Nucleoside analogs were the ﬁrst line of defense for the treat- ment of HIV infection in 1987 (36). Subsequent studies of var- ious combination therapies of indinavir, zidovudine, and lamivudine led to the beginnings of general combination ther- apy and the reﬁnement of HAART combination therapy. These early studies suggested that a prompt and aggressive drug therapy with three or more antiviral drugs from two or three classes of drugs might be more effective. HAART can reduce the plasma HIV virus levels to levels below the existing limits of detection (17).
Mechanisms of action. Nucleoside analogues are dideoxy- nucleoside analogues which are phosphorylated intracellu- larly into active triphosphate metabolites. The active form then competitively inhibits HIV reverse transcriptase by act- ing as an alternate substrate for the enzyme. This family of compounds lacks the 3¢-hydroxyl group, which leads to chain termination once the active metabolite is incorporated into the developing DNA strand. Figure 2.2 depicts the site of action of the existing and new antiretroviral drugs.
Zidovudine [AZT] (Retrovir®)
Zidovudine is the most extensively studied drug of all the anti- retrovirals. It is no longer used as monotherapy, except in parts of the world where other antiretroviral drugs are not available. It has been widely prescribed by practitioners after early studies revealed improved survival rates and delayed declines in CD4 counts in patients with HIV infection (36–38). As a result of monotherapy with zidovudine, resistant HIV strains have developed, which have limited the efﬁcacy of this treatment. After six months of therapy with zidovudine alone, HIV isolates with reduced susceptibility can be recovered (39,40). The quantity and frequency of resistant strains pro- gressively increases over time with monotherapy. As HIV-1 strains develop resistance to zidovudine therapy, those resis- tant strains have been proven to be transmittable to other per- sons (41–45). There are studies underway to develop a
Fig. 2.3 Trade names, structure, and uses of Zidovudine.
quantitative method to validate zidovudine resistance (46). There is a report that Korean red ginseng delays the develop- ment of resistance to zidovudine (47). The nucleoside analogue drugs are closely related and have similar mechanisms of action; there is cross-resistance among these compounds, but they have different side effect proﬁles (48). The structure of zidovudine, its brand names, and its approved usage are shown in Fig. 2.3. Zidovudine monotherapy is used for infants of indeterminate HIV status during the ﬁrst six weeks of life to prevent HIV transmission (16).
Phosphorylation of zidovudine. Poor phosphoryla- tion of zidovudine has been implicated in the intracel- lular accumulation of zidovudine monophosphate. This accumulation is associated with cytotoxicity as mediat- ed through mitochondrial damage (49).
Bone marrow suppression. The most frequently seen adverse effect of zidovudine is bone marrow suppres- sion, with severe anemia and/or neutropenia.
Coadministration with other drugs. Coadministra- tion with other drugs which may potentially suppress the bone marrow should be done cautiously, with fre- quent monitoring of hematologic parameters.
Gastrointestinal upset and/or nausea.
Hematoticity. Zidovudine may directly induce apoptosis by a hematotoxic mechanism and may be discontinued to restore T-cell levels and reduce apoptosis (50).
Neuropathy. Peripheral neuropathy with lactic acidosis and coproporphyria has been reported in a patient with human T-cell leukemia virus (HTLV)-1–associated T-cell leukemia (51).
Hepatotoxicity. There is one report of death from hepa- titis with lactic acidosis occurring in an individual who had discontinued zidovudine (due to nucleoside-in- duced acute hepatitis and lactic acidaemia) 18 months previously (52).
Myopathy or myositis.
Longitudinal melonychia. The most common cutane- ous manifestation of AZT use is longitudinal melony- chia which is usually noted after 2–6 weeks of therapy (53). The color of the affected nails has been described as “dark bluish or brownish.”
Other dermatologic manifestations. Skin pigmenta- tion, nonspeciﬁc macules and papules, pruritis, and urticaria are rarely reported.
Psoriasis. Patients with HIV infection may develop psori- asis which is very difﬁcult to treat using conventional therapy. An open-label study to determine the safety and efﬁcacy of AZT in HIV-associated psoriasis demonstrated that 90% of 19 evaluable patients had partial (58%) or complete (32%) improvement of their psoriasis (54). Other studies demonstrated that clinical improvement of HIV-associated psoriasis parallels a reduction of HIV viral load (55). Interestingly, AZT has also been given to HIV-negative patients with psoriasis. In a pilot study,
33% of these persons showed improvement in their pso- riasis, but no complete remissions occurred (56).
Pancreatitis. When compared with didanosine, stauvi- dine, and hydroxyurea, zidovudine causes the fewest cases of pancreatitis (57).
Pregnancy. Zidovudine has been shown to reduce peri- natal transmission. However, many women who are HIV-positive have reservations about taking the drug. Concerns revolve around fear of toxic effects on the mother, fear of toxic effects on the baby, fear of drug resistance, the belief that “healthy” women don’t need zidovudine, and having given birth to a healthy baby without using zidovudine. Clearly, additional educa- tional interventions are needed to increase the use of zidovudine during pregnancy to reduce perinatal trans- mission (58).
Pediatric patients. To reduce mother-to-child trans- mission of HIV, zidovudine is often prescribed. The treatment is not without complications. Lactic acid levels in the plasma often rise and these are associ- ated with possible mitochondrial dysfunction (59). Not only is zidovudine-resistance transferred from mothers to children, but also there is evidence that zidovudine-resistance develops in newborns almost immediately (60).
Didanosine [ddI] (Videx®)
Didanosine (ddI) is indicated for patients with HIV who are either unable to tolerate zidovudine or those who have became refractory to its effects. The structure, brand names, and approved usage of didanosine areshown in Fig. 2.4. In 1993, a partially randomized study compared zidovudine alone versus
Fig. 2.4 Trade names, structure, and uses of Didanosine.
different combination regimens of zidovudine and didanosine. The results showed more sustained increases in CD4-positive cell counts and more frequent decreases in plasma HIV-1 RNA titers among all combination regimens when compared with zidovudine alone (61). In cases of HIV-1-associated myelopa- thy, didanosine combined with zidovudine effected signiﬁcant neurological improvement (62).
Pancreatitis. The most serious side effect is pancreatitis which occurs in 7% of treated patients, with some fatal- ities reported. The use of hydroxyurea to potentiate the antiviral activity of didanosine yields a four-fold higher risk of pancreatitis (57).
Hyperamylasemia. Hyperamylasemia occurs in 20% of treated patients (63).
Coadministration with other drugs at risk to cause pancreatitis. Extreme caution should be used in pre- scribing concomitant drugs that may cause pancreatit- is, and only if necessary. If pancreatitis develops, it is usually reversible with prompt cessation of therapy.
Peripheral neuropathy. This occurs in 15% of treated patients and is related to the dose of didanosine, stage of disease, and combination therapy (64).
Fever and malaise. Fever and malaise are rare.
Ulcers. Oral and esophageal ulcers are rarely seen with ddI (65). One report notes Ofuji papuloerythroderma associated with ddI (66).
Antacid and antibiotic coadministration. Didanosine is an acid-labile compound which is formulated with an antacid buffer. It should be taken on an empty stomach, at least 30 minutes prior to or 2 hours after a meal, in order to avoid an unfavorable acidic envi- ronment. The quinolone antibiotics (e.g., ciproﬂoxacin) and certain antifungals, such as ketoconazole and
itraconazole, require an acidic environment for ab- sorption, and will be affected if administered with the antacid buffer found in didanosine. These drugs should be given at least 2 hours prior to or 6 hours after a dose of didanosine.
Coadministration with ribavirin. Coadministration of ribavirin with didanosine promotes mitochondrial toxicity. More studies need to be completed to deter- mine if reducing the dose of didanosine (when coad- ministered with ribavirin), changing the modalities of prescriptions, or avoiding concomitant prescriptions can avoid mitochondrial toxicity (67–69).
Stavudine [d4T] (Zerit®)
Stavudine (d4T) is indicated for AIDS patients in the later stages of disease who have proven either intolerant or unresponsive to the other antiretroviral drugs which are more commonly used. The structure, brand names, and approved usage of sta- vudine are shown in Fig. 2.5. When the effect of stavudine was studied in patients on therapy, the median virus titers in peripheral blood mononuclear cells were decreased by 1–2 logs and the plasma RNA content was reduced approximately 0.5 log from baseline median values at both 10 weeks and 52 weeks (70). Stavudine is administered orally as a capsule or in an oral solution. For adults and preadults weighing at least 132 pounds or more, 40 mg should be taken every 12 hours. For adults and
Fig. 2.5 Trade names, structure, and uses of Stavudine.
preadults weighing at least 66 but not more than 132 pounds,
30 mg should be taken every 12 hours. For children less than
66 pounds, 1 mg for every kg (0.45 mg per pound) of body weight should be given every 12 hours. For those patients with only one mutation conferring viral resistance to zidovudine, stavudine may be a reasonable alternative. The more muta- tions that are present, the less effective the stavudine will be as a replacement therapy (71).
The side effect proﬁle of stavudine is similar to that of zidovudine.
Peripheral neuropathy. The major side effect of stavu- dine is a dose-related peripheral neuropathy, affecting
20% of patients. Peripheral neuropathy is character- ized by a tingling, burning, numbness or pain in the hands or feet.
Lactic acidosis and severe hepatomegaly with ste- atosis. These adverse events have been reported in pa- tients using certain nucleoside analogues, such as stavudine and didanosine. Renal tubular dysfunction has occurred in at least one patient (72).
Mucocutaneous responses. Occasional erythema, ma- cules, and papules have been observed in patients tak- ing d4T (65). Esophageal ulcers are also rarely seen.
Lipoatrophy. Lipoatrophy is associated with mitochon- drial toxicity, lactic acidemia, and insulin resistance. Switching from stavudine or zidovudine to abacavir can lead to modest increases in limb fat, but clinical lipoatrophy does not resolve (73–75).
Neuromuscular weakness/respiratory failure. Hy- perlactatemia, a common stavudine adverse effect, is associated with a Guillain-Barre syndrome mimic. Twenty-two cases with seven deaths were reported. Should severe hyperlactatemia or motor weakness de- velop, the patient should be removed from the drug and supportive care supplied, including ventilation, as needed. If symptoms, such as fatigue, weight loss,
abdominal pain, nausea, vomiting, or dyspepsia, occur, the patient’s lactate levels should be monitored to pre- vent fatal lactic acidosis (76).
Zalcitabine [ddC] (Hivid®)
Zalcitabine (ddC), another synthetic nucleoside analogue, has minimal efﬁcacy when used alone, but is useful for combina- tion therapy in HIV patients. The structure, brand names, and approved usage for zalcitabine are shown in Fig. 2.6. Zalcitab- ine is a reverse transcriptase inhibitor. It is indicated, along with zidovudine, for patients with deteriorating HIV infection according to both clinical and immunological parameters (CD4 <300 /ml). The oral dosage is 0.75 three times daily. Most formulations are as 0.375-mg or 0.75-mg tablets. When zalcit- abine was taken with nelﬁnavir and zidovudine as combina- tion therapy, viral replication was suppressed, CD4 counts increased, and the quality of life improved for Nigerian patients with HIV (77). Triple therapy of saquinavir/stavu- dine/zalcitabine is reasonably well-tolerated with a rapid reduction in viral load and immunological improvement. It is considered to be an additional therapeutic option that is favor- able when compared with other triple therapy regimens (78). Saquinavir, zidovudine, and zalcitabine combination therapy is considered successful with some synergistic effect between saquinavir and zalcitabine (79,80). The opposite has been
Fig. 2.6 Trade names, structure, and uses of Zalcitabine.
reported for zalcitabine combined with zidovudine (81). Zalcit- abine combined with saquinavir alone was not sufﬁcient to increase signiﬁcantly the CD4 count even though there was a
79% clinical improvement in the patients (82). Zalcitabine is often coadministered with foscarnet, an antiviral used to treat cytomegalovirus infection, with no apparaent negative or pos- itive pharmacokinetic interaction (83).
Zalcitabine may contribute more to mitochondrial toxicity than lamivudine in that the exonuclease has more difﬁculty removing zalcitabine from the DNA chain (84).
Peripheral neuropathy. Peripheral neuropathy occurs in 17 to 30% of patients.
Pancreatitis. Severe pancreatitis may occur due to swelling of the pancreas.
Lactic acidosis. Lactic acidosis without hypoxemia may occur.
Hepatomegaly with steatosis. Hepatomegaly with steatosis may be severe.
Anemia, leucopenia, fatigue, and headache. Coadministration with metoclopramide, and with
aluminum and magnesium hydroxide prepara- tions (e.g., Maalox or Mylanta). These combinations administered with zalcitabine cause a decrease in the bioavailability of zalcitabine.
Coadministration with probenicid or cimetidine.
Coadministration with probenicid or cimetidine re- sults in a 50% increase in zalcitabine exposure as these drugs decrease elimination of zalcitabine and may in- crease chances for toxicity.
Cutaneous eruptions. Macular and papular eruptions have been reported to develop in 14 of 20 (70%) pa- tients treated with zalcitabine (85). This eruption usu- ally presented on day 10 or 11 of therapy.
Oral ulcers. Oral ulcers developed in nine of 14 patients on days four to six of treatment.
Esophageal ulcers. Esophageal ulcers have also been reported in 2–4% of patients treated with ddC (86). The eruption and ulcers usually resolve with continual ddC treatment.
Pregnancy and neonates. Pregnancy is not recom- mended either before or during administration of zal- citabine. The effect of zalcitabine on a developing fetus is unknown. In pigtailed macaque monkeys, adminis- tration of zalcitabine during the pregnancy did not af- fect the pharmacokinetics of the drug. In infant macaques, it appears that smaller and less frequent dosing in HIV-infected neonates is warranted than in older children and adults (87).
Renal impairment. Clearance of zalcitabine decreases in patients with renal impairment. Dosage adjust- ments may have to be made, especially in those with severe renal impairment (88).
Lamivudine [3TC] (Epivir®)
Lamivudine (3TC) is a synthetic nucleoside analogue that is FDA-approved for the treatment of HIV and chronic hepatitis B virus infections (See chapter 3 for a description of Hepatitis B infection). Combination therapy of lamivudine-interferon (IFN) to treat chronic hepatitis B has been suggested (89). Fig. 2.7
Fig. 2.7 Trade names, structure, and uses of Lamivudine.
highlights the molecular structure and brand names of lami- vudine. Recently, it was found that HIV-infected patients who received initial therapy with regimens including either stavu- dine or lamivudine had signiﬁcantly lower mortality and longer AIDS-free survival than those receiving initial thera- pies with regimens limited to zidovudine, didanosine, and zal- citabine (90). A combination of lamivudine and zidovudine (Combivir) has also been FDA-approved for the treatment of HIV infection. However, there are reports of recurrent hyper- sensitivity to Combivir (91). Lamivudine appears to have little or no genotoxicity (92). Lamivudine has greater efﬁcacy in treating Chinese patients with chronic hepatits B infection than does famciclovir (93).
Lamivudine has been incorporated into main-line pre- scriptions for HAART therapy. Lamivudine is often combined with zidovudine (Combivir) and abacavir with successful results regarding CD4 counts and general tolerance for the therapy (94).
Hepatotoxicity. In one rare case, an elderly man treated with lamivudine developed hepatic decompensation (95). Hepatic necrosis can also occur (96).
Peripheral neuropathy. Nausea /vomiting. Anorexia.
Headache. Malaise. Neutropenia.
Cutaneous responses. Alopecia, erythema, macules, papules, pruritis, and urticaria have been seen rarely with lamivudine (65).
Pediatric patients. In pediatric clinical trials, 14% of children on monotherapy and 15% of those on combina- tion therapy with lamivudine developed pancreatitis.
Mucocutaneous manifestations. When mucocutaneous manifestations are seen with Combivir, there appears to be an equal chance that zidovudine or lamivudine may be responsible.
Lamivudine resistance. One of the concerns of lamivu- dine use for the treatment of chonic hepatitis B is the emergence of a variety of genotypes for lamivudine re- sistance, particularly in HIV-1/HBV–coinfected pa- tients (97–99).
Abacavir [ABC] (Ziagen®)
Abacavir (ABC) is a second-generation NRTI given accelerated FDA approval for use in multi-drug cocktails. It is a synthetic carboxycyclic nucleoside with a 6-cyclopropylamino modiﬁca- tion. The structure, brand names, and approved usage are shown in Fig. 2.8. Abacavir is the most powerful nucleoside analogue and one of the most powerful antiretroviral drugs currently available. Its use results in reduction in viral loads and increases in CD4 counts which are unparalleled by any other nucleoside analogue and are similar to most potent PIs (100). Abacavir is normally administered as 300-mg doses twice daily although there is some indication that a 600-mg dose once daily is equally effective (101). In one study, abacavir plus zidovudine and lamivudine raised CD4 counts and low- ered plasma HIV RNA to undetectable levels in two-thirds of previously untreated patients (102). In addition, abacavir plus a PI lowered HIV viral loads in the majority of previously
Fig. 2.8 Trade names, structure, and uses of Abacavir.
untreated patients to undetectable levels (103,104). However, it should be noted that resistance to zidovudine and lamivu- dine gives cross-resistance to abacavir (105). In patients with lipoatrophy caused by stavudine or zidovudine sensitivity, aba- cavir results in modest increases in limb fat over 24 weeks (73). In patients who have previously been heavily treated with other nucleoside analogues, the addition of abacavir would be ineffective. Abacavir combined with zidovudine and lamivu- dine is now marketed as Trizivir for HAART therapy.
Hypersensitivity reactions. A serious and potentially le- thal hypersensitivity reaction to abacavir is seen in
2–5% of patients (106–110). Clinical presentation in- cludes fever to 39–40°C, macules, papules, and urticaria, fatigue, malaise, nausea, vomiting, diarrhea, abdominal pain, arthralgias, cough, and/or dyspnea. These clinical presentations may be associated with increased creatine phosphokinase (CPK), elevated liver function tests, and lymphopenia. These ﬁndings usually occur within the ﬁrst six weeks of therapy. The hypersensitivity reaction usually resolves with cessation of abacavir, but a rechal- lenge of the drug after this reaction can be fatal. All phy- sicians and patients should be aware of this potentially serous side effect. Therefore, patients taking ABC who develop a skin eruption associated with fever, gas- trointestinal symptoms, cough, dyspnea, and constitu- tional symptoms should be instructed to promptly contact their physician or, if severe, go to the nearest emergency room. Prednisolone may not be effective in treating hypersensitivity from drug toxicity (111).
Vertigo. Many HIV-positive patients report symptoms and signs of inner ear disease. Vertigo can cause signiﬁ- cant morbidity and prevent patients from living a nor- mal life. The appearance of vertigo with the introduction and removal of abacavir therapy implies that it may be a causative agent, with mitochondrial toxicity being the suspected mechanism (112).
Agranulocytosis after rash resolution. Several weeks after resolution of a slight rash, one patient devel- oped a fever, sore throat, ulcerated lips, diarrhea, and abdominal pain, probably the result of drug-related antibodies (113).
Hypersensitivity. Hypersensitivity includes not only rash, as described earlier, but anaphylactic shock (114–116). Many severe reactions seem to occur when abacavir is reintroduced after a previous cessation of treatment for hypersensitivity.
Emtricitabine (Emtriva, Coviracil, FTC)
Emtricitabine is a deoxycytidine nucleoside approved for use in combination with other antiretroviral agents (Fig. 2.9). It was tested in combination with didanosine and efavirenz against a stavudine, didanosine, and efavirenz combination. After 24 and 48 weeks, patients receiving the emtricitabine had signiﬁcantly higher rates of virologic suppression and ele- vated CD4 levels than the combination recipients. The dosage recommendation at this printing is one daily dose of 200 mg.
Mirochondrial toxicity. Mitochondrial toxicity is often associated with the use of NRTIs. To manage the tis- sue and drug-related toxicities (i.e., myopathy, periph- eral neuropathy, lactic acidosis), interruption of NRTI
Fig. 2.9 Trade names, structure, and uses of Emtricitabine.
therapy with a better-tolerated substitute should be considered (117).
The most common side effects during combination thera- py involving emitricitabine include:
Abdominal pain and /or diarrhea. Nausea and vomiting.
Other side effects:
Skin discoloration. Hyperpigmentation of soles of feet and /or palms of hands may occur. In most cases this has been mild and asymptomatic.
Reproductive proﬁle. A reproductive proﬁle has not been done on humans. However, in mice and rabbits, there were no increased numbers of malformations in embryofetal toxicology studies. Emtricitabine did not appear to affect fertility, sperm count, or early embry- onic development. Thus far, emtricitabine has a favor- able reproductive safety proﬁle (118).
Lamivudine resistance. The mutations associated with emtricitabine resistance are nearly identical to those that confer lamivudine resistance. Therefore, emtricit- abine most likely will not be beneﬁcial to patients who need to change treatment because of lamivudine resis- tance. Because of the high tendency for HIV to develop resistance to emtricitabine, it should be used only in regimens that normally fully suppress viral replication. Hepatitis B. Although not currently FDA-approved for this indication, emtricitabine is active against hepati-
tis B infection (119,120), as are interferon alpha and nucleoside analogs (121).
NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS
The class of NNRTIs is a chemically heterogeneous group of com- pounds that are entirely unrelated to nucleosides. They inhibit HIV replication at the same stage as nucleoside analogues, but
they noncompetitively bind directly to the active site of reverse transcriptase (122). (See Fig. 2.2 for the site of action.) These drugs are not substrates for the reverse transcriptase enzyme and are not incorporated into the developing viral DNA chain. They are also active in their native state and do not require phosphorylation to become an active metabolite (123). The NNRTIs are highly active for HIV-1, but have no activity against HIV-2. Resistance is a signiﬁcant problem with mono- therapy (124) and cross-resistance occurs among members of this class (125). However, there is no cross-resistance with nucleoside analogues (126). The NNRTIs are a suitable addi- tion for combination therapy, as they have in vitro synergistic activity with nucleoside analogues and PIs.
Nevirapine [NVP] (Viramune®)
In 1996, nevirapine was the ﬁrst NNRTI to become available. The structure, brand names, and FDA-approved usage for nevirapine are shown in Fig. 2.10. After binding to the HIV reverse transcriptase, this compound speciﬁcally blocks RNA- and DNA-dependent DNA polymerase activities by disrupting the catalytic site of the viral enzyme. Nevirapine is indicated for use in combination with nucleoside analogues in individuals with HIV-1 who have experienced clinical and/or immunologic deterioration while on an initial therapeutic regimen. Nevi- rapine has been found to be cost-effective when administered to sub-Saharan African women to prevent vertical HIV trans- mission to their fetuses/infants. Nevirapine is taken at the
Fig. 2.10 Trade names, structure, and uses of Nevirapine.
onset of labor and an infant dose is administered just after delivery (127). Resistance to nevirapine can develop quickly (128), and it is recommended that therapy be discontinued if no clinical beneﬁts are seen with its addition. When HAART combinations of nevirapine, stavudine, and didanosine are administered, elevated triglyceride and low-density lipopro- tein (LDL) levels may indicate a potential increased risk of coronary artery disease (129).
Induction of CYP3A enzymes. Nevirapine is exten- sively metabolized by the cytochrome P450 system, particularly by the isozyme CYP3A family. Because it leads to induction of CYP3A enzymes, other drugs that are similarly metabolized (i.e., PIs and rifampin) may have lower plasma concentrations, and dosage adjust- ments may be necessary.
Coadministration with Ketoconazole. Ketoconazole, an imidazole derivative used as a broad-spectrum an- tifungal agent, should not be coadministered with nevirapine.
Oral contraceptives. Oral contraceptives are contrain- dicated with nevirapine therapy because of signiﬁcant reductions in their plasma concentrations.
Rash. The most common toxicity reported with nevirap- ine is rash which is seen in at least 17% of patients and can be associated with a life-threatening hepatic reac- tion. Others report that a transient, self-limited rash develops in almost half of patients on nevirapine (124,130), typically within one to eight weeks of initia- tion of therapy. This eruption is usually erythematous and maculopapular and can be mild or moderately se- vere. It is typically located on the trunk, face, and extrem- ities, and may have associated pruritus. The eruption appears to be more prevalent in women (131) and can be associated with eosinophilia and systemic symp- toms (132). The rash becomes severe in 6 to 20% of patients, some of whom develop Stevens-Johnson
syndrome (133). Short-term prednisone administra- tion does not prevent nevirapine rash and may actually increase the incidence (134).
Stevens-Johnson syndrome. This syndrome may be di- agnosed prior to mucous membrane lesions by com- plaints of pain and/or tingling of the mucous membranes. Nevirapine should be stopped if this occurs. Intravenous immunoglobulin may abort Stevens-Johnson syndrome if given early (135,136). A dose escalation schedule for nev- irapine is recommended during initiation of therapy to reduce the risk of rash (137). If a patient on nevirapine develops a skin eruption, the dosage should not be in- creased until the rash resolves. If the rash is moist or ex- tensive, is associated with fever, or involves the mucous membranes, prompt and permanent cessation of nevirap- ine is indicated (138).
Coadministration with St. John’s wort. Herbal ex- tracts of St. John’s wort (Hypericum perforatum) are of- ten taken as an antidepressant. These extracts often contain inducers of hepatic enzymes and may cause clin- ically relevant drug interactions. With concomitant use of St John’s wort and nevirapine, nevirapine plasma concentration levels are lower and the efﬁcacy of the drug may be affected (139).
Delavirdine [DLV] (Rescriptor®)
In 1997, delavirdine (DLV) was the second NNRTI to gain FDA approval (Fig. 2.11). It is indicated for combination therapy of HIV-1, but its speciﬁc function in the current management of HIV has yet to be completely determined. In one study, delavir- dine was added to combination therapy in patients for whom multiple drug treatment had failed (140,141). Results showed a rapid and sustained decrease in the mean plasma HIV-1 RNA as well as a 66 to 90% increase in CD4-positive cells. Additional studies of the use of delavirdine in combination regimens are ongoing. Delavirdine is prescribed for adults as 400 mg three
Fig. 2.11 Trade names, structure, and uses of Delavirdine.
times a day. For children younger than 16 years, the use and dosage is determined by the physician. For patients with low levels and concentrations of stomach acid, delavirdine may be taken with orange or cranberry juice. Delavirdine may be taken with or without food but should be taken the same way for each dose. Delavirdine comes in tablet form and some patients may have trouble swallowing all the tablets. By dissolving the tab- lets in at least three ounces of water, the suspension can be mixed and swallowed immediately. For ritonavir-boosted PIs delavirdine increases drug exposure levels (142).
Hepatotoxicity. Hepatotoxicity has been associated with all NNRTIs, especially nevirapine (143,144). A retrospective study of the incidence of NNRTI hepato- toxicity indicates that there is no signiﬁcant difference among nevirapine, efavirenz, and delavirdine when treating HIV-positive patients coinfected with HBV and HCV (145).
Inhibition of enzymatic metabolism. Delavirdine is metabolized in the liver by cytochrome CYP3A en- zymes. Unlike nevirapine’s induction of these enzymes, delavirdine inhibits the enzymatic metabolism of itself and other affected drugs. This results in increased plasma levels of drugs which are metabolized by this enzymatic pathway.
Coadministration with other CYP3A enzymatic pathway drugs. Clarithromycin, cisapride, terfenadine,
astemizole, warfarin, PIs, certain benzodiazepines, and certain calcium channel blockers share the same enzymatic pathway (146). Coadministration of delavir- dine with these drugs and others may result in signiﬁ- cant and potentially life-threatening adverse effects.
Coadministration with anticonvulsants and anti- mycobacterial agents. Certain anticonvulsants and antimycobacterial agents are not recommended due to the decrease in plasma delavirdine levels. Certain H2 receptor antagonists reduce the gastrointestinal ab- sorption of delavirdine.
Coadministration of statins and protease inhibi- tors. HIV-positive patients with hypercholesterolemia must be careful as to which statins are used when tak- ing PIs such as delavirdine. For example, pravastatin and atorvastatin are recommended while lovastatin and simvastatin should be avoided. Although atorvas- tatin and delavirdine were coadministered as recom- mended, a case of rhabdomyolysis with acute renal failure has been reported (147).
Rash. The most frequent and signiﬁcant adverse effect with delavirdine is a rash, which occurred in 18% of clinical trial participants (138,140). The rash is typical- ly a diffuse, erythematous, maculopapular exanthem on the upper body and proximal arms, with or without pruritus. It usually arises within one to three weeks of treatment initiation, and resolves between 3 to 14 days after onset and usually does not require dose reduction or discontinuation (after interrupted treatment). A se- vere rash (requiring discontinuation of drug) was re- ported in 3.6% of subjects in the clinical trials (146). Delavirdine should be promptly discontinued if the rash is associated with fever, mucous membrane in- volvement, swelling, or arthralgias.
Erythema multiforme. Erythema multiforme occurs in approximately one of 1000 patients taking delavirdine. Stevens-Johnson syndrome. Stevens-Johnson syndrome has been reported in one of 1000 patients taking
Coadministration with antacids. Patients should wait at least one hour between taking an antacid and delavirdine for maximum efﬁcacy.
Pregnancy and breast-feeding. Delavirdine has not been studied in pregnant women although it has been shown to cause birth defects in animal studies. It is not known if delavirdine passes into the breast milk.
Efavirenz [EFV] (Sustiva®)
Efavirenz (EFV) is the most recently FDA-approved NNRTI. The structure, brand names, and approved uses are shown in Fig. 2.12. It is a potent drug that is well-tolerated and can be given once daily (138). As in the case of all NNRTIs, resistant viruses emerge rapidly when efavirenz is used as monother- apy. Thus, it cannot be used as a single agent to treat HIV-1 or added on as a sole agent to a failing regimen. It must be administered with a PI and/or an NRTI. The guidelines for the treatment of pediatric HIV infection have been altered to allow efavirenz to be substituted for the PI in the preferred regimen of two nucleoside analogues and a PI.
Efavirenz appears to have some unique characteristics. For example, in vitro studies indicate that high-level resis- tance will develop more slowly as it requires two mutations to occur before viral resistance is effective. Efavirenz, used in combination with zidovudine and lamivudine, resulted in complete remission of Kaposi’s sarcoma in an AIDS patient
Fig. 2.12 Trade names, structure, and uses of Efavirenz.
(149). Hepatotxicity, commonly reported with nevirapine, has not been reported with efavirenz (150). Although transmission of HIV can occur during antiretroviral therapy, there is some indication that efavirenz is present in the seminal plasma and could have antiviral activity within the male genital tract (151). Efavirenz has been substituted for PIs with the thought that persistent dyslipidemia from the PIs could be reduced. This has met with some success (152).
Metabolism inhibition. Efavirenz also competes for the CYP3A enzyme system, which results in the inhi- bition of the metabolism of certain drugs, leading to in- creases in their plasma concentrations.
Coadministration with astemizole, cisapride, mida- zolam, triazolam, clarithromycin, or ergot deriva- tives. Life-threatening adverse events could result (e.g., cardiac arrhythmias, prolonged sedation, or respiratory depression).
Coadministration with rifampin and phenobarbit- al. Other drugs that induce CYP3A activity, such as rifampin and phenobarbital, may lead to increased clearance of efavirenz and lower plasma concentrations. Central nervous system or psychiatric symptoms. In clinical trials, 52% of patients receiving efavirenz reported central nervous system (CNS) or psychiatric symptoms. Most of these adverse effects were mild in severity and included the following symptoms: dizzi- ness, somnolence, insomnia, confusion, impaired con- centration, amnesia, agitation, hallucinations, euphoria, abnormal dreaming, and abnormal thinking. Patients with high plasma levels of efavirenz (>4000 ug/l) were three times more likely to develop CNS toxicity. In some cases, the dosage may be reduced from 600 mg once a day to 400 mg once a day, particularly if the pa- tient has low body weight (153,154). Insomnia has been reported and may require a dosage adjustment
Delusions and inappropriate behavior. There have been reports of delusions and inappropriate behavior in patients treated with efavirenz, predominantly in those with a history of mental illness or substance abuse. Manic syndrome is also associated with efavirenz overdose (156).
Skin rash. Approximately 27% of patients treated with efavirenz in clinical trials developed a rash, typically described as morbilliform or maculopapular. The rash can be mild to moderate, occurs within the ﬁrst two weeks of therapy and usually requires discontinuation of drug in only 2% of patients. A rash associated with blistering of the face, trunk, and extremities, moist desquamation, or an ulceration occurred in only 1% of participants, requiring discontinuation of therapy (157). There is a report of one person developing a skin eruption after a single dose of efavirenz (158). A regi- men to desensitize a patient against efavirenz-induced skin eruptions has been described (159).
Cutaneous vasculitis. Leukocytoclastis vasculitis has developed in at least two patients soon after beginning treatment with efavirenz (160).
Stevens-Johnson syndrome and erythema multi- forme. One case each of erythema multiforme and Stevens-Johnson syndrome has been reported (i.e., one of 2200 recipients of EFV).
Severe skin rash. In patients without severe skin erup- tions, treatment can be continued, with resolution of the rash typically within one month. If therapy must be dis- continued because of a rash, it can later be reinitiated, with appropriate antihistamines and/or corticosteroids recommended during retreatment. Photoallergic der- matitis may occur after ultraviolet exposure to patients using efavirenz (161).
Pulmonary hypersensitivity. Efavirenz has been repor- ted to cause severe pulmonary hypersensitivity (162). Monitoring of blood cholesterol levels. Cholesterol
should be monitored in efavirenz-treated patients.
Gynecomastia. Gynecomastia without lipodystrophy has been reported in HIV-infected men treated with efavirenz (163).
Diabetic ketoacidosis. Diabetes mellitus and diabetic ketoacidosis can occur in patients taking PIs. In these cases, efavirenz may be substituted. Metformin may be useful in increasing the sensitivity of the peripheral tissues to the insulin (164).
Pregnancy. Pregnancy should be avoided in women re- ceiving efavirenz, as malformations have been ob- served in fetuses from efavirenz-treated monkeys (165). In women of child-bearing potential, a barrier method of contraception must always be used in combi- nation with another method, such as oral contracep- tives. A pregnancy test prior to the initiation of efavirenz is also necessary. At least one case of myelomeningo- cele has been reported in a newborn (166).
NUCLEOTIDE REVERSE TRANSCRIPTASE INHIBITORS Tenofovir Disoproxil Fumerate (Viread®)
Tenofovir is a nucleotide analog reverse transcriptase inhibitor. The best-known nucleotide analogues are the antivirals, ade- fovir (Hepsera) and cidofovir (Vistide), used for the treat- ment of hepatitis B and cytomegalovirus infections. Adefovir was discontinued as an HIV therapy due to proximal renal tubular dysfunction. See Fig. 2.13 for names, structure, and approved uses of tenofovir. It is FDA-approved for the treat- ment of HIV infection in combination with other anti-HIV therapies. The recommended dosage for tenofovir is 300 mg taken orally once each day. The lower number of dosages per day increases the probability that the patient will exercise medication compliance (167). The medication is in tablet form and may be taken with or without food. If patients have a decreased kidney function, the medication may need to be taken less frequently. Tenofovir resistance occurs and may be
Fig. 2.13 Trade names, structure, and uses of Tenofovir.
the result of several resistant mutations (168,169). However, there are reports that tenofovir can be used to treat HIV-1 strains that are nucleoside-resistant (170). Tenofovir is also active against hepatitis B virus. In one case, an HIV-positive patient with liver cirrhosis secondary to chronic hepatitis B and resistance to lamivudine was treated with tenofovir with signiﬁcant virologic and histopathologic improvements. This case was so successful that the patient was removed from the liver transplant program and has not had any further hepatic complications (171). Long-term administration of tenofovir (96 weeks), combined with exisiting antiretroviral therapy for patients with preexisting resistance mutations, showed signif- icant and durable reductions in HIV-1 RNA levels (172).
Gastric reactions. Nausea, vomiting, diarrhea, and ﬂatu- lence are the most common short-term events of teno- fovir (173).
Osteopenia. When taken with efavirenz and lamivu- dine, tenofovir was more likely to cause bone mineral density decreases than stavudine taken with efavirenz and lamivudine. Over time, this could lead to osteoporosis with bone breakage of the hip, spine, wrist, or other small bones.
Lipodystrophy. Redistribution, loss, or accumulation of body fat and/or increases in cholesterol, triglycerides, or other blood lipids may occur with any patient receiv- ing anti-HIV therapy.
Kidney toxicity. Numerous studies have reported kid- ney toxicity (and some cases of renal acidosis) with use of tenofovir (174–178). One of the risk factors associat- ed with tenofovir renal toxicity is the prior proximal re- nal tubular acidosis reported during adefovir therapy (179). Factors that increase the risk for developing hy- pophosphotemia include: patients receiving HAART, length of time on HAART, concurrent use of lopinavir- ritonavir, increased time since HIV diagnosis, and a history of nephrotoxic agents. Tenofovir is not associat- ed with mitochondrial toxicity or cytotoxicity (180,181).
Coadministration of tenofovir with didanosine and lamivudine and other triple-NRTI therapies. This combination is not recommended when considering a new treatment regimen for therapy-naïve or experi- enced patients with HIV infection. A 91% virological failure occurred, as deﬁned by a <2 log reduction in plasma HIV RNA levels, by week 12 of a clinical study. Patients treated with this combination of therapies should be considered for treatment modiﬁcation (182). Other triple-NRTI therapies have had suboptimal re- sponse. These include: 1) abacavir / lamivudine /zidovu- dine (183); 2) abacavir /didanosine/stavudine (184); and 3) abacavir/ lamivudine/tenofovir (185–187).
Reduction in lipid side effects. When patients receiving stavudine switched to tenofovir because of stavudine- induced side effects, most patients experienced a rapid and signiﬁcant decrease in triglyceride levels after the switch.
Coadministration with didanosine. Coadministra- tion with didanosine is not recommended except in closely monitored cases (188). Plasma concentrations of didanosine will increase with coadministration of tenfovir. Coadministration is not recommended for patients who weigh less than 60 kg, already have renal impairment, or are receiving current therapy with lopinavir-ritonavir, as pancreatitis may occur (189). Adjusting the didanosine dosage may be all that is needed to accommodate the systemic drug interaction (190,191).