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Drugs Used In HIV Treatment (HAART) and Their Interactions

Reading time: 25 minutes, 15 seconds

There are five types of drugs used in HIV treatment. These drugs do not cure HIV/AIDS but fight the infection. HIV treatment was and continues to be a menace to treat but a group of drugs known as antiretovirals has been developed to try and fight the infection.

Since the introduction of zidovudine in 1987, there have been substantial advances made in drugs used in HIV treatment.

In addition, greater knowledge of viral dynamics through the use of viral load and resistance testing has made clear that combination therapy with maximally efficacious and potent agents will reduce viral replication to the lowest possible level and decrease the likelihood of the emergence of resistance.

Thus, administration of highly active antiretroviral therapy (HAART), typically comprising a combination of 3 or 4 antiretroviral agents, has become the standard of care.

Such regimens may be composed of nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors, and a fusion inhibitor.

Viral susceptibility to specific agents varies among patients and may change with time, owing to the development of resistance. 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.

Classes of drugs used in HIV treatment

There are four classes of Drugs Used In HIV Treatment available:

  1. Nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs),
  2. Nonnucleoside reverse transcriptase inhibitors (NNRTIs),
  3. Protease inhibitors (PIs),
  4. Fusion inhibitors.

As new agents have become available, several older ones have had diminished usage, because of either suboptimal safety profile or inferior antiviral potency.

Treatment of HIV-Infected Individuals

Importance of Pharmacokinetic Knowledge of Drugs Used In HIV Treatment

Concurrent use of many medications is necessary for most HIV-infected patients. These medications include combinations of antiretroviral agents, prophylaxis or treatment for opportunistic infections, antiemetics, neuropsychiatric drugs, and opioid pain medications. Such extreme polypharmacy necessitates awareness of pharmacokinetic and pharmacodynamic interactions.

Perhaps the most important of the pharmacokinetic complications result from the metabolism of the NNRTI and PI agents by the CYP450 enzyme system, primarily the 3A4 isoform. Because many are inducers or inhibitors of CYP3A4 as well as substrates, drug-drug interactions may have marked clinical ramifications.

However, variable effects on different CYP450 isoforms may make interactions somewhat unpredictable. For example, in the treatment of tuberculosis, the use of rifampin, a standard antimycobacterial agent but also one of the most potent 3A4 inducers, may either decrease efficacy (eg, atazanavir, lopinavir) or increase toxicity (eg, saquinavir) of concurrent antiretroviral agents, owing to the alteration of serum levels.

Increased levels of rifabutin (associated with uveitis) or trazodone (causing hypotension, syncope), when co-administered with ritonavir, may markedly increase toxicity. Increased levels of clarithromycin used for treatment or prophylaxis of Mycobacterium avium infection or as an antibacterial agent, when co-administered with indinavir, ritonavir, and atazanavir, may increase the potential for QT interval prolongation.

Conversely, decreased levels of clarithromycin with efavirenz may reduce antibacterial efficacy. Most recently, these types of interactions have been used to advantage in the form of dual protease inhibitor regimens (boosted regimens), based on resultant increased plasma concentrations of the substrate (eg, lopinavir, saquinavir) when co-administered with an inducer (most often ritonavir). Improved drug exposure, increased antiviral potency, more convenient dosing, and improved tolerability result, thus improving patient adherence.

Classes of drugs used in HIV treatment.

Nucleoside & Nucleotide Reverse Transcriptase Inhibitors

The NRTIs act by competitive inhibition of HIV-1 reverse transcriptase and can also be incorporated into the growing viral DNA chain to cause termination. Each requires intracytoplasmic activation via phosphorylation by cellular enzymes to the triphosphate form. Most of the NRTIs have activity against HIV-2 as well as HIV-1.

Nucleoside analogs may be associated with mitochondrial toxicity, probably owing to the inhibition of mitochondrial DNA polymerase gamma, and they can increase the risk of lactic acidosis with hepatic steatosis, which may be fatal, as well as disorders of lipid metabolism. NRTI treatment should be suspended in the setting of rapidly rising aminotransferase levels, progressive hepatomegaly, or metabolic acidosis of unknown cause.

Abacavir

Abacavir is a guanosine analog that is well absorbed following oral administration (83%) and unaffected by food. The elimination half-life is 1.5 hours, and the intracellular half-life ranges from 12 to 26 hours. Cerebrospinal fluid levels are approximately one third those of plasma.

Hypersensitivity reactions, occasionally fatal, have been reported in approximately 5% of patients receiving abacavir.
Symptoms, which generally occur within the first 6 weeks of therapy, include fever, malaise, nausea, vomiting, diarrhea, and anorexia. Respiratory symptoms such as dyspnea, pharyngitis, and cough may also be present, and skin rash occurs in about 50% of patients.

Laboratory abnormalities such as mildly elevated serum aminotransferase or creatine kinase levels may be present but are not specific for the hypersensitivity reaction. Although the syndrome tends to resolve quickly with discontinuation of medication, rechallenge with abacavir results in return of symptoms within hours and may be fatal.

Other potential adverse events are rash, fever, nausea, vomiting, diarrhea, headache, dyspnea, fatigue, and pancreatitis (rare).

Didanosine

Didanosine (ddI) is a synthetic analog of deoxyadenosine. Oral bioavailability is 30 to 40%; dosing on an empty stomach is required. Cerebrospinal fluid concentrations of the drug are approximately 20% of serum concentrations. The elimination half-life is 1.5 hours, but the intracellular half-life of the activated compound is as long as 20–24 hours.

Buffered powder for oral solution and chewable tablets are taken twice daily; enteric-coated capsules can be taken once daily because of greater bioavailability.

The buffer in the tablets and powder interferes with the absorption of indinavir, delavirdine, dapsone, and itraconazole; therefore, concurrent administration is to be avoided. Because the tablets contain both phenylalanine (36.5 mg) and sodium (1380 mg), caution should be exercised in patients with phenylketonuria and those on sodium-restricted diets.

The major clinical toxicity associated with didanosine therapy is dose-dependent pancreatitis. Other risk factors for pancreatitis (eg, alcoholism, hypertriglyceridemia) are relative contraindications to administration of didanosine, and other drugs with the potential to cause pancreatitis, including zalcitabine and stavudine, should be avoided.

Other reported adverse effects include painful peripheral distal neuropathy, diarrhea (particularly with tablets and powder), hepatitis, esophageal ulceration, cardiomyopathy, and central nervous system toxicity (headache, irritability, insomnia). Asymptomatic hyperuricemia may precipitate attacks of gout in susceptible individuals.

Reports of retinal changes and optic neuritis in patients receiving didanosine, particularly in adults receiving high doses and in children, mandate periodic retinal examinations.

Fluoroquinolones and tetracyclines should be administered at least 2 hours before or after didanosine to avoid decreased antibiotic plasma concentrations due to chelation. Serum levels of didanosine are increased when co-administered with tenofovir and ganciclovir, thus increasing the risk of toxicity; they are decreased by atazanavir, delavirdine, ritonavir, tipranavir, and methadone.

Emtricitabine

Emtricitabine (formerly called FTC) is a fluorinated analog of lamivudine with a long intracellular half-life (> 39 hours), allowing for once-daily dosing. The oral bioavailability of the capsules is 93% and is unaffected by food, but penetration into the cerebrospinal fluid is low.

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, because of it's in vitro activity against HBV, patients co-infected with HIV and HBV should be closely monitored if treatment with emtricitabine is interrupted or discontinued, owing to the likelihood of hepatitis flares.

Because of their similar mechanisms of action and resistance profiles, the combination of lamivudine and emtricitabine is not recommended.

The most common adverse effects observed in patients receiving emtricitabine are headache, diarrhea, nausea, and asthenia. In addition, hyperpigmentation of the palms and/or soles may be observed (~ 3%), particularly in blacks (up to 13%).

Lamivudine

Lamivudine (3TC) is a cytosine analog with in vitro activity against HIV-1 that is synergistic with a variety of antiretroviral nucleoside analogs including zidovudine and stavudine against both zidovudine-sensitive and zidovudine-resistant HIV-1 strains.

Oral bioavailability exceeds 80% and is not food-dependent.

Potential adverse effects are headache, insomnia, fatigue, and gastrointestinal discomfort, although these are typically mild.

Lamivudine's bioavailability increases when it is co-administered with trimethoprim-sulfamethoxazole.

Lamivudine and zalcitabine may inhibit the intracellular phosphorylation of one another in vitro, thus decreasing potency; therefore, their concurrent use should be avoided if possible.

Stavudine

The thymidine analog stavudine (d4T) has high oral bioavailability (86%) that is not food-dependent. The dosage of stavudine should be reduced in patients with renal insufficiency and low body weight.

The major dose-limiting toxicity is a dose-related peripheral sensory neuropathy. The incidence of neuropathy may be increased when stavudine is administered with other neuropathy-inducing drugs such as didanosine and zalcitabine. Symptoms typically resolve completely upon discontinuation of stavudine; in such cases, a reduced dosage may be cautiously restarted.

Other potential adverse effects include pancreatitis, arthralgias, and elevation in serum aminotransferases. Lactic acidosis with hepatic steatosis, as well as fat atrophy, appears to occur more frequently in patients receiving stavudine than in those receiving other NRTI agents.

Moreover, because the co-administration of stavudine and didanosine may increase the incidence of lactic acidosis and pancreatitis, concurrent use should be avoided, if possible. This combination has been implicated in several deaths in HIV-infected pregnant women.

A rare side effect is a rapidly progressive ascending neuromuscular weakness. Since zidovudine may reduce the phosphorylation of stavudine, these two drugs should generally not be used together.

Tenofovir

Tenofovir is an acyclic nucleoside phosphonate (ie, nucleotide) analog of adenosine. Like the nucleoside analogs, tenofovir competitively inhibits HIV reverse transcriptase and causes chain termination after incorporation into DNA.

Tenofovir disopoxilfumarate is a water-soluble prodrug of active tenofovir. The oral bioavailability in fasted patients is approximately 25% and increases to 39% after a high-fat meal. Elimination occurs by a combination of glomerular filtration and active tubular secretion, and the dosage must be adjusted in patients with renal insufficiency.

Gastrointestinal complaints (eg, nausea, diarrhea, vomiting, flatulence) are the most common side effects but rarely require discontinuation of therapy.

Other potential adverse effects include headache and asthenia. Preclinical studies in several animal species have demonstrated bone toxicity (eg, osteomalacia); however, to date, there has been no evidence of bone toxicity in humans.

Cases of renal impairment, including acute renal failure and Fanconi's syndrome, have been reported in patients receiving tenofovir.

Tenofovir may compete with other drugs that are actively secreted by the kidneys, such as cidofovir, acyclovir, and ganciclovir. The combination of tenofovir with didanosine is associated with both decreased virologic efficacy and increased toxicity (due to increased didanosine levels) and therefore should be avoided.

Zalcitabine

Zalcitabine (ddC) is one of the drugs used in HIV treatment. It is a cytosine analog with high oral bioavailability (> 80%) and a relatively long intracellular half-life (10 hours) despite its elimination half-life of 1 to 2 hours. However, plasma levels decrease by 25 to 39% when the drug is administered with food or antacids.

Zalcitabine therapy is associated with a dose-dependent peripheral neuropathy that can be treatment-limiting in 10 to 20% of patients but appears to be slowly reversible if treatment is stopped promptly. The potential for causing peripheral neuropathy constitutes a relative contraindication to use with other drugs that may cause this toxicity, including stavudine, didanosine, and isoniazid. Decreased renal clearance caused by amphotericin B, foscarnet, and aminoglycosides may increase the risk of zalcitabine neuropathy.

The other major reported toxicity is oral and esophageal ulcerations. Pancreatitis occurs less frequently than with didanosine administration, but co-administration of other drugs that cause pancreatitis may increase the frequency of this adverse effect. Headache, nausea, rash, and arthralgias may occur but tend to be mild or resolve during therapy. Cardiomyopathy has rarely been reported.

The AUC of zalcitabine increases when co-administered with probenecid or cimetidine, and bioavailability decreases with concurrent antacids or metoclopramide. Lamivudine inhibits the phosphorylation of zalcitabine in vitro, potentially interfering with its efficacy.

Zidovudine

Zidovudine (azidothymidine; AZT) is a deoxythymidine analog that is well absorbed from the gut and distributed to most body tissues and fluids, including the cerebrospinal fluid, where drug levels are 60 to 65% of those in serum.

Zidovudine is eliminated primarily by renal excretion following glucuronidation in the liver. The clearance of zidovudine is reduced by approximately 50% in uremic patients, and toxicity may increase in patients with advanced hepatic insufficiency.

Zidovudine was the first among the drugs used in HIV treatment to be approved and has been well studied. The drug has been shown to decrease the rate of clinical disease progression and prolong survival in HIV-infected individuals. Efficacy has also been demonstrated in the treatment of HIV-associated dementia and thrombocytopenia.

In pregnancy, a regimen of oral zidovudine beginning between 14 and 34 weeks of gestation (100 mg five times a day), intravenous zidovudine during labor (2 mg/kg over 1 hour, then 1 mg/kg/h by continuous infusion), and zidovudine syrup to the neonate from birth through 6 weeks of age (2 mg/kg every 6 hours) has been shown to reduce the rate of vertical (mother-to-newborn) transmission of HIV by up to 23%.

The most common adverse effect of zidovudine is myelosuppression, resulting in macrocytic anemia (1 to 4%) or neutropenia (2 to 8%). Gastrointestinal intolerance, headaches, and insomnia may occur but tend to resolve during therapy.

Less frequent toxicities include thrombocytopenia, hyperpigmentation of the nails, and myopathy.

Very high doses can cause anxiety, confusion, and tremulousness.

Increased serum levels of zidovudine may occur with concomitant administration of probenecid, phenytoin, methadone, fluconazole, atovaquone, valproic acid, and lamivudine, either through inhibition of the first-pass metabolism or through decreased clearance.

Zidovudine may decrease phenytoin levels, and this warrants monitoring of serum phenytoin levels in epileptic patients taking both agents.

Hematologic toxicity may be increased during co-administration of other myelosuppressive drugs such as ganciclovir, ribavirin, and cytotoxic agents. Combination regimens containing zidovudine and stavudine should be avoided; antagonism has been demonstrated in vitro.

Another class of drugs used in HIV treatment is non-nucleoside reverse transcriptase inhibitors

Non-nucleoside reverse transcriptase inhibitors

The NNRTIs bind directly to HIV-1 reverse transcriptase, resulting in blockade 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.

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 the use of NNRTI agents as a component of HAART is their metabolism by the CYP450 system, leading to innumerable potential drug-drug interactions.

Delavirdine

Skin rash occurs in approximately 18% of patients receiving delavirdine; it typically occurs during the first 1 to 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.

The concurrent use of delavirdine with amprenavir/fosamprenavir and rifabutin is not recommended because of decreased delavirdine levels.

Efavirenz

Efavirenz can be given once daily because of its long half-life (40 to 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.

The principal adverse effects of efavirenz involve the central nervous system (dizziness, drowsiness, insomnia, headache, confusion, amnesia, agitation, delusions, depression, nightmares, euphoria); these may occur in up to 50% of patients and may be severe. However, they tend to resolve after the first month of treatment.

Skin rash has also been reported early in therapy in up to 28% of patients, is usually mild to moderate in severity, and typically resolves despite continuation.

Other potential adverse reactions are nausea, vomiting, diarrhea, crystalluria, elevated liver enzymes, and an increase in total serum cholesterol by 10 to 20%. High rates of fetal abnormalities 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. Therefore, efavirenz should be avoided in pregnant women, particularly in the first trimester.

Efavirenz is both an inducer and an inhibitor of CYP3A4, thus inducing its own metabolism and interacting with the metabolism of many other drugs.

Nevirapine

The oral bioavailability of nevirapine is excellent (~ 90%) and is not food-dependent.

In addition to its use as a component of a combination antiretroviral regimen, a single dose of nevirapine (200 mg) has been shown to be 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.

A rash occurs in approximately 17% of patients, most typically in the first 4 to 6 weeks of therapy, and is dose-limiting in about 7% of patients. When initiating therapy, gradual dose escalation over 14 days is recommended to decrease the incidence of rash.

Women may have a greater propensity for rash. Severe and life-threatening skin rashes have been rarely reported, including Stevens-Johnson syndrome and toxic epidermal necrolysis. Nevirapine therapy should be immediately discontinued in patients with a severe rash and in those with accompanying constitutional symptoms.

Hepatotoxicity occurs in about 4% of patients and appears to occur more frequently in those with higher pre-therapy CD4 cell counts (ie, > 250 cells/mm3 in women and > 400 cells/mm3 in men), in women, and in those with hepatitis B or C co-infection. Fulminant hepatitis may rarely occur, typically within the first 18 weeks of therapy and can be fatal.

Other adverse effects associated with nevirapine therapy are fever, nausea, headache, and somnolence.

Nevirapine is a moderate inducer of CYP3A metabolism, resulting in decreased levels of amprenavir, indinavir, lopinavir, saquinavir, efavirenz, and methadone if administered concurrently.

Drugs that induce the CYP3A system, such as tipranavir, rifampin, rifabutin, and St. John's wort, can decrease levels of nevirapine, whereas those that inhibit CYP3A activity, such as fluconazole, ketoconazole, and clarithromycin, can increase nevirapine levels.

Protease inhibitor is the third class of drugs used in HIV treatment.

Protease inhibitors

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. Protease is responsible for cleaving these precursor molecules to produce the final structural proteins of the mature virion core.

By preventing cleavage of the Gag-Pol polyprotein, protease inhibitors (PIs) result in the production of immature, noninfectious viral particles.

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.

Concurrent increases in triglyceride and LDL levels, along with glucose intolerance and insulin resistance, have also been noted. The cause is not yet known.

Protease inhibitors have been associated with increased spontaneous bleeding in patients with hemophilia A or B.

All of the antiretroviral PIs are substrates and inhibitors of 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.

It is noteworthy that the potent CYP3A4 inhibitory properties of ritonavir have been utilized to clinical advantage by having it "boost" the levels of other PI agents when given in combination.

Amprenavir

Amprenavir is rapidly absorbed from the gastrointestinal tract and can be taken with or without food. However, high-fat meals decrease absorption and thus should be avoided. 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 amprenavir are nausea, diarrhea, vomiting, perioral paresthesias, depression, and rash. Up to 3% of patients in clinical trials to date have had rashes (including Stevens-Johnson syndrome) severe enough to warrant drug discontinuation.

Amprenavir is both an inducer and an inhibitor of CYP3A4 and is contraindicated with numerous other drugs. 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.

Because the oral solution also contains vitamin E at several times the recommended daily dosage, supplemental vitamin E should be avoided.

Amprenavir is contraindicated in patients with a history of sulfa allergy because it is itself a sulfonamide. Lopinavir/ritonavir should not be co-administered with amprenavir owing to decreased amprenavir and increased lopinavir exposures. An increased dosage of amprenavir is recommended when co-administered with efavirenz (with or without the addition of ritonavir to boost levels).

Atazanavir

Atazanavir is a newer azapeptide PI with a pharmacokinetic profile that allows once-daily dosing. Its oral bioavailability is approximately 60 to 68%; the drug should be taken with food. 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.

The primary route of elimination is biliary; atazanavir should not be given to patients with severe hepatic insufficiency.

The most common adverse effects in patients receiving atazanavir in clinical trials were nausea, vomiting, diarrhea, abdominal pain, headache, peripheral neuropathy, and skin rash.

As with indinavir, indirect hyperbilirubinemia with overt jaundice may occur, in all likelihood owing to the inhibition of the UGT1A1 enzyme. Although bilirubinemia is not regularly associated with hepatic injury, the elevation of hepatic enzymes has also been observed, usually in patients with underlying hepatitis B or C infection.

In contrast to the other PIs, atazanavir does not appear to be associated with dyslipidemias, fat redistribution, or metabolic syndrome.

Atazanavir may be associated with electrocardiographic PR interval prolongation, which is usually inconsequential but may be exacerbated by other causative agents such as calcium channel blockers.

Tenofovir and efavirenz should not be co-administered with atazanavir unless ritonavir is added to boost levels.

Fosamprenavir

Fosamprenavir is a prodrug of amprenavir that is rapidly hydrolyzed by enzymes in the intestinal epithelium. Tablets may be taken with or without food. Because of its significantly lower daily pill burden, fosamprenavir tablets have replaced amprenavir capsules for adults.

All pharmacokinetic and pharmacodynamic attributes are those of amprenavir (see above).

 Indinavir

Indinavir must be consumed on an empty stomach for maximal absorption; however, if co-administered with ritonavir, it may be taken without regard to food. Oral bioavailability is about 65%.

The most common adverse effects are indirect hyperbilirubinemia and nephrolithiasis due to the crystallization of the drug. Nephrolithiasis can occur within days after initiating therapy, with an estimated incidence of 10 to 20%, and it may be associated with renal failure.

Consumption of at least 48 ounces of water daily is important to maintain adequate hydration and prevent nephrolithiasis.

Thrombocytopenia, elevations of serum aminotransferase levels, nausea, diarrhea, and irritability have also been reported. Insulin resistance may be more common with indinavir than with the other PI agents, 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 the development of thyroid adenomas.

Since indinavir is an inhibitor of CYP3A4, numerous and complex drug interactions can occur. A combination with ritonavir (boosting) allows for twice-daily rather than thrice-daily dosing and eliminates the food restriction associated with the 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 to 2 L/d) is advised.

Lopinavir/Ritonavir

Lopinavir 100/ritonavir 400 is a licensed combination in which subtherapeutic doses of ritonavir inhibit the CYP3A-mediated metabolism of lopinavir, thereby resulting in increased exposure to lopinavir. Trough levels of lopinavir are greater than the median HIV-1 wild-type 50% inhibitory concentration, thus maintaining potent viral suppression as well as providing a pharmacologic barrier to the emergence of resistance.

In this combination, therefore, ritonavir is acting as a pharmacokinetic enhancer rather than an antiretroviral agent. In addition to improved patient compliance due to reduced pill burden, lopinavir/ritonavir is generally well tolerated.

The absorption of lopinavir is enhanced with food. The oral solution contains alcohol. Lopinavir is extensively metabolized by the CYP3A isozyme of the hepatic cytochrome P450 system, which is inhibited by ritonavir. Serum levels of lopinavir may be increased in patients with hepatic impairment.

The most common adverse effects of lopinavir are diarrhea, abdominal pain, nausea, vomiting, and asthenia. Potential drug-drug interactions are extensive. Increased dosage of lopinavir/ritonavir is recommended when co-administered with efavirenz or nevirapine, which induce lopinavir metabolism. Concurrent use of fosamprenavir should be avoided owing to increased exposure to lopinavir with decreased levels of amprenavir.

Nelfinavir

The most common adverse effects associated with nelfinavir are diarrhea and flatulence. Diarrhea often responds to antidiarrheal medications but can be dose-limiting.

Like other PIs, nelfinavir is an inhibitor of the CYP3A system, and multiple drug interactions may occur. 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.

Nelfinavir has a favorable safety and pharmacokinetic profile for pregnant women compared with that of other PIs

 Ritonavir

Ritonavir is the most common used PI  among the drugs used in HIV treatment. It is an inhibitor of HIV-1 and HIV-2 proteases with high bioavailability (about 75%) that increases when the drug is given with food. Metabolism to an active metabolite occurs via the CYP3A and CYP2D6 isoforms; excretion is primarily in the feces. Caution is advised when administering the drug to persons with impaired hepatic function.

The most common adverse effects of ritonavir are gastrointestinal disturbances, paresthesias (circumoral and peripheral), elevated serum aminotransferase levels, altered taste, and hypertriglyceridemia. Nausea, vomiting, and abdominal pain typically occurs during the first few weeks of therapy. Slow dose escalation over 4–5 days is recommended to decrease the dose-limiting side effects.

Ritonavir is a potent inhibitor of CYP3A4; as such, co-administration with agents heavily metabolized by CYP3A must be approached with caution.

In addition, therapeutic levels of digoxin and theophylline should be monitored when co-administered with ritonavir owing to likely increase in their concentrations. However, the CYP3A4 inhibitory properties of ritonavir have been exploited to raise the trough concentration and prolong the half-life of more potent and less toxic PI agents.

Thus, lower than therapeutic doses of ritonavir are commonly given in combination with agents such as lopinavir, indinavir, or amprenavir to reduce the risk of resistance by increasing the time of drug exposure. Moreover, the prolonged half-life allows for less frequent dosing of the other PI agent, thus enhancing adherence.

Saquinavir

In its original formulation as a hard gel capsule (saquinavir-H; Invirase), Among the drugs used in HIV treatment, oral saquinavir is poorly bioavailable (only about 4% after food). It was therefore largely replaced in clinical use by a soft gel capsule formulation (saquinavir-S; Fortovase) in which absorption was increased approximately threefold.

However, the reformulation of saquinavir-H for once-daily dosing in combination with low-dose ritonavir has both improved antiviral efficacy and decreased the gastrointestinal side effects typically associated with saquinavir-S. Moreover, co-administration of saquinavir-H with ritonavir results in blood levels of saquinavir similar to those associated with saquinavir-S, thus capitalizing on the pharmacokinetic interaction of the two agents.

Both formulations of saquinavir should be taken within 2 hours after a fatty meal for enhanced absorption.

Reported adverse effects include gastrointestinal discomfort (nausea, diarrhea, abdominal discomfort, dyspepsia; these are more common with saquinavir-S) and rhinitis.

Saquinavir is subject to extensive first-pass metabolism by CYP3A4, and functions as a CYP3A4 inhibitor as well as a substrate; thus, it should be used with the same precautions regarding drug-drug interactions as are the other PIs.

Co-administration with the CYP3A4 inhibitor ritonavir has been adopted by clinicians because of the higher and thus more efficacious levels of saquinavir while enabling a reduction in daily dose and frequency of saquinavir. A decreased dose of saquinavir is recommended when coadministered with nelfinavir. Liver function tests should be monitored if saquinavir is co-administered with delavirdine or rifampin.

Tipranavir

Tipranavir is one of the newest drugs used in HIV treatment. Bioavailability is poor but is increased when taken with a high-fat meal. The drug is metabolized by the liver microsomal system. Tipranavir must be taken in combination with ritonavir to achieve effective serum levels.

It 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 are diarrhea, nausea, vomiting, abdominal pain, and rash; the latter is more common in women.

Liver toxicity, including life-threatening hepatic decompensation, has been observed and is more common in patients with chronic hepatitis B or C. In 2006 a black box warning was added noting a possible increase in intracranial hemorrhage in patients taking tipranavir.

Other potential adverse effects include depression; elevations in total cholesterol, triglycerides, and amylase; 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 P-glycoprotein transporter and thus may alter the disposition of many other drugs.

Concurrent administration of tipranavir with amprenavir or saquinavir should be avoided owing to decreased blood levels of the latter drugs.

Another class of drugs used in HIV treatment is Fusion Inhibitors.

Fusion Inhibitors

Enfuvirtide

Enfuvirtide (formerly called T-20) is the first representative of a new class of drugs used in HIV treatment: It is a fusion inhibitor that blocks entry into the cell.

Enfuvirtide, a synthetic 36-amino-acid peptide, 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 must be administered by subcutaneous injection.

Metabolism appears to be by proteolytic hydrolysis without the involvement of the CYP450 system. Elimination half-life is 3.8 hours.

The most common adverse effects associated with enfuvirtide therapy are local injection site reactions. Hypersensitivity reactions may rarely occur, are of varying severity, and may recur on rechallenge.

Eosinophilia has also been noted. No interactions have been identified that would require the alteration of the dosage of other antiretroviral drugs.


Post References

  • Pubmed, Kenya antiretroviral regimen guidelines

  • Revised on: 2021-07-10 03:09:32