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Antiretroviral therapy (ART) is the cornerstone of modern HIV management and typically consists of 3 medications from at least 2 antiretroviral classes. Although not curative, ART effectively suppresses viral replication, prolongs survival, and markedly reduces HIV transmission, transforming HIV into a chronic, manageable condition. Widespread use of ART has made progression to AIDS increasingly uncommon in many settings. Clinical studies show that combination ART reduces rates of AIDS, hospitalization, and mortality by 60% to 80%, supporting its use for both treatment and prevention, including in individuals with HIV-negative partners. Global and national initiatives emphasize early diagnosis and sustained viral suppression. UNAIDS 95-95-95 targets aim for widespread diagnosis, treatment, and viral control, while US strategies seek major reductions in new infections. This activity reviews ART use and highlights the importance of coordinated, interprofessional care to ensure safe, effective, and evidence-based HIV management. Objectives: Identify current FDA-approved antiretroviral therapy regimens, including emerging agents, for the treatment and prevention of HIV. Assess patients with HIV for comorbidities, contraindications, and potential drug–drug interactions that may affect ART selection. Select appropriate laboratory monitoring strategies to assess the safety and effectiveness of antiretroviral therapy over time. Strategize with the interprofessional healthcare team to address barriers to retention in HIV care and improve long-term viral suppression outcomes. Access free multiple choice questions on this topic.

Many HIV medicines have adverse effects and toxicity that may require supportive treatment, monitoring, and adjustment of the HIV regimen.[59] Nucleoside/Nucleotide Reverse Transcriptase Inhibitors NRTIs are characterized by mitochondrial toxicity, which can result in severe myopathy, hepatic failure, and potentially fatal lactic acidosis. When lactic acidosis is suspected, all NRTIs must be discontinued immediately and supportive management initiated. Zidovudine: Zidovudine causes dose-dependent bone marrow suppression, most commonly resulting in anemia and neutropenia. Toxicity may present more severely in overdose settings, including dosing errors in neonates. Stavudine: Stavudine has high mitochondrial toxicity and can cause severe lactic acidosis, hepatic steatosis, and painful peripheral neuropathy. Didanosine: Didanosine is associated with pancreatitis and peripheral neuropathy, and these reactions may be severe or life-threatening. Zalcitabine: Zalcitabine causes significant peripheral neuropathy with cumulative exposure. Abacavir: Abacavir can cause a potentially fatal hypersensitivity reaction linked to HLA-B*57:01. Immediate cessation is mandatory if symptoms develop. Lamivudine: Lamivudine is generally well tolerated, with rare cases of clinically relevant hypersensitivity or hepatotoxicity. Emtricitabine: Emtricitabine toxicity is uncommon, with cutaneous hyperpigmentation being the only notable drug-specific reaction. Tenofovir disoproxil fumarate: Tenofovir disoproxil fumarate may cause nephrotoxicity, including proximal tubular injury and Fanconi syndrome. It should be avoided in individuals with preexisting renal impairment. Tenofovir alafenamide: Tenofovir alafenamide has a lower nephrotoxicity rate but can cause dyslipidemia. Tenofovir is removed by hemodialysis with an extraction coefficient of about 54%. Non-Nucleoside Reverse Transcriptase Inhibitors NNRTIs frequently cause hepatic injury and severe dermatologic reactions. Certain drugs are associated with neuropsychiatric toxicity. First-Generation Non-Nucleoside Reverse Transcriptase Inhibitors

Tenofovir alafenamide: Tenofovir alafenamide has a lower nephrotoxicity rate but can cause dyslipidemia. Tenofovir is removed by hemodialysis with an extraction coefficient of about 54%. Non-Nucleoside Reverse Transcriptase Inhibitors NNRTIs frequently cause hepatic injury and severe dermatologic reactions. Certain drugs are associated with neuropsychiatric toxicity. First-Generation Non-Nucleoside Reverse Transcriptase Inhibitors Nevirapine: Therapy with nevirapine 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 typically occurs within the first 6 to 8 weeks of therapy. The presenting symptoms usually include abdominal pain and fatigue, followed by fever, rash, and jaundice. Most patients exhibit a cholestatic pattern of hepatic injury, but hepatocellular injury is also observed in severe cases. NVP hepatotoxicity can be severe and fatal, and cases requiring emergency liver transplantation have been reported. NVP should be promptly discontinued if serum aminotransferase levels rise to approximately 10 times the upper limit of normal, remain persistently above 5 times the upper limit of normal, or are accompanied by bilirubin elevations or hepatitis.[49] Efavirenz: Overdoses of efavirenz present with neuropsychiatric symptoms, and management is supportive. Second-Generation Non-Nucleoside Reverse Transcriptase Inhibitors Etravirine: Etravirine is associated with Stevens-Johnson syndrome and can cause hepatic enzyme elevations. Rilpivirine: Rilpivirine may prolong the QT interval at high concentrations and may worsen depressive symptoms in susceptible individuals. Doravirine: Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported with doravirine, and the drug should be discontinued immediately if these reactions occur. Protease Inhibitors These inhibitors have been associated with insulin resistance, type 2 diabetes, and lipodystrophy. Integrase Strand Transfer Inhibitors

Doravirine: Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported with doravirine, and the drug should be discontinued immediately if these reactions occur. Protease Inhibitors These inhibitors have been associated with insulin resistance, type 2 diabetes, and lipodystrophy. Integrase Strand Transfer Inhibitors Weight gain is frequently observed after starting INSTI-containing regimens in ART-naive individuals. Bictegravir and dolutegravir produce the most significant increases in body weight, and INSTIs cause more weight gain than NNRTIs or boosted PIs. Further research is needed to identify predictors and determine the long-term metabolic or cardiovascular implications. INSTIs may worsen psychiatric symptoms. Central nervous system–related adverse events, including headache, insomnia, dizziness, and depression, have been reported and are usually mild. Because depression is common in individuals with HIV, close monitoring is advised when initiating these drugs, particularly in those with a history of depression or those receiving antidepressants or other psychotropic medications.[69] Chemokine Receptor 5 Antagonist Maraviroc (entry inhibitor): Severe hepatotoxicity with allergic features, including fatal events, has been reported; if patients develop signs or symptoms of hepatitis (eg, elevated liver transaminases) with rash or systemic allergic reaction, maraviroc should be discontinued and hepatic laboratory parameters monitored.[56][70] Attachment Inhibitors Fostemsavir: In studies, administration at 4 times the recommended dose has prolonged the QTc interval; increases in hepatic transaminases have also been observed in individuals with coinfection with hepatitis B or C. Caution is advised when prescribing fostemsavir in patients with preexisting QTc prolongation or concomitant use of QT-prolonging drugs, and ECG and liver enzyme monitoring may be indicated. There is no known specific treatment for overdose with fostemsavir. An ECG should be obtained to measure the QTc interval, and the patient's clinical status should be monitored. If an overdose occurs, the patient should be monitored, and supportive therapy should be provided. Capsid Inhibitors

Fostemsavir: In studies, administration at 4 times the recommended dose has prolonged the QTc interval; increases in hepatic transaminases have also been observed in individuals with coinfection with hepatitis B or C. Caution is advised when prescribing fostemsavir in patients with preexisting QTc prolongation or concomitant use of QT-prolonging drugs, and ECG and liver enzyme monitoring may be indicated. There is no known specific treatment for overdose with fostemsavir. An ECG should be obtained to measure the QTc interval, and the patient's clinical status should be monitored. If an overdose occurs, the patient should be monitored, and supportive therapy should be provided. Capsid Inhibitors Lenacapavir: Injection-site reactions with subcutaneous administration are frequent; improper administration has been associated with severe reactions, including necrosis and ulceration; correct subcutaneous abdominal injection technique should be ensured, and persistent nodules or induration should be evaluated.[69] Postattachment Inhibitors Ibalizumab: Hypersensitivity reactions, including infusion-related reactions and anaphylaxis, have been reported following infusions of ibalizumab. If anaphylaxis occurs, ibalizumab should be discontinued immediately, and appropriate anaphylaxis treatment should be initiated. Immune reconstitution inflammatory syndrome (IRIS) is observed with the initiation of ART, particularly in HIV-infected patients who start treatment with a low CD4+ cell count and have an underlying opportunistic infection or malignancy. Key monitoring strategies include regular clinical evaluations for new or worsening symptoms; monitoring CD4+ cell counts and viral load to track immune recovery; and using specific tests, such as neuroimaging or chest x-rays, to assess for IRIS-related inflammation. In many cases, IRIS is self-limiting and only symptomatic treatment is required, in addition to treatment of the IRIS infection.[71][72] For individual drug-specific toxicity related to more recently approved drugs and multidrug regimens, especially in patients with hepatitis B, tuberculosis, or other opportunistic infections, consultation with a medical toxicologist and an infectious disease specialist is recommended. The National Poison Control Center should be contacted for the latest recommendations.

The management of patients with HIV is best achieved through an interprofessional team that includes physicians, nurse practitioners, physician assistants, infectious disease specialists, pharmacists (including infectious disease specialty pharmacists focused on antiretroviral therapy), and infectious disease nurses. The pharmacist should verify the selected regimen, assess for drug interactions, verify dosing, and assume responsibility for patient education. Nursing staff can initially assess treatment effectiveness and, in particular, patient compliance. They must also participate in patient education, as nonadherence can lead to therapeutic failure. All healthcare team members must emphasize adherence when appropriate, and any concerns regarding the regimen or compliance must be communicated to the treating physician. All interprofessional team members are responsible for patient monitoring, including compliance, and must document any concerns in the patient's medical record and promptly notify the appropriate team members to initiate corrective action; this open communication is crucial to the success of ART. Historically, the term "highly active ART" referred to multidrug regimens. Today, the accepted term is ART. Overwhelming data show that ART can improve survival and reduce the risk of opportunistic infections. Thus, healthcare professionals must understand these medications given their efficacy and potential adverse effects. Consultation with an infectious disease expert is recommended when there are uncertainties regarding ART. Infectious disease clinicians and other healthcare professionals play a key role in ensuring that adults and children with HIV receive safe and effective therapy. Infectious disease specialists and healthcare professionals are integral to the formulation of domestic and global policies to address infectious diseases and improve public health.[73]

Overwhelming data show that ART can improve survival and reduce the risk of opportunistic infections. Thus, healthcare professionals must understand these medications given their efficacy and potential adverse effects. Consultation with an infectious disease expert is recommended when there are uncertainties regarding ART. Infectious disease clinicians and other healthcare professionals play a key role in ensuring that adults and children with HIV receive safe and effective therapy. Infectious disease specialists and healthcare professionals are integral to the formulation of domestic and global policies to address infectious diseases and improve public health.[73] Poor retention in HIV care is associated with increased morbidity and mortality and a greater risk of HIV transmission. The Patient-Centered HIV Care Model (PCHCM) incorporates community-based pharmacists with clinicians. PCHCM demonstrated that close collaborations between pharmacists and clinicians can improve the retention of patients with HIV and enhance patient outcomes.[74] A study suggests that community pharmacy–based administration of long-acting injectable ART is generally well received and represents a promising strategy to expand access to HIV treatment. However, real-world implementation remains constrained by operational barriers, including inadequate staffing, limited pharmacist training, insufficient private space for injections, and inconsistent reimbursement pathways. Successful scale-up continues to depend on strong, bidirectional collaboration between HIV clinics and community pharmacies, which remains the central enabling factor for broader adoption.[75] Guidelines developed by organizations such as the CDC, FDA, and DHHS are essential for informing the implementation of evidence-based ART among healthcare professionals. Effective HIV management is best achieved through ongoing, collaborative efforts among physicians, infectious disease specialists, pharmacists, and nurses, who collectively tailor and optimize treatment for each patient. This interprofessional approach is crucial for rapid adaptation to updated protocols and the integration of newly approved medications to address the challenge of multidrug-resistant HIV. By leveraging each discipline's expertise, the risk of adverse drug events can be minimized while maintaining therapeutic effectiveness.