The primary drugs effective against HIV are antimetabolite inhibitors of viral reverse transcriptase and inhibitors of viral aspartate protease (Table 49–2). The current approach to treatment of infection with HIV is the initiation of treatment with 3 or more antiretroviral drugs, if possible, before symptoms appear. Such combinations usually include nucleoside reverse transcriptase inhibitors (NRTIs) together with inhibitors of HIV protease (PI). Highly active antiretroviral therapy (HAART) involving drug combinations can slow or reverse the increases in viral RNA load that normally accompany progression of disease. In many AIDS patients, HAART slows or reverses the decline in CD4 cells and decreases the incidence of opportunistic infections.
Drug management of HIV infection is subject to change. Updated recommendations can be obtained at the following websites: ATIS, http://www.hivatis.org; and NPIN, http://www.cdcnpin.org.
Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
To convert their RNA into dsDNA, retroviruses require virally encoded RNA-dependent DNA polymerase (reverse transcriptase). Mammalian RNA and DNA polymerases are sufficiently distinct to permit a selective inhibition of the viral reverse transcriptase.
NRTIs are prodrugs converted by host cell kinases to triphosphates, which not only competitively inhibit binding of natural nucleotides to the dNTP-binding site of reverse transcriptase but also act as chain terminators via their insertion into the growing DNA chain. Because NRTIs lack a 3′-hydroxyl group on the ribose ring, attachment of the next nucleotide is impossible. Resistance emerges rapidly when NRTIs are used as single agents via mutations in the pol gene; cross-resistance occurs but is not complete.
A guanosine analog, abacavir has good oral bioavailability and an intracellular half-life of 12–24 h. HIV resistance requires several concomitant mutations and tends to develop slowly. Hypersensitivity reactions, occasionally fatal, occur in 5% of HIV patients.
Oral bioavailability of ddI is reduced by food and by chelating agents. The drug is eliminated by the kidney, and the dose must be reduced in patients with renal dysfunction. Pancreatitis is dose-limiting and occurs more frequently in alcoholic patients and those with hypertriglyceridemia. Other adverse effects include peripheral neuropathy, diarrhea, hepatic dysfunction, hyperuricemia, and CNS effects.
Good oral bioavailability and renal elimination with long half-life permits once-daily dosing of emtricitabine. Because of the propylene glycol in the oral solution, the drug is contraindicated in pregnancy and young children and in patients with hepatic or renal dysfunction. Common adverse effects of the drug include asthenia, GI distress, headache, and hyperpigmentation of the palms and/or the soles.
Lamivudine is 80% bioavailable by the oral route and is eliminated almost exclusively by the kidney. In addition to its use in HAART regimens for HIV, lamivudine is also effective in hepatitis B infections. Dosage adjustment is needed in patients with renal insufficiency. Adverse effects of lamivudine are usually mild and include GI distress, headache, insomnia, and fatigue.
Stavudine has good oral bioavailability and penetrates most tissues, including the CNS. Dosage adjustment is needed in renal insufficiency. Peripheral neuropathy is dose-limiting and increased with coadministration of didanosine or zalcitabine. Lactic acidosis with hepatic steatosis occurs more frequently with stavudine than with other NRTIs.
Although it is a nucleotide, tenofovir acts like NRTIs to competitively inhibit reverse transcript and cause chain termination after incorporation into DNA. Tenofovir also has activity against HBV (see below). Oral bioavailability of tenofovir is in the range 25–40%, the intracellular half-life is more than 60 h, and the drug undergoes renal elimination. Tenofovir may impede the renal elimination of acyclovir and ganciclovir. Adverse effects include GI distress, asthenia, and headache; rare cases of acute renal failure and Fanconi's syndrome have been reported.
Zalcitabine has a high oral bioavailability. Dosage adjustment is needed in patients with renal insufficiency and nephrotoxic drugs (eg, amphotericin B, aminoglycosides) increase toxic potential. Dose-limiting peripheral neuropathy is the major adverse effect of ddC. Pancreatitis, esophageal ulceration, stomatitis, and arthralgias may also occur.
Formerly called azidothymidine (AZT), zidovudine is active orally and is distributed to most tissues, including the CNS. Elimination of the drug involves both hepatic metabolism to glucuronides and renal excretion. Dosage reduction is necessary in uremic patients and those with cirrhosis. The primary toxicity of zidovudine is bone marrow suppression (additive with other immunosuppressive drugs) leading to anemia and neutropenia, which may require transfusions. GI distress, thrombocytopenia, headaches, myalgia, acute cholestatic hepatitis, agitation, and insomnia may also occur. Drugs that may increase plasma levels of zidovudine include azole antifungals and protease inhibitors. Rifampin increases the clearance of zidovudine.
NRTIs and Lactic Acidosis
NRTI agents, taken alone or in combination with other antiretroviral agents, may cause lactic acidemia and severe hepatomegaly with steatosis. Risk factors include obesity, prolonged treatment with NRTIs, and preexisting liver dysfunction. Consideration should be given to suspension of NRTI treatment in patients who develop elevated aminotransferase levels.
Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs)
NNRTIs bind to a site on reverse transcriptase different from the binding site of NRTIs. Nonnucleoside drugs do not require phosphorylation to be active and do not compete with nucleoside triphosphates. There is no cross-resistance with NRTIs. Resistance from mutations in the pol gene occur very rapidly if these agents are used as monotherapy.
Drug interactions are a major problem with delavirdine, which is metabolized by both CYP3A4 and CYP2D6. Its blood levels are decreased by antacids, ddI, phenytoin, rifampin, and nelfinavir. Conversely, the blood levels of delavirdine are increased by azole antifungals and macrolide antibiotics. Delavirdine increases plasma levels of several benzodiazepines, nifedipine, protease inhibitors, quinidine, and warfarin. Delavirdine cause skin rash in up to 20% of patients, and the drug should be avoided in pregnancy because it is teratogenic in animals.
Efavirenz can be given once daily because of its long half-life. Fatty foods may enhance its oral bioavailability. Efavirenz is metabolized by hepatic cytochromes P450 and is frequently involved in drug interactions. Toxicity of efavirenz includes CNS dysfunction, skin rash, and elevations of plasma cholesterol. The drug should be avoided in pregnancy, particularly in the first trimester because fetal abnormalities have been reported in animals at doses similar to those used in humans.
Etravirine, the newest NNRTI approved for treatment-experienced HIV patients, may be effective against HIV strains resistant to other drugs in the group. The drug causes rash, nausea, and diarrhea. Elevations in serum cholesterol, triglycerides, and transaminase levels may occur. Etravirine is a substrate as well as an inducer of CYP3A4 and also inhibits CYP2C9 and CYP2C19 and may be involved in significant drug–drug interactions.
Nevirapine has good oral bioavailability, penetrates most tissues including the CNS, has a half-life of more than 24 h, and is metabolized by the hepatic CYP3A4 isoform. The drug is used in combination regimens and is effective in preventing HIV vertical transmission when given as single doses to mothers at the onset of labor and to the neonate. Hypersensitivity reactions with nevirapine include a rash, which occurs in 15–20% of patients, especially female. Stevens-Johnson syndrome and a life-threatening toxic epidermal necrolysis have also been reported. Nevirapine blood levels are increased by cimetidine and macrolide antibiotics and decreased by enzyme inducers such as rifampin.
The assembly of infectious HIV virions is dependent on an aspartate protease (HIV-1 protease) encoded by the pol gene. This viral enzyme cleaves precursor polyproteins to form the final structural proteins of the mature virion core. The HIV protease inhibitors are designer drugs based on molecular characterization of the active site of the viral enzyme. Resistance is mediated via multiple point mutations in the pol gene; the extent of cross-resistance is variable depending on the specific protease inhibitor. Protease inhibitors (PIs) have important clinical use in AIDS, most commonly in combinations with reverse transcriptase inhibitors as components of HAART. All of the PIs are substrates and inhibitors of CYP3A4 with ritonavir having the most pronounced inhibitory effect. The PIs are implicated in many drug–drug interactions with other antiretroviral agents and with commonly used medications.
This is a PI with a pharmacokinetic profile that permits once-daily dosing. Oral absorption of atazanavir requires an acidic environment—antacid ingestion should be separated by 12 h. The drug penetrates cerebrospinal and seminal fluids and undergoes biliary elimination. Adverse effects include GI distress, peripheral neuropathy, skin rash, and hyperbilirubinemia. Prolongation of the QTc interval may occur at high doses. Unlike most PIs, atazanavir does not appear to be associated with dyslipidemias, fat deposition, or a metabolic syndrome. However, it is a potent inhibitor of CYP3A4 and CYP2C9.
This drug is used in combination with ritonavir in treatment-experienced patients with resistance to other PIs. The drug is a substrate of CYP3A4. GI adverse effects and rash occur, and liver toxicity has been reported. Darunavir contains a sulfonamide moiety and should be used with caution in sulfonamide allergy.
Fosamprenavir is a prodrug forming amprenavir via its hydrolysis in the GI tract. The drug formulation includes propylene glycol and should not be used in children or in pregnant women. Fosamprenavir is often used in combination with low-dose ritonavir. The absorption of amprenavir is impeded by fatty foods. Amprenavir undergoes hepatic metabolism and is both an inhibitor and an inducer of CYP3A4. The drug causes GI distress, paresthesias, and rash, the latter sometimes severe enough to warrant drug discontinuation. Cross-allergenicity may occur with sulfonamides.
Oral bioavailability of indinavir is good except in the presence of food. Clearance is mainly via the liver, with about 10% renal excretion. Adverse effects include nausea, diarrhea, thrombocytopenia, hyperbilirubinemia, and nephrolithiasis. To reduce renal damage, it is important to maintain good hydration. Insulin resistance may be more common with indinavir than other PIs. Indinavir is a substrate for and an inhibitor of the cytochrome P450 isoform CYP3A4 and is implicated in drug interactions. Serum levels of indinavir are increased by azole antifungals and decreased by rifamycins. Indinavir increases the serum levels of antihistamines, benzodiazepines, and rifampin.
In this combination, a subtherapeutic dose of ritonavir acts as a pharmacokinetic enhancer by inhibiting the CYP3A4-mediated metabolism of lopinavir. Patient compliance is improved owing to lower pill burden and the combination is usually well tolerated.
This PI is characterized by increased oral absorption in the presence of food, hepatic metabolism via CYP3A4 and a short half-life. As an inhibitor of drug metabolism, nelfinavir has been involved in many drug interactions. Adverse effects include diarrhea, which can be dose-limiting. The drug has the most favorable safety profile of the PIs in pregnancy.
Oral bioavailability is good, and the drug should be taken with meals. Clearance is mainly via the liver, and dosage reduction is necessary in patients with hepatic impairment. The most common adverse effects of ritonavir are GI irritation and a bitter taste. Paresthesias and elevations of hepatic aminotransferases and triglycerides in the plasma also occur. Drugs that increase the activity of the cytochrome P450 isoform CYP3A4 (anticonvulsants, rifamycins) reduce serum levels of ritonavir, and drugs that inhibit this enzyme (azole antifungals, cimetidine, erythromycin) elevate serum levels of the antiviral drug. Ritonavir inhibits the metabolism of a wide range of drugs, including erythromycin, dronabinol, ketoconazole, prednisone, rifampin, and saquinavir.
Subtherapeutic doses of ritonavir inhibit the CYP3A-mediated metabolism of other protease inhibitors (eg, indinavir, lopinavir, saquinavir); this is the rationale for PI combinations that include ritonavir because it permits the use of lower doses of the other protease inhibitor.
Original formulations of saquinavir had low and erratic oral bioavailability. Reformulation for once-daily dosing in combination with low-dose ritonavir has improved efficacy with decreased GI side effects. The drug undergoes extensive first-pass metabolism and functions as both a substrate and inhibitor of CYP3A4. Adverse effects of saquinavir include nausea, diarrhea, dyspepsia, and rhinitis. Saquinavir plasma levels are increased by azole antifungals, clarithromycin, grapefruit juice, indinavir, and ritonavir. Drugs that induce CYP3A4 decrease plasma levels of saquinavir.
This is a newer drug used in combination with ritonavir in treatment-experienced patients with resistance to other PIs. The drug is a substrate and inducer of CYP3A4 and also induces P-glycoprotein transporters, possibly altering GI absorption of other drugs. For example, increased blood levels of the HMG-CoA reductase inhibitors (eg, lovastatin) may occur, thus increasing the risk for myopathy and rhabdomyolysis. GI adverse effects, rash, and liver toxicity have been reported.
Effects on Carbohydrate and Lipid Metabolism
The use of PIs in HAART drug combinations has led to the development of disorders in carbohydrate and lipid metabolism. It has been suggested that this is due to the inhibition of lipid-regulating proteins, which have active sites with structural homology to that of HIVprotease. The syndrome includes hyperglycemia and insulin resistance or hyperlipidemia, with altered body fat distribution. Buffalo hump, gynecomastia, and truncal obesity may occur with facial and peripheral lipodystrophy. The syndrome has been observed with PIs used in HAART regimens, with an incidence of 30–50% and a median onset time of approximately 1 yr duration of treatment.
HIV-1 infection begins with attachment of an HIV envelope protein called gp120 to CD4 molecules on surfaces of helper T cells and other antigen-presenting cells such as macrophages and dendritic cells. The attachment of many HIV strains involves a transmembrane chemokine receptor CCR5. This receptor, a human protein, is the target for maraviroc, which blocks viral attachment. Although resistance has occurred, there is minimal cross-resistance with other antiretroviral drugs.
Maraviroc is used orally and has good tissue penetration. It is a substrate for CYP3A4, and dosage adjustments may be needed in the presence of drugs that induce or inhibit this enzyme. Adverse effects of maraviroc include cough, diarrhea, muscle and joint pain, and increases in hepatic transaminases.
Enfuvirtide is a synthetic 36-amino-acid peptide. The drug binds to the gp41 subunit of the viral envelope glycoprotein, preventing the conformational changes required for the fusion of the viral and cellular membranes. There is no cross-resistance with other anti-HIV drugs, but resistance may occur via mutations in the env gene. Enfuvirtide is administered subcutaneously in combination with other anti-HIV agents in previously drug-treated patients with persistent HIV-1 replication despite ongoing therapy. Its metabolism via hydrolysis does not involve the cytochrome P450 system. Injection site reactions and hypersensitivity may occur. An increased incidence of bacterial pneumonia has been reported.
Integrase Strand Transfer Inhibitors
Raltegravir is a pyrimidine derivative that binds integrase, an enzyme essential to replication of both HIV-1 and HIV-2, inhibiting strand transfer. As a result, integration of reverse-transcribed HIV DNA into host cell chromosomes is inhibited. The drug has been used mainly in treatment-naïve HIV patients, usually in combination regimens. The drug is metabolized by glucuronidation and is not affected by agents that induce or inhibit hepatic cytochromes P450. However, if used with rifampin, which induces UDP-glucuronosyltransferase, the dose of raltegravir should be doubled. Adverse effects include nausea, diarrhea, dizziness, and fatigue. An increase in creatine kinase has been reported, with potential for myopathy or rhabdomyolysis.