Substantial advances have been made in antiretroviral therapy since the introduction of the first agent, zidovudine, in 1987. Six classes of antiretroviral agents are currently available for use: nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), fusion inhibitors, CCR5 co-receptor antagonists, and integrase strand transfer inhibitors (INSTIs) (Table 49–3). These agents inhibit HIV replication at different parts of the cycle (Figure 49–3).
Life cycle of HIV. Binding of viral glycoproteins to host cell CD4 and chemokine receptors leads to fusion of the viral and host cell membranes via gp41 and entry of the virion into the cell. After uncoating, reverse transcription copies the single-stranded HIV RNA genome into double-stranded DNA, which is integrated into the host cell genome. Gene transcription by host cell enzymes produces messenger RNA, which is translated into proteins that assemble into immature noninfectious virions that bud from the host cell membrane. Maturation into fully infectious virions is through proteolytic cleavage. NNRTIs, nonnucleoside reverse transcriptase inhibitors; NRTIs, nucleoside/nucleotide reverse transcriptase inhibitors.
TABLE 49–3Currently available antiretroviral agents. ||Download (.pdf) TABLE 49–3 Currently available antiretroviral agents.
|Agent ||Class of Agent ||Recommended Adult Dosage ||Administration Recommendation ||Characteristic Adverse Effects ||Comments |
|Abacavir ||NRTI1 ||300 mg bid or 600 mg qd ||Test to rule out the presence of the HLA-B5701 allele prior to initiation of therapy. ||Rash, hypersensitivity reaction, nausea; possible increase in myocardial infarction ||Avoid alcohol. |
|Atazanavir ||PI2 ||400 mg qd or 300 mg qd with ritonavir 100 mg qd or cobicistat 150 mg qd; adjust dose in hepatic insufficiency ||Take with food. Avoid concomitant antacids. Separate dosing acid-reducing agents by ≥10 h. ||Nausea, rash, myalgia, indirect hyperbilirubinemia, diarrhea, ↑ liver enzymes, prolonged PR interval ||See footnote 4. Avoid elvitegravir/cobicistat, etravirine, fosamprenavir, nevirapine, tipranavir. Avoid in severe hepatic insufficiency. The oral powder contains phenylalanine. |
|Darunavir ||PI2 || |
Treatment-naïve: 800 mg qd with ritonavir 100 mg qd or cobicistat 150 mg qd
Treatment-experienced: 600 mg bid with ritonavir 100 mg bid
|Take with food. ||Diarrhea, headache, nausea, rash, hyperlipidemia, ↑ liver enzymes, ↑ serum amylase ||See footnote 4. Avoid elvitegravir/ cobicistat and simeprevir. Avoid in patients with sulfa allergy. |
|Delavirdine ||NNRTI ||400 mg tid ||Separate dosing from ddI or antacids by ≥1 h. ||Rash, ↑ liver enzymes, headache, nausea, diarrhea ||See footnote 4. Avoid concurrent fosamprenavir. Teratogenic in rats. |
|Didanosine (ddI) ||NRTI1 || |
Tablets, 400 mg qd or 200 mg bid3 adjusted for weight
Buffered powder, 250 mg bid3
|Take on an empty stomach. ||Peripheral neuropathy, pancreatitis, diarrhea. ||Avoid concurrent neuropathic drugs (eg, stavudine, zalcitabine, isoniazid), ribavirin, or allopurinol. Chewable tablets contain phenylalanine. |
|Dolutegravir ||INSTI || |
INSTI-naïve: 50 mg qd
If co-administered with efavirenz, fosamprenavir/ritonavir, tipranavir/ritonavir, or rifampin or if certain INSTI mutations: 50 mg bid
|Separate dosing from antacids and polyvalent cations by ≥2 h. ||Insomnia, headache, hypersensitivity reaction, ↑ liver enzymes ||Avoid carbamazepine, dofetilide, nevirapine, phenobarbital, phenytoin. |
|Efavirenz ||NNRTI ||600 mg qd ||Take on an empty stomach, at bedtime. ||Neuropsychiatric symptoms, rash, ↑ liver enzymes, headache, nausea ||See footnote 4. Avoid elvitegravir/ cobicistat, etravirine, indinavir, simeprevir. Teratogenic in primates. |
|Elvitegravir ||INSTI || |
Treatment-naïve: 150 mg qd with cobicistat 150, emtricitabine 200, and tenofovir
Treatment-experienced: 85 mg–150 mg qd with a protease inhibitor
|Take with food. Separate dosing from antacids by ≥2 h. ||Diarrhea, rash, ↑ liver enzymes ||See footnote 4. Avoid efavirenz and nevirapine. |
|Emtricitabine ||NRTI1 ||200 mg qd3 || ||Headache, diarrhea, nausea, rash, hyperpigmentation ||Avoid concurrent lamivudine. |
|Enfuvirtide ||Fusion inhibitor ||90 mg subcutaneously bid || ||Injection site reactions, hypersensitivity reaction, insomnia, headache, dizziness, nausea, eosinophilia; possible increased bacterial pneumonia || |
|Etravirine ||NNRTI ||200 mg bid ||Take with food. ||Rash, nausea, diarrhea ||See footnote 4. Avoid atazanavir, efavirenz, elvitegravir/cobicistat, fosamprenavir, indinavir, tipranavir. |
|Fosamprenavir ||PI2 ||1400 mg bid or 700 mg bid with ritonavir 100 mg bid or 1400 mg daily with ritonavir 100–200 mg qd; adjust dose in hepatic insufficiency || ||Rash, diarrhea, nausea, headache, ↑ liver enzymes ||See footnote 4. Avoid elvitegravir/ cobicistat, etravirine, lopinavir/ritonavir, nevirapine. Avoid in patients with sulfa allergy or severe hepatic insufficiency. Avoid cimetidine, disulfiram, metronidazole, vitamin E, ritonavir oral solution, and alcohol with the oral solution. |
|Indinavir ||PI2 ||800 mg tid or 800 mg bid with ritonavir 100–200 mg bid; adjust dose in cirrhosis ||Best on an empty stomach. Drink at least 48 oz liquid daily. Separate dosing from ddI by ≥1 h. ||Nephrolithiasis, nausea, indirect hyperbilirubinemia, headache, diarrhea; possible increase in myocardial infarction ||See footnote 4. Avoid efavirenz and etravirine. |
|Lamivudine ||NRTI1 ||150 mg bid or 300 mg qd3 || ||Nausea, headache, dizziness, fatigue ||Do not administer with emtricitabine or zalcitabine. |
|Lopinavir/ritonavir ||PI/PI2 ||400/100 mg bid or 800/200 mg qd ||Separate dosing from ddI by 1 h. ||Diarrhea, nausea, hypertriglyceridemia, ↑ liver enzymes; possible increase in myocardial infarction ||See footnote 4. Avoid darunavir, elvitegravir/cobicistat, fosamprenavir, tipranavir. Avoid disulfiram and metronidazole with oral solution. |
|Maraviroc ||CCR5 inhibitor ||300 mg bid; 150 bid with CYP3A inhibitors; 600 mg bid with CYP3A inducers || ||Cough, muscle pain, diarrhea, sleep disturbance, ↑ liver enzymes; possible increase in myocardial infarction ||See footnote 4. Do not administer in patients with severe renal dysfunction. |
|Nelfinavir ||PI2 ||750 mg tid or 1250 mg bid ||Take with food. ||Diarrhea, nausea, flatulence ||See footnote 4. The oral powder contains phenylalanine. |
|Nevirapine ||NNRTI ||200 mg bid ||Dose-escalate from 200 mg daily over 14 days. ||Rash, hepatitis (occasionally fulminant), nausea, headache ||See footnote 4. Avoid atazanavir, dolutegravir, elvitegravir/cobicistat, fosamprenavir. Contraindicated with moderate or severe hepatic impairment. |
|Raltegravir ||INSTI ||400 mg bid || ||Nausea, headache, fatigue, muscle aches, ↑ amylase levels, ↑ liver enzymes ||The chewable tablets contain phenylalanine. |
|Rilpivirine ||NNRTI ||25 mg qd ||Take with food. Separate dosing from antacids or H2 blockers by ≥4 h. ||Headache, insomnia, depression, rash, ↑ liver enzymes ||See footnote 4. |
|Rilpivirine ||PI2 ||1000 mg bid with ritonavir 100 mg bid ||Take within 2 h of a full meal. ||Nausea, diarrhea, abdominal pain, dyspepsia, rash ||See footnote 4. Avoid darunavir, garlic capsules, tipranavir and drugs that increase the QT interval. Avoid in severe hepatic insufficiency. |
|Stavudine ||NRTI1 ||30–40 mg bid, depending on weight3 || ||Peripheral neuropathy, pancreatitis, rapidly progressive ascending neuromuscular weakness (rare) ||Avoid zidovudine and neuropathic drugs (eg, ddI, zalcitabine, isoniazid). |
|Tenofovir alafenamide ||NRTI1 ||10 mg qd with emtricitabine plus elvitegravir/cobicistat; 25 mg qd with emtricitabine ± rilpivirine || ||Gastrointestinal symptoms, headache, ↑ creatinine, proteinuria ||Avoid inducers of p-glycoprotein (rifampin, rifabutin, phenytoin, phenobarbital, St John’s Wort, tipranavir/ritonavir). Also avoid in severe renal insufficiency. |
|Tenofovir disoproxil fumarate ||NRTI1 ||300 mg qd3 || ||Nausea, diarrhea, vomiting, flatulence, headache, renal insufficiency ||Avoid atazanavir, didanosine, probenecid. |
|Tipranavir ||PI2 ||500 mg bid with ritonavir 200 mg bid ||Take with food. Separate from ddI by ≥2 h. Avoid antacids. ||Diarrhea, nausea, vomiting, abdominal pain, rash, ↑ liver enzymes, hyperlipidemia ||See footnote 4. Avoid concurrent atazanavir, elvitegravir/cobicistat, etravirine, fosamprenavir, lopinavir/ritonavir, saquinavir. Avoid in patients with severe hepatic insufficiency, who are at risk for bleeding, or with sulfa allergy. Avoid vitamin E with the oral solution. |
|Zidovudine ||NRTI1 ||200 mg tid or 300 mg bid3 || ||Macrocytic anemia, neutropenia, nausea, headache, insomnia, myopathy ||Avoid concurrent stavudine and myelosuppressive drugs (eg, ganciclovir, ribavirin). |
Knowledge of viral dynamics through the use of viral load and resistance testing has made it clear that combination therapy with maximally potent agents will reduce viral replication to the lowest possible level, thereby reducing the number of cumulative mutations and decreasing the likelihood of emergence of resistance. Thus, administration of combination antiretroviral therapy, typically including at least three antiretroviral agents with differing susceptibility patterns, has become the standard of care. Viral susceptibility to specific agents varies among patients and may change with time. Therefore, such combinations must be chosen with care and tailored to the individual, as must changes to a given regimen. In addition to potency and susceptibility, important factors in the selection of agents for any given patient are tolerability, convenience, and optimization of adherence. New drugs with high potency, low toxicity, and good tolerability increase the feasibility of early, lifelong treatment. As new agents have become available, several older ones have had diminished usage, because of either suboptimal safety or inferior efficacy. Zalcitabine (ddC; dideoxycytidine) is no longer marketed, and regimens containing zidovudine (AZT; azidothymidine), ddI (didanosine), or stavudine (d4T) are infrequently recommended as first-line regimens.
Decrease of the circulating viral load by antiretroviral therapy is correlated with enhanced survival as well as decreased morbidity. Also, the use of antiretroviral therapy strongly reduces the risk for heterosexual and same-sex HIV transmission.
Discussion of antiretroviral agents in this chapter is specific to HIV-1. Patterns of susceptibility of HIV-2 to these agents may vary; however, there is innate resistance to the NNRTIs and enfuvirtide as well as a lower barrier of resistance to NRTIs and PIs.
NUCLEOSIDE & NUCLEOTIDE REVERSE TRANSCRIPTASE INHIBITORS (NRTIs)
The NRTIs act by competitive inhibition of HIV-1 reverse transcriptase; incorporation into the growing viral DNA chain causes premature chain termination due to inhibition of binding with the incoming nucleotide (Figure 49–3). Each agent requires intracytoplasmic activation via phosphorylation by cellular enzymes to the triphosphate form.
Typical resistance mutations include M184V, L74V, D67N, and M41L. Lamivudine or emtricitabine therapy tends to select rapidly for the M184V mutation in regimens that are not fully suppressive. While the M184V mutation confers reduced susceptibility to abacavir, didanosine, and zalcitabine, its presence may restore phenotypic susceptibility to zidovudine. The K65R/N mutation is associated with reduced susceptibility to tenofovir, abacavir, lamivudine, and emtricitabine.
All NRTIs may be associated with mitochondrial toxicity, which may manifest as peripheral neuropathy, pancreatitis, lipoatrophy, and hepatic steatosis. Less commonly, lactic acidosis may occur, which can be fatal. NRTI treatment should be suspended in the setting of rapidly rising aminotransferase levels, progressive hepatomegaly, or metabolic acidosis of unknown cause. Lipoatrophy and insulin resistance may occur most frequently with use of the thymidine analogs stavudine and zidovudine, and least frequently with use of tenofovir, lamivudine, emtricitabine, and abacavir.
Abacavir is a guanosine analog that is well absorbed following oral administration (83%) and is unaffected by food. The serum half-life is 1.5 hours. The drug undergoes hepatic glucuronidation and carboxylation. Dosage reduction is recommended in mild hepatic impairment; no data are available for patients with moderate or severe liver disease. Since the drug is metabolized by alcohol dehydrogenase, serum levels of abacavir may be increased with concurrent alcohol (ie, ethanol) ingestion. Cerebrospinal fluid levels are approximately one-third those of plasma. Abacavir is one of the NRTI agents recommended for use in pregnancy (Table 49–5).
Hypersensitivity reactions, occasionally fatal, have been reported in up to 8% of patients receiving abacavir and may be more severe in association with once-daily dosing. Symptoms, which generally occur within the first 6 weeks of therapy, include fever, fatigue, nausea, vomiting, diarrhea, and abdominal pain. Dyspnea, pharyngitis, and cough, and elevations in serum aminotransferase or creatine kinase levels may also be present, with skin rash in ~50% of patients. Rechallenge is contraindicated. Screening for HLA-B*5701 before initiation of abacavir therapy is important to identify patients with an increased risk for abacavir-associated hypersensitivity reaction (see Table 5–4). Although the positive predictive value of this test is only about 50%, it has a negative predictive value approaching 100%.
Rash occurs in approximately 5% of patients, typically in the first 6 weeks of treatment. Less frequent adverse events are fever, nausea, vomiting, diarrhea, headache, dyspnea, fatigue, and pancreatitis. In some studies but not in others, abacavir has been associated with an increased risk of myocardial infarction. The class effects of mitochondrial toxicity and disorders of lipid metabolism seem to be less common with abacavir than with other nucleoside analogs.
Didanosine (ddI) is a synthetic analog of deoxyadenosine. Oral bioavailability is approximately 40%. Buffered or enteric-coated formulations are necessary to prevent inactivation by gastric acid. Cerebrospinal fluid concentrations of the drug are approximately 20% of serum concentrations. Serum half-life is 1.5 hours, but the intracellular half-life of the activated compound is 20–24 hours. The drug is eliminated by both cellular metabolism and renal excretion.
The major clinical toxicities associated with didanosine therapy are peripheral distal sensory neuropathy and dose-dependent pancreatitis. Therefore, co-administration with drugs or conditions that increase the risk of either (eg, alcohol abuse, hypertriglyceridemia, pregnancy, zalcitabine, stavudine, isoniazid, vincristine, ribavirin, and hydroxyurea), should be avoided. Other reported adverse effects include diarrhea (particularly with the buffered formulation), hepatitis, esophageal ulceration, cardiomyopathy, central nervous system toxicity (headache, irritability, insomnia), and hypertriglyceridemia. Concurrent stavudine increases the risk of lactic acidosis. Reports of retinal changes and optic neuritis in patients receiving didanosine, particularly in adults receiving high doses and in children, mandate periodic retinal examinations.
Increased levels of didanosine when administered with tenofovir necessitate dose reduction. Concurrent allopurinol or ribavirin is contraindicated. The buffer in didanosine tablets interferes with the absorption of delavirdine and nelfinavir, necessitating separation in time. The chewable tablets contain phenylalanine, which can be harmful to patients with phenylketonuria.
Emtricitabine (FTC) is a fluorinated analog of lamivudine with a long intracellular half-life (>24 hours), allowing for once-daily dosing. Oral bioavailability of the capsules is 93% and is unaffected by food, but penetration into the cerebrospinal fluid is low. Elimination is by both glomerular filtration and active tubular secretion. The serum half-life is about 10 hours.
Emtricitabine is one of the NRTI agents recommended for use in pregnancy (Table 49–5). The combination of tenofovir and emtricitabine is recommended as pre-exposure prophylaxis to reduce HIV acquisition in high-risk persons.
Both emtricitabine and lamivudine may select for the M184V/I mutation and therefore should not be used together.
The most common adverse effects observed in patients receiving emtricitabine are headache, diarrhea, nausea, and rash. Hyperpigmentation of the palms or soles may be observed (~ 3%), particularly in African Americans (up to 13%). Clinically significant drug-drug interactions involving emtricitabine have not been identified. Due to its activity against HBV, exacerbation of HBV may occur if therapy is interrupted or discontinued in patients co-infected with HIV.
Lamivudine (3TC) is a cytosine analog with in vitro activity against both HIV-1 and HBV.
Oral bioavailability exceeds 80% and is not food-dependent. The mean cerebrospinal fluid:plasma ratio of lamivudine is 0.1–0.2. Serum half-life is 2.5 hours, whereas the intracellular half-life of the triphosphorylated compound is 11–14 hours. Lamivudine is predominantly eliminated in the urine by active organic cation secretion.
Lamivudine is one of the recommended NRTI agents for use in pregnant women (Table 49–5).
Adverse effects are uncommon but include headache, dizziness, insomnia, fatigue, dry mouth, and gastrointestinal discomfort. Due to its activity against HBV, exacerbation of HBV may occur if therapy is interrupted or discontinued in patients co-infected with HIV and HBV. Since both emtricitabine and lamivudine may select for the M184V/I mutation, these agents should not be used together. Levels of lamivudine may increase when administered with trimethoprim-sulfamethoxazole. Lamivudine and zalcitabine may inhibit the intracellular phosphorylation of one another; therefore, their concurrent use should be avoided if possible.
The thymidine analog stavudine (d4T) has high oral bioavailability (86%) that is not food-dependent. The serum half-life is 1.1 hours, the intracellular half-life is 3.0–3.5 hours, and mean cerebrospinal fluid concentrations are 55% of those of plasma. Excretion is by active tubular secretion and glomerular filtration.
The major toxicity is a dose-related peripheral sensory neuropathy; incidence may be increased with concomitant neurotoxic drugs such as didanosine, vincristine, isoniazid, or ribavirin, or in patients with advanced immunosuppression. Other potential adverse effects are pancreatitis, arthralgias, and elevation in serum aminotransferases. Caution is advised in patients with liver dysfunction. A rare adverse effect is a rapidly progressive ascending neuromuscular weakness. Lactic acidosis with hepatic steatosis, as well as lipodystrophy, appear to occur more frequently in patients receiving stavudine than in those receiving other NRTI agents. Stavudine should not be administered with didanosine due to increased risk of both lactic acidosis and pancreatitis. This combination has been implicated in several deaths in HIV-infected pregnant women. Since zidovudine may reduce the intracellular phosphorylation of stavudine, these two drugs should not be used together.
TENOFOVIR DISOPROXIL FUMARATE
Tenofovir is an acyclic nucleoside phosphonate (ie, nucleotide) analog of adenosine with activity against HIV and HBV. Like the nucleoside analogs, tenofovir competitively inhibits HIV reverse transcriptase and causes chain termination after incorporation into DNA. However, only two rather than three intracellular phosphorylations are required for active inhibition of DNA synthesis.
Tenofovir disoproxil fumarate is a water-soluble prodrug of active tenofovir. The oral bioavailability increases from 25% in the fasted state to 39% after a high-fat meal. The prolonged serum (12–17 hours) and intracellular half-lives allow once-daily dosing. Elimination occurs by both glomerular filtration and active tubular secretion, and dosage adjustment in patients with renal insufficiency is recommended.
Tenofovir disoproxil fumarate is one of the NRTI agents recommended for use in pregnancy (Table 49–5). The combination of tenofovir and emtricitabine is recommended as pre-exposure prophylaxis to reduce HIV acquisition in high-risk persons.
Gastrointestinal complaints (eg, nausea, diarrhea, vomiting, flatulence) are the most common adverse effects but rarely require discontinuation. Since tenofovir is formulated with lactose, these may occur more frequently in patients with lactose intolerance. Cumulative loss of renal function has been observed, possibly increased with concurrent use of boosted PI regimens. Acute renal failure and Fanconi’s syndrome have also been reported. For this reason, tenofovir should be used with caution in patients at risk for renal dysfunction. Serum creatinine levels should be monitored during therapy and tenofovir discontinued for new proteinuria, glycosuria, or calculated glomerular filtration rate <30 mL/min. Tenofovir-associated proximal renal tubulopathy causes excessive renal phosphate and calcium losses and 1-hydroxylation defects of vitamin D; loss of bone mineral density and osteomalacia have been reported. Tenofovir may compete with other drugs that are actively secreted by the kidneys, such as cidofovir, acyclovir, and ganciclovir. Concurrent use of probenecid is contraindicated. Tenofovir levels may increase, and levels of telaprevir decrease, when these agents are co-administered. Due to its activity against HBV, exacerbation of HBV may occur if therapy is interrupted or discontinued in patients co-infected with HIV and HBV.
Tenofovir alafenamide is a phosphonoamidate prodrug of tenofovir that is currently available in co-formulation with other antiretroviral agents (with emtricitabine, with elvitegravir plus cobicistat plus emtricitabine, and with rilpivirine plus emtricitabine). Plasma levels of active tenofovir in plasma are approximately 90% lower with tenofovir alafenamide than with tenofovir disoproxil, since metabolism occurs in lymphocytes and macrophages (as well as hepatocytes and some other cells) rather than blood.
Tenofovir alafenamide is a substrate of P-glycoprotein, and levels of tenofovir can be affected by inhibitors or inducers of P-glycoprotein. Ritonavir and cobicistat can increase plasma concentrations of tenofovir, while darunavir can decrease tenofovir concentrations.
Tenofovir alafenamide appears to have less renal and bone toxicity than tenofovir disoproxil fumarate; however this is still under investigation. It does not require dose adjustment in patients with creatinine clearance >30 mL/min.
Tenofovir alafenamide is a substrate of P-glycoprotein, and levels of tenofovir can be affected by inhibitors or inducers of P-glycoprotein. Ritonavir and cobicistat can increase plasma concentrations of tenofovir, while darunavir can decrease tenofovir concentrations.
Adverse effects appear to be uncommon but may include gastrointestinal symptoms or headache. Tenofovir alafenamide is active against hepatitis B and has been approved for treatment of HBV infection.
Zidovudine (azidothymidine; AZT) is a deoxythymidine analog that is well absorbed (63%) and distributed to most body tissues and fluids, including the cerebrospinal fluid, where drug levels are 60–65% of those in serum. Although the serum half-life averages 1 hour, the intracellular half-life of the phosphorylated compound is 3–4 hours, allowing twice-daily dosing. Zidovudine is eliminated primarily by renal excretion following glucuronidation in the liver.
Zidovudine was the first antiretroviral agent to be approved and has been well studied. Studies evaluating the use of zidovudine during pregnancy, labor, and postpartum showed significant reductions in the rate of vertical transmission, and zidovudine remains one of the NRTI agents recommended for use in pregnant women (Table 49–5). Zidovudine is also recommended as an option for postexposure prophylaxis in individuals exposed to HIV.
The most common adverse effects of zidovudine are macrocytic anemia (1–4%) and neutropenia (2–8%). Gastrointestinal intolerance, headaches, and insomnia may occur but tend to resolve during therapy. A symptomatic myopathy may occur with prolonged use. Lipoatrophy appears to be more common in patients receiving zidovudine or other thymidine analogs. High doses can cause anxiety, confusion, and tremulousness.
Induction or inhibition of glucuronidation may alter serum levels of zidovudine when co-administered with atovaquone, lopinavir/ritonavir, probenecid, or valproic acid. Concurrent stavudine is contraindicated due to competitive inhibition of intracellular phosphorylation.
NONNUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS (NNRTIs)
The NNRTIs bind directly to HIV-1 reverse transcriptase (Figure 49–3), resulting in allosteric inhibition of RNA- and DNA-dependent DNA polymerase activity. The binding site of NNRTIs is near to but distinct from that of NRTIs. Unlike the NRTI agents, NNRTIs neither compete with nucleoside triphosphates nor require phosphorylation to be active.
The second-generation NNRTIs (etravirine, rilpivirine) have higher potency, longer half-lives and reduced side-effect profiles compared with older NNRTIs (delavirdine, efavirenz, nevirapine).
Baseline genotypic testing is recommended prior to initiating NNRTI treatment because primary resistance rates range from approximately 2% to 8%. NNRTI resistance occurs rapidly with monotherapy and can result from a single mutation. The K103N and Y181C mutations confer resistance to the first-generation NNRTIs, but not to etravirine or rilpivirine. Other mutations (eg, L100I, Y188C, G190A) may also confer cross-resistance among the NNRTI class. However, there is no cross-resistance between the NNRTIs and the NRTIs; in fact, some nucleoside-resistant viruses display hypersusceptibility to NNRTIs.
As a class, NNRTI agents tend to be associated with varying levels of gastrointestinal intolerance and skin rash, the latter of which may infrequently be serious (eg, Stevens-Johnson syndrome). A further limitation to use of NNRTI agents as a component of antiretroviral therapy is their metabolism by the CYP450 system, leading to innumerable potential drug-drug interactions (Tables 49–3 and 49–4). All NNRTI agents are substrates for CYP3A4 and can act as inducers (nevirapine), inhibitors (delavirdine), or mixed inducers and inhibitors (efavirenz, etravirine). Given the large number of non-HIV medications that are also metabolized by this pathway (see Chapter 4), drug-drug interactions must be expected and looked for; dosage adjustments are frequently required and some combinations are contraindicated.
TABLE 49–4Clinically significant drug-drug interactions pertaining to two-drug antiretroviral combinations.1 ||Download (.pdf) TABLE 49–4 Clinically significant drug-drug interactions pertaining to two-drug antiretroviral combinations.1
|Agent ||Drugs That Increase Its Serum Levels ||Drugs That Decrease Its Serum Levels |
|Atazanavir ||Ritonavir ||Didanosine, efavirenz, elvitegravir/cobicistat, etravirine, fosamprenavir, nevirapine, stavudine, tenofovir, tipranavir |
|Darunavir ||Indinavir ||Efavirenz, lopinavir/ritonavir, saquinavir |
|Delavirdine2 || ||Didanosine, fosamprenavir |
|Didanosine ||Tenofovir ||Atazanavir, ritonavir |
|Dolutegravir || ||Efavirenz, etravirine, nevirapine |
|Efavirenz2 ||Darunavir || |
|Elvitegravir3 ||Ritonavir ||Efavirenz, nevirapine |
|Etravirine ||Atazanavir, delavirdine, indinavir, lopinavir/ritonavir ||Efavirenz, nevirapine, ritonavir, saquinavir, tipranavir |
|Fosamprenavir ||Atazanavir, delavirdine, etravirine, ritonavir ||Didanosine, efavirenz, lopinavir/ritonavir, maraviroc, nevirapine, tipranavir |
|Indinavir ||Darunavir, delavirdine, nelfinavir, ritonavir ||Didanosine, efavirenz, etravirine, nevirapine |
|Lopinavir/ritonavir ||Darunavir ||Didanosine, efavirenz, fosamprenavir, nelfinavir, nevirapine, tipranavir |
|Maraviroc ||Atazanavir, darunavir, lopinavir/ritonavir, nevirapine, saquinavir, ritonavir ||Efavirenz, etravirine, tipranavir |
|Nelfinavir ||Delavirdine, indinavir, ritonavir, saquinavir || |
|Nevirapine2 ||Fosamprenavir || |
|Raltegravir ||Atazanavir ||Etravirine, tipranavir |
|Rilpivirine2 ||Darunavir, lopinavir/ritonavir || |
|Saquinavir ||Atazanavir, delavirdine, indinavir, lopinavir/ritonavir, nelfinavir, ritonavir ||Efavirenz, etravirine, nevirapine, tipranavir |
|Tenofovir alafenamide ||Ritonavir ||Darunavir |
|Tenofovir disoproxil fumarate ||Atazanavir || |
|Tipranavir || ||Efavirenz |
Delavirdine has an oral bioavailability of about 85%, but this is reduced by antacids or H2-blockers. It is extensively bound (~98%) to plasma proteins and has correspondingly low cerebrospinal fluid levels. Serum half-life is approximately 6 hours.
Skin rash occurs in up to 38% of patients receiving delavirdine; it typically occurs during the first 1–3 weeks of therapy and does not preclude rechallenge. However, severe rash such as erythema multiforme and Stevens-Johnson syndrome have rarely been reported. Other possible adverse effects are headache, fatigue, nausea, diarrhea, and increased serum aminotransferase levels. Delavirdine has been shown to be teratogenic in rats, causing ventricular septal defects and other malformations at dosages not unlike those achieved in humans. Thus, pregnancy should be avoided when taking delavirdine.
Delavirdine is extensively metabolized by CYP3A and CYP2D6 enzymes. Therefore, there are numerous potential drug-drug interactions to consider (Tables 49–3 and 49–4). The concurrent use of delavirdine with fosamprenavir is not recommended because of bidirectional interactions. Co-administration of delavirdine with indinavir or saquinavir prolongs the elimination half-life of the latter agents, thus allowing them to be dosed twice rather than thrice daily.
Efavirenz can be given once daily because of its long half-life (40–55 hours). It is moderately well absorbed following oral administration (45%). Since toxicity may increase owing to increased bioavailability after a high-fat meal, efavirenz should be taken on an empty stomach. Efavirenz is principally metabolized by CYP3A4 and CYP2B6 to inactive hydroxylated metabolites; the remainder is eliminated in the feces as unchanged drug. It is highly bound to albumin (~ 99%), and cerebrospinal fluid levels range from 0.3% to 1.2% of plasma levels.
The principal adverse effects of efavirenz involve the central nervous system. Dizziness, drowsiness, insomnia, nightmares, and headache tend to diminish with continued therapy; dosing at bedtime may also be helpful. Psychiatric symptoms such as depression, mania, and psychosis have been observed in the weeks following initiation and may necessitate discontinuation. Skin rash has been reported early in therapy in up to 28% of patients; the rash is usually mild to moderate in severity and typically resolves despite continuation. Rarely, rash has been severe or life-threatening. Other potential adverse reactions are nausea, vomiting, diarrhea, crystalluria, elevated liver enzymes, and an increase in total serum cholesterol by 10–20%. High rates of fetal abnormalities, such as neural tube defects, occurred in pregnant monkeys exposed to efavirenz in doses roughly equivalent to the human dosage; several cases of congenital anomalies have been reported in humans. Efavirenz is one of the NNRTI agents recommended for use in pregnancy (Table 49–5), but should be initiated after the first 8 weeks due to birth defects observed in a primate study.
TABLE 49–5The use of antiretroviral agents in pregnancy. ||Download (.pdf) TABLE 49–5 The use of antiretroviral agents in pregnancy.
As both an inducer and an inhibitor of CYP3A4, efavirenz induces its own metabolism and interacts with the metabolism of many other drugs (Tables 49–3 and 49–4). Co-administration with boceprevir, elvitegravir/cobicistat, etravirine, indinavir, itraconazole, ketoconazole, and simeprevir is contraindicated. Levels of efavirenz may be reduced by concomitant nevirapine. Levels of lopinavir/ritonavir, maraviroc, methadone, and telaprevir may be reduced when administered with efavirenz.
Etravirine, a diarylpyrimidine, was designed to be effective against strains of HIV that had developed resistance to first-generation NNRTIs due to mutations such as K103N and Y181C. Although etravirine has a higher genetic barrier to resistance than the other NNRTIs, mutations selected by etravirine usually are associated with resistance to efavirenz, nevirapine, and delavirdine.
Etravirine should be taken with a meal to increase systemic exposure. It is highly protein-bound and is primarily metabolized by the liver. Mean terminal half-life is ~41 hours.
The most common adverse effects of etravirine are rash, nausea, and diarrhea. The rash is typically mild and usually resolves after 1–2 weeks without discontinuation of therapy. Rarely, rash has been severe or life-threatening. Laboratory abnormalities include elevations in serum cholesterol, triglyceride, glucose, and hepatic aminotransferase levels. Aminotransferase elevations are more common in patients with HBV or HCV co-infection.
Etravirine is a substrate as well as an inducer of CYP3A4 and an inhibitor of CYP2C9 and CYP2C19 and thus has potential for numerous drug-drug interactions (Tables 49–3 and 49–4). Some of the interactions are difficult to predict. For example, etravirine may decrease itraconazole and ketoconazole concentrations but increase voriconazole concentrations. Etravirine should not be given with atazanavir, clopidogrel, efavirenz, elvitegravir/cobicistat, fosamprenavir, indinavir, and tipranavir. In addition, co-administration with clarithromycin or with the antimalarial agent artemether/lumefantrine should be avoided if possible.
The oral bioavailability of nevirapine is excellent (>90%) and is not food-dependent. The drug is highly lipophilic and achieves cerebrospinal fluid levels that are 45% of those in plasma. Serum half-life is 25–30 hours. It is extensively metabolized by the CYP3A isoform to hydroxylated metabolites and then excreted, primarily in the urine.
A single dose of nevirapine (200 mg) is effective in the prevention of transmission of HIV from mother to newborn when administered at the onset of labor and followed by a 2-mg/kg dose to the neonate within 3 days of delivery. However, nevirapine is no longer recommended for use in pregnancy due to the potential for adverse events and low barrier to resistance.
Rash, usually a maculopapular eruption that spares the palms and soles, occurs in up to 20% of patients, usually in the first 4–6 weeks of therapy. Although typically mild and self-limited, rash is dose-limiting in about 7% of patients. Women appear to have an increased incidence of rash. When initiating therapy, gradual dose escalation over 14 days is recommended to decrease the incidence of rash. Severe and life-threatening skin rashes, including Stevens-Johnson syndrome and toxic epidermal necrolysis, are rare but are more common than with other NNRTIs. Nevirapine therapy should be immediately discontinued in patients with severe rash and in those with accompanying constitutional symptoms; since rash may accompany hepatotoxicity, liver tests should be assessed. Symptomatic liver toxicity may occur in up to 4% of patients, may be severe, and is more frequent in those with higher pretherapy CD4 cell counts (ie, >250 cells/mm3 in women and >400 cells/mm3 in men), in women, and in those with HBV or HCV co-infection. Fulminant, life-threatening hepatitis has been reported, typically within the first 18 weeks of therapy. Other adverse effects include fever, nausea, headache, and somnolence.
Nevirapine is a moderate inducer of CYP3A metabolism, resulting in numerous potential drug-drug interactions (see Tables 49–3 and 49–4). Co-administration of artemether/lumefantrine, atazanavir, dolutegravir, elvitegravir/cobicistat, fosamprenavir, ketoconazole, and rifampin should be avoided.
Rilpivirine, a diarylpyrimidine, must be administered with a meal (preferably high fat or >400 kcal). Its oral bioavailability is dependent on an acid gastric environment for optimal absorption; thus antacids and H2-receptor antagonists should be separated in time and proton pump inhibitors are contraindicated. The drug is highly protein bound and the terminal elimination half-life is 50 hours.
Rilpivirine is one of the NNRTI agents recommended for use in pregnancy (Table 49–5). Rilpivirine is primarily metabolized by CYP3A4, and drugs that induce or inhibit CYP3A4 may thus affect the clearance of rilpivirine (see Table 49–3). However, clinically significant drug-drug interactions with other antiretroviral agents have not been identified to date.
The most common adverse effects associated with rilpivirine therapy are rash, depression, headache, insomnia, and increased serum aminotransferases. Increased serum cholesterol, and fat redistribution syndrome have also been reported. Higher doses have been associated with QTc prolongation. Inhibition of renal tubular secretion of creatinine causes a reversible elevation in serum creatinine, but glomerular filtration rate is not affected.
PROTEASE INHIBITORS (PIs)
During the later stages of the HIV growth cycle, the gag and gag-pol gene products are translated into polyproteins, and these become immature budding particles. The HIV protease is responsible for cleaving these precursor molecules to produce the final structural proteins of the mature virion core. By preventing post-translational cleavage of the Gag-Pol polyprotein, protease inhibitors (PIs) prevent the processing of viral proteins into functional conformations, resulting in the production of immature, noninfectious viral particles (Figure 49–3). Unlike the NRTIs, PIs do not need intracellular activation.
Specific genotypic alterations that confer phenotypic resistance are fairly common with these agents, thus contraindicating monotherapy. Some of the most common mutations conferring broad resistance to PIs are substitutions at the 10, 46, 54, 82, 84, and 90 codons; the number of mutations may predict the level of phenotypic resistance. The I50L substitution emerging during atazanavir therapy has been associated with increased susceptibility to other PIs. Darunavir and tipranavir appear to have improved virologic activity in patients harboring HIV-1 resistant to other PIs.
As a class, PIs are associated with gastrointestinal intolerance, which may be dose-limiting, and lipodystrophy, which includes both metabolic (hyperglycemia, hyperlipidemia) and morphologic (lipoatrophy, fat deposition) derangements. A syndrome of redistribution and accumulation of body fat that results in central obesity, dorsocervical fat enlargement (buffalo hump), peripheral and facial wasting, breast enlargement, and a cushingoid appearance has been observed, least commonly with atazanavir. PIs may be associated with cardiac conduction abnormalities, including PR and QT interval prolongation. A baseline electrocardiogram and avoidance of other agents causing prolonged PR or QT intervals should be considered. Abacavir, lopinavir/ritonavir, and fosamprenavir/ritonavir have been associated with an increased risk of cardiovascular disease in some, but not all, studies. Drug-induced hepatitis and rare severe hepatotoxicity have been reported to varying degrees with all PIs; the frequency of hepatic events is higher with tipranavir/ritonavir than with other PIs. Unconjugated hyperbilirubinemia may occur with atazanavir or indinavir. Whether PI agents are associated with bone loss and osteoporosis after long-term use is under investigation. PIs have been associated with increased spontaneous bleeding in patients with hemophilia A or B; an increased risk of intracranial hemorrhage has been reported in patients receiving tipranavir/ritonavir. Darunavir, amprenavir, fosamprenavir, and tipranavir are sulfonamides; caution should be used in patients with a history of sulfa allergy.
All of the antiretroviral PIs are extensively metabolized by CYP3A4, with ritonavir having the most pronounced inhibitory effect and saquinavir the least. Some PI agents, such as amprenavir and ritonavir, are also inducers of specific CYP isoforms. As a result, there is enormous potential for drug-drug interactions with other antiretroviral agents and other commonly used medications (Tables 49–3 and 49–4). Expert resources about drug-drug interactions should be consulted, as dosage adjustments are frequently required and some combinations are contraindicated. It is noteworthy that the potent CYP3A4 inhibitory properties of ritonavir are used to clinical advantage by having it “boost” the levels of other PI agents when given in combination, thus acting as a pharmacokinetic enhancer rather than an antiretroviral agent. Ritonavir boosting increases drug exposure, thereby prolonging the drug’s half-life and allowing reduction in frequency; in addition, the genetic barrier to resistance is raised.
Atazanavir is an azapeptide PI with a pharmacokinetic profile that allows once-daily dosing. Atazanavir requires an acidic medium for absorption and exhibits pH-dependent aqueous solubility; therefore, it should be taken with meals. Separation of ingestion from acid-reducing agents by at least 12 hours is recommended and concurrent proton pump inhibitors are contraindicated. Atazanavir is able to penetrate both the cerebrospinal and seminal fluids. The plasma half-life is 6–7 hours, which increases to approximately 11 hours when co-administered with ritonavir. The primary route of elimination is biliary; atazanavir should not be given to patients with severe hepatic insufficiency.
Boosted atazanavir is one of the recommended PI agents for use in pregnant women (Table 49–5).
The most common adverse effects in patients receiving atazanavir are diarrhea and nausea; vomiting, abdominal pain, headache, and peripheral neuropathy may also occur. Skin rash, reported in ~20% of patients, is generally mild; however severe rash and Stevens Johnson syndrome have been reported. As with indinavir, indirect hyperbilirubinemia with overt jaundice may occur in approximately 10% of patients, owing to inhibition of the UGT1A1 glucuronidation enzyme. Elevation of serum aminotransferases has separately been observed, usually in patients with underlying HBV or HCV co-infection. Kidney stones, gallstones, PR prolongation, and decreased bone mineral density have also been reported. In contrast to the other PIs, atazanavir does not appear to be associated with dyslipidemia or hyperglycemia. The oral powder contains phenylalanine, which can be harmful to patients with phenylketonuria.
As an inhibitor of CYP3A4, CYP2C9, and UGT1A1, the potential for drug-drug interactions with atazanavir is great (Tables 49–3 and 49–4). Due to decreased atazanavir levels, atazanavir should not be administered with bosentan, elvitegravir/cobicistat, etravirine, fosamprenavir, nevirapine, proton pump inhibitors, or tipranavir. Tenofovir and efavirenz should not be co-administered with atazanavir unless ritonavir is added to boost levels. In addition, co-administration of atazanavir with other drugs that inhibit UGT1A1, such as irinotecan, may increase its levels. Atovaquone and voriconazole levels may be decreased with coadministration, and levels of maraviroc and ranolazine may be increased.
Darunavir must be co-administered with ritonavir or cobicistat. Darunavir should be taken with meals to improve bioavailability. It is highly protein-bound and primarily metabolized by the liver.
Boosted darunavir is one of the PI agents recommended for use in pregnancy (Table 49–5).
Adverse effects include diarrhea, nausea, headache, and increases in amylase and hepatic aminotransferase levels. Rash occurs in 2–7% of patients and may occasionally be severe. Liver toxicity, including severe hepatitis, has been reported, such that liver function tests should be monitored; the risk may be higher for persons with HBV, HCV, or other chronic liver disease. Darunavir contains a sulfonamide moiety and may cause a hypersensitivity reaction, particularly in patients with sulfa allergy.
Darunavir both inhibits and is metabolized by the CYP3A enzyme system, conferring many possible drug-drug interactions (Tables 49–3 and 49–4). In addition, the co-administered ritonavir is a potent inhibitor of CYP3A and CYP2D6, and an inducer of other hepatic enzyme systems. Co-administration with elvitegravir/cobicistat or simeprevir is contraindicated due to bidirectional drug-drug interactions. Levels of cyclophosphamide, digoxin, and simeprevir may be increased when administered with darunavir, and levels of paroxetine and sertraline may be decreased.
Fosamprenavir is a prodrug of amprenavir that is rapidly hydrolyzed by enzymes in the intestinal epithelium. Because of its significantly lower daily pill burden, fosamprenavir tablets have replaced amprenavir capsules for adults. Fosamprenavir is most often administered in combination with low-dose ritonavir.
After hydrolysis of fosamprenavir, amprenavir is rapidly absorbed from the gastrointestinal tract, and its prodrug can be taken with or without food. However, high-fat meals decrease absorption and thus should be avoided. The plasma half-life is relatively long (7–11 hours). Amprenavir is metabolized in the liver and should be used with caution in the setting of hepatic insufficiency.
The most common adverse effects of fosamprenavir are headache, nausea, diarrhea, perioral paresthesias, depression. Fosamprenavir contains a sulfa moiety and may cause a rash in up to 19% of patients, sometimes severe enough to warrant drug discontinuation.
Amprenavir is both an inducer and an inhibitor of CYP3A4 (Tables 49–3 and 49–4). Co-administration of elvitegravir/cobicistat, etravirine, lopinavir/ritonavir, nevirapine, posaconazole, or ranolazine is contraindicated. The oral suspension, which contains propylene glycol, is contraindicated in young children, pregnant women, patients with renal or hepatic failure, and those using metronidazole or disulfiram. Also, the oral solutions of amprenavir and ritonavir should not be co-administered because the propylene glycol in one and the ethanol in the other may compete for the same metabolic pathway, leading to accumulation of either. Because the oral solution contains vitamin E at several times the recommended daily dosage, supplemental vitamin E should be avoided.
Indinavir requires an acidic environment for optimum solubility and therefore must be consumed on an empty stomach or with a small, low-fat, low-protein meal for maximal absorption (60–65%). The serum half-life is 1.5–2 hours, protein binding is ~60%, and the drug has a high level of cerebrospinal fluid penetration (up to 76% of serum levels). Excretion is primarily fecal. An increase in AUC by 60% and in half-life to 2.8 hours in the setting of hepatic insufficiency necessitates dose reduction.
The most common adverse effects of indinavir are unconjugated hyperbilirubinemia and nephrolithiasis due to urinary crystallization of the drug. Nephrolithiasis can occur within days after initiating therapy, with an estimated incidence of approximately 10%. Acute renal failure and interstitial fibrosis have also been reported. Consumption of at least 48 ounces of water daily is important to maintain adequate hydration, and serum creatinine levels should be monitored. Nausea, diarrhea, sicca syndrome, headache, blurred vision, and elevations of serum aminotransferase levels have also been reported. Insulin resistance may be more common with indinavir than with the other PIs, occurring in 3–5% of patients. In some studies but not in others, indinavir has been associated with a higher risk of myocardial infarction. There have also been rare cases of acute hemolytic anemia.
Since indinavir is an inhibitor of CYP3A4, numerous and complex drug interactions can occur (Tables 49–3 and 49–4). Boosting with ritonavir allows for twice-daily rather than thrice-daily dosing and eliminates the food restriction associated with use of indinavir. However, there is potential for an increase in nephrolithiasis with this combination compared with indinavir alone; thus, a high fluid intake (1.5–2 L/d) is advised. Indinavir should not be co-administered with astemizole, cerivastatin, efavirenz, ergotamine, etravirine, lovastatin, pimozide, rifampin, simvastatin, terfenadine, or triazolam. Levels of amlodipine, levodopa, and trazodone may be increased with concurrent administration of indinavir.
Lopinavir is available only in combination with low-dose ritonavir as a pharmacologic “booster” via inhibition of its CYP3A-mediated metabolism, resulting in increased exposure and a reduced pill burden.
Lopinavir is highly protein bound (98–99%), and its half-life is 5–6 hours. It is extensively metabolized by CYP3A, which is inhibited by ritonavir. Lopinavir/ritonavir is one of the recommended antiretroviral agents for use in pregnant women (Table 49–5).
The most common adverse effects of lopinavir are diarrhea, nausea, vomiting, increased serum lipids, and increased serum aminotransferases (more common in patients with HBV or HCV co-infection). Prolongation of the PR and/or QT interval may occur. In some studies but not in others, lopinavir/ritonavir has been associated with a higher risk of myocardial infarction. Pancreatitis has rarely been reported. Ritonavir-boosted lopinavir may be more commonly associated with gastrointestinal adverse events than other PIs.
Potential drug-drug interactions are extensive (Tables 49–3 and 49–4). Levels of lamotrigine and methadone may be reduced with co-administration, and levels of bosentan may be increased. Concurrent use of darunavir, elvitegravir/cobicistat, fosamprenavir, and tipranavir is contraindicated. Since the oral solution of lopinavir/ritonavir contains alcohol, concurrent disulfiram and metronidazole are contraindicated. The oral solution also contains propylene glycol, contraindicating the co-administration of other drugs containing propylene glycol.
Nelfinavir has high absorption in the fed state (70–80%), undergoes metabolism by CYP3A, and is excreted primarily in the feces. The plasma half-life in humans is 3.5–5 hours, and the drug is more than 98% protein-bound.
The most common adverse effects associated with nelfinavir (10–30%) are diarrhea and flatulence. Diarrhea responds to anti-diarrheal medications but may be dose-limiting. Nelfinavir is an inhibitor of the CYP3A system, and multiple drug interactions may occur (Tables 49–3 and 49–4). An increased dosage of nelfinavir is recommended when co-administered with rifabutin (with a decreased dose of rifabutin), whereas a decrease in saquinavir dose is suggested with concurrent nelfinavir. Do not co-administer with astemizole, cerivastatin, cisapride, ergotamine, lovastatin, omeprazole, pimozide, quinidine, rifampin, simvastatin, or terfenadine. The oral powder contains phenylalanine, which can be harmful to patients with phenylketonuria.
Ritonavir has a high bioavailability (~75%) that increases with food. It is 98% protein-bound and has a serum half-life of 3–5 hours. Metabolism to an active metabolite occurs via the CYP3A and CYP2D6 isoforms; excretion is primarily in the feces. Ritonavir as a pharmacologic “booster” is one of the recommended antiretroviral agents for use in pregnant women (Table 49–5).
Adverse effects of full-dose ritonavir include asthenia, gastrointestinal disturbances, and hepatitis; these are greatly reduced with the lower doses used for boosting. Dose escalation over 1–2 weeks decreases these side effects. Other potential adverse effects include altered taste, paresthesias (circumoral or peripheral), elevated serum aminotransferase and lipid levels, headache, elevations in serum creatine kinase, and pancreatitis. Inhibition of renal tubular secretion of creatinine causes a reversible elevation in serum creatinine, but glomerular filtration rate is not affected.
Ritonavir is a potent inhibitor of CYP3A4, resulting in many potential drug interactions (Tables 49–3 and 49–4). However, this characteristic has been used to great advantage when ritonavir is administered in low doses (100–200 mg twice daily) in combination with any of the other PI agents, to permit lower or less frequent dosing (or both) with greater tolerability as well as the potential for greater efficacy against resistant virus. Therapeutic levels of digoxin and theophylline should be monitored when co-administered with ritonavir. The concurrent use of saquinavir and ritonavir is contraindicated due to an increased risk of QT prolongation (with torsades de pointes arrhythmia) and PR interval prolongation. Concurrent simeprevir is also contraindicated.
In its original formulation as a hard gel capsule, oral saquinavir was poorly bioavailable (~4% after food). However, reformulation of saquinavir for once-daily dosing in combination with low-dose ritonavir has both improved antiviral efficacy and decreased gastrointestinal adverse effects. A previous formulation of saquinavir in soft gel capsules is no longer available.
Saquinavir should be taken within 2 hours after a fatty meal for enhanced absorption. Saquinavir is 97% protein-bound, and serum half-life is approximately 2 hours. Saquinavir has a large volume of distribution, but penetration into the cerebrospinal fluid is negligible. Excretion is primarily in the feces. Gastrointestinal discomfort (nausea, diarrhea, abdominal discomfort, dyspepsia) may occur. When administered in combination with low-dose ritonavir, there appears to be less dyslipidemia or gastrointestinal toxicity than with some of the other boosted PI regimens. Since prolongation of the QT interval and torsades de pointes have rarely been reported, saquinavir should not be used in patients with congenital long QT syndrome, AV block, refractory hypokalemia or hypomagnesemia, or in combination with drugs that both increase saquinavir plasma concentrations and prolong the QT interval. The concurrent use of saquinavir and ritonavir may confer an increased risk of QT or PR prolongation.
Saquinavir is subject to extensive first-pass metabolism by CYP3A4 and functions as a CYP3A4 inhibitor as well as a substrate; thus, there are many potential drug-drug interactions (Tables 49–3 and 49–4). Increased saquinavir levels when co-administered with omeprazole necessitate close monitoring for toxicities. Digoxin levels should be monitored. Liver tests should be monitored if saquinavir is co-administered with delavirdine or rifampin. Concurrent darunavir or tipranavir is contraindicated.
Tipranavir is a newer PI indicated for use in treatment-experienced patients who harbor strains resistant to other PI agents. It is used in combination with ritonavir to achieve effective serum levels.
Bioavailability is poor but is increased when taken with a high-fat meal. The drug is metabolized by the liver microsomal system and is contraindicated in patients with hepatic insufficiency. Tipranavir contains a sulfonamide moiety and should not be administered to patients with known sulfa allergy.
The most common adverse effects of tipranavir are diarrhea, nausea, vomiting, and abdominal pain. An urticarial or maculopapular rash occurs in 10–14%, and may be more common with co-administered ethinyl estradiol. Liver toxicity, including life-threatening hepatic decompensation, has been observed and may be more common than with other PIs, particularly in patients with chronic HBV or HCV infection. Because of an increased risk for intracranial hemorrhage in patients receiving tipranavir/ritonavir, the drug should be avoided in patients with head trauma or bleeding diathesis. Other potential adverse effects include depression, elevation in serum amylase, increased serum lipids, and decreased white blood cell count.
Tipranavir both inhibits and induces the CYP3A4 system. When used in combination with ritonavir, its net effect is inhibition. Tipranavir also induces the P-glycoprotein transporter and thus may alter the disposition of many other drugs (Tables 49–3 and 49–4). Concurrent use with atazanavir, elvitegravir/cobicistat, etravirine, fosamprenavir, lopinavir/ritonavir and saquinavir should be avoided. Supplemental vitamin E is contraindicated in patients receiving the oral solution.
The process of HIV-1 entry into host cells is complex; each step presents a potential target for inhibition. Viral attachment to the host cell entails binding of the viral envelope glycoprotein complex gp160 (consisting of gp120 and gp41) to its cellular receptor CD4. This binding induces conformational changes in gp120 that enable access to the chemokine receptors CCR5 or CXCR4. Chemokine receptor binding induces further conformational changes in gp120, allowing exposure to gp41 and leading to fusion of the viral envelope with the host cell membrane and subsequent entry of the viral core into the cellular cytoplasm.
Enfuvirtide is a synthetic 36-amino-acid peptide fusion inhibitor that blocks HIV entry into the cell (Figure 49–3). Enfuvirtide binds to the gp41 subunit of the viral envelope glycoprotein, preventing the conformational changes required for the fusion of the viral and cellular membranes.
Enfuvirtide, which must be administered by subcutaneous injection, is the only parenterally administered antiretroviral agent. Metabolism appears to be by proteolytic hydrolysis without involvement of the CYP450 system. Elimination half-life is 3.8 hours.
Resistance to enfuvirtide can result from mutations in gp41; the frequency and significance of this phenomenon are being investigated. However, enfuvirtide lacks cross-resistance with the other currently approved antiretroviral drug classes.
The most common adverse effects are local injection site reactions, consisting of painful erythematous nodules. Although frequent, these are typically mild-to-moderate in severity and rarely lead to discontinuation. Other potential side effects include insomnia, headache, dizziness, and nausea. Hypersensitivity reactions may rarely occur, are of varying severity, and may recur on rechallenge. Eosinophilia is the primary laboratory abnormality seen with enfuvirtide administration. In Phase 3 studies, bacterial pneumonia was seen at a higher rate in patients who received enfuvirtide than in those who did not receive enfuvirtide. No drug-drug interactions have been identified that would require the alteration of the dosage of concomitant antiretroviral or other drugs.
Maraviroc is approved for use in combination with other antiretroviral agents in adult patients infected only with CCR5-tropic HIV-1. Maraviroc binds specifically and selectively to the host protein CCR5, one of two chemokine receptors necessary for entrance of HIV into CD4+ cells. Since maraviroc is active against HIV that uses the CCR5 co-receptor exclusively, and not against HIV strains with CXCR4, dual, or mixed tropism, co-receptor tropism should be determined by specific testing before maraviroc is started. Substantial proportions of patients, particularly those with advanced HIV infection, are likely to have virus that is not exclusively CCR5-tropic.
The absorption of maraviroc is rapid but variable, with the time to maximum absorption generally 1–4 hours after ingestion of the drug. Most of the drug (≥ 75%) is excreted in the feces, whereas approximately 20% is excreted in urine. The recommended dose of maraviroc varies according to renal function and the concomitant use of CYP3A inducers or inhibitors (Table 49–3). Maraviroc is contraindicated in patients with severe or end-stage renal impairment and caution is advised when used in patients with preexisting hepatic impairment and in those co-infected with HBV or HCV. Maraviroc has excellent penetration into the cervicovaginal fluid, with levels almost four times higher than the corresponding concentrations in blood plasma.
Resistance to maraviroc is associated with one or more mutations in the V3 loop of gp120. However, emergence of CXCR4 virus (either previously undetected or newly developed) appears to be a more common cause of virologic failure than the development of resistance mutations. There appears to be no cross-resistance with drugs from any other class, including the fusion inhibitor enfuvirtide.
Maraviroc is a substrate for CYP3A4 and therefore requires adjustment in the presence of drugs that interact with these enzymes (Tables 49–3 and 49–4). It is also a substrate for P-glycoprotein, which limits intracellular concentrations of the drug. The dosage of maraviroc must be decreased if it is co-administered with strong CYP3A inhibitors (eg, delavirdine, ketoconazole, itraconazole, clarithromycin, or any protease inhibitor other than tipranavir) and must be increased if co-administered with CYP3A inducers (eg, efavirenz, etravirine, carbamazepine, phenytoin, or St. John’s wort). Concurrent use of rifampin is contraindicated.
Potential adverse effects of maraviroc include upper respiratory tract infection, cough, pyrexia, rash, dizziness, muscle and joint pain, diarrhea, sleep disturbance, and elevations in serum aminotransferases. Hepatotoxicity has been reported, which may be preceded by a systemic allergic reaction (ie, pruritic rash, eosinophilia, or elevated IgE); discontinuation of maraviroc should be prompt if this constellation occurs. Myocardial ischemia and infarction have been observed in patients receiving maraviroc; therefore caution is advised in patients at increased cardiovascular risk. There is an increased risk of postural hypotension in patients with severe renal impairment.
There has been concern that blockade of the chemokine CCR5 receptor—a human protein—may result in decreased immune surveillance, with a subsequent increased risk of malignancy or infection. To date, however, there has been no evidence of an increased risk of either malignancy or infection in patients receiving maraviroc.
INTEGRASE STRAND TRANSFER INHIBITORS (INSTIs)
This class of agents binds integrase, a viral enzyme essential to the replication of both HIV-1 and HIV-2. By doing so, it inhibits strand transfer, the third and final step of provirus integration, thus interfering with the integration of reverse-transcribed HIV DNA into the chromosomes of host cells (Figure 49–3). As a class, these agents tend to be well tolerated, with headache and gastrointestinal effects the most commonly reported adverse events. Their use in combination antiretroviral regimens or with cobicistat (ie, elvitegravir) means that additional adverse events and/or drug-drug interactions need to be considered as well. The available data suggest that effects upon lipid metabolism are favorable compared with efavirenz and PIs. Rare severe events include systemic hypersensitivity reactions and rhabdomyolysis.
The frequency of dosing of dolutegravir depends on the presence or absence of integrase inhibitor-associated resistance mutations and the concurrent use of efavirenz, fosamprenavir/ritonavir, tipranavir/ritonavir, or rifampin. Dolutegravir should be taken 2 hours before or 6 hours after cation-containing antacids or laxatives, sucralfate, oral iron supplements, oral calcium supplements, or buffered medications. Peak plasma concentrations occur within 2–3 hours of ingestion. Dolutegravir is highly protein bound (99%). The terminal half-life is ~14 hours. Serum levels may be reduced in patients with severe renal insufficiency.
Adverse effects of dolutegravir are infrequent but may include insomnia, headache, increased serum aminotransferase levels, and, rarely, rash. A hypersensitivity reaction, including rash and systemic symptoms, has been reported; the drug should be discontinued immediately if this occurs and not restarted. Dolutegravir increases serum creatinine by inhibiting tubular secretion of creatinine but has no effect on actual glomerular filtration rate.
Dolutegravir is primarily metabolized via UGT1A1 with some contribution from CYP3A. Therefore, multiple drug-drug interactions may occur (Table 49–3 and 49–4). Levels of dolutegravir may decrease when co-administered with efavirenz, etravirine, nevirapine, rifampin, or rifapentine, in some instances necessitating increased doses of dolutegravir or boosting or both. Co-administration with the metabolic inducers oxcarbazepine, phenytoin, phenobarbital, carbamazepine, and St. John’s wort should be avoided. Dolutegravir inhibits the renal organic cation transporter OCT2, thereby increasing plasma concentrations of drugs eliminated via OCT2 such as dofetilide and metformin. For this reason, co-administration with dofetilide is contraindicated and close monitoring, with potential for dose adjustment, is recommended for co-administration with metformin.
Elvitegravir should be taken with food, and it should be taken 2 hours before or 6 hours after cation-containing antacids or laxatives, sucralfate, oral iron supplements, oral calcium supplements, or buffered medications. Peak levels occur within 4 hours of ingestion; elvitegravir is highly protein bound (>98%).
Elvitegravir requires boosting with an additional drug, such as cobicistat (a pharmacokinetic enhancer that inhibits CYP3A4 as well as certain intestinal transport proteins) or ritonavir. Cobicistat inhibits renal tubular secretion of creatinine; therefore, fixed-dose combinations need to be adjusted for renal function.
There appear to be few adverse effects associated with elvitegravir per se but may include diarrhea, rash, and elevation in hepatic aminotransferases.
Elvitegravir is primarily metabolized by CYP3A enzymes, so drugs that induce or inhibit the action of CYP3A may affect serum levels of elvitegravir (Table 49–3 and 49–4). In addition, cobicistat and ritonavir strongly inhibit CYP3A. Elvitegravir levels may be lowered by concurrent efavirenz or nevirapine, rifampin, rifabutin, carbamazepine, phenytoin, or St. John’s wort. Concurrent use of azole antifungal drugs is contraindicated due to a potential increase in elvitegravir levels; rifabutin levels may also be increased by concurrent elvitegravir. Elvitegravir also induces CYP2D9 and may lower concentrations of substrates of this enzyme. With the fixed dose combination, concurrent alfuzosin or atazanavir, cisapride, darunavir, efavirenz, etravirine, fosamprenavir, ledipasvir, lopinavir/ritonavir, methylprednisolone, midazolam, nevirapine, pimozide, prednisolone, rifampin, rifabutin are contraindicated.
Absolute bioavailability of the pyrimidinone analog raltegravir has not been established but does not appear to be food-dependent. Terminal half-life is ~ 9 hours. The drug does not interact with the cytochrome P450 system but is metabolized by glucuronidation, particularly UGT1A1. Therefore, concurrent use of inducers or inhibitors of UGT1A1 such as rifampin and rifapentine may necessitate dosage adjustment of raltegravir. The chewable tablets contain phenylalanine, which can be harmful to patients with phenylketonuria.
Raltegravir is one of the antiretroviral agents recommended for use in pregnancy (Table 49–5).
Adverse effects of raltegravir are uncommon but include nausea, headache, fatigue, muscle aches, and increased serum amylase and aminotransferase levels. Severe, potentially life-threatening and fatal skin reactions have been reported, including Stevens-Johnson syndrome, hypersensitivity reaction, and toxic epidermal necrolysis.