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Mechthild Vocks-Hauck

Perinatal (vertical) HIV infection has become rare in since the introduction of antiretroviral transmission prophylaxis and elective cesarean section. While the vertical HIV transmission rate ranged amounted to about 15 % in Europe at the beginning of the nineties, it now amounts to only a few percent (Connor 1994, European Collaborative Study 2005). Postpartum HIV infections are avoidable provided that HIV-infected mothers do not breastfeed. At the same time as transmission prophylaxis was introduced, the treatment of HIV infection changed too. Nowadays, pregnancy is no longer a general contraindication for antiretroviral therapy (Agangi 2005, CDC 2006 a)).

The following chapter summarizes the recommendations of different guidelines for HIV therapy in pregnancy.

Reference is made to the European (Coll 2002, British HIV Association 2005), German (DAIG), and Austrian AIDS societies (OEAG) (DAIG 2005) as well as American Guidelines (CDC 2005 a) and b)). In addition, detailed and continuously updated recommendations of the US guidelines are to be found on the HIVATIS website: http://hiv.net/link.php?id=190.

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HIV therapy in pregnancy Starting HIV therapy during pregnancy It is important to distinguish between women with and without a therapy indication of their own. In the case of a maternal indication, treatment is begun as a rule in week 13 + 0 of gestation, otherwise from week 32 + 0. The assessment of indications for therapy and drug selection is similar to that in non-pregnant patients (chapter ART 2005). Since the CD4 T-lymphocyte count decreases physiologically by approximately 10-20 % in pregnant patients, the threshold values should be adjusted upwards accordingly before treatment is started. Following the recommendations of the German/Austrian guidelines and the CDC (2006 b), antiretroviral therapy in symptom-free patients should begin - when CD4+ T-cell count is below 200-350/µl (15-20% relative) and/or - with a viral load of > 50,000-100,000 copies/ml HIV RNA (by RT-PCR or 3.0 version b-DNA). Before initiating therapy , a resistance test, and, if necessary, subtyping should be carried out (see chapter on Resistance). When setting up a treatment plan, it is important that: § AZT (Retrovir™) should be one component of the combination - if the result of the resistance test and the expected toxicity are favorable; and Efavirenz (Sustiva™, Stocrin™) should be avoided because of possible teratogenic effects in the first trimester, but also the combination of DDI + D4T should not be used, and Even if maximum suppression of viral activity is achieved during pregnancy, this is no guarantee for the prevention of HIV transmission. Therefore, prophylaxis to reduce perinatal HIV transmission is also recommended in sufficiently treated pregnant patients (see below i). Table 1: Special features of anti-HIV therapy in pregnancy Explanation of risk: Only AZT is approved for perinatal transmission prophylaxis HIV resistance testing, if necessary HIV subtyping No efavirenz (Sustiva™) in the first trimester (teratogenicity) No d4T+ddI (Zerit™+Videx™) because of mitochondriopathies Nevirapine related hepatotoxicity in women with CD4+ T-cell counts > 250/µl Raised toxicity through combination therapy, therefore monthly controls of lactate, hepatic transaminase levels, viral load, CD4+ T-cell count Therapeutic plasma drug level measurement (TDM) and possible dose adaptation Continuation of treatment during pregnancy More and more HIV-infected women, in whom pregnancy has been diagnosed, have been pretreated with antiretroviral agents.As a rule, if pregnancy is diagnosed after the first trimester, the antiretroviral therapy should be continued. Interruption of treatment might give rise to an increase in viral load and a possible deterioration of immune function causing the danger of disease progression and, ultimately, of reduction of the immune status of mother and fetus. AZT should be administered as a component of a combination regimen starting at 32 weeks of gestation at the latest. Women in whom pregnancy is diagnosed during the first trimester should be informed about the benefits and risks of treatment in this period. In cases of reduced immune status, in particular, antiretroviral therapy could be continued even in the first trimester under careful laboratory and ultrasonic controls. However, substances that can have a toxic effect on the embryo should not be administered during early pregnancy (Table 1). Interruption of treatment in the first trimester Women who have to discontinue antiretroviral treatment during pregnancy, e.g. because of hyperemesis, should only restart therapy when drug tolerance can be expected. In this case, as in all others, the rule is: withdraw all drugs simultaneously and re-administer them simultaneously, with the exception of NNRTIs. In other cases - especially if pregnancy is diagnosed very early - the fear of possible embryotoxic effects may lead to an interruption of antiretroviral therapy until the end of the first trimester . There are indications that after interruption of treatment in pregnancy, complete viral suppression is much more difficult in the further course (Liuzzi 2006). A continuously updated summary of the current state of knowledge about antiretroviral drugs in pregnancy can be found on the internet at the web address http://hiv.net/link.php?id=189. If treatment is interrupted, all drugs (NRTIs and PIs) should be withdrawn and readministered simultaneously in order to prevent development of resistance. As it is usually not possible to determine pregnancy duration exactly, the restart is mostly initiated at the gestational age of 13 + 0 weeks. Due to their long half-life, NNRTIs should be withdrawn up to three weeks before NRTIs: alternatively, the NNRTI can be replaced beforehand by a boosted PI. Because of the complicated interruption strategy, however, a therapy containing nevapirin is usually continued in practice. Combination therapy for the duration of pregnancy It is becoming more and more common to offer a combination therapy to pregnant patients with a plasma HIV RNA level of only 1,000 -10,000 copies/ml from the second trimester (CDC 2006a) onward or 32 + 0 weeks of gestation. This approach is based on the assumption that any decrease in viral load translates into a lowering of the transmission risk. With a viral load of less than 1,000 HIV RNA copies/ml, the advantage of cesarean section compared with vaginal delivery can no longer be verifiedShapiro 2004). For this reason, in the USA as well as in some European countries, vaginal delivery is considered an option for women on antiretroviral combination therapy whose HIV status at the time of delivery is less than 1,000 copies/ml and/or undetectable and in whom no obstetric complications are expected.These cases are increasing in Europe, the rates have now reached over 30% (Rodrigues 2006). Since the study data are not yet definitive and C-section is still accepted as being safer (ECS 2005), countries such as Germany still prefer to use this mode of delivery. Treatment monitoring In addition to measuring the hemoglobin concentration to exclude an AZT-associated anemia, transaminases for potential hepatic toxicity, and lactate level to detect lactic acidosis early, the CD4+ T-cell number and viral load should be monitored at monthly intervals. If PIs are part of the treatment, it is of particular importance to monitor the blood glucose level closely (El Betuine 2006). Resistences and plasma level are determined at the beginning of and, if appropriate, in case of failure of treatment. Special aspects of HIV therapy in pregnancy Because embryotoxicity cannot be excluded and hepatic metabolism is altered in pregnancy, and also in some cases reduced plasma levels, some basic rules must be taken into consideration (CDC 2006 a)) (Table 2). It is important to understand that a detectable plasma viral load always necessitates a resistance test. AZT resistance was verified, for example, in the United States in approximately 17 % of the women during pregnancy and up to 73% of infected neonates, who therefore seem to have an unfavorable prognosis in these cases (Vignoles 2006). Table 2: Antiretroviral agents in pregnancy Preferred NRTIs (full placenta transfer) AZT + 3TC AZT + ddI AZT is metabolized in the placenta; mitochondriopathy risk: ddC > ddI > d4T > AZT > 3TC > ABC > TDF Alternative NRTIs (full placenta transfer) d4T + 3TC Abacavir Tenofovir Emtricitabine No side-effects for PACTG 332 Only little published experience No published data in humans Alternative to 3TC, barely any experience NNRTIs (full placenta transfer) Nevirapine General use in perinatal prophylaxis; Hepatic toxicity ­ especially in > 250 CD4 cells; enzyme induction, rapid resistance PIs (minimal placenta transfer) Nelfinavir Indinavir Ritonavir Lopinavir/r Saquinavir SGC Amprenavir Fosamprenavir Atazanavir Tipranavir Darunavir Once frequent use; but unboosted Hyperbilirubinemia, nephrotoxicity Only as booster Some experience, plasma level low ? Low plasma levels, only boosted Some experience, solution contraindicated Little experience Initial experience; indir. Hyperbilirubinemia, also with neonates Case reports Case reports Entry Inhibitors T-20 Intial experience (case reports) Antiretroviral agents in pregnancy Nucleoside reverse transcriptase inhibitors (NRTIs) Nucleoside analogs cross the placenta (Chappuy 2004) and can cause toxic damage not only to the mother but also to the child. According to experience to date, 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 or neurological development dysfunction in HIV-exposed children after HAART could be detected (Alimenti 2006). 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 %. Retardation of auditory evoked potentials (Poblano 2004), as well as nonspecific changes in cerebral MRTs in children perinatally exposed to AZT (plus 3TC) (Tardieu 2005) have been interpreted as a sign of neurotoxicity. 24 months after combined nucleoside exposure, raised lactate values as well as impairment of hematopoeiesis can still be demonstrated in children. Even after eight years, neutrophil granulocytes were reduced in perinatally NRTI-exposed children (ECS 2004). Severe mitochondriopathies have been observedduring a combination therapy of the nucleoside analogues d4T+ddI. Tenofovir proved to be harmless when given for a short time (Rodman 2006). Non-nucleoside reverse transcriptase inhibitors (NNRTIs) In perinatal prevention, nevirapine has been employed successfully, particularly in combination with AZT. Because of enhanced risk of liver toxicity during the first 18 weeks of treatment in women with a CD4+ T-cell count more than 250/µl, treatment should be monitored closely and at short intervals, especially in the time of dose escalation (Boehringer 2004). Nevirapine in pregnant women with over 250 CD4 cells/µl is only recommended following very careful assessment of the benefit-risk ratio (CDC 2005a)). In a retrospective study of 197 pregnant women, toxic side effects were observed in 5.6%, which led to stopping the treatment in 3.6% (Joao 2006). Perinatal single and two-dose prophylaxis has resulted in the development of drug resistance (Flys 2005). 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 (neural tube impairments, Bristol-Myers Squibb 2004) efavirenz is not used during the first trimester of pregnancy and only after the second in cases with no alternative treatment option providing reliable contraception is practiced after delivery (CDC 2006 b)). Following isolated cases of neural tube defects, which caused the FDA to allocate efavirenz to category D, however, no further cases of teratogenicity due to this substance have been reported (Beckermann 2006) Protease inhibitors (PIs) The use of protease inhibitors must be monitored carefully, especially in the later stages of pregnancy (monthly in the third trimester), due to a possible diabetogenic effect (Beitune 2005, Hitti 2006) and hepatic toxicity. Hyperlipidemia also occurs more frequently (Floridia 2006). Presently, most experience relates to nelfinavir (Timmermans 2005). Since Nelfinavir is not boosted, and the plasma level can be reduced (Khuuong-Josses 2006), the substance is now used less often than in the past. 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. lopinavir/r plasma levels are also lowered during pregnancy, especially in the third trimester (Mirocknick 2006). With Atazanavir/r, mild hyperbilirubin anemia were describes in neonates (Morris 2005b). Past conjecture that there are increased deformities under PIs have since been disproved, especially since PIs are scarcely able to cross the placenta due to the molecule size. An increase in premature births in cases of HAART containing PIs (ECS 2004), also failed to find confirmation in other studies to date (Morris 2005a, Tuomala 2005). According to a current study, there may be an increased risk of eclampsia (Suy 2006). Alfa-fetoprotein levels are said to be increased under PI regimes, but the serum levels of unconjugated oestriol and human choriongonadotropine are not (Einstein 2004). Entry or fusion inhibitors T-20 was administered to pregnant women with multiresistant viruses with partial success, in combination with tipranavir also (Wensing 2006). Failures of therapy with perinatal HIV infection are described. There is probably no possibility of crossing the placenta (Brennan-Benson 2006). 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 "harmlessness 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, atazanavir, 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 that 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 (Efavirenz) 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." This category applies to efavirenz. 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. 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. Viral resistances make up over 20% of the remaining infection rate of less than 2% (Birkhead 2006). Table 3: Known risk factors for perinatal HIV transmission High maternal viral load Low CD4+ T-cell count AIDS in the mother Vaginal delivery (at a viral load > 1,000 copies without ART 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 with different partners 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 Antiretroviral transmission prophylaxis Combination prophylaxis iIf the viral load is > 10,000 copies/ml, combination prophylaxis should be introduced temporarily from 32 + 0 weeks gestation until immediately after birth (Table 4). In the case of high-risk pregnancies (e.g. multigravidity), the prophylaxis is begun at 29 + 0 weeks of gestation. A monoprophylaxis or the combination of AZT+3TC is problematic because of the possible development of resistance (Mandelbrot 2001). Therefore, HAART prophylaxis is increasingly being used, with a boosted PI. Combinations containing nevapirin should only be administered after careful consideration of the benefit-risk ratio. Table 4: Combination prophylaxis with combination therapy containing AZT in cases with a viral load > 10,000 RNA copies/ml, but otherwise only standard risk After resistance testing starting at 32 + 0 weeks gestation: 2 x 250-300 mg AZT (rarely as a "mono"-prophylaxis at a viral load << 10,000 copies/ml) + a second NRTI + plus PI/r boosted During delivery (elective cesarean section from 37+0 weeks gestation to week 37 + 6): IV infusions of AZT as standard prophylaxis: 2 mg/kg i.v. as a "loading dose" for 1 h to approx. 3 h preoperatively 1 mg/kg i.v. intraoperatively until delivery of the infant In neonates AZT monoprophylaxis: 2 mg/kg orally every 6 hours within 6 hours post partum for 2-4 weeks or 1.5 mg/kg i.v. every 6 hours within 6 hours post partum for 10 days Prophylaxis in ART-pretreated pregnant women In pregnant women who have already been pretreated with ART, AZT should be integrated into the combination therapy starting at 32+0 weeks gestation. When using combinations containing d4T, this agent should be substituted by another active component because of AZT antagonism. In cases of anemia or AZT resistances, other NRTI are used, e.g. 3TC, DDI, abacavir or tenofovir. Procedure in cases with additional pregnancy risks The pregnancy risks mentioned in Table 5 require an intensified prophylaxis. The risk of transmission is reduced here, even in the case of sufficient HIV therapy. In premature infants, for example, perinatal HIV transmissions only occurred when the mothers had received no prophylaxis or only an AZT monoprophylaxis (Aagaard-Tillery 2006). Intrapartum prophylaxis without antepartum regimens If the diagnosis of HIV infection is only established at the time of delivery, mother and newborn receive a dual or triple combination prophylaxis with AZT (plus 3TC and/or nevirapine) in cases of highly increased risk (high viral load and/or medical complications during delivery). Simple prophylaxis Pregnant women as of week 32 of gestation who do not require therapy thanks to their immune status and who have a low viral load (considerably below 10,000, after CDC below 1,000 copies/ml) and a normal course of pregnancy can be given AZT monotherapy with an elective C-section. This regimen is, however, only administered in 10% of casesl, not only because AZT-resistant viruses have been increasingly identified, but also because the risk (albeit a low one) of resistance formation under monotherapy cannot be neglected. The use of AZT alone during pregnancy should be mentioned here because it remains topical under teratogenic aspects. Treatment during delivery Elective cesarean section in cases of uncomplicated course of pregnancy Cesarean section is carried out swiftly by experienced obstetricians prior to the onset of labor from 37+0 up to 37+6 weeks of gestation using the Misgav-Ladach technique, which reduces bleeding. Blunt preparation and the delivery of the child within the intact amniotic sac are considered ideal (Schäfer 2001). A vaginal delivery in women under long-term HAART with a negative viral load is possible (CDC 2006a). High-risk pregnancy Cesarean section in cases of multigravidity should be carried out using the same technique as for a cesarean section in a single pregnancy. In this context, the skill and experience of the operating surgeon are especially important. Cesarean sections in cases of premature infants are also important to avoid hypoxia in the neonate; the special aspects of chemoprophylaxis have been described above. In cases with a premature rupture of membranes of less than four hours duration, a section is expedient for prophylactic reasons, providing the clinical situation at that stage of delivery still permits. If the rupture of membranes has lasted more than four hours, the advantage of cesarean section compared to vaginal delivery is no longer expected. Nevertheless, vaginal delivery should occur as swiftly as possible, since the HIV transmission risk increases by about 2 % per hour. The extension of the prophylactic scheme (Table 5 and 7) is important. The risks of transmission are lower in the case of undetectable viral load. Unknown HIV status in cases of known risk If, at the time of delivery, the HIV status is unknown and the existence of a risk is known, an HIV test can still be offered to the patient . Although specificity is high, it is still considered inadequate. Thus, the combined use of two rapid tests from different manufacturers is ideal. If one of the two tests is negative, there is probably no infection. Table 5: Risk adapted prophylaxis in the case of complications during pregnancy and delivery Increased risk Mother Child Multigravidity AZT monoprophylaxis poss. Combination therapy e.g. AZT + 3TC + PI/r from week 29 + 0 gestation ŽWithin 6 h post partum AZT 4 x 2 mg/kg orally for 4 weeks (if necessary, after 10 days i.v. shift to roal application Early onset of labor Combination therapy, e.g. AZT + 3TC + PI/r Within 6 h post partum AZT 4 x 2 mg/kg orally 4-6 weeks plus 1 single dose nevirapine 2 mg/kg after 48-72 h *,**. AZT dosage for premature birth (PB) < week 35 of gestation: 2 x 2 mg/kg orally or 2 x 1.5 mg/kg i.v. from day 15: 3 x 2 mg/kg orally (for premature birth < week 30 of gestation as of day 29. Premature birth Week 33+0 - 36+6 of gestation** Maternal AZT prophylaxis < 4 weeks In addition to AZT or a combination therapy: nevirapine* As for early onset of labor (see above) *see chapter on NNRTIs ** for premature babies, a triple prophylaxis is also possible (see below): but 3TC should be administered to premature babies only with great reticence Table 6:Prophylaxis procedure in the case of complications during pregnancy and delivery in cases of highly increased risk Highly increased risk Mother Child Premature birth < week 33+0 of gesation Prematurely ruptured membranes Amniotic infection syndrome Elevated viral load at the end of pregnancy In addition to AZT or a combination therapy: nevirapine* AZT (dosage see above) for 4-6 weeks plus 3TC** 2 x 2 mg/kg for 4-6 weeks plus nevirapine* 2 mg/kg within 2 to 48 h + 2. Dose 48-72 h post partum (if no NVP pre-delivery or < 2h between intake and delivery). (If nevirapine pre-delivery, then only 1 after 48-72 h.) Incision injury of child Ingestion of hemorrhagic amniotic fluid Diagnosis: HIV infection only post partum. *see chapter on NNRTIs ** 3TC should be administered to premature babies only with great reticence Therapy of neonates Postnatal standard prophylaxis The postnatal transmission prophylaxis should begin, if possible, within the first 6 hours following birth with oral or - in the case of gastrointestinal symptoms - intravenous AZT prophylaxis. In Germany, the duration of the oral standard prophylaxis has been shortened from six to two (to four) weeks (Vocks-Hauck 2001). Prophylaxis in cases of increased risk (multiple neonates, premature infants) In multiple-birth neonates without further risk, AZT prophylaxis of four weeks duration is recommended. In addition, premature infants receive nevirapine, which is given either once to the mother before delivery and once to the premature infant, or twice postnatally. If maternal nevirapine administration occurs less than an hour before delivery, then the newborn receives its first dose within the first 48 hours (Stringer 2003). If nevirapine was a part of the combination therapy for the mother, the dose is doubled to 4 mg/kg in newborns because of possible enzyme induction. In addition, newborns receive an extended AZT prophylaxis according to the regimen proposed for premature infants (see below) for the duration of four to six weeks. Prophylaxis in cases of highly increased transmission risk In neonates with additional transmission risks, a combination prophylaxis with AZT+3TC is recommended, as well as two doses of nevirapine. However, the pharmacokinetic data available on HAART is extremely limited. A strongly increased risk exists, for example, after premature rupture of membranes, in cases of amniotic infection syndrome, high viral load prior to delivery, lacking transmission prophylaxis and incision injury of the child during cesarean section, as well as in cases where the amniotic fluid sucked from the gastrointestinal or respiratory tract of the newborn is hemorrhagic. Procedure in cases of no pre- and intranatal prophylaxis Combination prophylaxis of AZT+3TC should start within the first 6 to 12 hours after delivery. In addition, a perinatal nevirapine prophylaxis with two-fold administration is recommended. If HIV infection is discovered only after birth, a combination prophylaxis, begun within 48 hours, seems to be far more effective than a prophylaxis, which is initiated only after 3 days (transmission rates 9.2 % vs. 18.4 %, Wade 1998). However, even then, a certain positive effect of AZT prophylaxis as opposed to no prophylaxis can still be verified (18.4 % vs. 26.6 %) (Table 6).Therefore, even late initiation of post-natal prophylaxis (> 3 days) can still make sense. Further studies for HIV prevention in neonates A survey of studies about the pharmacokinetics in pregnancy and neonates is given in Table 7 (Ronkavilit 2001 & 2002, Mirochnik 2005). In order to continuously improve HIV therapy during pregnancy and the chemoprophylaxis of perinatal HIV infection, a thorough documentation of clinical data is necessary. In the US, the "Antiretroviral Pregnancy Registry" is an extensive therapy register that helps to evaluate the potential teratogenicity of antiretrovirals on the basis of "case reports" on HIV-exposed neonates: Antiretroviral Pregnancy Registry, Research Park, 1011 Ashes Drive, Wilmington NC 28405 Tel. (international) 910-265-0637 or +44-1895-825-005, e-mail: Registry@pharmaresearch.com; http://www.apregistry.com/contact.htm Table 7: Studies on antiretroviral prophylaxis in neonates Drug Average daily dose Most frequent side effects Study AZT Zidovudine Retrovir™ 4x2 mg/kg, 2x2 mg/kg in PI*< 35 GW, from 15th day: 3x2 mg/kg* , in PI < 30 GW from 29th day Anemia,n eutropenia Mitochondriopathy in combination with 3TC (P)ACTG's 076, 316, 321, 353, 354, 358; HIVNET 012 III PACTG 331(PI) 3TC Lamivudine Epivir™ 2x2 mg/kg in neonates (< 30 days) GI SE, vomiting, Mitochondriopathy in combination Incompatibility in premature infants PACTG 358 ddI Didanosine Videxâ 2x50 mg/m2 from 14th day Diarrhea, pancreatitis, mitochondriopathy in combination PACTG 239,249; HIV-NAT d4T Stavudine Zerit™ 2 x 0.5 mg/kg from 14th day Mitochondriopathy in combination PACTG 332, 356; HIV-NAT ABC Abacavir Ziagen™ 1x2-4 mg/kg; > 1 month 2x8 mg/ kg (Study) Hypersensitivity reaction, mitochondriopathy, lactic acidosis PACTG 321 NVP Nevirapine Viramuneâ 1x2-4 mg/kg or 1x120 mg/m2 for 14 days, thereafter 2x3.5-4 mg/kg or 2x120 mg/m2 ,,maximal 400 mg/m2 Rash, hepatotoxicity, hyperbilirubinanemia PACTG 316,356, HIVNET 012 NFV Nelfinavir Viraceptâ 2x40 mg/kg (Study) from 1 week up to 6 weeks; GI SE: particularly diarrhea PACTG 353, 356 RTV Ritonavir Norvirâ 1x350 mg/m2 or 2x350 mg/m2 for 4 weeks (Study) Hyperbilirubinemia, gastrointestinal SE PACTG 354 I=infant; PI = premature infant; MI = mature born infant; SD = single dose; (P)ACTG = (Pediatric) AIDS Clinical Trial Group; HIV-NAT = HIV-Netherlands Australia Thailand Research Collaboration; NN = neonate; GI SE = Gastrointestinal side effect; GW = gestation week Reference: Except for AZT in mature born infants, the dosage is taken from the studies. 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