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* AIDS/HIV
Psychosomatics 45:262-270, June 2004
© 2004 The Academy of Psychosomatic Medicine

Antiretrovirals, Part 1: Overview, History, and Focus on Protease Inhibitors

Gary H. Wynn, M.D., Michael J. Zapor, M.D., Ph.D., Benjamin H. Smith, M.D., Glenn Wortmann, M.D., Jessica R. Oesterheld, M.D., Scott C. Armstrong, M.D., F.A.P.M., and Kelly L. Cozza, M.D., F.A.P.M.

From the Department of Medicine, Walter Reed Army Medical Center; and the Uniformed Services University of the Health Sciences F. Edward Hébert School of Medicine, Bethesda, Md. (Drs. Wynn, Zapor, Smith, Wortmann, and Cozza). Dr. Oesterheld is the Medical Director of the Spurwink School, Portland, Me., and an Instructor of the Family Medicine Program at the University of New England School of Osteopathy, Biddeford, Me. Dr. Armstrong is the Co-Medical Director, Center for Geriatric Psychiatry, Tuality Forest Grove Hospital, Forest Grove, Ore., and Associate Clinical Professor of Psychiatry, Oregon Health Sciences University, Portland, Ore. Drs. Cozza, Armstrong, and Oesterheld are co-authors of the Concise Guide to Drug Interaction Principles for Medical Practice: Cytochrome P450s, UGTs, P-glycoproteins, 2nd edition. (American Psychiatric Publishing, Inc., 2003). Address all correspondence to Dr. Cozza, Psychiatrist, Infectious Disease Service, Ward 63, Department of Medicine, Walter Reed Army Medical Center, 6900 Georgia Ave., Washington, DC 20307-5001; kelly.cozza{at}na.amedd.army.mil (e-mail).
The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of the Army or the Department of Defense.

ABSTRACT

This column is the first in a series on HIV/AIDS antiretroviral drugs. This first review summarizes the history of HIV/AIDS and the development of highly active antiretroviral therapy (HAART) and highlights why it is important for non-HIV specialists to know about these drugs. There are four broad classes of HIV medications used in varying combinations in HAART: the protease inhibitors, nucleoside analogue reverse transcriptase inhibitors, the non-nucleoside reverse transcriptase inhibitors, and cell membrane fusion inhibitors. This paper reviews the mechanism of action, side effects, toxicities, and drug interactions of the protease inhibitors.

Human immunodeficiency virus/autoimmune deficiency syndrome (HIV/AIDS) patients now meet many health care providers as they navigate through the course of their illness. The panoply of antiretrovirals can be daunting to the non-HIV specialist. Our colleagues at Walter Reed Army Medical Center’s Infectious Disease Service present an overview of the antiretrovirals. This multi-part synopsis is intended to provide succinct information regarding the potential side effects, toxicities, and drug interactions of medications commonly used in the management of the HIV-infected patient. Up-to-the-minute information on these medications, including dosing strategies, may be found at websites such as www.medscape.com/hiv/aids, and http://hivinsite.ucsf.edu/

We start with a brief overview of the history of HIV/AIDS and the development of treatment approaches, with special focus on the mechanism of action, side effects, toxicities, and drug interactions of the protease inhibitor class of antiretrovirals. Future topics in this series will include the nucleoside reverse transcriptase inhibitors (NRTIs), the non-nucleoside reverse transcriptase inhibitors (NNRTIs), the cell membrane fusion inhibitors, and a summary of the interactions of all of these classes with illicit and abused substances/drugs.

>Why Is Antiretroviral Knowledge Important to the Non-HIV Specialist?
As HIV-infected patients receive better treatment options, what was once viewed as a relentless and progressive fatal disease is now seen as a chronic and manageable long struggle with complicated treatments and their effects. There are many patients in our clinic who are living productive and relatively healthy lives while having carried the virus with them since the mid-1980s. With longevity comes a broader need for health care. HIV patients’ general health care is now frequently provided by primary care and psychiatry, particularly if a patient is thought to be medically nonadherent.

Highly active antiretroviral therapy (HAART) became available in 1996 and generally includes at least three different antiretrovirals administered in combination (sometimes referred to as a "cocktail"), which results in tremendous pill burdens, side effects, toxicities, and complicated drug interactions. Strict adherence to the "cocktail" is imperative to limit the development of viral resistance to HAART. Henry1 states, "... the major goal of HIV treatment is to maintain the long-term health of the patient while avoiding drug-related toxicity and preserving viable future treatment options."

Noxious side effects, adverse drug reactions, and drug interactions may lead to nonadherence to HAART, placing the patient at risk for treatment failure. Ammassari et al.2 surveyed adherence and side effects and reported that "nausea, anxiety, confusion, vision problems, anorexia, insomnia, taste perversion and abnormal fat distribution were significantly associated with non-adherence." Heath et al.3 found 70% of HIV patients who participated in a cross-sectional survey were intentionally nonadherent to their treatment over the preceding year. The subjects with one severe symptom or side effect from their antiretrovirals were twice as likely to report intentional nonadherence, and the risk of nonadherence increased with each additional side effect. Psychiatric patients are at increased risk of nonadherence.4,5 In another cross-sectional survey,6 HIV patients identified as psychologically disordered on the General Health Questionnaire had significantly worse adherence to their antiretroviral regimens than those HIV patients surveyed without psychological symptoms.

THE PROTEASE INHIBITORS

Presently, there are four broad classes of HIV medications which collectively comprise HAART: 1) protease inhibitors, 2) nucleoside analogue reverse transcriptase inhibitors (NRTIs), 3) non-nucleoside reverse transcriptase inhibitors (NNRTIs), and 4) cell membrane fusion inhibitors. The protease inhibitors are selective, competitive inhibitors of protease, an enzyme crucial to viral maturation, infection, and replication. The NRTIs inhibit viral replication by interfering with viral RNA-directed DNA polymerase (reverse transcriptase). Similarly, NNRTIs inhibit viral replication by acting as a specific, non-competitive reverse transcriptase inhibitor, disrupting that enzyme’s catalytic site. The recently introduced cell membrane fusion inhibitor enfuvirtide (Fuzeon®) blocks uptake of the virus by the lymphocyte.

Protease inhibitors constitute the largest class of drugs in the current fight against HIV. They act at a very late stage in the HIV replication process. When the virus infects a cell, the cell’s replication systems are shifted or coerced to making lengthy precursor viral proteins under the direction of the virus. These precursors are bunched together as they prepare to bud out of the cell, causing cell lysis and death. Right before the proteins leave the cell, they need to be cleaved by a protease enzyme called "HIV protease" (a member of the aspartyl-protease enzyme family, which includes renin and pepsin). The protease inhibitor class of medications stops the cell’s ability to cleave the proteins into active viral particles.

The benefit of acting at such a late stage in replication is the relative small locus of activity. The requirement for all viral proteins to be enzymatically cleaved at this location creates a bottleneck and allows for a very specific and effective means of disrupting viral replication. The downside of this mechanism is that it only blocks the end result rather than initiation of infection. In essence, it is a virastatic rather than viracidal effect.

Generalizations About Protease Inhibitors
Problems that arise from all the protease inhibitors include gastrointestinal disruptions, dysfunctions of lipid and glucose metabolism, sexual dysfunction, hepatic toxicity, and increased risk of bleeding. There are also drug-drug interactions that are common to the entire class.

Gastrointestinal effects:
Many patients experience a myriad of gastrointestinal symptoms when either initiating protease inhibitor therapy or changing from one regimen to another. These symptoms frequently cause discontinuation of therapies and can be a major hurdle to effective treatment. d’Arminio Monforte et al.7 found that 25% of patients discontinued therapy because of the toxicity of their regimen. Nausea and vomiting are among the most frequent complaints, with some studies as high as 75%.8 These symptoms generally abate over 4–6 weeks of therapy, but some patients continue to experience symptoms indefinitely. Monitoring and treatment of these symptoms can be among the most clinically relevant interventions.9 Tayrouz et al.10 found that ritonavir increased the levels of loperamide three-fold, indicating that less loperamide may be necessary for effect. Patients need to be warned about loperamide toxicity if they are switched from another medication to ritonavir. In patients with severe gastrointestinal distress and wasting with concomitant depression, we find that the tricyclic antidepressants can help greatly with loose stools, poor appetite, and weight loss as well as with mood. Careful blood-level monitoring of the tricyclics is important, especially with a "pan-cytochrome P450 inhibitor" like ritonavir, but this is easily accomplished, and a great guide to therapeutic monitoring.

Lipodystrophy, hyperglycemia, and hyperlipidemia:
Lipodystrophy is fat redistribution with accumulation of neck and abdominal fat, occassionaly a "buffalo hump," and is usually associated with loss of facial, buttocks, and extremity fat. It is resistant to treatment, often not reducing even with discontinuation of the offending agent. Some patients become unrecognizable from their pretreatment body habitus and facial features. Many are turning to plastic surgery for some relief. Glucose intolerance, sometimes leading to diabetes and frank diabetic ketoacidosis, has been increasingly reported.11,12 Hyperlipidemia is closely associated with both hyperglycemia and fat redistribution, and may place HIV patients receiving HAART at increased risk of cardiovascular disease.13 Protease inhibitors suppress the breakdown of the nuclear sterol regulatory element binding proteins (nSREBP) in adipose tissue. Suppressing the breakdown of nSREBP results in increased fatty acid and cholesterol biosynthesis in the liver, leading to lipodystrophy and insulin resistance in adipose tissue.14 The combination of protease inhibitors with lipid-lowering agents or "statins" may lower lipid levels and possibly reduce cardiovascular risk but may also lead to rhabdomyolysis if a statin is chosen that is incompatible with the protease inhibitors (see "Inhibition" section).

Sexual dysfunction:
Sexual dysfunction occurs very commonly with regimens containing protease inhibitors,15 more than most other therapies. Some studies, such as that of Lallemand et al.,16 found the rate of sexual dysfunction as high as 70% with protease inhibitor therapies. Thus far, research has not identified the cause of decreased libido, erectile dysfunction, and delayed ejaculation as a result of protease inhibitor therapy. Sildenafil (Viagra®) must be used with care in combination with ritonavir and saquinavir because of inhibition of sildenafil’s cytochrome P450 3A4 metabolism.17 Patients are warned not to exceed 25 mg in a 48-hour period to avoid increased risk of side effects of sildenafil.18 This interaction is likely to occur with all protease inhibitors. Protease inhibitors have not been specifically studied in vitro or in vivo in combination with the newer erectile dysfunction drugs vardenafil (Levitra®) and tadalafil (Cialis®).

Liver toxicity:
All drugs in the protease inhibitor class have been associated with liver injury, most commonly with high dose ritonavir. About one-third of all protease inhibitor-treated patients experience some liver-associated enzyme elevations because of the initiation or adjustment of a protease inhibitor regimen, but these toxicities are usually mild and transient.19,20 Co-infection with hepatitis C or hepatitis B virus is an important risk factor for potential liver injury due to protease inhibitors.21 Alcohol intake can also increase the risk of liver injury.19

Drug-drug interactions:
Drug interactions account for many of the complications from HAART. The following subsection will review metabolic inhibition and induction of and by the protease inhibitors as well as P-glycoprotein interactions.

Inhibition is when a drug or other compound blocks or reduces the activity of metabolic enzymes. The net effect is usually to increase parent compound and its effects while preventing the production of metabolites and restricting elimination. All protease inhibitors are inhibitors of metabolism in the cytochrome P450 system, specifically at the 3A4 enzyme. The same warnings apply to the protease inhibitors as to ciprofloxacin (Cipro®), clarithromycin (Biaxin®), diltiazem (Cardizem®, Tiazac®, and others), erythromycin (E-mycin® and others), itraconazole (Sporanox®), ketoconazole (Nizoral®), and nefazodone (Serzone®). These drugs all inhibit 3A4 metabolism and can greatly affect drugs with narrow therapeutic indices. For example, a patient taking carbamazepine developed vomiting, vertigo, and elevated liver enzymes with increased serum concentrations of the anticonvulsant within 12 hours of the first dose of ritonavir.22 Patients taking anti-migraine medications containing ergotamine who are started on ritonavir regimens risk loss of limbs or death from ergotism.23,24

Other protease inhibitors, although less potent 3A4 inhibitors than ritonavir, have also demonstrated clinically significant inhibition. There have been several case reports of rhabdomyolysis caused by the interaction of a protease inhibitor with HMG-CoA reductase inhibitors or "statins." The interaction of simvastatin (Zocor®) and nelfinavir (Viracept®) caused severe rhabdomyolysis and death.25 As a general rule, simvastatin should not be prescribed with a protease inhibitor. Nelfinavir significantly increased levels of atorvastatin (Lipitor®) through inhibition of CYP 3A4 while having no interaction with pravastatin (Pravachol®).26–28 Liver transplant patients may develop sirolimus and tacrolimus toxicity from protease inhibitor interactions.29,30

Protease inhibitor metabolism is also affected by other potent 3A4 inhibitors, since all protease inhibitors are metabolized at the 3A4 enzyme. Any drug with a more potent 3A4 inhibition may slow the metabolism of the protease inhibitor. Ritonavir and ketoconazole are considered two of the most potent 3A4 inhibitors in current use, and the other potent inhibitors that may affect the rest of the protease inhibitors include ciprofloxacin, clarithromycin, diltiazem, erythromycin, itraconazole, nefazodone, and grapefruit juice. Inhibition of protease inhibitor metabolism by these agents may increase protease inhibitor effectiveness or lower the necessary dose (as is seen when ritonavir is used to augment other protease inhibitors or lopinavir). Inhibition of protease inhibitor metabolism may also worsen side effects and toxicity, placing patients at greater risk of headache, nausea, and diarrhea as well as hepatitis and pancreatitis and may also lead to nonadherence. More important, the discontinuation of the more potent inhibitor co-prescribed with a protease inhibitor would result in a rapid return to the uninhibited state and may quickly reduce circulating levels of the protease inhibitor, placing the patient at risk for developing viral resistance to this class of drug.

Induction is when a drug or other compound increases or "revs up" the activity of metabolic enzymes, usually by enhancing the synthesis of the metabolic machinery itself, increasing the number of sites available for further metabolism. The net effect is usually to decrease parent compound and its effects while enhancing the production of metabolites and increasing the amount of drug ready for elimination. Rifamycins, carbamazepine (Tegretol®), phenytoin (Dilantin®), ethanol, and barbiturates are "pan-inducers" of multiple cytochrome P450 enzymes. St. John’s wort, efavirenz (Sustiva®), and nevirapine (Viramune®) are all specific 3A4 inducers.31,32 Hamzeh et al.33 found that coadministration of indinavir (Crixivan®) and rifabutin caused both significant increases in rifabutin levels and decreases in indinavir levels. Induction of protease inhibitor metabolism may reduce circulatory levels of the protease inhibitor, placing the patient at risk for developing viral resistance, which leads to HIV treatment failure.34

P-glycoproteins can be inhibited and induced. P-glycoproteins are found in many sites, including the villus tips of enterocytes in the jejunum (often right next to gut-wall cytochrome P450 3A4 enzymes) and in the endothelial cells of the blood-brain barrier.35 They are responsible for effluxing or "pumping out" substances from cells. They are the "gatekeepers" that influence the bioavailability and pharmacokinetics of drugs in the gut and liver and prevent drug penetration into the brain, testes, and placenta. Protease inhibitors are all substrates of P-glycoproteins, which may explain why it is difficult for antiretrovirals to adequately penetrate the blood-brain barrier and other sanctuaries.

When inhibited, P-glycoproteins no longer keep compounds out of the areas they protect, and drug concentration may increase if the drug in question is a P-glycoprotein substrate. Loperamide (Imodium®), a P-glycoprotein substrate, is an opiate-based antidiarrheal that is normally transported out of the brain, thwarting any CNS opiate effect. When P-glycoprotein inhibitors like quinidine are administered with loperamide, opiate toxicity and respiratory depression may occur.36 P-glycoproteins may also be induced by drugs like St. John’s wort,37 making the P-glycoproteins even more effective at keeping compounds out of the cells they protect.

P-glycoproteins may be responsible for or may enhance many of the drug-drug interactions found with the protease inhibitors.38–40 Ritonavir initially inhibits P-glycoprotein, which may allow for other substrates to then "pass" the barrier and achieve higher serum levels in the circulation, either at the gut wall or the blood-brain barrier. This P-glycoprotein inhibition in conjunction with 3A4 inhibition would have an additive inhibitory effect and would raise drug levels of dual P-glycoprotein and 3A4 substrates more than expected. In vitro, extended exposure to ritonavir then induces P-glycoprotein protein expression, reducing the drug’s ability to "pass the barrier" and effectively diminishing the bioavailability of the P-glycoprotein substrate.41 Lopinavir exhibits the same pattern of initial inhibition then induction of P-glycoproteins as ritonavir.42 There are reports of protease inhibitors apparently inducing the metabolism of drugs such as methadone, and it may be that P-glycoprotein effects are part of the explanation.43–45

Specifics About Each Protease Inhibitor
The currently available protease inhibitors are presented in Table 1, with their most common dosages, daily pill burden, drug and food interactions, side effects and toxicities, and a list of contraindicated co-medications. Protease inhibitor metabolism is summarized in Table 2. A few of the protease inhibitors deserve special mention.


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TABLE 1. Currently Available Protease Inhibitorsa




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TABLE 2. Protease Inhibitor Metabolisma



Atazanavir (Reyataz®):
Atazanavir is both metabolized by and inhibits the cytochrome P450 3A4 enzyme. In addition, atazanavir inhibits a phase II glucunoridation enzyme UGT 1A1. UGT 1A1 is responsible for the metabolism of hemoglobin. According to the Reyataz® package insert, inhibition of this phase II enzyme results in inefficient metabolism of hemoglobin and may lead to direct or unconjugated hyperbilirubinemia.

Ritonavir (Norvir®):
Ritonavir is the most potent 3A4 inhibitor in the protease inhibitor group. In vitro studies have found its inhibitory potency to be slightly less than that of ketoconazole, with amprenavir being an order of magnitude less.57 Ritonavir also is a potent inhibitor of the 2D6, 2C9, and 2C19 enzymes. In vitro, ritonavir is also a moderate inhibitor of the 2B6 enzyme, which is a major metabolic site for buproprion (Wellbutrin®).58 Theoretically, ritonavir may inhibit the metabolism of buproprion, possibly increasing the risk of side effects and toxicity, including seizures. It is important to note that despite widespread clinical use, there have been no published studies or case reports of this interaction. Some examples of inhibition by ritonavir were given under an earlier section. Jover et al.59 described a manic HIV patient being treated with ritonavir who became comatose after receiving two risperidone doses of 3 mg each. According to the Norvir® package insert, ritonavir inhibits risperidone’s cytochrome P450 metabolic sites 2D6 and 3A4. Ritonavir with indinivir also resulted in new-onset of extrapyramidal symptoms when co-administered with risperidone.60 Greenblatt et al.61 utilized a single-dose, blinded, four-way crossover study in healthy volunteers to demonstrate that initial and short-term exposure to ritonavir reduced clearance, prolonged half-life, and increased plasma concentrations of trazodone, as well as increased sedation, fatigue, and worsened performance. Trazodone is metabolized at 3A4, and its active metabolite is metabolized at 2D6.62 Zolpidem is metabolized at 3A4. We have had patients treated with ritonavir who experienced >15 hours of sedation with a single 5-mg dose of zolpidem.

Some ritonavir interactions may take longer to become apparent. An HIV patient taking ritonavir was administered the glucocorticoid budesonide (Entocort®) for radiation colitis. Within 14 days the patient had developed acute hepatitis (ALT=660).63 Budesonide is used for inflammatory bowel disease because its 90% first-pass clearance allows high dosage within the lumen of the bowel. When 3A4 metabolism of budesonide was inhibited by ritonavir, a large amount of the drug accumulated, which led to hepatic parenchymal damage. There have been case reports of patients taking ritonavir who developed Cushing’s syndrome after 5 months of inhaled fluticasone (Flovent) due to ritonavir’s inhibition of 3A4 metabolism of the corticosteroid.64,65 Although inhibition of the substrates at 3A4 was immediate, the pharmacodynamic effects of the higher concentrations of substrate became apparent over time.

Ritonavir, after several weeks, also induces 3A4 metabolism. The balance between induction and inhibition can be quite variable and often unpredictable, ranging from net inhibition to net induction. This necessitates close clinical monitoring for several weeks when introducing ritonavir to a patient. Ritonavir has been found to increase or induce the metabolism of meperidine, resulting in increased levels of the neurotoxic metabolite normeperidine, and has been found to reduce the AUC and Cmax of ethinyl estradiol,34,66 placing patients at risk for breakthrough bleeding and pregnancy. Ritonavir is also an inducer of the enzymes 1A2, 2C9, and 2C19. In one case study, a patient maintained on a regimen of acenocoumarol (a mixture of R- and S-warfarin, metabolized at 1A2 and 2C9, respectively) was initiated on ritonavir therapy. The patient’s INR decreased dramatically even when the dose of acenocoumarol was tripled.67 As noted earlier, ritonavir may also be a P-glycoprotein inhibitor and inducer.

Lopinavir-Ritonavir (Kaletra®):
Lopinavir/ritonavir is a combination drug containing ritonavir and lopinavir. Ritonavir, via 3A4 inhibition, increases lopinavir plasma levels for improved clinical results. Interestingly, lopinavir induces glucuronidation. This phase II metabolism induction can greatly reduce levels of the NRTIs zidovudine and abacavir, reducing effectiveness and resulting in viral resistance. Lopinavir has also been found to be a P-glycoprotein inhibitor and inducer.42 This complicated pharmacokinetic and P-glycoprotein profile has led to some unexpected clinical findings.

Lopinavir/ritonavir has led to increases in tacrolimus blood concentrations via 3A4 inhibition,30,68 and decreases in blood concentration (increased clearance) of methadone and ethinyl estradiol. In vitro, lopinavir/ritonavir also inhibits 2D6 metabolism, but clinical studies are pending (personal communication from C. Koch, Pharm.D., Medical Information Specialist, and R. Hodd, M.D., Medical Director, Abbott Laboratories, December 19, 2000).

SUMMARY

Antiretroviral drugs have dramatically changed the survival rate for HIV/AIDS. They are also a complicated group of medications with significant side effects, toxicities, and drug interactions. Non-HIV specialists will encounter patients taking antiretrovirals and will be faced with assisting with the life-changing complications these drugs bring to HIV/AIDS patients. The protease inhibitors are the group with the most difficult drug-drug interactions to monitor. In brief, all protease inhibitors may cause nausea, diarrhea, headache, sexual dysfunction, hepatic toxicity, and risk of bleeding. Lipodystrophy, glucose intolerance, and hyperlipidemia result in grave morbidity. All protease inhibitors are susceptible to significant drug-drug interactions. All protease inhibitors are inhibitors of the cytochrome P450 3A4 enzyme, and ritonavir is a "pan-inhibitor" of multiple P450 enzymes. This pattern of enzyme inhibition may slow the metabolism of co-administered drugs and may cause frank toxicity, including death, with drugs that have narrow therapeutic indices and must be metabolized via the enzymes that protease inhibitors inhibit. Ritonavir and lopinavir/ritonavir combination drugs also induce cytochrome P450 enzymes and may reduce the effectiveness of co-administered drugs like oral contraceptives or immunosuppressants for organ transplants. The protease inhibitors also have provided clinical evidence of the importance of P-glycoproteins in the maintenance of effective drug concentrations. All protease inhibitors are substrates of P-glycoproteins, which limits oral availability and blood-brain barrier penetration of these agents. Ritonavir and lopinavir seem to be dual inhibitors and inducers of P-glycoproteins, making predictions about potential drug interactions difficult. A working knowledge of the protease inhibitors—including the pill burdens, side effects, toxicities, and drug interactions of these therapies—is of benefit for all clinicians.

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