NNRTI's - No nucleotides reverse transcriptase inhibitors
PI - Protease inhibitors
Entry inhibitors
The NNRTIs bind directly to HIV-1 reverse transcriptase (Figure 49–4), resulting in allosteric inhibition of RNA- and DNA-dependent DNA polymerase. 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. In addition, they lack in vitro activity against HIV-2
A further limitation to use of NNRTI agents as a component of HAART 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.
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. Thus, pregnancy should be avoided when taking delavirdine.
Delavirdine is extensively metabolized to inactive metabolites by the CYP3A and CYP2D6 enzymes
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, and headache tend to diminish with continued therapy
Etravirine may be effective against strains of HIV that have developed resistance to first-generation NNRTIs, depending on the number of mutations present. The most common symptomatic adverse effects of etravirine are rash, nausea, and diarrea. it has many therapeutically significant drug-drug interactions
Nevirapine
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 to women at the onset of labor and followed by a 2-mg/kg oral dose to the neonate within 3 days after delivery. There is no evidence of human teratogenicity. However, resistance has been documented after this single dose. 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
Protease Inhibitors
Protease inhibitors are active against both HIV-1 and HIV-2; unlike the NRTIs, however, they do not need intracellular activation
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 in patients receiving antiretroviral therapy. These abnormalities may be particularly associated with the use of PIs, although the recently licensed atazanavir appears to be an exception (see below). Concurrent increases in triglyceride and LDL levels, along with hyperglycemia and insulin resistance, have also been noted. The cause is not yet known.
Whether PI agents are associated with bone loss and osteoporosis after long-term use is controversial and under active investigation. PIs have been associated with increased spontaneous bleeding in patients with hemophilia A or B. All the antiretroviral PIs are extensively metabolized by CYP3A4, with ritonavir having the most pronounced inhibitory effect and saquinavir the least. It is noteworthy that the potent CYP3A4 inhibitory properties of ritonavir have been 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. It should be taken with a light meal to enhance bioavailability. Atazanavir requires an acidic medium for absorption and exhibits pH-dependent aqueous solubility; therefore, separation of ingestion from acid-reducing agents by at least 12 hours is recommended. 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 most common adverse effects in patients receiving atazanavir are diarrhea and nausea; vomiting, abdominal pain, headache, peripheral neuropathy, and skin rash may also occur. As with indinavir, indirect hyperbilirubinemia with overt jaundice may occur (7–8%) owing to inhibition of the UGT1A1 glucuronidation enzyme. Elevation of hepatic enzymes has also been observed, usually in patients with underlying HBV or HCV co-infection. In contrast to the other PIs, atazanavir does not appear to be associated with dyslipidemia, fat redistribution, or the metabolic syndrome. Atazanavir may be associated with electrocardiographic PR-interval prolongation, As an inhibitor of CYP3A4 and CYP2C9, the potential for drug-drug interactions with atazanavir is great (Tables 49–3 and 49–4). Atazanavir AUC is reduced by 76% when combined with omeprazole; thus, the combination is to be avoided. In addition, co-administration of atazanavir with other drugs that inhibit UGT1A1, such as indinavir and irinotecan, is contraindicated because of enhanced toxicity. Tenofovir and efavirenz should not be co-administered with atazanavir unless ritonavir is added to boost levels.
Darunavir is licensed as a PI to be co-administered with ritonavir in treatment-experienced patients with resistance to other PIs.
Symptomatic adverse effects of darunavir include diarrhea, nausea, headache, and rash. Laboratory abnormalities include dyslipidemia (though possibly less frequent than with other boosted PI regimens) and increases in amylase and hepatic transaminase levels.
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
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 by CYP3A4 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, and rash. Up to 3% of patients may experience rashes (including Stevens-Johnson syndrome) severe enough to warrant drug discontinuation
The oral solution, 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. /ritonavir should not be co-administered with amprenavir owing to decreased amprenavir and increased lopinavir exposures.
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 approximately 60%, and the drug has a high level of cerebrospinal fluid penetration (up to 76% of serum levels). Excretion is primarily fecal. The most common adverse effects of indinavir are indirect hyperbilirubinemia and nephrolithiasis due to crystallization of the drug. Nephrolithiasis can occur within days after initiating therapy, with an estimated incidence of approximately 10%. Consumption of at least 48 ounces of water daily is important to maintain adequate hydration. Thrombocytopenia, elevations of serum aminotransferase levels, nausea, diarrhea, insomnia, dry throat, dry skin, and indirect hyperbilirubinemia have also been reported. Insulin resistance may be more common with indinavir than with the other PIs, occurring in 3–5% of patients. There have also been rare cases of acute hemolytic anemia. In rats, high doses of indinavir are associated with development of thyroid adenomas.
Lopinavir should be taken with food to enhance bioavailability. The drug is highly protein bound (98–99%), and its half-life is 5–6 hours. Lopinavir is extensively metabolized by CYP3A, which is inhibited by ritonavir. The most common adverse effects of lopinavir are diarrhea, abdominal pain, nausea, vomiting, and asthenia. Elevations in serum cholesterol and triglycerides are common. Increased dosage of lopinavir/ritonavir is recommended when co-administered with efavirenz or nevirapine, which induce lopinavir metabolism. There is no evidence of human teratogenicity of lopinavir/ritonavir; short-term safety in pregnant women has been demonstrated for mother and infant.
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 are diarrhea and flatulence
Ritonavir has a high bioavailability (about 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. Potential adverse effects of ritonavir, particularly when administered at full dosage, are gastrointestinal disturbances, paresthesias (circumoral or peripheral), elevated serum aminotransferase levels, altered taste, headache, hypertriglyceridemia, hypercholesterolemia, and elevations in serum creatine kinase
its original formulation as a hard gel capsule (saquinavir-H; Invirase), oral saquinavir is poorly bioavailable (only about 4% after food). However, reformulation of saquinavir-H for once-daily dosing in combination with low-dose ritonavir has both improved antiviral efficacy and decreased gastrointestinal adverse effects.
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.
Tipranavir is a newer PI for treating patients with resistance to other PI agents. Bioavailability is poor but is increased when taken with a high-fat meal. The most common adverse effects from tipranavir are diarrhea, nausea, vomiting, abdominal pain, and rash (urticarial or maculopapular); the latter may be accompanied by systemic symptoms or desquamation. Tipranavir should be discontinued in patients with increased serum transaminase levels to more than 10 times the upper limit of normal. Because of an increased risk for intracranial hemorrhage in patients receiving tipranavir, the drug should be avoided in patients with head trauma or bleeding diathesis. Other potential adverse effects include depression; elevations in total cholesterol, triglycerides, and amylase. Tipranavir both inhibits and induces the CYP3A4 system. When used in combination with ritonavir, its net effect is inhibition.
Entry inhibitors: Enfuvirtide is a synthetic 36-amino-acid peptide fusion inhibitor that blocks entry into the cell (Figure 49–4). 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. It has no activity against HIV-2. Enfuvirtide must be administered by subcutaneous injection. Metabolism appears to be by proteolytic hydrolysis without involvement of the CYP450 system. Elimination half-life is 3.8 hours.
Maraviroc binds specifically and selectively to CCR5, one of two coreceptors necessary for entrance of HIV into CD4+ cells, thus blocking entry of CCR5-tropic HIV into these cells. Maraviroc is to be used in adults with CCR5-tropic (also known as R5) HIV-1 infection that are experiencing virologic failure due to resistance to other antiretroviral agents. Studies have shown that 52–60% of patients in whom at least two antiviral regimens had failed were infected with R5 HIV. Since maraviroc is active against HIV that uses the CCR5 coreceptor exclusively, and not against HIV strains with CXCR4, dual, or mixed tropism, tropism testing should be performed before initiating treatment with maraviroc.
American Guideline Protocole (Choose at least one option from red and blue)
Efavirenz OR ( Ritonavir + (Atazanavir OR Fosamprenavir OR Saquinavir)) + ((Emtricitabine OR Lamivudine) + (Abacavir OR Tenofovir))
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