Continuing Education Activity

Highly active antiretroviral therapy (HAART) is a medication regimen used to manage and treat human immunodeficiency virus type 1 (HIV-1). It is composed of several drugs in the antiretroviral classes of medications. This activity outlines the indications, mechanism of action, and contraindications for various HAART medications in the management of HIV. This activity will highlight the mechanism of action, adverse event profile, and other key factors pertinent to the interprofessional healthcare team members in the care of patients with HIV-1 and related conditions.

Objectives:

• Describe the treatment considerations for patients with HIV.
• Identify the most common adverse events associated with highly active antiretroviral therapy (HAART) medications.
• Summarize the significant monitoring parameters in patients on highly active antiretroviral therapy (HAART) therapy.
• Outline the importance of collaboration and communication amongst the interprofessional team to ensure appropriate selection of Highly active antiretroviral therapy (HAART) regimens to improve HIV- positive patient outcomes.

Indications

Highly active antiretroviral therapy (HAART) is a treatment regimen typically comprised of a combination of three or more antiretroviral drugs. HAART may also be called antiretroviral therapy (ART) or combination antiretroviral therapy (cART). A key cornerstone of HAART is the co-administration of different drugs that inhibit viral replication by several mechanisms so that the propagation of a virus with resistance to a single agent becomes inhibited by the action of the other two agents. Management of a HAART regimen is a multifaceted process that should be administered by, or in consultation with, a provider with specific training as defined by the Infectious Diseases Society of America. This approach is central to optimizing patient care, as studies have demonstrated provider experience positively correlates with improved patient outcomes.[1][2][3][4] 

This combination therapy is primarily indicated to treat human immunodeficiency virus type 1 (HIV-1) infected patients. For the treatment of HIV, there are more than 25 different medications in six different classes, for which a detailed discussion will follow in further sections. The standard of care for most treatment-naïve patients is a combination of two nucleoside reverse transcriptase inhibitors (typically tenofovir-emtricitabine) plus one non-nucleoside reverse transcriptase inhibitor or integrase strand transfer inhibitor. Alternative classes or different drugs within each class may be recommended when patients have concurrent conditions or medication interactions, as detailed further below.[5][6][7][8][9][10]

Goals of HAART in Patients with HIV Infections[8]

• Reduce morbidity and mortality (AIDS and non-AIDS associated causes)
• Improve the quality of life
• Reduce plasma viral RNA load
• Prevent transmission to others (sex partners, needle-sharing partners, mother to infant)
• Prevent drug resistance
• Improve immune function

Reducing the transmission of HIV-1 to others is a primary goal of HAART. With the use of HAART, a reduction of HIV-1 RNA levels has been shown to reduce the risk of sexual transmission to partners to nearly zero in some studies, even among couples that engaged in condomless sexual acts. A combination of these drugs is also available for uninfected patients who engage in high-risk behavior and has been demonstrated to reduce the risk of acquiring HIV infection by more than 90%. For pregnant patients, the use of HAART is critical in the prevention of mother-to-child transmission. The preferred regimen usually includes a combination of dual nucleoside reverse transcriptase inhibitors (NRTIs) plus a protease or integrase inhibitor; however, dosage adjustments may be necessary to account for pharmacokinetic changes during pregnancy. This treatment is started as soon as possible and continued several months after birth to prevent vertical transmission through breast milk. Intrapartum zidovudine may work to reduce perinatal transmission in patients with a viral load greater than 1000 copies/mL at 38 weeks, and infants may also receive zidovudine as prophylaxis. Patients have the best results when they have started treatment before fertilization, so it is important to screen at-risk patients early.[11][12][13][14][15][16]

HAART is also utilized in the treatment of HIV-2, though currently, there is no specific guideline of recommendations for HIV-2 treatment. Instead, HIV-2 management is under HIV-1 guidelines with some modifications. Genetic differences render HIV-2 intrinsically resistant to certain HAART medication classes (non-nucleoside reverse transcriptase inhibitors) and decrease the efficacy of others (protease inhibitors and fusion inhibitors). Research is ongoing to determine the best initial treatment for patients infected with HIV-2 or dually infected with HIV-1/2.[17][18]

Some NRTIs, lamivudine, and tenofovir, are also indicated in the treatment of hepatitis B (HBV). Monotherapy is unlikely to be sufficient to treat chronic HBV; therefore, a combination of nucleoside/nucleotide analogs and interferon-alpha is generally recommended. However, some recent studies have shown that while combination therapy has shown higher biological suppression, the sustained response with combination therapy is comparable to single therapy regimens.[19][20][21]

Mechanism of Action

There are six main classes of HAART agents that target different stages in the viral lifecycle. A fundamental cornerstone of HAART is the co-administration of different drugs that inhibit HIV replication by several mechanisms so that the propagation of a virus with resistance to a single agent is inhibited by the action of the other two agents. Some agents may be co-formulated to increase ease of patient compliance with these medications.

Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTIs)[22][23][24]

• NRTIs require intracellular phosphorylation via host enzymes before they can inhibit viral replication. These agents are nucleoside or nucleotide analogs with an absent hydroxyl at the 3’ end that are incorporated into the growing viral DNA strand. They competitively bind to reverse transcriptase and cause premature DNA chain termination as they inhibit 3’ to 5’ phosphodiester bond formation.
• Examples include: abacavir, didanosine, lamivudine, stavudine, tenofovir, and zidovudine

Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs) 

• NNRTIs bind to HIV reverse transcriptase at an allosteric, hydrophobic site. These agents cause a stereochemical change within reverse transcriptase, thus inhibiting nucleoside binding and inhibition of DNA polymerase.
• Examples include delavirdine, efavirenz, nevirapine, and rilpivirine.

Protease inhibitors (PIs)[25]

• PIs competitively inhibit the proteolytic cleavage of the gag/pol polyproteins in HIV-infected cells. These agents result in immature, non-infectious virions.
• PIs are generally used in patients who fail their initial HAART regimen and should be administered with boosting agents such as ritonavir or cobicistat.
• Examples include atazanavir, darunavir, indinavir.

Integrase Strand Transfer Inhibitors (INSTIs)[26][27] 

• Integrase inhibitors bind viral integrase and prevent viral DNA from being incorporated into the host cell chromosome.
• Examples include: dolutegravir, elvitegravir, raltegravir

Fusion inhibitors (FIs)

• Fusion inhibitors bind to the envelope glycoprotein gp41 and prevent viral fusion to the CD4 T-cells.
• Examples include enfuvirtide.

Chemokine Receptor Antagonists (CCR5 Antagonists)[28]

• CCR5 antagonists selectively and reversibly block entry into the CD4 T-cells by preventing interaction between CD4 cells and the gp120 subunit of the viral envelope glycoprotein.
• Examples include maraviroc.

Administration

The timing of treatment initiation for HIV-1 infection has been a topic of much research and discussion among physicians. Current recommendations are that HAART should be initiated within seven days of a confirmed HIV diagnosis and detectable virology, regardless of CD4 count or clinical symptoms. Early HAART initiation, vs. waiting for CD4 counts to decline as were the previous recommendations, has been shown to reduce severe AIDS and AIDS-associated illnesses.[5][6][7][8]

Many of these medications are administered orally, once a day, in a co-formulated combination tablet. However, some medications are not yet in combination formulas, thus creating a large pill burden for patients who require a regimen of three or four drugs twice daily. The increased number of pills can decrease patient adherence, particularly for patients in resource-limited settings, patients with dysphagia, or patients who struggle with the financial burden of a HAART regimen. For patients who have dysphagia or trouble swallowing for any reason, there are liquid preparations or crushable tablets, though dosages may need to be adjusted. The Food and Drug Administration has recently been approving medications containing two or three-drug, a fixed-dose regimen in a single tablet. Combination medications with once-daily dosing are preferred as these regimens have been shown to increase patient compliance up to three times over more complex dosing regimens.[9][29][30] 

The dosages and preferred regimens may be adjusted based on various factors, including concomitant use of CYP inducers/inhibitors, renal or hepatic impairment, baseline resistance, childbearing potential, and comorbid conditions such as cardiovascular disease, hepatitis B, or tuberculosis. The healthcare professional should ensure they have a detailed patient history to review options for each patient’s distinct condition before selecting a HAART combination. 

Adverse Effects

Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTIs)[24][31][32][33][34]

• NRTIs are known to cause mitochondrial toxicity that may present as peripheral neuropathy and lactic acidosis that can be fatal. Some NRTIs may also cause bone marrow suppression, anemia, and lipodystrophy.
• Tenofovir is typically well tolerated but may cause kidney injury or decreased bone mineral density. Other medications require consideration in patients with a history of renal impairment (eGFR less than 60 mL/min/1.73m) or osteoporosis. Discontinuation of tenofovir formulas will warrant clinical and laboratory monitoring of hepatic function because discontinuation may cause an acute exacerbation of HBV.
• Abacavir is associated with a CD8 mediated hypersensitivity reaction in patients with the HLA-B*5701 mutation.
• Didanosine is rarely used due to the risk of pancreatitis and hepatomegaly.

Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs)[35][36]

• NNRTIs may cause rashes that typically resolve within one month but may progress to Stevens-Johnson’s syndrome, so patients should discontinue the medication if they develop a severe rash with blistering or desquamation. Hepatitis, including fulminant hepatitis progressing to liver failure, can occur as early as six weeks into starting therapy. This class of medications does not have absolute restrictions on use in pregnancy, but some evidence indicates a risk of neural tube defects. Occasionally, QT prolongation can occur with the use of NNRTIs (most commonly with rilpivirine). NNRTIs also cause a range of interactions with hepatic cytochrome P450 enzymes, so concurrent medications must be checked closely for dosage adjustments or interaction concerns.
• Efavirenz is known to cause a range of psychiatric and CNS effects, including but not limited to vivid dreams, delusions, sleep disturbances, dizziness, headaches, increased suicidality, psychosis-like behavior, and mania.

Protease Inhibitors (PIs)[37][38]

• PI class effects include hepatotoxicity, insulin resistance, hyperglycemia, hyperlipidemia, lipodystrophy, and PR interval prolongation.
• Other PIs, including indinavir and saquinavir, are no longer used due to inefficiency, increased resistance, and unfavorable side effects such as an increased risk of nephrolithiasis.

Integrase Inhibitors (INSTIs)[39][40][41]

• INSTIs are generally well-tolerated, and in many cases, they are favorable as the third agent in a HAART regimen due to their neutral effects on cholesterol and triglyceride levels. Some patients may experience dizziness, sleep disturbances, or depression. Reports exist of rhabdomyolysis and myopathy in patients taking raltegravir and dolutegravir, so patients require monitoring for increases in creatine phosphokinase (CK).
• Dolutegravir can block the secretion of creatinine and occasionally cause a decrease in the GFR.[42] It can also interact with several medications, including those that inhibit/induce CYP3A4 enzymes, metformin, rifampin, and antiepileptics.

Fusion Inhibitors (FIs)[43]

• Enfuvirtide is generally well tolerated though some patients may experience injection site reactions.

Chemokine Receptor Antagonists (CCR5 antagonists)[44][45]

• Maraviroc is generally well tolerated though some patients may experience dizziness or skin rashes. There is a risk of hepatotoxicity with allergic features, so patients should be monitored closely for symptoms of allergic reactions or hepatic dysfunction. Drug-drug interactions should be a consideration if patients are taking concurrent CYP3A4 inhibitors or inducers.

Contraindications

There are no outright contraindications to HAART therapy; all patients clinicians determined as HIV positive should start on a treatment regimen immediately, regardless of their CD4 count. There are contraindications to specific antiretroviral medications, but healthcare providers should find a different HAART combination for patients with these specific comorbidities. HAART should be administered by, or in consultation with, a provider with specific training defined by the HIV-Medicine Association of the Infectious Diseases Society of America.[4]

• Patients with a history of hepatic dysfunction should avoid efavirenz, tenofovir-disoproxil fumarate (TDF), and maraviroc.
• Patients with a history of renal dysfunction should avoid or adjust dosages of tenofovir, maraviroc, and atazanavir.
• Patients with a history of psychiatric illnesses should avoid efavirenz and dolutegravir.[36][39][40]
• Patients of childbearing potential, pregnant, or breastfeeding should avoid NNRTIs, dolutegravir, bictegravir, stavudine, didanosine, and ritonavir. The preferred regimen typically includes a combination of dual NRTIs (zidovudine) plus a protease or integrase inhibitor; however, dosage adjustments may be necessary to account for pharmacokinetic changes during pregnancy.[41][46]
• Patients with a risk or history of torsades de pointes or cardiovascular disease should avoid efavirenz and abacavir.
• Patients with concurrent TB should be switched to rifabutin in their TB management as protease inhibitors, and NNRTIs should not be used with rifampin.
• Patients with concurrent HBV are not treatment limited; however, higher HBV DNA viral loads have correlated with a greater risk of hepatotoxicity with HAART usage.[47]
• Patients at high risk of inconsistent medication use, or patients who have failed initial therapy, are at risk of viral resistance. These patients should avoid medications with a low barrier to resistance, such as NNRTIs, raltegravir, and elvitegravir.[48][49]
• Patients who test positive for HLA-B*5701 should avoid abacavir due to the high risk for a delayed hypersensitivity reaction.

Monitoring

HAART regimens are essential to improve patient outcomes and reduce transmission of HIV, but medication management is a dynamic process that must be monitored by healthcare professionals. Proper utilization and adherence to a HAART regimen are essential to ensure a therapeutic response and prevent viral resistance. Healthcare professionals should obtain a detailed history and screening before initiating a regimen and consider factors such as comorbid conditions (cardiovascular disease, osteoporosis, renal dysfunction, hepatitis B, hepatitis C, psychiatric conditions, tuberculosis, drug abuse), desire to become pregnant, commitment to contraception usage, pill burden of the regimen, financial burden, prior HAART usage, and drug interactions. Patients living in a resource-limited setting with a history of substance misuse or a history of psychiatric illness are considered at high risk of non-compliance. Healthcare providers should be vigilant to ensure optimal health outcomes.[8][30][50][30]

Baseline testing prior to initiation of HAART should include: plasma HIV-1 viral load (or HIV antibody or HIV serology), CD4 count and percentage, viral genotype assay to detect drug resistance, complete blood count with differential, basic chemistry panel with blood urea nitrogen, and creatinine, fasting glucose/hemoglobin A1C, alanine and aspartate aminotransferases, and total bilirubin. Additional screenings for pregnancy, sexually transmitted infections, and AIDS-defining illnesses are appropriate at this time. HAART should initiate immediately after obtaining resistance testing, and regimens can be adjusted after obtaining the results of a resistance profile of the virus. Additional testing may vary based on the HAART regimen under consideration. If considering using abacavir, haplotype testing for HLA-B*5701 is necessary. If maraviroc is an option under consideration, a tropism assay is essential before starting therapy. Healthcare providers should help maximize patient compliance through education about viral resistance, nonjudgmental conversations about prevention and adherence, and minimizing the pill burden on patients using co-formulated medications whenever possible.[51][52][53]

HIV viral load should be tested two to eight weeks after initiation of HAART, then every four to eight weeks until the levels fall below the assay’s limit of detection (typically less than 20 to 50 copies/mL). If viral suppression does not occur after 24 weeks despite patient medication adherence, providers should retest resistance and adjust medications. Once patients are stable on their HAART regimen, follow-up visits should be scheduled every three to six months. All patients should have HIV-1 RNA viral load and CD4 count monitored to assess progress, as well as repeats of complete blood count with differential, basic chemistry panel with blood urea nitrogen and creatinine, fasting glucose/hemoglobin A1C, alanine and aspartate aminotransferases, and total bilirubin to assess for medication toxicity. Follow-up appointments may also include BMI and waist circumference monitoring to assess for lipodystrophy. This list is not all-inclusive, as other clinical indicators and patient histories may warrant further evaluation.[51]

Enhancing Healthcare Team Outcomes

Currently, the standard of care for a treatment-naïve patient with HIV-1 is a three-drug, highly active antiretroviral therapy (HAART) regimen that is started as soon as possible after a patient tests positive for HIV. A foundation of HAART is the administration of drugs that inhibit HIV viral replication at several stages in the lifecycle through different mechanisms to prevent viral resistance to any single agent. However, the selection of these drugs and the life-long treatment of a patient with HIV can be complex. Management of a HAART regimen is a multifaceted process that should be administered by, or in consultation with, a provider with specific training as defined by the HIV-Medicine Association of the Infectious Diseases Society of America. This approach is crucial to optimize patient care as studies have demonstrated provider experience positively correlates with improved patient outcomes.

Healthcare professionals should work as an interprofessional team to ensure they have a comprehensive patient history before selecting a HAART combination. Additionally, a board-certified infectious disease pharmacist specializing in HIV and HAART is an invaluable consulting member of the interprofessional healthcare team. Nurses will help monitor therapy, note progress or lack thereof, and verify patient compliance with therapy, which is of paramount importance with HAART. As always, healthcare team coordination and patient education are critical components to maximize patient adherence, prevent further spread of disease, and provide continuity of care to the patients.[2][3][4][3] Interprofessional teamwork will optimize the therapeutic benefit of HAART, resulting in improved patient outcomes and quality of life. [Level 5]