NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS | Kickoff

NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS

1 Jun

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).

Adverse Events

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).

Special Considerations

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).

Adverse Events

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).

Special Considerations

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).

Adverse Events.

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).

Adverse Events

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.

Special Considerations

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).

Adverse Events

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).

Special Considerations

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.

Adverse Events

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.

Adverse Events

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:

Headache.

Abdominal pain and /or diarrhea. Nausea and vomiting.

Fatigue.

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.

Special Considerations

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).

Adverse Events

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).

Special Considerations

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).

Adverse Events

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

delavirdine (148).

Special Considerations

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).

Adverse Events

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

(155).

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).

Special Considerations

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).

Adverse Events

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).

Special Considerations

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).

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