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Table 2 Comments on the initial anti-retroviral combinations/substances

From: German-austrian recommendations for HIV1-therapy in pregnancy and in HIV1-exposed newborn - update 2008

Initial combinations and substances

Comment

Nucleoside analogs for which most experience has been gained

Zidovudine + Lamivudine (also as Combivir®)

Most clinical experience has been gained with the use of these substances. One additional rationale for application of zidovudine is the metabolization of this drug in the placenta which might contribute to the transmission preventing effect [51, 52].

Some cases of lethal mitochondriopathies were reported in non infected children after maternal zidovudine/lamivudine-therapy [7, 8]. Data about long term toxicity especially carcinogenicity/genotoxicity as a matter of incorporation of nucleoside analogs into DNA [112] are lacking. In case of therapeutic failure changed pharmacokinetics of nucleoside analogs because of pregnancy must to be taken into consideration [113].

Alternatives

Stavudine + Lamivudine

Zidovudine+Didanosine

Didanosine +Lamivudine

Abacavir

Tenofovir:

Less clinical experience in pregnancy. Increased attention relating to potential side effects.

Use of Abacavir only after testing for HLA-B*5701 [136] to avoid hypersensitivityreaction. So far no increased rate of malformation in humans [57], but individual reports of malformations [67].

In animal studies, where Tenofovir was applied in higher doses than usual in humans, reduced bone density and renal damage were observed [135].

NNRTI

Nevirapine:

Caution: raised liver enzymes, more allergic reactions since pharmacokinetics are altered during pregnancy [49]. Increased liver toxicity in pregnancy especially with CD4-counts > 250/μl. With longer administration enzyme induction of the cytochrome P450 system and therefore accelerated metabolization of nevirapine not only in the expectant mother but also in the newborn [53]. A single normal dose applied before birth and to the newborn is therefore not sufficient for prophy laxis of HIV1-transmission, if nevirapine has already been given over a longer period during the course of the pregnancy.

Protease inhibitors, for which most experience has been accrued [50]:

In common:

Lopinavir + Ritonavir (= Kaletra®) or Saquinavir (Fortovase®) + Ritonavir

Because of the poor ability of most PIs to cross the placenta (no or poor data: Fos-Amprenavir [57, 113, 125], Darunavir [57, 113], Tipranavir,) no therapeutic levels are to be expected in the fetal compartment [54–56]. As such, no relevant adverse effect frequency is to be expected amongst the fetuses, but it is still unclear whether therapeutic drug-levels in the fetus are necessary or helpful to inhibit vertical HIV1-transmission.

No increased rate of malformations in humans [57, 126]

Until now rare published studies about the use in pregnancy [54, 57, 113] but as yet no incidence for unusual or unexpected adverse effects [57].

Alternatives:

Nelfinavir

Ritonavir

Indinavir + Ritonavir

Up to now most experiences in pregnancy have been accrued for Nelfinavir [57, 113, 126], but an anti-retroviral therapy with an unboosted PI is no more recommended as optimal therapeutic regimen in adults [29].

Contraindicated as a mono-PI because of poor compatibility; can be applied at low doses to boost plasma levels of other PI's.

High number of tablets, relevant side effects [57]. With Indinavir there is an increased need for water uptake to prevent the formation of kidney stones in the mother.

New substances:

T-20 (fusion inhibitor)

Atazanavir

Emtricitabin

Fosamprenavir

Tipranavir

Darunavir

Maraviroc

Raltegravir

Should only be used in heavily pretreated pregnant women as part a of antiretroviral salvage therapy based on resistance testing. Because of the high molecular weight a transplacental passage is not expected and could so far not proved [121]. Some case reports show no adverse effects [57, 127].

Insufficient data for use in pregnancy [28, 57, 113], does not cross placenta [127].

As yet at the most single case reports [80], no recommendation due to the risk of malformations possible [57].