Overview of HIV Management and Treatment

Release Date: June 1, 2014

Expiration Date: June 30, 2016

FACULTY:

Donna Sym, PharmD
Associate Clinical Professor
College of Pharmacy and Health Sciences,
St. John's University
Queens, New York
Clinical Preceptor
North Shore University Hospital
Manhasset, New York

John M. Conry, PharmD, BCPS, AAHIVP
Clinical Professor and Assistant Dean
for Service Programs
College of Pharmacy and Health Sciences,
St. John's University
Queens, New York
Clinical Coordinator of Pharmaceutical Care Services
Project Renewal
New York, New York

FACULTY DISCLOSURE STATEMENTS:

Drs. Sym and Conry have 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.

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Pharmacy
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Credits: 2.0 hours (0.20 ceu)
Type of Activity: Knowledge

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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 enhance participants' knowledge about HIV infection, classes of antiretrovirals, and optimal highly active antiretroviral treatment regimens used for HIV therapy.

OBJECTIVES:

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

  1. Discuss the epidemiology and risk factors of HIV infection.
  2. Identify the pathophysiology associated with HIV infection.
  3. Describe various tests utilized in the management of HIV infection.
  4. Review the classes of ARVs used in the treatment of HIV infection and identify barriers to adherence.

ABSTRACT: To date, more than 35 million people worldwide have died from HIV/AIDS. Initially, no treatment options existed, which meant that HIV/AIDS was inevitably a terminal illness; however, the advent of highly active antiretroviral therapy has rendered HIV/AIDS a still potentially life-threatening, but largely chronic and frequently manageable, disease. At present, more than 30 medications are available to treat HIV, and a number of novel agents are being investigated. Pharmacists can use their medication expertise to ensure correct dosing, recommend appropriate combinations, conduct proper screening for drug interactions, and monitor for and help manage adverse effects of treatment.

More than 30 years have passed since HIV was identified as the cause of AIDS. Worldwide, an estimated 36 million people have died secondary to AIDS-related illnesses.1 Although HIV infection remains uncurable, scientific knowledge continues to advance, and medications are being developed to help control replication of the virus and to prevent HIV-related complications. These advances have transformed HIV infection from an acute, inevitably fatal disease to a potentially life-threatening, but frequently manageable, chronic disorder.

With their unique education and skills, pharmacists play an integral role in the management of HIV-infected patients. This article will provide an overview of the current management of HIV, with special emphasis on a detailed review of the various antiretrovirals (ARVs) and their application to patient care. This review focuses on HIV-1—the predominant type of HIV in the United States—and the management of HIV infection in ARV-naïve adults.

Epidemiology

In 2012, approximately 35.3 million people worldwide were living with HIV.1 An estimated 2.3 million people were newly infected in 2012, representing a 33% reduction since 2001. Similarly, AIDS-related deaths have decreased by 30% since peaking in 2005 (2.3 million in 2005 and 1.6 million in 2012, respectively). HIV clearly continues to be a major global public health issue, and despite some significant degree of success, it continues to require attention, improved access to medications and care, research, and funding.

In the U.S., approximately 1.1 million people are infected with HIV.2 To highlight the importance of HIV screening and testing, >15% of HIV-infected persons are unaware of the infection. During the past decade, the number of people with HIV in the U.S. has risen. The increased prevalence is not unexpected and is considered to be largely the result of large-scale access to effective antiretroviral therapy (ART) that prolongs life, along with a relatively stable number of people (approximately 50,000) newly infected with HIV each year.2

Despite increased HIV awareness and education, the rate of new infections in the U.S. continues to be high.2 Among new HIV infections in men, the most likely route of transmission is male-to-male sexual contact, followed by heterosexual sex and then by injection drug use.2,3 Among new HIV infections in women, the most likely route of transmission is heterosexual sex, followed by injection drug use. In 2010, men who have sex with men accounted for 63% of all new HIV infections, heterosexual sex accounted for 25%, and injection drug users accounted for 8%. Mother-to-infant transmission, tainted blood products, and occupational exposure of healthcare workers via needlesticks are other known mechanisms of transmission. HIV disproportionately affects African American and Hispanic/Latino individuals.2

Pathophysiology

After a person is infected with HIV, the virus attacks various cells of the immune system, most notably T-cell lymphocytes. T-cell lymphocytes are frequently referred to as CD4 cells because they have CD4 receptors on their surface, the site of HIV virus attachment. The CD4 cell's vital role is to regulate cell-mediated immunity, thereby fighting infection and maintaining health in an immunocompetent individual. HIV infection of CD4 cells causes their destruction, and the production of new CD4 cells is inhibited. This results in a cyclical process that eventually leads to immune-system destruction and renders the HIV-infected person vulnerable to the development of opportunistic infections, increased morbidity, and mortality. Without ART, the average survival time of an HIV-infected patient is 10 to 15 years.4

HIV Testing

Patients can choose from a variety of FDA-approved, commercially available HIV tests that assess samples of plasma, serum, saliva, oral fluid, or urine for infection. Many of these tests screen for antibodies to HIV-1 and/or HIV-2 (the presence of HIV-1 and/or HIV-2 antibodies indicates that the person's blood has been infected with HIV). Other products test directly for the presence of HIV RNA.

Currently, two anonymous and confidential FDA- approved OTC self-tests are available: the Home Access HIV-1 Test and the OraQuick In-Home HIV Test. For the Home Access test, a dried blood specimen must be mailed to a laboratory for analysis, and results typically are provided in 3 to 7 business days. The OraQuick test requires a sample of fluid from the patient's mouth, with results typically available in 20 to 40 minutes. Patients should be advised that the OraQuick test is a screening test only; confirmation with a diagnostic test is required if the result is positive. More information on testing and a complete list of FDA-approved screening and diagnostic HIV assays are available at www.fda.gov.

These screening and diagnostic tests are highly accurate; however, in rare cases, false-negatives and false- positives may occur. The most common cause of a false-negative result is testing during the period between the initial exposure to HIV and the development of HIV antibodies. It can take up to 2 months for a newly infected person to develop HIV antibodies.4

Management of HIV Infection

Currently, more than 30 different FDA-approved single-formulation and combination ARVs are available to manage HIV infection. ARVs are typically used in combination to maximize their efficacy in HIV treatment, usually incorporating at least two different pharmacologic classes in each regimen. A variety of factors must be taken into account when ART initiation is being considered, including the patient's clinical status, baseline CD4 count and viral load (HIV RNA), prior experience with ARVs, baseline genotype resistance testing, baseline pertinent laboratory tests (including renal and hepatic function), concomitant use of prescription/OTC medication and herbal products, and willingness to accept and adhere to ART.

The difficulty of balancing the efficacy of ARVs against the risks has led to the development of guidelines both domestically and internationally.5-8 To stay current with the constantly evolving field of HIV-related research, these guidelines are frequently revised, incorporating the most recent advances in HIV practice and research. In the U.S., the Department of Health and Human Services (DHHS) guidelines, which are developed by leading HIV clinicians and researchers, remain the principal source for treating HIV-infected patients.5, The most recent version of the DHHS guidelines was published on May 1, 2014. This document is available, along with other pertinent HIV-related guidelines and information, at http://aidsinfo.nih.gov.

The goals of ART are to reduce HIV-associated morbidity and prolong survival duration and quality; restore and preserve immunologic function; maximally and durably suppress plasma HIV viral load (VL); and prevent HIV transmission.5 These aims can be accomplished through appropriate selection of and adherence to recommended ART, the use of pretreatment drug- resistance testing, and appropriate prophylaxis and treatment of opportunistic infections (OIs). Accordingly, a patient's CD4 count typically is checked at care initiation, 3 months after beginning ART, and every 3 to 6 months thereafter; VL is measured within 2 to 4 weeks after ART initiation, every 4 to 8 weeks until VL suppression, and then every 3 to 4 months; and clinical outcomes, such as symptoms and OI development, are routinely monitored. Frequent monitoring of CD4 counts, especially in patients with higher counts (>300 cells/mm3) and consistently suppressed VL, is generally not required.

The decision to begin ART is multifactorial and must be carefully considered. The current DHHS guidelines include recommendations for the appropriate timing of ART.5 Based on the scope of clinical research demonstrating positive patient and population outcomes from earlier therapy initiation, the guideline advises ART initiation in all HIV-infected patients, regardless of CD4 cell count or VL. ART is recommended to reduce the risk of disease progression and to prevent transmission. The DHHS guidelines state that the patient must be willing and able to commit to treatment, as well as understand the benefits and risks of therapy and the importance of adherence. This key point allows the option of deferring therapy while continuing to monitor and engage with patients who are not yet ready for therapy or demonstrate clinical and/or psychosocial factors that would hinder adherence; in this way, the development of drug resistance and poor patient outcomes can be minimized.5

For patients choosing to start therapy, adherence can still be a challenge, since ART is typically a lifelong commitment. Poor adherence has been associated with the following barriers: mental illness, neurocognitive impairment, substance-abuse issues, low health literacy, poverty, homelessness, denial, younger age, and non-disclosure of HIV-positive status.5 HIV-related stigma compromises adherence by undermining social support and adaptive coping. Concealment of HIV status to avoid stigma may contribute to treatment interruptions, leading to poor adherence.9

ART adherence could improve through the adoption of stigma-reducing interventions.9 Clinical multidisciplinary care settings that are nonjudgmental and supportive may improve adherence.5 However, more research on adherence and its measurement and improvement is necessary.10 The CDC-initiated HIV/AIDS Prevention Research Synthesis (PRS) Project has identified interventions that can improve adherence, such as home visits, directly administered ART, peer support, needs assessment, medication education, tailored medication regimens, and identification of barriers to adherence. Pager messaging—including medication reminders; information about advantages of adherence, adverse effects (AEs) and how to manage them, drug interactions, proper medication storage, drug resistance, and interpretation of laboratory values; and entertainment comments—also can be helpful.11

Once the decision is made to initiate therapy, an appropriate, evidence-based combination ART regimen must be selected. Such regimens typically include two nucleoside reverse transcriptase inhibitors (NRTIs) plus a nonnucleoside reverse transcriptase inhibitor (NNRTI) or protease inhibitor (PI) or an integrase strand transfer inhibitor (INSTI). This three-drug "cocktail," which combines potent ARVs, is termed highly active antiretroviral therapy (HAART). HAART is critical for viral suppression and prevention of viral mutations that can lead to resistance. The current DHHS guidelines discuss preferred and alternative ARV regimens. TABLE 1 contains a brief summary; more comprehensive details regarding proper timing, types of ART, and evidence are found in the guidelines.5


ARVs

ARVs are classified by their method of inhibition in the viral life cycle, namely, their mechanism of action (FIGURE 1). The following sections will review the classes of ARVs. Drug interactions are seen with many of these agents, especially substrates, inducers, or inhibitors of the CYP450 enzyme pathway. An all-inclusive discussion of these interactions is beyond the scope of this article. See the DHHS guidelines for more information about drug interactions.


Entry Inhibitors

Entry of the HIV virus into the CD4 cell is the first step in the retrovirus life cycle. On the surface of the virus envelope are glycoprotein (gp)120 and gp41, which have an affinity for CD4 cells. gp120 interacts with the CD4 surface and binds to additional chemokine receptors there, either C-C chemokine receptor type 5 (CCR5) or C-X-C chemokine receptor type 4 (CXCR4). This binding causes conformational changes to the HIV envelope and exposes gp41, which mediates fusion with the cellular membrane. The two currently approved entry agents, enfuvirtide and maraviroc, target gp41 and CCR5, respectively.12

Enfuvirtide, a fusion inhibitor, blocks the conformational change in gp41, thereby inhibiting fusion of the HIV virus to the CD4 cell. Because enfuvirtide undergoes catabolism and does not affect the CYP450 enzymes or N-acetyltransferase, there are no known significant drug interactions. Although the drug is well tolerated, the most common AE, occurring in almost all patients, is injection-site reactions (i.e., pain, erythema, ecchymosis, and nodule/cyst formation). Increased incidences of bacterial pneumonia and hypersensitivity reactions (HSRs) have also been reported. An advantage, however, is that enfuvirtide has little effect on body composition and serum lipids.5,13,14

Maraviroc prevents the interaction between gp120 and CCR5, thereby inhibiting fusion with the CD4 cell.12 It is, therefore, a selective CCR5 chemokine receptor antagonist and is effective only against CCR5- tropic virus, not CXCR4-tropic virus or mixed tropic virus; a tropism assay must be performed prior to initiation to confirm the presence of CCR5-tropic virus.14 Common AEs include fever, rash, upper respiratory infection, cough, dizziness, myalgias and arthralgias, hepatotoxicity, and orthostatic hypotension, especially in patients with severe renal insufficiency.5,14 Maraviroc is metabolized by the CYP3A4 pathway, so drug interactions with other agents that use this pathway are an issue. Maraviroc and enfuvirtide are not recommended as first-line therapy or as part of alternative therapy.5

NRTIs

Upon entry into the cell, single-stranded viral RNA is converted into double-stranded DNA, which is then incorporated into the chromosome of the host cell. The HIV enzyme reverse transcriptase (RT; also known as RNA-dependent DNA polymerase) is necessary for this task. NRTIs interfere with the activity of RT and impede the generation of full-length viral DNA. NRTIs were the first drug class approved to treat HIV; zidovudine was introduced in 1987. NRTIs are prodrugs and must be phosphorylated to become active. Tenofovir, a nucleotide monophosphate analogue, also requires phosphorylation to attain full activity.12

NRTIs (TABLE 2) are generally eliminated renally and must be dose-adjusted in the presence of renal impairment. The exception is abacavir, which is cleared by hepatic glucuronidation and alcohol dehydrogenase. Abacavir can also induce HSRs, which are rare but potentially fatal. Symptoms include fever, skin rash, fatigue, nausea, vomiting, headache, myalgia, arthralgia, and respiratory symptoms. Symptoms usually start within 6 weeks of therapy initiation and resolve within 72 hours after discontinuation. HSR incidence ranges from 2.3% to 9%; however, this differs by ethnicity, with a low incidence among African American and Asian populations. An ethnic correlation indicates a genetic predisposition to the reaction.15


A correlation was found between HSRs and the human leukocyte antigen HLA-B*5701. It is theorized that abacavir binds to an antigen-binding cleft in HLA- B*5701, changing its shape and chemistry and altering its ability to bind to typical endogenous peptides. This new immunologic peptide activates T-cell response and produces cytokines that induce an idiosyncratic adverse drug reaction. Prior to starting abacavir, patients are screened for HLA-B*5701 to reduce HSR incidence. Patients who test positive should not be initiated on abacavir; those who test negative may be initiated, but should be monitored. Patients who experience HSRs to abacavir should never be rechallenged.15 Conflicting data exist regarding an association between abacavir use and myocardial infarction, particularly in patients with preexisting cardiac risk factors.16

NRTIs have a low affinity for human DNA polymerase- alpha and -beta; but some agents inhibit DNA polymerase-gamma, the mitochondrial enzyme.17 Inhibition of the mitochondrial enzyme results in inhibition of mitochondrial DNA synthesis and causes toxicities such as anemia, granulocytopenia, myopathy, peripheral neuropathy (PN), lypodistrophy, pancreatitis, lactic acidosis with or without hepatomegaly, and hepatic steatosis.17

Not all agents in this class have the same affinity for DNA polymerase-gamma. The newer agents lamivudine, emtricitabine, and tenofovir have a lower affinity and do not cause mitochondrial toxicity. Lamivudine and emtricitabine are the least toxic agents in this class.18 Rare but fatal AEs, such as lactic acidosis with or without hepatomegaly and hepatic steatosis, are listed as a black box warning for all NRTIs; however, older agents (i.e., zidovudine, stavudine, and didanosine) are more commonly associated with this AE.19 Zidovudine is more often associated with severe anemia, neutropenia, and myopathy.20 Stavudine and didanosine more often cause pancreatitis and PN.18 Tenofovir, unfortunately, has also been associated with renal dysfunction, resulting in hypophosphatemia, serum creatinine elevation, Fanconi syndrome, and (rarely) acute renal failure.21 Clinically significant pharmacokinetic drug interactions are uncommon with this class, as these agents are not involved with the CYP450 pathway.18

NRTIs have been formulated as combination products (TABLE 3) to reduce pill burden. Combivir, the first combination product, has been used for many years and is listed as a preferred dual-NRTI option for pregnant women.6 Trizivir is no longer favored for initial therapy because of its inferior virologic efficacy compared with other regimens.5,22 Truvada is utilized in many initial NRTI regimens recommended by current guidelines because of its excellent virologic response, but patients should be monitored closely for renal toxicities. Epzicom is an alternative to Truvada; however, it may have a lower virologic response in patients with a higher VL (TABLE 1).5


NNRTIs

NNRTIs (TABLE 4) act as noncompetitive RT inhibitors by forming a hydrophobic pocket next to the active site, thereby changing its conformation and greatly reducing its activity.12 NNRTIs are different from NRTIs in that they do not require intracellular phosphorylation to attain activity. They are eliminated by the CYP450 enzyme pathway and are not active against HIV-2.18


Developed in 1996, nevirapine (NVP) was the first NNRTI. NVP, a CYP3A4 enzyme inducer, induces its own metabolism, resulting in a half-life reduction from ~45 hours after one dose to 25 to 30 hours after 2 weeks. The immediate-release formula has a once-daily dosing schedule for the first 2 weeks, followed by a twice-daily regimen thereafter. The extended-release formula is dosed daily following the 2-week lead-in regimen. The most common AE is rash, which can range from mild to severe enough to result in discontinuation. Hepatotoxicity with increased transaminases can occur, and deaths from fulminant hepatitis have been reported. Therefore, liver function should be closely monitored for the first 3 months of therapy.23 A higher risk of hepatic events was seen in women with pretreatment CD4 cell counts >250 cells/mm3 and men with pretreatment CD4 counts >400 cells/mm3. Because of this toxicity, it is suggested that NVP therapy be initiated only in women and men with CD4 counts below these values.5 NVP does not increase serum lipid profiles.24

Delavirdine is rarely prescribed now owing to its short half-life and thrice-daily dosing. It is a substrate and inhibitor of CYP3A4, and achlorhydria can decrease absorption. Rash, the most common AE seen early in treatment, can resolve. Elevated hepatic enzymes and hepatic failure have been reported.18

Efavirenz, which has been used since the late 1990s, is a recommended initial treatment option when combined with tenofovir/emtricitabine.5 Its long half-life (40-55 hours) allows for once-daily dosing. The drug is typically administered at bedtime on an empty stomach for optimal absorption and fewer AEs. Efavirenz, which is metabolized by CYP3A4 and 2B6, is an inducer of 3A4 and an inhibitor of 3A4, 2C9, and 2C19. Its major toxicities involve the central nervous system (CNS), with more than half of patients experiencing dizziness, sleep disturbances, vivid dreams, nightmares, impaired concentration, and hallucinations. These AEs may subside after 3 to 4 weeks, but if they continue, drug discontinuation could result. Other AEs include rashes, severe skin reactions, and dyslipidemia. Teratogenicity is documented in animal studies, and case reports of neural tube defects from first-trimester exposure in humans have been published. Therefore, regimens without efavirenz should be strongly considered for women who are attempting to conceive or are sexually active and not using effective birth control.5,6,25 Efavirenz can cause false-positive urine screening tests for cannabinoids, but this depends upon the assay used.14

Etravirine, a second-generation NNRTI, has a higher barrier to resistance and can retain antiviral activity even if resistance-associated mutations to first-generation NNRTIs are present. This is due to the drug's ability to adapt to changes at the RT binding site caused by mutations. Etravirine is a substrate of CYP3A4, 2C9, 2C19, and uridine diphosphate glucuronyltransferase (UGT); it induces CYP3A4, weakly inhibits CYP2C9, and moderately inhibits CYP2C19. It has a long half-life (41 hours) and is dosed twice daily. It is well tolerated, with a low incidence of CNS AEs. Common AEs are rash, nausea and diarrhea, and severe skin reactions; HSRs and hepatic failure are rare.26-28

Rilpivirine, the newest second-generation NNRTI, also has a higher barrier to resistance because of its ability to adapt to changes at the binding site. It has a long half-life (50 hours) and is metabolized by CYP3A4. Rilpivirine is well tolerated, and the most common AEs are headache, rash, and insomnia. Particular caution is recommended when rilpivirine is used in patients with depressive disorders, as the drug may exacerbate these conditions. Rilpivirine demonstrated noninferiority to efavirenz; however, virologic failure occurred in patients with a VL >100,000 copies/mL and pretreatment CD4 counts <200 cells/mm3. Therefore, this agent should be used only in treatment-naïve patients with a VL ≤100,000 copies/mL and CD4 counts >200 cells/mm.5,29

Combination products that incorporate an NNRTI- based regimen include Atripla (efavirenz + emtricitabine/ tenofovir) and Complera (rilpivirine + emtricitabine/ tenofovir).

INSTIs

After the HIV virus converts from single-stranded RNA into double-stranded DNA, it must incorporate itself into the host cell's nucleus, an action that requires HIV-1 integrase enzyme to complete. Integrase inhibitors (TABLE 5) prevent the activity of the integrase enzyme.14,30 Agents in this class may be used first-line and are also used to treat viral strains with resistance to other antiviral classes.


Raltegravir is the first selective INSTI to be approved. It is metabolized by glucuronidation mediated by UGT1A1 and avoids the CYP450 system. The half-life of raltegravir is 7 to 12 hours, warranting twice-daily dosing. The drug is well tolerated and is not associated with clinically relevant dyslipidemia or hypercholesterolemia. The most common AEs are hepatotoxicity, diarrhea, nausea, and headache. Exacerbation of depression and myopathy have been reported.30,31

Elvitegravir is not available as a single agent, but is combined with emtricitabine/tenofovir and the pharmacokinetic enhancer cobicistat in the product Stribild. It has a convenient dosing regimen of one tablet once daily. Mutations can result in resistance to elvitegravir that will also confer resistance to raltegravir. Elvitegravir is well tolerated, with diarrhea and nausea the most common AEs.32 See TABLE 3. Cobicistat is a pharmacokinetic enhancer of elvitegravir with an equivalent boosting effect of 100 mg of ritonavir. It is a more selective inhibitor of CYP3A4 than ritonavir and has a lesser potential for off-target drug interactions; it has no anti-HIV activity, however.33,34

Dolutegravir, a second-generation INSTI, has a half-life of 14 hours and high serum concentrations, allowing for once-daily dosing. It is metabolized by UGT1A1 with some CYP3A4 involvement and is a substrate of P-glycoprotein. It is well tolerated, and the most common AEs are nausea, diarrhea, headache, and insomnia. Dolutegravir can cause transient and reversible increases in serum creatinine owing to inhibition of tubular secretion of the renal transporter organic cation transporter 2. Advantages are superior efficacy to raltegravir in patients on failed therapy (demonstrated in the SAILING trial), continued activity in HIV strains resistant to raltegravir and elvitegravir, and absence of need for a pharmacokinetic enhancer.35,36

PIs

Once integrated, HIV DNA—a provirus—can remain inactive; however, if activated by a host signal, the provirus will use the host enzyme, RNA polymerase, to create copies of its HIV genetic material and make short strands of messenger RNA (mRNA). The mRNA is used as a template to make long chains of HIV proteins. The HIV protease enzyme then cuts these long chains into smaller individual HIV proteins. The smaller HIV proteins combine with copies of HIV's genetic material to assemble a new virus particle. This new virus leaves the cell to infect other CD4 cells. PIs (TABLE 6) prevent the protease enzyme from cleaving these long protein chains, thereby halting the transformation of the HIV virus into a mature infectious form.37


PIs are the most potent agents available to date, but they require a boosting agent to inhibit their metabolism and increase their levels.12 As a class, they have long half-lives, allowing for once- or twice-daily dosing. As CYP450 substrates and inhibitors, PIs cause many drug interactions with other medications utilizing this pathway.18 AEs common to this class are diarrhea, hyperglycemia, hyperlipidemia, abnormal fat distribution, hepatotoxicity, bleeding episodes (in hemophilia), osteonecrosis, and osteoporosis.5,38 Ritonavir, originally developed as a PI for HIV treatment, is no longer used in this capacity. Since it is the most potent CYP3A4 inhibitor, it is employed as a pharmacokinetic enhancer to increase drug levels of other PIs. Only small amounts of ritonavir are necessary, and doses of 100 mg or 200 mg are currently used. Gastrointestinal (GI) intolerance is a common AE.18

The following PIs are not recommended in the current DHHS guidelines for initial treatment. Saquinavir, the first PI (approved in 1995), is no longer favored owing to its high pill burden and PR and QT prolongation requiring an ECG prior to therapy initiation. Therapy should not be initiated if the pretreatment QT interval is >450 msec.5,14 Indinavir has a high pill burden and has an incidence of nephrolithiasis requiring at least 2 L of water daily. It also causes unconjugated hyperbilirubinemia, resulting in increased indirect serum bilirubin that is generally asymptomatic and not associated with serious long-term sequelae.5,14,39

Tipranavir requires higher doses of boosting by ritonavir, which may have a more profound effect on elevating lipids and triglycerides. It has also been associated with fatal hepatotoxicity and intracranial hemorrhage. Tipranavir contains a sulfa moiety that causes transient rash in 10% of patients.5,14,40

Nelfinavir requires administration with high-fat foods to optimize absorption, and levels are not improved by ritonavir boosting. It is primarily metabolized by CYP2C19 and 3A4 and has an active metabolite comparable to that of the parent compound; however, it has inferior virologic efficacy. The major AE is severe diarrhea.5,14,41

Lopinavir is the only PI coformulated with ritonavir. The DHHS guidelines suggest it as an alternative PI. Lopinavir has a higher incidence of GI intolerance and hyperlipidemia and a slightly increased risk of myocardial infarction compared with the preferred PIs.5,16,42

Fosamprenavir, a prodrug of amprenavir, is dephosphorylated to active amprenavir in the intestinal mucosa. It has improved bioavailability and a lesser pill burden than amprenavir; therefore, amprenavir is no longer marketed. Skin rash (contains sulfa moiety), headache, and nephrolithiasis have been reported.5,43

Atazanavir is recommended as an initial treatment option. It has a convenient once-daily dosing regimen and is well tolerated. Atazanavir has no significant effect on blood glucose or insulin levels and has a lower propensity to alter total cholesterol and triglyceride levels. AEs such as indirect hyperbilirubinemia, cholelithiasis, and nephrolithiasis have occurred.5,44

Darunavir, another recommended initial treatment option, demonstrated better virologic response than lopinavir/ritonavir in both treatment-naïve and treatment-experienced patients. AEs include skin rash (contains sulfa moiety), Stevens-Johnson syndrome, toxic epidermal necrolysis, and hepatotoxicity.5,45

Investigational ARVs

Research to develop novel agents for the treatment of HIV continues, and promising ARVs are in clinical development. Some of the more promising drugs are briefly summarized below, but it is important to note that these agents are still being evaluated in clinical trials; thus, this information is preliminary and may change with future research. NRTIs in development include festinavir (BMS-986001), which appears to be similar to stavudine but has less mitochondrial toxicity and may result in lower renal and metabolic effects, and GS-7340, a prodrug of tenofovir that appears to achieve considerably higher intracellular concentrations and lower plasma concentrations than the currently used tenofovir. Higher plasma concentrations may be responsible for renal and bone toxicities; therefore, this prodrug may result in fewer AEs.46

MK-1439, an NNRTI, is another promising compound. It has good oral bioavailability, a reduced potential for toxicity, and activity against strains with resistance to other NNRTIs.46

BMS 663068 is an entry inhibitor that binds directly to viral gp120 and blocks binding to the CD4 receptor. Albuvirtide, a fusion inhibitor related to enfuvirtide, binds to the HIV gp41 envelope protein. It must be given IV, and injection-site reactions have been observed; however, owing to its long half-life, only weekly injections may be necessary.46

GSK1265744, an INSTI, is being studied as oral and long-acting SC and IM formulations. Like dolutegravir, it has activity against raltegravir- and elvitegravir-resistant virus and may be used unboosted in a low-dose, once-daily oral administration.46,47

The use of cobicistat as a pharmacokinetic enhancer of darunavir has also been studied. The fixed-dose combination (FDC) product darunavir 800 mg/cobicistat 150 mg was compared with darunavir 800 mg/ritonavir 100 mg. The pharmacokinetics of the fixed-dose combination product were within the limits of bioequivalence to darunavir with ritonavir given as single separate agents. The advantages of this fixed-dose combination product are a lesser pill burden and potentially fewer GI and hyperlipidemia AEs associated with ritonavir.48

Researchers are also investigating the efficacy of ARVs applied topically to mucosal areas to prevent HIV transmission.49 The NNRTI dapivirine (TMC120), which has poor oral bioavailability, is being studied for use in a vaginal matrix ring composed of silicone elastomer that delivers the drug over a 28-day period.49,50 Tenofovir 1% gel has also been evaluated as a topical application that can be used both vaginally and rectally prior to and after coitus.49 More studies are necessary to determine the effectiveness of these agents.

Conclusion

Over the past 30 years, the prognosis associated with HIV-positive status has changed from impending death to a generally manageable chronic illness. This is due to the development of numerous medications in various classes that target key sites to prevent viral replication. A combination of at least three highly active ARVs is necessary to suppress the virus and prevent mutations that cause resistance. Adherence to HAART is critical to treatment success. HAART can be complicated, and pharmacists can use their medication expertise to assure correct dosing, appropriate ARV combinations, accurate screening for drug interactions, and monitoring and management of AEs experienced by the patient.

REFERENCES

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