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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 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.

Adverse Events

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:

Diarrhea. Nausea.

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).

Special Considerations

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).

Adverse Events

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).

Special Considerations

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).

Adverse Events

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).

Gilberts 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).

Special Considerations

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).

Adverse Events

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).

Special Considerations

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).

Adverse Events

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.

Special Considerations

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.

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