Since the introduction of zidovudine (AZT) in the late 1980s, there have been major advances in the treatment of HIV/AIDS, leading to improved survival among patients. Advances include not only the discovery and development of new medications with activity against the virus, but also a better understanding on how to use these medications.

Using a combination of antiretroviral (ARV) agents with different targets against the virus has become the standard of treatment for HIV. Antiretroviral therapy is often referred to as “highly active antiretroviral therapy” or HAART, which includes a combination of at least three drugs. Currently there are 22 FDA-approved ARV agents that belong to four classes: nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), and entry inhibitors (EIs). In the near future, there will an additional class of ARV agents called the integrase inhibitors, as well as a new type of entry inhibitor.

In general, for patients new to treatment, the classes of medications are combined into two different types of regimens.

1) NNRTI-based (1 NNRTI + 2 NRTI), or

2) PI-based (1-2 PI + 2 NRTI)

The decision to choose between the NNRTI-based regimen or the PI-based regimen is based on many different factors such as presence of HIV resistance, gender, and the presence of other disease states.

Goals of Treatment

Discussing the goals of treatment is important before getting into the details of the medications. Unfortunately, completely eliminating the virus from the human body cannot be done with the available treatments. The virus hides in many cells and compartments of the body that cannot be eliminated even when the virus is suppressed by medication.

Even though the goal of treatment is not to eliminate HIV from the body, the medications are still effective. There are several goals of treatment to keep in mind.

1) reduce HIV-related illnesses and death

2) improve quality of life

3) restore and preserve immune function

4) sustain a suppressed viral load

The best way to achieve these treatment goals (improve immune function and suppress the viral load) is to adhere to the treatment. Taking the medication as prescribed every day is critical for the success of the treatment and to prevent the virus from developing drug resistance. The medications for HIV are very effective if taken appropriately. Poor adherence has been shown to increase the likelihood of failure of the medications and has been associated with increased illnesses and death.

In short, less than perfect adherence leads to the development of drug resistance, limiting the effectiveness of therapy. This is why it is important to determine if the patient is truly ready to start medications. Some of the common reasons for not taking the medications include the size and number of pills, medication toxicities, and food and water requirements.

Who needs treatment?

There are certain patients who should be started on treatment immediately. This includes patients with a history of an AIDS-defining illness or severe symptoms of HIV infection and those patients who have no symptoms with a CD4+ T-cell count that is less than 200. Patients with a T-cell count between 201 and 350 and no symptoms should be offered treatment. Patients with a T-cell count above 350 and an HIV viral load greater than 100,000 copies/mL may wait to start therapy, but some health care providers may be inclined to start therapy. The decision to start therapy for patients with no symptoms is a complex issue and must be discussed between the health care provider and the patient. For those patients with T-cell count above 350 and HIV viral load less 100,000 copies/mL, it is not recommended to start therapy. If the patient has hepatitis or another health problem, therapy may be recommended.

Shouldn’t everybody be on therapy?

Being on treatment has benefits but it can be associated with risks as well. For those patients with no symptoms (based on the criteria listed above), some health care providers may decide to wait to start treatment.

Some of the benefits of waiting to start HIV treatment include

1) avoiding treatment-related side effects

2) saving treatment options for the future

3) delaying development of drug resistance if virus is not suppressed

4) having patients understand the demands of treatment, and

5) decreasing the time the patient is on treatment in order to avoid treatment fatigue

Some of the risks of waiting to start therapy include

1) allowing the virus to continue damaging the immune system

2) the possible increased risk of progression to AIDS, and

3) the possible increased risk of transmission to others
It cannot be emphasized enough that starting treatment in a patient with no symptoms and a CD4 count greater than 350 is a complex issue and must be discussed thoroughly between the health care provider and the patient.

Available Treatments

There are four classes of anti-HIV medications available:

1) the nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs)

2) the non-nucleoside reverse transcriptase inhibitors (NNRTIs)

3) the protease inhibitors (PIs), and

4) the entry inhibitors (EIs)

NRTIs

These were the first antiretroviral agents to be used for the treatment of HIV. These agents chemically are similar to naturally occurring elements of HIV’s DNA. They work by stopping reverse transcriptase, a viral enzyme, which is responsible for copying viral RNA to DNA within the human cell.

The currently approved NRTIs for HIV treatment in the U.S. are AZT (zidovudine, Retrovir), ddI (didanosine, Videx), d4T (stavudine, Zerit), 3TC (lamivudine, Epivir), abacavir (ABC, Ziagen), and FTC (emtricitabine, Emtriva). Tenofovir (Viread) is the first nucleotide (with a “t”), but in many sources is considered to be in the same class as the NRTIs. There are also two-in-one NRTI combinations: Combivir (AZT with 3TC), Epzicom (3TC and abacavir), and Truvada (FTC with tenofovir), plus the three-in-one combo Trizivir (AZT, 3TC, and abacavir).

The NRTIs are considered the “backbone” of treatment and it is recommended to use at least two of them when starting treatment along with either a NNRTI or PI. The four NRTI combination products help improve adherence to HIV therapy by decreasing the number of pills. Both Combivir and Truvada are recommended by the U.S. Department of Health and Human Services (DHHS) HIV treatment guidelines for patients who are new to treatment.

The most common side effects in this class are related to the stomach, including nausea and vomiting. See the guidelines at www.aidsinfo.gov for more information, as well as the Positively Aware annual HIV drug guide, in the January/February issue. It is important to remember that these potential side effects range from mild to severe, with most of the severe side effects rarely occurring. It is important to discuss any side effects with your health care provider. Serious side effects that may occur with some of the NRTIs include pancreatitis, peripheral neuropathy, and lactic acidosis.

NNRTIs

Like NRTIs, these drugs inhibit the viral enzyme reverse transcriptase. However, they structurally bind to reverse transcriptase through a different way, changing its structure to make the enzyme less available. Efavirenz is now available in a combination product that combines three medications into one pill. It combines tenofovir, emtricitabine, and efavirenz together, allowing for one pill to be taken once daily.

Currently the guidelines recommend efavirenz as the preferred NNRTI. This is not the recommended medication for women who are sexually active and may become pregnant (not on birth control), because it can be harmful to an unborn child.

Both nevirapine and efavirenz can cause a rash ranging from mild to a serious life-threatening syndrome. Contact your health care provider if you have a rash of any sort. Also let your health care provider know if you are taking other medications, herbals, or vitamins, because they may affect your medications. Again, see the guidelines or the drug guide for more information.

PIs

The third class of antiretrovirals is called the HIV protease inhibitors (PIs). PIs revolutionized HIV treatment in the mid-1990s and continue to improve survival of patients infected with HIV.

Protease is a viral enzyme responsible for clipping a complex viral protein into functional proteins that are essential for the maturation and assembly of virus particles. Activity of this enzyme is critical for the completion of HIV life cycle.

There are currently 10 PIs approved by the U.S. Food and Drug Administration (FDA) for HIV treatment in the U.S.: saquinavir (Invirase); ritonavir (Norvir); indinavir (Crixivan); nelfinavir (Viracept); amprenavir (Agenerase); lopinavir/ritonavir (Kaletra); atazanavir (Reyataz); fosamprenavir (Lexiva); tipranavir (Aptivus); and most recently darunavir (Prezista). Both tipranavir and darunavir are currently being used in more treatment-experienced patients, not newly diagnosed patients.

Low-dose ritonavir is used to help boost the levels of other PIs in order to get better viral suppression. The ritonavir increases the concentrations of the second PI, allowing for less frequent dosing. The ritonavir dose used to boost the second PI concentration ranges from 100-400 mg daily, which is low dose and cannot be used alone. The combinations of ritonavir with saquinavir, indinavir, fosamprenavir, atazanavir, or lopinavir have been successfully used in both treatment-naïve and experienced patients.

The currently recommended PIs for newly diagnosed patients by the guidelines include Reyataz + Norvir or Lexiva + Norvir twice daily, or Kaletra twice daily. These were selected because of their potency, barrier to resistance, convenience, and tolerability.

Protease inhibitors can have many drug interactions with other medications (non-HIV medications, herbals, etc.), some of which can be very dangerous, so it important to tell your health care provider every medication you are taking. The side effects related to this class of medications are most commonly involving the stomach including nausea, vomiting, and diarrhea. Diarrhea can be managed by taking either calcium supplements or taking anti-diarrhea medication (such as loperamide).

Also, PIs can cause increased cholesterol, so it is important to have your cholesterol checked prior to starting these medications and during treatment. PIs have also been associated with increased blood sugars and changes in fat distribution. It is important to discuss these effects with your health care provider. Luckily the increased cholesterol can be treated with many common cholesterol medications but again, it is important to discuss with your health care provider.

Again, see the guidelines or the drug guide for more in-depth information, including a look at each drug individually.

EIs

Enfuvirtide (Fuzeon) is the first in a new class of drugs called entry inhibitors. These agents block the joining of HIV with the human cell before the virus enters it and begins the copying process. Enfuvirtide is indicated for use in combination with other antiretroviral agents in treatment-experienced patients who continue to have evidence of a high viral load even when on antiretroviral therapy (because they have drug resistance). Unlike other antiretrovirals, enfuvirtide is administered by injection under the skin. The dose is 90 mg (1 mL) twice daily injected into the upper arm, thigh, or abdomen. The most common side effects in studies were local injection site reactions that were described as painful, swollen, or harden cysts.

Summary

HIV medications and treatment strategies have improved tremendously since the 1980s. The medications are very effective in suppressing the virus if taken correctly and taken everyday. It is important to keep in mind the goals of treatment, such as lengthening survival and improving quality of life, when faced with challenges related to medications. The medications may have side effects but it is important to remember that many of the side effects are mild and can be managed by supportive medications. Some of the long-term side effects can be managed by other medications as well as a healthy lifestyle and close monitoring by your health care provider. HIV treatment is a great luxury in this world, so learn to use it wisely and enjoy its benefits!

Rupali Jain, Pharm.D., BCPS, is an HIV specialist at the University of Washington Medical Center, Seattle, Washington.

References:
1. Jain R, Clark NM, Diaz-Linares M, Grim S. Limitations of Current Antiretroviral Agents and Opportunities for Development, Curr Pharm Des 2006, Volume 12: Issue 36
2. Department of Health and Human Services, Guidelines for Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents; October 10, 2006.