Goodman and Gilman Manual of Pharmacology and Therapeutics

Section VII
Chemotherapy of Microbial Diseases

chapter 59
Antiretroviral Agents and Treatment of HIV Infection

The pharmacotherapy of HIV infection is a rapidly moving field. Three-drug combinations are the minimum standard of care for this infection, so current agents constitute several thousand possible regimens. Knowing the essential features of the pathophysiology of this disease and how chemotherapeutic agents affect the virus and the host is critical in developing a rational approach to therapy. Unique features of this drug class include the need for lifelong administration to control virus replication and the possibility of rapid emergence of permanent drug resistance if these agents are not used properly.


Human immunodeficiency viruses (HIVs) are lentiviruses, a family of retroviruses evolved to establish chronic persistent infection with gradual onset of clinical symptoms. Replication is constant following infection, and although some infected cells may harbor nonreplicating virus for years, in the absence of treatment there generally is no true period of viral latency following infection. Humans and nonhuman primates are the only natural hosts for these viruses.

There are 2 major families of HIV. Most of the epidemic involves HIV-1; HIV-2 is more closely related to simian immunodeficiency virus (SIV) and is concentrated in western Africa. HIV-1 is genetically diverse, with at least 5 distinct subfamilies or clades. HIV-1 and HIV-2 have similar sensitivity to most antiretroviral drugs, although the non-nucleoside reverse transcriptase inhibitors (NNRTIs) are HIV-1-specific and have no activity against HIV-2.

VIRUS STRUCTURE. HIV is a typical retrovirus with a small RNA genome of 9300 base pairs. Two copies of the genome are contained in a nucleocapsid core surrounded by a lipid bilayer, or envelope, that is derived from the host cell plasma membrane (Figure 59–1). The viral genome encodes 3 major open reading frames: gag encodes a polyprotein that is processed to release the major structural proteins of the virus; pol overlaps gag and encodes 3 important enzyme activities—an RNA-dependent DNA polymerase or reverse transcriptase with RNAase activity, protease, and the viral integrase; and env encodes the large transmembrane envelope protein responsible for cell binding and entry. Several small genes encode regulatory proteins that enhance virion production or combat host defenses. These include tat, rev, nef, and vpr.


Figure 59–1 Replicative cycle of HIV-1 and sites of action of available antiretroviral agents. Available antiretroviral agents are shown in blue. cDNA, complementary DNA; gp120 + gp41, extracellular and intracellular domains, respectively, of envelope glycoprotein; mRNA, messenger RNA; RNase H, ribonuclease H; RT, reverse transcriptase. (Adapted from Hirsch MS, D′Aquila RT. Therapy for human immunodeficiency virus infection. N Engl J Med, 1993; 328:1686–1695.)

VIRUS LIFE CYCLE (see Figure 59–1). HIV tropism is controlled by the envelope protein gp160 (env). The major target for env binding is the CD4 receptor present on lymphocytes and macrophages, although cell entry also requires binding to a coreceptor, generally the chemokine receptor CCR5 or CXCR4. CCR5 is present on macrophage lineage cells. Most infected individuals harbor predominantly the CCR5-tropic virus; HIV with this tropism is responsible for nearly all naturally acquired infections. A shift from CCR5 to CXCR4 utilization is associated with advancing disease, and the increased affinity of HIV-1 for CXCR4 allows infection of T-lymphocyte lines. A phenotypic switch from CCR5 to CXCR4 heralds accelerated loss of CD4+ helper T cells and increased risk of immunosuppression. Whether coreceptor switch is a cause or a consequence of advancing disease is still unknown, but it is possible to develop clinical AIDS without this switch.

The gp41 domain of env controls the fusion of the virus lipid bilayer with that of the host cell. Following fusion, full-length viral RNA enters the cytoplasm, where it undergoes replication to a short-lived RNADNA duplex; the original RNA is degraded by RNase H to allow creation of a full-length double-stranded DNA copy of the virus. Because the HIV reverse transcriptase is error prone and lacks a proofreading function, mutation is quite frequent and occurs at ~3 bases out of every full-length (9300-base-pair) replication. Virus DNA is transported into the nucleus, where it is integrated into a host chromosome by the viral integrase in a random or quasi-random location.

Following integration, the virus may remain quiescent, not producing RNA or protein but replicating as the cell divides. When a cell that harbors the virus is activated, viral RNA and proteins are produced. Structural proteins assemble around full-length genomic RNA to form a nucleocapsid. The envelope and structural proteins assemble at the cell surface, concentrating in cholesterol-rich lipid rafts. The nucleocapsid cores are directed to these sites and bud through the cell membrane, creating new enveloped HIV particles containing 2 complete single-stranded RNA genomes. Reverse transcriptase is incorporated into virus particles so replication can begin immediately after the virus enters a new cell.

HOW THE VIRUS CAUSES DISEASE. Sexual acquisition of HIV infection is likely mediated by one or, at most, a handful of infectious virus particles. Soon after infection, there is a rapid burst of replication peaking at 2-4 weeks, with ≥109 cells becoming infected. This peak is associated with a transient dip in the number of peripheral CD4+ (helper) T lymphocytes. As a result of new host immune responses and target cell depletion, the number of infectious virions as reflected by the plasma HIV RNA concentration (also known asviral load) declines to a quasi-steady state. This set point reflects the interplay between host immunity and the pathogenicity of the infecting virus. In the average infected individual, several billion infectious virus particles are produced every few days.

Eventually, the host CD4+ T lymphocyte count begins a steady decline, accompanied by a rise in the plasma HIV RNA concentration. Once the peripheral CD4 cell count falls below 200 cells/mm3, there is an increasing risk of opportunistic diseases and ultimately death. Sexual acquisition of CCR5-tropic HIV-1 is associated with a median time to clinical AIDS of 8-10 years. Some patients, termed long-term nonprogressors, can harbor HIV for more than 2 decades without significant decline in peripheral CD4 cell count or clinical immunosuppression; this may reflect a combination of favorable host immunogenetics and immune responses.

An important question relevant to treatment is whether HIV disease is a consequence of CD4+ lymphocyte depletion alone. Most natural history data suggest that this is true. Regardless, successful therapy is based on inhibition of HIV replication; interventions designed specifically to boost the host immune response without exerting a direct antiviral effect have had no reliable clinical benefit.


Current treatment assumes that all aspects of disease derive from the direct toxic effects of HIV on host cells, mainly CD4+ T lymphocytes. The goal of therapy is to suppress virus replication as much as possible for as long as possible. The current standard of care is to use at least 3 drugs simultaneously for the entire duration of treatment.

Current guidelines in the U.S. recommend starting therapy in all those with a CD4 count of ≤350 cells/mm3. Treatment is also recommended for HIV-infected pregnant women, those with HIV nephropathy, and those with concurrent hepatitis B virus infection requiring treatment regardless of CD4 count. Increasing evidence supports the value of antiretroviral therapy in preventing transmission of the virus from person to person. In the foreseeable future, treatment may be recommended for all infected adults and children.

Drug resistance is a key problem. There is a high likelihood that all untreated infected individuals harbor viruses with single-amino-acid mutations conferring some degree of resistance to every known antiretroviral drug because of the high mutation rate of HIV and the tremendous number of infectious virions. Thus, a combination of active agents is required to prevent drug resistance, analogous to strategies employed in the treatment of tuberculosis (see Chapter 56). Intentional drug holidays, also known as structured treatment interruptions, allow the virus to replicate anew, increase the risk of drug resistance and disease progression, and are not recommended.

The expected outcome of initial therapy in a previously untreated patient is an undetectable viral load (plasma HIV RNA <50 copies/mL) within 24 weeks of starting treatment. Mathematical models of HIV replication suggested that 3 is the minimum number of agents required to guarantee effective long-term suppression of HIV replication without resistance. In treatment-naive patients, a regimen containing a non-nucleoside plus 2 nucleoside reverse transcriptase inhibitors is as effective as a regimen containing an additional nucleoside, indicating the equivalence of these 3-drug and 4-drug regimens. Four or more drugs may be used simultaneously in pretreated patients harboring drug-resistant virus, but the number of agents a patient can take is limited by toxicity and inconvenience.

Failure of an antiretroviral regimen is defined as a persistent increase in plasma HIV RNA concentrations in a patient with previously undetectable virus, despite continued treatment with that regimen. This indicates resistance to 1 or more drugs in the regimen and necessitates a change in treatment. The selection of new agents is therefore informed by the patient’s treatment history and viral resistance testing. Treatment failure generally requires implementation of a completely new combination of drugs. Adding a single active agent to a failing regimen is functional monotherapy if the patient is resistant to all drugs in the regimen. The risk of failing a regimen depends on the percentage of prescribed doses taken during any given period of treatment.

As antiretroviral therapy becomes more effective and easier to take, long-term toxicity of these drugs is of greater concern. An important consequence of long-term therapy is the development of a metabolic syndrome (HIV lipodystrophy syndrome) characterized by insulin resistance, fat redistribution, and hyperlipidemia, that occurs in 10-40% of treated patients. Clinical features include peripheral fat wasting (lipoatrophy), central fat accumulation including enlarged breasts and buffalo hump, insulin resistance and hyperglycemia, and elevations in serum cholesterol and triglycerides. Lipodystrophy has been associated with an increased risk of myocardial infarction in virologically controlled patients. A potential concern that applies to all protease inhibitors and NNRTIs is clinically significant pharmacokinetic drug interactions. All agents in these 2 drug classes can act as inhibitors and/or inducers of hepatic CYPs and other drug metabolizing enzymes, as well as drug transport proteins.

An increasingly recognized complication of initiating antiretroviral therapy is accelerated inflammatory reaction to overt or subclinical opportunistic infections or malignancies. This immune reconstitution inflammatory syndrome (IRIS) is most commonly seen when initiating therapy in individuals with low CD4 counts and/or advanced HIV disease. Infections commonly associated with IRIS include tuberculosis and other mycobacterial diseases, cryptococcosis, hepatitis virus infections, and Pneumocystis pneumonia.

Drugs Used to Treat HIV Infection


The HIV-encoded, RNA-dependent DNA polymerase, also called reverse transcriptase, converts viral RNA into proviral DNA that is then incorporated into a host cell chromosome. Available inhibitors of this enzyme are either nucleoside/nucleotide analogs or non-nucleoside inhibitors (Table 59–1). Nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) prevent infection of susceptible cells but do not eradicate the virus from cells that already harbor integrated proviral DNA. Nearly all patients starting antiretroviral treatment do so with at least 1 agent from this class. Figure 59–2 shows the mechanism of action of NRTIs, which involves phosphorylation by host cells to the active inhibitory form.

Table 59–1

Antiretroviral Agents Approved for Use in the U.S.



Figure 59–2 Mechanism of nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs). Zidovudine is depicted; Table 59–1 lists other agents in the NRTI class. Nucleoside and nucleotide analogs must enter cells and be phosphorylated to generate synthetic substrates for reverse transcriptase. The fully phosphorylated analogs block replication of the viral genome both by competitively inhibiting incorporation of native nucleotides and by terminating elongation of nascent proviral DNA because they lack a 3′-hydroxyl group.

All but 1 of the drugs in this class are nucleosides that must be triphosphorylated at the 5′-hydroxyl to exert activity. The sole exception, tenofovir, is a nucleotide monophosphate analog that requires 2 additional phosphates to acquire full activity. These compounds inhibit both HIV-1 and HIV-2, and several have broad-spectrum activity against other human and animal retroviruses; emtricitabine, lamivudine, and tenofovir are active against hepatitis B virus (HBV), and tenofovir also has activity against herpesviruses (see Chapter 58).

The selective toxicity of these drugs depends on their ability to inhibit the HIV reverse transcriptase without inhibiting host cell DNA polymerases. Although the intracellular triphosphates for all these drugs have low affinity for human DNA polymerase-α and polymerase-β, some do inhibit human DNA polymerase-γ, which is the mitochondrial enzyme. As a result, the important toxicities common to this class of drugs result in part from the inhibition of mitochondrial DNA synthesis. These toxicities include anemia, granulocytopenia, myopathy, peripheral neuropathy, and pancreatitis. Lactic acidosis with or without hepatomegaly and hepatic steatosis is a rare but potentially fatal complication seen with stavudine, zidovudine, and didanosine. Phosphorylated emtricitabine, lamivudine, and tenofovir have low affinity for DNA polymerase-γ and are largely devoid of mitochondrial toxicity.

Table 59–2 summarizes the pharmacokinetic properties of NRTIs approved for treating HIV infection. A notable pharmacological feature of these agents is the elimination of the intracellular nucleoside di- or tri-phosphate, which is the active form. In general, the phosphorylated anabolites are eliminated from cells much more gradually than the parent drug is eliminated from the plasma. As a result, available NRTIs are dosed once or twice daily.

Table 59–2

Pharmacokinetic Properties of Nucleoside Reverse Transcriptase Inhibitorsa


These drugs are not major substrates for hepatic CYPs. Pharmacokinetic drug interactions involving tenofovir and protease inhibitors are likely to be explained by inhibition of OATP drug transporters (seeChapter 5). High-level resistance to NRTIs, especially thymidine analogs, occurs slowly by comparison to non-NRTIs and first-generation protease inhibitors. High-level resistance can occur rapidly with lamivudine and emtricitabine. Cross-resistance is common but often confined to drugs having similar chemical structures. Several nucleoside analogs have favorable safety and tolerability profiles and are useful in suppressing the emergence of HIV isolates resistant to the more potent drugs in combination regimens.

ZIDOVUDINE. Zidovudine (AZT) is a synthetic thymidine analog (see structure in Figure 59–2) with potent activity against a broad spectrum of retroviruses including HIV-1, HIV-2, and human T-cell lymphotrophic viruses (HTLVs) I and II. Zidovudine is active in lymphoblastic and monocytic cell lines but has no impact on cells already infected with HIV. Zidovudine appears to be more active in activated than in resting lymphocytes because the phosphorylating enzyme, thymidine kinase, is S-phase-specific. Zidovudine is FDA-approved for the treatment of adults and children with HIV infection and for preventing mother-to-child transmission; it also is recommended for post-exposure prophylaxis in HIV-exposed healthcare workers. Zidovudine (RETROVIR) is marketed in oral tablets, capsules, and solution as well as a solution for intravenous injection. Zidovudine is available in coformulated tablets with lamivudine (COMBIVIR) or with lamivudine and abacavir (TRIZIVIR).

MECHANISMS OF ACTION AND RESISTANCE. Intracellular zidovudine is phosphorylated to zidovudine 5′-triphosphate. Zidovudine 5′-triphosphate terminates the elongation of proviral DNA because it is incorporated by reverse transcriptase into nascent DNA but lacks a 3′-hydroxyl group. The monophosphate competitively inhibits cellular thymidylate kinase, and this may reduce the amount of intracellular thymidine triphosphate. Zidovudine 5′-triphosphate only weakly inhibits cellular DNA polymerase-α but is a more potent inhibitor of mitochondrial polymerase-γ. Because the conversion of zidovudine 5′-monophosphate to diphosphate is very inefficient, high concentrations of the monophosphate accumulate inside cells and may serve as a precursor depot for formation of triphosphate. As a consequence, there is little correlation between extracellular concentrations of parent drug and intracellular concentrations of triphosphate, and higher plasma concentrations of zidovudine do not increase intracellular triphosphate concentrations proportionately.

Resistance to zidovudine is associated with mutations at reverse transcriptase codons 41, 44, 67, 70, 210, 215, and 219. These mutations are referred to as thymidine analog mutations (TAMs) because of their ability to confer cross-resistance to other thymidine analogs such as stavudine. The M184V substitution in the reverse transcriptase gene associated with the use of lamivudine or emtricitabine greatly restores sensitivity to zidovudine. The combination of zidovudine and lamivudine produces greater long-term suppression of plasma HIV RNA than does zidovudine alone.

ADME. Zidovudine is absorbed rapidly and reaches peak plasma concentrations within 1 h. Table 59–2 summarizes the drug’s pharmacokinetic profile, which is not altered significantly during pregnancy; drug concentrations in the newborn approach those of the mother. Parent drug crosses the blood-brain barrier relatively well and also is detectable in breast milk, semen, and fetal tissue.

UNTOWARD EFFECTS. Patients initiating zidovudine treatment often complain of fatigue, malaise, myalgia, nausea, anorexia, headache, and insomnia; these symptoms usually resolve within a few weeks. Erythrocytic macrocytosis is seen in ~90% of patients but usually is not associated with anemia. Chronic zidovudine administration has been associated with nail hyperpigmentation. Skeletal muscle myopathy can occur and is associated with depletion of mitochondrial DNA, most likely as a consequence of inhibition of DNA polymerase-γ. Serious hepatic toxicity, with or without steatosis and lactic acidosis, is rare but can be fatal.

PRECAUTIONS AND INTERACTIONS. Zidovudine is not a substrate or inhibitor of CYPs. However, probenecid, fluconazole, atovaquone, and valproic acid may increase plasma concentrations of zidovudine, probably through inhibition of glucuronosyl transferases. Zidovudine can cause bone marrow suppression and should be used cautiously in patients with preexisting anemia or granulocytopenia and in those taking other marrow-suppressive drugs. Stavudine and zidovudine compete for intracellular phosphorylation and should not be used concomitantly.

STAVUDINE. Stavudine (d4T) is a synthetic thymidine analog that is active in vitro against HIV-1 and HIV-2. Stavudine (ZERIT) is approved for use in HIV-infected adults and children, including neonates.

MECHANISMS OF ACTION AND RESISTANCE. Intracellular stavudine is sequentially phosphorylated stavudine 5′-triphosphate. Like zidovudine, stavudine is most potent in activated cells, probably because thymidine kinase, which produces the monophosphate, is an S-phase-specific enzyme. Stavudine resistance is seen most frequently with mutations at reverse transcriptase codons 41, 44, 67, 70, 210, 215, and 219, which are mutations associated with zidovudine resistance. Resistance mutations for stavudine appear to accumulate slowly. Cross-resistance to multiple nucleoside analogs has been reported following prolonged therapy.

ADME. Table 59–2 summarizes the agent’s PK data. Stavudine is well absorbed and reaches peak plasma concentrations within 1 h; bioavailability is not affected by food. The drug penetrates well into the CSF, achieving concentrations that are ~40% of those in plasma. Placental concentrations of stavudine are about half those of zidovudine. The drug undergoes active tubular secretion, and renal elimination accounts for ~40% of parent drug; thus, dose should be adjusted in patients with renal insufficiency.

UNTOWARD EFFECTS. The most common serious toxicity of stavudine is peripheral neuropathy. Although this may reflect mitochondrial toxicity, stavudine is a less potent inhibitor of DNA polymerase-γ than either didanosine or zalcitabine, suggesting that other mechanisms may be involved. Stavudine is also associated with a progressive motor neuropathy characterized by weakness and in some cases respiratory failure, similar to Guillain-Barré syndrome.

Lactic acidosis and hepatic steatosis are associated with stavudine use, and may be more common when stavudine and didanosine are combined. Acute pancreatitis is not highly associated with stavudine but is more common when stavudine is combined with didanosine than when didanosine is given alone. Of all nucleoside analogs, stavudine use is associated most strongly with fat wasting (lipoatrophy). Stavudine has fallen out of favor in the developed world largely because of this toxicity.

PRECAUTIONS AND INTERACTIONS. Stavudine is mainly renally cleared and is not subject to metabolic drug interactions. The incidence and severity of peripheral neuropathy may be increased when stavudine is combined with other neuropathic medications; thus, drugs such as ethambutol, isoniazid, phenytoin, and vincristine should be avoided. Combining stavudine with didanosine leads to increased risk and severity of peripheral neuropathy and potentially fatal pancreatitis; therefore, these 2 drugs should not be used together. Stavudine and zidovudine compete for intracellular phosphorylation and should not be used concomitantly.

LAMIVUDINE. Lamivudine is a cytidine analog reverse transcriptase inhibitor that is active against HIV-1, HIV-2, and HBV. Lamivudine (EPIVIR) is approved for HIV in adults and children ≥3 months of age. Lamivudine has been effective in combination with other antiretroviral drugs in both treatment-naive and experienced patients and is a common component of therapy, given its safety, convenience, and efficacy. Lamivudine (EPIVIR-HBV) is approved for treatment of chronic hepatitis B.

MECHANISMS OF ACTION AND RESISTANCE. Lamivudine enters cells by passive diffusion and is sequentially phosphorylated to lamivudine 5′-triphosphate, which is the active anabolite. Lamivudine has low affinity for human DNA polymerases, explaining its low toxicity to the host. High-level resistance to lamivudine occurs with single-amino-acid substitutions, M184V or M184I. These mutations can reduce in vitro sensitivity to lamivudine as much as 1000-fold. The M184V mutation restores zidovudine susceptibility in zidovudine-resistant HIV and also partially restores tenofovir susceptibility in tenofovir-resistant HIV harboring the K65R mutation. This effect may contribute to the sustained virologic benefits of zidovudine and lamivudine combination therapy.

ADME. Table 59–2 summarizes the PK parameters for this drug. Lamivudine is excreted primarily unchanged in the urine; dose adjustment is recommended for patients with a creatinine clearance <50 mL/min. Lamivudine freely crosses the placenta into the fetal circulation.

UNTOWARD EFFECTS. Lamivudine is one of the least toxic antiretroviral drugs. Neutropenia, headache, and nausea have been reported at higher than recommended doses. Pancreatitis has been reported in pediatric patients.

PRECAUTIONS AND INTERACTIONS. Because lamivudine also has activity against HBV, caution is warranted in using this drug in patients coinfected with HBV or in HBV-endemic areas: discontinuation of lamivudine may be associated with a rebound of HBV replication and exacerbation of hepatitis.

ABACAVIR. Abacavir (ZIAGEN), a synthetic purine analog, is approved for the treatment of HIV-1 infection, in combination with other antiretroviral agents. Abacavir is available in a co-formulation with zidovudine and lamivudine (TRIZIVIR) for twice-daily dosing and in a co-formulation with lamivudine (EPZICOM) for once-daily dosing. Abacavir is approved for use in adult and pediatric patients ≥3 months of age, with dosing in the latter based on body weight.

MECHANISMS OF ACTION AND RESISTANCE. Abacavir is the only approved antiretroviral that is active as a guanosine analog. It is sequentially phosphorylated in the host cell to carbovir 5′-triphosphate, which terminates the elongation of proviral DNA because it is incorporated by reverse transcriptase into nascent DNA but lacks a 3′-hydroxyl group. Clinical resistance to abacavir is associated with 4 specific substitutions: K65R, L74V, Y115F, and M184V. In combination, these substitutions can reduce susceptibility by up to 10-fold. K65R confers cross-resistance to all nucleosides except zidovudine. An alternate pathway for abacavir resistance involves mutations at codons 41, 210, and 215.

ADME. Table 59–2 summarizes the PK parameters for this agent. The presence of food does not affect the oral bioavailability of abacavir. Abacavir is neither a substrate nor an inhibitor of CYPs. Its CSF/plasma AUC ratio is ~0.3.

UNTOWARD EFFECTS. The most important adverse effect of abacavir is a unique and potentially fatal hypersensitivity syndrome characterized by fever, abdominal pain, and other GI complaints; a mild maculopapular rash; and malaise or fatigue. Respiratory complaints (cough, pharyngitis, dyspnea), musculoskeletal complaints, headache, and paresthesias are less common. The presence of concurrent fever, abdominal pain, and rash within 6 weeks of starting abacavir is diagnostic and necessitates immediate discontinuation of the drug. Abacavir must never be restarted once discontinued for hypersensitivity. The hypersensitivity syndrome (in 2-9% of patients) results from a genetically mediated immune response linked to both the HLA-B*5701 locus and the M493T allele in the heat-shock locus Hsp70-Hom. The latter gene is implicated in antigen presentation, and this haplotype is associated with aberrant tumor necrosis factor-α release after exposure of human lymphocytes to abacavir ex vivo.

PRECAUTIONS AND INTERACTIONS. Abacavir is not associated with any clinically significant pharmacokinetic drug interactions. However, a large dose of ethanol (0.7 g/kg) increased the abacavir plasma AUC by 41% and prolonged the elimination t1/2 by 26% possibly owing to competition for alcohol dehydrogenase, which produces the dehydro metabolite of the drug (see Table 59–2).

TENOFOVIR. Tenofovir disoproxil is a derivative of adenosine 5′-monophosphate that lacks a complete ribose ring; it is the only nucleotide analog currently marketed for the treatment of HIV infection. Tenofovir is available as the disoproxil prodrug, which substantially improves oral absorption. It is active against HIV-1, HIV-2, and HBV. Tenofovir (VIREAD) is FDA-approved for treating HIV infection in adults in combination with other antiretroviral agents and for the treatment of chronic hepatitis B in adults.

MECHANISMS OF ACTION AND RESISTANCE. Tenofovir disoproxil is hydrolyzed rapidly to tenofovir, which is phosphorylated by cellular kinases to its active metabolite, tenofovir diphosphate (which is actually a triphosphate: the parent drug is a monophosphate). Tenofovir diphosphate is a competitive inhibitor of viral reverse transcriptases and is incorporated into HIV DNA to cause chain termination because it has an incomplete ribose ring. Although tenofovir diphosphate has broad-spectrum activity against viral DNA polymerases, it has low affinity for human DNA polymerase-α, polymerase-β, and polymerase-γ, which is the basis for its selective toxicity.

Specific resistance occurs with a K65R substitution that has been associated with clinical failure of tenofovir-containing regimens. Tenofovir sensitivity and virologic efficacy also are reduced in patients harboring HIV isolates with high-level resistance to zidovudine or stavudine. The M184V mutation associated with lamivudine or emtricitabine resistance partially restores susceptibility in tenofovir-resistant HIV harboring the K65R mutation.

ADME. Table 59–2 shows PK data for tenofovir. Following an intravenous dose, 70-80% of the drug is recovered unchanged in the urine; thus, doses should be decreased in those with renal insufficiency. Tenofovir is not known to inhibit or induce CYPs.

UNTOWARD EFFECTS. Tenofovir generally is well tolerated, with few significant adverse effects reported except for flatulence. Rare episodes of acute renal failure and Fanconi syndrome have been reported, and this drug should be used with caution in patients with preexisting renal disease. Tenofovir use is associated with small declines in estimated creatinine clearance after months of treatment in some patients; because the dose needs to be reduced in renal insufficiency, renal function (creatinine and phosphorus) should be monitored regularly. Since tenofovir also has activity against HBV, caution is warranted in using this drug in patients coinfected with HBV: discontinuation of tenofovir may be associated with a rebound of HBV replication and exacerbation of hepatitis. Tenofovir can increase the AUC of didanosine and the 2 drugs probably should not be used together.

EMTRICITABINE. Emtricitabine (EMTRIVA) is a cytidine analog that is chemically related to lamivudine and shares many of its properties. Emtricitabine is active against HIV-1, HIV-2, and HBV. The drug is FDA-approved for treating HIV infection in adults in combination with other antiretroviral agents and is available co-formulated with tenofovir ± efavirenz.

MECHANISMS OF ACTION AND RESISTANCE. Emtricitabine enters cells by passive diffusion and is sequentially phosphorylated to its active metabolite, emtricitabine 5′-triphosphate. High-level resistance to emtricitabine occurs with the same mutations affecting lamivudine (mainly M184V), although these appear to occur less frequently with emtricitabine. The M184V mutation restores sensitivity to zidovudine and in zidovudine-resistant HIV partially restores sensitivity to tenofovir in tenofovir-resistant HIV harboring the K65R mutation. The same K65R mutation confers resistance to emtricitabine and the other cytidine analog lamivudine, as well as didanosine, stavudine, and abacavir.

ADME. Table 59–2 summarizes pharmacokinetic data for emtricitabine. Orally administered drug is absorbed rapidly and well; the drug can be taken without regard to meals. Emtricitabine is excreted primarily unchanged in the urine, thus, the dose should be reduced in patients with creatinine clearances of <50 mL/min.

UNTOWARD EFFECTS. Emtricitabine is one of the least toxic antiretroviral drugs and has few significant adverse effects. Prolonged exposure has been associated with hyperpigmentation of the skin, especially in sun-exposed areas. Because emtricitabine also has in vitro activity against HBV, caution is warranted in using this drug in patients co-infected with HBV and in regions with high HBV seroprevalence.

PRECAUTIONS AND INTERACTIONS. Emtricitabine is not metabolized to a significant extent by CYPs, and it is not susceptible to any known metabolic drug interactions.

DIDANOSINE. Didanosine (2′,3′-dideoxyinosine; ddI) is a purine nucleoside analog that is active against HIV-1, HIV-2, and other retroviruses including HTLV-1. The drug (VIDEX, VIDEX EC) is FDA-approved for adults and children with HIV infection in combination with other antiretroviral agents. This drug is no longer widely prescribed in the developed world because of the availability of agents with less toxicity.

MECHANISMS OF ACTION AND RESISTANCE. Didanosine enters cells via a nucleoside transporter and is sequentially phosphorylated by cellular enzymes to the triphosphate, the active anabolite that functions as an antiviral adenosine analog. Resistance to didanosine is associated with mutations at reverse transcriptase codons 65 and 74. The L74V substitution, which reduces susceptibility 5- to 26-fold in vitro, is seen most commonly in patients failing to respond to didanosine. Other nucleoside analog mutations, including TAMs, can contribute to didanosine resistance even though the drug does not appear to select for these mutations de novo. The reverse transcriptase insertion mutations at codon 69 produce cross-resistance to all current nucleoside analogs, including didanosine.

ADME. Table 59–2 summarizes some major pharmacokinetic parameters for didanosine. The drug is acid labile, and thus is administered with an antacid buffer. Food decreases didanosine bioavailability. All formulations of didanosine must be administered at least 30 min before or 2 h after eating. This complicates dosing of didanosine in combination with antiretroviral drugs that must be given with food, as is the case for most HIV protease inhibitors. Didanosine is excreted both by glomerular filtration and by tubular secretion; doses therefore must be adjusted in patients with renal insufficiency.

UNTOWARD EFFECTS. The most serious toxicities associated with didanosine include peripheral neuropathy and pancreatitis, both of which are thought to be a consequence of mitochondrial toxicity. Didanosine should be avoided in patients with a history of pancreatitis or neuropathy. Patients complain of pain, numbness, and tingling in the affected extremities. If the drug is stopped as soon as symptoms appear, the neuropathy should improve or resolve. However, irreversible neuropathy can occur with continued use. Retinal changes and optic neuritis also have been reported. Coadministration of other drugs that cause pancreatitis or neuropathy (i.e., stavudine) also will increase the risk and severity of these symptoms. Ethambutol, isoniazid, vincristine, cisplatin, and pentamidine also should be avoided. Serious hepatic toxicity occurs very rarely but can be fatal. Other reported adverse effects include elevated hepatic transaminases, headache, and asymptomatic hyperuricemia and portal hypertension.

PRECAUTIONS AND INTERACTIONS. Buffering agents included in didanosine formulations can interfere with the bioavailability of some coadministered drugs because of altered pH or chelation with cations in the buffer. For example, didanosine greatly reduces the AUCs of ciprofloxacin and indinavir; concentrations of ketoconazole and itraconazole, whose absorption is pH dependent, also are diminished. These interactions generally can be avoided by separating administration of didanosine from that of other agents by at least 2 h after or 6 h before the interacting drug. The enteric-coated formulation of didanosine does not alter ciprofloxacin or indinavir absorption. Didanosine is excreted renally, and shared renal excretory mechanisms provide a basis for interactions with oral ganciclovir, allopurinol, and tenofovir. Methadone decreases the didanosine AUC by ~60%.


NNRTIs include a variety of chemical substrates that bind to a hydrophobic pocket in the p66 subunit of the HIV-1 reverse transcriptase, in a site distant from the active site (Figure 59–3). These compounds induce a conformational change in the 3-dimensional structure of the enzyme that greatly reduces its activity, and thus they act as noncompetitive inhibitors. Because the binding site for NNRTIs is virus-strain-specific, the approved agents are active against HIV-1 but not HIV-2 or other retroviruses and should not be used to treat HIV-2 infection. These compounds also have no activity against host cell DNA polymerases. The 4 approved NNRTIs are nevirapine, efavirenz, etravirine, and delavirdine. Table 59–3summarizes their pharmacokinetic properties.


Figure 59–3 Mechanism of non-nucleoside reverse transcriptase inhibitors (NNRTIs).

Table 59–3

Pharmacokinetic Properties of Non-nucleoside Reverse Transcriptase Inhibitorsa


Agents in this class share a number of properties. All approved NNRTIs are eliminated from the body by hepatic metabolism. Efavirenz, etravirine, and nevirapine are moderately potent inducers of hepatic drug-metabolizing enzymes including CYP3A4; delavirdine is mainly a CYP3A4 inhibitor. Pharmacokinetic drug interactions are thus an important consideration with this class of compounds. All NNRTIs except etravirine are susceptible to high-level drug resistance caused by single-amino-acid changes in the NNRTI-binding pocket (usually in codons 103 or 181). Exposure to even a single dose of nevirapine in the absence of other antiretroviral drugs is associated with resistance mutations in up to one-third of patients. These agents are potent and highly effective but must be combined with at least 2 other active agents to avoid resistance.

The use of efavirenz or nevirapine in combination with other antiretroviral drugs is associated with favorable long-term suppression of viremia and elevation of CD4+ lymphocyte counts. Efavirenz is a common component of first regimens for treatment-naive patients indue to its convenience, tolerability, and potency. Rashes occur frequently with all NNRTIs, usually during the first 4 weeks of therapy. Rare cases of potentially fatal Stevens-Johnson syndrome have been reported with nevirapine, efavirenz, and etravirine. Fat accumulation can be seen after long-term use of NNRTIs, and fatal hepatitis has been associated with nevirapine use.

NEVIRAPINE. Nevirapine (VIRAMUNE) is a dipyridodiazepinone NNRTI with potent activity against HIV-1. The drug is FDA-approved for the treatment of HIV-1 infection in adults and children in combination with other antiretroviral agents. Nevirapine should never be used as a single agent or as the sole addition to a failing regimen. Nevirapine is approved for use in infants and children ≥15 days old, with dosing based on body surface area. Single-dose nevirapine has been used commonly in pregnant HIV-infected women to prevent mother-to-child transmission.

ADME. Table 59–3 summarizes the PK data for this agent. Nevirapine is well absorbed and its bioavailability is not altered by food or antacids. The drug readily crosses the placenta and has been found in breast milk. Nevirapine is a moderate inducer of CYPs and induces its own metabolism. To compensate for this, it is recommended that the drug be initiated at a dose of 200 mg once daily for 14 days, with the dose then increased to 200 mg twice daily if no adverse reactions have occurred.

UNTOWARD EFFECTS. The most frequent adverse events associated with nevirapine are rash (in ~16% of patients) and pruritus. In most patients the rash resolves with continued administration of drug; administration of glucocorticoids may cause a more severe rash. Life-threatening Stevens-Johnson syndrome is rare but occurs in up to 0.3% of recipients. Clinical hepatitis occurs in up to 1% of patients. Severe and fatal hepatitis has been associated with nevirapine use, and this may be more common in women with CD4 counts >250 cells/mm3, especially during pregnancy. Other reported side effects include fever, fatigue, headache, somnolence, and nausea.

PRECAUTIONS AND INTERACTIONS. Because nevirapine induces CYP3A4, this drug may lower plasma concentrations of coadministered CYP3A4 substrates. Methadone withdrawal has been reported in patients receiving nevirapine, presumably as a consequence of enhanced methadone clearance. Plasma ethinyl estradiol and norethindrone concentrations decrease by 20% with nevirapine; alternative methods of birth control are advised.

EFAVIRENZ. Efavirenz (SUSTIVA) (see structure in Figure 59–3) is an NNRTI with potent activity against HIV-1. The drug should be used only in combination with other effective agents and should not be added as the sole new agent to a failing regimen. Efavirenz is used widely in the developed world because of its convenience, effectiveness, and long-term tolerability. Especially popular is the once-daily single pill co-formulation of efavirenz, tenofovir, and emtricitabine (ATRIPLA). Efavirenz plus 2 nucleoside reverse transcriptase inhibitors remains a preferred regimen for treatment-naive patients. Efavirenz can be safely combined with rifampin and is useful in patients also being treated for tuberculosis. Efavirenz is approved for adult and pediatric patients ≥3 years of age and weighing at least 10 kg.

ADME. Table 59–3 summarizes the PK data for this agent. Efavirenz is well absorbed from the GI tract, but there is diminished absorption of the drug with increasing doses. Bioavailability (AUC) is increased by 22% with a high-fat meal. Efavirenz is >99% bound to plasma proteins and, as a consequence, has a low CSF-to-plasma ratio of 0.01. The drug should be taken initially on an empty stomach at bedtime to reduce side effects. Efavirenz is cleared mainly by CYP2B6 and to a lesser extent by CYP3A4. The parent drug is not excreted renally to a significant degree. The long elimination t1/2 permits once-daily dosing.

UNTOWARD EFFECTS. The most important adverse effects of efavirenz involve the CNS. Up to 53% of patients report some CNS or psychiatric side effects, but <5% discontinue the drug for this reason. Patients commonly report dizziness, impaired concentration, dysphoria, vivid or disturbing dreams, and insomnia. CNS side effects generally become more tolerable and resolve within the first 4 weeks of therapy. Rash occurs frequently with efavirenz (27%), usually in the first few weeks of treatment, resolving spontaneously and rarely requiring drug discontinuation. Life-threatening skin eruptions such as Stevens-Johnson syndrome are rare. Other side effects reported with efavirenz include headache, increased hepatic transaminases, and elevated serum cholesterol. Efavirenz is the only antiretroviral drug that is unequivocally teratogenic in primates. Women of childbearing potential therefore should use 2 methods of birth control and avoid pregnancy while taking efavirenz.

PRECAUTIONS AND INTERACTIONS. Efavirenz is a moderate inducer of hepatic enzymes, especially CYP3A4, but also a weak to moderate CYP inhibitor. Efavirenz decreases concentrations of phenobarbital, phenytoin, and carbamazepine; the methadone AUC is reduced by 33-66% at steady state. Efavirenz reduces the rifabutin AUC by 38% on average. Efavirenz has a variable effect on HIV protease inhibitors: indinavir, saquinavir, and amprenavir concentrations are reduced; ritonavir and nelfinavir concentrations are increased. Drugs that induce CYPs 2B6 or 3A4 (e.g., phenobarbital, phenytoin, and carbamazepine) would be expected to increase the clearance of efavirenz and should be avoided.

ETRAVIRINE. Etravirine is a diarylpyrimidine NNRTI that is active against HIV-1. Etravirine is unique in its ability to inhibit reverse transcriptase that is resistant to other NNRTIs. The drug appears to have conformational and positional flexibility in the NNRTI binding pocket that allow it to inhibit the function of the HIV-1 reverse transcriptase in the presence of common NNRTI resistance mutations. Etravirine (INTELENCE) is approved for use only in treatment-experienced HIV-infected adults. NNRTI-experienced patients should not receive etravirine plus NRTIs alone. Etravirine has not yet been approved for pediatric use.

ADME. Table 59–3 summarizes the PK data for this agent. Food increases the etravirine AUC by 50%, and it is recommended that the drug be administered with food. Methyl- and dimethyl-hydroxylated metabolites are produced in the liver primarily by CYPs 3A4, 2C9, and 2C19, accounting for most of the elimination of this drug. No unchanged drug is detected in the urine.

UNTOWARD EFFECTS. The only notable side effect of etravirine is rash (17% vs. placebo value of 9%), usually occurring within a few weeks of starting therapy and resolving within 1-3 weeks. Severe rash including Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported.

PRECAUTIONS AND INTERACTIONS. Etravirine is an inducer of CYP3A4 and glucuronosyl transferases, and an inhibitor of CYPs 2C9 and 2C19, and can therefore be involved in a number of clinically significant pharmacokinetic drug interactions. Etravirine can be combined with darunavir/ritonavir, lopinavir/ritonavir, and saquinavir/ritonavir without the need for dose adjustments. The dose of maraviroc should be doubled when these 2 drugs are combined. Etravirine should not be administered with tipranavir/ritonavir, fosamprenavir/ritonavir, or atazanavir/ritonavir in the absence of better data to guide dosing. Etravirine should not be combined with efavirenz, nevirapine, or delavirdine. Unlike other NNRTIs, etravirine does not appear to alter the clearance of methadone.


Delavirdine is a bisheteroarylpiperazine NNRTI that selectively inhibits HIV-1. This agent shares resistance mutations with efavirenz and nevirapine. Delavirdine is well absorbed, especially at pH <2. Antacids, histamine H2-receptor antagonists, proton pump inhibitors, and achlorhydria may decrease its absorption. The drug can be administered irrespective of food. Delavirdine clearance is primarily through oxidative metabolism by CYP3A4, with <5% of a dose recovered unchanged in the urine. At the recommended dose of 400 mg 3 times daily, the elimination t1/2 is 5.8 h.

The most common side effect of delavirdine is rash (18-36%), usually in the first few weeks of treatment and often resolving despite continued therapy. Severe dermatitis, including erythema multiforme and Stevens-Johnson syndrome, is rare. Elevated hepatic transaminases and hepatic failure also have been reported, as has neutropenia (rare). Delavirdine is both a substrate for and an inhibitor of CYP3A4 and can alter the metabolism of other CYP3A4 substrates. Delavirdine increases the plasma concentrations of most HIV protease inhibitors.


HIV protease inhibitors (PIs) are peptide-like chemicals that competitively inhibit the action of the virus aspartyl protease (Figure 59–4). This protease is a homodimer consisting of two 99-amino acid monomers; each monomer contributes an aspartic acid residue that is essential for catalysis. The preferred cleavage site for this enzyme is the N-terminal side of proline residues, especially between phenylalanine and proline. Human aspartyl proteases (i.e., renin, pepsin, gastricsin, and cathepsins D and E) contain only 1 polypeptide chain and are not significantly inhibited by HIV PIs.


Figure 59–4 Mechanism of action of the HIV protease inhibitor saquinavir. Shown here is a phenylalanine-proline target peptide sequence (in blue) for the protease enzyme (in golden brown) with chemical structures of the native amino acids (in lower box) to emphasize homology of their structures to that of saquinavir (at top).

Table 59–4 summarizes pharmacokinetic data for these agents. Clearance is mainly through hepatic oxidative metabolism. All except nelfinavir are metabolized predominantly by CYP3A4 (and nelfinavir’s major metabolite is cleared by CYP3A4). All approved HIV PIs have the potential for metabolic drug interactions. Most of these drugs inhibit CYP3A4 at clinically achieved concentrations, although the magnitude of inhibition varies greatly, with ritonavir by far the most potent. It is now a common practice to combine HIV PIs with a low dose of ritonavir to take advantage of that drug’s remarkable capacity to inhibit CYP3A4 metabolism. Doses of 100 or 200 mg once or twice daily are sufficient to inhibit CYP3A4 and increase (“boost”) the concentrations of most concurrently administered CYP3A4 substrates. The enhanced pharmacokinetic profile of HIV PIs administered with ritonavir reflects inhibition of both first-pass and systemic clearance, resulting in improved oral bioavailability and a longer elimination t1/2 of the coadministered drug. This allows a reduction in both drug dose and dosing frequency while increasing systemic concentrations. Combinations of darunavir, lopinavir, fosamprenavir, and atazanavir with ritonavir are approved for once-daily administration.

Table 59–4

Pharmacokinetic Properties of HIV-1 Protease Inhibitorsa


Most HIV PIs are substrates for the P-glycoprotein efflux pump (P-gp) (see Chapter 5). These agents generally penetrate less well into semen than do NRTIs and NNRTIs. HIV PIs have a high interindividual variability that may reflect differential activity of intestinal and hepatic CYPs. The speed with which HIV develops resistance to unboosted PIs is intermediate between that of nucleoside analogs and NNRTIs. Initial (primary) resistance mutations in the enzymatic active site confer only a 3- to 5-fold drop in sensitivity to most drugs; these are followed by secondary mutations often distant from the active site that compensate for the reduction in proteolytic efficiency. Accumulation of secondary resistance mutations increases the likelihood of cross-resistance to other PIs.

GI side effects including nausea, vomiting, and diarrhea are common, although symptoms resolve within 4 weeks of starting treatment. With potent activity and favorable resistance profiles, these drugs are a common component of regimens for treatment-experienced patients. However, the virologic benefits of these drugs must be balanced against short- and long-term toxicities, including the risk of insulin resistance and lipodystrophy.

SAQUINAVIR. Saquinavir is a peptidomimetic hydroxyethylamine that inhibits both HIV-1 and HIV-2 replication (Figure 59–4). Typical of HIV PIs, high-level resistance requires accumulation of multiple resistance mutations. The drug is available as a hard-gelatin capsule (INVIRASE). When combined with ritonavir and nucleoside analogs, saquinavir produces viral load reductions comparable with those of other HIV protease inhibitor regimens.

ADME. Table 59–4 summarizes the pharmacokinetic profile of this agent. Fractional oral bioavailability is low owing mainly to first-pass metabolism, and so this drug should always be given in combination with ritonavir. Low doses of ritonavir increase the saquinavir steady-state AUC by 20- to 30-fold. Substances that inhibit intestinal but not hepatic CYP3A4 (e.g., grapefruit juice) can increase the saquinavir AUC by ~3-fold.

UNTOWARD EFFECTS. The most frequent side effects of saquinavir are GI: nausea, vomiting, diarrhea, and abdominal discomfort. Most side effects of saquinavir are mild and short lived, although long-term use is associated with lipodystrophy.

PRECAUTIONS AND INTERACTIONS. Saquinavir clearance is increased with CYP3A4 induction. Coadministration of inducers of CYP3A4 such as rifampin, phenytoin, or carbamazepine lowers saquinavir concentrations and should be avoided. The effect of nevirapine or efavirenz on saquinavir may be reversed with ritonavir.

RITONAVIR. Ritonavir (NORVIR) is a peptidomimetic HIV protease inhibitor designed to complement the C2 axis of symmetry of the enzyme active site. Ritonavir is active against both HIV-1 and HIV-2 (perhaps slightly less active against HIV-2). Ritonavir is mostly used as a pharmacokinetic enhancer (CYP3A4 inhibitor); the low doses used for this purpose are not known to induce ritonavir resistance mutations. The drug is used infrequently as the sole protease inhibitor in combination regimens because of GI toxicity.

ADME. Table 59–4 summarizes the pharmacokinetic profile of this agent. Interindividual variability in pharmacokinetics is high, with variability exceeding 6-fold in trough concentrations among patients given 600 mg ritonavir every 12 h as capsules.

UNTOWARD EFFECTS. The major side effects of ritonavir are GI and include dose-dependent nausea, vomiting, diarrhea, anorexia, abdominal pain, and taste perversion. GI toxicity may be reduced if the drug is taken with meals. Peripheral and perioral paresthesias can occur at the therapeutic dose of 600 mg twice daily. These side effects generally abate within a few weeks of starting therapy. Ritonavir also causes dose-dependent elevations in serum total cholesterol and triglycerides, as well as other signs of lipodystrophy.

PRECAUTIONS AND INTERACTIONS. Ritonavir is one of the most potent known inhibitors of CYP3A4. Thus, ritonavir should be used with caution in combination with any CYP3A4 substrate and should not be combined with drugs that have a narrow therapeutic index such as midazolam, triazolam, fentanyl, and ergot derivatives. Ritonavir is a mixed competitive and irreversible inhibitor of CYP 3A4 and its effects can persist for 2-3 days after the drug is discontinued. Ritonavir is also a weak inhibitor of CYP2D6. Potent inducers of CYP3A4 activity such as rifampin may lower ritonavir concentrations and should be avoided or their dosage adjusted. Capsule and solution formulations of ritonavir contain alcohol and should not be administered with disulfiram or metronidazole. Ritonavir is also a moderate inducer of CYP3A4, glucuronosyl S-transferase, and possibly other hepatic enzymes and drug transport proteins. The concentrations of some drugs therefore will be decreased in the presence of ritonavir. Ritonavir reduces the ethinyl estradiol AUC by 40%, and alternative forms of contraception should be used.

Use of Ritonavir as a CYP3A4 Inhibitor. Ritonavir inhibits the metabolism of all current HIV PIs and is frequently used in combination with most of these drugs, with the exception of nelfinavir, to enhance their pharmacokinetic profile and allow a reduction in dose and dosing frequency of the coadministered drug. Ritonavir also overcomes the deleterious effect of food on indinavir bioavailability. Low doses of ritonavir (100 or 200 mg once or twice daily) are just as effective at inhibiting CYP3A4 and are much better tolerated than the 600 mg twice-daily.

FOSAMPRENAVIR. Fosamprenavir (LEXIVA) is a phosphonooxy prodrug of amprenavir that has increased water solubility and improved oral bioavailability. Fosamprenavir is as effective, and generally better tolerated than amprenavir, and as a result, amprenavir is no longer marketed. The drug is active against both HIV-1 and HIV-2. Fosamprenavir has long-term virologic benefit in treatment-naive and treatment-experienced patients, with or without ritonavir, in combination with nucleoside analogs. Twice-daily fosamprenavir/ritonavir produces virologic outcomes equivalent to lopinavir/ritonavir in both treatment-naive and treatment-experienced patients. Fosamprenavir is approved for use in treatment-naive pediatric patients ≥2 years of age and treatment-experienced patients ≥6 years of age, at a dose of 30 mg/kg twice daily or 18 mg/kg plus ritonavir 3 mg/kg twice daily.

Amprenavir’s primary resistance mutation occurs at HIV protease codon 50. Primary resistance occurs less frequently at codon 84.

ADME. Table 59–4 summarizes the pharmacokinetic profile of this agent. The phosphorylated prodrug is ~2000 times more water soluble than amprenavir. Fosamprenavir is dephosphorylated rapidly to amprenavir in the intestinal mucosa. Meals have no significant effect on fosamprenavir pharmacokinetics.

UNTOWARD EFFECTS. The most common adverse effects associated are GI and include diarrhea, nausea, and vomiting. Hyperglycemia, fatigue, paresthesias, and headache also have been reported. Fosamprenavir can produce skin eruptions; moderate to severe rash (in up to 8% of recipients) may occur within 2 weeks of starting therapy. Fosamprenavir has fewer effects on plasma lipid profiles than lopinavir-based regimens.

PRECAUTIONS AND INTERACTIONS. Inducers of hepatic CYP3A4 activity (e.g., rifampin and efavirenz) may lower plasma amprenavir concentrations. Because amprenavir is both a CYP3A4 inhibitor and inducer, pharmacokinetic drug interactions can occur and may be unpredictable, especially if the drug is given without ritonavir.

LOPINAVIR. Lopinavir is structurally similar to ritonavir but is 3- to 10-fold more potent against HIV-1. This agent is active against both HIV-1 and HIV-2. Lopinavir is available only in co-formulation with low doses of ritonavir (KALETRA) as a CYP3A4 inhibitor. Lopinavir has antiretroviral activity comparable with that of other potent HIV PIs and better than that of nelfinavir. Lopinavir also has considerable and sustained antiretroviral activity in patients who failed previous HIV protease inhibitor–containing regimens.

Treatment-naive patients who fail a first regimen containing lopinavir generally do not have HIV protease mutations but may have genetic resistance to the other drugs in the regimen. For treatment-experienced patients, accumulation of 4 or more HIV protease inhibitor resistance mutations is associated with a reduced likelihood of virus suppression after starting lopinavir.

ADME. Table 59–4 summarizes the pharmacokinetic profile of this agent. The adult lopinavir/ritonavir dose is 400/100 mg (2 tablets) twice daily, or 800/200 mg (4 tablets) once daily. Lopinavir/ritonavir should not be dosed once daily in treatment-experienced patients. Lopinavir/ritonavir is approved for use in pediatric patients ≥14 days, with dosing based on either weight or body surface area. A pediatric tablet formulation is available for use in children >6 months of age. Lopinavir is absorbed rapidly after oral administration. Food has a minimal effect on bioavailability. Although the tablets contain lopinavir/ritonavir in a fixed 4:1 ratio, the observed plasma concentration ratio for these 2 drugs following oral administration is nearly 20:1, reflecting the sensitivity of lopinavir to the inhibitory effect of ritonavir on CYP3A4. Both lopinavir and ritonavir are highly bound to plasma proteins, mainly to α1-acid glycoprotein, and have a low fractional penetration into CSF and semen.

UNTOWARD EFFECTS. The most common adverse events reported with the lopinavir/ritonavir co-formulation are GI: loose stools, diarrhea, nausea, and vomiting. Laboratory abnormalities include elevated total cholesterol and triglycerides. It is unclear whether these side effects are due to ritonavir, lopinavir, or both.

PRECAUTIONS AND INTERACTIONS. Concomitant administration of agents that induce CYP3A4, such as rifampin, may lower plasma lopinavir concentrations considerably. St. John’s wort is a known inducer of CYP3A4, leading to lower concentrations of lopinavir and possible loss of antiviral effectiveness. Coadministration of other antiretrovirals that can induce CYP3A4, including amprenavir, nevirapine or efavirenz, may require increasing the dose of lopinavir. The liquid formulation of lopinavir contains 42% ethanol and should not be administered with disulfiram or metronidazole. Ritonavir is also a moderate CYP inducer at the dose employed in the co-formulation and can adversely decrease concentrations of some coadministered drugs (e.g., oral contraceptives). There is no direct proof that lopinavir is a CYP inducer in vivo; however, concentrations of some coadministered drugs (e.g., amprenavir and phenytoin) are lower with the lopinavir/ritonavir co-formulation than would have been expected with low-dose ritonavir alone.

ATAZANAVIR. Atazanavir is an azapeptide protease inhibitor that is active against both HIV-1 and HIV-2.

THERAPEUTIC USE. In treatment-experienced patients, atazanavir (REYATAZ) 400 mg once daily without ritonavir was inferior to the lopinavir/ritonavir co-formulation given twice daily. The combination of atazanavir and low-dose ritonavir had a similar viral-load effect as the lopinavir/ritonavir co-formulation in 1 study, suggesting that this drug should be combined with ritonavir in treatment-experienced patients and perhaps in treatment-naive patients with high baseline viral load. Atazanavir, in combination with ritonavir, is approved for treatment of pediatric patients >6 years of age, with dosing based on weight. The primary atazanavir resistance mutation occurs at HIV protease codon 50 and confers ~9-fold decreased susceptibility. High-level resistance is more likely if 5 or more additional mutations are present.

ADME. Table 59–4 summarizes the pharmacokinetic profile of this agent. Atazanavir is absorbed rapidly after oral administration. A light meal increases the AUC by 70%; a high-fat meal increases the AUC by 35%. It is therefore recommended that the drug be administered with food. Absorption is pH dependent, and proton pump inhibitors or other acid-reducing agents substantially reduce atazanavir concentrations after oral dosing. The mean elimination t1/2 of atazanavir increases with dose, from 7 h at the standard 400-mg once-daily dose to nearly 10 h at a dose of 600 mg. The drug is present in CSF at <3% of plasma concentrations but has excellent penetration into seminal fluid.

UNTOWARD EFFECTS. Like indinavir, atazanavir frequently causes unconjugated hyperbilirubinemia, although this is not associated with hepatotoxicity. Postmarketing reports include hepatic adverse reactions of cholecystitis, cholelithiasis, cholestasis, and other hepatic function abnormalities. Other side effects reported with atazanavir include diarrhea and nausea, mainly during the first few weeks of therapy. Overall, 6% of patients discontinue atazanavir because of side effects during 48 weeks of treatment. Patients treated with atazanavir have significantly lower fasting triglyceride and cholesterol concentrations than patients treated with nelfinavir, lopinavir, or efavirenz. Atazanavir is not known to cause glucose intolerance or changes in insulin sensitivity.

PRECAUTIONS AND INTERACTIONS. Because atazanavir is metabolized by CYP3A4, concomitant administration of agents that induce CYP3A4 (e.g., rifampin) is contraindicated. Atazanavir is also a moderate inhibitor of CYP3A4 and may alter plasma concentrations of other CYP3A4 substrates. Atazanavir is a moderate UGT1A1 inhibitor and increases the raltegravir AUC by 41-72%. Ritonavir significantly increases the atazanavir AUC and reduces atazanavir systemic clearance. Proton pump inhibitors (PPIs) reduce atazanavir concentrations substantially with concomitant administration. PPIs and H2 blockers should be avoided in patients receiving atazanavir without ritonavir.

DARUNAVIR. Darunavir is a nonpeptidic protease inhibitor that is active against both HIV-1 and HIV-2. Darunavir binds tightly but reversibly to the active site of HIV protease but has also been shown to prevent protease dimerization. At least 3 darunavir-associated resistance mutations are required to confer resistance. Darunavir (PREZISTA) in combination with ritonavir is approved for use in HIV-infected adults.

ADME. Table 59–4 summarizes the pharmacokinetic profile of this agent. Darunavir/ritonavir can be used as a once-daily (800/100 mg) or twice-daily (600/100 mg) regimen with nucleosides in treatment-naive adults and as a twice-daily regimen (with food) in treatment-experienced adults. Darunavir/ritonavir twice daily is approved for use in pediatric patients >6 years of age, with dosing based on weight. Darunavir is absorbed rapidly after oral administration with ritonavir, with peak concentrations occurring 2-4 h. Ritonavir increases darunavir bioavailability by up to 14-fold. When combined with ritonavir, the mean elimination t1/2 of darunavir is ~15 h and the AUC is increased by an order of magnitude.

UNTOWARD EFFECTS. Because darunavir must be combined with a low dose of ritonavir, drug administration can be accompanied by all of the side effects caused by ritonavir, including GI complaints in up to 20% of patients. Darunavir, like fosamprenavir, contains a sulfa moiety, and rash has been reported in up to 10% of recipients. Darunavir/ritonavir is associated with increases in plasma triglycerides and cholesterol, although the magnitude of increase is lower than that seen with lopinavir/ritonavir. Darunavir has been associated with episodes of hepatotoxicity.

PRECAUTIONS AND INTERACTIONS. Because darunavir is metabolized by CYP3A4, concomitant administration of agents that induce CYP3A4 (e.g., rifampin) is contraindicated. The drug interaction profile of darunavir/ritonavir is dominated by those expected with ritonavir. Darunavir/ritonavir 600/100 twice daily increases the maraviroc AUC by 340%; the maraviroc dose should be reduced to 150 mg twice daily when combined with darunavir.

INDINAVIR. Indinavir is a peptidomimetic HIV protease inhibitor. Indinavir (CRIXIVAN) lacks significant advantages over other HIV PIs and is no longer widely prescribed because of problems with nephrolithiasis and other nephrotoxicities.

ADME. Table 59–4 summarizes the pharmacokinetic profile of this agent. Indinavir is absorbed rapidly after oral administration, with peak concentrations achieved in ~1 h. High-calorie, high-fat meals reduce plasma concentrations by 75%; thus, indinavir must be taken with ritonavir or while fasting or with a light low-fat meal. Indinavir has the lowest protein binding of the HIV PIs, with only 60% of drug bound to plasma proteins. As a consequence, indinavir has higher fractional CSF penetration than other drugs in this class. The short t1/2 of indinavir makes thrice-daily (every 8 h) dosing necessary unless the drug is combined with ritonavir, which reduces indinavir clearance, allowing twice-daily dosing regardless of meals.

UNTOWARD EFFECTS. A unique and common adverse effect of indinavir is crystalluria and nephrolithiasis, stemming from the poor solubility of the drug (lower at pH 7.4 than at pH 3.5). Nephrolithiasis occurs in ~3% of patients. Patients must drink sufficient fluids to maintain dilute urine and prevent renal complications. Risk of nephrolithiasis is related to higher plasma drug concentrations. Indinavir frequently causes unconjugated hyperbilirubinemia. This is generally asymptomatic and not associated with serious long-term sequelae. Prolonged administration of indinavir is associated with the HIV lipodystrophy syndrome. Indinavir has been associated with hyperglycemia and can induce a state of relative insulin resistance. Dermatologic complications have been reported, including hair loss, dry skin, dry and cracked lips, and ingrown toenails.

PRECAUTIONS AND INTERACTIONS. Patients taking indinavir should drink at least 2 L of water daily to prevent renal complications. This is especially problematic for those who live in warm climates. Because indinavir solubility decreases at higher pH, antacids or other buffering agents should not be taken at the same time. Didanosine formulations containing an antacid buffer should not be taken within 2 h before or 1 h after indinavir. Indinavir is metabolized by CYP3A4 and is a moderately potent CYP3A4 inhibitor. Indinavir should not be coadministered with other CYP3A4 substrates that have a narrow therapeutic index.

NELFINAVIR. Nelfinavir is a nonpeptidic protease inhibitor that is active against both HIV-1 and HIV-2. Nelfinavir (VIRACEPT) is approved for the treatment of HIV infection in adults and children in combination with other antiretroviral drugs. Long-term virologic suppression with nelfinavir-based combination regimens is significantly inferior to lopinavir/ritonavir, atazanavir, or efavirenz-based regimens. Nelfinavir is well tolerated in pregnant HIV-infected women but detection of a potentially carcinogenic contaminant led to a recommendation that the drug not be used pregnant women.

The primary nelfinavir resistance mutation (D30N) is unique to this drug and results in a 7-fold decrease in susceptibility. Isolates with only this mutation retain full sensitivity to other HIV PIs. Less commonly, a primary resistance mutation occurs at position 90, which can confer cross-resistance. Secondary resistance mutations can accumulate and these are associated with further resistance to nelfinavir, as well as cross-resistance to other HIV PIs.

ADME. Table 59–4 summarizes the pharmacokinetic profile of this agent. A moderate-fat meal increases the AUC 2- to 3-fold; higher concentrations are achieved with high-fat meals. Intraindividual and interindividual variabilities in plasma nelfinavir concentrations are large as a consequence of variable absorption. Nelfinavir is the only HIV protease inhibitor whose pharmacokinetics are not substantially improved with ritonavir. Its major hydroxy-t-butylamide metabolite, M8, is formed by CYP2C19 and has antiretroviral activity similar to that of the parent drug. This is the only known active metabolite of any HIV protease inhibitor. Nelfinavir induces its own metabolism.

UNTOWARD EFFECTS. The most important side effect of nelfinavir is diarrhea and loose stools, which resolve in most patients within the first 4 weeks of therapy. Otherwise, nelfinavir is generally well tolerated. It has been associated with glucose intolerance, elevated cholesterol levels, and elevated triglycerides.

PRECAUTIONS AND INTERACTIONS. Because nelfinavir is metabolized by CYPs 2C19 and 3A4, concomitant administration of agents that induce these enzymes may be contraindicated (as with rifampin) or may necessitate an increased nelfinavir dose (as with rifabutin). Nelfinavir is a moderate inhibitor of CYP3A4 and may alter plasma concentrations of other CYP3A4 substrates. Nelfinavir also induces hepatic drug-metabolizing enzymes, reducing the AUC of ethinyl estradiol by 47% and norethindrone by 18%. Combination oral contraceptives therefore should not be used as the sole form of contraception in patients taking nelfinavir. Nelfinavir reduces the zidovudine AUC by 35%.

TIPRANAVIR. Tipranavir is a non-peptidic protease inhibitor that is active against both HIV-1 and HIV-2. Tipranavir (APTIVUS) is approved for use only in treatment-experienced adult and pediatric patients whose HIV is resistant to 1 or more PIs. Combining tipranavir/ritonavir with at least 1 other active antiretroviral drug, usually enfuvirtide, greatly improves virologic responses. Tipranavir/ritonavir is approved for use in adults and pediatric patients >2 years of age, with pediatric dosing based on weight or body surface area.

Because most HIV strains sensitive to tipranavir are also sensitive to darunavir, darunavir is preferred for most treatment-experienced patients because of its better tolerability and toxicity profile.

ADME. Table 59–4 summarizes the pharmacokinetic profile of this agent. Tipranavir must be administered with ritonavir because of poor oral bioavailability. The recommended regimen of tipranavir/ritonavir 500/200 mg twice daily includes a ritonavir dose higher than that of other boosted HIV PIs; lower doses of ritonavir should not be used. Food does not alter pharmacokinetics in the presence of ritonavir but may reduce GI side effects.

UNTOWARD EFFECTS. Tipranavir use has been associated rarely with fatal hepatotoxicity and also with intracranial hemorrhage (including fatalities) and bleeding episodes in patients with hemophilia. The drug has anticoagulant properties in vitro and in animal models that are potentiated by vitamin E. Tipranavir is more likely to cause elevation in lipids and triglycerides than other boosted PIs, possibly due to the higher dose of ritonavir. Tipranavir contains a sulfa moiety, and ~10% of treated patients report a transient rash. The current formulation contains a high amount of vitamin E; patients should not take supplements containing this vitamin.

PRECAUTIONS AND INTERACTIONS. Like ritonavir, tipranavir is a substrate, inhibitor, and inducer of CYP enzymes. Tipranavir/ritonavir reduces the concentrations (AUC) of all coadministered PIs by 44-76% and should not be administered with any of these agents. This reflects the combined effect of the increased ritonavir dose, as well as tipranavir’s unique capacity among PIs to induce expression of the P-glycoprotein drug transporter.


The 2 drugs available in this class, enfuvirtide and maraviroc, have different mechanisms of action (see Figure 59–1). Enfuvirtide inhibits fusion of the viral and cell membranes mediated by gp41 and CD4 interactions. Maraviroc is a chemokine receptor antagonist and binds to the host cell CCR5 receptor to block binding of viral gp120.

MARAVIROC. Maraviroc blocks the binding of the HIV outer envelope protein gp120 to the CCR5 chemokine receptor (Figure 59–5). Maraviroc (SELZENTRY) is approved for use in HIV-infected adults who have baseline evidence of predominantly CCR5-tropic virus. The drug has no activity against viruses that are CXCR4-tropic or dual-tropic. Maraviroc retains activity against viruses that have become resistant to antiretroviral agents of other classes because of its unique mechanism of action.


Figure 59–5 Mechanism of action of the HIV entry inhibitor maraviroc.

HIV can develop resistance to this drug through 2 distinct pathways. A patient starting maraviroc therapy with HIV that is predominantly CCR5-tropic may experience a shift in tropism to CXCR4- or dual/mixed-tropism predominance. This is especially likely in patients harboring low-level but undetected CXCR4- or dual/mixed-tropic virus prior to initiation of maraviroc. Alternatively, HIV can retain its CCR5-tropism but gain resistance to the drug through specific mutations in the V3 loop of gp 120 that allow virus binding in the presence of inhibitor.

ADME. Maraviroc is the only antiretroviral drug approved at 3 different starting doses, depending on concomitant medications. When combined with most CYP3A inhibitors, the starting dose is 150 mg twice daily; when combined with most CYP3A inducers, the starting dose is 600 mg twice daily; for other concomitant medications, the starting dose is 300 mg twice daily. The oral bioavailability of maraviroc, 23-33%, is dose-dependent. Food decreases bioavailability, but there are no food requirements for drug administration. Elimination is mainly via CYP3A4 with an elimination t1/2 of 10.6 h.

UNTOWARD EFFECTS. Maraviroc is generally well tolerated. One case of serious hepatotoxicity with allergic features has been reported, but in controlled trials significant (grade 3 or 4) hepatotoxicity was no more frequent with maraviroc than with placebo.

PRECAUTIONS AND INTERACTIONS. Maraviroc is a CYP3A4 substrate and susceptible to pharmacokinetic drug interactions involving CYP3A4 inhibitors or inducers. Maraviroc is not itself a CYP inhibitor or inducer in vivo, although high-dose maraviroc (600 mg daily) can increase concentrations of the CYP2D6 substrate debrisoquine.

ENFUVIRTIDE. Enfuvirtide is a 36-amino-acid synthetic peptide that is not active against HIV-2 but is broadly effective against laboratory and clinical isolates of HIV-1. Enfuvirtide (FUZEON) is FDA-approved for use only in treatment-experienced adults who have evidence of HIV replication despite ongoing antiretroviral therapy. The drug’s cost and route of administration (subcutaneous injection twice daily) limit its use to those with no other treatment options.

MECHANISMS OF ACTION AND RESISTANCE. The amino acid sequence of enfuvirtide is derived from the transmembrane gp41 region of HIV-1 that is involved in fusion of the virus membrane lipid bilayer with that of the host cell membrane. The peptide blocks the interaction between the N36 and C34 sequences of the gp41 glycoprotein by binding to a hydrophobic groove in the N36 coil. This prevents formation of a 6-helix bundle critical for membrane fusion and viral entry into the host cell. Enfuvirtide inhibits infection of CD4+ cells by free virus particles. Enfuvirtide retains activity against viruses that have become resistant to antiretroviral agents of other classes. HIV can develop resistance to this drug through specific mutations in the enfuvirtide-binding domain of gp41.

ADME. Enfuvirtide is the only approved antiretroviral drug that must be administered parenterally. The bioavailability of subcutaneous enfuvirtide is 84% compared with an intravenous dose. Pharmacokinetics of the subcutaneous drug are not affected by site of injection. The major route of elimination for enfuvirtide has not been determined. The mean elimination t1/2 of parenteral drug is 3.8 h, necessitating twice-daily administration.

UNTOWARD EFFECTS. The most prominent adverse effects of enfuvirtide are injection-site reactions. Most patients (98%) develop local side effects including pain, erythema, and induration at the site of injection; 80% of patients develop nodules or cysts. Use of enfuvirtide has been associated with a higher incidence of lymphadenopathy and pneumonia. Enfuvirtide is not known to alter the concentrations of any coadministered drugs.


Chromosomal integration is a defining characteristic of retrovirus life cycles and allows viral DNA to remain in the host cell nucleus for a prolonged period of inactivity or latency (see Figure 59–1). Because human DNA is not known to undergo excision/reintegration, this process is an excellent target for antiviral intervention. The HIV integrase inhibitor, raltegravir, prevents the formation of covalent bonds between host and viral DNA—a process known as strand transfer—presumably by interfering with essential divalent cations in the enzyme’s catalytic core.

RALTEGRAVIR. Raltegravir blocks the catalytic activity of the HIV-encoded integrase, thus preventing integration of viral DNA into the host chromosome (Figure 59–6). Raltegravir has potent activity against both HIV-1 and HIV-2. Raltegravir retains activity against viruses that have become resistant to antiretroviral agents of other classes because of its unique mechanism of action. Raltegravir (ISENTRESS) is approved for use in HIV-infected adults.


Figure 59–6 Mechanism of action of the HIV integrase inhibitor raltegravir.

ADME. Peak concentrations of raltegravir occur ~1 h after oral dosing. Elimination is biphasic, with an α-phase t1/2 of ~1 h and a terminal β-phase t1/2 of 12 h, with the α-phase predominating. The pharmacokinetics of raltegravir are highly variable. Moderate- and high-fat meals increase raltegravir apparent bioavailability (AUC) by as much as 2-fold; a low-fat meal decreases AUC modestly (46%); however, there are no food requirements for raltegravir administration. The drug is 83% protein bound in human plasma. Raltegravir is eliminated mainly via glucuronidation by UGT1A1.

UNTOWARD EFFECTS. Raltegravir is generally well tolerated, with little clinical toxicity. The most common complaints are headache, nausea, asthenia, and fatigue. Creatine kinase elevations, myopathy, and rhabdomyolysis have been reported, as has exacerbation of depression.

PRECAUTIONS AND INTERACTIONS. As a UGT1A1 substrate, raltegravir is susceptible to pharmacokinetic drug interactions involving inhibitors or inducers of this enzyme. Atazanavir, a moderate UGT1A1 inhibitor, increases the raltegravir AUC 41-72%. Tenofovir increases the raltegravir AUC by 49%, but the mechanism for this interaction is unknown. When raltegravir is combined with the CYP inducer rifampin, the raltegravir dose should be doubled to 800 mg twice daily. Raltegravir has little effect on the pharmacokinetics of the usual coadministered drugs.

Future Treatment Guidelines

Several expert panels issue periodic recommendations for use of antiretroviral drugs for treatment-naive and treatment-experienced adults and children. In the U.S., the Panel on Clinical Practices for Treatment of HIV Infection issues updated guidelines approximately every 6 months; their most recent guidelines can be accessed at (Department of Health and Human Services).

Current treatment recommendations center around making 2 important clinical decisions:

• When to start therapy in treatment-naive individuals

• When to change therapy in individuals who are failing their current regimen

The specific drugs recommended may change as new choices become available and clinical research data accumulate. Selection of drugs in the developed world will be driven by genotypic and phenotypic resistance testing. However, future treatment guidelines will likely continue to be driven by 3 principles:

• Use of combination therapy to prevent the emergence of resistant virus

• Emphasis on regimen convenience, tolerability, and adherence to chronically suppress HIV replication

• Realization of the need for lifelong treatment under most circumstances

Treatment guidelines are not sufficient to dictate all aspects of patient management. Prescribers of antiretroviral therapy must maintain a comprehensive and current fund of knowledge regarding this disease and its pharmacotherapy. Because the treatment of HIV infection is a long-lived and complex affair, and because mistakes can have dire and irreversible consequences for the patient, the prescribing of these drugs should be limited to those with specialized training.