Protease Inhibitors: a New Weapon and a New Strategy Against HIV

Home , Didanosine, Lamivudine, Nucleoside analogue, Stavudine, Zalcitabine

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Protease inhibitors: A new weapon and a new strategy against HIV

Kenneth D. Phillips University of Tennessee - Knoxville, [email protected]

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Recommended Citation Phillips, K. D. (1996). Protease inhibitors: A new weapon and a new strategy against HIV. Journal of the Association of Nurses in AIDS Care, 7(5), 57-71.

This Article is brought to you for free and open access by the Nursing at TRACE: Tennessee Research and Creative Exchange. It has been accepted for inclusion in Faculty Publications and Other Works -- Nursing by an authorized administrator of TRACE: Tennessee Research and Creative Exchange. For more information, please contact [email protected]. Protease Inhibitors: A New Weapon and a New Strategy Against HIV

Kenneth D. Phillips, PhD, RN

Until recently, reverse transcriptase inhibitors Kenneth D. Phillips, PhD, RN, is Assistant Professor, University of South Carolina, Columbia, SC. have been the mainstay for treating HIV infection. Now, three protease inhibitors have A decade and a half after acquired immunodeficiency syndrome (AIDS) was first identified, this life-threaten- been approved. Early evidence suggests that ing illness continues to elude a cure. Until recently, reverse transcriptase inhibitors have been the mainstay triple therapy delays the progression of HIV for treating HIV infection (Fischl et al., 1987; Weber, 1993; Yarchoan et al., 1986; Yarchoan et al., 1989). In 1995, a infection. An understanding of these new drugs new classification of drugs, protease inhibitors, was added to the armamentarium for treating HIV infection. and treatment strategies is imperative for Although the data are limited, early evidence suggests that a combination of reverse transcriptase inhibitors and clinicians. This article (1) reviews HIV's protease inhibitors delays the progression of HIV disease and prolongs the lives of H1V- infected people (Collier et structure and replication process, (2) discusses al., 1996). Only one brief report regarding the use of protease inhibitors in combination therapy to treat HIV currently approved reverse transcriptase and infection was found in the nursing literature (New Wave, 1996). The purpose of this paper is to review HIV's repli- protease inhibitors, (3) describes the cation process, discuss the different classifications of antiretroviral agents, describe anfiretroviral drugs' mode antiretroviral drugs" modes of action, (4) of action, and describe nursing implications for monitoring dients on these antiretroviral drugs. discusses important nursing implications for Replication of the Human Immunodeficiency Virus monitoring clients on these drugs, and (5) In order to understand how antiviral drugs work in presents current scientific evidence regarding the combating HIV, it is important to understand the structure and life cycle of the HW. effectiveness of combination therapy strategies. Structure of the Human Immunodeficiency Virus Key words: Antiretroviral therapy, HIV/AIDS, HIV is the retrovirus responsible for AIDS (Barr6- protease inhibitors, reverse transcriptase Sinoussi et al., 1983; Gallo & Wong-Staal, 1985; Montagnier, 1985). Retroviruses contain their genetic inhibitors material on two single strands of ribonucleic acid (RNA) rather than deoxyribonucleic acid (DNA). HIV consists of an envelope and a core (Figure 1). The outer envelope contains two important glycoproteins, gp120 and gp41. Glycoprotein 120 enables HIV to bind to T helper cells and other host cells that have a CD4+ receptor site on

JANAC Vol.7, No. 5, Septembe1~Octobe~1996 57 Protease Inhibitors: A New Weapon and a New Strategy Against HIV

Figure 1. Structure of the Human Immunodeficiency Virus Table 1. Components of the Human Immunodeficiency Virus

Protein Coded Location Function

9gp120 Coat glycoprotein Allows the HIV to bind to CD4+ receptor sites such as T helper cells. 9gp 41 Coat glycoprotein Allows the HIV envelope to fuse with the plasma membrane of a cell bearing a CD4+ receptor site. 9p17 Coat protein Becomes part of the outer coat of the new Figure by Tammy Simpson, University of South Carolina, HIM. College of Nursing. Used with permission. 9p24 Core protein Forms the core capsid, which surrounds the viral RNA and enzymes. their cell membranes, and gp41 enables the viral enve- 9p6 Core protein Becomes part of the lope to fuse with the host cell membrane. The envelope nucleocapsid. is lined with a viral protein, p17. 9p7 Core protein Becomes part of the The core is surrounded by a membrane that is made nucleocapsid. up of three proteins, p24, p6, and p7. The core contains 9Reverse Core enzyme Converts viral RNA to a two strands of viral RNA and enzymes--reverse tran- transcriptase single strand of viral DNA. The strand of scriptase, RNAse, polymerase, integrase, and protease viral RNA and the (Fauci, 1993; Gallo, 1987,1988; Greene, 1993; Haase, 1990). newly formed viral Table I summarizes the virus' main components. DNA remain attached. 9RNAse Core enzyme Degrades the RNA tem- Life-Cycle of the Human Immunodeficiency Virus plate from the DNA, leaving a single strand Figure 2 represents HIV's replication process. The of DNA. Roman numerals refer to the stages in HIV's replication 9Polymerase Core enzyme Makes an exact copy of process. HIV replication takes place inside host cells bear- the single strand of ing a CD4+ marker. A brief summary of the stages of DNA and causes the H1V replication is presented to illustrate the point in the two strands of viral DNA to join. life cycle of HIV that antiretroviral drugs work. 9Integrase Core enzyme Inserts the newly 9Stage I. Glycoprotein 120 binds to the CD4+ pro- formed double strand of tein on host cells. viral DNA into the DNA of the host cell. 9Stage II. Glycoprotein 41 facilitates fusion of the 9Protease Core enzyme Cleaves the proteins of viral coat with the CD4+ cell membrane. noninfectious, immature virions, thus making 9Stage III. Once inside the cell, the virus undergoes them infectious. an uncoating process and releases two single strands of RNA into the cytoplasm of the CD4+ cell. Adapted from Gallo, 1987,1988; Greene, 1993; Haase, 1990

58 JANAC Vol. 7, No. 5, September-Octobe~ 1996 Figure 2. Life Cycle of the Human Immunodeficiency Virus

~,&A gp41

IV. gp120 DN~

II.

VII.

Figure by Tammy Simpson, University of South Carolina, College of Nursing. Used with permission.

9Stage IV. A single strand of DNA is copied from 9Stage VII. During this stage, immature virions are the RNA by the enzyme reverse transcriptase. released from the host cell through the process of Reverse transcriptase contains two other enzymes: budding. These virions, which are noninfectious, RNAse and polymerase. RNAse is necessary to contain large precursor proteins that must be bro- remove the RNA from the DNA copy. Then, poly- ken into smaller glycoproteins, proteins, and merase makes another exact copy of the viral DNA enzymes before they become infectious. and causes the two strands of DNA to join. 9Stage VIII. By the action of protease, these large 9Stage V. The newly formed double strand of viral precursor proteins are split into a variety of smaller DNA moves into the nucleus of the host cell, glycoproteins, proteins, and enzymes that are where it is incorporated into the DNA of the host essential for the virus to become a mature, infec- cell by the enzyme integrase. The host cell begins tious retrovirus. to make messenger RNA (mRNA). Then, mRNA There are several points in the life cycle of HIV where moves from the host cell nucleus to the ribosomes, a great deal of research has been directed at finding drug where it guides the production of viral proteins. therapies for HIV infection. The research has been Transfer RNA (tRNA) carries amino acids from the directed at preventing the: (1) binding of gp120 to the host cell cytoplasm to the ribosomes. CD4+ receptor sites, (2) fusion of the viral coat with the 9Stage VI. In the ribosomes, the amino acids are cell membrane of the CD4+ receptor site, (3) uncoating of assembled into large, inactive precursor proteins. the virus once inside the host cell, (4) synthesis of viral

JANAC Vol.7, No. 5, September-October,1996 59 Protease Inhibitors: A New Weapon and a New Strategy Against HIV

DNA from viral RNA by the action af reverse transcrip- used alone, slows development of resistance to zidovu- tase, (5) degradation of viral RNA leaving it attached to dine (Eron et al., 1995). Clients taking zidovudine plus the newly formed strand of viral DNA, (6) insertion of larnivudine showed significant improvements in CD4+ viral DNA into the host cell DNA by the integrase, (7) counts and viral load (Eron et al.). Table 2 summarizes protein synthesis in the rough endoplasmic reticulum of the nucleoside analogue reverse transcriptase inhibitors. the host cell, (8) budding, and (9) maturation of the newly formed HIV by the action of protease (Johnston & Protease Inhibitors Hoth, 1993; Weber, 1993). Presently, the greatest success in treating HW infection has been the use of reverse tran- Proteases are enzymes that split the peptide bonds of scriptase inhibitors and protease inhibitors. Reverse tran- larger proteins into smaller proteins (Roose & Van scriptase inhibitors work in Stage Ill by preventing tran- Noorden, 1995). HIV protease helps HIV mature (Kohl et scription of viral RNA into viral DNA. Protease al., 1988; Peng, Ho, Chang, & Chang, 1989; Tang, Lin, inhibitors work in Stage VIII by preventing the cleavage Hartsuck, & Lin, 1992). HIV protease is part of the precur- of precursor proteins into mature viral proteins. sor protein gp160 (Buegelski et al., 1994). HIV protease autocleaves itself from the precursor protein gp160 Classifications of Antiretroviral Drugs (Buegelski, Kirsh, & Hart, 1994). Following autodeavage, gpl60 is cleaved into the two glycoproteins of the viral coat Reverse Transcriptase Inhibitors (Decroly et al., 1994). Then, HIV protease promotes maturation of HIV by splitt~g retroviral precursor polyproteins Reverse transcriptase inhibitors comprise the first major into structurally essential glycoproteins and proteins effective classification of antiretroviral drugs. Reverse tran- (Krausslich & Wimmer, 1988; Robins & Plattner, 1993; scriptase is an enzyme found in retroviruses that is neces- T~sdale et al., 1995). Thus, HIV protease allows immature, sary for their replication. The reverse transcriptase noninfectious virions to become mature, infectious virions. inhibitors have shown effectiveness in preventing infection Glycoprotein 160 is a polyprotein precursor that is of uninfected CD4+ cells (Fischl et al., 1987; Lambert et al., encoded by the gag- pol region of the HIV genome. H1V 1990; Merigan et al., 1989; Yarchoan et al., 1989). They do protease splits gp160 into gp120 and gp41 (Decroly et al., not block viral production by CD4+ cells that are chroni- 1994). By chopping gp160 into its component parts, I-tW cally infected (Ashorn et al., 1990; Dreyer et al., 1989; protease promotes binding (gp120) of the virus to the Kempf et al., 1990; McQuade et al., 1990; Meek et al., 1990; CD4+ receptor site and fusion (gp41) of the viral coat Reedijk et al., 1995; Rich et al., 1990; Roberts et al., 1990). with the CD4+ cell membrane. There are eight possible Nucleoside analogues, such as AZT, are substituted cleavage sites on gp160. Nine mature proteins are for natural substrates used to manufacture viral DNA. formed by the action of protease: (1) p17, (2) p24, (3) an The growing chains of viral DNA are prematurely termi- unknown protein, (4) p7, (5) p6, (6) protease, (7) reverse nated, thus preventing viral replication. Since HIV transcriptase, (8) RNAse, and (9) integrase (Buegeiski et mutates so rapidly (Martin, Redshaw, & Thomas, 1995), al., 1994; Debouck et al., 1987; Gelderblom et al., 1990). resistance of HW to reverse transcriptase inhibitors and The proteins of HIV are summarized in Table 1. other antiretroviral drugs frequently occurs early in the Protease inhibitors prevent maturation of newly course of therapy and hinders their effectiveness formed virions by preventing the cleavage of HIV's (Boucher et al., 1992; Fitzgibbon et al., 1992; Larder, polyproteins (Ashore et al., 1990; Kohl et al., 1988; Loeb, Darby, & Richman, 1989; Reichman et al., 1993). This Hutchinson, Edgell, Farmerie, & Swanstrom, 1989; Tang problem can be reduced by using drug combinations. et al., 1992). Thus, protease inhibitors prevent immature, For example, lamivudine, which is not effective when noninfectious viruses from becoming mature, infectious

60 JANAC VoL 7, No. 5, September-October, 1996 Table 2. Reverse Transcriptase Inhibitors

Reverse Transcriptase Inhibitor Adult Dose Adverse Effects Nursing Implications Zidovudine 200 mg orally q8h Anemia Monitor the client's complete (azidothymidine; AZT; ZDV) Granulocytopenia blood count. Myopathy Myositis Instruct client to report muscle pain and fatigue.

Didanosine Body weight > 132 lbs: 200 mg Pancreatitis Since ddI is degraded in acid, (dideoxyinosine; ddI) orally q12h Peripheral neuropathy tablets must be crushed, Hepatotoxicity chewed, or dispersed in water Body weight < 132 lbs: 125 mg to release the buffer or given orally q12h with a buffered powder.

Inform dient to report abdominal pain, nausea, and vomiting.

Zalcitabine 0.75 mg orally q8h Pancreatitis Inform client to report abdomi- (dideoxycytidine; ddC) Peripheral neuropathy nal pain, nausea, and vomiting. Mouth ulcers Esophageal ulcers Instruct client to monitor for Cardiomyopathy signs of peripheral neuropathy. Anaphylaxis

Stavudine (D4T) Body weight > 132 lbs: 40 mg Peripheral neuropathy Instruct client to monitor for orally q12h Neutropenia signs of peripheral neuropathy. Hepatotoxicity Body weight < 132 lbs: 30 mg Anemia Observe for indication of neu- orally q12h tropenia.

Lamivudine (3TC) 150 mg orally ql2h Pancrealitis May be administered with or Peripheral neuropathy without food. Headache Myalgia Inform client to report abdominal pain, nausea, and vomiting.

Instruct client to monitor for signs of peripheral neuropathy.

Adapted from Olin, B. (1996). Facts and comparisons. St. Louis: Lippincott. ones (Debouck et al., 1987; Gottlinger, Sodroski, & navir) that have been approved by the Food and Drug Haseltine, 1989; Kohl et al., 1988; Tang et al., 1992). Many Administration (FDA) are summarized in Table 3. antiretrovirally active protease inhibitors have been Saquinavir. Saquinavir has been associated with developed (Buegelski et al., 1994; Tk~ctale et al., 1995). The significant increases in CD4+ cell counts and few side three protease inhibitors (saquinavir, ritonavir, and indi- effects (Kitchen, Stewart, Bragman, & Weber, 1995). It

JANAC Vol. 7, No. 5, September-Octobe~ 1996 61 Protease Inhibitors: A New Weapon and a New Strategy Against HIV

Table 3. Protease Inhibitors

Protease Inhibitor Adult Dose Adverse Effects Nursing Implications

Saquinavir 600 mg orally q8h Diarrhea Instruct client to take with a Abdominal discomfort meal to increase absorption. Nausea Photosensitivity Grapefruit juice may increase bioavaflability.

Instruct client to avoid prolonged exposure to direct sun- light until sensitivity to sun- light is known.

Ritonavir 600 mg orally q12h Diarrhea Instruct client to take with Nausea food.

Observe for elevations in serum triglycerides, AST, ALT, GGT, CPK, and uric acid.

Avoid coadministration of nonsedating antihistamines, sedative hypnotics, or antiarrhythmics (may be life- threat- ening).

Indinavir 800 mg orally q8h Kidney stones Instruct client not to take with Hyperbilirubinemia meals; however, if gastric dis- tress occurs, take with a light snack.

If didanosine is also prescribed, instruct client to take the two drugs one hour apart.

Instruct client to increase oral fluid intake.

Adapted from Olin, B. (1996). Facts and comparisons. St. Louis: Lippincott.

is usually used in combination with either AZT or a HIV- infected cohort, some clinicians believe it may be nuceloside analog (Davey, Goldschmidt, & Sande, most beneficial to combine saquinavir with either zal- 1996). Saquinavir is more effective in combination citabine (ddC) or didanosine (ddI) (Davey et al., 1996). with AZT when the client has not taken AZT previ- Ritonavir. Ritonavir has been associated with signifi- ously. Since AZT has been widely prescribed in the cantly increased CD4+ counts (Danner et al., 1995;

62 JANAC Vol. 7, No. 5, September-October, 1996 Kelleher, Carr, Zaunders, & Cooper, 1996; Markowitz et be delayed by combining zidovudine with a protease al., 1995), increased CD8+ counts (Kelleher et al.), inhibitor (Schapiro, Winters, & Merigan, 1995) or lamivu- increased responsiveness to new antigens as measured by dine (Davey et al., 1996). In cross-resistance, development phytohemagglutinin antigen [PHA] mitogen blastogene- of resistance to one drug results in the development of sis (KeUeher et al.), increased responsiveness to previously resistance to other drugs of the same classification or encountered antigens (Kelleher et al.), and decreased viral other classifications. Cross-resistance is extremely prob- load (Danner et al.; Kelleher et al.; Markowitz et al.). lematic in HIV infection. Resistance to one protease Following treatment with ritonavir, significant decreases inhibitor may result in cross-resistance to other anfiretro- in CD4+ cells bearing a CD38 receptor site following treat- viral drugs, in particular other protease inhibitors (Chen ment with fitonavir have been observed (Kelleher et al.); et al., 1995; Condra et al., 1995). A mutation of only one this may be a very important finding, since an increase in genetic sequence results in cross- resistance to stavudine these cells is associated with disease progression (Giorgi et [d4T], didanosine [ddI], and dideoxycytidine [ddC] al., 1994; Levacher et al., 1992). (Merigan, 1995). The term resistance- reversal connotes the Indinavir. In clinical trials, dramatic reductions in concept that the development of resistance to one viral load and improvements in CD4+ cell counts have antiretroviral drug undoes the resistance that has devel- been reported in clients receiving indinavir. In fact, used oped to another drug. An example of this is the pheno- in combination with AZT and 3TC, viral loads have been typic resistance-reversal noted in the coadministration of reduced to undetectable levels (Davey et al., 1996). zidovudine and lamivudine (Boucher et al., 1993; Merigan; Staszewski, 1995). Triple Therapy: A New Strategy Saquinavir, plus zidovudine, plus dideoxycytidine. Phase II clinical trials indicate that combinations of Protease inhibitors have shown effectiveness when saquinavir (SQV), zidovudine (ZDV), and dideoxycyti- used as a monotherapy (Danner et al., 1995; Kelleher et dine (ddC) synergistically decrease H1V replication. In a al., 1996; Markowitz et al., 1995; Massari et al., 1996). study conducted by Collier et al. (1996), three treatment However, synergistic effects have been demonstrated regimens were used: (1) saquinavir (SQV), plus zidovu- when reverse transcriptase inhibitors and the protease dine (ZDV), plus dideoxycytidine (ddC); (2) zidovudine inhibitors are combined (Collier et al., 1996; Kageyama et (ZDV) plus dideoxycytidine (ddC); and (3) zidovudine al., 1992). The term synergy identifies the concept that the (ZDV) plus saquinavir (SQV). Patients receiving a com- beneficial effects of two or more drugs are greater when bination of saquinavir (SQV), plus zidovudine (ZDV), the drugs are combined than would be expected if either plus dideoxycytidine (ddC) demonstrated the greatest of the drugs was used alone. Synergistic effects have been increase in CD4+ counts and the greatest decrease in noted when certain reverse transcriptase inhibitors are viral load (Collier et al.). combined: (1) zidovudine [AZT] and lamivudine [3TC], Ritonavir, plus zidovudine, plus zalcitabine. The (2) zidovudine [AZT] and didanosine [dbl.], and (3) effects of a six-month regimen of ritonavir, plus zidovu- zidovudine [AZT] and zalcitabine [ddC] (Merigan, 1995). dine, plus zalcitabine were studied in a group of 21 HIV's ability to develop resistance to drugs is a major patients (Abramowicz, 1996). Viral load decreased to obstacle to effective treatment (Richman, 1993). The term undetectable levels in 5 of the 21 participants (Third resistance refers to the concept that a previously effective Conference on Human Retroviruses and Opportunistic anfiretroviral drug becomes ineffective due to viral muta- Infections, 1996) as reported in The Medical Letter on tions. Viral mutations and subsequent resistance may be Drugs and Therapeutics. slowed by using a combination of drugs (Vella et al., Indinavir, plus zidovudine, plus lamivudine. HIV 1995). For instance, resistance of HIV to zidovudine may viral load decreased to undetectable levels over a four

JANAC VoL 7, No. 5, September-October, 1996 63 Protease Inhibitors: A New Weapon and a New Strategy Against HIV

month treatment period in 20 of 22 clients taking patient more prone to drug toxicity. Third, assess zidovudine (AZT), plus lamivudine (3TC), plus indi- patients for a history of pancreatitis, symptoms of pan- navir. The participants in this study had an average creatitis (i.e., abdominal pain, nausea, and vomiting), CD4+ cell count of 175/mm 3 (Third Conference on risk factors for pancreatitis (i.e., cholelithiasis and Human Retroviruses and Opportunistic Infections, ethanol abuse), and elevations in either serum amylase 1996) as reported in The Medical Letter on Drugs and or serum lipase, which may indicate pancreatitis. Therapeutics (Abramowicz, 1996). In a separate study, a Pancreatitis is a potentially lethal side effect of nucleo- six-month course of indinavir, zidovudine, and side analogues. Fourth, assess for early signs of periph- lamivudine lowered HIV viral load to undetectable eral neuropathy (i.e., intermittent numbness, tingling, levels in 11 of 19 patients. The 'participants were previ- or pain in hands or feet). Fifth, perform a complete ously untreated and had an average CD4+ lymphocyte nutritional assessment (i.e., height, weight, serum albu- count of 150 cells/mm 3 (Third Conference on Human min, serum transferrin, serum prealbumin, and a 24- Retroviruses and Opportunistic Infections, 1996) as hour diet recall). Sixth, if the client is female, assess her reported in The Medical Letter on Drugs and pregnancy status. Zidovudine has been shown to be Therapeutics. effective in preventing the vertical transmission of HIV from the mother to the fetus without harming the fetus Nursing Implications when administered after the first 14 weeks of pregnancy. However, drugs other than zidovudine have not Nurses use a holistic approach in the prescription and been as thoroughly tested in pregnancy. The other administration of medications. Administering antiretro- nucleoside analogues should be given during preg- viral drugs requires special attention to all stages of the nancy only when the benefits clearly outweigh the nursing process. risks. See Table 2. Protease inhibitors..No major toxicities have been Assessment observed as a result of taking either of the three approved protease inhibitors. However, coadministra- A complete assessment should be performed prior tion of ritonavir and non-sedating antihistamines, seda- to prescribing or administering any medication. When tive hypnotics, or antiarrhythmics may produce life- threat- administering antiretroviral drugs, nurses need to be ening situations such as oversedation, respiratory an~t, or especially careful to determine the patient's allergies cardiac arrest (see Table 4, Abramowicz, 1996; Olin, 1996). to medications (name of medication and type of reac- Coadministration of these drugs with protease inhibitors tion) and assess past opportunistic infections and other than ritonavir has led to s'nnilar life- threatening reac- malignancies. tions. Always identify all the drugs the client is taking Nucleoside analogues. Data from a complete blood before prescribing or administering ritonavir. count, lymphocyte subset enumeration, and a chemical profile should be available prior to administering a Plan nucleoside analogue. Six assessments must be performed before administering a nucleoside analogue: During the planning phase, measurable goals are First, ensure that the patient does not have anemia mutually established between the client and the nurse. In (hemoglobin < 9.5 g/dl) or granulocytopenia (< addition, the nurse makes a thorough assessment of all 1000/mm3). If either is present, special precautions are the patient's drugs, including over-the-counter and needed when administering zidovudine. Second, check street drugs. In addition to the drug, route, dosage, and for elevated serum creatinine, which could make the frequency, the nurse must know whether the client is

64 JANAC Vol.7, No. 5, September-Octobe~1996 Table 4. Examples of Nonsedating Antihistamines, Sedative Hypnotics, and Antiarrhythmics*

Nonsedating Antihistamines Sedative Hypnotics Antiarrhythmics Miscellaneous

Astemizole Alprazolam Amiodarone Bupropion Terfenadine Clorazepate Bepridil Cisapfide Diazepam Encainide Clozapine Estazolam Flecainide Meperidine Flurazepam Propafenone Piroxicam Midazolam Quire'dine Propoxyphene Triazolam Rifabufin Zolpidem

Adapted from Olin, B. (1996). Facts and comparisons. St. Louis: Lippincott. * Not an indusive list

able to take the medication independently. If not, does will not prevent the transmission of HIV. Table 5 outlines he or she have adequate social support to help with additional client instructions. taking the medications? Does the client have adequate resources for obtaining the drug (i.e., money, insur- Ev~uation ance, transportation)? Since it is never enough to sim- ply say, "Take your medicine," nurses must plan Evaluation is an ongoing process and is performed at methods for teaching the client about the medicines, every contact with the client. Assess for past or present and must make themselves available to answer ques- opportunistic infections or malignancies. A complete tions that arise after the client leaves the office. For blood count should be drawn at frequent intervals and instance, the client may ask, "It is my birthday. Can I the results evaluated. If the client develops anemia or have a glass of wine with my medications?" Nurses granulocytopenia, a drug may need to be withdrawn, can help the client find a way to procure the pre- the dosage changed, or another drug such as epoietin scribed medications and to incorporate these medica- alfa recombinant or granulocyte colony stimulating fac- tions into his or her life. Be familiar with industry, tor added. Liver, pancreatic, and renal values also should social, or governmental compassionate drug programs be assessed at regular intervals. for indigent patients. Evaluation of antiretroviral therapy is based on viral markers. Three viral markers have been more significant Implementation than others in monitoring disease progression and treatment effectiveness: CD4+ cell counts, p24 antigenemia, Clients should be taught the name, dosage, route, and and viral load. frequency of any drug being prescribed. Apprise the CD4+ cell counts. The normal CD4+ cell count ranges client of possible side effects and any special precautions from 589 to 1505 cells/~tl (Fischbach, 1996). T that must be taken while taking a particular drug. helper/inducer cells (CD4+) are invaded and destroyed Provide written instructions in addition to verbal ones. by HIV. So a decline in CD4+ cells generally signifies dis- Inform the client that current drugs are not a cure and ease progression (Flaskerud & Ungvarski, 1995) and

JANAC Vol.7, No. 5, September-Octobe~ 1996 65 Protease Inhibitors: A New Weapon and a New Strategy Against HIV

Table 5. Client Instructions indicates that the treatment strategy should be re- exam- ined (Davey et al., 1996). Instruct client to: CD4+ cells can be destroyed by four processes: (1) binding of gp120 can lead to preprogrammed cell death Recognize and report the signs and symptoms of peripheral neuropathy fi.e., numbness, tingling, or pain in the known as apoptosis; (2) binding of gp120 can terminate hands and feet). cell division known as anergy; (3) gp120 on the surface of virions budding from the surface of an infected CD4+ cell 2. Recognize and report the signs and symptoms of acute can bind to CD4+ receptors on other CD4+ cells, causing pancreatitis (i.e., abdominal pain., nausea, or vomiting). them to tear; or (4) multiple CD4+ cells clump together in 3. Recognize and report early signs and symptoms of anemia a process known as syncytium formation, resulting in the (i.e., shortness of breath, increased weakness, tiredness, death of many CD4+ cells at one time (Peterson, 1995). fatigue, lightheadedness, dizziness, or palpitations). Antiretroviral treatment has been reserved for a CD4+ 4. Drink 2-3 liters of fluids per da3a cell count less than 500 ceUg/n'lIn 3. Therapy should be initi- 5. Report signs of opportunistic infections in the mouth (i.e., ated in clients who have a progressive dedine of CD4+ cells furry tongue, mouth lesion, or thrush), in the vagina (i.e., to 500 cells/mm3 or in clients with a CD4+ cell count greater itching, burning, redness, or discharge), or in the rectum than 500 cells/ram3, if their CD4+ cells are rapidly declining (i.e, itching, drainage). (Davey et al., 1996). Undoubtedl)4 new recommendations 6. Avoid nonprescription medications unless approved by a be forthcoming regarding combination therapy. healthcare provider. The CD4+ cell count is an indirect marker of HIV replication. Therefore, the cell count may rise in response 7. Takedrugs as scheduled to maintain an appropriate blood level of the drug. to an infection other than HIV or decline transiently in response to stimuli other than increased viral replication 8. Avoid drug "holidays" (periods when the drug is not (Davey et al., 1996; Harrigan, 1995; Merigan, 1995). This taken), which may allow the development of resistant strains of HIM limits the significance of the CD4+ cell count in tracking the progression of the disease or the effectiveness of ther- 9. Takesaquinavir, ritonavir with food. apy. In fact, it remains controversial whether CD4+ 10. Take didanosine, indinavir, or zalcitabine on an empty counts have utility in predicting disease progression or stomach. survival (Choi, Lagakos, Schoole)~ & Volberding, 1993). However, in general, a significant reduction of the CD4+ 11. Takestavudine, zidovudine, or lamivudine with or without food. cell count suggests that the treatment strategy needs to be re-examined and that the treatment plan may need to 12. Chew, crush, or disperse didanosine in water before swal- be changed (Davey et al., 1996). lowing to release the buffer or to take it with a buffered p24 antigenemia. Another test that is used as a powder. marker of disease progression is the p24 antigen test. The 13. Understand that the long- term side effects of these drugs p24 antigen is one of the core proteins. Early after infec- remain unknown. tion antibodies to p24 appear. In the p24 antigen test, a 14. Takeprophylactic drugs to prevent opportunistic infec- spectrophotometer is used to measure the optical density tions and malignancies. that develops when p24 antigen in a patient's serum 15. Use contraceptives to prevent pregnancy while taking complexes with recombinant p24 antibody and is sub- antiretroviral drugs (remind the client that effective barrier jected to the enzyme linked anti-p24 ELISA test. The methods are needed to prevent the transmission of HW). greater the optical density, the greater the concentration of p24 antigen in the patient's serum. Antibody forma-

66 JANAC Vol.7, No. 5, September-Octobez;1996 tion is one of the major problems associated with this dienYs viral load fails to drop or does not drop by 0.5 log10 reliability of this test. In vivo, the HIV-infected person following treatment, the approach should be re-evaluated, makes antibodies to p24 in his or her serum. These anti- and the care plan may need to be modified (Davey et al., bodies attach to the p24 in the serum. In v/tro, the recom- 1996). Viral load determinations are recommended at base- binant antibodies are unable to attach to the p24 antigen line, prior to beginning antiretroviral therapj6 and approxi- unless the serum is treated with an acid wash. This acid mately one month after beginning or changing antiretrovi- wash procedure releases the attachment of the p24 anti- ral therapy (Sax & Flory, 1996). Table 6 summarizes the gen- antibody complex, but it decreases the reliability of interpretation of HIV viral load testing. this test. Therefore, its usefulness as a marker of disease progression is limited (Piliero & Libman, 1996). Special Considerations The p24 antigen test provides diagnostic information in infants born to HIV-infected mothers. In the early Clients should be advised to avoid "drug holidays" months after delivery, maternal antibodies to HIV and (periods of time when drugs are not taken). Drug holi- other maternal antibodies persist in the infant. The infant days permit activation of viral replication and increase with antibodies to HIV may or may not be HIV- infected. the risk of mutation and the development of resistant The presence of p24 antigen in the serum of the new strains. Resistance to one protease inhibitor may be con- born allows early diagnosis and treatment of HIV infec- ferred on other protease inhibitors and thus limit future tion (Cooper & Pelton, 1996). treatment options. Viral load. Viral load is a significant step in treating Avoid coadministration of nonsedating antihistamines, HIV infection. HVA RNA levels have greater power to sedative hypnotics, or anfiarrhythmics. When these drugs predict disease progression than CD4+ cell count alone are administered with the protease inhibitors, life threaten- (O'Brien et al., 1996). Since viral load is a direct marker of ing or lethal complications may arise (Olin, 1996). Examples viral replication, it does not rise and fall in relationship to of each of the nonsedating antihistamines, sedative hyp- the white blood cell count. However, HIV viral load can notics, and antiarrhythmics are provided in Table 4. transiently increase in the presence of illnesses such as Avoid coadministration of antiretroviral drugs with pneumonia or influenza (Sax & Flory, 1996). Viral load similar adverse effects (Merigan, 1995). For instance, measures the presence of viral RNA in the plasma, but avoid simultaneous use of didanosine [ddI] and not in other tissues (Davey et al., 1996). dideoxycytidine [ddC], because acute pancreatitis and Four methods are currently used to measure viral peripheral neuropathy are adverse reactions of both load: (1) quantitative competitive polymerase chain reac- drugs (Davey et al., 1996; Merigan). tion [PCR], (2) nucleic acid sequence-based amplification Nurses approach every aspect of patient care holisti- [NASBA], (3) branched- chain DNA [b-DNA], and (4) cally, including the prescription and administration of the amplicor microwell plate assay (Harrigan, 1995). medications. Quite often, nurses work more closely with In the early, asymptomatic stage of HIV infection, viral the client than other clinicians. The nurse's responsibility load may be about 5,000 virions/ml (Merigan, 1995). It rises goes far beyond prescription and administration of a as the disease progresses and declines in response to effec- medication. Nurses help people find resources to pro- tive anfiretroviral therapy (Davey et al., 1996). In advanced cure medications, teach them the effects and side effects stages of HIV infection, viral load may be as much as I mil- of their medications, teach them how to take their medi- lion virions/ml (Merigan). A rise in viral load indicates cation to obtain maximum benefit, and help them find increased viral replication. A reduction in viral load greater ways to incorporate drug therapies into their lives. When than 0.5 log10 following initiation of treatment indicates that an informed decision is made by the client to discontinue the antiretroviral therapy is effective (Davey et al., 1996). If a antiretroviral therapy, the nurse supports the client.

JANAC Vol. 7, No. 5, September-October, 1996 67 Protease Inhibitors: A New Weapon and a New Strategy Against HIV

Table 6. Interpretation of H1V RNA V'tral Load

Viral Load Clinical Significance of Results

< 10,000 copies per mm 3 Low risk of disease progression 10,000 to 100,000 copies per mm 3 Moderate risk of disease progression > 100,000 copies per mm3 High risk of disease progression

Adapted from Sax, P., & Flory, J. (1996). Information for patients: Viral load testing. AIDS Clinical Care, 8, p. 31

Discussion Boucher, C., Cammack, N., Schipper, P., Schuurman, B., Rouse, P., Wainberg~ M. A., & Cameron, J. (1993). High-level resistance to (-) enantiomeric 2'-deoxy-3'thyacytidine in vitro is due to one amino Protease inhibitors and triple therapy provide a acid substitution in the catalytic site of human immunodeficiency new level of hope in the search for an effective treat- virus type 1 reverse transcriptase. Antimicrobial Agents and Chemotherapy, 37, 2231 -2234. ment for HIV infection (Wlodawer & Erickson, 1993). However, the advent of HIV protease inhibitors pre- Boucher, C., O'Sullivan, B., Mulder, J., Ramautarsing, C., Kellam, P., sents new research questions. Which combination of Darby, G., Lange, J., Goldsmith, J., & Larder, B. (1992). Ordered appearance of zidovudine resistant mutations during treatment of drugs is best for a particular group of clients? At what 18 human immunodeficiency virus-positive subjects. Journal of point should a client be started on a particular combi- Infectious Diseases, 165,105-110. nation of drugs? Buegelski, P., Kirsh, R., & Hart, T. (1994). HIV protease inhibitors: Although slower than that of zidovudine, develop- Effects on viral maturation and physiologic function in ment of resistance to HIV protease inhibitors has been macrophages. Journal of Leukocyte Biology, 56, 374-380. noted (Markowitz et al., 1995; Martin et al., 1995; T~sdale Chen, Z., Li, Y., Schock, H., Hall, D., Chen, E., & Kuo, L. (1995). Three- et al., 1995). This resistance reminds us that the search for dimensional structure of a mutant HIV-1 protease displaying cross- definitive prevention and treatment must continue. The resistance to all protease inhibitors in clinical trials. The Journal of progress made with triple therapy is very encouraging. Biological Chemistry, 270, 21433-21436. Strategies for treating HIV infection are rapidly increas- Choi, S., Lagakos, S., Schooley, R., & Volberding, P. (1993). CD4 super ing. Nurses, especially advanced practice nurses provid- (+) lymphocytes are an incomplete surrogate marker for clinical ing care for HIV-infected individuals, must keep current progression in persons with asymptomatic HIV infection taking zidovudine. Annals of Internal Medicine, 118, 674-680. with new medications that are being released. Existing drugs, new drugs, combinations of those drugs, and Collier, A., Coombs, R., ~hoenfeld, D., Bassett, R., TLrnpone,J., Baruch, direct measurement of RNA viral load will allow indi- A., Jones, M., Facey, K., Whitacre, C., McAuliffe, V. J., Friedman, H., Merigan, T., Reichman, R., Hooper, C., & Corey, L. (1996). Treaiment vidualization of treatment strategies. of human immunodeficiency virus infection with saquinavir, zidovudine, and zalcitabine. New England Journal of Medicine, 334, References 1011 - 1017. Condra, J., Schleif, W., Blahy, O., Gabryelski, L., Graham, D. J., Abramowicz, M. (1996). New drugs for HIV infection. The Medical Quintero, J., Rhodes, A., Robbins, H., Roth, E., Shivaprakash, M., Letter on Drugs and Therapeutics, 38(972), 35-38. ~tus, D., Yang, T., Teppler, H., Squires, K., Deutsch, P., & Emini, E. (1995). In vivo emergence of HW-1 variants resistant to multiple Ashorn, P., McQuade, T., Thaisrivong, S., Tomasselli, A., Barr6- protease inhibitors. Nature, 374, 569-571. Sinoussi, F., Chermann, J., Rey, F., Nugeyre, M., Chamaret, S., Gruest, J., Dauguet, C., Axler-Blin, C., Vezinet-Brun, E, Rouzioux, Cooper, E., & Pelton, S. (1996). Overview of pediatric HIV infection. In C., Rozenbaum, W., & Montagnier, L. (1983). Isolation of a T-lym- H. Ulbman & R. V~Fltzburg (F_~.), HIV infection: A primary care man- photropic retrovirus from a patient at risk for acquired immune ual (3rd ed., pp. 631-650). Boston: Little, Brown. deficiency syndrome (AIDS). Science, 220, 868-871.

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Electronically, on CD-ROI, online, and/or magnetic Tang, J., Lin, Y., Co, E., Hartsuck, J., & Lin, X. (1992). Understanding tape a broad range of ProQuest databases available, protease: Can it be translated into effective therapy against AIDS. including abstract-and index, ASCll full-text, and innovative furl-image format Scandinavian Journal of Clinical and Laboratory Investigation, 52(Suppl. 210), 127-135. Call roll-free 800-52 F0600, ext 2888, for more information, or f111out the coupon below: Tarpley, W., & Moss, B. (1990). An inhibitor of the protease blocks maturation of human and simian immunodeficiency viruses and Company/Institution spread infection. Proceedings of the National Academy of Science, 87, Add~ss 7472 - 7476. C~ty/State/Zip Phone ( ) Third conference on human retroviruses and opportunistic infections. (1996, rm ,ntele~ted~n the follow,rigtitLe(s) February). Washington, DC: Infectious Diseases Society of America. UMI 8C0-521-~ ~ll-f~e A Bell & Howell C~pany 31)-761-1203f~x Box 78 3O0 Notch Z~b R~a Ann Arbor,HI 48106

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