Published in the Bulletin of Experimental Treatments for AIDS 1999 Year-End issue, by the San Francisco AIDS Foundation.

Year-End 1999 Table of Contents

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Antiretroviral Pharmacology: Issues and Management

Stephen C. Piscitelli, PharmD

Treatment of HIV infection has become increasingly complicated. Once limited in therapeutic options, clinicians now can choose from 14 different approved antiretrovirals and numerous other agents in clinical trials. Highly active antiretroviral therapy (HAART) today may be a "protease-sparing" regimen built on a foundation of powerful new non-nucleoside reverse transcriptase inhibitors (NNRTIs) and nucleoside reverse transcriptase inhibitors (NRTIs). Alternatively, clinicians may choose "mega-HAART" regimens, immunomodulators, or potentiators (drugs that raise the blood levels of other drugs) such as hydroxyurea (Hydrea). All of these options can be overwhelming for the HIV health-care provider, let alone the patient. This review attempts to provide some perspective on the numerous pharmacologic options currently available.

Nucleoside analog reverse transcriptase inhibitors (NRTIs) are still considered the "backbone" of HIV therapy (Table 1). NRTIs inhibit the HIV enzyme called reverse transcriptase, which allows the HIV RNA to make a DNA copy of itself. This DNA is then integrated into the nucleus of the target cell (i.e., CD4 cell) so that the virus can then use the cell's own machinery to replicate itself. It is important to note that NRTIs are prodrugs that must be converted inside the cell to their active form.

It is this intracellular half-life that determines the dosing interval, not the blood plasma half-life, which is very short (1-3 hours). Because concentrations are sustained inside the cell, nearly all agents in this class can be administered twice daily. Recently, ddI (Videx) was approved as a once-daily drug. All of these agents except ddI, which must be administered on an empty stomach, can be taken without regard to meals.

Hydroxyurea is not an NRTI, but it has been shown to potentiate (augment) the effectiveness of ddI. Several clinical trials have demonstrated the enhanced antiviral effect of NRTIs when combined with hydroxyurea, although the CD4 cell response may be blunted.

Non-nucleoside analog reverse transcriptase inhibitors (NNRTIs) also inhibit HIV reverse transcriptase, but at a different site on the enzyme than the site targeted by NRTIs. Thus, NNRTIs do not compete with NRTIs and drugs from both classes can be given together. Three NNRTIs are currently FDA-approved (Table 2), although numerous other compounds are in various stages of development. Recent data from the DuPont 006 study and the ATLANTIC study (an ongoing multicenter North American and European trial comparing protease-inclusive and protease-sparing antiretroviral regimens) show that NNRTIs combined with two NRTIs are similar in effectiveness to a protease inhibitor-based regimen.

Nevirapine (Viramune) and efavirenz (Sustiva) have long plasma half-lives that exceed 40 hours. Efavirenz is given once daily while nevirapine is administered twice daily, although studies are evaluating a once-daily nevirapine regimen. All NNRTIs have been associated with the development of rash in a significant number of people. Efavirenz also causes transient central nervous system (CNS) related adverse effects including dizziness, disorientation, and vivid dreams, and is usually prescribed to be taken at bedtime to minimize these effects.

Protease inhibitors act on the HIV protease enzyme, which functions as "molecular scissors" to cleave large precursor polyproteins at the end of the HIV life cycle. Of the five protease inhibitors currently available (Table 3), all have problems associated with their formulations. In general, the pill burden involved in this class of antiretrovirals is undesirably large, ranging from six capsules per day with indinavir to 18 capsules per day with saquinavir (Fortovase). In addition, liquid formulations of ritonavir (Norvir) and amprenavir (Agenerase) have a very unpleasant taste.

Many protease inhibitors have food restrictions and need to be taken either with food (saquinavir [Invirase, Fortovase], ritonavir, and nelfinavir [Viracept]) or on an empty stomach or with a low-fat meal (indinavir). Drug interactions are also numerous (see discussion below). Despite these complications, protease inhibitors remain very effective drugs. Indeed, some protease inhibitors have been shown to keep virus fully suppressed for three years and longer. Studies are looking at combining protease inhibitors to design easier-to-take regimens; for example, when indinavir is taken with ritonavir, rather than on an empty stomach, it can be taken twice daily, with food (see discussion below).

Drugs can be classified as substrates, inducers, and inhibitors of the cytochrome P450 (CYP450) enzymes (see following section). A substrate is a drug that is metabolized by these CYP450 system pathways and whose concentrations in the blood may be decreased or increased by the use of concomitant drugs. An inducer is a drug that increases drug metabolism, thus decreasing blood levels of the substrate drugs. For example, rifampin (Rifadin) is a potent enzyme inducer that will decrease levels of the protease inhibitors by as much as 80%. Inhibitors are drugs that impair drug metabolism, decreasing clearance of substrate drugs and thus increasing their blood levels. Ketoconazole (Nizoral) is a classic inhibitor of CYP3A4, and can increase saquinavir levels over 150%.

Drug Interactions

HIV-related medications can trigger numerous drug interactions. Many are minor in nature and do not require any changes to an individual's regimen. Other interactions, however, can lead to life-threatening toxicity and must be avoided. Other drug interactions can be used strategically to maximize the benefits of antiretroviral therapy.

Drug interactions may be pharmacokinetic or pharmacodynamic in nature. Pharmacokinetic drug interactions involve combinations that either increase or decrease the blood levels of one or both of the drugs involved. Pharmacodynamic interactions are those that affect drug efficacy, involving combinations that lead to additive or synergistic toxicity or efficacy.

Most pharmacokinetic interactions are related to the CYP450 system, which all protease inhibitors and NNRTIs can alter, thereby affecting drug metabolism. The CYP450 system is the major drug-metabolizing enzyme system, consisting of many families of enzymes; only a few are important in humans. CYP450 enzymes are classified by families denoted by a number (e.g., CYP3), then by subfamilies by a letter (e.g., CYP3A), and then by specific isozymes (functionally similar enzymes) by a second number (e.g., CYP3A4).

Drug interactions can either be harmful to the individual or can be used to optimize therapy. For instance, concomitant use of protease inhibitors or delavirdine (Rescriptor) with certain nonsedating antihistamines, such as astemizole (Hismanol) and terfenadine (Seldane), or cisapride (Propulsid) can lead to life-threatening arrhythmias (irregularities of the heartbeat) and death. Ergot derivatives, used to treat migraine headaches, also should be avoided since these agents can cause significant peripheral vasoconstriction (narrowing of blood vessel cavities) and ischemia (localized tissue anemia).

Concomitant use of benzodiazepines with protease inhibitors may lead to oversedation in some patients. Sildenafil (Viagra) levels have also been shown to be increased 11-fold with ritonavir and three-fold with saquinavir. To avoid adverse effects when using sildenafil in combination with a protease inhibitor, only a 25 mg dose of sildenafil should be taken and the dose should not be repeated for 48 hours.

It is important to remember that drug interactions are often bidirectional. In other words, antiretrovirals may alter blood levels of concomitant medications, but their own concentrations may be altered as well. For example, rifampin will reduce blood levels of protease inhibitors by 80% or more. This combination should be avoided as it could lead to the development of resistance; people requiring therapy for tuberculosis (TB) may instead take rifabutin (Mycobutin) at the properly adjusted dose (Table 4). Using the NNRTIs efavirenz and nevirapine together with protease inhibitors may require a dosage adjustment since both NNRTIs can decrease protease inhibitor levels (Table 4).

The use of dual protease inhibitors to increase drug levels in the plasma, enhance efficacy, decrease pill burden, and improve adherence has become an important feature of many HIV regimens. The inhibition of CYP3A4 by ritonavir can improve the pharmacokinetic profile of the second protease inhibitor and result in a greater antiviral effect.

Saquinavir (Fortovase formulation) bioavailability is poor and requires administration of 18 capsules per day, given as the sole protease inhibitor. In combination with ritonavir, however, saquinavir levels increase 20-fold or more, allowing for a dosage reduction with fewer pills. With 400 mg twice daily of ritonavir, the dose of saquinavir can be reduced from 1,200 mg three times daily to 400 mg twice daily. Nelfinavir can also increase saquinavir concentrations by about five-fold; the dose of saquinavir should be lowered to 800 mg three times daily or 1,200 mg twice daily when using this combination.

Recently, combination ritonavir/indinavir (Crixivan) has gained much attention since the problematic food restrictions and three times daily dosing of indinavir can be overcome with this combination. Indinavir must be taken every eight hours either on an empty stomach or with a light, fat-free snack. Its trough (lowest) concentrations are variable, and blood levels of the drug may fall below the IC90 (the drug concentration that eliminates 90%) of HIV at the end of the dosage interval.

Combining indinavir with ritonavir allows for twice-daily dosing with food, and increased indinavir trough concentrations. Three twice-daily regimens are being evaluated: 800 mg/100 mg, 800 mg/200 mg, and 400 mg/400 mg. Ongoing trials will determine which regimen is best. Higher indinavir doses may increase the risk of kidney stones, but since those regimens contain lower doses of ritonavir, they may be better tolerated.

Dual administration of nelfinavir and indinavir also leads to increased concentrations of both drugs, with a 51% and 83% increase in indinavir AUC (area under the curve, a measure of the concentration of a drug in the bloodstream over a defined period of time, usually 24 hours) and nelfinavir AUC, respectively.

Similarly, Abbott Laboratories' investigational protease inhibitor, ABT-378, is being administered with ritonavir to produce high and sustained concentrations throughout the twice daily dosing interval. Combining low-dose ritonavir (100 mg) and ABT-378 with NRTIs or NNRTIs produces a potent antiretroviral combination in clinical studies.

Many medications used in the treatment of HIV infection have overlapping toxicities (Table 5). While it is always best to choose drugs with different side effect profiles, doing so often is not an option due to previous response, intolerance, or resistance. Evaluating adverse effects may be challenging, especially when multiple drugs with the same side effect profiles are being used concomitantly. This situation is further complicated by the fact that other disease processes (e.g., hepatitis) may be causing the problem.

For instance, various medications used in treating HIV disease cause neutropenia (an abnormally low number of neutrophils, a type of white blood cell), including AZT (Retrovir), cidofovir (HPMPC, Vistide), TMP-SMX (Bactrim, Septra), and ganciclovir (Cytovene). In many cases, supportive care with G-CSF (Neupogen) may be required to continue the regimen. Other examples of overlapping toxicities include nephrotoxicity (kidney damage) with adefovir (Preveon) and foscarnet (Foscavir) or pancreatitis with ddI and pentamidine (Pentam). These toxicities generally require discontinuation of medications. For other, specific side effects, such as diarrhea or nausea, reduced dosages or supportive medications (e.g., antidiarrheals, antiemetics) are often sufficient for managing these toxicities, so that changing the regimen is not required.

A common dilemma involves trying to identify the drug causing the adverse effect. For example, rifabutin, efavirenz, and hydroxyurea all are associated with increases in liver function tests. In fact, numerous drugs are associated with increasing liver function tests, including all antiretrovirals, antifungal, and anti-tuberculosis (antimycobacterial) drugs. One strategy is stopping all medications until the side effects resolve and then restarting the drugs sequentially, as tolerated.

Alternatively, single drugs may be removed one by one, and/or substituted in the regimen to see if the laboratory values resolve. Single drug changes and sequential addition of antiretroviral agents are not ideal in the treatment of HIV infection; therefore, the decision of how to manage side effects needs to be carefully considered.

The syndrome of lipodystrophy and metabolic complications such as hyperlipidemia (excess lipids or fat in the blood) and hyperglycemia (excess sugar in the blood) also appear to be caused by many antiretrovirals. While protease inhibitors originally were considered to be the causative agents, it is now clear that NRTIs and NNRTIs also are associated with these effects. Some of these syndromes have also been reported in people who have never received antiretroviral therapy. Various studies are evaluating alternative treatment strategies (e.g., switching to a new class of drugs), antilipid therapy with statins and fibrates, and therapy with metformin (Glucophage) for hyperglycemia. In addition, a great deal of research is ongoing to discover the mechanism behind these adverse effects.

Many of the current antiretrovirals have a large pill burden, which means that a large number of capsules or tablets must be swallowed each day. As mentioned earlier, regimens containing protease inhibitors require taking anywhere from six capsules per day (indinavir) to 18 capsules per day (saquinavir). For some people, the number of pills taken each day may exceed 40, a factor that often leads to poor adherence. Newer formulations of many antiretrovirals are now available (e.g., Combivir) or in clinical development (e.g., a new formulation of amprenavir) to reduce the large pill burden. Some regimens, such as abacavir (Ziagen) and Combivir or nevirapine and Combivir, may entail as few as four pills per day. Ideally, individuals with HIV and their providers will work together to develop a convenient and effective regimen.

Many anti-HIV drugs are now available in liquid formulations for use by children or by adults with dysphagia (painful or difficult swallowing). AZT, ddI, d4T (Zerit), 3TC (Epivir), ritonavir, amprenavir, and nelfinavir are all available in liquid or powder form. Because the ritonavir and amprenavir solutions are unpalatable to many people, a variety of methods have been tried to improve the taste (including taking the solutions with chocolate, shredded wheat, or peanut butter).

Storage

All medications, HIV-related or otherwise, should be kept out of the reach of children. Outdated medications should be discarded. In general, drugs should be kept in a cool, dry area, away from excessive heat, light, and moisture. Medications should not be stored in rooms that may be damp, such as the kitchen or bathroom.

Some antiretrovirals have specific storage requirements. Indinavir is sensitive to moisture and should be kept in its original container, which contains several desiccants (drying agents). A one-day supply may be removed and kept in a smaller vial with a desiccant for convenience. Indinavir should not, however, be placed in a one- or two-week pillbox for storage.

Although saquinavir and ritonavir may be left at room temperature for 30 days after dispensing, these formulations are best stored in the refrigerator. Excessive heat will alter the pills or cause them to congeal and stick together.

Storage problems are especially difficult for homeless persons or those living in shelters or temporary housing.

Conclusion

In addition to the 14 currently available antiretrovirals, numerous agents are in clinical development. While most of the newest drugs are in the three classes of agents now available, most also have an additional advantage or benefit. For example, a new drug may have once-daily dosing, a better resistance profile, or improved tolerability. Other drugs in development with novel mechanisms of action-such as the fusion inhibitor T-20-are being studied. (T-20 is limited, however, by the fact that it must be administered subcutaneously.)

The best antiretroviral strategies are those that achieve plasma drug levels well in excess of the concentrations needed to inhibit viral replication. The protease inhibitor ABT-378/r and dual protease inhibitor combinations (e.g., indinavir/ritonavir) are currently among the most promising strategies against HIV, which continues to be an elusive virus.

Stephen C. Piscitelli, PharmD, is a member of the Clinical Center Pharmacy Department at the National Institutes of Health.

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Page last updated 8 January 2000