HIV/AIDS: A Primer for Pharmacists

Release Date: August 1, 2010

Expiration Date: August 31, 2012

FACULTY:

Suzanne Albrecht, PharmD, MSLIS
Freelance Medical Writer
Woodstock, Illinois

FACULTY DISCLOSURE STATEMENTS:

Dr. Albrecht has no actual or potential conflicts of interest in relation to this activity.

Postgraduate Healthcare Education, LLC, does not view the existence of relationships as an implication of bias or that the value of the material is decreased. The content of the activity was planned to be balanced, objective, and scientifically rigorous. Occasionally, authors may express opinions that represent their own viewpoint. Conclusions drawn by participants should be derived from objective analysis of scientific data.

ACCREDITATION STATEMENT:

Pharmacy
acpePostgraduate Healthcare Education, LLC is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.
UAN: 0430-0000-10-025-H02-P
Credits: 2.0 hours (0.20 ceu)
Type of Activity: Knowledge

TARGET AUDIENCE:

This accredited activity is targeted to pharmacists. Estimated time to complete this activity is 120 minutes.

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DISCLAIMER:

Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patients’ conditions and possible contraindications or dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities.

GOAL:

To provide an overview of HIV and AIDS, including clinical features, diagnosis, and treatment strategies.

OBJECTIVES:

After completing this activity, the participant should be able to:

  1. Explain the life cycle of HIV, including tropism.
  2. Identify means of transmission and risk factors.
  3. Explain HIV testing, including when it is indicated.
  4. Describe the antiretroviral therapy (ART) agents from each of the five classes.
  5. Evaluate a patient’s medical history and select the appropriate ART.

AIDS is a serious and often fatal condition marked by a severe compromise in immunity. Caused by HIV, AIDS was first recognized in 1981.1 An estimated 1.1 million people in the United States were infected with diagnosed or undiagnosed HIV/AIDS at the end of 2006. Based on numbers given by the 34 states that reported new diagnoses in 2006, the Centers for Disease Control and Prevention (CDC) estimated an additional 56,300 new cases nationwide in 2006.2 More than 44,000 new cases—74% occurring in males—were diagnosed in those states in 2007.2

Since 2008, all 50 states, the District of Columbia, and five dependent areas (American Samoa, Guam, the U.S. Virgin Islands, Puerto Rico, and the Northern Mariana Islands) have used the same confidential name-based system to report HIV/AIDS data. This facilitates compilation of data.3

To enable the standardization of reporting and compiling public-health data, HIV is classified into three stages. In 2008, this classification system was revised and a new HIV-infection case definition was developed. This definition does not pertain to clinical diagnosis; it is meant for reportable cases only, to aid in public-health surveillance.4 One criterion for HIV infection in adults and adolescents aged ≥13 years is a positive result from an HIV antibody screening test (i.e., enzyme-linked immunosorbent assay [ELISA]) confirmed by positive result from a supplemental HIV antibody screening test (i.e., Western blot or indirect immunofluorescence assay). An alternative criterion is a positive result or a report of a detectable quantity on any of the following HIV virologic tests: HIV nucleic acid (either DNA or RNA) detection, HIV p24 antigen, or HIV isolation (culture).4

HIV infection is classified as stage 1, stage 2, stage 3, or stage unknown. Stage 1 is a CD4 T-cell count ≥500/mcL or CD4 T-cell percentage of total lymphocytes of ≥29 and no AIDS-defining condition. Stage 2 is a CD4 T-cell count between 200 and 499 cells/ mcL or CD4 T-cell percentage of total lymphocytes between 14 and 28 and no AIDS-defining condition. Stage 3 (AIDS) is a CD4 T-cell count 200/mcL or CD4 T-cell percentage of total lymphocytes of <14 or documentation of an AIDS-defining condition. Stage unknown means that there is no information on CD4 T-cell count or percentage or on AIDS-defining conditions. Classification always goes from less severe to more severe; once an infection has been classified, it cannot be reclassified to a less severe stage. If the CD4 T-cell count and the CD4 T-cell percentage are available but fall into different stages, the more severe stage is selected.4

HIV and Its Life Cycle

HIV is a single-stranded (RNA) retrovirus. Transcription is the process of synthesizing RNA from a DNA template. In the case of retroviruses, this process is reversed. In HIV, DNA is synthesized using the viral RNA as a template via an enzyme called reverse transcriptase (RT).1 There are two types of HIV: HIV-1 and HIV-2. HIV-1 causes the majority of AIDS cases.1 HIV-2 is less virulent and less transmissible, but it still can cause AIDS.1

The replication cycle of HIV-1 is divided into two phases: the early phase and the late phase. The early phase starts with the virus entering the cell.5 Glycoprotein 120 (gp120) on the surface of the HIV-1 virus binds to a primary binding site on CD4 cells.1,5 After binding to gp120, the virus reacts with a chemokine coreceptor, a process called tropism.1,5 The two major coreceptors used by HIV are CC-chemokine receptor 5 (CCR5) and CXC chemokine receptor 4 (CXCR4).1,5,6 HIV strains that affect T cells use CXCR4 as the major coreceptor (T-tropic, or X4, strains); strains that use CCR5 as the major coreceptor infect macrophages (M-tropic, or R5, strains).5,6 Strains that use both receptors are dual-tropic. A patient may be infected with one of these strains, or with a mixture of strains. R5 strains, the variants most often transmitted, are responsible for most sexually transmitted infections.1,6 R5 strains are non–syncytium-inducing (syncytium is a fusion of cells).1

In the early course of HIV infection, R5 is the dominant strain.6 X4 infection occurs later in the disease progression and is syncytium-inducing.1 Upon interaction with the coreceptor, there is a conformational change of the HIV-1 glycoprotein 41 (gp41) that allows fusion of the viral and cellular membranes.5 Once the viral RNA enters the cell, RT transcribes the viral RNA into a double-stranded DNA molecule. Upon completion of reverse transcription, the DNA is integrated into the host nuclear chromosomes via an enzyme called integrase.1,5 Integration is problematic because it allows for a chronic latent infection. In essence, the HIV is “hidden” in the cells. For this reason, the ability to cure HIV has been greatly hampered.1

The late phase of the life cycle starts with transcription of the viral DNA to RNA via the host’s RNA polymerase II.5 After replication of the viral RNA, the necessary proteins are synthesized, resulting in a nucleocapsid that encompasses the single-stranded viral RNA.1,5 This is the immature virion, which buds through the host membrane.1,5 Immature virions are incapable of infecting host cells.1 Maturation into infectious virus occurs via an enzyme called protease.1,5 Ultimately, most host cells and some uninfected bystander cells are destroyed through cell lysis caused by the budding virions, T lymphocyte–induced cell killing, formation of syncytia, and aptosis.1

Transmission

HIV is primarily transmitted sexually, parenterally, or perinatally (also called vertical transmission).1 For women, the risk factors are heterosexual sex (83%) and injection-drug use (16%). For men, the main risk factors are having sex with men (71%), heterosexual sex (14%), and injection-drug use (10%).2

With sexual transmission, there is a higher risk with receptive intercourse than with insertive intercourse.1 There are some strategies for reducing the risk of sexual transmission. Using a condom reduces the risk of transmitting HIV by 20-fold.1 Circumcision has been estimated to reduce the risk of HIV transmission by 60%.1 Casual contact with an infected individual is not a significant risk factor.1

The use of contaminated needles by drug abusers is the most common means by which the virus is transmitted parenterally.1 Health care workers have a small risk of contracting the virus, most commonly by a needlestick. There is a 0.3% risk of transmitting HIV via a percutaneous needlestick injury and a 0.09% risk after exposure to a mucous membrane.7 Certain factors increase the likelihood of HIV transmission. One factor is exposure to a larger quantity of infected blood (e.g., from a device—i.e., needle—in which blood is visible; a device placed directly into a vein or artery; or a deep injury); another factor is exposure to blood from a person with a terminal illness.7 Because the health care system follows rigorous screening practices, it is extremely rare for parenteral transmission to occur through blood or tissue products.1

Perinatal, or vertical, transmission occurs when the virus is transmitted from mother to fetus or infant. This is the most common cause of pediatric infection.1 Although transmission can sometimes take place in utero, it most often occurs close to the time of birth or during birth.1 The virus may also be transmitted through breastfeeding. For this reason, HIV-positive mothers are discouraged from breastfeeding.1 Without antiretroviral therapy (ART) and breastfeeding, there is a 25% risk of mother-to-infant transmission. ART decreases this risk.1

It is of paramount importance to counsel patients that even when their viral load is below detectable levels (approximately 50 copies/mL) and they are asymptomatic, they are still infectious and should avoid sexual and drug-use behaviors associated with HIV transmission.1

Signs and Symptoms

While the clinical presentation of HIV infection can vary, in 40% to 90% of cases it resembles mononucleosis. Symptoms include sore throat, fever, fatigue, weight loss, myalgia, diarrhea, nausea, vomiting, lymphadenopathy, and night sweats. In 40% to 80% of patients, a morbilliform (measleslike) or maculopapular rash may be visible on the trunk. A high viral load (106 copies/mL) is present during primary HIV infection, along with a low CD4 cell count. Symptoms may last up to 2 weeks, and 15% of patients may require hospitalization.1 Symptoms will eventually resolve in response to the innate immunologic reaction to the presence of the virus. Even though plasma RNA decreases substantially during this time, HIV replication continues at approximately 10 billion viruses per day, along with the destruction of the immune system.1 In the absence of treatment, the viral load will eventually stabilize at a certain level called the set point. The set point corresponds directly to the time of onset of AIDS morbidity and mortality; i.e., the higher the set point, the worse the prognosis.1

HIV Testing

It takes at least 3 to 4 weeks from the time of initial exposure for the body to develop antibodies to the virus. By 6 months, 95% of individuals will have manufactured antibodies against HIV-1.1

A number of tests are available to detect the presence of HIV infection. The most common is the ELISA, which detects the presence of antibodies to HIV-1.1 Other technologies include Western blot and immunofluorescence assay, which are used as confirmatory tests, and polymerase chain reaction tests for HIV nucleic acids.1,8 These assays all require a sample of plasma, serum, or oral fluid.8

In 1996, an anonymous home-testing kit, the Home Access HIV-1 Test System (also marketed under the name Home Access HIV-1 Express Test System), was approved by the FDA. The patient mails in a dried blood spot and calls for the results in a week. This is currently the only FDA-approved test kit on the market.8

The CDC has issued recommendations for HIV testing. These recommendations appear below.

Adults and Adolescents: The CDC recommends that, in all health care settings (e.g., hospital emergency departments, urgent-care clinics, inpatient services, sexually transmitted disease [STD] clinics, substance-abuse treatment clinics, tuberculosis clinics, other public-health clinics, community clinics, correctional health care facilities, and primary care settings), HIV screening be performed routinely in all patients aged 13 to 64 years unless the prevalence of undiagnosed HIV infection in the patient population of that location has been documented to be less than 1 in 1,000 patients. If the percentage of undiagnosed individuals is not known, voluntary screening should be started.

All patients who begin treatment for tuberculosis (TB) should be routinely screened. All patients receiving treatment for STDs should be screened after each occurrence, regardless of whether they are engaging in high-risk behavior.9 Patients engaging in high-risk behaviors (injection-drug users and their sex partners, those who exchange sex for money or drugs, sex partners of HIV-infected people, men who have sex with men, and heterosexual individuals who have had [or whose partner has had] more than 1 sex partner since their last HIV test) should be tested at least once per year.9 Patients should be encouraged to be tested before starting a new sexual relationship. Whenever a health care provider has been exposed to a patient’s blood or bodily fluids, the patient should be informed of the incident and tested for HIV unless recent test results are available.9

Testing should be on an opt-out basis, meaning that the patient should be informed verbally or in writing that the test will be performed and then be given the option of declining the test. The informed consent should include an explanation of HIV infection and the implications of negative or positive results. A separate consent for HIV testing is not recommended; it should be incorporated into the patient’s general consent form for medical care. If a patient declines an HIV test, this should be documented in the patient’s medical record.9

Adults and Adolescents Presenting With Signs or Symptoms: Diagnostic testing should be performed in all patients presenting with signs or symptoms of HIV infection or an opportunistic infection characteristic of AIDS. In this case, a plasma RNA test should be done, along with an HIV antibody test.9 It should be verbally explained to the patient that testing will be performed, why testing is indicated, and what the implications of a positive or negative result are. The patient should then be given the opportunity to decline testing. Once the patient has been informed, his or her general consent for medical treatment should be considered sufficient for diagnostic HIV testing. Testing should always be voluntary, and there should be access to clinical care, prevention counseling, and support services for patients who test positive.9

Pregnant Women and Their Infants: The CDC recommends that all pregnant women be screened for HIV infection along with the normal prenatal screens. An opt-out system should be employed that enables the patient to decline testing after being informed that testing is advised.9 The patient should receive verbal or written information that includes an explanation of HIV infection, a description of interventions that can employed to prevent mother-to-infant transmission, and an explanation of positive and negative results.9 If the patient declines HIV testing, this should be noted in her medical record. Women should be tested as early as possible during each pregnancy; a patient who declines should be encouraged to reconsider at a subsequent visit. A second HIV test during the third trimester is indicated in patients who receive health care in areas with a high incidence of HIV/ AIDS in women aged 15 to 45 years; patients who receive health care in facilities that identify at least 1 HIV-infected pregnant woman per 1,000; patients who engage in high-risk behaviors; and patients who have signs or symptoms consistent with acute HIV infection. In the last scenario, a plasma RNA test should be conducted, along with an anti-HIV antibody test.9

During labor, a rapid HIV test should be performed in a patient without a documented HIV status, unless she opts out. If the results of the rapid test are positive, prophylactic ART should be started immediately, before confirmation is received.9

If the mother’s HIV status is unknown, a rapid HIV test should be done on the infant, unless the mother declines. If positive, prophylactic ART should be started. It is most effective when initiated within the first 12 hours after birth.9

Monitoring Disease Progression

HIV infection is monitored using two surrogate markers: CD4 cell count and viral load. Viral load, which determines the amount of virus in the blood, is reported as copies of HIV RNA per mL of plasma.1 The extent of HIV replication is demonstrated by the level of plasma HIV RNA. The CD4 cell count is measured in cells per microliter. Higher viral loads are associated with a greater rate of CD4 cell destruction, whereas the CD4 cell count is a measure of the damage already done to the immune system by HIV infection.1 CD4 cell counts and HIV-1 RNA measurements should be determined at baseline.6 The CD4 cell count should be tested every 3 to 4 months in order to determine when to start ART, response to therapy, and whether a medication alteration is needed.10 Viral load is the most important indicator of therapeutic response. Ideally, a patient’s viral load should be below the limit of detection—approximately 50 copies/mL.6,10 This is usually accomplished within 12 to 24 weeks following initiation of ART.10

Antiretroviral Therapy

Since HIV is incurable and can never be completely cleared from the body, the goals of ART are to maximize the suppression of viral replication and to preserve immunologic function.6 These goals are usually accomplished by reducing the plasma HIV-1 RNA level to less than 50 copies/mL and maintaining it at that level.6

ART can prevent vertical transmission of HIV. It also is used prophylactically in the case of HIV exposure.6

Upon initiation of ART, a condition known as immune reconstitution syndrome may occur. This is an immune response to inactive or residual opportunistic infections. Another phenomenon commonly seen with ART is a redistribution of fat. Abdominal fat accumulation, dorsocervical fat enlargement (buffalo hump), peripheral wasting, enlargement of the breasts, and cushingoid appearance may occur.11 These adverse events are not specific to any one ART combination; they have been observed in different combinations.11

There are 32 FDA-approved products on the market for the treatment of AIDS. These include single agents and combination products with two or three agents. The existence of combination products means that it is important to ensure that there is no duplication of ingredients. The patient should be counseled on each agent and advised about accidental duplication. Currently, six classes of drugs are available: nucleoside RT inhibitors (NRTIs), nonnucleoside RT inhibitors (NNRTIs), protease inhibitors (PIs), a fusion inhibitor, an entry inhibitor, and an integrase strand transfer inhibitor. The patient must be on more than one medication in order to improve efficacy and prevent resistance.1

Nucleoside RT Inhibitors

NRTIs work in two ways. Upon phosphorylation, they compete with the natural substrate of RT. They are then incorporated in the viral DNA, which results in DNA chain termination.6,11 As a class, they can cause myopathy, hepatic steatosis, neuropathy, and lactic acidosis.5 Patients should be aware of the signs and symptoms of lactic acidosis, which include weakness, myalgia, dyspnea, unusual or unexpected stomach discomfort (including nausea, vomiting, or pain), dizziness, arrhythmia or tachycardia, and feeling cold (especially the limbs).11 Patients must be counseled that lactic acidosis is a medical emergency.

Currently, seven NRTI moieties are available. Cross-resistance has been documented between members of this class.5

Emtricitabine (Emtriva): Approved in July 2003. In patients co-infected with HIV and hepatitis B virus (HBV), there have been cases of acute exacerbations of HBV upon discontinuation of emtricitabine. Liver function should be monitored for several months after the drug is stopped, and anti-HBV therapy may be needed. Because emtricitabine does not inhibit CYP450 enzymes, no dose adjustment is necessary for hepatic impairment. However, if the creatinine clearance is less than 50 mL/min or dialysis is required, the dose should be reduced or the dosing interval should be increased. Emtricitabine may be taken with or without food and is pregnancy category C.11

Lamivudine (Epivir): Approved in November 1995. Lamivudine is also approved for the treatment of HBV (Epivir-HBV, which contains a lower concentration of the drug). As with emtricitabine, caution should be exercised when discontinuing lamivudine in HBV–co-infected patients. Acute HBV exacerbations may occur. Lamivudine is primarily eliminated unchanged by the kidneys. Dosing should be modified in patients with renal impairment. Hepatic impairment should not require any alteration in dose. Lamivudine may be taken without regard to food and is pregnancy category C.12

Zidovudine (Retrovir): Approved in March 1987. Bone-marrow suppression and symptomatic myopathy have been associated with the use of zidovudine. Patients coinfected with hepatitis C virus (HCV) who are taking ribavirin have suffered exacerbations of anemia. Some HCV–co-infected patients taking interferon alfa with or without ribavirin have experienced hepatic decompensation (sometimes fatal). Dosing may need to be adjusted for renal or hepatic dysfunction. Zidovudine may be taken with or without food and is pregnancy category C.13

Didanosine (Videx, Videx EC): Approved in October 1991; enteric-coated capsule approved in October 2000. Pancreatitis (sometimes fatal) has been associated with the use of didanosine. Other adverse events include noncirrhotic portal hypertension and optic neuritis (inflammation of the optic nerve). In pregnant women, lactic acidosis (fatal) has occurred when didanosine was given concomitantly with stavudine. The dose of didanosine should be reduced for renal impairment. Didanosine must be taken on an empty stomach and is pregnancy category C.14

Tenofovir (Viread): Approved in October 2001. This drug is indicated for HBV also. As with emtricitabine and lamivudine, there have been instances of acute exacerbations of HBV in co-infected patients upon stopping tenofovir. Loss of bone mineral density has been reported with the use of the drug. Tenofovir is not metabolized by CYP450 enzymes, but the dose should be reduced for moderate-to-severe renal impairment. The drug may be taken without regard to food and is pregnancy category B.15

Stavudine (Zerit, Zerit XR): Approved in June 1994. Pancreatitis has occurred when this drug was taken in combination with didanosine. It is of interest to note that pancreatitis has been reported in patients taking didanosine alone. Because stavudine is minimally metabolized in the liver, dose reduction is not indicated for hepatic impairment.16 Renal function should be assessed prior to initiation of tenofovir, as well as regularly throughout treatment, to determine whether it is necessary to discontinue the drug, modify the dose, or replace it altogether.6 With renal impairment or dialysis, however, a decrease in dose is recommended. Stavudine may be taken with or without food and is pregnancy category C.16

Abacavir (Ziagen): Approved in December 1999. Abacavir has been associated with serious, sometimes fatal, multiorgan hypersensitivity reactions. There is a genetic predisposition to this reaction, and patients who carry the HLA-B*5701 allele are at higher risk. However, a hypersensitivity reaction can take place in someone who does not have this allele. If a hypersensitivity reaction occurs, the drug should be stopped and never be restarted. A medication card must be dispensed with every new prescription and refill. Abacavir is contraindicated in moderate-to-severe hepatic impairment, and patients with renal impairment require a dose reduction. Abacavir may be taken without regard to food and is pregnancy category C.17

Nonnucleoside RT Inhibitors

NNRTIs bind noncompetitively to RT at a different site than do NRTIs. Because the two classes bind at different sites, they may be given together.1 There is no benefit to combining two NNRTIs, however.18 Since NNRTIs are metabolized by CYP3A (and, in some cases, other CYP isoforms), there are many drugs that must be used with caution or avoided altogether. These include ergot derivatives, cisapride, pimozide, St. John’s wort, midazolam, triazolam, clarithromycin, azole antifungals, certain calcium channel blockers, certain antiarrythmics, warfarin, hydroxymethyl glutaryl coenzyme inhibitors, rifabutin, rifampin, certain immunosuppressants, phosphodiesterase type 5 inhibitors, and ethinyl estradiol.18-21 This list is not comprehensive. The pharmacist must review each prescription thoroughly to evaluate other potential interactions. Serious, sometimes fatal, skin reactions can occur with NNRTIs; overall, however, less toxicity is associated with NNRTIs than with NRTIs.5 Resistance develops quickly with NNRTIs, but this may be slowed if NNRTIs are taken with NRTIs.5

There are four NNRTIs. Cross-resistance has been documented between members of this class.1

Etavirine (Intelence): Approved in January 2008. Peripheral neuropathy has been reported with the use of etavirine. No dosage adjustment is required for mild-to-moderate hepatic or renal impairment. Etavirine should be taken following a meal and is pregnancy category B.18

Delaviridine (Rescriptor): Approved in April 1997. It may be given with or without food and is pregnancy category C.19

Efavirenz (Sustiva): Approved in September 1998. Severe depression, suicidal ideation, nervous system symptoms (dizziness, insomnia, impaired concentration, somnolence, abnormal dreams, hallucinations) can occur within 1 to 2 days of initiation and usually resolve in 2 to 4 weeks. Taking the drug at bedtime can help alleviate these symptoms. Hepatotoxicity (especially with pre-existing hepatic disease or co-infection with HBV or HCV), convulsions, and hyperlipidemia have been reported with efavirenz. The drug should be taken on an empty stomach. Efavirenz is pregnancy category D, and fetal harm can occur in the first trimester.20

Nevirapine (Viramune): Approved in June 1996. Hepatotoxicity, sometimes fatal, has been reported with nevirapine. If hepatotoxicity should occur, the drug should be stopped and never be restarted. Nevirapine is contraindicated in moderate-to-severe hepatic impairment. There is no need for dose adjustment for renal impairment. Nevirapine may be taken without regard to food and is pregnancy category B.21

Protease Inhibitors

PIs bind to the viral enzyme protease in the late phase of the viral replication life cycle. They prevent cleavage of the viral Gag and Gag-Pol polyproteins, thereby preventing the maturation of virions. (Only mature virions can infect other cells.)1,5,22 As a class, PIs have the potential to cause hyperglycemia, hyperlipidemia, and severe (sometimes fatal) skin rashes. The patient may develop diabetes mellitus (DM) or lose glycemic control of pre-existing DM. There also have been reports of spontaneous bleeding in patients with hemophilia, and many PIs can cause clinical hepatitis.22-31 Like NRTIs, PIs are primarily metabolized by the CYP3A enzyme system, so these classes share some common drug reactions. They have in common those interactions listed for NRTIs. In addition, PIs interact with fluticasone, salmeterol, alfuzosin, bosentan, colchicine, certain antacids (including proton pump inhibitors and H-5 antagonists), and dexamethasone.22-31 There are also other interactions specific to each individual entity. Ritonavir (a PI) inhibits the metabolism of other PIs, and it is always used in combination with other PIs to boost their concentration.1

There are currently 10 PIs. Cross-resistance has been documented between members of this class.22

Amprenavir (Agenerase): Approved in April 1999. Amprenavir is a sulfonamide. The capsules contain vitamin E, so patients should be advised not to use vitamin E supplements. The capsules and oral solution are not equivalent on a mg-per-mg basis. The oral solution contains a large amount of propylene glycol and is contraindicated in children under the age of 4 years. Amprenavir may be taken with or without food; however, it should not be taken with a high-fat meal. The drug is pregnancy category C, but the oral solution should not be given to pregnant women owing to its high propylene glycol content.22

Tipranavir (Aptivus): Approved in June 2005. The drug has been associated with fatal and nonfatal intracranial hemorrhages. Like amprenavir, tipranavir is a sulfonamide, and the oral solution contains vitamin E, which is used as a surfactant. Tipranavir should not be given to treatment-naïve patients. It is used in patients who are infected with a strain that is resistant to one or more of the PIs. Although this has not been studied, there should be no need for a dose reduction for renal impairment. Tipranavir may be taken without regard to food and is pregnancy category C.23

Indinavir (Crixivan): Approved in March 1996. Acute hemolytic anemia, sometimes fatal, has been associated with this drug. Other things to watch for include nephrolithiasis or urolithiasis, hyperbilirubinemia, and interstitial nephritis. Indinavir should be taken on an empty stomach, but it may be taken with low-fat, low-calorie food or drink. It is pregnancy category C.24

Saquinavir (Invirase): Approved in December 1995. Renal impairment should have no effect on dosing, although this has not been studied. Saquinavir should not be taken within 2 hours of a meal and is pregnancy category B.25

Lopinavir/Ritonavir (Kaletra): Approved in September 2000. Pancreatitis has been reported with the use of lopinavir/ritonavir. Hyperlipidemia is a risk factor. Since ritonavir is included in this formulation, all precautions for ritonavir should be considered. Dose adjustment for renal impairment should not be necessary with lopinavir/ritonavir, although this has not been studied. The product should be taken with food and is pregnancy category C.26

Fosamprenavir (Lexiva): Approved in October 2003. Fosamprenavir has been associated with hemolytic anemia and nephrolithiasis. The tablets may be taken with or without food, but the oral suspension must be taken with food in children and without food in adults. Fosamprenavir is pregnancy category C.27

Ritonavir (Norvir): Approved in March 1996. Pancreatitis has been reported with the use of ritonavir. Ritonavir also has been shown to cause PR interval elongation, so caution must be exercised in patients with ischemic disease, myopathy, or arrhythmia. No dose reduction is needed for mild-to-moderate hepatic or renal insufficiency. Ritonavir should be taken with food and swallowed whole, not crushed or chewed. It is pregnancy category B.28

Darunavir (Prezista): Approved in June 2006. Darunavir is a sulfonamide. It does not require a dose adjustment in patients with mild-to-moderate hepatic or renal impairment. Darunavir is not recommended in patients with severe hepatic impairment. It should be taken with food and is pregnancy category C.29

Atazanavir (Reyataz): Approved in June 2003. Most patients taking atazanavir experience asymptomatic hyperbilirubinemia, which does not require a dose reduction. Nephrolithiasis has been reported in patients taking atazanavir. The drug should not be administered to patients with severe hepatic impairment, and it is not recommended in patients with any stage of hepatic impairment. Atazanavir may require a dose reduction for renal impairment. It should be taken with food and is pregnancy category C.30

Nelfinavir (Viracept): Approved in March 1997. Viracept oral powder contains phenylalanine. Patients with phenylketonuria should avoid the powder dosage form. Dose reduction probably is not necessary in patients with renal impairment. Nelfinavir should be taken with food and is pregnancy category B.31

Fusion Inhibitor: Enfuvirtide

Currently the only approved (March 2003) fusion inhibitor, enfuvirtide (Fuzeon) prevents fusion of the HIV-1 and CD4 cellular membranes by binding to the viral gp41 site. If the virus cannot fuse with the cellular membrane, it cannot enter the cell. Enfuvirtide is injected subcutaneously twice daily. The injection site must be rotated each time. The drug does not inhibit CYP450 enzymes, and no dose adjustment is required for hepatic or renal impairment. It is pregnancy category C.32

Entry Inhibitor (CCR5 Antagonist): Maraviroc

Maraviroc (Selzentry) was approved in August 2007. It blocks the CCR5 chemokine coreceptor, which prevents R5 HIV-1 from entering the CD4 cells.33 Tropism needs to be determined to assess whether maraviroc will be of benefit.6 An allergic reaction resulting in hepatic toxicity has been reported with maraviroc. An increased risk of myocardial infarction and ischemic disease also has been observed. Caution should be used in hepatic impairment and/or cardiovascular disease. Other adverse reactions are upper respiratory infections, pyrexia, cough, rash, and dizziness. A substrate of CYP3A, maraviroc has the potential to interact with medications metabolized by the same isoform. It may be taken with or without food and is pregnancy category C.33

Integrase Strand Transfer Inhibitor: Raltegravir

Raltegravir (Isentress), approved in October 2007, inhibits the HIV enzyme integrase, thereby rendering viral DNA incapable of being inserted (or integrated) into the host cell genome. Myopathy and rhabdomyolysis (and elevated creatinine kinase) have been reported with the use of raltegravir. Dose adjustment is not necessary for renal impairment or mild-to-moderate hepatic impairment. It may be taken with or without food and is pregnancy category C.34

Treatment Guidelines

The U.S. Department of Health and Human Services (DHHS) published updated guidelines for the treatment of HIV/AIDS in December 2009.10 It is important to note that research is constantly being done, and ideas concerning the management of HIV/AIDS change quickly. Practitioners need to keep abreast of these changes in order to provide optimal treatment.

Upon initial diagnosis, certain tests should be performed. These include CD4 cell count, viral load, resistance testing (to determine drug susceptibility), HBV, basic chemistry (electrolytes, blood urea nitrogen, serum creatinine, fasting glucose), liver-function tests, fasting lipid profile, and urinalysis (to determine renal function).10

When to initiate therapy is contingent upon many factors. No evidence points to any benefit of starting ART upon initial diagnosis. Things to be considered include the number and frequency of pills, comorbid conditions, expected tolerability of the regimen, medication costs, expected patient adherence, and potential adverse events (both long- and short-term). Once treatment is started, it may not be discontinued.6 The risks of ART are drug toxicity and viral resistance.

There are risks in delaying initiation of ART. Untreated HIV infection has been shown to be associated with many non–AIDS-defining conditions such as cardiovascular disease, kidney disease, liver disease, and malignancy.10

Monitoring Treatment Efficacy

CD4 cell count is used to determine whether a treatment regimen is working. An increase in CD4 cell count of 50 to 150 cells/mm3 per year is considered an adequate response. There should be greater progress in the first 3 months.10 CD4 cell count should be tested every 3 to 4 months.

Viral load is used to determine response to ART. This should be tested within 2 to 4 weeks (but not more than 8 weeks) of initiating treatment. It should then be measured every 4 to 8 weeks until it falls below the limit of detection. After a regimen is changed, viral load should be determined within the first 2 to 8 weeks of the alteration. Once the patient is stable on the regimen, viral load should be rechecked every 3 to 4 months.10

Initiating ART

When to initiate treatment should be made on a case-by-case basis. As noted earlier, there are pros and cons to starting ART early and to delaying ART. The DHHS has issued guidelines on when to start ART in treatment-naïve patients (TABLE 1).10

table 1

Certain factors must be considered when an initial ART regimen is being selected. Things that must all be taken into account are comorbid conditions (cardiovascular disease, chemical dependency, liver disease, psychiatric illness, renal disease, TB); potential drug toxicities; potential drug interactions; pregnancy status (or potential to become pregnant); results of drug-resistance testing; gender and CD4 cell count, if considering nevirapine; HLA-B*5701 testing, if considering abacavir; tropism, if considering maraviroc; patient compliance; and convenience (pill burden, dosing schedule, food and fluid considerations).10 The DHHS recommends that a treatment-naïve patient be placed on two NRTIs and a ritonavir-boosted PI, an NNRTI, or an integrase strand transfer inhibitor (presently, only raltegravir is approved).10 The preferred regimens are tenofovir/emtricitabine (NRTIs) and efavirenz (NNRTI) or atazanavir/ritonavir (or darunavir/ritonavir, if patient is taking >20 mg omeprazole daily) (PI), or raltegravir.

If there are contraindications or other reasons the patient cannot be started on one of these regimens, the DHHS guidelines suggest alternative regimens. These alternative regimens are effective and tolerable, but are not considered ideal. The NNRTI-based regimens are lamivudine/abacavir or zidovudine (NRTI) and efavirenz (NNRTI) or zidovudine/lamivudine and nevirapine (NNRTI). The PI-based regimens are lamivudine/abacavir or zidovudine and atazanavir/ritonavir (PI), or fosamprenavir and either lamivudine/abacavir or zidovudine or tenofovir/emtricitabine, or lopinavir/ritonavir and either lamivudine/abacavir or zidovudine or tenofovir/emtricitabine, or saquinavir and tenofovir/emtricitabine. There are other acceptable regimens, but they are less satisfactory and should be used only if any of the above regimens prove impossible.10

If the patient experiences immunologic failure, the possible causes need to be assessed. These may include noncompliance, pharmacokinetic issues (such as drug interactions, not taking as directed with regard to food, or malabsorption issues), or drug resistance.10 Substitutions must be made as appropriate, with consideration given to exposure to previous drugs, current medications (and potential adverse reactions or drug interactions), resistance testing, and the patient’s ability to adhere to the medication schedule.

Prophylaxis

There are guidelines to prevent HIV infection after exposure to the virus. There are guidelines for prophylaxis for health care workers, for perinatal transmission, and for nonoccupational exposure. See TABLE 2.

table 2

Conclusion

The management of HIV is multifaceted and complex. Many agents from five different classes of drugs are available. To maximize efficacy and prevent the development of resistance, a patient needs to be taking at least two drugs; a three-drug regimen is preferred. The pharmacist has an integral role in the management of HIV-infected patients. Noncompliance is a major reason for the development of drug resistance; the pharmacist, by scrutinizing the patient’s drug regimen for duplication, potential interactions, and toxicity, can work with the patient to maximize compliance and therapeutic outcomes. Since research is ongoing and the concepts regarding the management of HIV infection are always evolving, it is the duty of the pharmacist to keep current with therapeutic guidelines.

REFERENCES

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  8. Food and Drug Administration. Complete list of donor screening assays for infectious agents and HIV diagnostic assays. www.fda.gov/BiologicsBloodVaccines/BloodBlood Products/ApprovedProducts/LicensedProductsBLAs/Blood DonorScreening/InfectiousDisease/ucm080466.htm. Accessed May 18, 2010.
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  10. 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. December 1, 2009:1-161. www.aidsinfo.nih. gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed May 28, 2010.
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  14. Videx EC (didanosine) package insert. Princeton, NJ: Bristol-Myers Squibb; January 2010.
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