HIV/AIDS Pharmacotherapy

Fifteen years into the global AIDS epidemic, a cure remains elusive. But for many patients, early, aggressive, and well- managed use of new combination therapies is paying off in improved functioning, lower rates of opportunistic infections, and prolonged survival. Here's a look at the latest strategies.

Manohar L. Sethi

Over 30 million people worldwide are infected with HIV. Since the first cases of AIDS were reported in the United States in the early 1980s, approximately five million new cases of HIV infection have been reported to the Centers for Disease Control and Prevention (CDC). Current CDC statistics on AIDS case distribution by sex, ethnicity, and age at diagnosis are presented in Figure 1. Various kinds of drugs are used to treat AIDS patients, but none cures the disease. The main impediment to progress toward eradicating HIV infection is that the virus mutates rapidly and quickly becomes resistant to drug therapy, posing an ongoing challenge in terms of both infection control and disease treatment. Pharmacists have assumed an increasingly important role in monitoring and fine-tuning HIV drug therapy for maximal effectiveness. To fulfill this role, pharmacists need to be knowledgeable about the expanding host of anti-HIV drugs. This article explores the drug properties of the currently available agents, including their chemistry, pharmacokinetics, side effects, adverse effects, toxicity, and drug interaction potential. It also offers basic guidance on the optimal use of these agents in management of HIV infection.

Rationale of Drug Therapy
AIDS is a retroviral infection caused by HIV. Retroviruses contain an RNA-directed DNA polymerase, reverse transcriptase (RT), and HIV proteases. Both enzymes play an important role in the HIV life cycle. RT forms a "provirus" that integrates into host cell DNA and multiplies by utilizing the metabolic activity of the host cell. HIV enzymes direct the infected cells to produce viral proteins and assemble into the viral particles. HIV proteases release viral particles from the infected cells via a budding process. The complete virus infects other normal cells and attacks the body's immune system by impairing the activity of T-cell lymphocytes of white blood cells. In advanced HIV infection there is a loss of immunity and development of AIDS-related diseases called opportunistic infections.

Two broad categories of drugs are used to treat HIV infection: RT inhibitors, which are effective in treating the initial infection but are less effective in later stages of HIV disease because of rapid mutation of the virus; and protease inhibitors (PIs), which block the formation and release of viral particles from the infected cells. Although each type of drug is used to treat AIDS, combined use of RT inhibitors and PIs has a synergistic effect in decreasing the viral load to a negligible limit. Thus combination ("cocktail") treatment consisting of three anti-HIV drugs, including one or two PIs, produces an optimal antiretroviral effect. Combined use of RT inhibitors and PIs has increased drug therapy compliance and survival rates. For optimal effect, however, it is suggested that anti-HIV treatment be started as soon as possible following the diagnosis of HIV infection. Ongoing measurement of viral load, tolerability of drugs, and pharmacokinetic interactions are among the key factors in the pharmacologic management of AIDS patients.

The RT inhibitor zidovudine (ZDV) was the first drug used in AIDS patients. While ZDV prolonged the life of patients, it failed to eliminate viral infection. Side effects and viral resistance to ZDV posed other major hurdles. To overcome these difficulties, ZDV was combined with other RT inhibitors, but these combinations still did not produce adequate disease control, ostensibly because of the drugs' single mode of action.

New FDA-approved PIs have gained importance because of their ability to reduce HIV viral plasma load and increase CD4⁺ cell counts. Although PIs have an advantage over RT inhibitors, development of PI resistance and toxicity are limiting factors in management of AIDS patients. A new approach to treating AIDS patients involves use of combination therapy including one or more RT inhibitors and a PI. These double- or triple-drug combinations have proved more effective in saving lives and reducing treatment costs, as such combinations act on different cell cycles of viral infection. Another investigative approach to treating AIDS is to combine anti-HIV drugs with immunomodulators and agents that inhibit HIV from binding, fusion, and entry to host cells.

RT Inhibitors
RT is an RNA-directed DNA polymerase present in retroviruses that cause AIDS and certain types of leukemia. Retroviruses, with the help of RT, direct the synthesis of a DNA copy (proviral DNA). The proviral DNA integrates into the host DNA and directs the infected cell to produce retroviral proteins. The latter are assembled to form retroviral particles that infect normal cells to cause AIDS and AIDS-related-complex diseases. RT inhibitors are used in AIDS to check retroviral proliferation. Two types of RT inhibitors are discussed below.

Nucleoside Agents
These drugs include ZDV, ddI, ddC, D4T, and 3TC. Zidovudine, or ZDV (Retrovir),¹⁵ was the first anti-HIV drug approved by the FDA. Chemically, it is a dideoxy-nucleoside, 3'-azido-2',3'-dideoxythymidine (AZT). ZDV is well absorbed after oral administration and its bioavailability is 66%. The plasma half-life of ZDV is one hour. The cerebrospinal fluid:plasma ratio of ZDV is approximately 0.60.

ZDV does not cure AIDS but prolongs life by increasing CD4⁺ cell counts. Early use of ZDV is recommended to delay opportunistic infections and improve immunological response.¹⁶ ZDV has interaction potential with amphotericin, flucytosine, ganciclovir, phenytoin, probenecid, methadone, pentamidine, and pyrimethamine. ZDV has toxic effects, which include bone marrow suppression, as indicated by granulocytopenia, anemia, and myopathy.¹⁷ ZDV is recommended for both symptomatic and asymptomatic patients when CD4⁺ cell counts fall below 500 cells/mm³. After about nine months of therapy with ZDV, HIV resistance develops.¹⁸

Didanosine,¹⁹ 2', 3'-dideoxyinosine or ddI (Videx), is a purine dideoxynucleoside formed from ddA by deamination. The oral bioavailability of the drug is approximately 25% at doses of 7 mg/kg or less. The concentration of ddI in cerebrospinal fluid is 21% of the simultaneous plasma concentration. Following oral administration, the drug half-life ranges from 36 minutes to one hour. Use of ddI significantly decreases p24 antigen levels and increases CD4⁺ cell counts. Viral resistance to ddI occurs after about one year of treatment. Combined use of ddI and AZT is beneficial because of the agents' differing toxicity profiles. The major side effects of ddI are painful peripheral neuropathy and pancreatitis, and minor side effects include abdominal pain, nausea, and vomiting. The use of certain other drug products, such as pentamidine, sulfonamides, and cimetidine, should be avoided during ddI use.

Zalcitabine,²⁰ 2',3'-dideoxycytidine or ddC (Hivid), is a useful alternative to ZDV. Its oral bioavailability is 87%, and its plasma half-life is approximately one hour. Side effects of ddC include stomatitis, rash, fever, malaise, arthritis, and arthralgia. In low doses (0.005 mg/kg every four hours), ddC produces a sustained decrease in p24 antigen level and increased CD4⁺ cell counts. Following oral administration, the bioavailability of ZDV is less than 80% which is further reduced with food. The mean maximum plasma concentration of the drug is also reduced from 25.2 ng/mL to 15.5 ng/mL when the drug is taken with food. The drug penetrates the blood-brain barrier. The major toxicity of ZDV is peripheral neuropathy, in which case, it should be discontinued. Pancreatitis occurs in some cases when ddC is given alone or in combination with ZDV.

Lamivudine,²² 2',3'-dideoxy-3'-thiacytidine or 3TC (Epivir), is an analogue of dideoxycytidine that is structurally similar to ddC. 3TC differs from ddC in that the 3'-carbon of the ribose ring is replaced with sulfur. Thus the absence of a free 3'-hydroxyl group in the structure of 3TC does not allow it to form phosphodiester linkages, resulting in termination of chain formation. 3TC in a dose of 600 mg/day has been shown to reduce HIV cells by 75%; the reduction in viral load with combined use of 3TC and ZDV is as high as 94%. 3TC is rapidly absorbed through the GI tract and may be administered with or without food. The majority of the drug is eliminated unchanged in urine. The mean elimination half-life is 5-7 hours. The bioavailability of 3TC is approximately 86%. After oral administration of 2 mg/kg twice daily, peak serum 3TC concentration is approximately 2 µg/mL.

Combivir is a combination of 3TC and ZDV approved by the FDA for slowing of HIV disease progression.²³ Combivir consists of two drugs in one tablet, which is helpful in preventing development of viral resistance and enhancing patient adherence to drug regimens. It can be taken with or without food.

The combination of 3TC and ddI, ddC, or D4T is used in advanced HIV infection. 3TC is usually well tolerated but can produce minor side effects such as fatigue, headache, GI upset, neuropathy, insomnia, myalgia, and arthralgia. Co-administration of 3TC and trimethoprim/sulfamethoxazole results in an increase in 3TC area under the plasma concentration time curve (AUC), a decrease in 3TC oral clearance, and a decrease in 3TC renal clearance.

Non-nucleoside Agents
Some non-nucleoside drugs have been shown to be active against HIV-1 but not HIV-2 RT activity. Although these drugs contain a unique tricyclic moiety, they do not produce diazepine-like activity. They are highly specific to HIV-1 infection. Non-nucleosides have action similar to that of nucleosides in producing a synergistic antiretroviral effect. Most of these drugs are synthesized via protein structure-based drug design methodologies. Their use as HIV monotherapies may be limited by the rapid onset of HIV resistance, as well as hypersensitivity reactions. However, the potential for interactions involving non-nucleoside drugs and protease inhibitors (i.e., saquinavir, indinavir, and ritonavir) are not yet well defined. Interactions of non-nucleosides with clarithromycin, ketoconazole, rifabutin, and rifampin are currently under investigation.

Recently three non-nucleoside drugs were approved by the FDA. Nevirapine²⁴ (Viramune) is a dipyridodiazepinone derivative that binds directly to RT. It blocks RNA- and DNA-dependent DNA polymerase activities by disrupting the enzyme's catalytic site. The activity of nevirapine does not compete with template or nucleoside triphosphate. Nevirapine and its analogues exhibit antiretroviral effect against AZT-resistant HIV strains. Use of nevirapine in combination with ZDV and ddI produces approximately18% higher CD4⁺ cell counts than have been observed in patients receiving ZDV and ddI, with a comparable decrease in viral load. Therefore, nevirapine is recommended along with nucleosides for HIV-1 infected patients who have experienced clinical and/or immunological deterioration. Significant side effects of nevirapine include liver dysfunction and skin rashes. Nevirapine is rapidly absorbed after oral administration, and its bioavailability is approximately 95%. Peak plasma nevirapine concentrations of 2 ± 0.4 µg/mL are obtained four hours after a single 200-mg dose. Following multiple doses, nevirapine concentrations appear to increase linearly in the dose range of 200-400 mg/day. Nevirapine is about 60% bound to plasma proteins in the plasma concentration range of 1-10 µg/mL. It readily crosses the placenta and is found in breast milk.

Delavirdine²⁵ (Rescriptor) is a bis- (heteroaryl)piperazine non-nucleoside RT inhibitor specific for HIV-1 infection. The FDA has approved use of this drug in combination with other anti-HIV drugs. In phase I and phase II clinical trials, delavirdine produced sustained improvements in CD4⁺ cell counts, p24 antigen levels, and RNA viral load. It yielded promising results when used in two- or three-drug combinations including nucleoside drugs. Delavirdine is contraindicated for patients receiving rifampin and rifabutin. The combination of delavirdine with ddI or ddC has additive or synergistic effects. Combined use of delavirdine and ZDV has proved more beneficial for treating early HIV infection. Combined use of delavirdine and nevirapine has an antagonistic effect on HIV-1 RT inhibition. The 50% inhibitory concentration for delavirdine against RT activity was 6.0 nM. Delavirdine is metabolized to its N-desisopropyl metabolite in the liver, and its pharmacokinetic activity is non-linear. Skin rashes are the major side effect of delavirdine therapy.

Efavirenz²⁶(Sustiva), a new non-nucleoside RT inhibitor, was approved by the FDA in September 1997. Its chemical structure is 1,4-dihydro-2H-3,1-benzoxazin-2-ones. Efavirenz is a potent inhibitor of wild-type HIV-1 RT, which is inhibited up to 95% in an efavirenz concentration of 1.5 mM. In combination with indinavir, a mean reduction in HIV RNA of 1.68 log, and an increase in CD4⁺ counts of 96 cells/mm³ have been reported. In clinical trials, coadministration of efavirenz with indinavir reduced indinavir concentrations (AUC) by approximately 35%. Efavirenz is given once a day in combination with standard drugs such as AZT and lamivudine. Since it is given once daily, efavirenz reduces the number of pills that the patient must swallow. Used in combination with other anti-HIV drugs, efavirenz is a good option for reducing many side effects. It is good for both adults and children and may be less expensive than other components of combination therapy.

Reported side effects with efavirenz include dizziness, headache, diarrhea, insomnia, impaired concentration, abnormal dreams, and drowsiness. The most common adverse effect is rash. It is recommended that efavirenz be taken at bedtime, with or without food. General precautions include avoidance of driving or operating machinery. The drug is contraindicated in patients receiving astemizole, cisapride, midazolam, triazolam, or ergot derivatives.

Protease Inhibitors²⁶
HIV protease is an enzyme that is essential for viral growth. It is responsible for the post-translation modification of core proteins into structural proteins. These proteins are products of the pol gene. The gag and gag-pol genes form products that are translated as polyproteins and form immature viral particles. HIV proteinase activates RT activity and plays an important role in the release of infectious viral particles. Thus inhibition of protease and pol gene activity is central to HIV pharmacotherapy. HIV protease inhibitors prevent budding of infectious viral particles from the infected cells. Consequently, the infectivity of HIV-1 is diminished. Several drugs have been designed to target HIV-1 protease activity. In view of the great demand for effective anti-HIV drugs, the FDA approved the PIs saquinavir and ritonavir under an accelerated approval process.

The following is an overview of the properties of currently available PIs, in chronological order of FDA approval:

Saquinavir
Saquinavir hard-gel capsule²⁷ (Invirase) was the first PI approved by the FDA, in December 1995. A carboxamide derivative specifically designed to inhibit HIV proteinase and prevent post-translational formation of viral proteins, saquinavir is a potent inhibitor of HIV-1 and HIV-2 proteinases without prior metabolic activation. At 12 nM concentration, saquinavir has a 50% inhibition of normal HIV, and at 11 nM it has a 50% inhibition of ZDV-resistant HIV.

Saquinavir is used to treat advanced HIV infection in selected patients. It is used concomitantly with either ZDV in untreated patients or in ddC-treated patients after prolonged ZDV therapy. Although such combined therapy has not been shown to slow disease progression, increased CD4⁺ cell counts have been achieved in patients treated in both the United States and Europe. Triple therapy with saquinavir, ZDV, and ddC is more effective than double therapy with saquinavir and ZDV or ddC. Overall, combination therapy appears helpful in reducing HIV disease mortality rates. The 50% inhibitory concentration of saquinavir in both acutely and chronically infected cells is 1-30 nM. In combination with ZDV, ddC, or ddI, the activity of saquinavir is increased without increased cytotoxicity. The bioavailability of saquinavir in a single 600-mg dose following a high-fat meal is about 4%. Approximately 30% of a 600-mg dose of saquinavir reaches the liver, where it exhibits first-pass metabolism. The metabolites are mono- and di-hydroxylated compounds, which are not active. Saquinavir has a plasma half-life of approximately 1.8 hours.

Saquinavir is well tolerated with ZDV and/or ddC. GI disturbances are the most common major adverse effects; minor side effects include headache, rhinitis, and nausea. Saquinavir interacts with rifampin, rifabutin, phenobarbital, phenytoin, dexamethasone, and carbamazepine, and concomitant use of these drugs reduces the plasma concentration of saquinavir. Astemizole, cisapride, and terfenadine are contraindicated for patients taking saquinavir. With concomitant use of ketoconazole or ranitidine, the relative bioavailability of saquinavir is increased.

Ritonavir
Ritonavir²⁸ (Norvir) was approved by the FDA in March 1996. Chemically it is a 5-thiazolylmethyl ester derivative. Ritonavir is a peptidomimetic inhibitor of both the HIV-1 and HIV-2 proteases. After a 600-mg dose of oral solution, peak concentrations are obtained after approximately two and four hours in fasting and non-fasting conditions, respectively. Under non-fasting conditions, peak ritonavir concentrations are decreased 23% and the extent of absorption is decreased 7%, as compared with fasting conditions. In two separate studies, the capsule and oral solution indicated an AUC of 129.5 ± 47.1 and 129.0 ± 39.3 µg•h/mL, respectively, when a 600-mg dose was given under non-fasting conditions.

Ritonavir is contraindicated with several compounds, including clarithromycin, desipramine, ethinyl estradiol, rifabutin, sulfamethoxazole, and trimethoprim, because of increased concentrations of these drugs in the plasma. Ritonavir alone or in combination with 3TC, ZDV, saquinavir, or ddC increases CD4+ cell counts and decreases HIV RNA particle levels. Cross-resistance between ritonavir and RT inhibitors is unlikely because of the drugs' different modes of action and the enzymatic pathways involved. Common adverse reactions to ritonavir are GI and neurological disturbances, which have been observed when the drug is used alone or in combination with other nucleoside analogues.

Ritonavir is used for the treatment of advanced HIV infection. In combination with nucleoside drugs, it reduces the risk of clinical progression and death. Because of its good oral bioavailability, ritonavir is available in capsule and oral solution dosage forms. The oral solution should be refrigerated.

Indinavir
Indinavir sulfate⁹ (Crixivan), a pentonamide derivative of the hydroxyaminopentane amide class of peptidomimetics, was approved by the FDA in March 1996. It inhibits infectious HIV protease, which is responsible for the proteolytic cleavage of the viral protein precursors into the individual functional proteins. HIV has shown drug resistance in some patients. Cross-resistance of indinavir has been observed with other PIs, but not with the RT inhibitors. For this reason, indinavir is beneficial when used with ZDV and other nucleoside drugs.¹³

In fasting patients, indinavir is rapidly absorbed, and a plasma peak concentration occurs in about one hour. At a dose of 800 mg every eight hours, the peak plasma concentration is approximately 300 nM. The drug is bound about 60% to human plasma proteins. The half-life of indinavir is approximately 1.8 hours. Indinavir has interaction potential with rifabutin and ketoconazole because of increase or decrease in drug concentration, respectively, in the plasma. Co-administration with antiviral nucleoside analogues, such as cimetidine, quinidine, trimethoprim/sufamethoxazole, fluconazole, and isoniazid, results in increased indinavir activity. Although a corresponding decline in progression of HIV infection has not been established, combined use of indinavir with other antiviral agents (e.g., AZT, 3TC, ddI, ddC, d4T) has been found to boost CD4⁺ cell counts. Combined use of indinavir and ZDV, or indinavir, ZDV, and 3TC, effectively reduces serum viral RNA. The drug is contraindicated for patients taking terfenadine, astemizole, cisapride, triazolam, or midazolam because of inhibition of the metabolism of these drugs, which can result in cardiac arrhythmias and prolonged sedation. Adverse reactions to indinavir include nephrolithiasis, asymptomatic hyperbilirubinemia, and GI problems such as anorexia, constipation, dyspepsia, and gastritis. The drug is well absorbed if taken on an empty stomach or if taken with water one hour before or two hours after a light meal. The dose should be reduced to 600 mg every eight hours if given concurrently with ketoconazole. Indinavir is available in 200-mg or 400-mg capsules, and its activity is increased when used in conjunction with RT inhibitors. Indinavir should be stored in a tightly closed container, since the capsules are sensitive to moisture.

Nelfinavir
Nelfinavir⁸ (Viracept), a butylcarboxamide derivative, is a non-peptidic drug synthesized by protein structure-based techniques. It prevents post-translational processing by releasing immature non-infectious viral particles, interfering with processing of gag and gag-pol polyproteins into HIV functional core proteins. It is effective in HIV-1 and ZDV-resistant strains with 50% effective concentrations ranging from 9-60 nM (95% effective dose is 0.04 µg/mL). After intravenous administration, the elimination half-life ranges from 1-1.4 hours. Nelfinavir given 750 mg twice daily reduces plasma HIV RNA below detectable levels and also increases CD4⁺ cell counts.

In combination with D4T, nelfinavir reduces HIV viral load by about 98% after four weeks. It is well tolerated when used with other nucleosides (AZT, ddI, 3TC, or D4T), antifungals, or antibiotics. It causes diarrhea and other side effects seen with non-nucleoside drugs. Following oral administration, peak levels in plasma range from 0.34 µg/mL (10 mg/kg in the dog) to 1.7 µg/mL (in the rat after dosing with 50 mg/kg). When taken with food, nelfinavir results in AUC values 27%-50% higher than those observed when the drug is taken without food. Nelfinavir is slowly absorbed, and its bioavailability in dogs has been established at 47%.

Saquinavir Soft-Gel
Saquinavir soft-gel capsule³⁰ (Fortovase) was recently approved by the FDA, largely because this formulation demonstrated improved antiviral effects as compared with the hard-gel capsule. In a dosage of 1200 mg three times daily, the soft-gel capsule formulation has been found to produce plasma concentrations eight times higher than those in patients taking saquinavir hard-gel capsule 600 mg three times daily. Saquinavir soft-gel capsule is usually given in combination with two nucleoside RT inhibitors two hours after a meal for optimal results.

Improvements in reduction of HIV RNA levels and increased CD4⁺ cell counts have been reported with combined use of soft-gel saquinavir and a nucleoside RT inhibitor and nelfinavir. Combination therapy is much more effective and well tolerated than combination therapy with the saquinavir hard-gel formulation by patients with moderate-to-advanced AIDS. The mode of action of the saquinavir soft-gel capsule formulation is similar to that of the hard-gel capsule in preventing post-translational viral processing. In combination with a nucleoside RT inhibitor and/or nelfinavir, it offers the advantage of being generally well tolerated by most HIV-infected patients. The most common side effects are GI disturbances. The soft-gel formulation is contraindicated for patients receiving terfenadine, astemizole, cisapride, triazolam, midazolam, or ergot derivatives.

Monitoring Considerations
The pharmacist's primary roles in HIV disease pharmacotherapy are to help ensure appropriate drug dosing, to educate patients and caregivers on appropriate drug administration, and to monitor for signs of overdose, adverse effects, and other indications of suboptimal therapeutic response. To fulfill these critical roles and be an integral member of the treatment team, pharmacists must be knowledgeable of a wide range of issues that can have a major impact on the effectiveness of anti-HIV drug therapy. These issues include:

• Variability in the bioavailability, pharmacokinetics and clinical effects of some anti-HIV medications when taken with or without food
• Potential drug-drug interactions (e.g., development of pancreatitis or neuropathy with combined use of ddI and ddC)
• The propensity of some anti-HIV medications to cross the blood-brain barrier or placenta
• Potential development of resistance or cross-resistance to one or more anti-HIV drug therapies
• Potential adverse drug effects (e.g., development of anemia in patients receiving AZT; hyperglycemia with protease inhibitors/AZT).

Despite the emergence of broad consensus on many treatment issues, HIV disease pharmacotherapy remains as much an art as a science. Therefore, if patients are experiencing adverse effects or other problems, pharmacists should convey their concerns to physicians in an inquiring rather than accusatory tone. For example, use of AZT in combination with protease inhibitors often leads to development of lipid or glucose abnormalities including liver dysfunction. In most cases, the physician is well aware of these effects but has decided that the benefits of continued HIV suppression far outweigh the detrimental impact on lipid and glucose levels.

Similarly, while CD4⁺ counts and viral loads are considered two of the most important clinical indicators in monitoring of HIV disease progression and the effectiveness of drug therapy, there are no definitive standards, only broad guidelines, regarding appropriate target levels in patients at different stages of HIV disease progression. Before concluding, for example, that a low CD4⁺ count or adverse effects signal a need to switch to a different treatment approach, the pharmacist should seek clarification from the physician. In other words, ask before you accuse.

In the event of a therapeutic failure, it's particularly important for the pharmacist to be assiduous in history taking to determine exactly which anti-HIV monotherapies and combination therapies have already been used in a given patient. Only by gathering information on all past treatment strategies and adverse effects can the pharmacist make appropriate recommendations regarding future management.

Final Notes
This article is intended to present a concise overview of current pharmacotherapeutic management of HIV infection and full-blown AIDS. A full understanding of HIV disease and AIDS, however, can be gained only through acquisition and regular updating of knowledge encompassing topics such as risk factors for HIV infection, infection and infection control precautions, etiologic considerations, modes of transmission, vaccine research and development, and HIV antibody testing, as well as retroviral structures and the HIV life cycle-a body of knowledge clearly far beyond the scope of this article.

Pharmacists who plan to increase their involvement in HIV/AIDS care are strongly advised to consult the biomedical literature for the most recent published reports in each of the above-listed topic areas.

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