Antiretroviral agents in pregnancy

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Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

Nucleoside analogs cross the placenta and can cause toxic damage not only to the mother but also to the child. The main problems are anemia and, when using combination therapy, lactate acidosis.

On the basis of pregnancies observed to date, it can be maintained that frequently used nucleoside analogs such as AZT, 3TC and d4T, do not increase teratogenicity by more than twofold (Antiretroviral Pregnancy Registry 2004). Most of our experience is related to AZT administration. Follow-ups of more than 20,000 children who had received AZT prophylaxis did not show any serious side effects. An analysis of the causes of death of 223 children, who died within the first five years of life, ruled out drug-related causes (The Perinatal Safety Review Working Group 2000). In other studies, no damage to mitochondrial DNA could be detected (Vi-gano 2004).

In contrast to these findings, in a prospective study by Barret et al. (2003) on 2,644 ART-exposed non-infected children, neurological symptoms with persistent mitochondrial dysfunction were reported in 0.26 %. 24 months after combined nucleo-

side exposure, raised lactate values as well as impairment of hematopoeiesis can still be demonstrated in children (Alimenti 2003, Mofenson 2004).

So far, severe mitochondriopathies have been observed at least twice in pregnant women taking a combination therapy of the nucleoside analogues d4T+ddI plus nelfinavir or nevirapine (Sarner 2002). For this reason, the combination d4T+ddI is advised against in pregnancy (Bristol-Myers 2001). Hepatic toxicity with hyperbilirubinemia was described under AZT+3TC+efavirenz therapy. Following the administration of AZT+3TC+nelfinavir, one pregnant woman died of sudden acute liver failure (Hill 2001). Tenofovir did not show any maternal toxicity in animal experiments, but did cause a fetal growth retardation of 13 % as well as a slight decrease in the bone mineral density (Tarantal 2002).

Non-nucleoside reverse transcriptase inhibitors (NNRTIs)

In perinatal prevention, nevirapine was employed successfully, particularly in combination with AZT. Perinatal single and two-dose prophylaxis has resulted in the development of drug resistance (Jackson 2000). Toxic liver injury has been described, particularly in the first 18 weeks of longer treatment regimens, especially if the CD4 cell count is more than 250/mm3. Therefore frequent controls of efficacy and potential side effects are vital. If a mother gives birth less than two hours following nevirapine administration, or has not received any prior nevirapine at all, the newborn should receive a dose of nevirapine immediately after birth and a further dose after 48-72 hours (Stringer 2003). Because of embryonic toxicity in the rhesus monkey and also in humans, efavirenz is not used during the first trimester of pregnancy and only after the second in cases without an alternative treatment option and if reliable contraception is practiced after delivery. (CDC 2005).

Protease inhibitors (PIs)

The use of protease inhibitors must be monitored carefully, especially in the later stages of pregnancy, due to a possible diabetogenic effect and hepatic toxicity. Presently, most experience relates to nelfinavir (Bryson 2002). However, in combination therapies, toxic side effects have also been described (see above). Indinavir can lead to hyperbilirubinemia and nephrolithiasis; the plasma levels can be lowered (Kosel 2003). As with indinavir, saquinavir should also be boosted with ritonavir in pregnancy (Acosta 2004). Ritonavir and lopinavir plasma levels are also lowered during pregnancy (Scott 2002, Stek 2004).

A Swiss research group suspected that the use of combination therapy might cause an increase in premature birth rate and a higher rate of malformations. Malformations appear to be rather unlikely due to the minimal placental transfer of PIs (Mar-zolini 2002) and have not been confirmed by other studies either. With regard to the premature birth rate, the available data is inconsistent (increases were reported by the European Collaborative Study 2003, Thorne 2004, Bekerman 2004; no increases were reported by Mandelbrot 2001 and Tuomala 2002). The serum levels of HCG and estrogens were not reduced in women on PI-therapy (Einstein 2004).

FDA classification for drugs in pregnancy

The FDA has classified the potential toxicity of drugs in pregnancy into the categories A-D. All HIV virustatic agents belong to the categories B-D, since "harmless-

ness through studies on the human being" (= category A) does not apply to any of these drugs.

FDA category B is defined as follows: "Animal studies have revealed no evidence of harm to the fetus; however, there are no adequate and well-controlled studies in pregnant women". The FDA category B includes ddI, emtricitabine, tenofovir, ata-zanavir, saquinavir, ritonavir, nelfinavir and enfuvirtide (T-20). FDA category C is defined as follows: "Animal studies have shown an adverse effect and there are no adequate and well-controlled studies in pregnant women. Use in pregnancy should occur only after careful benefit/risk appraisal." All other drugs, which were not mentioned in category B, fall into the FDA category C. Efavirenz falls into category D because of neural tube defects in humans after first trimester exposure.

FDA category D is defined as follows: "Adequate well-controlled or observational studies in pregnant women have demonstrated a risk for the fetus. Nevertheless, the benefits of therapy may outweigh the potential risk." For example, the drug may be acceptable if it is needed in a life-threatening situation or serious disease for which safer drugs cannot be used or are ineffective.

Prevention of perinatal HIV infection

In approximately 75 % of cases, HIV is transmitted prior to, or during the last weeks prior to birth. About 10 % of vertical HIV infections occur before the third trimester, and 10-15 % are caused by breastfeeding.

The probability of HIV transmission to a neonate correlates with the viral load. This also seems to apply to women who are being treated with antiretroviral drugs (Table 3). If the viral load is undetectable using currently available tests, the probability of transmission is indeed extremely low; however, infections have also been described under such circumstances (Ioannidis 2001). Likewise, premature births and premature rupture of membranes are associated with an increased infection risk for the child.

For this reason, reduction in the level of plasma viremia and improvement in the immune status of pregnant women are vital prophylactic measures. If a mother is treated with antiretrovirals, these drugs should continue to be taken, if possible, during delivery at the usual scheduled intervals in order to achieve the maximum effect and to minimize the risk of developing resistance.

Table 3: Known risk factors for perinatal HIV transmission

High maternal viral load

Low CD4 cell count

AIDS in the mother

Vaginal delivery

Premature rupture of membranes of > 4 h Pre-term infants (< 37 weeks of gestation) Breastfeeding

For the general prevention of mother-to-child transmission of HIV, pregnant women should be warned not to use intravenous drugs or to have unprotected sex because of the increased risk of HIV transfer in these cases.

In addition to the indicated or optional antiretroviral therapy of the mother, the following rules should be observed regarding chemoprophylaxis

• Antiretroviral prophylaxis before and during delivery

• Elective cesarean section before onset of labor, because vaginal delivery with a viral load of > 1,000 HIV-RNA copies/ml increases the transmission risk

• Postnatal chemoprophylaxis of the infants (post-exposure prophylaxis)

• No breastfeeding

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