The PIs were introduced in 1995 as a promising new category of antiretrovirals that work by a different mechanism than the reverse transcriptase inhibitors (192). These compounds block a separate virus-speciﬁc enzyme known as HIV protease. Mechanism of action. Inhibition of the protease enzyme prevents the cleavage of viral polyproteins in the ﬁnal stage of viral protein processing (See Fig. 2.2 for site of action.). With- out the HIV protease activity, mature HIV virions cannot be assembled and released from infected cells, which results in the production of defective, noninfectious viral particles (193). While the reverse transcriptase inhibitors prevent replication only in newly infected cells, PIs block enzyme activity in both newly infected and chronically infected cells (194).
Adverse events. When compared to the nucleoside analogues, the PIs are more potent in reducing viral load (126,195), but are associated with the major morbidity of lipodystrophy as well as possible increased mortality secondary to coronary artery dis- ease (48). All of the PIs have been shown to be associated with increases in weight and body mass index as well as an improved quality of life. Unfortunately, the chemical structures of these drugs are remarkably complex and are difﬁcult to syn- thesize on a large-scale basis, resulting in high costs (126). Enzymatic inhibition. Protease inhibitors are all meta- bolized by hepatic microsomal enzymes (i.e., P450) to a certain degree that may cause signiﬁcant drug interactions with some of these compounds. Since the list of such drugs that are con- traindicated with PIs is constantly evolving, a comprehensive resource such as www.hivatis.org should be consulted before initiating any drug with hepatic metabolism concomitantly with PIs or NNRTIs. Furthermore, none of the PIs adequately penetrate into the CNS.
Cross resistance. Cross-resistance commonly occurs among several of the PIs (196), and these drugs should be used only in combination with the reverse transcriptase inhibitors. Speciﬁc observations. Protease inhibitor use is associated with fat redistribution, hyperlipidemia, hyperglycemia with insulin resistance, and probable increases in coronary artery disease with variable frequency (197–201). These changes may occur as isolated observations or they may occur together. Similar observations have been reported in HIV-infected patients not receiving PIs, but the incidence in persons receiv- ing PI-containing HAART regimens appears to be increasing (202–204).
Lipodystrophy syndrome. Fat distribution abnormalities result in a “wasting” appearance (“slim disease”) and abnormal fat accumulation in localized areas (“protease pouch,” “buffalo hump,” and “crix belly”) (205–220). Some studies have shown that saquinavir, ritonavir, and nelﬁnavir all reduce the devel- opment of fat cells from stem cells in vitro. In addition, they increase the metabolic destruction of fat in existing fat cells. It is postulated that loss of deposited fat in the body could lead to high levels of LDL, cholesterol, and triglycerides. An alterna- tive mechanism could involve retinoids (221). When retinoids are combined with PIs, complex reactions occur in certain genes. It is postulated that indinavir may cause some effects resembling lipodystrophy by changing retinoid signaling. Therefore, patients taking PIs may be advised to avoid vitamin A supplements. Still another hypothesis suggests that PIs, which show approximately 60% homology with lipoprotein receptor-related protein and cytoplasmic retinoic acid-binding- protein type I, may bind to lipoprotein receptor-related proteins and result in hypertriglyceridemia and lipodystrophy (222). Abnormal adipose distribution. Human aspartic proteases playing a role in adipose regulation may be downregulated by PIs, resulting in abnormal adipose deposition (223).
Insulin resistance and associated cardiovascular risk. Metformin reduces insulin resistance and related cardiovas- cular risk parameters in patients with lipodystrophy (224). Surgical interventions. Liposuction, reduction mammoplasty, fat transfer to cheeks, and other forms of cosmetic surgery
have been used to treat the lipodystrophy syndrome with vary- ing success (225,226).
Saquinavir [SQV] (Invirase®: Hard Gel; Fortovase®: Soft Gel)
Saquinavir (SQV) was the ﬁrst PI to be approved for the treatment of HIV-1 and HIV-2. It is a synthetic, transition- state peptidomimetic which inhibits the HIV protease and prevents the infectivity of the viral particle. When given as the original hard gel form (Invirase), saquinavir is limited by extremely poor absorption. After reformulation as a soft gel cap (Fortovase), saquinavir was predicted to have a ﬁve- fold increased bioavailability (205) and greater viral load reduction (206). This would make it more useful in potent triple-combination therapies (227). However, the increase in bioavailability was not as high as predicted. The uptake of saquinavir may improve with high-fat meals and/or admin- istration with grapefruit juice (228), but this may cause plasma concentrations to be too low for good antiviral activ- ity. Saquinavir can be combined with ritonavir for better efﬁ- cacy and availability (229). “Average” doses for saquinavir are
600 mg three times a day for adults for oral capsules. The soft gelatin capsules require 1200 mg three times per day. The capsules and the soft gelatin capsules are not inter- changeable. In both cases, children’s (under the age of 16 years) dosages must be calculated based on the body mass of the child and other factors. The structure, brand names, and approved uses for saquinavir are shown in Fig. 2.14. Saquinavir competes for CYP3A enzymes and inhibits the metabolism of similarly metabolized drugs.
Rare events include a burning or prickling sensation, confusion, dehydration, dry or itchy skin, fruity mouth odor, increased hunger, increased thirst, increased urination, nausea, skin rash, unusual tiredness, and weight loss.
Less common or rare side effects include:
Fig. 2.14 Trade names, structure, and uses of Saquinavir.
Abdominal discomfort. Dyspepsia.
Blood sugar levels. New-onset diabetes mellitus and hyperglycemia have been reported with all of the PI drugs (207).
Liver disease. Saquinavir may be more potent in patients with liver disease because of slower removal of medicine from the body. Dosage adjustments may be necessary
Coadministration with terfenadine, cisapide, triaz- olam, midazolam, or ergot derivatives. Coadministra- tion with terfenadine, cisapride, triazolam, midazolam, or ergot derivatives may cause potentially serious reac- tions. Several other drug interactions occur that may in- crease or decrease drug plasma concentrations of either compound, requiring dosage adjustments.
Ritonavir [RTV] (Norvir®)
In March 1996, ritonavir (RTV) was the second PI to receive FDA approval. Brand names, chemical structure, and uses are shown in Fig. 2.15. In a randomized, double-blind, placebo- controlled trial, ritonavir was added to the previous treat- ment regimens (with up to two nucleoside drugs) in patients with advanced HIV-1 disease (230). Results revealed that the addition of ritonavir lowered the complications of AIDS and
Fig. 2.15 Trade names, structure, and uses of Ritonavir.
prolonged survival in these patients, although earlier inter- vention would likely have been much more effective. Coad- ministration of ritonavir with amprenavir results in a synergistic relationship between the two (231). Indinavir and ritonavir combinations have improved pharmacokinetic properties with twice-daily dosing with food (232). Ritonavir is taken orally as a capsule or in an oral solution. Adults take 600 mg two times a day in capsule form. For the oral solution, adults take 600 mg two times a day. Children’s dosages are to be determined by the physician, but the capsules are not nor- mally used for children. Ritonavir is often used to boost HIV PI combinations to reduce pill burden and improve the phar- macokinetic proﬁle of other PIs but with mixed results (233).
Hepatotoxicity. Ritonavir is associated with higher rates of severe hepatotoxicity in HIV/HCV-coinfected patients when compared with other protease inhibi- tors. Hepatotoxicity also is prevalent in patients with alcohol abuse or intravenous drug use (234).
Gastric upsets. The most common adverse effects seen with ritonavir include signiﬁcant nausea / vomiting and diarrhea. It is recommended that this drug be taken with a large meal to decrease diarrhea and cramping.
Circumoral paresthesias and peripheral paresthe- sias. Other less frequent side effects include circumoral paresthesias (for up to ﬁve weeks), peripheral pares- thesias, taste perversion, and hepatitis.
Hypermenorrhea. Four cases of hypermenorrhea associ- ated with the use of ritonavir have been reported (235). Hypertriglyceridemia and pancreatitis. Pancreatitis due to a ritonavir-induced hypertriglyceridemia in a
HIV-patient has been reported (236).
Maculopapular eruption and fever. Occasionally, a few days after treatment was initiated, maculopapular eruption and fever have been reported (237). In some cases clinical improvement occurred despite continua- tion of therapy, while in others treatment was stopped. Ingrown toenails. Ingrown toenails are associated with
indinavir/ritonavir combination therapy (238).
Hyperparathyroidism, osteopenia, and bone pain.
Ritonavir has been implicated in in vitro studies in which ritonavir, nelﬁnavir, and indinavir have an effect on vitamin D metabolism and differentiation of osteo- cytes (239). Extreme bone pain has been reported, pos- sibly as an idiosyncratic reaction to ritonavir (240). Calcium inhibition has been reported by others and may result in children on ritanovir experiencing im- paired growth (241,242).
Drug interactions. Ritonavir is associated with numer- ous drug interactions and adverse effects, which have limited its widespread use. It is a considerably strong inhibitor of the cytochrome P450 system, which leads to increased serum levels of other hepatically metabo- lized drugs. Therefore, coadministration with carbam- azepines should not occur. Ritonavir has been associated with carbamazepine toxicity (243).
Coadministration with cisapride, terfenadine, astem- izole, antiarrythmics (e.g., quinidine, amiodarone, encainide, and ﬂecainide), and certain sedative / hypnotics. Because of potential serious and life- threatening reactions, the use of ritonavir is contrain- dicated with the following: cisapride, terfenadine, astemizole, certain antiarrythmics (e.g., quinidine,
amiodarone, encainide, and ﬂecainide), and certain sedative/hypnotics (e.g., midazolam, diazepam, triaz- olam, and ﬂurazepam).
Coadministration with the tuberculosis drugs rifam- pin and rifabutin. Rifampin decreases the blood plasma levels of protease inhibitors by 80%. Rifabutin is expected to decrease the level of interaction by only
32%. Patients taking tuberculosis drugs concomitant- ly with ritanovir should be monitored for liver func- tion as both drugs have a tendency to cause severe liver toxicity (244).
Coadministration of budesonide and ritonavir. Budes- onide is metabolized by cytochrome P-450 3A and is
90% eliminated by ﬁrst-pass hepatic clearance. When combined with ritanovir, the metabolism of budesonide is reduced as the cytochrome P-450 3A is inhibited by ritanovir. This might cause bedesonide to accumulate and cause acute hepatitis, as has been reported in one patient (245).
Sexual dysfunction. Ritonavir is signiﬁcantly associat- ed with sexual dysfunction in men when compared with indinavir, nelﬁnavir, and saquinavir. The latter three were also associated with sexual dysfunction but were not statistically signiﬁcant (246).
Patient compliance and virologic potency. Conven- tional dosing of ritonavir (400–600 mg twice daily) can result in high rates of intolerance. A study of lower doses of ritonavir supports the use of low-dose ritonavir to improve the activity of current PIs in twice-daily regimens. The relative efﬁcacy of ritonavir combined with other PIs has not been proﬁled (247).
Indinavir [IDV] (Crixivan®)
Also approved in March 1996, indinavir (IDV) (when com- bined with zidovudine and lamivudine) reduces viral loads to undetectable levels after 16 weeks of therapy in approxi- mately 90% of patients (248). The structure of indinavir, brand names, and uses are shown in Fig. 2.16. Indinavir is taken
Fig. 2.16 Trade names, structure, and uses of Indinavir.
orally on an empty stomach, either one hour before a meal or two hours after a meal with at least eight ounces of water. For those who experience a stomach upset with indinavir, it may be taken with a light meal, but grapefruit juice should not be coadministered. Patients should drink at least 48 ounces of water or other liquids every 24 hours. Indinavir has a signiﬁcant number of adverse effects associated with it. For example, the administration of combination antiretroviral prophylaxis for healthy individuals with nonoccupational exposure to HIV resulted in those receiving zidovudine and lamivudine with indinavir being more likely to experience nausea, rash, anorexia, insomnia, and abdominal pain. Two of the 16 patients experienced nephrolithiasis or toxic hepatitis (249).
Like ritonavir, saquinavir, nelﬁnavir, and delavirdine, indinavir is a potent inhibitor of the cytochrome P450 pathway, result- ing in similar drug interactions and contraindications.
Nephrolithiasis. Due to the poor solubility of indinavir in urine, nephrolithiasis was reported in 9% of clinical trial subjects on indinavir (48). In some cases, renal in- sufﬁciency or acute renal failure have developed. Indi- viduals at greater risk for nephrolithiasis include those with a low body mass index or those receiving trime- thoprim/sulfamethoxazole prophylaxis (250). The risk
for all patients can be minimized by adequate oral hydration.
Lipodystrophy. Women are more at risk to develop lipo- dystrophy than men, and this risk increases with age and increasing exposure to antiretroviral therapy. The duration of indinavir use, in particular, may represent an additional contribution for the development of lipo- dystrophy with a tendency for central obesity (251).
Crystalluria. Patients treated with indinavir are often prone to precipitate and form deposits inside cortical and medullary ducts with later development of kidney stones in 4 to 12% of patients. This may be alleviated by reduc- ing the drug dosage or by drug withdrawal. Crystalluria may be used as a monitor for the risk of urolithiasis. Crytalluria is found in 20–67% of indinavir-treated patients (252).
Homocysteinemia. Protease-inhibitors tend to cause ho- mocysteinaemia which can be an increased risk for car- diovascular risk and for accelerated atherosclerosis (253). Diabetes and hyperglycemia. Blood glucose levels may rise in patients who are prescribed PIs (254). The prevalence of fat atrophy and fat accumulation can be characterized by using several signs of body fat loss or gain. For the fat atrophy group these are: fat loss in the extremities, fat loss in the hips / buttocks, and sunken cheeks. Signs for the fat accumulation group are: en- larged abdomen, other facial structure changes, and
presence of a dorsal cervical fat pad (255).
Renal atrophy. Hanabusa et al. reported two cases of HIV-positive patients on prolonged indinavir treat- ment who developed renal atrophy (256).
Pharyngitis. Gastrointestinal upset.
Hemolytic anemia. Reported rarely.
Hyperbilirubinemia. Indinavir therapy is associated with a 6–25% incidence of asymptomatic, unconjugated hyper- bilirubinemia (257,258). Mechanistic studies in rats indi- cate that hyperbilirubinemia is due to indinavir-mediated impairment of bilirubin-conjugating activity (259).
Gilbert’s syndrome. Gilbert’s syndrome is a benign, in- herited condition of deﬁcient bilirubin conjugation, occur- ring in 5 to 10% of the general population. Gilbert’s genotype is associated with a 50% reduction in bilirubin- conjugation activity in homozygotes (260).
Rash. An erythematous, maculopapular skin eruption frequently occurs within two weeks of initiating thera- py with indinavir. The rash usually begins in a local- ized area and then spreads to other regions of the body, often with associated pruritus. Most patients are able to continue therapy despite this skin eruption.
Paronychia of the large toes. Bouscarat et al. (261) have also described 42 HIV-infected patients on indi- navir who developed hypertrophic paronychia of the great toes, many with pyogenic granuloma-like lesions. This number represented 4% of their total patients on indinavir therapy.
Xerosis and alopecia. Other cutaneous side effects of indinavir include xerosis and alopecia (262).
Stevens-Johnson syndrome. There has been one report of Stevens-Johnson syndrome caused by indinavir (263). Erectile dysfunction. Homosexuality, CD4 cell count, viral load, and indinavir treatment are independent variables predictive of erectile dysfunction. Indinavir has been associated with peripheral neuropathy caus-
ing erectile dysfunction (264).
Coadministration with acyclovir. Concomitant acy- clovir nearly doubles the risk of indinavir-associated renal complications. In one study, events occurred in nearly 26% of the cases, many of which could have been avoided. Careful monitoring should be done if acyclovir is prescribed with indinavir (265).
Coadministration with other drugs. Many drugs ei- ther increase or decrease the amount of indinavir in the body and care must be taken to adjust dosages. Physicians should consult the available literature when
prescribing PIs. Cannabinoids do not have any effect on antiretroviral efﬁcacy (266).
Nelﬁnavir [NFV] (Viracept®)
FDA-approved in March 1997, nelﬁnavir (NFV) is a powerful and well-tolerated drug which is indicated in initial combina- tion regimens for HIV therapy. The actual effect and mecha- nism of action for nelﬁnavir on the clinical progression of HIV infection have not been determined. The structure and brand names are given in Fig. 2.17. NFV causes potent and durable suppression of viral replication (like indinavir and ritonavir) when used in combination with two nucleoside analogues (267). If salvage antiretroviral treatment (when insufﬁcient drug potency occurs, resistance develops, pharmacological issues arise, or poor adherence to other therapies occurs) is needed, a possible replacement for indinavir and ritonavir is nelﬁnavir combined with two nucleoside analogs (268). Nelﬁnavir is either a tablet or a powder to be taken orally, usually three times a day with a meal or a light snack. The powder can be added to a variety of liquids, including water, milk, formula, soy milk, or dietary supplements. All of the liquid must be consumed to obtain the maximum effect of the drug. Children can be given the oral powder with physicians determining the dosage for children under 2 years of age. Chil- dren 2–13 years of age are given doses of 20–30 mg / kg of body
Fig. 2.17 Trade names, structure, and uses of Nelﬁnavir.
weight (9–13.6 mg/lb of body weight) three times a day with food. Adults and teenagers are usually given 750-mg tablets three times a day with food (269). Both nelﬁnavir and indi- navir have no effect on accelerated bone loss (270).
When compared with other PIs, nelﬁnavir has a more favor- able side effect proﬁle (138). The majority of its adverse effects are of mild intensity.
Diarrhea. Diarrhea is the most common side effect, oc- curring in 13 to 20% of treated patients (138). This may be controlled symptomatically with the use of pancreli- pase enzyme preparations.
Upset stomach, gas, or stomach pain. These are usu- ally mild symptoms, but patients may complain of se- vere symptoms or symptoms that do not go away.
Levels of blood sugar. As with the other PIs, new- onset diabetes mellitus, hyperglycemia, and hyper- triglyceridemia have been reported. Patients should be aware that more frequent urination, increased thirst, weakness, dizziness, and headaches may be a sign of developing diabetes. Nelﬁnavir may induce insulin re- sistance and activate basal lipolysis to contribute to the development of diabetes (271). Even with all the negative reports of nelﬁnavir usage on blood sugar lev- els, nelﬁnavir or nelﬁnavir/saquinavir combination therapy can used to replace ritonavir with the likelihood that lipid markers will improve over time. Cholesterol levels do not improve signiﬁcantly and high-density li- poprotein (HDL) cholesterol may rise, but the most sig- niﬁcant results are seen in the lowering of triglyceride levels (272).
Lipodystrophy syndrome and gynecomastia. Changes in body fat are caused by a spectrum of clinical and metabolic abnormalities. These changes may also be responsible for gynecomastia and female breast hyper- trophy. These two emerging effects of antiretroviral therapy may cause less adherence to drug therapy due
to cosmetic and psychological problems in patients (273). Bone marrow fat decreases with nelﬁnavir usage during antiretroviral therapy (274).
Hyperlipidemia. In children treated with protease inhib- itors, hyperlipidemia has not been shown to increase the risk for development of cardiovascular disease (275).
Adhesive capsulitis of the shoulder. Adhesive capsuli- tis, occurring in the shoulder, can be one side-effect of nelﬁnavir therapy. This has been successfully treated by analgesic therapy with calcitonine and physiotherapy for passive mobilization of the shoulders (276).
Coadministration with terfenadine, astemizole, cisapride, triazolam, and midazolam. Caution should be taken with coadministration with terfenadine, astemizole, cisapride, triazolam, and midazolam, be- cause life-threatening arrhythmia or prolonged seda- tion may occur due to the inhibition of the cytochrome P450 pathway.
Genetic resistance. The primary mutation D30N was thought to be the main cause of nelﬁnavir resistance. In one study, 26 of 38 of patients who were nelﬁnavir- resistant had secondary mutations that affected nelﬁ- navir resistance. The remaining two had only one direct mutational substitution (D30N) (277).
Although delta-9-tetrahydrocannabinol (THC) is adminis- tered orally as dronabinol to treat anorexia in AIDS patients, many patients elect to smoke marijuana for easier titration and, perhaps, better effect. Most patients use a cannabinoid to stimulate appetite and manage other antiretroviral side effects. Neither dronabinol nor marijuana is likely to impact PI antiretroviral efﬁcacy (266).
Amprenavir [APV] (Agenerase®)
Amprenavir (APV) received FDA approval in April 1999 and is indicated for use in combination regimens with other
Fig. 2.18 Trade names, structure, and uses of Amprenavir.
antiretroviral agents. The chemical structure, brand names, and approved uses are shown in Fig. 2.18. Interestingly, amprenavir has been shown to lower virus levels in semen as well as in plasma. In addition, treatment in combination with two nucle- oside analogues reduced viral loads to less than 400 copies/ml in 15 of 37 treated pediatric patients in phase III clinical tri- als. Researchers at the University of Texas Southwest Medical Center have found that HIV-infected patients taking PIs spend fewer days in the hospital and have lower overall health care costs, despite the high cost of PI treatment (278). Amprenavir has a long half-life which permits twice-daily dos- ing. It can be taken with or without food and does not require a liquid carrier. Amprenavir should be taken one hour before or one hour after taking antacids or didanosine. For adults, the dosage is 1200 mg twice daily. For patients who weigh less than 50 kg, the dosage is prescribed at 20 mg/kg twice daily for solid formulation or 1.5 ml/kg twice daily for the liquid for- mulation. The simplicity of dosage may be helpful in increasing patient compliance in taking the antiretroviral regimen. Pre- clinical and clinical data indicate that amprenavir is unlikely to cause metabolic disturbances such as lipid and glucose abnormalities and fat redistribution. In addition, there is a distinct resistance proﬁle that permits both naïve and experi- enced PI users to take amprenavir (279).
Grade four toxicity levels occurred for elevated serum creatine phosphokinase levels in 2.8% of patients; elevated triglycerides
in 2.4% of patients; and neutropenia in 2.2% of patients. These are low numbers when compared with other antiretrovirals, and amprenavir is considered to have an acceptable safety proﬁle and is generally well-tolerated with other antiretrovi- ral regimens (279). Patients should not drink alcoholic bever- ages when taking oral amprenavir.
The other chief side effects of amprenavir are usually mild to moderate in intensity and include:
Perioral paresthesias. Some patients experience a tin- gling sensation around the mouth.
Diarrhea. Up to 9% of patients reported diarrhea (279).
Nausea/vomiting. Up to 13% of patients reported nau- sea; 6.7% reported vomiting (279).
Blood sugar levels. Like other PIs, amprenavir has been associated with diabetes mellitus and hyperglyce- mia. Five percent of treated individuals developed grade three toxicity levels for elevated triglycerides.
Acute hemolytic anemia.
Rash. A maculopapular rash develops in 28% of patients, with or without pruritus.
Stevens-Johnson syndrome. Severe skin reactions, such as Stevens-Johnson syndrome, have occurred in
1% of treated patients.
Neutropenia. Grade three toxicity occurred in 3–4% of patients with grade three toxicity for neutropenia.
Central nervous system toxicity. Physicians should monitor patients who receive the oral solution of am- prenavir for possible effects, including stupor, seizures, tachycardia, hemolysis, renal problems, and lactic aci- dosis. The liquid formulation of amprenavir is 55% propy- lene glycol that is used to achieve solubility of amprenavir, whereas the solid form only contains 5% propylene glycol. The liquid form should be used only when the am- prenavir capsules or other PIs will not work with spe- ciﬁc patients (280). There has been one reported case of an HIV-positive patient who developed hallucinations, disorientation, buzzing in the ears, and vertigo when switching from indinavir/ritonavir therapy to am- prenavir oral solution. Once removed from the therapy, he returned to normal (281).
Coadministration with grapefruit juice. Coadminis- tration of amprenavir with grapefruit juice can reduce the maximum concentration of the drug when com- pared with administration with water. However, the concentration curve is not signiﬁcantly challenged so the grapefruit juice does not clinically affect am- prenavir pharmacokinetics (282).
Young children and pregnant women. Children un- der 4 years of age and pregnant women should not take amprenavir liquid.
Liver and kidney disease. Those patients with liver or kidney failure should not take liquid amprenavir.
Coadministration with disulﬁram (Antabuse) or metronidazole (Flagyl). Oral amprenavir should not be prescribed for patients taking disulﬁram or metron- idazole.
Erectile dysfunction. Use of amprenavir with sildena- ﬁl (Viagra) may increase the retention of sildenaﬁl in the body. This could result in low blood pressure, changes in vision, and penile erection lasting more than 4 hours.