Antiviral agents II: drugs for HIV infection and related opportunistic infections

In this chapter we discuss drug therapy of infection with the human immunodeficiency virus (HIV), the microbe that causes acquired immunodeficiency syndrome (AIDS). HIV promotes immunodeficiency by killing CD4 T lymphocytes (CD4 T cells), which are key components of the immune system (see Chapter 67). As a result of HIV-induced immunodeficiency, patients are at risk of opportunistic infections and certain neoplasms.

It is important to appreciate that HIV infection is not synonymous with AIDS, which develops years after HIV infection is acquired. The definition of AIDS, established by the Centers for Disease Control and Prevention (CDC) in 1993, is a syndrome in which the individual is HIV positive and has either (1) CD4 T-cell counts below 200 cells/mL or (2) an AIDS-defining illness. Included in the CDC’s long list of AIDS-defining illnesses are Pneumocystis pneumonia, cytomegalovirus retinitis, disseminated histoplasmosis, tuberculosis, and Kaposi’s sarcoma.

Since being identified as a new disease in 1981, AIDS has become a global epidemic. In the United States, nearly 1.2 million people are now infected, about 50,000 more become infected each year, and nearly 600,000 have died since the epidemic began. Worldwide, an estimated 33 million people are now infected, and about 25 million have died, including 270,000 children in 2007 alone. However, there is good news: According to a United Nations report, released in 2011, the number of new HIV infections and HIV-related deaths is on the decline, due in large part to more widespread use of HIV drugs.

Therapy of HIV infection has made dramatic advances. Today, standard antiretroviral therapy (ART) consists of three or four drugs. These combinations, often referred to as HAART (for highly active antiretroviral therapy), can decrease plasma HIV to levels that are undetectable with current technology, and can thereby delay or reverse loss of immune function, decrease certain AIDS-related complications, preserve health, prolong life, and decrease HIV transmission. In the United States, ART has reduced AIDS-related deaths by 72%—from a peak of 50,000 in 1995 to 16,000 in 2008. However, these benefits have not come without a price: ART is expensive, poses a risk of long-term side effects and serious drug interactions, and must continue lifelong. Accordingly, if treatment is to succeed, patients must be highly motivated and well informed about all aspects of the treatment program. A strong support network is extremely valuable too.

ART cannot cure HIV infection. Although treatment can greatly reduce HIV levels—often rendering the virus undetectable—discontinuation has consistently been followed by a rebound in HIV replication. Because ART does not eliminate HIV, patients continue to be infectious and must be warned to avoid behaviors that can transmit the virus to others.

Understanding this chapter requires a basic understanding of the immune system. Accordingly, you may find it helpful to read Chapter 67 before proceeding.

Pathophysiology

Characteristics of HIV

HIV is a retrovirus. Like all other viruses, retroviruses lack the machinery needed for self-replication, and hence are obligate intracellular parasites. However, in contrast to other viruses, retroviruses have positive-sense, single-stranded RNA as their genetic material. Accordingly, in order to replicate, retroviruses must first transcribe their RNA into DNA. The enzyme employed for this process is viral RNA-dependent DNA polymerase, commonly known as reverse transcriptase. (The enzyme is called reverse transcriptase to distinguish it from DNA-dependent RNA polymerase, the host enzyme that transcribes DNA into RNA, which is the usual [“forward”] transcription process.) The name retrovirus is derived from the first two letters of reverse and transcriptase.

There are two types of HIV, referred to as HIV-1 and HIV-2. HIV-1 is found worldwide, whereas HIV-2 is found mainly in West Africa. Although HIV-1 and HIV-2 differ with respect to genetic makeup and antigenicity, they both cause similar disease syndromes. Not all drugs that are effective against HIV-1 are also effective against HIV-2.

The principal cells attacked by HIV are CD4 T cells (helper T lymphocytes). As discussed in Chapter 67, these cells are essential components of the immune system. They are required for production of antibodies by B lymphocytes and for activation of cytolytic T lymphocytes. Accordingly, as HIV kills CD4 T cells, the immune system undergoes progressive decline. As a result, infected individuals become increasingly vulnerable to opportunistic infections, a major cause of death among people with AIDS. HIV targets CD4 T cells because the CD4 proteins on the surface of these cells provide points of attachment for HIV (see below). Without such a receptor, HIV would be unable to connect with and penetrate these cells. Once HIV has infected a CD4 T cell, the cell dies in about 1.25 days. It is important to appreciate that only a few percent of CD4 T cells circulate in the blood; the vast majority reside in lymph nodes and other lymphoid tissues.

In addition to infecting CD4 T cells, HIV infects macrophages and microglial cells (the central nervous system [CNS] counterparts of macrophages), both of which carry CD4 proteins. Since macrophages and microglial cells are resistant to destruction by HIV, they can survive despite being infected. As a result, they serve as a reservoir of HIV during chronic infection.

Structure of HIV

The structure of HIV is very simple. As shown in Figure 94–1, the HIV virion (ie, the entire virus particle) consists of nucleic acid (RNA) surrounded by core proteins, which in turn are surrounded by a capsid (protein shell), which in turn is surrounded by a lipid bilayer envelope (derived from the membrane of the host cell).

Figure 94–1 Structure of the human immunodeficiency virus.
Note that HIV has two single strands of RNA, and that each strand is associated with a molecule of reverse transcriptase. (gp41 = glycoprotein 41, gp120 = glycoprotein 120.)

The central core contains two separate but identical single strands of RNA, each with its own molecule of reverse transcriptase attached. The RNA serves as the template for DNA synthesis.

The outer envelope of HIV contains glycoproteins that are needed for attachment to host cells. Each glycoprotein (gp) consists of two subunits, known as gp41 and gp120. The smaller protein (gp41) is embedded in the lipid bilayer of the viral envelope; the larger protein (gp120) is connected firmly to gp41. (The numbers 41 and 120 simply indicate the mass of these glycoproteins in thousands of daltons.)

Replication cycle of HIV

The replication cycle of HIV is depicted in Figure 94–2. The numbered steps below correspond to the numbers in the figure.

Figure 94–2 Replication cycle of the human immunodeficiency virus.
See text for description of events. (CCR5 = CCR5 co-receptor, CD4 = CD4 receptor, CXCR4 = CXCR4 co-receptor, dsDNA = double-stranded DNA, gp120 = glycoprotein 120, mRNA = messenger RNA, ssDNA = single-stranded DNA, ssRNA = single-stranded RNA.)

• Step 1—The cycle begins with attachment of HIV to the host cell. The primary connection takes place between gp120 on the HIV envelope and a CD4 protein on the host cell membrane. Other host proteins, known as co-receptors, act in concert with CD4 to tighten the bond with HIV. Two of these co-receptors—known as CCR5 and CXCR4—are of particular importance. One drug—maraviroc—blocks HIV entry by binding CCR5.

• Step 2—The lipid bilayer envelope of HIV fuses with the lipid bilayer of the host cell membrane. Fusion is followed by release of HIV RNA into the host cell. One drug—–enfuvirtide—–works by blocking the fusion process.

• Step 3—HIV RNA is transcribed into single-stranded DNA by HIV reverse transcriptase. Twelve antiretroviral drugs inhibit this enzyme.

• Step 4—Reverse transcriptase converts the single strand of HIV DNA into double-stranded HIV DNA.

• Step 5—Double-stranded HIV DNA becomes integrated into the host’s DNA, under the direction of a viral enzyme known (aptly) as integrase. One drug—raltegravir—inhibits this enzyme.

• Step 6—HIV DNA undergoes transcription into RNA. Some of the resulting RNA becomes the genome for daughter HIV virions (step 6a). The rest of the RNA is messenger RNA that codes for HIV proteins (step 6b).

• Step 7—Messenger RNA is translated into HIV glycoproteins (step 7a) and HIV enzymes and structural proteins (step 7b).

• Step 8—The components of HIV migrate to the cell surface and assemble into a new virus. Prior to assembly, HIV glycoproteins become incorporated into the host cell membrane (step 8a). In steps 8b and 8c, the other components of the virion migrate to the cell surface, where they undergo assembly into the new virus.

• Step 9—The newly formed virus buds off from the host cell. As indicated, the outer envelope of the virion is derived from the cell membrane of the host.

• Step 10—In this step, which occurs either during or immediately after budding off, HIV undergoes final maturation under the influence of protease, an enzyme that cleaves certain large polyproteins into their smaller, functional forms. If protease fails to cleave these proteins, HIV will remain immature and noninfectious. HIV protease is the target of several important drugs.

TABLE 94–1

Acute Retroviral Syndrome: Associated Signs and Symptoms

The middle phase of HIV infection is characterized by prolonged clinical latency. Blood levels of HIV remain relatively low, and most patients are asymptomatic. However, as noted above, HIV continues to replicate despite apparent dormancy. Because of persistent HIV replication, CD4 T cells undergo progressive decline. The average duration of clinical latency is 10 years.

During the late phase of HIV infection, CD4 T cells drop below a critical level (200 cells/mL), rendering the patient highly vulnerable to opportunistic infections and certain neoplasms (eg, Kaposi’s sarcoma). The late phase is when AIDS occurs.

Many patients with HIV infection experience neurologic complications. Both the peripheral and central nervous systems may be involved. Peripheral neuropathies affect 20% to 40% of patients and may develop at any time over the course of HIV infection. In contrast, CNS complications usually occur late in the disease. Symptoms of CNS injury include decreased cognition, reduced concentration, memory loss, mental slowness, and motor complaints (eg, ataxia, tremors). Neuronal injury may be the direct result of HIV infection, or may develop secondary to an opportunistic infection in the CNS.

Classification of antiretroviral drugs

At this time, we have five types of antiretroviral drugs. Three types—reverse transcriptase inhibitors, integrase strand transfer inhibitors (INSTIs), and protease inhibitors (PIs)—inhibit enzymes required for HIV replication. The other two types—fusion inhibitors and chemokine receptor 5 (CCR5) antagonists—block viral entry into cells. As discussed below, the reverse transcriptase inhibitors are subdivided into two groups: nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), which are structural analogs of nucleosides or nucleotides, and (2) non-nucleoside reverse transcriptase inhibitors (NNRTIs). Drugs that belong to these groups are listed in Table 94–2. All NRTIs, NNRTIs, PIs, INSTIs, and CCR5 antagonists are administered orally, and one NRTI—zidovudine—may also be given IV. The one fusion inhibitor available—enfuvirtide [Fuzeon]—is administered subQ.

TABLE 94–2

Classification of Antiretroviral Drugs

Generic Name	Trade Name	Abbreviation
DRUGS THAT INHIBIT HIV ENZYMES
Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTIs)
Single-Drug Products
Abacavir	Ziagen	ABC
Didanosine	Videx	ddI
Emtricitabine	Emtriva	FTC
Lamivudine	Epivir	3TC
Stavudine	Zerit	d4T
Tenofovir	Viread	TDF
Zidovudine	Retrovir	ZDV
Fixed-Dose Combinations
Abacavir/lamivudine	Epzicom	ABC/3TC
Abacavir/lamivudine/zidovudine	Trizivir	ABC/3TC/ZDV
Zidovudine/lamivudine	Combivir	ZDV/3TC
Emtricitabine/tenofovir	Truvada	FTC/TDF
Emtricitabine/tenofovir/efavirenz*	Atripla	FTC/TDF/EFV
Emtricitabine/tenofovir/rilpivirine^†	Complera	FTC/TDF/RPV
Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Delavirdine	Rescriptor	DLV
Efavirenz	Sustiva	EFV
Etravirine	Intelence	ETR
Nevirapine	Viramune	NVP
Rilpivirine	Edurant	RPV
Protease Inhibitors
Atazanavir	Reyataz	ATV
Darunavir	Prezista	DRV
Fosamprenavir	Lexiva, Telzir	FPV
Indinavir	Crixivan	IDV
Nelfinavir	Viracept	NFV
Ritonavir	Norvir	RTV
Saquinavir	Invirase	SQV
Tipranavir	Aptivus	TPV
Lopinavir/ritonavir	Kaletra	LPV/r
Integrase Strand Transfer Inhibitor
Raltegravir	Isentress	RAL
DRUGS THAT BLOCK HIV ENTRY INTO CELLS
Fusion Inhibitor
Enfuvirtide	Fuzeon	T-20
CCR5 Antagonist
Maraviroc	Selzentry, Celsentri	MVC

^*Efavirenz is an NNRTI, not an NRTI.

^†Rilpivirine is an NNRTI, not an NRTI.

Nucleoside/nucleotide reverse transcriptase inhibitors

The nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) were the first drugs used against HIV infection, and remain mainstays of therapy today. In fact, these drugs constitute the backbone of all treatment regimens. As their name suggests, the NRTIs are chemical relatives of naturally occurring nucleosides or nucleotides, the building blocks of DNA. Antiretroviral effects derive from suppressing synthesis of viral DNA by reverse transcriptase. To be effective, all of the NRTIs must first undergo intracellular conversion to their active (triphosphate) forms. The NRTIs have few drug interactions, and most can be taken without regard to meals. Rarely, these agents cause a potentially fatal syndrome characterized by lactic acidosis and hepatomegaly with steatosis; pregnant women taking two NRTIs may be at increased risk. At this time, seven NRTIs are available. Major properties are summarized in Table 94–3.

TABLE 94–3

Properties of Nucleoside/Nucleotide Reverse Transcriptase Inhibitors

	Abacavir (ABC)	Didanosine (ddI)	Emtricitabine (FTC)	Lamivudine (3TC)	Stavudine (d4T)	Tenofovir (TDF)	Zidovudine (ZDV)
Trade Name	Ziagen	Videx, Videx EC	Emtriva	Epivir	Zerit	Viread	Retrovir
Formulations	Tablets: 300 mg PO soln: 20 mg/mL	EC capsules: 125, 200, 250, 400 mg Buffered powder for PO soln: 100, 167, 250 mg	Capsules: 200 mg PO soln: 10 mg/mL	Tablets: 150, 300 mg PO soln: 10 mg/mL	Capsules: 15, 20, 30, 40 mg PO soln: 1 mg/mL	Tablets: 300 mg	Capsules: 100 mg Tablets: 300 mg PO soln: 10 mg/mL IV soln: 10 mg/mL
Dosage	300 mg 2 times/day or 600 mg once/day	EC capsules: ≥60 kg: 400 mg once/day (or 250 mg once/day with tenofovir) <60 kg: 250 mg once/day (or 200 mg once/day with tenofovir) PO solution: ≥60 kg: 200 mg 2 times/day <60 kg: 125 mg 2 times/day	Capsules: 200 mg once/day PO soln: 240 mg once/day	Adults: 150 mg 2 times/day or 300 mg once/day Children: 4 mg/kg 2 times/day (max 150 mg 2 times/day)	>60 kg: 40 mg 2 times/day <60 kg: 30 mg 2 times/day Note: WHO recommends 30 mg 2 times/day regardless of weight	300 mg once/day	200 mg 3 times/day or 300 mg 2 times/day
Impact of Food	Take without regard to meals—but alcohol increases levels by 41%	Take 30 min before meals or 2 hr after	Take without regard to meals	Take without regard to meals	Take without regard to meals	Take without regard to meals	Take without regard to meals
Bioavailability	83%	30%–40%	93%	86%	86%	39% (with food)	60%
Serum Half-life	1.5 hr	1.5 hr	10 hr	5–7 hr	1 hr	17 hr	1.1 hr
Intracellular Half-life	12–26 hr	More than 20 hr	More than 20 hr	18–22 hr	7.5 hr	More than 60 hr	7 hr
Elimination	Metabolized by alcohol dehydrogenase, then excreted in the urine	Partial metabolism followed by renal excretion	Renal excretion	Renal excretion (unchanged)	Partial metabolism followed by renal excretion	Renal excretion	Hepatic metabolism followed by renal excretion
Adverse Effects	• Lactic acidosis * • Potentially fatal hypersensitivity reactions (fever, rash, nausea, vomiting, fatigue, abdominal pain, respiratory symptoms) • Possible increased risk of MI	• Lactic acidosis * • Pancreatitis • Peripheral neuropathy • GI: nausea, diarrhea • Retinal changes, optic neuritis • Insulin resistance/diabetes • Possible increased risk of MI	• Minimal toxicity • Lactic acidosis * • Hyperpigmentation of palms and soles • GI: nausea, diarrhea • Headache • Rash • In patients co-infected with HBV, withdrawing emtricitabine may result in severe acute exacerbation of hepatitis.	• Minimal toxicity • Lactic acidosis * • In patients co-infected with HBV, withdrawing lamivudine may result in severe acute exacerbation of hepatitis.	• Lactic acidosis * • Pancreatitis • Peripheral neuropathy • Rapidly progressive neuromuscular weakness (rare) • Lipoatrophy • Hyperlipidemia • Insulin resistance/diabetes	• Lactic acidosis * • Asthenia • Headache • GI: nausea, diarrhea, vomiting, flatulence • Renal insufficiency • Osteomalacia • Possible decreased BMD • In patients co-infected with HBV, withdrawing tenofovir may result in severe acute exacerbation of hepatitis.	• Lactic acidosis * • Bone marrow suppression: anemia, neutropenia • GI intolerance • Headache • Insomnia • Myopathy • Nail pigmentation • Hyperlipidemia • Lipoatrophy • Insulin resistance/diabetes

BMD = bone mineral density, EC = enteric coated, HBV = hepatitis B virus, MI = myocardial infarction, WHO = World Health Organization.

^*Lactic acidosis with hepatic steatosis is a rare but potentially fatal toxicity associated with all NRTIs.

Adapted from Guidelines for the Use of Antiretroviral Agents in HIV-1–Infected Adults and Adolescents, prepared by the Panel on Clinical Practices for Treatment of HIV Infection, convened by the DHHS, as updated on October 14, 2011.

Zidovudine

Zidovudine [Retrovir] was the first NRTI available and will serve as our prototype for the group. The drug is an analog of thymidine, a naturally occurring nucleoside. When employed in combination with other antiretroviral drugs, zidovudine can decrease viral load, increase CD4 T-cell counts, delay onset of disease symptoms, and reduce symptom severity. The drug’s principal dose-limiting toxicities are severe anemia and neutropenia. Abbreviations for this agent are ZDV (for zidovudine) and AZT (for azidothymidine, its original name).

Mechanism of antiviral action

Zidovudine inhibits HIV replication by suppressing synthesis of viral DNA. To do this, zidovudine must first undergo intracellular conversion to its active form, zidovudine triphosphate (ZTP). As ZTP, the drug acts as a substrate for reverse transcriptase. However, when ZTP becomes incorporated into the growing DNA strand, it prevents reverse transcriptase from adding more bases. As a result, further growth of the strand is blocked. In addition to causing premature strand termination, ZTP competes with natural nucleoside triphosphates for binding to the active site of reverse transcriptase; the result is competitive inhibition of the enzyme.

Therapeutic use

Zidovudine is used to treat infection with HIV-1. Because monotherapy with any antiretroviral drug can rapidly lead to resistance, zidovudine should always be combined with other antiretroviral agents. Zidovudine penetrates to the CNS better than most other antiretroviral drugs, and hence can be especially valuable for relieving cognitive symptoms. Zidovudine is also the drug of choice for preventing mother-to-infant HIV transmission during labor and delivery. The role of zidovudine and other agents in the management of HIV infection is discussed at length later in the chapter.

Pharmacokinetics

Zidovudine is readily absorbed in the presence or absence of food, and distributes to all tissues, including the CNS. After entering the blood, some of the drug is taken up by cells and converted to ZTP, the active form. The remainder undergoes rapid hepatic conversion to an inactive metabolite. Both zidovudine and its inactive metabolite are eliminated by renal excretion. The plasma half-life of the drug is 1.1 hours, and the intracellular half-life is 7 hours.

Adverse effects

Anemia and neutropenia from bone marrow suppression.

Severe anemia and neutropenia are the principal toxic effects. Multiple transfusions may be required. The risk of hematologic toxicity is increased by high-dose therapy, advanced HIV infection, deficiencies in vitamin B₁₂ and folic acid, and concurrent use of drugs that are myelosuppressive, nephrotoxic, or directly toxic to circulating blood cells. Anemia and neutropenia generally resolve following zidovudine withdrawal.

Hematologic status (hemoglobin concentration and neutrophil counts) should be determined before treatment and at least every 4 weeks thereafter. Hemoglobin levels may fall significantly within 2 to 4 weeks; neutrophil counts may not fall until after week 6. For patients who develop severe anemia (hemoglobin below 5 gm/dL or down 25% from baseline) or severe neutropenia (neutrophil count below 750 cells/mL or down 50% from baseline), zidovudine should be interrupted until there is evidence of bone marrow recovery. If neutropenia and anemia are less severe, a reduction in dosage may be sufficient. Transfusions may permit some patients to continue drug use.

Granulocyte colony-stimulating factors may be given to reverse zidovudine-induced neutropenia. Also, if erythropoietin levels are not already elevated, epoetin alfa (recombinant erythropoietin) can be given to reduce transfusion requirements in patients with anemia. Granulocyte colony-stimulating factors and epoetin alfa are discussed in Chapter 56.

Lactic acidosis with hepatic steatosis.

Rarely, zidovudine causes a syndrome of lactic acidosis with severe hepatomegaly (liver enlargement) and hepatic steatosis (fatty degeneration of the liver). Symptoms include nausea, vomiting, abdominal pain, malaise, fatigue, anorexia, and hyperventilation (blowing off carbon dioxide can reduce acidosis). Left untreated, the syndrome can be fatal. Diagnosis is based on lactic acid measurement in arterial blood. If clinically significant lactic acidosis is present, zidovudine should be discontinued. Lactic acidosis is caused by toxicity to mitochondria.

Combining NRTIs during pregnancy may increase the risk of lactic acidosis. Fatalities have occurred in pregnant women who were taking the NRTIs didanosine and stavudine. Because lactic acidosis and hepatitic steatosis are potential side effects of all NRTIs, it may be prudent to avoid combining any of these drugs during pregnancy.

Other adverse effects.

Gastrointestinal effects (anorexia, nausea, vomiting, diarrhea, abdominal pain, stomach upset) occur on occasion. Possible CNS reactions include headache, insomnia, confusion, anxiety, nervousness, and seizures. Additional adverse effects include myopathy (damage to muscle fibers), nail pigmentation, insulin resistance/diabetes, hyperlipidemia, and lipoatrophy.

Drug interactions

Drugs that are myelosuppressive, nephrotoxic, or directly toxic to circulating blood cells can increase the risk of zidovudine-induced hematologic toxicity. Notable among these is ganciclovir, an antiviral agent used to treat cytomegalovirus retinitis, a common infection in patients with AIDS. Other drugs of concern include dapsone, pentamidine, pyrimethamine, trimethoprim/sulfamethoxazole, amphotericin B, flucytosine, vincristine, vinblastine, and doxorubicin.

Preparations, dosage, and administration

Preparations.

Zidovudine [Retrovir] is available in three oral formulations—capsules (100 mg), tablets (300 mg), and solution (10 mg/mL)—and a solution for IV use (10 mg/mL). The drug is also available in combination with lamivudine under the trade name Combivir, and in combination with lamivudine and abacavir under the trade name Trizivir.

Oral therapy.

Hematologic monitoring should be done every 2 weeks. If severe anemia or severe neutropenia develops, treatment should be interrupted until there is evidence of bone marrow recovery. If anemia or neutropenia is mild, a reduction in dosage may be sufficient.

Intravenous therapy: adults with pneumocystis pneumonia.

Intravenous zidovudine is indicated for adults with AIDS who have a history of cytologically confirmed Pneumocystis pneumonia or a CD4 T-cell count below 200 cells/mL. The IV dosage is 1 to 2 mg/kg (infused over 1 hour) every 4 hours around-the-clock. Rapid infusion and bolus injection must be avoided. Intravenous therapy should be stopped as soon as oral therapy is appropriate.

Intravenous solutions are prepared by withdrawing the calculated dose from the stock vial and diluting it to 4 mg/mL (or less) in 5% dextrose for injection. The solution should not be mixed with biologic or colloidal fluids (eg, blood products, protein solutions) and should be administered within 8 hours (if held at room temperature) or within 24 hours (if held under refrigeration).

Intravenous therapy: preventing mother-to-infant transmission.

Intravenous dosing of the mother during labor and the infant after birth is discussed below under Preventing Perinatal HIV Transmission.

Other NRTIs

Didanosine

Actions and uses.

Didanosine [Videx, Videx EC], also known as dideoxyinosine (ddI), is an analog of inosine, a naturally occurring nucleoside. The drug is taken up by host cells, where it undergoes conversion to its active form, dideoxyadenosine triphosphate (ddATP). Like the active form of zidovudine, ddATP suppresses viral replication primarily by causing premature termination of the growing DNA strand. In addition, ddATP competes with natural nucleoside triphosphates for binding to the active center of reverse transcriptase, and thereby further suppresses DNA synthesis. In clinical trials, didanosine increased CD4 T-cell counts, decreased viremia, and reduced symptoms in patients with AIDS.

Didanosine is approved only for HIV-1 infection. Because monotherapy with any antiretroviral drug can rapidly lead to resistance, the regimen should always include other antiretroviral drugs.

Pharmacokinetics.

Didanosine is administered orally, and bioavailability is low (about 35%). Absorption is greatly reduced by food and gastric acidity. To decrease gastric acidity, and thereby enhance absorption, older formulations of didanosine [Videx] contain buffering agents; newer formulations [Videx EC] are protected by an enteric coating. Didanosine crosses the blood-brain barrier poorly; levels in cerebrospinal fluid are only 20% of those in plasma. Much of the drug (35% to 60%) is excreted unchanged in the urine. The plasma half-life in patients with normal renal function is 1.5 hours, but is 3 times longer in patients with renal failure. The intracellular half-life is more than 20 hours.

Adverse effects.

Pancreatitis.

Pancreatitis, which can be fatal, is the major dose-limiting toxicity. The incidence is 3% to 17%. Patients should be monitored for indications of developing pancreatitis (increased serum amylase in association with increased serum triglycerides; decreased serum calcium; and nausea, vomiting, or abdominal pain). If evolving pancreatitis is diagnosed, didanosine should be withdrawn. The risk of pancreatitis is increased by a history of pancreatitis or alcoholism and by use of IV pentamidine. Caution should be exercised in such patients.

Lactic acidosis with hepatic steatosis.

Like all other NRTIs, didanosine can cause lactic acidosis with hepatic steatosis. Fatalities have occurred in several pregnant women taking didanosine plus stavudine. Accordingly, the manufacturer warns against combining these drugs during pregnancy, unless resistance to all other antiretrovirals leaves no option. Because lactic acidosis and hepatic steatosis are potential side effects of all NRTIs, it may be prudent to avoid combining didanosine with any of these drugs during pregnancy.

Other adverse effects.

Additional adverse effects include diarrhea (28%), peripheral neuropathy (20%), chills or fever (12%), and rash or pruritus (9%). Postmarketing data indicate the drug may also cause retinal changes, optic neuritis, and insulin resistance/diabetes, and may increase the risk of myocardial infarction (MI). In contrast to zidovudine, didanosine causes minimal bone marrow suppression.

Drug interactions.

For treatment of HIV infection, didanosine can be used in various regimens (see Table 94–8). Buffered didanosine formulations can interfere with the absorption of drugs that require gastric acidity, including delavirdine and indinavir. Ribavirin and allopurinol can increase levels of didanosine, and may thereby pose a risk of toxicity. Accordingly, these combinations should be avoided.

Preparations, dosage, and administration.

Didanosine is available in two formulations: enteric-coated capsules [Videx EC], and a buffered powder for oral solution [Videx].

Both formulations.

Because absorption is greatly reduced by food, didanosine should be administered on an empty stomach, either 30 minutes before meals or 2 hours after. Because didanosine is eliminated by the kidneys, dosage must be reduced in patients with renal impairment.

Enteric-coated capsules.

Didanosine enteric-coated capsules [Videx EC] are available in four strengths: 125, 200, 250, and 400 mg. For patients who weigh 60 kg or more, the dosage is 400 mg once daily (or 250 mg once daily with tenofovir. For patients who weigh less than 60 kg, the dosage is 250 mg once daily (or 200 mg once daily with tenofovir).

Buffered powder for oral solution.

Didanosine powder for oral solution is available in bottles (2 and 4 gm) for pediatric use. Prior to dispensing, the pharmacist must reconstitute the powder to make a 20-mg/mL solution. Dosage is 200 mg twice daily (for patients over 60 kg) or 125 mg twice daily (for patients under 60 kg).

Stavudine

Actions and uses.

Stavudine [Zerit], also known as didehydrodeoxythymidine (d4T), is an analog of thymidine, a naturally occurring nucleoside. Following uptake by cells, stavudine is converted to its active form, stavudine triphosphate. The active drug then suppresses HIV replication by (1) causing premature termination of the growing DNA strand and (2) competing with natural nucleoside triphosphates for binding to reverse transcriptase.

Stavudine is indicated only for infection with HIV-1. Like all other drugs for HIV, stavudine should be combined with other antiretroviral agents to decrease the risk of resistance.