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Clinical Update: New Drugs for HIV/AIDS.

The advent of drug therapy to treat the human immunodeficiency virus (HIV) has dramatically improved the health of people living with this virus and the diseases it causes, including acquired immunodeficiency disease (AIDS). The rate for U.S. AIDS deaths declined in 1996 and dropped again in 1997. Patients are now spending fewer days in the hospitals, and opportunistic infections are on the decline. This improved picture for people with HIV/AIDS is felt to be largely due to more effective antiretroviral therapy (Steinhart, 1998). The use of HIV combination antiretroviral therapy increased from 24% in 1995 to 65% in 1996 (Carmichael, 1998).

But the war on AIDS is not over yet. The virus has shown an ability to become resistant to several of the medications used in 1996-1997. However, a variety of new drugs and drug combinations are being intensely studied in clinical trials, and several received FDA approval in 1998. It's important for nurses to be aware of what the future holds for HIV drug therapy, to better inform their patients about treatment options (see Table 1).
Table 1.
HIV Drugs 1999

    Nonnucleoside           Nucleoside Reverse
Reverse Transcriptase    Transcriptase Inhibitors
 Inhibitors (NNRTI)              (NRTI)

     Rescriptor                 Combivir
(delavirdine mesylate)   (lamivudine/zidovudine)

      Viramune                   Epivir
    (nevirapine)              (lamivudine)

       Sustiva                  Retrovir
 (efavirenz; DMP-266)    (zidovudine; AZT; ZDV)

                                 Zerit
                            (stavudine; d4T)

                                 Hivid
                           (zalcitabine; ddC)

                                 Videx
                            (didanosine; ddl)

                                 Ziagan
                             (abacavir; 1592)

   Nucleotide Analogue       Protease Inhibitors (PI)

      (*)Preveon                    Crixivan
(adefovir dipivoxil; PMEA)         (indinavir)

                                 Norvir (ritonavir)

                               Fortovase (saquinavir)

                                        Viracept
                                 (nelfinavir mesylate)

                             (*) Agenerase[TM] (amprenavir;
                                  141W94, VX-478)


(*) Drugs in clinical trials

Clinical research studies on new anti-HIV drug therapies were presented at the 12th World AIDS Conference in Geneva. Scientists and physicians from around the world have been actively involved in a variety of clinical trials to investigate new drugs and combinations of these medications with agents currently in use.

Some health care providers are concerned with "pill burden load" that may detract from patients' abilities to comply/adhere with multiple dose, daily medication regimes. Several pharmaceutical companies are looking at ways to simplify drug regimens. On the other hand, some researchers are combining four, five, or six drugs in an aggressive pursuit of the virus, in order to achieve HIV suppression. For the future, new forms of therapy with different antiviral activity may be the medications that hold the key to defeating HIV infection (Deeks, 1998; Rochon, 1998).

The purpose of this review is to discuss four new anti-HIV agents: Sustiva[TM] (efavirenz), Ziagen[TM] (abacavir), Agenerase[TM] (amprenavir), and Preveon[R] (adefovir dipivoxil). The nursing implications in treating HIV with new drug formulations and combinations are explored.

Sustiva

Sustiva (efavirenz; formerly called DMP-266) is a new non-nucleoside reverse transcriptase inhibitor from DuPont Merck. It was approved by the FDA in September 1998. It works by binding directly to the HIV-1 reverse transcriptase enzyme. Because it inhibits both RNA-dependent and DNA-dependent DNA polymerase activity, it blocks the virus' ability to reproduce. However, laboratory studies revealed that isolates resistant to Sustiva emerged in tissue cultures. Therefore, Sustiva must be taken in combination therapy, with other anti-HIV medications, to prevent drug resistance and achieve optimal results.

An advantage for Sustiva over other drugs is that Sustiva only needs to be taken once a day. The present dose is 600 mg (three 200 mg tablets), taken in combination with other anti-HIV medications. The most common side effects have been CNS symptoms: lightheadedness, an inability to concentrate, anxiety, and dysphoria. CNS effects are seen in approximately half the patients taking Sustiva. Patients have reported flu-like symptoms, headache, and fatigue. However, these symptoms usually resolve after the patient has been on therapy for a few weeks. Symptoms can be reduced by splitting the dose into twice-a-day dosing, or taking the medication at bedtime. Rashes are another common side effect but usually resolve without requiring any change in therapy. When used in combination with other antiretroviral agents, nausea, vomiting, diarrhea, and headache were noted.

Like several other HIV drugs, Sustiva is both an inducer and competitive inhibitor of the cytochrome P450 CYP3A4 isoenzyme. Therefore, all drugs metabolized by the P450 system should be monitored carefully for effect and toxicity when used in combination with Sustiva. At this time studies have shown no effect on plasma concentrations of zidovudine (Retrovir[R], AZT[R]); lamivudine (3TC[R]; Epivir[R]) and fluconazole (Diflucan[R]). When given in combination with indinavir (Crixivan[R]), it decreases indinavir's concentration by 30% to 35%. Therefore, the dose of indinavir should be increased to 1,000 mg every 8 hours. A decrease was also noted when saquinavir was co-administered with Sustiva, so the use of Sustiva in combination with saquinavir as the sole protease inhibitor is not recommended. Although Sustiva reduces clarithromycin plasma levels by 38%, no interactions have been shown with azithromycin.

Because of possible fetal malformation, pregnant women should not take Sustiva and women taking Sustiva should always use at least two types of contraceptive methods, including the use of a reliable barrier device. Mothers who are breast feeding should not take Sustiva. Patients should also be advised to avoid taking Sustiva with high-fat meals. It may be taken with meals of normal fat content.

Ziagen and Agenerase

Glaxo Wellcome has two new drugs. Ziagen (abacavir, formerly called 1592) was approved by the FDA in December 1998. Ziagen is a nucleoside analogue reverse transcriptase inhibitor. The drug appears to have as high a level of antiviral potency as the protease inhibitors. However, resistance to Ziagen develops very slowly, making it potentially a very useful component of a combination anti-HIV regimen.

In clinical trials to date, involving more than 3,000 patients, Ziagen has been well tolerated. The most common adverse events included headache, nausea, vomiting, malaise and rash. Two to three percent of patients taking Ziagen have experienced a hypersensitivity reaction. The reaction is characterized by fever plus any one or all of the following: nausea (with or without vomiting), malaise, and sometimes an accompanying rash. The onset of reaction was 3 to 42 days (median 9 days) after starting therapy. Symptoms usually resolved within 1 to 2 days after the drug was stopped.

However, patients experiencing this reaction should not restart therapy with Ziagen. Rare cases of a life-threatening hypersensitivity reaction have occurred in patients who resumed treatment after the initial hypersensitivity reaction. There has been one case of a fatal hypersensitivity reaction. Consequently, if patients experience an initial hypersensitivity reaction, they should not try this drug again.

Ziagen has been studied in combination with five protease inhibitors. Preliminary data show that combining Ziagen with any of the protease inhibitors (amprenavir, saquinavir, indinavir, nelfinavir, or ritonavir) may result in potent antiretroviral activity.

Agenerase (amprenavir; formerly 141W94, VX - 478) is a new protease inhibitor drug from Vertex and Glaxo Wellcome in Phase III clinical trials. Agenerase is being studied in combination with nucleoside analogues and other protease inhibitors. A twice-daily dose of amprenavir is in research. The studies to date show that combining amprenavir with any one of three currently available protease inhibitors (saquinavir, indinavir, nelfinavir) may result in highly potent antiviral regimens that are well tolerated by most patients. Combining two protease inhibitors together may further maximize the strength of anti-HIV treatment regimens.

The most commonly reported adverse events associated with Agenerase in clinical trials have been nausea, vomiting, headache, and rash. When combined with other protease inhibitors, the most common side effects were diarrhea, perioral tingling/numbness, nausea and vomiting, headache, cutaneous events, abdominal pain, and flatulence.

Preveon

Preveon (adefovir dipivoxil) is a new drug from Gilead Sciences. The mechanism of action for this nucleotide analogue is different from other nucleoside reverse transcriptase inhibitors. To become activated, the nucleoside analogue drugs must be phosphorylated by a series of cellular kinases. The nucleotide analogue drugs already contain the initial phosphate group, so this new class of drugs may prove to be more active in a broader range of cells (Barditch-Crovo et al., 1997).

The most common side effects associated with patients in the clinical trials have been dose-related gastrointestinal effects, including nausea and anorexia and renal toxicity. Elevations in liver transaminase and serum creatinine, and decreases in serum carnitine, have also been noted. Historically, patients with low carnitine levels have had symptoms such as weakness, fatigue, low blood sugar, confusion, and abnormal liver tests. To prevent potential problems with low carnitine, patients on Preveon are required to also take L-carnitine (one 500 mg pill taken once a day) to prevent a decrease in their carnitine blood levels. Adefovir also appears to have activity against other types of viral infection, such as hepatitis B and cytomegalovirus. Therefore, HIV-positive patients who also have these co-infections may have an added benefit from this drug. Preveon is being tested in clinical trials using two different dosages, 120 mg once a day, and 60 mg once a day, and patients are being monitored for signs of toxicity.

Changes in Drug Formulations and Combinations

Combivir. Combivir[R] was introduced last year by Glaxo Wellcome. This medication combines Retrovir (AZT, zidovudine) and Epivir (3TC, lamivudine) into one tablet. Therefore, instead of four tablets a day, patients only need to take two tablets. This has been extremely helpful for patients who were having problems keeping up with multiple doses of medications ("pill burden overload"). Glaxo Wellcome has also released Retrovir in a 300 mg tablet, that is taken twice a day. This reduces the pill count from six capsules a day to only two tablets a day.

Fortovase. Roche Pharmaceuticals introduced Fortovase[R], which is a new formulation of saquinavir. Fortovase is indicated for use in combination with other antiretroviral agents for treating HIV infection. Although Fortovase (saquinavir) is similar to Invirase (saquinavir mesylate), they are not bioequivalent and should not be used interchangeably.

Fortovase is a soft gel capsule. The recommended dosage is six capsules (1,200 mg) taken 3 times a day (total of 3,600 mg), taken with meals or within 2 hours after a meal. Fortovase, like Invirase, is generally well tolerated. The most common side effects reported by patients are diarrhea, nausea, abdominal discomfort, and dyspepsia. Once brought to room temperature (at or below 77 [degrees] F), the capsules must be used within 3 months. Patients who live in hot climates or whose homes are hot in the summer should keep Fortovase refrigerated (but never frozen). The bottle should be kept tightly sealed.

Certain drugs cannot be co-administered with Fortovase because of the potential for serious cardiac arrhythmias or prolonged sedation. These drugs include antihistamines (astemizole, terfenadine), antimigraines (ergot derivatives), GI motility agents (cisapride), and sedatives/hypnotics (midazolam, triazolam).

Ritonavir. Abbott Laboratories has stopped production of Norvir (ritonavir) capsules due to production problems with crystallization of the medication within the capsule. Patients on Norvir have been switched to the liquid formulation of the drug at the same dosage and frequency. Liquid Norvir is stored at room temperature (68 [degrees] - 77 [degrees] F and should be shaken well prior to use. Rapid shaking of the bottle will help dissolve harmless crystals that form in the liquid. Advise patients that there are several ways to make the medication taste more palatable. These include using a straw; eating a popsicle before and after to numb the taste buds; eating something sweet or salty after the dose; coating the tongue with peanut butter or chocolate; or eating peanut butter after taking the dose. There is no projected date from Abbott as to when capsules will again be available.

The multiple combinations that can be studied, by mixing and matching the different drug categories, plus the drugs within each category, make for a promising future in HIV/AIDS therapy. There are at least 18 different combinations presently in clinical trials, and some of these are illustrated in Table 2.
Table 2.
Examples of Current Clinical Drug Combination Trials Being Studied

               Clinical Drug Study (Four Groups)

Delavirdine   Delavirdine +   Delavirdine +   Nelfinavir +
(NNRTI) +     Nelfinavir +    Nelfinavir +    ddl + d4T
Nelfinavir    d4T(NRTI)       ddl + d4T
(PI) + ddl    versus          versus
(NRTI)
versus

                Clinical Drug Study (Three Groups)

Delavirdine +            Delavirdine +            Delavirdine +
Zidovudine (NRTI) +      Indinavir + 3TC(NRTI)    Zidovudine
Indinavir (PI) versus    versus                   + Indinavir
                                                  + 3TC (NRTI)

         Clinical Drug Study: Trial Dosages (Three Groups)

Adefovir                 Indinavir bid +          Adefovir
(+ L-carnitine)          Zidovudine bid + 3TC     (+ L-carnitine)
daily + Indinavir        bid versus               daily + Indinavir
bid + 3TC bid versus                              bid + Zidovudine
                                                   bid + 3TC bid


New HIV drugs are tested and evaluated in humans during clinical drug trials. There are usually four phases to any drug trial (see Table 3). Phase III trials include the largest number of participants. If good results are obtained from participants in this phase, the pharmaceutical company can apply for FDA approval to sell the drug.
Table 3.
How HIV Drugs Get Approved

Phase I         Phase II        Phase III       Phase IV

Tests the       Enroll          Can include     Post-marketing
                several         up to a few     studies.
safety of       hundred         thousand
new drugs       people, and     people, and     Not clearly
for humans,     take 1-2        often last      regulated, and
                years,          more than       not conducted
                                a year.         very often.
New drugs       Randomized;
are given to    control group   Randomized      Can monitor
humans for      gets either     and blinded     drug's long-term
the first       standard        With good       effectiveness
time            treatment or    results, the    and side
Everyone        a placebo.      manufacturer    effects, or cost
receives the                    can apply for   effectiveness.
new drug.       Blinded study   FDA approval
                (no one         to sell the     Can compare
Limited to      knows who is    drug.           new drugs to
less than 100   in which                        other drugs
people, and     group).                         approved for
take less                                       the same
than a year.                                    condition.


Source: New Mexico AIDS InfoNet Fact Sheet Number 105. Available: http://www.aidsinfonet.org/

In the Future

An understanding of the structure and HIV viral life cycle is guiding researchers to develop and study new categories of drugs to fight HIV. Table 4 depicts some of these developments.
Table 4.
New Categories of Anti-HIV Drugs

Integrase Inhibitors     Zinc Fingers   Fusion Inhibitors

Dicaffeoylquinic acids    Cl - 1012           T-20


Integrase inhibitors. Integrase is an enzyme that is used to incorporate HIV into the DNA of a cell. All retroviruses, including HIV, have integrases, but normal cells do not. Researchers are looking for ways to manufacture drugs that can serve as integrase inhibitors, and stop viral replication by interfering at this new point in the virus's life cycle. HIV integrase inhibitors with antiviral action are actively being studied. The combined administration of inhibitors of HIV integrase, reverse transcriptase, and protease may reduce the risk of acquired resistance during the treatment of HIV/AIDS. However, a variety of technical problems have deterred the quest for an integrase inhibitor.

Zinc fingers. According to the National Cancer Institute, chains of amino acids, called zinc fingers, found in cellular proteins which bind to DNA or messenger RNA, may be the next focused area for HIV drug research. Structurally, HIV's zinc fingers are part of the virus's p7 nucleocapsid (NC) protein. They are needed for zinc binding, which is crucial to viral replication. These structures are so important that nearly all retroviruses must have at least one. Zinc fingers are a part of HIV that help assemble new viruses as they are leaving an infected cell. When the zinc fingers are blocked, HIV makes copies of itself that do not work. That means that HIV can not infect new cells. CI-1012 is one of two zinc-finger inhibitors that are now in clinical trials. Additionally, researchers at the National Cancer Institute are studying ways to potentially create a HIV vaccine from NC-mutant HIV strains with inactive zinc fingers.

Fusion inhibitors. T-20 is a new drug from Trimeris Inc. that fights HIV by interfering with the virus's ability to attach to a cell membrane. This novel antiviral drug is designed to block both virus-to-cell and cell-to-cell membrane fusion, thereby preventing a critical early step in the spread of viral infection. The drug is administered via a continuous subcutaneous infusion pump (similar to insulin pumps for diabetics). T-20 is presently in Phase II clinical trials.

New drugs. Several other anti-HIV drugs are currently being tested by pharmaceutical companies. They include: MKC-442, a non-nucleoside reverse transcriptase inhibitor from Triangle Pharmaceuticals; ABT-378, a second-generation protease inhibitor from Abbott; and PNU-140690, a third-generation nonpeptidic protease inhibitor from Pharmacia Upjohn. It is expected that preliminary findings from these clinical trials will be reported within the next year.

Nursing Implications

HIV drug therapy is rapidly changing and growing, as new knowledge about the virus evolves. Helping educate patients about new treatment options will continue to be an important component of nursing practice.

Issues with noncompliance or nonadherence to medication therapy has become a major topic in HIV care. The drugs are expensive and if doses are skipped, the patient runs the risk of viral mutation leading to drug resistance. Nurses can assist patients in adhering to their drug schedule by helping them select medication regimes that are compatible with the patient's lifestyle. The more complicated regimens that require multiple pills and every 8 hour dosing may not be the protocol of choice for the active individual, or the disorganized person. Interventions to enhance compliance can include supervised therapy, improving the nurse-client relationship, and patient education. These need to be combined with ethnocentric interventions, incorporate personspecific variables, and be tailored to individual needs (Crespo-Fierro, 1997). Clinicians should encourage the active participation of HIV-positive persons in their own treatment to help patients take their medications more successfully (Lerner, Gulick, & Dubler, 1998). Additionally, when patients on HIV combination therapy are hospitalized, nurses can help promote adherence by ensuring that patients are allowed to continue to take their medications, adjusting the institution's routine medication schedule to concur with the patient's home medication schedule, and checking with the physician before holding medications when the patient is placed NPO for a routine procedure (Jones, Holloman, & Baggett, 1998).

Conclusion

Adult health nurses in general and advanced practice roles are challenged to stay abreast of the latest developments in treatment protocols for HIV/AIDS. A number of promising agents have been released in the last 18 months. These drugs are frequently employed in combination with other drugs currently in use and with new medications. Because of the cost and complexity of treatment protocols, the effects of the disease, and patient factors, adherence to these complex and demanding protocols is not always easy or complete. Consequently, while the promise of more effective medications to treat HIV/AIDS offers hope for the future, the disease still presents many serious obstacles for the health care team.

References

Barditch-Crovo, P., Toole, J., Hendrix, C.W., Cundy, K.C., Ebeling, D., Jaffe, H.S., & Lietman, P.S. (1997). Anti-HIV activity, safety and pharmacokinetics of adefovir dipivoxil in HIV-infected patients. Journal of Infectious Diseases, 176(2), 406-413.

Carmichael, C. (1998). Epidemiology of HIV. Florida AETC Network HIV/AIDS Newsletter, 23, 1-5.

Crespo-Fierro, M. (1997). Compliance/adherence and care management in HIV disease. Journal of the Association of Nurses in AIDS Care, 8(4), 43-54.

Deeks, S.G. (1998). Antiretroviral agents: The next generation. AIDS Clinical Care, 10(5), 33-36, 39.

Jones, S.G., Holloman, F., & Baggett, T. (1998). Compliance: Do we practice what we preach? Conference Proceedings Book, 11th Annual Conference of the Association of Nurses in AIDS Care, November 16, 1998, San Antonio, TX, p. 80.

Lerner, B.H., Gulick, R.M., & Dubler, N.N. (1998). Rethinking nonadherence: Historical perspectives on triple-drug therapy for HIV disease. Annals of Internal Medicine, 129(7), 573-578.

Rochon, D. (1998). Emerging Issues in HIV treatment. HIV Frontline, 32, 1-3.

Steinhart, C. (1998). Clinical practice update. Florida AETC Network HIV/AIDS Newsletter, 24, 1-4, 9.

Sande Gracia Jones, PhD(c), ARNP, ACRN, C, CS, is a Clinical Nurse Specialist/Nurse Practitioner, AIDS/TB, HIV Critical Pathways Program, Mount Sinai Medical Center, Miami Beach, FL, and is a doctoral nursing candidate at Barry University, Miami.

Thomas H. Baggett, RPh, MBA, is Clinical Pharmacist, Special Immunology/Oncology, Mount Sinai Medical Center, Miami Beach, FL.
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Author:Jones, Sande Gracia; Baggett, Thomas H.
Publication:MedSurg Nursing
Geographic Code:1USA
Date:Apr 1, 1999
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