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Therapy for mothers and prevention for neonates
Perinatal (vertical) HIV infection has become rare since the introduction of antiret-roviral transmission prophylaxis and elective cesarean section. While the verticalHIV transmission rate ranged from 15 to 20 % in the United States and Europe atthe beginning of the nineties, it now amounts to only a few percent (Connor 1994,European Collaborative Study 2001, Marcollet 2002, Hollwitz 2004). PostpartumHIV infections are avoidable provided that HIV-infected mothers do not breastfeed.
At the same time as transmission prophylaxis was introduced, the treatment of HIVinfection changed too. Nowadays, pregnancy is no longer a contraindication forantiretroviral therapy as long as individual maternal circumstances are taken intoconsideration (Cooper 2002, Agangi 2005, CDC 2005 a)).
The following chapter summarizes the recommendations of different guidelines forHIV therapy in pregnancy and perinatal chemoprophylaxis.
Reference is made to the European (Coll 2002), German (DAIG), and AustrianAIDS societies (OEAG) (DAIG 2003) as well as American Guidelines (CDC 2005a) and b)). In addition, detailed and continuously updated recommendations of theUS guidelines are to be found on the HIVATIS website:http://hiv.net/link.php?id=190.
HIV therapy in pregnancy
Starting HIV therapy during pregnancy
The assessment of indications for therapy and drug selection is similar to that innon-pregnant patients (chapter ART 2005). Since the CD4 T-lymphocyte countdecreases physiologically by approximately 10-20 % in pregnant patients, thethreshold values should be corrected accordingly before treatment is started. Fol-lowing 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 3.0version b-DNA).
Before initiating therapy with one of the common combination regimens, a resis-tance 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 ofthe resistance test is favorable; and
2) Efavirenz (Sustiva™, Stocrin™) should be avoided because of possible terato-genic 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 isno guarantee for the prevention of HIV transmission. Therefore, prophylaxis to re-duce perinatal HIV transmission is also recommended in sufficiently treated preg-nant 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
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, hepatictransaminase 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 ther-
apy 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 in-
formed 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 beexpected. In this case, as in all others, the rule is: withdraw all drugs simultaneouslyand re-administer them simultaneously, but avoid functional monotherapy if drugshave a long plasma half-life.
In other cases − especially if pregnancy is diagnosed very early − the fear of possi-ble embryotoxic effects may lead to an interruption of antiretroviral therapy untilthe end of the first trimester or 13 weeks of gestation. At present, however, there isnot enough data available to give an unambiguous recommendation for each indi-vidual case. The clinical, immunological and virological situation of the patient
(Bucerri 2003) and the known or expected effects on the fetus must be consideredbefore making a decision. A continuously updated summary of the current state ofknowledge about antiretroviral drugs in pregnancy can be found on the internet atthe web address http://hiv.net/link.php?id=189.
If treatment is interrupted, all drugs (NRTIs and PIs) should be withdrawn and re-administered simultaneously in order to prevent development of resistance. As it isusually not possible to determine pregnancy duration exactly, the restart is mostlyinitiated at the gestational age of 13 weeks. Functional monotherapy after discon-tinuation regimens with NNRTIs should be avoided. Pharmacokinetic data demon-strate that detectable drug levels may persist up to three weeks after discontinuationof nevirapine. It is recommended either to continue the dual nucleoside analogcomponents for a period of time after nevirapine discontinuation (Chaix 2005), orto replace nevirapine by a (boosted) PI, or continue the NNRTI including regimen.
In case of conception under nevirapine, the therapy is usually continued duringearly 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 aplasma HIV RNA level > 1,000 –10,000 copies/ml from the second trimester (CDC2005a) onward or 32 weeks of gestation, e.g. in Germany, is increasingly the sub-ject of discussion in specialized medical literature. Combination therapy is offeredto the patient as a means of “better” prevention, even if it is not indicated on thebasis of the immunological and virological situation. This approach is based on theassumption that a decrease in viral load translates into a lowering of the transmis-sion risk.
Furthermore, the possibility that a very low viral load might make vaginal deliver-ies possible is being discussed. With a viral load of less than 1,000 HIV RNA cop-ies/ml, the advantage of cesarean section compared with vaginal delivery can nolonger be verified in women receiving HAART (Shapiro 2004). For this reason, inthe USA as well as in some European countries such as France and Switzerland,vaginal delivery is considered an option for women on antiretroviral combinationtherapy whose HIV status at the time of delivery is less than 1,000 copies/ml and/orundetectable and in whom no obstetric complications are expected. Since the studydata 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.
In addition to measuring the hemoglobin concentration to exclude an AZT-associated anemia, transaminases for potential hepatic toxicity, and lactate level todetect lactic acidosis early, the CD4+ T-cell number and viral load should bemonitored at monthly intervals. If PIs are part of the treatment, it is of particularimportance to monitor the blood glucose level closely (Watts 2004).
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 amnioticinfection syndrome.
Hepatitis B infection of the mother can be passed on during delivery and calls forsimultaneous vaccination (active and passive) of the newborn. Perinatal transfer ofhepatitis C infection is promoted by HIV infection – just as the hepatitis C infectionmay promote the transfer of HIV (Schuval 2004). In this constellation, C-section isof particular significance (Mok 2005, Schackman 2004). CMV infection is passedon to the child intrauterinely and perinatally and may also promote intrauterine in-fection with HIV. Cytomegaloviruses in HIV-infected women receiving AZT ornevirapine prophylaxis could be detected in the amniotic fluid (Mohlala 2005).
30 % of children infected with HIV perinatally, who have an early manifestation ofAIDS 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 inpregnancy, some basic rules must be taken into consideration (CDC 2005 a)) (Table2). It is important to understand that a detectable plasma viral load always necessi-tates a resistance test. AZT resistance was verified, for example, in the UnitedStates in approximately 17 % of the women during pregnancy (Palumbo 2001), andinfected children seem to have an unfavorable prognosis in these cases (The ItalianRegister for HIV Infection in Children 1999).
Table 2: Antiretroviral agents in pregnancy
AZT is metabolized in the placenta; mitochon-
driopathy risk: ddC > ddI > d4T > AZT > 3TC >
Alternative to 3TC, barely any experience
Hepatic toxicity ↑ in pregnancy; enzyme induc-
tion, resistance mutation rate about 20 % evenwhen administered once/twice
Frequent use; often replaced by boosted PIs
Antiretroviral agents in pregnancy
Nucleoside reverse transcriptase inhibitors (NRTIs)
Nucleoside analogs cross the placenta (Chappuy 2004) and can cause toxic damagenot 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 frequentlyused nucleoside analogs such as AZT, 3TC and d4T, do not increase teratogenicityby more than twofold (Antiretroviral Pregnancy Registry 2004). Most of our expe-rience is related to AZT administration. Follow-ups of more than 20,000 childrenwho had received AZT prophylaxis did not show any serious side effects. An analy-sis of the causes of death of 223 children, who died within the first five years oflife, ruled out drug-related causes (The Perinatal Safety Review Working Group2000). 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 2,644ART-exposed non-infected children, neurological symptoms with persistent mito-chondrial dysfunction were reported in 0.26 %. Retardation of auditory evoked po-tentials (Poblano 2004), as well as nonspecific changes in cerebral MRTs in chil-dren perinatally exposed to AZT (plus 3TC) (Tardieu 2005) have been interpretedas a sign of neurotoxicity. 24 months after combined nucleoside exposure, raisedlactate values as well as impairment of hematopoeiesis can still be demonstrated inchildren (Alimenti 2003, Mofenson 2004). Even after eight years, neutrophilgranulocytes were reduced in perinatally NRTI-exposed children (ECS 2004). Sofar, severe mitochondriopathies have been observed at least twice in pregnantwomen taking a combination therapy of the nucleoside analogues d4T+ddI plusnelfinavir or nevirapine (Sarner 2002). For this reason, the combination d4T+ddI iscontraindicated in pregnancy (Bristol-Myers 2001). Hepatic toxicity with hyperbili-rubinemia was described under AZT+3TC+efavirenz therapy. Following the ad-ministration of AZT+3TC+nelfinavir, one pregnant woman died of sudden acuteliver failure (Hill 2001). Tenofovir did not show any maternal toxicity in animalexperiments, but did cause a fetal growth retardation of 13 % as well as a slightdecrease in the bone mineral density (Tarantal 2002).
Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
In perinatal prevention, nevirapine has been employed successfully, particularly incombination with AZT. Because of enhanced risk of liver toxicity during the first18 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 timeof dose escalation. Nevirapine in pregnant women is only recommended followingvery careful assessment of the benefit-risk ratio (CDC 2005a)).
Perinatal single and two-dose prophylaxis has resulted in the development of drugresistance (Jackson 2000, Flys 2005). If a mother gives birth less than two hoursfollowing nevirapine administration, or has not received any prior nevirapine at all,the newborn should receive a dose of nevirapine immediately after birth and a fur-ther dose after 48-72 hours (Stringer 2003, Jackson 2006). Because of embryonictoxicity in the rhesus monkey and also in humans (neural tube impairments, Bristol-
Myers Squibb 2004) efavirenz is not used during the first trimester of pregnancyand only after the second in cases with no alternative treatment option providingreliable 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 laterstages of pregnancy, due to a possible diabetogenic effect (Beitune 2005) and he-patic toxicity. Presently, most experience relates to nelfinavir (Bryson 2002). How-ever, in combination therapies, toxic side effects have also been described (Morris2005) (see above). Indinavir can lead to hyperbilirubinemia and nephrolithiasis; theplasma levels can be lowered (Kosel 2003). As with indinavir, saquinavir shouldalso be boosted with ritonavir in pregnancy (Acosta 2004). Ritonavir and lopinavirplasma levels are also lowered during pregnancy (Scott 2002, Stek 2004).
A Swiss research group suspected that the use of combination therapy might causean increase in premature birth rate and a higher rate of malformations. Malforma-tions 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 thepremature birth rate, the available data is inconsistent (increases were reported bythe European Collaborative Study 2003, Thorne 2004, Bekerman 2004; no in-creases 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 catego-ries 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 ofthese drugs.
FDA category B is defined as follows: “Animal studies have revealed no evidenceof harm to the fetus; however, there are no adequate and well-controlled studies inpregnant 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 ef-fect and there are no adequate and well-controlled studies in pregnant women. Usein pregnancy should occur only after careful benefit/risk appraisal.” All other drugsthat were not mentioned in category B fall into the FDA category C. Efavirenz fallsinto category D because of neural tube defects in humans after first trimester expo-sure.
FDA category D (Efavirenz) is defined as follows: “Adequate well-controlled orobservational studies in pregnant women have demonstrated a risk for the fetus.
Nevertheless, the benefits of therapy may outweigh the potential risk.” For exam-ple, the drug may be acceptable if it is needed in a life-threatening situation or seri-ous 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 lastweeks prior to birth. About 10 % of vertical HIV infections occur before the thirdtrimester, and 10-15 % are caused by breastfeeding.
The probability of HIV transmission to a neonate correlates with the viral load. Thisalso seems to apply to women who are being treated with antiretroviral drugs (Ta-ble 3). If the viral load is undetectable using currently available tests, the probabil-ity of transmission is indeed extremely low; however, infections have also beendescribed under such circumstances (Ioannidis 2001). Likewise, premature birthsand premature rupture of membranes are associated with an increased infection riskfor the child.
For this reason, reduction in the level of plasma viremia and improvement in theimmune status of pregnant women are vital prophylactic measures. If a mother istreated with antiretrovirals, these drugs should continue to be taken, if possible,during delivery at the usual scheduled intervals in order to achieve the maximumeffect and to minimize the risk of developing resistance.
Table 3: Known risk factors for perinatal HIV transmission
Premature rupture of membranes of > 4 h
Pre-term infants (< 37 weeks of gestation)
For the general prevention of mother-to-child transmission of HIV, pregnantwomen should be warned not to use intravenous drugs or to have unprotected sexbecause of the increased risk of HIV transfer in these cases.
In addition to the indicated or optional antiretroviral therapy of the mother, the fol-lowing 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 transmis-sion risk
• Postnatal chemoprophylaxis of the infants (post-exposure prophylaxis)• No breastfeeding
Antiretroviral transmission prophylaxis
Standard combination antiretroviral regimens for the treatment of HIV infectionshould be discussed and offered to all pregnant women with HIV regardless of theviral load. They are clearly recommended if the viral load is > 10,000 copies/ml.
Combination prophylaxis should be introduced temporarily from 32+0 weeks ges-tation until immediately after birth (Table 4).
The combination of AZT+3TC is problematic because of the possible developmentof resistance in the M184 codon (Mandelbrot 2001). Therefore, HAART prophy-laxis is increasingly being used.
Table 4: Combination prophylaxis with combination therapy containing AZT in cases with aviral 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
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 beintegrated into the combination therapy starting at 32+0 weeks gestation. Whenusing combinations containing d4T, this agent should be substituted by another ac-tive 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
Mother: in addition to AZT or a combination
Child: dual combination therapy in the neonate
Highly increased risk
Premature infants < 33+0 weeks of ges-
Mother: In addition to AZT or a combination
Child: triple combination prophylaxis (Table 7)
Rise of the viral load towards the end ofpregnancy
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 nevirapinemonoprophylaxis 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 ofrapid 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, motherand newborn receive a dual or triple combination prophylaxis with AZT (plus 3TCand/or nevirapine) in cases of highly increased risk (high viral load and/or medicalcomplications during delivery).
Starting at 32 weeks gestation with a time-limited monoprophylaxis with AZTmight 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 re-sistance formation under monotherapy cannot be neglected. The use of AZT aloneduring pregnancy is mentioned for the sake of completeness; in practice, it is nowout-dated and hardly ever used.
Table 6: AZT monoprophylaxis in the case of low virus load (clearly less than10,000 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
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
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 preg-
Cesarean section is carried out swiftly by experienced obstetricians prior to the on-set of labor from 37+0 up to 37+6 weeks of gestation using the Misgav-Ladachtechnique, which reduces bleeding. Blunt preparation and the delivery of the childwithin the intact amniotic sac are considered ideal (Schäfer 2001). A vaginal deliv-ery in women under HAART with undetectable viral load appears to be possible,because no increased vertical transmission rates are found compared to electivecesarean section in pregnant women with a viral load under 1,000 HIV RNA cop-ies/ml (Shapiro 2004, ECS 2005). In some European countries such as France andSwitzerland and in the United States, women falling into this category can now de-liver a child vaginally. In Europe, the percentage of vaginal births increased from12 % in 1999 to 24 % in 2002 (Thorne 2004).
Cesarean section in cases of multigravidity should be carried out using the sametechnique as for a cesarean section in a single pregnancy. In this context, the skilland experience of the operating surgeon are especially important. Cesarean sectionsin cases of premature infants are also important to avoid hypoxia in the neonate; thespecial aspects of chemoprophylaxis have been described above.
In cases with a premature rupture of membranes of less than four hours duration, asection is expedient for prophylactic reasons, providing the clinical situation at thatstage 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 nolonger expected. Nevertheless, vaginal delivery should occur as swiftly as possible,since the HIV transmission risk increases by about 2 % per hour. The extension ofthe 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 isknown, an HIV test can still be offered to the patient (Bulterys 2004). Althoughspecificity is high, it is still considered inadequate. Thus, the combined use of tworapid 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 first6 hours following birth with oral or – in the case of gastrointestinal symptoms –intravenous AZT prophylaxis. In Germany, the duration of the oral standard pro-phylaxis has been shortened from six to two (to four) weeks (Vocks-Hauck 2001).
Prophylaxis in cases of increased risk (multiple neonates, premature
In multiple-birth neonates without further risk, AZT prophylaxis of four weeks du-ration is recommended. In addition, premature infants receive nevirapine, which isgiven either once to the mother before delivery and once to the premature infant, ortwice postnatally. If maternal nevirapine administration occurs less than an hourbefore 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 regi-men proposed for premature infants (see below) for the duration of four to sixweeks.
Prophylaxis in cases of highly increased transmission risk
In neonates with additional transmission risks, a combination prophylaxis withAZT+3TC is recommended. A strongly increased risk exists, for example, afterpremature rupture of membranes, in cases of amniotic infection syndrome, highviral load prior to delivery, lacking transmission prophylaxis and incision injury ofthe child during cesarean section, as well as in cases where the amniotic fluidsucked from the gastrointestinal or respiratory tract of the newborn is hemorrhagic.
Table 7: Postnatal antiretroviral prophylaxis/treatment for infants of HIV-positive mothers
delivery: (where appropriate,switch to oral administrationafter 10 days i.v.)
of low viral load and withoutobstetric risks
AZT dosage in premature in-fants < 35 weeks of gestation:AZT 2 x 2 mg/kg orally or2 x 1.5 mg/kg i.v., from 15th day:3 x 2 mg/kg orally, in infant< 30 weeks of gestation startingfrom day 29
Highly increased risk
bination with 3TC: gas-trointestinal SE, mito-
nevirapine or later <2hrs, oneadditional dose 48-72h pp. If
*in premature infants, a triple combination prophylaxis is also possible, but use 3TC cau-tiously, **Nevirapine: if no prenatal administration was possible, first adm. immediately andsecond adm. within 48-72 hrs postpartum. Dosage adaptation if possible enzyme induction incase of previous maternal NVP therapy; administration of the 1st dose < 2 hrs prepartal 2nddose 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
I=infant; PI = premature infant; MI = mature born infant; SD = single dose; (P)ACTG = (Pedi-atric) AIDS Clinical Trial Group; HIV-NAT = HIV-Netherlands Australia Thailand ResearchCollaboration; 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 con-text 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 hoursafter delivery. In addition, a perinatal nevirapine prophylaxis with two-fold admini-stration is recommended.
If HIV infection is discovered only after birth, a combination prophylaxis, begunwithin 48 hours, seems to be far more effective than a prophylaxis, which is initi-ated 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 prophy-laxis 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 givenin Table 8 (Ronkavilit 2001 & 2002, Wade 2004, Kovacs 2005, Mirochnik 2005,Best 2006).
In order to continuously improve HIV therapy during pregnancy and the chemopro-phylaxis of perinatal HIV infection, a thorough documentation of clinical data isnecessary. In the US, the “Antiretroviral Pregnancy Registry” is an extensive ther-apy register that helps to evaluate the potential teratogenicity of antiretrovirals onthe basis of “case reports” on HIV-exposed neonates:Antiretroviral Pregnancy Registry, Research Park, 1011 Ashes Drive, WilmingtonNC 28405; Kontakt: http://www.apregistry.com/contact.htm.
Acosta EP, Bardeguez A, Zorrilla C et al. Pharmacokinetics of Saquinavir plus low dose ritonavir inhuman immunodeficiency virus-infected pregnant women. Antimicrob Agents Chemother 2004; 48:430-6.
Agangi A, Thorne C, Newell ML:European Collaborative Study. Increasing likehood of further live birthsin HIV-infected women in recent years. BJOG 2005; 112:881-7. http//hiv.net/link.php?id=15957987
Alimenti A, Burdge DR, Ogilvie GS et al. Lactic acidemia in HIV-uninfected infants exposed to perinatalantiretroviral therapy. Pediatr Infect Dis 2003; 22: 782-9. http//hiv.net/link.php?id=14506368
Barret B, Tardieu M, Rustin P et al. Persistent mitochondrial dysfunction in HIV-1-exposed but unin-fected infants: clinical screening in large prospective cohort. AIDS 2003; 17: 1769-85.
Beitune PE, Duarte G, Foss MC et al. Effect of antiretroviral agents on carbohydrate metabolism inHIV-1 infected pregnant women. Diabetes Metab Res Rev 2005. http://hiv.net/link.php?id=16021650
Bekerman K, Covington D, Garcia P et al. Association between antiretroviral therapy during pregnancyand prematurity/low birth weight. 11th CROI 2004, San Francisco.
Best BM, Mirochnick M, Caparelli EV et al. Impact of pregnancy on abacavir phamacokunetics. AIGS2006;20:553-60. http://hiv.net/link.php?id=16470119
Bristol-Myers warns of AIDS drugs use. AIDS Read. 2001; 11: 82.
Bristol-Myers Squibb company: Efavirenz drug label, revised December 2004 .
10. Bryson Y, Stek A, Mirochnik M et al. Pharmakocinetics, antiviral activity and seafety of nelfinavir (NFV)
in combination with ZDV/3TC in pregnant HIV-infected women and their infants: PACTG 353 cohort 2.
Abstract 795, 9th CROI 2002, Seattle.
11. Bucceri AM, Somigliana E, Matrone R et al. Discontinuing combination antiretroviral therapy during the
first trimester of pregnancy: insights from plasma HIV-1 RNA viral load and CD4 cell count. Am J Ob-stet Gynecol; 189: 545-51. http://hiv.net/link.php?id=14520232
12. Bulterys M, Jamieson DJ, O‘Sullivan MJ et al. Rapid HIV-1 testing during labor: a multicenter Study.
13. Capparelli E, Mirochnick M, Dankner WM et al. Zidovudine pharmakokinetics in premature infants
exposed to HIV. J Pediatr 2003; 142: 47-52.
14. Centers for Disease Control (CDC). Recommendations for use of antiretroviral drugs in pregnant HIV-
1-infected women for maternal health and interventions to reduce perinatal HIV-1 transmission in theUnited States. February 24, 2005 a). http://www.aidsinfo.nih.gov
15. Centers for Disease Control (CDC). Guidelines for the use of antiretroviral agents in HIV-infected
adults and adolescents. Recommentations of the panel on clinical practices for treatment of HIV.
MMWR 2002; 51 (RR-7): 1-55. Update April 07, 2005 b). http://www.aidsinfo.nih.gov
16. Chaix ML, Dabis F, Ekoueve D et al. Addition of 3 days of ZDV+3TC postpartum to a short course of
ZDV+3TC and single-dose NVP provides low rate of NVP resistance mutations and high efficacy inpreventing peri-partum HIV-1-transmission ANRS DITRAME Plus, Abidjan, Cote Dìvoire. Abstract72LB, 12th CROI Boston 2005,.
17. Chappuy H, Treluyer JM, Julien V, et al. Maternal-fetal transfer and amniotic fluid accumulation of
nucleoside analogue reverse transcriptase inhibitors in HIV-infected pregnant women. AntimicrobAgents Chemother 2004;48: 4332-6. http://hiv.net/link.php?id=15504861
18. Coll O, Fiore S, Floridia M et al. Pregnancy and HIV-infection: a European consensus on management.
AIDS 2002; 16 Suppl 2: 1-18. http//hiv.net/link.php?id=12479261
19. Connor EM, Sperling RS, Gelber R, et al. Reduction of maternal-infant transmission of HIV type 1 with
zidovudine treatment. N Engl J Med 1994; 331:1173-80. htttp://hiv.net/link.php?id=7935654
20. Cooper ER, Charutat M, Mofenson L, et al. Combination antiretroviral strategies for the treatment of
pregnant HIV-1-infected women and prevention of perinatal HIV-1-transmission. J Aquir Immune DeficSyndr 2002; 29: 484-94. http://hiv.net/link.php?id=11981365
21. Deutsche AIDS-Gesellschaft (DAIG), Österreichische AIDS-Gesellschaft (ÖAG), Robert Koch Institut
et al. Deutsch-Österreichische Empfehlungen zur HIV-Therapie in der Schwangerschaft. Stand Juni2005. http://www.rki.de/INFEKT/AIDS_STD/BR_LINIE/BR_LINIE.HTM
22. Einstein FH, Wright RL, Trentacoste R et al. The impact of protease inhibitors on maternal serum
screening analyte levels in pregnant women who are HIV- positive. Am J Obstet Gyneol 2004,191:1004-1008.http://hiv.net/link.php?id=15467580
23. European Collaborative Study. HIV-infected pregnant women and vertical transmission in Europe since
1986. AIDS 2001; 15: 761-70. http://hiv.net/link.php?id=11371691
24. European Collaborative Study. Exposure to antiretroviral therapy in utero or early life: the health of
uninfected children born to HIV-infected women. J Acquir Immune Defic Syndr 2003; 32: 380-7http://hiv.net/link.php?id=12640195
25. European Collaborative Study. Levels and patterns of neutrophil cell counts over the first 8 years of life
in children of HIV-infected mothers. AIDS 2004; 18: 2009-2017. http://hiv.net/link.php?id=15577622
26. European Collaborative Study. Mother- to- child transmission of HIV infection in the era of highly
active antiretroviral therapy. Clin Infect Dis 2005; 40: 458-65. http://hiv.net/link.php?id=15668871
27. Flys T, Nissley DV, Claasen CW et al. Sensitive drug-resistance assays reveal long-term persistence
of HIV-1 variants with K103N nevirapine (NVP) resistance mutation in some women and infants afterthe administration of single-dose nevirapine. J Infect Dis 2005; 192: 24-9.
28. Jackson JB, Parsons T Musoke P , et al. Association of Cord blood nevirapine concentration with
reported timing of dose and HIV-1 transmission. AIDS 2006; 20: 212-17.
29. Hill JB, Sheffield JS, Zeeman GG, Wendel GD. Hepatotoxicity with antiretroviral treatment of pregnant
women. Obstet Gynecol 2001; 98: 909-11. http://hiv.net/link.php?id=11704198
30. Hollwitz B, Gingelmaier A, Gröger S et al. Course of pregnancy and fetal outcome of 594 HIV-exposed
pregnancies in German reference centers 1999-2003. Abstract ThPeE7973, XV World AIDS Confer-ence, Bangkok, 2004.
31. Ioannidis JP, Abrams EJ, Ammann A, et al. Perinatal transmission of HIV type I by pregnant women
with RNA virus loads < 1000 copies/ml. J Infect Dis 2001; 183: 539-45.
32. Jackson JB, Mracnz M, Guay L, et al. Identification of the K103N resistance mutation in Ugandan
women receiving nevirapine to prevent HIV-1 vertical transmission. AIDS 2000; 14: 111-5.
33. Kovacs A, Cowles MK, Britto P et al. Pharmacokinetics of didanosine and drug resistance mutation in
infants exposed to zidovudine during gestation or postnatally and treated with didanosine or zidovudinein the first three months of life. Pediatr Infect Dis J 2005; 24: 503-9. http://hiv.net/link.php?id=15933559
34. Kosel BW, Beckerman KP, Hayashi S, et al. Pharmakokinetics of nelfinavir and indinavir in HIV-1-
infected pregnant women. AIDS 2003; 17: 1195-9. http://hiv.net/link.php?id=1281952
35. Mandelbrot L, Landreau-Mascaro A, Rekacewicz C, et al. Lamivudine-zidovudine combination for
prevention of maternal-infant tansmission of HIV-1. JAMA 2001; 285: 2083-93.
36. Marcollet A Goffinet F, Firtion G, et al. Differences in postpartum morbidity in women who are infected
with the HIV after elective cesarean delivery, emergency cesarean delivery, or vaginal delivery. Am JObstet Gymecol 2002; 186:784-9. http://hiv.net/link.php?id=11967508
37. Marzolini C, Rudin C, Decostered LA, et al. Transplacental passage of protease inhibitors at delivery.
AIDS 2002; 18: 889-93. http://hiv.net/link.php?id11919490
38. Mirochnick M, Caparelli. Pharmakokinetics of antiretrovirals in pregnant women. Clin Pharmacokinet
2004; 43:1071-87 http://hiv.net/link.php?id=15568888
39. Mirochnick M, Stek A, Acevedo M et al. Safety and pharmacokinetics of nelfinavir coadministered with
zidovudine and lamivudine in infants during the first 6 weeks of life. J Acquir Immune Defic Syndr 2005:39. http://hiv.net/link.php?id=15905735
40. Mofenson LM, Lu M, Pacheco S, et al. Perinatal antiretroviral (ARV) exposure and effect on hemato-
poiesis in HIV-exposed, uninfected children: the women and infants transmission study (WITS). 15thWorld AIDS Conference 2004, Bangkok, Abstract ThPeB7024.
41. Mohlala BK, Tucker TJ, Besser MR et al. Investigation of HIV in amniotic fluid from HIV-infected preg-
nant women at full term. J Infect Dis 2005 192:488-91. http://hiv.net/link.php?id=15995963
42. Mok J, Pembrey I, Tovo PA , Newell M; for the European Paediatric Hepatits C Virus Network. When
does mother to child transmission of hepatitis C virus occur ? Obstet Gynecol Surv 2005; 60: 572-574.
43. Morris AB, Dobles AR, Cu-Uvin S et al. Protease inhibitor use in 233 pregnancies. J Acquir Immune
Defic Syndr 2005; 40: 30-33. http://hiv.net/.link.php?id=16123678
44. Noguera A , Fortuny A, Munoz-Almagro C et al. Hyperlactatemia in human immunodeficiency virus-
uninfected infants who are exposed to antiretrovirals. Pediatrics 2004; 114: e598-603.
45. Palumbo P, Holland B, Dobbs T et al. Antiretrovirals resistance mutations among pregnant HIV type-I-
infected women and their newborns in the United States: Vertical transmission and clades. J Infect Dis2001; 184: 1120-6. http://hiv.net/link.php?id=11598834
46. Poblano A, Figueroa I, Figueroa-Damian, Schnaas I. Effects of prenatal exposure to Zidovudine and
Lamivudine on brainstem auditory evoked potentials in infants from HIV-infected women. Proc WestPharmacol Soc 2004; 47: 46-9. http://hiv.net/link.php?id=15633610
47. Poirier MC, Olivero OA, Walker DM, Walker VE. Perinatal genotoxicity and carcinogenicity of antiretro-
viral nucleoside analog drugs. Toxicol Appl Pharmacol 2004; 199: 151-61.
48. Rongkavilit C, Thaithumyanon P, Chuenyam T, et al. Pharmacokinetics of stavudine and didanosine
coadministered with nelfinavir in HIV-exposed neonates. Antimicrob Agents Chemother 2001; 45:3585-90. http://hiv.net/link.php?id=11709344
49. Rongkavilit C, van Heeswijk RP, Limpongsanurak S, et al. Dose-escalation study of the safety and
pharmacokinetics of nelfinavir in HIV-exposed neonates. J Aquir Immun Defic Syndr 2002; 29:455-63.
50. Sarner L, Fakoya A. Acute onset lactic acidosis and pancreatitis in the third trimester of pregnancy in
HIV-1 positive women taking antiretroviral medication. Sex Transm Infect 2002; 78: 58-9.
51. Schackman BR, Oneda K, Goldie SJ. The cost-effectiveness of elective Cesarean delivery to prevent
hepatitis C transmission in HIV-coinfected women. AIDS 2004; 18: 1827-34.
52. Schäfer A. HIV und Schwangerschaft. L’Age-Stehr J, Helm EB (Hrsg). AIDS und die Vorstadien. Ein
Leitfaden für Praxis und Klinik. In Springer Verlag 2001; Bd 1: 1-18.
53. Schuval S, Van Dyke RB, Lindsey JC et al. Hepatitis C prevalence in children with perinatal human
immunodeficiency virus infection enrolled in a long-term follow up protocol. Arch Pediat Adolesc Med2004; 158: 1007-13. htttp://hiv.net/link.php?id=15466691
54. Scott GB, Rodman JH, Scot WA, et al. Pharmacokinetics and virologic response to ritonavir (RTV) in
combination with zidovudine (ZDV) and lamivudine (3TC) in HIV-1-infected pregnant women and theirinfants. Abstract 794, 9th CROI 2002, Seattle.
55. Shapiro D, Tuomola R, Pollack H, et al. Mother-to-child transmission risk according to antiretrovirals,
mode of delivery, and viral load in 2895 U.S. women (PACTG 367). Abstract 99, 11th CROI 2004, SanFrancisco.
56. Stek A, Mirochnik M, Capparelli E, et al. Reduced lopinavir exposure during pregnancy. Preliminary
pharmacokinec results from PACTG 1026. Abstract ThPeE7981, 15th World AIDS Conference 2004,Bangkok.
57. Stringer JS, Sinkala M, Chapman V, et al. Timing of the maternal drug dose and risk of perinatal HIV
transmission in the setting of intrapartum and neonatal single dose nevirapine. AIDS 2003; 17: 1165-69. http://hiv.net/link.php?id=14654326
58. Tarantal AF, Castllo O, Ekert JE, et al. Fetal and maternal outcome after administration of tenofovir to
gravid rhesus monkeys (Macaca mulatta). J Aquir Immune Defic Syndr 2002; 29: 207-20.
59. Tardieu M, Brunelle F, Raybaud C et al. Cerebral MR imaging in uninfected children born to HIV-
seropositive mothers and perinatally exposed to zidovudine. AJNR Am J Neuroradiol 2005; 26: 695-701. http://hiv.net/link.php?id=15814907
60. The Italian Register for HIV Infection in Children. Rapid disease progression in perinatally Infected
children born to mothers receiving zidovudine monotherapy during pregnancy. AIDS 1999; 13: 927-33.
61. The Perinatal Safety Review Working Group. Nucleoside exposure in the children of HIV-infected
women receiving antiviral drugs: absence of clear evidence for mitochondrial disease in children whodied before 5 years of age in five united states cohorts. J Aquir Immune Defic Syndr Hum Retrovirol2000; 15: 261-8. http://hiv.net/link.php?id=11115957
62. Thorne C, Patel D, Newell M,. Increased risk of adverse pregnancy outcomes in HIV-infected women
wth highly active antiretroviral therapy in Europe. AIDS 2004; 19:2337-9.
63. Timmermans S, Tempelman C, Godfried MH et al. Nelfinavir and nevirapine side effects during preg-
nancy. AIDS 2005; 19: 795-9. http://hiv.net/link.php?id=15867493
64. Tuomala RE, Watts DH, Li d, et al. Improved obstretic outcomes and few maternal toxicities are asso-
ciated with antiretroviral therapy, including highly active antiretroviral therapy during pregnancy. J Ac-quir Immune Defic Syndr. 2005: 1-38. http//hiv.net/link.php?id=15764963
65. Vigano A, Bianchi R, Schneider L, et al. Lack of hyperlactataemia and impaired mitochondrial DNA
content in CD4+ cells of HIV-uninfected infants exposed to perinatal antiretroviral therapy. Abstract942, 11th CROI 2004, San Francisco
66. Vocks-Hauck M. HIV-Infektion und AIDS bei Neugeborenen, Kindern und Jugendlichen. In L’Age-Stehr
J, Helm EB (Hrsg). AIDS und die Vorstadien. Ein Leitfaden für Klinik und Praxis. Springer Verlag2001; Bd 1: 1-49.
67. Wade NA, Bearkhead GS, Warren BL, et al. Abbreviated regiments of zidovudine prophylaxis and
perinatal transmission of the HIV. N Engl J Med 1998; 339: 1409-14. http://hiv.net/link.php?id=9811915
68. Wade NA, Unadkad JD, Huang S, et al. Pharmacokinetics and safety of stavudine in HIV-infected
pregnant women and their infants: Pediatric AIDS Clinical Trials Group protocol 332. J Infect Dis 2004;190: 2167-74. http://hiv.net//link.php?id=15551216
69. Watts DH, Balasubramanian R, Maupin RT, et al. Maternal toxicity and pregnancy complications in
human immunodefiency virus-infected women receiving antiretroviral therapy: PACTG 316. Am J Ob-stet Gynecol 2004; 190: 506-16. http://hiv.net/link.php?id=15551216
A Primal-Dual Bicriteria Distributed Algorithm for Capacitated Abstract In this paper we consider the capacitated vertex cover problem which is the variant of vertex coverwhere each node is allowed to cover a limited number of edges. We present an efficient, deterministic,distributed approximation algorithm for the problem. Our algorithm computes a (2 + ǫ)-approximatesolution which violates th
CASA CIVIL DA PRESIDÊNCIA DA REPÚBLICA SECRETARIA EXECUTIVA/ARQUIVO NACIONAL COORDENAÇÃO REGIONAL NO DISTRITO FEDERAL Eu, _______________________________________________________________________________________, portador(a) da Carteira de Identidade nº_____________________________________, expedida pela _________, e do CPF nº__________________, filho(a) de_____________________