Revista aids 4 05.indb

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Update on the Teratogenicity of Efavirenz
efavirenz-containing regimens, most of which were In March 2005, Bristol-Myers Squibb and the FDA first-trimester exposures. Birth defects occurred in notified healthcare professionals of revisions of the five of 188 live births with first-trimester exposure, prescribing information for efavirenz. The pregnancy and in zero of 13 live births with second- or third- category for the drug has changed from category C trimester exposure. None of these prospectively re- (risk of fetal harm cannot be ruled out) to category ported defects were neural tube defects. However, D (positive evidence of fetal risk). This change is a there have been four retrospective reports (i.e. after result of four retrospective reports of neural tube the results of the pregnancy were known) of findings defects in infants born to women with first-trimester consistent with neural tube defects, including three exposure to efavirenz, including three cases of me- cases of meningomyelocele. Al four mothers were ningomyelocele and one Dandy Walker syndrome. exposed to efavirenz-containing regimens in the first As efavirenz may cause fetal harm when adminis- trimester. Although a causal relationship of these tered during the first trimester to a pregnant woman, events to the use of efavirenz has not been estab- pregnancy should be avoided in women receiving lished, similar defects have been observed in pre- During the development of efavirenz, animal stud- In summary, women of childbearing potential should ies were performed to assess the potential for birth undergo pregnancy testing before initiation of efa- defects. Malformations were observed in three of virenz and be advised of fetus risk in case they 20 fetuses/infants from efavirenz-treated cynomol- become pregnant. If the drug is used during the gus monkeys (versus zero of 20 concomitant con- first trimester of pregnancy, or if the patient be- trols) in a developmental toxicity study. The pregnant comes pregnant while taking this drug, the patient monkeys were dosed throughout pregnancy (post- should be apprised of the potential harm to the coital days 20-150) with efavirenz 60 mg/kg daily, a fetus. Although there are no adequate, wel -con- dose resulting in plasma drug concentrations simi- trol ed studies in pregnant women, efavirenz should lar to those in humans given 600 mg/day of efavi- be used during the first trimester of pregnancy only renz. Anencephaly and unilateral anophthalmia if the potential benefit justifies the potential risk to were observed in one monkey fetus, microphthal- the fetus, such as in pregnant women without other mia was observed in another fetus, and cleft palate therapeutic options.
was observed in a third fetus. Efavirenz crosses the placenta in cynomolgus monkeys and produces fetal blood concentrations similar to human mater- An increase in fetal resorption was observed in rats given efavirenz doses that produced peak plas- ma concentrations and area under the curve (AUC) New Stanford’s Guidelines for Interpreting
values in female rats equivalent to or lower than Drug Resistance Mutations
those achieved in humans given 600 mg once daily In September 2005, a simple one-page guide of efavirenz. It produced no reproductive toxicities was released by the Stanford’s team in which the when given to pregnant rabbits at doses that pro- clinical significance of drug-resistance mutations in centrations similar to and HIV was updated. Interestin without the prior written permission g new views about re- AUC values approximately half of those achieved in sistance mutations and patterns merit further atten- humans given 600 mg once daily of efavirenz. tion and discussion. Summarized below are some of Limited data are available regarding birth defects the main caveats.
occurring after intrauterine exposure to efavirenz. 1. Resistance mutations to nucleoside analogues The outcomes of pregnancy have been reviewed for are classified in four major groups. First, thymi- 206 women (207 fetuses) after being exposed to dine analogue mutations (TAMs), which pro- mote the unblocking of the nascent DNA chain sidered for the first time for changes such as caused by nucleoside analogs, and are mainly rt65R and rt74V for AZT; rt184V for AZT, d4T selected by AZT and/or d4T, but cause cross- and TDF; pro88S for amprenavir; and pro50L resistance to other nucleoside analogs. Second, TAM-associated mutations (involving codons This update is very useful as a pocket guide for 44D, 69D, 75I and 118I), which are general y clinicians caring for HIV-infected patients, who often selected in combination with TAMs. Third, dis- are not experts in the interpretation of resistance criminatory mutations (65R, 74V, 115F, 184V), mutations. Efforts to translate the complex world of which are mainly selected by TDF, ddI, ABC, and genotypic resistance into simple advice are much 3TC/FTC, respectively. Fourth, Q151M complex, appreciated.
which cause resistance to al nucleoside ana- logues, although to a lesser extent to 3TC/FTC 2. Resistance to non-nucleoside analogues re- sults from changes in three different regions of the RT gene: positions 98-108, 179-190, and Liver Toxicity is not Increased with Nevirapine
225-238. The most frequent mutations causing Once a Day
intermediate or high-level resistance to these In the 2NN study (van Leth, et al. Lancet 2004; compounds are 103N/S, 181C/I/V, 188L, 190A/ 363:1253-63), an international, multicenter, randomized, prospective trial in which nevirapine (NVP) once 3. Resistance mutations to protease inhibitors (PI) daily (QD) was compared to NVP twice daily and are clustered into four groups. First, “major” efavirenz (EFV), a higher incidence of liver enzyme mutations, which are quite specific: 30N for elevations was found in the NVP QD arm with respect nelfinavir, 48V/M for saquinavir, 50V for ampre- to the other two arms. In Dublin, during the 10th Eu- navir, 50L for atazanavir, 82A/T/F/S for indinavir ropean AIDS Conference (EACS 2005), a sub-analy- and lopinavir, 84V/A/C for al PI, and 90M for sis was presented (Storfer, et al. abstract PE9.6/2) in which it was highlighted that al the cases of ex- 4. The second group of PI-resistance mutations cess liver toxicity due to NVP QD in the 2NN trial are positioned in the flap region and includes occurred in a single center from Thailand, which for the first time mutation 47A, which charac- had recruited 162 out of the total 967 HIV-infected teristical y cause high-level resistance to lopi- patients included in the study who received a sin- gle non-nucleoside. Moreover, when only men and 5. The third group of PI-resistance changes are women with less than 400 and 250 cel s/µl, respec- general y accessory mutations and appear along tively, were considered (as currently recommended for with “major” mutations. They include mutation patients initiating NVP) there were no significant dif er- 88S, which characteristical y cause high-level ences between the three study arms in the incidence resistance to nelfinavir and atazanavir.
of liver enzyme elevations outside of Thailand.
6. Final y, the last group of PI-resistance muta- This information is relevant since an increasing tions is represented by polymorphic changes, number of antiretroviral regimens are becoming for with the exception of 10F. They contribute to once daily use, particularly using combo pil s such resistance only when present along with other as Kivexa® (abacavir plus lamivudine) or Truvada® “major” PI-resistance mutations.
(tenofovir plus emtricitabine). These new data wil 7. The impact of each change in resistance is reassure the use of NVP QD in clinical practice.
estimated semi-quantitatively as high, interme- diate, or low level, as wel as “contributing” to resistance. Moreover, hypersusceptibility is con-

Source: http://aidsreviews.com/files/2005_07_4_246-247.pdf