Continuing Education for Pharmacy Technicians

Continuing Education for Pharmacy Technicians HIV/AIDS TREATMENT Michael Denaburg, Pharm.D. Birmingham, AL Objectives: 1. Identify drugs and drug classes currently used in the management of HIV infected patients. 2. Identify appropriate dosing, storage conditions, and major adverse effects of commonly used HIV medications. 3. Identify preferred drugs used in the treatment of naïve HIV infected patients. INTRODUCTION HIV is the human immunodeficiency virus that can lead to acquired immune deficiency syndrome or AIDS. 1 There are two types of HIV: HIV-1 and HIV-2. Both types destroy specific cells called CD4+ T cells. 1 CD4+ T-cells are used by the body s immune system to help fight diseases. 1 HIV symptoms begin within a few weeks after becoming infected with the virus. Patients can experience flu-like symptoms or no symptoms at all. 1 People living with HIV may appear to be healthy for several years; however, HIV is still affecting them. Even though patients might feel healthy, they can still benefit from medications used to treat HIV. 1 These medications can limit or slow down the damage to the immune system and improve the patient s health and may reduce transmission of the HIV virus to other people. 1 The primary goal of antiretroviral therapy (ART) is to reduce HIV-associated morbidity and mortality, restore and preserve immunologic function, suppress plasma HIV viral load, and prevent HIV transmission. 2 To do this, ART is used to maximally inhibit HIV replication. There are several broad steps in HIV replication. The first of which is attachment and fusion of the virus to CD4 receptors on lymphocytes and macrophages. 3 Most HIV infected people also have additional coreceptors, such as CCR5 or CxCR4, which are required for the virus to enter the host cell. 3 Once the virus has entered the cell and uncoated, the virus genomic RNA undergoes reverse transcription into DNA, which is then incorporated into the DNA of the host cell. 3 After transcription and translation, where the virus is reassembled, it then is released from the host cell and can mature. 3 Medications currently approved by the Food and Drug Administration (FDA) for the treatment of HIV work to inhibit various parts of this replication process. 3 There are several preferred and alternative antiretroviral (ARV) regimens available for use, each carrying different dosing frequencies, drug interactions, and potential side effects. 2 Once ART is deemed appropriate, most patients will be initiated on at least two, and preferably three, active drugs from two or more drug classes in order to achieve viral suppression. 2 There are more than 20 approved medications in 6 different drug classes including nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), fusion inhibitors (FIs) CCR5 antagonists, and integrase strand transfer inhibitors (INSTIs). 2 Considerations for which medications to use should be individualized to the patient and based on virologic efficacy, patient s comorbid conditions, potential adverse drug effects, potential drug-drug interactions with other medications, pregnancy, drugresistance testing, patient adherence and convenience (including pill burden, dosing frequency, and food and fluid considerations). 2 Possible regimens include two NRTIs with an NNRTI, a PI, an INSTI, or a CCR5 antagonist. 2 All of these regimens have been shown to suppress HIV RNA levels and CD4 increases in most patients in clinical trials. 2 1

MEDICATIONS Nucleoside Reverse Transcriptase Inhibitors (NRTIs) There are currently seven NRTI medications currently FDA approved for the treatment of HIV: abacavir (ABC), didanosine (ddl), emtricitabine (FTC), lamivudine (3TC), stavidine (d4t), tenofovir (TDF), zidovudine (ZDV). 2,3 These drugs inhibit RNA-dependent DNA polymerase (reverse transcriptase), which converts viral RNA into proviral DNA. 3 As mentioned earlier, multiple medications are used to treat HIV infected patients in order to achieve viral suppression. The established backbone of this combination ART is the use of dual NRTIs. 2 These dual NRTIs are then used in conjunction with a medication from one of the other classes. Most dual-nrtis consist of a primary NRTI plus either 3TC or FTC. 2 Guidelines recommend that the preferred combination is TDF/FTC which is available as a coformulation. 2 Together, these fixed dose combinations can be given as one tablet once a day to improve adherence and achieve viral suppresion. 2 All of the NRTIs, with the exception of ddl, can be taken without food restrictions and can be stored at room temperature. 2 While these agents are considered the backbone of ART, there have been serious adverse effects associated with some NRTIs. The most serious and life-threatening adverse reactions have been associated with d4t, ddl, and ZDV. 2 These three drugs have been shown to cause serious cases of lactic acidosis with hepatic steatosis. 2-3 Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) NNRTI s work in a similar fashion to NRTIs, by acting as non-competitive inhibitors of reverse transcriptase. 3 NNRTIs bind to a site on the enzyme that is not essential for the function of the enzyme and cause the enzyme to change its three-dimensional shape and thus reduce the activity. The two most commonly used NNRTIs are efavirenz (EFV) and nevirapine (NVP), in combination with the backbone, dual NRTIs. 2,3 In addition to EFV and NVP, there are two more agents in this class: delavirdine (DLV) and etravirine (ETR). All of these agents have been shown to demonstrate virologic potency and durability. Guidelines currently recommend that EFV be used over NVP as initial therapy in naïve patients due to its potency and tolerability, as well as its once daily dosing. NVP and ETR must be given twice a day. DLV is the only agent in this class that requires three times daily dosing. Like the NRTIs, major side effects can occur, with the most common being rash, including Stevens- Johnson syndrome. 2 Protease Inhibitors (PIs) Protease inhibitors is currently the largest class of medications. Currently nine PIs are FDA approved for the treatment of HIV: atazanavir (ATV), darumavir (DRV), fosamprenavir (FPV), indinavir (IDV), lopinavir/ritonavir (LPV/r), nelfinavir (NFV),ritonavir (RTV), saquinavir (SQV), and tipranavir (TPV). 2,3 These agents work by preventing essential structural and enzymatic components from reaching their mature form. 3 Each PI has its own characteristics and adverse effects. 2 The majority of them however have been shown to be associated with a number of metabolic abnormalities, like changes in cholesterol (dyslipidemia) and insulin resistance, and gastrointestinal adverse effects. 2 Most agents also are boosted with RTV, since it inhibits liver enzymes to prolong the half-life of the active PI. 2 This reduces the number of pills that the patient would have to take if the active PI was not boosted with RTV, and could improve patient adherence. 2 However, boosting with RTV can potentially cause the increased risk for adverse 2

effects and a greater potential for drug-drug interactions. 2 For patients who have not been previously treated for HIV, the preferred PI agents are atazanavir boosted with ritonavir (ATV/r) or darumavir boosted with ritonavir (DRV/r). 2 ATV and DRV both can be stored at room temperature and should be taken with food. 2,3 RTV capsules should be refrigerated but can be left at room temperature for up to 30 days. 2 RTV tablets do not require refrigeration and the oral solution should not be refrigerated. Integrase Strand Transfer Inhibitors (INSTIs) Raltegravir (RAL) is the only medication within this class currently approved. 2,3 This drug plays a vital role in the replication cycle in that RAL prolongs the time period of inactivity or latency by allowing viral DNA to remain in the host cell. This essentially inhibits the virus from being integrated into the host DNA. 3 RAL in combination with TDF/FTC in treatment-naïve patients has been shown to have similar virologic and immunologic responses compared with EFV after 96 weeks of treatment. 2 However, there is less experience with RAL than EFV or boosted PI regimens for initial therapy. 2 It has a lower genetic barrier to resistance and has to be given twice daily. 2,3 In addition, there are adverse effects such as nausea, headache, pyrexia, CPK elevation, muscle weakness and rhabdomyolysis. 3 Fushion Inhibitors (FIs) Enfurvitide (T20) is the only fusion inhibitor and is available as an injectable powder that has to be reconstituted before administering. 3 T20 is a 36- amino-acid synthetic peptide that prevents the crucial binding of glycoproteins located within the viral and host cell membranes. 2 It is given as a subcutaneous shot twice daily and can be stored at room temperature until reconstituted. 2,3 Once reconstituted, it should be stored in a refrigerator and used within 24 hours. 2,3 Like other agents, it has adverse effects that include local injection site reactions, increased risk of bacterial pneumonia, and hypersensitivity reactions such as rash, fever, nausea and vomiting. 2,3 However, there have been no trials in ART-treatment-naïve patients. Because of this, T20 should not be used as initial therapy. 2 CCR5 As mentioned previously, CCR5 is a coreceptor necessary for the entry of HIV into the host cell. 3 Miravaroc (MVC) blocks the binding of HIV to this coreceptor and is currently the only agent FDA approved in its class. 2,3 Recent guidelines, suggest that MVC has shown virologic responses that are no worse than EFV and fewer adverse effects. 2 However, there are some drawbacks. It requires viral tropism testing and twice daily dosing. Dosing is also dependent on the presence or absence of other drugs that might alter liver enzymes. 2 MVC also has adverse effects such as abdominal pain, musculoskeletal symptoms, rash, upper respiratory tract infections, hepatotoxicity, and orthostatic hypertension. 3 CONCLUSION The information provided within this continuing education module is intended to better familiarize you with the different medications currently FDA approved for the treatment of HIV and how they are most commonly used. Remember that as a pharmacy technician, you are a tremendous asset to the pharmacy team and by continuing to learn about current medications within the pharmacy, you continue to contribute to that team. 3

References 1. CDC Web site. http://www.cdc.gov/hiv/topics/basic/. Accessed March 21, 2011. 2. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. January 10, 2011; 1 166http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed March 21, 2011. 3. Flexner C. Antiretroviral agents and treatment of HIV infection. In: Brunton LL, eds. Goodman and Gilman s The Pharmacological Basis of Therapeutics. 12th ed. New York, NY: McGraw-Hill; 2011:1623-1663. 4

HIV Drugs Quiz True / false 1. The preferred combination of nucleoside reverse transcriptase inhibitors includes the tenofovir/emtricitabine combination. 2. Which of the following products has food restrictions affecting its administration? a. Didanosine b. Abacavir c. Lamivudine d. Stavudine 3. Which of the following agents have been associated with serious cases of lactic cidosis with hepatic steatosis? a. Stavudine b. Didanosine c. Zidovudine d. All of the above True / false 4. Efavirenz should be used preferentially over nevirapine for initial therapy in antiretroviral naïve patients. 5. Which of the following non-nucleoside reverse transcriptase inhibitors should be administered twice daily? a. Nevirapine b. Delavirdine c. Zidovudine d. Abacavir 6. Which antiretroviral class represents the largest class of antiretroviral medications? a. Nucloeside reverse transcriptase inhibitors. b. Non-nucleoside reverse transcriptase inhibitors c. Protease inhibitors d. Integrase strand transfer inhibitors 7. Which antiretroviral drug class is typically boosted with ritonavir? a. Nucleoside reverse transcriptase inhibitors. b. Non-nucleoside reverse transcriptase inhibitors c. Protease inhibitors d. Integrase strand transfer inhibitors 8. Which of the following drug formulations should be refrigerated? a. Ritonavir tablets b. Ritonavir oral solution c. Ritonavir capsules d. Ritonavir troches 9. Which of the following medications is an integrase strand transfer inhibitor? a. Lamivudine b. Fosamprenavir c. Etravirine d. Raltegravir 10. Which of the following agents is available as an injectable powder that has to be reconstituted prior to administration? a. Enfuvirtide b. Saquinavir c. Tipranavir d. Didanosine