7/6/2021 Highly Active Antiretroviral Therapy (HAART) - StatPearls - NCBI Bookshelf

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Highly Active Antiretroviral Therapy (HAART)

Authors

Julie S. Eggleton1; Shivaraj Nagalli2.

Affiliations
1 California Northstate University
2 Yuma Regional Medical Center

Last Update: April 7, 2021.

Continuing Education Activity

Highly active antiretroviral therapy (HAART) is a medication regimen used in the management and treatment of
human immunodeficiency virus type 1 (HIV-1). It is composed of several drugs in the antiretroviral classes of
medications. This activity outlines the indications, 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 members of the interprofessional healthcare team 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 values to monitor 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.

Earn continuing education credits (CME/CE) on this topic.

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 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
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]

The goals of HAART in patients with HIV infections include[8]:

Reduce morbidity and mortality (AIDS and non-AIDS associated causes)

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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 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 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 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 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, rilpivirine

Protease inhibitors (PIs) [25]

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PIs competitively inhibit the proteolytic cleavage of the gag/pol polyproteins in HIV infected cells. These
agents result in immature, noninfectious virions.

PIs are generally used in patients that are failing 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.
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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
have interactions 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 find to be 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 as 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.

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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 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 with a history of psychiatric illness, are considered high risk of noncompliance,
and 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 by 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]
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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 a team to ensure they have a comprehensive patient history before selecting a
HAART combination. Additionally, a board-certified infectious disease pharmacist who specializes 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.

Continuing Education / Review Questions

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Earn continuing education credits (CME/CE) on this topic.

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References
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