable levels, should avoid sexual and drug-use behaviors linked to giving or getting HIV and other infections.

Treatment follow-up

Your doctor will check your blood counts, your T helper cell counts, measure the viral load in your blood, and watch your health while you are on anti-HIV drugs. At some point, your viral load may begin to creep up after it has been down for a while. This can happen quickly if you miss doses. It can also mean the virus is growing resistant to one or more of the drugs you are on, and your doctor may test your blood to see which other drugs might work for you. Most people will need to change drug regimens at some point, but staying on schedule can make them last longer.

Can I stop my anti-HIV drugs?

Many people would like to sometimes stop anti-HIV treatment and just take a break. Some people who do this can get worse very quickly, especially if they already have AIDS or very poor immune function. Most doctors do not recommend stopping treatment, except in a few limited cases (like after a woman takes it during pregnancy, if she only did it to reduce her infant's risk). There are times, such as if you need surgery, that you won't be able to take your medicines for a few days. These interruptions should be very short, and your doctor should plan with you about when and for how long you are stopping.

It is important that people getting treatment stick closely to their drug schedule. Missing doses of drugs lets the virus to grow back very quickly, and increases the risk of drug resistance. Stopping one anti-HIV drug while taking the others may allow the virus to quickly develop resistance to the other drugs. (See the information on "Drug resistance" above.) If you are having problems with the regimen, talk to your doctor and find out if an easier one can be worked out before you stop taking your drugs. If you are having a reaction to one of your drugs, contact your doctor right away to find out how to safely manage it. With a serious reaction, all of your drugs may need to be stopped at once, but your doctor can help you get on a different combination quickly.