Management of HIV/AIDS in older patients–drug/drug interactions and adherence to antiretroviral therapy

Figures & data

Table 1 DHHS recommended and alternative cART programs for treatment naïve patients

Recommended Regimens

Integrase (INSTI) based cART

DTG/ABC*/3TC (co-formulated as Triumeq)

DTG + TDF/FTC

EVG/cobi/TDF/FTC (co-formulated as Strbild) (only if pre-treatment est crcl >/= 70 ml/min)

RAL + TDF/FTC

Protease Inhibitor (PI) based cART

DRV/r + TDF/FTC

Alternative Regimens

Nonnucleoside reverse transcriptase inhibitor (NNRTI) based cART:

EFV/TDF/FTC (co-formulated as Atripla)

RPV/TDF/FTC (co-formulated as Complera) (only for pre-treatment viral load >100,000 copies/ml and CD4 >200 cells/mm^3)

Protease Inhibitor (PI) based cART

ATV/cobi + TDF/FTC (only if pre-treatment estimated crcl >/= 70ml/min)

ATV/r + TDF/FTC

DRV/cobi + ABC*/3TC

DRV/r + ABC*/3TC

DRV/cobi + TDF/FTC (only if pre-treatment estimated crcl >/= 70ml/min)

Notes:

* ABC should not be used unless individual is confirmed to be HLA-B*5701 negative. Data from Panel on Antiretroviral Guidelines for Adults and Adolescents. Initiating antiretroviral therapy in treatment-naive patients. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. Department of Health and Human Services. Available from: http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf. Section accessed May 6, 2015.¹²

Abbreviations: DHHS, Department of Health and Human Services; cART, combination antiretroviral therapy; NNRTI, nonnucleoside reverse transcriptase inhibitor; EFV, efavirenz; TDF, tenofovir disoproxil fumarate; FTC, emtricitabine; PI, protease inhibitor; ATV/r, atazanavir/ritonavir; DRV/r, darunavir/ritonavir; INSTI, integrase; DTG, dolutegravir; ABC, abacavir; 3TC, lamivudine; EVG, elvitegravir; RAL, raltegravir; RPV, rilpivirine.

Table 2 Commonly used antiretroviral therapy and associated adverse effects

Protease inhibitors
Atazanavir (ATV) Reyataz	Indirect hyperbilirubinemia PR interval prolongation: first-degree symptomatic AV block reported Hyperglycemia Fat maldistribution		Cholelithiasis Nephrolithiasis Renal insufficiency Serum transaminase elevations Hyperlipidemia (especially with RTV boosting) Skin rash
Darunavir (DRV) Prezista	Skin rash (10%): DRV has a sulfonamide moiety; Stevens–Johnson syndrome, toxic epidermal necrolysis, acute generalized exanthematous pustulosis, and erythrema multiforme have been reported		Hepatotoxicity Diarrhea, nausea Headache Hyperlipidemia Serum transaminase elevation Hyperglycemia Fat maldistribution
Ritonavir (RTV) Norvir	GI intolerance, nausea, vomiting, diarrhea Paresthesia (circumoral and extremities) Hyperlipidemia (especially hypertriglyceridemia) Asthenia Hepatitis		Taste perversion Hyperglycemia Fat maldistribution Possible increased bleeding episodes in patients with hemophilia
Nonnucleoside reverse transcriptase inhibitors
Efavirenz (EFV) Sustiva	Rash Neuropsychiatric symptoms Increased transaminase levels Hyperlipidemia		False-positive results with some cannabinoid and benzodiazepine screening assays reported Teratogenic in nonhuman primates and potentially teratogenic in humans
Rilpivirine (RPV) Edurant Etravirine (ETR) Intelence	Rash Depression, insomnia, headache HSRs, characterized by rash, constitutional findings, and sometimes organ dysfunction, including hepatic failure, have been reported		Hepatotoxicity Nausea Rash, including Stevens–Johnson syndrome
Nucleoside reverse transcriptase inhibitors
Lamivudine (3TC) Epivir	Minimal toxicity		Severe acute exacerbation of hepatitis may occur in HBV coinfected patients who discontinue 3TC
Tenofovir Disoproxil Fumarate (TDF) Viread	Renal insufficiency, Fanconi syndrome, proximal tubulopathy Osteomalacia, decrease in bone mineral density Potential decrease in bone mineral density		Severe acute exacerbation of hepatitis may occur in HBV coinfected patients who discontinue TDF Asthenia, headache, diarrhea, nausea, vomiting, and flatulence
Zidovudine (ZDV) Retrovir	Bone marrow suppression: macrocytic anemia or neutropenia Nausea, vomiting, headache, insomnia, asthenia Nail pigmentation Lipoatrophy Myopathy		Lactic acidosis/severe hepatomegaly with hepatic steatosis (rare but potentially life threatening toxicity) Hyperlipidemia Insulin resistance/diabetes mellitus
Abacavir (ABC) Ziagen	Hypersensitivity reaction: patients who test positive for HLA-B*5701 are at highest risk. HLA screening should be done before initiation of ABC. Rechallenge is not recommended Symptoms of HSR may include fever, rash, nausea, vomiting, diarrhea, abdominal pain, malaise, or fatigue or respiratory symptoms such as sore throat, cough, or shortness of breath		Some cohort studies suggest increased risk of MI with recent or current use of ABC, but this risk is not substantiated in other studies
Emtricitabine (FTC) Emtriva	Minimal toxicity Hyperpigmentation/skin discoloration		Severe acute exacerbation of hepatitis may occur in HBV coinfected patients who discontinue FTC
Integrase inhibitors
Dolutegravir (DTG) Tivicay Elvitegravir (EVG)	Insomnia Headache Nausea Diarrhea Elevated cholesterol		HSRs including rash, constitutional symptoms, and organ dysfunction (including liver injury) have been reported
Raltegravir (RAL) Isentress	Nausea Headache Diarrhea Pyrexia	CPK elevation, muscle weakness, and rhabdomyolysis Rash, including Stevens–Johnson syndrome, HSR, and toxic epidermal necrolysis
CCR5 antagonists
Maraviroc (MVC) Selzentry	Abdominal pain Cough Dizziness Musculoskeletal symptoms Pyrexia Rash Upper respiratory tract infections	Hepatotoxicity, which may be preceded by severe rash or other signs of systemic allergic reactions Orthostatic hypotension, especially in patients with severe renal insufficiency

Notes:

Data from Panel on Antiretroviral Guidelines for Adults and Adolescents. Initiating antiretroviral therapy in treatment-naive patients. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. Department of Health and Human Services. Available from: http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf. Section accessed October 28, 2014.¹²

Abbreviations: AV, atrioventricular; GI, gastrointestinal; HBV, hepatitis B virus; HLA, human leukocyte antigen; MI, myocardial infarction; HSR, hypersensitivity; CPK, creatine phosphokinase.

Table 3 Description of the metabolic pathways, interaction potential, usual daily dose, and dose adjustment recommendations for renal/hepatic impairment for commonly utilized antiretroviral therapy

Medication generic name (abbreviation) Brand name	Metabolism/elimination/potential for interactions	Usual daily dose	Dose in renal insufficiency			Dose in hepatic impairment
Protease inhibitors
Atazanavir (ATV) Reyataz	CYP3A4 inhibitor and substrate, CYP 2C8 (weak inhibitor), UGT1A1 inhibitor	300 mg once daily with boosting agent (RTV 100 mg or COBI 150mg)	No dosage adjustment for patients with renal dysfunction who do not require HD ARV-naive patients on HD: ATV 300 mg + RTV 100 mg once daily ARV-experienced patients on HD: ATV or RTV/r not recommended			Child-Pugh Class B: 300 mg once daily Child-Pugh Class C: not recommended RTV boosting is not recommended in patients with hepatic impairment (Child-Pugh Class B or C)
Darunavir (DRV) Prezista	CYP3A4 inhibitor and substrate, CYP 2C9 inducer	ARV naive or no DRV mutations: DRV 800 mg + boosting agent (RTV 100 mg or COBI 150 mg), otherwise DRV 600 mg + RTV 100 mg twice daily	No dosage adjustment necessary			Mild-to-moderate hepatic impairment: no dosage adjustment Severe hepatic impairment: not recommended
Ritonavir (RTV) Norvir	CYP3A4.2D6 substrate; potent 3A4, 2D6 inhibitor Inducer of CYP1A2, CYP 2C8, CYP2C9, CYP2C19, and UGT1A1	As a PI-boosting agent: 100–400 mg per day	No dosage adjustment necessary			Refer to recommendations for the primary PI used
Nonnucleoside reverse transcriptase inhibitors
Efavirenz (EFV) Sustiva	Substrate of CYPs 2B6, 2A6, and 3A4. Inhibits: 2C9, 2C19, 3A4. Induces: 3A4, 2B6	600 mg once daily, given before bedtime on an empty stomach	No dosage adjustment necessary			No dosage recommendation, use caution in patients with hepatic impairment
Rilpivirine (RPV) Edurant	CYP3A4 substrate	25 mg once daily (take with a meal)	No dosage adjustment necessary			Child-Pugh Class A or B: no dosage adjustment Child-Pugh Class C: no dosage recommendation
Etravirine (ETR) Intelence	CYP3A4, 2C9, and 2C19 substrate 3A4 inducer; 2C9 and 2C19 inhibitor	200 mg twice daily	No dosage adjustment necessary			Child-Pugh Class A or B: no dosage adjustment Child-Pugh Class C: no dosage recommendation
Nucleoside reverse transcriptase inhibitors
Lamivudine (3TC) Epivir	Renal excretion: 70%	300 mg once daily or 150 mg twice daily	CrCl (mL/min) 30–49 15–29 5–14 <5 or on HD On dialysis days, take dose after dialysis	Dose 150 mg q24h 1×150 mg, then 100 mg q24h 1×150 mg, then 50 mg q24h 1×50 mg, then 25 mg q24h		No dosage adjustment necessary
Tenofovir disoproxil fumarate (TDF) Viread	Renal excretion – primary route of elimination	300 mg once daily	CrCl (mL/min) 30–49 10–29 <10 and not on HD on HD On dialysis days, take dose after dialysis	Dose 300 mg q48h 300 mg twice weekly (every 72–96 hours) No recommendation 300 mg q7 days		No dosage adjustment necessary
Zidovudine (ZDV) Retrovir	Metabolized to azidothymidine glucuronide. Renal excretion of azidothymidine glucuronide	300 mg twice daily	CrCl (mL/min) <15 or HD On dialysis days, take dose after dialysis	Dose 100 mg tid or 300 mg once daily		No dosage recommendation
Abacavir (ABC) Ziagen	Metabolized by alcohol dehydrogenase and glucuronyl transferase. Renal excretion of metabolites: 82%	300 mg twice daily or 600 mg once daily	No dosage adjustment necessary			Child-Pugh Score 5–6: 200 mg twice daily (use oral solution) Child-Pugh Score >6: contraindicated
Emtricitabine (FTC) Emtriva	Renal excretion: 86%	200 mg oral capsule once daily or 240 mg (24 mL) oral solution once daily	CrCl (mL/min) 30–49 15–29 <15, HD, CAPD On dialysis days, take dose after dialysis	Capsule 200 mg q48h 200 mg q72h 200 mg q96h	Solution 120 mg q24h 80 mg q24h 60 mg q24h	No dosage recommendation
Integrase inhibitors
Dolutegravir (DTG) Tivicay	UGT1A1-mediated glucuronidation Minor contribution from CYP3A4	50 mg once daily or 50 mg twice daily	No dosage adjustment necessary			Child-Pugh Class A or B: no dosage adjustment Child-Pugh Class C: not recommended
Elvitegravir (EVG).	CYP3A4 substrate; UGT1A1 substrate	150 mg or 85 mg daily (depending on concomitant ART/formulation)	No dose adjustment necessary for renal function. The dosing form of Stribild (which contains EVG/COBI/TDF/FTC) should not be initiated when CrCl <70 mL. Stribild should be discontinued if CrCl declines to <50 mL/min			Mild-to-moderate hepatic impairment: no dosage adjustment Severe hepatic impairment: not recommended
Raltegravir (RAL) Isentress	UGT1A1-mediated glucuronidation	400 mg twice daily	No dosage adjustment necessary			Mild-to-moderate hepatic impairment: no dosage adjustment Severe hepatic impairment: no recommendation
CCR5 antagonists
Maraviroc (MVC) Selzentry	CYP3A4 substrate	Usual dose 300 mg twice daily. With strong CYP 3A4 inhibitors: 150 mg twice daily With strong CYP3A4 inducers: 600 mg twice daily	CrCl <30 mL/min or on HD Without Potent CYP3A inhibitors or inducers: 300 mg bid; reduce to 150 mg bid if postural hypotension occurs With potent CYP3A inducers or inhibitors: not recommended			No dosage recommendations Concentrations will likely be increased in patients with hepatic impairment
Pharmacokinetic enhancer
Cobicistat (COBI), Tybost	CYP3A4 substrate; Inhibitor of CYP3A4 and CYP2D6	150 mg once daily	With TDF: not recommended starting with a CrCl <70ml/min. Use not recommended if CrCl <50ml/min. Without TDF: no dose adjustments necessary			Child-Pugh Class A-B: No adjustment necessary. Child-Pugh Class C: No data available

Notes: Data from Panel on Antiretroviral Guidelines for Adults and Adolescents. Initiating antiretroviral therapy in treatment-naive patients. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. Department of Health and Human Services. Available from: http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf. Section accessed May 26, 2015.

Abbreviations: HD, hemodialysis; CrCl, Creatinine clearance; ARV, antiretroviral.

Table 4 cART medications associated with increased hyperlipidemia

NRTI class

Abacavir (including combination pill Epzicom and Trizivir), stavudine, zidovudine (including combination pill Combivir and Trizivir)

NNRTI class

Efavirenz (including combination pill Atripla)

PI classa

Lopinavir (including combination pill Kaletra), saquinavir, ritonavir,indinavir, nelfinavir, fosamprenavir

Stribild

Notes:

a Atazanavir and darunavir are also associated with hyperlipidemia, but to a lesser extent as compared with the other PIs.

Abbreviations: NRTI, nucleoside reverse transcriptase inhibitor; NNRTI, nonnucleoside reverse transcriptase inhibitor; PI, protease inhibitor; cART, combination antiretroviral therapy.

Table 5 Approaches to enhance compliance with antiretroviral therapy

1. Targeted antiretroviral medication education (written and oral) in accordance with the patient’s level of health literacy to include: indication for their cART, expectations with therapy and response to therapy, administration requirements, and anticipated side effects (helpful fact sheets can be found on http://www.aidsinfonet.org/categories)^Citation60

2. Targeted education regarding the importance of compliance/adherence for control of HIV (a helpful patient fact sheet can be found on http://www.aidsinfonet.org/fact_sheets/view/405)^Citation61

3. Medication organizing devices (pill organizers, pillboxes, unit dose packaging, blister packaging, etc)

4. Reminder devices: calendars, medication checklists, smartphone apps, alarms

5. Incorporation of medication taking with patient’s daily routine and/or selection of appropriate ART that minimizes adverse effects that disrupt daily routine

6. Involvement of family members, significant others, and caregivers when able

Abbreviations: cART, combination antiretroviral therapy; ART, antiretroviral therapy.

Panel on Antiretroviral Guidelines for Adults and AdolescentsInitiating antiretroviral therapy in treatment-naive patients Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and AdolescentsDepartment of Health and Human Services Available from: http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf. Section accessed. What to start: Initial combination regimens for the antiretroviral naive patientAccessed May 26, 2015

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Aidsinfonet.org [webpage on the Internet] Available from: http://www.aidsinfonet.orgAccessed February 11, 2014

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Aidsinfonet.org [webpage on the Internet] Available from: http://www.aidsinfonet.org/fact_sheets/view/405Accessed February 11, 2014

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