What is Trizivir

• Trizivir is an anti-HIV medication. It is in a category of HIV medicines called nucleoside reverse transcriptase inhibitors (NRTIs). Trizivir prevents HIV from entering the nucleus of healthy T-cells. This prevents the cells from producing new virus and decreases the amount of virus in the body.

• Trizivir is marketed by GlaxoSmithKline. It was approved by the U.S. Food and Drug Administration (FDA) for use by people living with HIV in 2000.

• Trizivir is a combination of three previously approved drugs: 300mg of Retrovir (AZT), 150mg of Epivir (3TC), and 300mg of Ziagen (abacavir). Trizivir should be prescribed by a healthcare provider for patients who need to take all three drugs. For patients only taking AZT and 3TC, a combination tablet called Combivir is available. Also, any of these three drugs can be purchased individually for use in combination with other anti-HIV drugs.

• As with all the NRTI drugs, the combination of Ziagen, Retrovir plus Epivir works by terminating the growing DNA (gene) chain of HIV as it is tries to reproduce itself. This results in an inability of the viral RNA to replicate and stops HIV from incorporating its genetic material into the genetic material of the human cell. This stops HIV infection at a very early stage of infection.

• When taking regularly as prescribed, Trizivir combination therapy usually leads to a decrease in HIV viral load (RNA) in the blood and an increase in the CD4+ T cell count. The use of Trizivir or its individual component drugs has been associated with decreased rates of AIDS opportunistic infections, improved quality of life and increased survival.

Important Safety Information

Hypersensitivity Reaction (HSR)

TRIZIVIR contains abacavir sulfate, which has been associated with serious and sometimes fatal hypersensitivity reactions. Hypersensitivity to abacavir is a multi-organ clinical syndrome usually characterized by a sign or symptom in 2 or more of the following groups:

	Symptom(s)
Group 1	Fever
Group 2	Rash
Group 3	Nausea, vomiting, diarrhea, or abdominal (stomach area) pain
Group 4	Generally ill feeling, extreme tiredness, or achiness
Group 5	Shortness of breath, cough, or sore throat

• Discontinue TRIZIVIR as soon as a hypersensitivity reaction is suspected. Permanently discontinue TRIZIVIR if hypersensitivity cannot be ruled out, even when other diagnoses are possible

• Following a hypersensitivity reaction to abacavir, NEVER restart TRIZIVIR or any other abacavir-containing product because more severe symptoms can occur within hours and may include life-threatening hypotension and death

• Re-introduction of TRIZIVIR or any other abacavir-containing product, even in patients who have no identified history or unrecognized symptoms of hypersensitivity to abacavir therapy, can result in serious or fatal hypersensitivity reactions. Such reactions can occur within hours

HSR Is Clinically Characterized and Recognizable

• With a median onset of 9 days, symptoms typically appear in the first 6 weeks,* but may occur anytime

• Characterized by symptoms indicating multi-organ/body system involvement

• Symptoms worsen with continued therapy, but often resolve upon discontinuation of abacavir; when HSR is suspected, discontinue therapy with abacavir

• HSR was reported in approximately 8% of patients receiving abacavir BID in 9 recent clinical trials (range 2% to 9%)

• Across GlaxoSmithKline's series of 37 clinical trials with abacavir, the frequency of hypersensitivity reaction was 5.4%

Adverse Events/Toxicity

• Zidovudine has been associated with hematologic toxicity including neutropenia and severe anemia, particularly in patients with advanced HIV disease. Prolonged use of zidovudine has been associated with symptomatic myopathy.

• Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including abacavir, lamivudine, zidovudine, and other antiretrovirals.

TRIZIVIR Tablets are contraindicated in patients with hepatic impairment.

• Severe acute exacerbations of hepatitis B have been reported in patients who are co-infected with hepatitis B virus (HBV) and HIV and have discontinued lamivudine, which is one component of TRIZIVIR. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue TRIZIVIR and are co-infected with HIV and HBV. If appropriate, initiation of anti-hepatitis B therapy may be warranted.

• Hepatic decompensation (some fatal) has occurred in HIV/HCV co-infected patients receiving combination antiretroviral therapy for HIV and interferon with or without ribavirin. Patients receiving interferon with or without ribavirin and TRIZIVIR should be closely monitored for treatment-associated toxicities, especially hepatic decompensation, neutropenia, and anemia. Discontinuation of TRIZIVIR should be considered as medically appropriate.

• Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including TRIZIVIR. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment.

• Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and "cushingoid appearance" have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.

• The most common adverse events (≥5% Grades 2-4) were nausea (19%), headache (13%), malaise and fatigue (12%), nausea and vomiting (10%), hypersensitivity reaction (8%), diarrhea (7%), fever and/or chills (6%), depressive disorders (6%), musculoskeletal pain (5%), skin rashes (5%), ear/nose/throat infections (5%), viral respiratory infections (5%), and anxiety (5%).

Trizivir drug resistance means that HIV is still able to reproduce in a person who is taking the drug. Since Trizivir consists of Ziagen, Retrovir and Epivir, this usually implies multi-drug resistant HIV. However, understanding resistance to Trizivir means first to understand resistance to each drug.

HIV resistance to Ziagen increases with an increasing number of mutations. In abacavir monotherapy trials, point mutations in the reverse transcriptase (RT) developed at positions K65R, L74V, Y115F, and M184V. The M184V and L74V mutations were the most frequently observed in these trials. High-grade Ziagen resistance may result from moderate to high resistance to both Retrovir ("TAMS") and Epivir (M184V), the gene mutations associated with multi-drug resistance ("Q151M" and the 69 insertion) or from a unique mutation such as K65R. Physicians and patients should note that in clinical trials, many patients with prolonged nucleoside analogue exposure or who had HIV-1 isolates with multiple NRTI mutations had a limited response to Ziagen. Some strains of HIV with resistance to Ziagen may also show resistance to Epivir, Videx (didanosine) and Hivid (zalcitabine).

HIV resistance to Retrovir increases with an increasing number of HIV gene mutations. They generally occur in a stepwise accumulation of the mutations. There are five or six more-common ones (occurring at gene codon location numbers 41, 67, 70, 210, 215 and 219) and these are referred to as "thymidine associated mutations" ("TAMS") or "nucleoside associated mutations" ("NAMS"). If two or more are present, a higher level of resistance occurs and this may affect other NRTI drugs, including Zerit. A very high level of resistance occurs when there are four or five of these mutations. Interestingly, low level Retrovir resistance (two mutations) can be reversed by the most common resistance pattern with Epivir ("M184V," see below). Other gene mutations ("Q151M" and the 69 insertion) not only cause high level resistance to Retrovir, but to all the other five marketed NRTI drugs ("multi-drug resistance" also to Epivir, Videx, Zerit, Ziagen).

HIV resistance to Epivir commonly results from the development of the "M184V" mutation (sometimes preceded by a "M184I" mutation) in the gene that codes for ("blueprint of") HIV's "reverse transcriptase" enzyme. This mutation has been shown to reverse low level resistance to Retrovir (i.e., only one or two Retrovir mutations as noted above). There is also some evidence that the HIV strain with the "M184V" mutation is weaker, or less "fit", in its ability to grow or replicate. In fact, when the mutation developed in patients who took Epivir monotherapy years ago, many of them still had a partial suppression of viral load, when compared to baseline. These findings are supported by what happens with patients more recently. In a meta-analysis (combining results) of five different clinical trials with 477 patients taking triple combination therapy that included Epivir, the M184V mutation was present in 92% after 12-48 weeks. Yet, the majority maintained viral load suppression, even with the M184V mutation. Moreover, in another study among patients taking Epivir plus Retrovir for one year and who had the M184V mutation, there was a significantly greater reduction in HIV viral load than among those patients without the mutation. The M184V mutation is not the only one that occurs with Epivir. Other mutations that are also associated with Epivir resistance are the K65R, the 69 insertion, Q151M, and the combination of E44D/A and V118I. However, this information represents newer data, and the significance of these findings needs confirmation in larger studies. Cross-resistance between Epivir and Retrovir usually does not occur (unless the "Q151M" or "69S" mutation is present). The M184V mutation does, however, lead to some cross-resistance with Videx, Hivid, and even Zerit in some patients, although this resistance may not be clinically relevant.