Also see parts one, two and three.
Although 18 approved medications are now available to treat HIV infection, the process of deciding how best to use them has become complex. Making decisions about whether or when to start HIV treatment -- and which drug combinations will work best for you -- presents complex challenges for both a person living with HIV and health care providers. Because there is now so much information to absorb and interpret, communication and an open mind will be the keys to a successful treatment regimen. A critical first step is to learn all that you can about the antiretroviral (ARV) drugs that are available today, and even about the ones that are likely to gain FDA approval in the near future.
Another important lesson to learn early on is that there is no cookie-cutter approach to selecting an ARV regimen. In other words, there is no right or wrong approach; you and your physician together need to select the treatment that will work best for you as an individual. Two key factors will help determine when to start therapy and which medications to use:
Your physical health -- meaning your viral load (VL), T-cell count, how you feel, and any conditions besides HIV
Your willingness and ability to take all of your HIV medications according to the instructions provided by your doctor and pharmacist
Routine blood tests for your viral load and T-cell count can help determine how healthy your immune system is and when you should start or switch therapy. The T-cell count may be the most critical factor to consider in deciding when to start treatment, because it provides a strong indication of how much damage HIV has caused to the immune system.
Viral load plays a less critical role in deciding when to start treatment, but it can still provide vital information for some people who have not yet started treatment. For example, if your T-cell count is 250 and your viral load is over 100,000, your T-cell count could fall below 200 before it is measured again three to six months later. This is because the higher a person's viral load is, the faster the T-cell count is likely to decline. A high viral load could mean that the T-cell count will continue downward and should be playing a role in deciding whether to start treatment.
Two major medical organizations regularly issue treatment guidelines that make general recommendations about when people living with HIV should start or switch anti-HIV therapy. One is the federal agency that is responsible for setting U.S. health-related policies, National Institutes of Health (www.aidsinfo.nih.gov/guidelines/). The other is an association of leading professionals specializing in HIV research and treatment, the International AIDS Society-USA (IAS-USA, www.iasusa.org/pub/index.html).
The two sets of guidelines make somewhat different recommendations about when to start ARV therapy. However, both guidelines strongly urge therapy for people who have AIDS-related symptoms or a T-cell count between 200 and 350. Research indicates that individuals who begin ARV treatment after their T-cell counts have fallen below 200 may experience a less successful treatment course than those who begin when their T-cell counts are higher than 200.
A matter that is still controversial is whether to start ARV therapy "early," which currently is considered to be having a T-cell count higher than 350. Some experts prefer to start therapy early, before the T-cell count shows that the immune system has been seriously compromised. Others believe that starting therapy early will not produce better results and that therapy should wait until the T-cell count has fallen below 350, though not below 200.
Once you and your doctor have decided that it is time to start therapy, you'll need to make equally difficult decisions about what combination of medications will work best for you. Both the IAS-USA and the federal guidelines agree that, whatever initial ARV regimen you decide on, therapy should aim to decrease viral load to the lowest level possible -- that is, undetectable as determined by viral load testing -- for as long as possible. This means that you should select the strongest ARV drug combination that suits your clinical condition and lifestyle needs.
Besides T-cell count and VL, certain non-HIV issues play important roles in determining an ARV regimen that will be effective and that you can adhere to over the long haul. Be sure to discuss with your health care provider:
Any dietary restrictions
Limitations related to your daily routine (work, school, children, and so on)
Your support system of family and friends
Other medications you need to take
An ARV drug regimen should consist of at least three drugs, usually from at least two of the four different classes of ARV drugs:
Protease inhibitors (PIs)
Nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs)
Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
Above all, it is important that you understand exactly how and when you should take the combination of drugs you select. Here are some key questions that you should clarify with your physician:
Should you take your pills with food or on an empty stomach?
How many times a day should you take each drug?
What should you do if you miss a dose?
What should you do if you don't feel well when starting therapy?
Make sure you know the answers to these questions before starting your regimen. Fortunately, ARV regimens do not have to be difficult to take. For example, some HIV drugs need to be taken only once a day, and at least one combination involves taking just three pills, once a day (Viread, Videx-EC, and Sustiva).
What to Expect After Starting Treatment
After a person begins anti-HIV therapy, his or her viral load (VL) should drop dramatically. After two weeks of treatment, VL typically drops at least 90%. For example, a starting VL of 100,000 should drop to 10,000 or less within two weeks. (By the eighth week, the viral load should have dropped even more, with the goal being to go below the level of the viral load test's ability to detect any viral particles. That is, the VL should become undetectable.) For someone with a very high viral load, up to 16 weeks may pass before the VL becomes undetectable. Many physicians still use the VL test in which undetectable means fewer than 400 copies of HIV. However, more and more doctors prefer to use the ultrasensitive tests that can detect as few as 50, or even 20, copies. In many, if not most, cases, the T-cell count will likely increase by 100-200 cells during the first 12 to 18 months of treatment.
To make sure your VL remains undetectable, you will need to visit your doctor's office every three to six months to have it checked. An increase in VL during ARV treatment could mean that drug resistance has developed. You should also be sure that your doctor's lab always uses the same type of VL test. This is because there are two different types of test, and test results from the different types should not be compared directly. Even when the same type of test is used regularly, you and your doctor need to interpret any changes in VL. The VL needs to change by at least a factor of three (3 times) before the change is considered meaningful. For example, an increase from 10,000 to 25,000 copies may be due only to the sensitivity of the test and may not reflect an actual change in viral load. A T-cell count should also be performed at the same time as the VL test.
Even if you are not due to have another set of lab tests done, do not hesitate to discuss with your provider any problems that you are having with your ARV regimen. If you find that you have trouble taking every dose on time or are experiencing side effects, you and your doctor may be able to find a different combination that is easier to take or has fewer side effects. Doing this sooner rather than later is crucial. Having a regimen that you can adhere to for the long run will help the treatment work best. Strict adherence to your treatment regimen will mean that resistance will take a longer time to develop and you won't have to consider new treatment regimens so soon.
When a Regimen Fails
In spite of best efforts to adhere to an HIV treatment regimen, nearly everyone with HIV will at some point need to switch to a different regimen. This can happen for several reasons:
Viral load begins to climb
The T-cell count consistently declines
HIV-related illness occurs
Side effects worsen
Occurrence of any of these developments is called "treatment failure," which is a more harsh-sounding term that it really is. Treatment failure basically means that the anti-HIV drugs you are currently taking are no longer doing what they should. The key tool for determining whether treatment failure has occurred is a VL test to check for the amount of virus in your blood. If your viral load does not decrease significantly and stay down while you are using highly active antiretroviral therapy (HAART), your T-cell count could decrease and you could be at risk for symptoms of HIV disease progression.
If any of the following occurs, your ARV treatment may not be working the way it should:
If your viral load does not decrease by 90% within eight weeks after starting therapy.
If your viral load does not become undetectable within 16 weeks after starting HAART.
If a VL that had been undetectable becomes detectable, the test should be done again. This is to be sure that the increase was not due to an error or is not just a temporary blip. If the second test confirms the results of the first, you should discuss with your doctor whether you need to consider switching therapies.
If your viral load increases significantly, most specialists would recommend a change in treatment. This is because a VL that is increasing while you stick with the same regimen can mean that your HIV is becoming increasingly resistant.
If your T-cell count drops significantly or if it drops continuously, your ARV therapy may not be working well enough.
HIV can stop responding to HAART for a number of reasons, but the good news is that you and your health care provider can control some of these:
For some people with high viral loads before starting therapy -- for example, more than 1 million copies -- VL may not become undetectable using a three-drug combination. Some specialists prescribe four or more drugs to control very high viral loads.
Poor drug absorption can also lead to treatment failure. Absorption refers to the amount of drug that is absorbed into the bloodstream after being swallowed or injected. Regular vomiting or diarrhea due to ARV medications or other reasons may affect the amount of drug that remains in the system to get absorbed. Not following dietary requirements carefully can also affect the amount of drug that is absorbed by the body. Some drugs must be taken either on an empty stomach or with food. Be sure to ask your doctor to explain any food or liquid restrictions required for each drug in your regimen -- and discuss any nausea, vomiting, or diarrhea you are experiencing.
Drug-drug interactions can affect the levels of drug in the body. This can prevent the drug from working well enough or can cause adverse reaction. Drug interactions can occur from ARV drugs in combination with other medications you may be taking -- such as, painkillers, antifungal drugs, birth-control pills, or antibiotics. Tell your doctor about all medications you are taking -- both prescription and over-the-counter -- before starting ARV therapy, and from then on.
Not adhering exactly to the directions for taking each drug in your regimen can be a major cause of the ineffectiveness of ARV drugs. However, this is one problem over which you can have a lot of control. If you are missing doses of your anti-HIV drugs or do not clearly understand how you need to take them, discuss this with your doctor immediately.
Drug resistance -- which refers to the tiny changes, or mutations, in HIV's genetic structure that can make the virus less sensitive to ARV drugs -- is one of the most common and serious reasons for treatment failure. Some of the things that can contribute to the development of drug resistance include the factors listed above, so understanding what resistance is and how it can be avoided is important.
Dealing With Side Effects
If you started HAART recently and are experiencing a major side effect, like serious or persistent diarrhea, feel free to talk with your doctor about switching the drug that is causing the problem for one that offers the same strength but with fewer or more tolerable side effects. Your health care provider may also suggest things you can do to help control problems like diarrhea, without having to switch to a different HIV medication.
Of course, people who have been taking HAART for some time and have an undetectable viral load can also experience serious side effects. Perhaps the best-known example of this is lipodystrophy, which many researchers believe is due at least in part to ARV therapy. Lipodystrophy refers to body-shape changes and increased levels of fats (triglycerides and cholesterol) and sugar in the blood.
Furthermore, high cholesterol or triglycerides in an HIV-positive person can be treated according to the guidelines for the general population published by the National Cholesterol Education Project (www.nhlbi.nih.gov/about/ncep/index.htm). Be sure to discuss with your doctor any changes in body shape that you feel you are experiencing -- and make sure to have a regular blood lipid screening performed.
Dealing With Resistance Problems
The primary reason that HIV becomes resistant is the mistakes that the virus makes as it replicates. Because HIV replicates very rapidly, it makes many mistakes, leading to mutations in the virus's genetic code. These mutations then cause anti-HIV medications to work less and less well. Therefore, holding down replication is the key to limiting the development of resistance.
A number of HIV mutations caused by treatment with one drug can cause your HIV to become resistant to other drugs in the same class as the one that led to that particular mutation. This is called cross-resistance, and it poses one of the biggest hurdles in switching ARV regimens. Cross-resistance is most difficult among PIs and NNRTIs. For example, if your HIV has become resistant to Sustiva (efavirenz), it is likely also fairly resistant to Viramune (nevirapine).
Both the federal and IAS-USA guidelines support the use of drug-resistance testing in these situations:
When viral load becomes detectable (to more than 1,000 copies) while on ARV therapy
When VL fails to become undetectable within about 16 weeks of starting a new ARV regimen
Not all insurance companies, Medicaid programs, and other third-party payers cover the high costs of resistance tests. This may eventually change, because both guidelines now officially recommend using them. If your viral load is increasing while on therapy, ask your doctor about having an HIV drug-resistance test. If your doctor can prove that it is medically necessary, your third-party payer may agree to cover the cost.
Deciding What to Switch To
Like figuring out when to start therapy and what drugs to start with, deciding when to switch therapies and what drugs to switch to is a complex process. The choices of ARV regimens available to you will depend on which drugs you are now taking and those you have used in the past. This is because of the resistance patterns that your HIV might have developed to either specific drugs or whole classes of drugs.
You and your physician should consider the following federal guidelines when selecting a different treatment regimen:
If your viral load becomes detectable while taking your current ARV drug regimen, you should have a second VL test to confirm the results. A VL can show a one-time blip that will disappear with a second test.
In most cases, just switching one drug or just adding one drug to a failing regimen is not advisable. The best approach is to use at least two new drugs or, preferably, an entirely new combination. If a drug-resistance test shows that your HIV is resistant to only one drug in your regimen, it may be possible to replace only that drug.
Among the PIs, avoid switching from Norvir (ritonavir) to Crixivan (indinavir) or vice versa, as high-level cross-resistance is likely.
Among the NNRTIs, switching from one NNRTI (like Sustiva) to another (like Viramune) to control viral load is not likely to work because of cross-resistance between the two.
People who have extensive treatment experience -- meaning they have used most of the approved HIV medications -- have special problems in switching ARV regimens. Treatment strategies for such individuals are often referred to as salvage therapy.
One possible approach is to "recycle" drugs that you have used in previous ARV regimens. Drugs that you stopped using for reasons other than development of resistance (due, for example, to side effects) may be the best candidates for recycling. Recycling drugs to which you are resistant is much less likely to help. Before doing so, discuss with your doctor the possibility of performing an appropriate resistance test to see if you may be able to recycle any of the drugs you have used before. If you and your doctor agree on a combination of drugs to which your HIV has only low-level resistance, this type of salvage treatment may be able to reduce your VL to a low level again.
Another option is "mega-HAART," a strategy that uses a combination of up to nine anti-HIV drugs. The idea behind this approach is that, no matter how many drugs and drug combinations a person has taken, the virus in his or her body is not likely to be resistant to all of the drugs in such a complex regimen. Of course, adherence and side effects will pose serious difficulties with this strategy.
Treatment intensification is another form of salvage therapy. Intensification means adding one or two additional drugs to an existing regimen. It does not mean increasing the dose of any of the drugs in your regimen. This might be an option for people who are unable to achieve an undetectable viral load within four to six months after starting therapy. Intensification may also work for someone who has been on HAART with an undetectable VL, but whose VL has recently become detectable again.
To intensify a regimen, your doctor can prescribe a fourth anti-HIV drug, often the protease inhibitor Norvir (ritonavir). Although ritonavir can have undesirable interactions with a number of other medications, it can also raise the blood levels of other PIs and some NNRTIs. These increased levels can help put additional pressure on the virus, with the goal of reducing it to an undetectable level.
Continuing With a "Failing" Regimen
Sometimes people on HAART may experience a VL that becomes detectable, while their T-cell counts remain relatively high or even increase. If you are in this situation, your provider may recommend continuing on your current regimen, particularly if you have already used most of the available anti-HIV drugs. This strategy may be most appropriate for those with a high T-cell count and no symptoms of HIV progression. Other specialists feel that continuing on a failing regimen, with an increasing viral load, could cause your HIV to become even more resistant to other drugs, even ones that have not yet been approved.
Some newly approved HIV medications and others that are expected to be approved this year should offer improved treatment choices for many HIV-positive people, both those deciding when to start therapy and those needing to switch ARV regimens:
Zerit XR: This once-a-day extended-release formulation of Zerit received FDA approval early this year.
Fuzeon: This first drug in the new class of ARV treatments known as fusion inhibitors was approved by the FDA in early March.
Atazanavir: By the middle of 2003, most observers expect this protease inhibitor to be approved. One expected advantage is that atazanavir does not cause adverse effects in blood lipids.
fos-Amprenavir (908): A reformulated version of this protease inhibitor will likely receive approval later this year. (see "A Different Class")
Helping to Chart Your Treatment Course
HIV treatment will probably never become a truly simple matter. However, you can take a number of measures to help direct the course and success of your HIV treatment:
Learn as much as you can about current and future HIV treatments and how they work.
Communicate openly and regularly with all your health care providers and your personal support network.
Do all that you can to adhere strictly to the requirements of your anti-HIV treatment regimen.
In the foreseeable future, drugs that are simpler to take and drugs that do not have the same resistance patterns as the current ones will become available. Doing all that you can today will leave you in a stronger position to benefit from these upcoming developments.
Steve McGuire is a Chicago-based writer and consultant specializing in medicine, public policy, and nonprofit issues. He can be reached at: email@example.com.
What About Logs?
Log is short for "logarithm," which is a mathematical term used to describe a change by a factor of 10 (that is, "times 10") in the quantity of whatever is being measured. Put another way, logs are a shorthand way to express a very large number. A log is the number of times 10 must be multiplied by itself to equal a certain number.
In relation to HIV, logs are sometimes used to state a patient's total viral load. For example, a viral load of 100,000 is log5 because it equals to 10 x 10 x 10 x 10 x 10.
Most people with HIV, however, have read or heard "log" used as the way to state how much their viral load has gone up or down. For example, if the baseline viral load is 20,000 copies/ml plasma, then a 1-log increase equals a 10-fold (10 times) increase, or 200,000 copies/ml. A 2-log increase equals 2,000,000 copies/mL plasma, or a 100-fold increase. As another example, a reduction in viral load from 100,000 to 1,000 copies/ml is a 2-log (or 99 percent) reduction. However, a half-log (0.5 log) change is not a five-fold difference, but a change of 3.16-fold.
Understanding Resistance Tests
Genotype TestsIf highly active antiretroviral therapy (HAART) is no longer working well for a patient, genotypic resistance testing helps medical providers make decisions about switching to a different therapy. It does this by identifying which drug or drugs in a HAART cocktail the patient's HIV has become resistant to. Genotype tests look for specific changes, called mutations, in the genetic code of an individual's HIV that are known to be associated with resistance to particular antiretroviral drugs. A genotype test will determine the genetic code of a person's HIV by examining a sample of the virus from the patient's blood to identify any mutations in the virus. HIV that does not have any mutations is called wild type virus, which is the most common form of HIV. This usually means that antiretroviral drugs can still work against the virus.
Phenotype TestsPhenotype tests aim to see how an individual patient's HIV actually responds when it is exposed to specific antiretroviral medications. Technicians grow a sample of a patient's HIV in the lab and then expose the virus to different antiretroviral medications. The phenotype test will determine if the virus grows slower or faster when each drug is present. If the HIV sample grows faster, the virus is more "resistant" to that drug. If the sample of virus grows slower, the virus is considered "susceptible" to the medication. This means the medicine will still work for that patient.