HIV Antiretroviral Therapy

Mechanism of Action

NRTIs

NRTIs compete with natural deoxynucleotides for incorporation into a growing viral DNA chain. However, NRTIs lack a 3'-hydroxyl group on the deoxyribose moiety. This difference results in incorporating an NRTI, and the next incoming deoxynucleotide cannot form the following 5', 3' phosphodiester bond needed to extend the DNA chain. The result is a chain termination in DNA synthesis.

NNRTIs

NNRTIs block reverse transcriptase (RT) by directly binding to the enzyme. Though NNRTIs do not get incorporated into the viral DNA, they inhibit the movement of protein domains of RT that are essential to carrying out the DNA synthesis.

Protease Inhibitors

Protease inhibitors bind HIV-1 protease and block proteolytic cleavage of protein precursors necessary for producing viral particles.

Fusion Inhibitors

Fusion inhibitors disrupt binding, fusion, and entry of HIV virions into a human cell. Enfuvirtide binds to gp41 and disrupts membrane attachment.

CCR5 Antagonist

Maraviroc blocks the CCCR receptor on the T-cell to prevent viral attachment.

Integrase Inhibitors

Integrase inhibitors block the action of integrase, preventing the viral genome from inserting itself into the DNA of a host cell.

Postattachment Inhibitors

This class is a monoclonal antibody that binds CD4, inhibiting viral entry into the cell.

Pharmacokinetic Enhancers

Pharmacokinetic enhancers inhibit human CYP3A protein, increasing plasma concentration of other anti-HIV drugs.[8]

Administration

The standard of care in an HIV regimen is to prevent HIV mutation. As a patient will take these medications orally, there are now several options that combine three to four drugs into one pill for better patient compliance due to once-daily administration. This dosing increases both adherence and long-term effectiveness. Ibalizumab is an exception, as it is an injectable agent.[9]

Patients are tested and educated to take all of their medications correctly to reduce resistance and cross-resistance to similar drugs to those they are taking. Medication adherence is difficult due to adverse effects following an HIV regimen. Common barriers to adherence include trouble swallowing pills, a busy schedule (shift work), unstable living or housing situations, alcohol or drug use, fear of disclosing HIV status, and lack of insurance. Before starting an HIV regimen, strategies such as 7-day pillboxes, phone applications, and alarms should be in place. Patients must have stable mental health and not be taking illicit drugs to have better adherence.[10][11]

Use in Specific Patient Populations

Hepatic impairment

Guidance for treating HIV in patients with hepatic impairment is as follows:

• In patients with moderate or severe hepatic impairment: Regimens that are not recommended include efavirenz/TDF and TDF/lamivudine.[12][13] 
• In patients with Child-Pugh Class B or C: Abacavir, abacavir/lamivudine, and dolutegravir/abacavir/lamivudine are not recommended due to the abacavir component; nevirapine is contraindicated; and the use of TAF is not recommended.[14] 
• General guidance: Abacavir and nevirapine are contraindicated in patients with hepatic impairment.

Renal impairment

Caution should be exercised if the patient is on a tenofovir-containing regimen due to potential nephrotoxicity. The CDC's recommendations are as follows: 

• Creatinine clearance (CrCl) less than 30 mL/min: Elvitegravir, cobicistat, TDF, and emtricitabine should not be initiated. 
• Regimens not recommended: Efavirenz, TDF/emtricitabine, doravirine/TDF/lamivudine, efavirenz/TDF/lamivudine, and rilpivirine/TDF/emtricitabine
• Recommended regimens: Use the individual component antiretrovirals (ARVs) and modify doses according to creatinine clearance.
• General guidance: Avoid any combination containing tenofovir due to the risk of potential nephrotoxicity; dolutegravir/lamivudine, abacavir/lamivudine, and dolutegravir/ abacavir/lamivudine are not recommended. 

For patients on hemodialysis whose CrCl is less than 30 mL/min, the recommendations are as follows:

• TAF/emtricitabine: One tablet once daily. On hemodialysis days, administer after dialysis.
• Bictegravir/TAF/emtricitabine: One tablet once daily. On hemodialysis days, administer after dialysis.
• Elvitegravir/cobicistat/TAF/emtricitabine: One tablet once daily. On hemodialysis days, administer after dialysis.
• Rilpivirine/TAF/emtricitabine: One tablet once daily. On hemodialysis days, administer after dialysis.
• Darunavir/cobicistat/TAF/emtricitabine: One tablet once daily. On hemodialysis days, administer after dialysis.[14]

Pregnancy considerations

The preferred regimen is integrase strand transfer inhibitor (INSTI)-based therapy such as dolutegravir, emtricitabine, and tenofovir.[15] The dolutegravir, emtricitabine, and TAF had the lowest frequency of composite adverse pregnancy outcomes and neonatal deaths.[16] According to CDC guidelines, COVID-19 vaccination is strongly recommended for all pregnant patients with HIV infection.[17]

Breastfeeding considerations

Breastfeeding is not recommended for patients who are confirmed or presumed to have HIV infection. Infants exposed perinatally to HIV should receive postpartum ARV prophylaxis to decrease the risk of perinatal transmission. The patient should be counseled that maternal antiretroviral therapy reduces but does not eliminate the risk of HIV transmission to the infant. Hence, mothers should use safe and affordable infant feeding alternatives.[18] Four-week zidovudine antiretroviral prophylaxis is frequently used in newborns whose mothers received ART during pregnancy and had adequate viral suppression four weeks before delivery. Higher rates of hematologic toxicity have been observed in infants who received zidovudine (ZDV) plus lamivudine (3TC) and other combination infant ARV regimens (such as ZDV plus 3TC plus nevirapine [NVP]) than in those who received ZDV alone.[19] 

Another study combined zidovudine/lamivudine/NVP prophylaxis for neonates with high-risk infants and did not significantly increase the risk of short-term toxicity compared with ZDV-monotherapy.[20] Prevention of Pneumocystis jirovecii pneumonia requires prophylaxis with trimethoprim-sulfamethoxazole for infants delivered to mothers with HIV.[21]

Adverse Effects

The following adverse effects have been associated with HIV medications:

• NRTIs: Hypersensitivity reaction or rash, neutropenia, myopathy, anemia, neuropathy, mitochondrial toxicity, lactic acid build-up, pancreatitis, fever, rash, nausea, vomiting, diarrhea, abdominal pain, fatigue, achiness, shortness of breath, sore throat, dark-colored urine, lipoatrophy, and jaundice [22]
• NNRTIs: Severe rash, allergic reactions, depression, impaired concentration, headache, sleep disturbance, abnormal dreams, mood changes, jaundice, dark-colored urine, fatigue, nausea and vomiting, peripheral neuropathy, mouth sores, conjunctivitis, myopathy, blisters, and trouble breathing
• Protease inhibitors: Irregular heart rhythm, lipodystrophy, severe rash, jaundice, dizziness, lightheadedness, heartburn, fatigue, myopathy, conjunctivitis, mouth sores, mouth numbness, kidney stones, blisters, dark-colored urine, pancreatitis, painful swelling, and abdominal pain
• Fusion inhibitors: Injection site reactions, infection, trouble breathing, fever, blood in urine, dark-colored urine, low blood pressure, neutropenia, chills and shivering, and cough
• CCR5 antagonists: Allergic reaction, jaundice, dark-colored urine, vomiting, abdominal pain, fever, fatigue, myopathy, mouth and skin blisters, facial swelling, trouble breathing, upper respiratory tract infections, cough, joint pain, myopathy, pain below ribs, heart problems, and loss of appetite
• Integrase inhibitors: Allergic hypersensitivity reaction, rash, jaundice, dark-colored urine, pale bowel movements, diarrhea, flatulence, nausea and vomiting, loss of appetite, abnormal dreams, pruritus, pain below ribs, mouth and skin blisters, and fatigue
• Postattachment inhibitors: Immune reconstitution inflammatory syndrome
• Pharmacokinetic enhancers: Increased serum creatinine, proteinuria, nausea, diarrhea, headache, acute kidney injury, and kidney failure

Some long-term adverse effects of HIV medicines are hepatotoxicity, kidney failure, heart disease, diabetes/insulin resistance, hyperlipidemia, osteoporosis, suicidal ideation or depression, and nervous system deficits.[23][24]

Contraindications

The following contraindications are associated with HIV medications:

• Abacavir: Patients with the HLA-B*5701 allele or prior hypersensitivity reaction to abacavir or moderate or severe hepatic impairment [25]
• Emtricitabine: Patients with previously demonstrated hypersensitivity to any of the components of the products
• Lamivudine: Patients with a previous hypersensitivity reaction to lamivudine
• TDF: Previous hypersensitivity or glomerular filtration rate less than 50
• Zidovudine: Patients who have had potentially life-threatening allergic reactions (eg, anaphylaxis, Stevens-Johnson syndrome) to any of the components of the formulations
• Efavirenz: Patients with clinically significant hypersensitivity (eg, Stevens-Johnson syndrome, erythema multiforme, or toxic skin eruptions) to any of the ingredients of this product; coadministration of efavirenz with elbasvir and grazoprevir is contraindicated.
• Etravirine: Hypersensitivity
• NVP: In patients with moderate or severe (Child-Pugh Class B or C, respectively) hepatic impairment or for use as occupational and nonoccupational postexposure prophylaxis regimens. Women with CD4 greater than 250 or men with CD4 greater than 400 due to an increased probability of hypersensitivity reaction. Hepatotoxicity is largely cholestatic but demonstrates hepatocellular pattern as well. In some cases, reports of clinically apparent hepatotoxicity are present after the first eight weeks of therapy but can be severe and fatal.[26]
• Rilpivirine: Contraindicated for coadministration with all of the following: carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifampin, rifapentine, dexamethasone, St. John’s wort, esomeprazole, lansoprazole, omeprazole, pantoprazole, and rabeprazole
• Atazanavir: In patients with previously demonstrated clinically significant hypersensitivity (eg, Stevens-Johnson syndrome, erythema multiforme, or toxic skin eruptions) to any of the formulation ingredients; concurrent administration of medications that are highly dependent on cytochrome P450 3A4 (CYP3A) or UDP Glucuronosyl transferase Family 1 Member A1 (UGT1A1) for clearance is associated with elevated plasma concentrations of the interacting drugs and severe life-threatening events (when coadministered with drugs that strongly induce CYP3A4, atazanavir may lead to lower exposure and loss of formulations' efficacy).
• Darunavir: Coadministration of formulations is contraindicated with medications highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and life-threatening events.
• Fosamprenavir: In patients with previously demonstrated clinically significant hypersensitivity (eg, Stevens-Johnson syndrome), to any of the components of this product or amprenavir; when coadministered with medications that are highly dependent on CYP3A4 for clearance and for which elevated plasma concentrations are associated with serious and life-threatening events. 
• Ritonavir: Contraindicated in patients with known hypersensitivity, for example, toxic epidermal necrolysis or Stevens-Johnson syndrome, to ritonavir or any of its ingredients. Ritonavir is contraindicated with medications highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and life-threatening reactions. It is also contraindicated with drugs that are potent CYP3A inducers, where significantly reduced lopinavir plasma concentrations may correlate with the potential for loss of virologic response and possible resistance and cross-resistance.[27]
• Saquinavir: Contraindicated in those with congenital long QT syndrome, those with refractory hypokalemia or hypomagnesemia, and with concurrent administration with drugs that increase saquinavir plasma concentrations and prolong the QT interval. It is also contraindicated in people with complete atrioventricular block without implanted pacemakers or patients at high risk of complete atrioventricular block. In addition, it is contraindicated in patients with clinically significant hypersensitivity (eg, anaphylactic reaction, Stevens-Johnson syndrome) to saquinavir, saquinavir mesylate, or any of its ingredients; in patients with severe hepatic impairment. It is also contraindicated with drugs that are CYP3A substrates, for which increased plasma levels may result in serious or life-threatening reactions.
• Tipranavir: Use of tipranavir is contraindicated with concurrent administration of drugs highly dependent on CYP3A4 for clearance or potent CYP3A4 inducers due to increased risk of intracranial bleeding. Tipranavir is also contradicted in moderate to severe hepatic impairment.[28]
• Enfuvirtide: Known hypersensitivity to enfuvirtide or any of its components
• Maraviroc: This drug is contraindicated in patients with severe renal impairment or end-stage renal disease (CrCl <30 mL per minute) who concomitantly take potent CYP3A inhibitors or inducers.
• Dolutegravir: Previous hypersensitivity reaction to dolutegravir or receiving dofetilide due to the potential for higher dofetilide plasma concentrations and the risk for severe and life-threatening events
• Raltegravir: None
• Ibalizumab: None
• Cobicistat: The concomitant use of cobicistat with atazanavir is contraindicated with drugs dependent on CYP3A or UGT1A1 for clearance and for which elevated plasma concentrations of the interacting drugs are due to serious life-threatening events. Darunavir and cobicistat should not be coadministered with drugs highly dependent on CYP3A for clearance, which may lead to increased plasma concentrations and life-threatening events.

Monitoring

The following tests should be performed to monitor patients on HIV antiretroviral therapy:

Initial Assessment (Start of Therapy)

• CD4 count
• HIV viral load
• Resistance testing
• HLA-B 5701 testing
• Tropism testing
• Hepatitis B serology
• Hepatitis C screening
• Complete blood count (CBC) with differential
• Basic chemistry 
• Alanine transaminase (ALT), aspartate transaminase (AST), bilirubin
• Fasting lipid profile
• Fasting glucose and hemoglobin A1C
• Urinalysis
• Pregnancy test 

Every 3 to 6 Months

• CD4 count for the first 2 years of antiretroviral therapy or if viremia develops
• HIV viral load
• Basic chemistry
• ALT, AST,  bilirubin
• CBC with differential if on zidovudine
• Fasting glucose and hemoglobin A1C if abnormal before

Every 6 Months

• CBC with differential
• Urinalysis if on bictegravir/emtricitabine/TAF) or efavirenz/emtricitabine/TDF

Every 12 Months

• After 2 years, if the CD4 count is 300 to 500, then every 12 months; if CD4 is greater than 500, monitoring is optional.
• Hepatitis B serology may be repeated unless the patient is immunized.
• Screen for hepatitis C if the patient is at risk.
• Fasting lipid profile
• Fasting glucose and hemoglobin A1C
• Urinalysis
• Quantiferon tuberculosis test

Treatment Failure or Modification

• CD4 count
• HIV viral load
• Resistance testing
• Hepatitis B serology
• Hepatitis C screening
• Basic chemistry
• ALT/AST/bilirubin
• CBC with differential
• Fasting lipid profile
• Fasting glucose and hemoglobin A1C
• Urinalysis
• Pregnancy test
• Tropism testing[29]

Toxicity

Many HIV medicines have adverse effects that may require supportive treatment, monitoring, and adjustment of the HIV regimen.[23]

• NVP: Therapy with NVP is associated with significant transaminase elevations in 4% to 20% of patients and symptomatic elevations in 1% to 5% of patients. Among the more than 20 antiretroviral agents, NVP is perhaps the most common cause of serious, clinically apparent acute liver injury. The clinically apparent liver injury due to nevirapine is as high as 1%, with fatalities ensuing in approximately 0.1% of treated patients. The onset of injury is within the first 6 to 8 weeks of therapy. The presenting symptoms are typically abdominal pain and fatigue, followed by fever, rash, and jaundice. Most patients have a cholestatic hepatic injury pattern, but hepatocellular injury is also observed in severe cases. NVP hepatotoxicity can be severe and fatal, and cases requiring emergency liver transplantation have been described. NVP should be promptly discontinued if serum aminotransferase levels rise about 10 times the upper limit of normal, persistently above 5 times above the upper limit of normal, or if associated with bilirubin elevations or hepatitis.[26]
• Tenofovir: Long-term tenofovir is associated with nephrotoxicity and Fanconi syndrome and should be avoided in patients with preexisting renal impairment.
• Zidovudine: Zidovudine-associated myelosuppression manifests with neutropenia and anemia, and its overdose has been described in neonates receiving HIV prophylaxis.
• Efavirenz: Overdoses of efavirenz present with neuropsychiatric manifestations.
• Protease inhibitors: These have been associated with insulin resistance, type II diabetes mellitus, and lipodystrophy.
• NRTIs: Mitochondrial toxicity associated with using NRTIs leads to myopathy, liver failure, and lactic acidosis. Lactic acidosis is fatal if not recognized. In patients with lactic acidosis, NRTIs must be immediately stopped, and clinicians should immediately administer supportive care.[30]

Enhancing Healthcare Team Outcomes

The management of patients with HIV is best with an interprofessional team that includes doctors, nurse practitioners, physician assistants, infectious specialists, pharmacists (including infectious disease specialty pharmacists who focus on antiretroviral treatment), and infectious disease nurses. The pharmacist should verify the chosen regimen, check for drug interactions, verify dosing, and assume responsibility for patient counseling. Nursing can initially assess treatment effectiveness and, particularly, patient compliance. They also must participate in patient education because improper compliance can lead to disastrous therapeutic failure. All healthcare team members must press the point of compliance when they have the opportunity, and any concerns about the regimen or compliance require communication with the treating physician. All interprofessional team members bear responsibility for patient monitoring, especially for compliance, and must record any concerns in the patient's medical record and reach out to the appropriate team member(s) immediately to take corrective action; this open communication is crucial to the success of HAART.

Overwhelming data show that HAART can improve survival and reduce the risk of opportunistic infections. Thus, healthcare workers need to understand these medications because of their effectiveness and the potential adverse effects. A consultation with an infectious disease expert is recommended when any doubts exist regarding HAART. Infectious disease clinicians and other healthcare professionals ensure adults and children with HIV receive safe and effective therapy. Infectious specialists and healthcare professionals are integral to formulating domestic and global infectious disease policies to improve public health.[31] Poor retention in HIV care is associated with higher morbidity and mortality and a greater risk of HIV transmission. The Patient-Centered HIV Care Model incorporates community-based pharmacists with clinicians. PCHCM displayed that close collaborations between pharmacists and clinicians can improve the retention of patients with HIV, enhancing patient outcomes.[32] Only with a complete "all in," collaborative interprofessional team approach can ART have its best chance for therapeutic success while minimizing adverse events.