Starting Anti-HIV Therapy

Deciding when to start anti-HIV therapy and what treatments to start with can leave many people feeling overwhelmed with choices. The discussion following, however, will demonstrate that the choices may be fewer and simpler than they appear at first. Charting your course of therapy options up front, outlining what therapies you will start with when you're ready and what you will switch to if that option doesn't work out, is the hallmark of long-term planning. You can then proceed to the next combination with confidence rather than being overwhelmed by the fact that your first choice didn't work out as you had expected.

Most strategic decision-making processes begin by formulating a list of questions to consider. Some of the answers can only come from you; others your doctor can help answer. Several important questions about starting anti-HIV therapy are included here.

When to Start

Periodically the Federal Guidelines committee (comprised of researchers, doctors, people living with HIV and their advocates) updates a set of guidelines for the use of anti-HIV medications. Often referred to as the "Federal Guidelines" or simply the "Guidelines," the excerpts presented in the chart below are for adults and adolescents starting anti-HIV treatment.

Starting Anti-HIV Therapy in Women and Women Who Are Pregnant

The basic Guidelines for when to start therapy are largely the same for women who are pregnant or trying to get pregnant as for other adults. If a woman is pregnant and has a low CD4+ cell count and a high viral load, she must make decisions about protecting her health as well as the health of her developing baby. Some doctors recommend that women wait to begin treatment until the second trimester (13th week of pregnancy). The first trimester (first 12 weeks of pregnancy) is when the baby's major organs are developing and the potential for birth defects from medications are most likely to occur during this period. Some anti-HIV medications should NOT be taken during pregnancy. For a more thorough discussion, read Project Inform's publication, "Pregnancy and HIV."

Some anti-HIV drugs interact with oral contraceptives (i.e., The Pill). More detailed information on these interactions may be found in Project Inform's publication, "Drug Interactions." It may be necessary to adjust the dose of the contraceptives or use other methods for birth control.

What Is the Best Combination for People Starting Anti-HIV Therapy?

The question of what combination of anti-HIV drugs a person should use as first-line therapy can appear confusing at first. There are, however, only a few factors to consider and these effectively narrow the range of choices for first-line therapy. These include:

• the potency of the combination,

• the ease of use and number of pills, and

• the potential for short- and long-term side effects.

If you have determined that you are ready to start anti-HIV therapy, there are some clear guidelines that can help you make an informed decision about which medications to use.

Remember the Goals of Anti-HIV Therapy

An effective combination should lower your viral load as low as possible (preferably to undetectable), and increase your CD4+ cell count, without causing debilitating side effects or negatively affecting your quality of life. It should also be easy enough to take, given your schedule, that you are able to take every dose as prescribed (i.e., adhere well). The issue of adherence to medications cannot be stressed enough. A number of different studies have found that an inability to maintain a high level of adherence is the most common reason that a combination stops working. Project Inform's publication, "Adherence: Keeping Up With Your Meds," can help you prepare for and maintain good adherence.

There are four different classes of anti-HIV drugs approved for use. These are:

1. Nucleoside Analog Reverse Transcriptase Inhibitors (NRTIs) and Nucleotide Analog Reverse Transcriptase Inhibitors (NtRTIs)

2. Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

3. Protease Inhibitors, sometimes called PIs; and,

4. Entry Inhibitors

The November 2003 Federal Guidelines list the following two combinations as "preferred" first-line regimens, because they are believed to have good potency and are easy to take:

• Combivir + efavirenz (d4T + 3TC or tenofovir + 3TC may be used in place of Combivir).

• Combivir + Kaletra (d4T + 3TC may be used in place of Combivir).

The Guidelines also list more than a dozen other alternative combinations that may be less potent, carry a somewhat higher side effect profile, have to be taken more often or that require taking more pills.

Not all "alternative" combinations, however, are equal. In fact, several are likely to be better than others and may be nearly equal to the "preferred" regimens. These include using:

• nevirapine instead of efavirenz;

• FTC instead of 3TC;

• atazanavir instead of Kaletra; and

• other ritonavir-boosted protease inhibitors instead of Kaletra.

Nucleoside Analog Reverse Transcriptase Inhibitors (NRTIs) and Nucleotide Analog Reverse Transcriptase Inhibitors (NtRTIs)

NRTIs are almost always used as part of anti-HIV regimens. Usually two NRTIs are combined with another class of drugs. Sometimes three NRTIs are used together as a complete first-line combination. Although there are a number of different drugs in this class, there are few combinations that are considered for first-line treatment. This is because most of the drugs other than AZT, 3TC, d4T and tenofovir are either seen as less potent, have too many side effects or are difficult to use. Even with d4T, there are growing concerns about its potential for causing long-term side effects.

FTC is a newly approved drug, likely to be interchangeable with 3TC. Tenofovir is also a newer drug. Since it works against most NRTI resistant virus, some recommend saving it for use in second- and third-line combinations.

Trizivir (AZT + 3TC + ABV) is the only approved triple nucleoside combination available in one pill. This combination can be taken alone, without combining it with drugs of any other class. There is concern, however, that Trizivir may not be as potent for first-line therapy as other combinations, particularly in people whose viral load is very high (more than 100,000). Since future combinations may depend on at least one or two of these three drugs in order to work effectively, using Trizivir as first-line therapy can significantly impact future available options. For these reasons, Trizivir may only be an appropriate first-line option in situations where a person requires an extremely simple regimen or cannot tolerate NNRTIs or PIs.

Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

As part of first-line therapy, NNRTIs are invariably used in combination with two NRTI drugs. Efavirenz-based combinations have consistently proven both potent and durable when compared to a number of other combinations. Efavirenz has been selected by the Federal Guidelines panel as a preferred drug for first-line therapy.

While the Guidelines recommend efavirenz over nevirapine, there are occasions where nevirapine may be a more attractive choice. This is particularly true for people who wish to save protease inhibitors for later, but who are concerned about the neurological (brain-related) side effects of efavirenz. Pregnant women and women trying to get pregnant should avoid efavirenz and may consider nevirapine a better option. Women in general shouldn't feel a particular benefit to choosing nevirapine over efavirenz, but women who are pregnant or trying to conceive need to be aware of the risks of efavirenz use during pregnancy.

All of the NNRTIs are highly cross resistant with one another, meaning that when the virus becomes resistant to one it will likely be resistant to the others, making them less useful. Of the three drugs in this class, delavirdine is used least often. This is because it must be taken three times per day and has interactions with a number of other medications.

Protease Inhibitors (PIs)

Kaletra (lopinavir + ritonavir) was likely selected as a preferred drug as it is a potent drug and simple to take. Atazanavir also appears to be potent, when boosted with ritonavir. It has some of the lowest potential for side effects of all the PIs and as a once-a-day drug it is easy to use.

Other protease inhibitor combinations may be used as first-line therapy, but most require that a low dose of ritonavir be added as a booster so that they become more potent and are able to be taken less frequently and at lower doses. Aside from Kaletra, other ritonavir-boosted PIs have not been well studied for first-line therapy use.

Entry Inhibitors (EIs)

Although enfuvirtide has many positive attributes, it is not able to be taken in pill form and has to be given through injection. For this reason, it is unlikely that enfuvirtide will ever be considered a desirable first-line therapy and it is currently approved for use only in situations where other combinations have already failed.

What to Start First: NNRTIs, Protease Inhibitors or Neither?

Researchers have reported on dozens of different first-line treatment regimens, but no large study has been completed that demonstrates which is best to start with. We know that when viral load remains under 50 for at least one year on therapy, virus will usually remain suppressed for at least another two years, assuming good adherence. Combinations containing efavirenz or Kaletra have been most likely to achieve this result in studies.

Some data show that when a person starts anti-HIV therapy using a protease inhibitor, they will likely be able to use efavirenz successfully as second-line therapy. There are less data on the reverse scenario. There are even fewer data showing the long-term therapy implications of starting a combination with three NRTIs together, like Trizivir. Developing a longer-term treatment strategy requires weighing the theoretical risks and benefits.

When a person's virus develops a high level of resistance to one drug in a specific class, it will generally have at least some resistance to the other drugs in that class. This is called cross resistance. When resistance occurs, it causes the drug to be less potent. Thus, even with more than twenty approved drugs, it is only possible to come up with two or possibly three highly potent combinations in a row.

Some believe that the best first-line strategy is to take whatever is most potent. Studies so far indicate that the most powerful and durable effects come from a person's first combination. The longer a person can stay on his or her first combination without significant side effects or resistance developing, the better. If a person can go five years or longer, the hope is that more new drugs will have been approved in the meantime, which will allow a greater number of second- and third-line therapy options. Kaletra is considered the most potent and durable first-line anti-HIV medication.

Others feel that saving potent and longer lasting medications for second-line therapy is the better strategy. Starting with a combination containing an NNRTI or only NRTIs is likely to work well for many people and spares protease inhibitors for later. It is hoped that the NNRTI and NRTIs will have fewer long-term side effects. The theory has merit, but there are no studies to prove that this is the superior long-term strategy.

Whichever choice you make, it's probably wisest to have a good fall-back strategy if your first combination doesn't work as well as you hoped. Decide in advance what your definition of treatment failure is and what your next combination will be.

Your doctor may have strong opinions about when to start therapy or which combination they think will be best for you. Your opinion and your concerns count too. Share them with your doctor so that he or she can help you build the best treatment strategy for you. Project Inform's publication, "Building a Cooperative Doctor/Patient Relationship," offers a number of tips for building a relationship with your doctor that works best for you.

Because it is your life and your body that will be affected, only you can ultimately decide how you wish to balance the need to keep your virus in control with potential risks for HIV disease progression and side effects of medications. Remember to ask questions: of yourself, your doctor, other people living with HIV and information sources like Project Inform. Take your time, be prepared and then enjoy life to the fullest, knowing you have made the best decision you possible could have.

Back to the Project Inform Perspective January 2004 contents page.