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Mechthild Vocks-Hauck

Perinatal (vertical) HIV infection has become rare since the introduction of antiretroviral transmission prophylaxis and elective cesarean section. While the vertical HIV transmission rate ranged from 15 to 20 % in the United States and Europe at the beginning of the nineties, it now amounts to only a few percent (Connor 1994, European Collaborative Study 2001, Marcollet 2002, Hollwitz 2004). 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 contraindication for antiretroviral therapy as long as individual maternal circumstances are taken into consideration (Cooper 2002, Agangi 2005, CDC 2005 a)).

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

Reference is made to the European (Coll 2002), German (DAIG), and Austrian AIDS societies (OEAG) (DAIG 2003) 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 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 corrected accordingly before treatment is started. Following the recommendations of the German/Austrian guidelines and the CDC, antiretroviral therapy in symptom-free patients should begin - when CD4+ T-cell count is below 200-350/µl 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 with one of the common combination regimens, a resistance test should be carried out (see chapter on Resistance). When setting up a treatment plan, it is important that: 1) AZT (Retrovir™) should be one component of the combination - if the result of the resistance test is favorable; and 2) Efavirenz (Sustiva™, Stocrin™) should be avoided because of possible teratogenic effects in the first trimester, and 3) The combination ddI (Videx™) + d4T (Zerit™) should not be used because of possible severe mitochondriopathies (Bristol-Myers 2001). 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 in the section Antiretroviral transmission prophylaxis). Table 1: Special features of anti-HIV therapy in pregnancy Explanation of risk: Only AZT is approved for perinatal transmission prophylaxis HIV resistance testing No efavirenz (Sustiva™) in the first trimester (teratogenicity) No hydroxyurea (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 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, but avoid functional monotherapy if drugs have a long plasma half-life. 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 or 13 weeks of gestation. At present, however, there is not enough data available to give an unambiguous recommendation for each individual case. The clinical, immunological and virological situation of the patient (Bucerri 2003) and the known or expected effects on the fetus must be considered before making a decision. 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 weeks. Functional monotherapy after discontinuation regimens with NNRTIs should be avoided. Pharmacokinetic data demonstrate that detectable drug levels may persist up to three weeks after discontinuation of nevirapine. It is recommended either to continue the dual nucleoside analog components for a period of time after nevirapine discontinuation (Chaix 2005), or to replace nevirapine by a (boosted) PI, or continue the NNRTI including regimen. In case of conception under nevirapine, the therapy is usually continued during early pregnancy because of the complicated interruption strategy. Combination therapy for the duration of pregnancy The suggestion of offering a combination therapy to pregnant patients with a plasma HIV RNA level > 1,000 -10,000 copies/ml from the second trimester (CDC 2005a) onward or 32 weeks of gestation, e.g. in Germany, is increasingly the subject of discussion in specialized medical literature. Combination therapy is offered to the patient as a means of "better" prevention, even if it is not indicated on the basis of the immunological and virological situation. This approach is based on the assumption that a decrease in viral load translates into a lowering of the transmission risk. Furthermore, the possibility that a very low viral load might make vaginal deliveries possible is being discussed. 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 verified in women receiving HAART (Shapiro 2004). For this reason, in the USA as well as in some European countries such as France and Switzerland, 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. 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 (Watts 2004). Coinfections The diagnosis and therapy of genital infections are essential. Chlamydia infection, trichomoniasis, and bacterial vaginosis correlate with premature delivery. The latter increases the transmission risk, as do premature rupture of membranes and amniotic infection syndrome. Hepatitis B infection of the mother can be passed on during delivery and calls for simultaneous vaccination (active and passive) of the newborn. Perinatal transfer of hepatitis C infection is promoted by HIV infection - just as the hepatitis C infection may promote the transfer of HIV (Schuval 2004). In this constellation, C-section is of particular significance (Mok 2005, Schackman 2004). CMV infection is passed on to the child intrauterinely and perinatally and may also promote intrauterine infection with HIV. Cytomegaloviruses in HIV-infected women receiving AZT or nevirapine prophylaxis could be detected in the amniotic fluid (Mohlala 2005). 30 % of children infected with HIV perinatally, who have an early manifestation of AIDS due to PCP, are co-infected with CMV. Special aspects of HIV therapy in pregnancy Because embryotoxicity cannot be excluded and hepatic metabolism is altered in pregnancy, some basic rules must be taken into consideration (CDC 2005 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 (Palumbo 2001), and infected children seem to have an unfavorable prognosis in these cases (The Italian Register for HIV Infection in Children 1999). 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 ­ in pregnancy; enzyme induction, resistance mutation rate about 20 % even when administered once/twice PIs (minimal placenta transfer) Nelfinavir Indinavir Ritonavir Lopinavir/r Saquinavir SGC Amprenavir/ Fosamprenavir Atazanavir Frequent use; often replaced by boosted PIs Hyperbilirubinemia, nephrotoxicity Poor tolerance, only as booster Some experience Low plasma levels, only boosted Few data No experience No experience; indir. hyperbilirubinemia Entry Inhibitors T-20 Only 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. 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 (Noguera 2004, Poirier 2004, Vigano 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 %. 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 (Alimenti 2003, Mofenson 2004). Even after eight years, neutrophil granulocytes were reduced in perinatally NRTI-exposed children (ECS 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 contraindicated 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 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. Nevirapine in pregnant women is only recommended following very careful assessment of the benefit-risk ratio (CDC 2005a)). Perinatal single and two-dose prophylaxis has resulted in the development of drug resistance (Jackson 2000, 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, Jackson 2006). 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 2005 a) and b)). 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 (Beitune 2005) and hepatic toxicity. Presently, most experience relates to nelfinavir (Bryson 2002). However, in combination therapies, toxic side effects have also been described (Morris 2005) (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 (Marzolini 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 "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." 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+ T-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 Antiretroviral transmission prophylaxis Combination prophylaxis Standard combination antiretroviral regimens for the treatment of HIV infection should be discussed and offered to all pregnant women with HIV regardless of the viral load. They are clearly recommended if 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). The combination of AZT+3TC is problematic because of the possible development of resistance in the M184 codon (Mandelbrot 2001). Therefore, HAART prophylaxis is increasingly being used. 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 + a second NRTI + plus NNRTI or (boosted) PI (a third NRTI is rarely used) 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. Procedure in cases with additional pregnancy risks The pregnancy risks mentioned in Table 5 require an intensified prophylaxis. Table 5: Risk adapted prophylaxis in the case of complications during pregnancy and delivery Increased risk Multigravidity Mother: AZT monoprophylaxis, or combination therapy, e.g. AZT + 3TC + nevirapine or AZT + 3TC + nelfinavir/(boosted) PI from 29+0 weeks gestation Children: 4 weeks AZT (Table 7) Early onset of labor Mother: combination therapy, e.g. AZT + 3TC + nevirapine or AZT + 3TC + nelfinavir/(boosted) PI Premature infants from 33+0 to 36+6 weeks of gestation or AZT-prophylaxis of < 4 weeks Mother: in addition to AZT or a combination therapy: nevirapine* Child: dual combination therapy in the neonate (Table 7) Highly increased risk Premature infants < 33+0 weeks of gestation Premature rupture of membranes > 4 h or Amniotic infection syndrome or Rise of the viral load towards the end of pregnancy Mother: In addition to AZT or a combination therapy: nevirapine Child: triple combination prophylaxis (Table 7) Incision injury of the child or Ingestion of hemorrhagic amniotic fluid or HIV infection diagnosed only post partum Child: triple combination prophylaxis (Table 7) * In the case of preceding nevirapine therapy during pregnancy: reduced plasma half-life, therefore: increase nevirapine dose or alternative extension of therapy; after nevirapine monoprophylaxis 20 % resistant strains in the mother. Thus, combination, where appropriate, with 2 NRTIs over 1-3 weeks (for example ddI, AZT+ddI or d4T+ddI; not 3TC because of rapid resistance development) or combination with (boosted) PI is advised. 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 Starting at 32 weeks gestation with a time-limited monoprophylaxis with AZT might be an appropriate option for women with HIV-RNA levels well below 10,000 copies/ml (DAIG 2005), and preferably in those with < 1,000 copies/ml (CDC 2005 a)) who wish to restrict exposure of their fetus to antiretroviral drugs (CDC 2005a)). This regimen is, however, controversial, not only because AZT-resistant viruses have been increasingly identified, but also because the risk of resistance formation under monotherapy cannot be neglected. The use of AZT alone during pregnancy is mentioned for the sake of completeness; in practice, it is now out-dated and hardly ever used. Table 6: AZT monoprophylaxis in the case of low virus load (clearly less than 10,000 copies/ml), asymptomatic HIV infection and uncomplicated pregnancy course (out-dated because of the risk of development of resistance) After resistance testing starting at 32 + 0 weeks gestation 2 x 250-300 mg AZT per os During delivery (elective cesarean section from 37+0 up to 37+6 weeks gestation): 2 mg/kg AZT i.v. as "loading dose" over 1 h to approx. 3 h preoperatively 1 mg/kg AZT i.v. intraoperatively until the delivery of the child In neonates AZT monoprophylaxis: 2 mg/kg AZT orally every 6 hours within 6 hours postpartum for 2-4 weeks or 1.5 mg/kg AZT i.v. every 6 hours within 6 hours postpartum for 10 days 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 HAART with undetectable viral load appears to be possible, because no increased vertical transmission rates are found compared to elective cesarean section in pregnant women with a viral load under 1,000 HIV RNA copies/ml (Shapiro 2004, ECS 2005). In some European countries such as France and Switzerland and in the United States, women falling into this category can now deliver a child vaginally. In Europe, the percentage of vaginal births increased from 12 % in 1999 to 24 % in 2002 (Thorne 2004). 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. 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 (Bulterys 2004). 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. 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. 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. Table 7: Postnatal antiretroviral prophylaxis/treatment for infants of HIV-positive mothers Standard risk Drug Side effect Uncomplicated pregnancy and delivery with complete pre- and intrapartal transmission prophylaxis AZT, within 6 h after birth: 4 x 2 mg/kg orally for 2-4 weeks or 4 x 1.5 mg/kg i.v. for 10 days Anemia, neutropenia; gastrointestinal irritation Increased risk Multiple birth AZT orally or i.v., within 6 h after delivery: (where appropriate, switch to oral administration after 10 days i.v.) 4 x 2 mg/kg orally for 4 weeks see above Premature labor Pre-term infants 33+0 up to 36+6 weeks of gestation * Early labor Therapy < 4 weeks in cases of low viral load and without obstetric risks AZT, within 6 h after birth (see above): 4 x 2 mg/kg orally for 4-6 weeks plus Single dose of nevirapine of 2 mg/kg after 48-72 hrs. ** AZT dosage in premature infants < 35 weeks of gestation: AZT 2 x 2 mg/kg orally or 2 x 1.5 mg/kg i.v., from 15th day: 3 x 2 mg/kg orally, in infant < 30 weeks of gestation starting from day 29 AZT: see above, particularly anemia Nevirapine: hepatotoxicity, rash Highly increased risk Premature infants < 33 + 0 weeks of gestation** Prematurely ruptured membranes Amniotic infection Elevated viral load at the end of pregnancy, also if no prophylaxis Incision injury of neonate Ingestion of hemorrhagic amniotic fluid HIV infection diagnosed at birth AZT (dosage see above) for 4-6 weeks plus 3TC* 2 x 2 mg/kg for 4-6 weeks plus Nevirapine** 2mg/kg as SD within 2h until 48h. If no prenatal nevirapine or later <2hrs, one additional dose 48-72h pp. If prenatal nevirapine, then only one dose after 48-72hrs. AZT: As above, in combination with 3TC: gastrointestinal SE, mitochondriopathy (lactate) Nevirapine: hepatotoxicity, exanthema (not to be expected after two doses) *in premature infants, a triple combination prophylaxis is also possible, but use 3TC cautiously, **Nevirapine: if no prenatal administration was possible, first adm. immediately and second adm. within 48-72 hrs postpartum. Dosage adaptation if possible enzyme induction in case of previous maternal NVP therapy; administration of the 1st dose < 2 hrs prepartal 2nd dose immediately after birth and 3rd dose after 48-72 hrs. AF = amniotic fluid; NN = neonate; pp = postpartum; SE = side effect Table 8: Studies on antiretroviral prophylaxis in neonates Drug Average daily dose Most frequent side effects Study AZT Zidovudine Retrovir™ 8 mg/kg in 4 SD; 4 mg/kg in 2 SD in PI*< 35 GW, from 15th day: 6 mg/kg* in 3 SD, in PI < 30 GW from 29th day Anemia, neutropenia Mitochondriopathy in combination with 3TC (P)ACTG's 076, 316, 321, 353, 354, 358; HIVNET 012 III PACTG 331(PI) 3TC Lamivudine Epivir™ 4 mg/kg in 2 SD in neonates (< 30 days) GI SE, vomiting, Mitochondriopathy in combination Incompatibility in premature infants PACTG 358 ddI Didanosine Videx™ 100 mg/m2 in 2 SD from 14th day Diarrhea, pancreatitis, mitochondriopathy in combination PACTG 239, 249; HIV-NAT d4T Stavudine Zerit™ 1 mg/kg in 2 SD from birth to 13 days, 2 mg/kg in 2 SD from 14th day Mitochondriopathy in combination PACTG 332, 356; HIV-NAT ABC Abacavir Ziagen™ Up to 4 mg/kg in 2 SD; > 1 month 16 mg/ kg in 2 SD (Study) Hypersensitivity reaction (no restart), mitochondriopathy, lactic acidosis PACTG 321 NVP Nevirapine Viramune™ 2-4 mg/kg as SD or 120 mg/m2 for 14 days, thereafter 7-8 mg/kg or 240 mg/m2 in 2 SD, maximal 400 mg/m2 Rash, hepatotoxicity, no restart after symptomatic hepatic event PACTG 316,356, HIVNET 012 NFV Nelfinavir Viracept™ 80 mg/kg in 2 SD (Study) from 1 week and 6 weeks; 110-150 mg/kg in 2 or 3 SD at 2 months GI SE: particularly diarrhea PACTG 353, 356 PENTA 7 RTV Ritonavir Norvir™ 350 mg/m2 as SD or 700 mg/m2 in 2 SD 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. Antiretroviral substances that are not approved, should be used in neonates only in the context of studies, if possible. 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 7). Further studies for HIV prevention in neonates A survey of studies about the pharmacokinetics in pregnancy and neonates is given in Table 8 (Ronkavilit 2001 & 2002, Wade 2004, Kovacs 2005, Mirochnik 2005, Best 2006). Studies 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; Kontakt: http://www.apregistry.com/contact.htm. References 1. Acosta EP, Bardeguez A, Zorrilla C et al. Pharmacokinetics of Saquinavir plus low dose ritonavir in human immunodeficiency virus-infected pregnant women. Antimicrob Agents Chemother 2004; 48: 430-6. 2. Agangi A, Thorne C, Newell ML:European Collaborative Study. Increasing likehood of further live births in HIV-infected women in recent years. BJOG 2005; 112:881-7. http//hiv.net/link.php?id=15957987 3. Alimenti A, Burdge DR, Ogilvie GS et al. Lactic acidemia in HIV-uninfected infants exposed to perinatal antiretroviral therapy. Pediatr Infect Dis 2003; 22: 782-9. http//hiv.net/link.php?id=14506368 4. Barret B, Tardieu M, Rustin P et al. Persistent mitochondrial dysfunction in HIV-1-exposed but uninfected infants: clinical screening in large prospective cohort. AIDS 2003; 17: 1769-85. http://hiv.net/link.php?id=12891063 5. Beitune PE, Duarte G, Foss MC et al. Effect of antiretroviral agents on carbohydrate metabolism in HIV-1 infected pregnant women. Diabetes Metab Res Rev 2005. http://hiv.net/link.php?id=16021650 6. Bekerman K, Covington D, Garcia P et al. Association between antiretroviral therapy during pregnancy and prematurity/low birth weight. 11th CROI 2004, San Francisco. 7. Best BM, Mirochnick M, Caparelli EV et al. Impact of pregnancy on abacavir phamacokunetics. AIGS 2006;20:553-60. http://hiv.net/link.php?id=16470119 8. Bristol-Myers warns of AIDS drugs use. AIDS Read. 2001; 11: 82. 9. 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