ACIDIC COLA Determining phosphoric acid concentration in Author Péter Kele, Petrik Lajos Vocational School H- 1146 Budapest, Thököly út 48; firstname.lastname@example.org Languages available English, Hungarian Summary Food grade phosphoric acid is used to acidify foods and beverages such as various colas, but not without controversy about its health effects. Phosphoric acid, used in ma
sydneyrx2014.com Online ED Drugstore is an 1st. pharmacy providing a personal service to the society in Australia. Over 50,000 extremely satisfied buyers! We're your prescription drug store kamagra australia and have provided trusted service to families in Australia for over 15 years.
LayoutInfant Antiretroviral Prophylaxis (Last updated January 29, 2013; last reviewed July 31, 2012)
The 6-week neonatal component of the zidovudine chemoprophylaxis regimen is recommended for all HIV-exposed neonates to reduce perinatal transmission of HIV (AI).
Zidovudine, at gestational age-appropriate doses, should be initiated as close to the time of birth as possible, preferably within 6 to 12 hours of delivery (AII).
Infants born to HIV-infected women who have not received antepartum antiretroviral (ARV) drugs should receive prophylaxis with zidovudine given for 6 weeks combined with three doses of nevirapine in the first week of life (at birth, 48 hours later, and 96 hours after the second dose), begun as soon after birth as possible (AI).
In other scenarios, the decision to combine other drugs with the 6-week zidovudine regimen should be made in consultation with a pediatric HIV specialist, preferably before delivery, and should be accompanied by counseling of the mother on the potential risks and benefits of this approach (BIII).
In the United States, the use of ARV drugs other than zidovudine and nevirapine cannot be recommended in premature infants because of lack of dosing and safety data (BIII).
The National Perinatal HIV Hotline (1-888-448-8765) provides free clinical consultation on all aspects of perinatal HIV, Rating of Recommendations: A = Strong; B = Moderate; C = Optional
Rating of Evidence: I = One or more randomized trials with clinical outcomes and/or validated laboratory endpoints; II = One or
more well-designed, nonrandomized trials or observational cohort studies with long-term clinical outcomes; III = Expert opinion General Considerations for Choice of Infant Prophylaxis
All HIV-exposed infants should receive postpartum antiretroviral (ARV) drugs to reduce perinataltransmission of HIV. The 6-week neonatal zidovudine chemoprophylaxis regimen is recommended for allHIV-exposed infants.1, 2 Table 9 shows recommended zidovudine dosing based on the status of maternalantepartum ARV regimens. Infants born to mothers who have received standard antepartum and intrapartumARV prophylaxis and have undetectable viral loads are at very low risk of HIV transmission and shouldreceive the 6-week zidovudine regimen alone.
The risk of transmission is increased when maternal viral load at delivery is high or maternal antepartumand/or intrapartum prophylaxis was not received. Most experts feel that the potential benefit of combiningzidovudine infant prophylaxis with additional ARV drugs may exceed the risk of multiple drug exposure toinfants born to: a. mothers who received antepartum and intrapartum ARV drugs but who had suboptimal viral suppression at delivery, particularly if delivery was vaginal; b. mothers who received only intrapartum ARV drugs;c. mothers who received neither antepartum nor intrapartum ARV drugs; andd. mothers with known ARV drug-resistant virus.
In each of these situations, there is a spectrum of transmission risk that depends on a number of maternal andinfant factors, including maternal viral load, mode of delivery, and gestational age at delivery. The risks andbenefits of infant exposure to ARV drugs in addition to zidovudine will differ depending on where the Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States mother/child falls in the risk spectrum. For example, an infant delivered vaginally to a mother with an HIVRNA level ≥100,000 copies/mL at delivery has a higher risk of acquiring HIV infection than an infant bornby cesarean delivery to a mother with an HIV RNA level of approximately 10,000 copies/mL at delivery.
Thus, a generic recommendation cannot be made regarding use of combination drug regimens for infantprophylaxis. Each situation needs to be considered individually, balancing potential benefits (in terms ofpreventing perinatal transmission of HIV) with risks (in terms of toxicity to the infant). In addition,appropriate drug formulations and dosing regimens for neonates are incompletely defined and data areminimal on the safety of combination drugs in the neonate (see Short-Term Antiretroviral Drug Safety andChoice for Neonatal Prophylaxis and the Guidelines for the Use of Antiretroviral Agents in Pediatric HIVInfection). Recent data from the NICHD-HPTN 040/PACTG 1043 study have provided guidance for management ofinfants born to women who received no ARV prophylaxis during pregnancy. In this study, 1,746 infants bornto HIV-infected women who did not receive any ARV drugs during pregnancy were randomized to 3 infantprophylaxis regimens: the standard 6-week zidovudine regimen; 6 weeks of zidovudine plus 3 doses ofnevirapine given during the first week of life (first dose at birth–48 hours, second dose 48 hours after firstdose, and third dose 96 hours after second dose); and 6 weeks of zidovudine plus 2 weeks oflamivudine/nelfinavir. The risk of intrapartum transmission was significantly lower compared with 6 weeksof zidovudine alone in the 2- and 3-drug arms (2.2% and 2.5%, respectively, vs. 4.9% for zidovudine alone;P = .046 for each experimental arm vs. zidovudine alone).3 Although transmission rates with the 2combination regimens were similar, neutropenia was significantly more common with the 3-drug regimenthan with the 2-drug or zidovudine-alone regimen (27.5% vs. 15%, P <.0001). In other studies, significantlyhigher rates of neutropenia and anemia have been reported with coadministration of zidovudine andlamivudine to infants.4 Thus, based on comparable efficacy and reduced toxicity, the Panel recommends 6weeks of zidovudine plus 3 doses of nevirapine for infants whose mothers have not received antepartumARVs (Table 9).
In all other scenarios, decisions about use of combination ARV prophylaxis in infants should be made inconsultation with a pediatric HIV specialist before delivery, if possible, and should be accompanied by adiscussion with the mothers about potential risks and benefits of this approach. Despite the paucity of available data, the use of combination ARV prophylaxis for infants in high-risksituations is increasing. Surveillance of obstetric and pediatric HIV infection in the United Kingdom andIreland through the National Study of HIV in Pregnancy and Childhood noted that between 2001 and 2004,9% of HIV-exposed infants received triple-drug prophylaxis compared with 13% between 2005 and 2008.5Similarly, in a web-based poll of 134 U.S.-based perinatal HIV service providers, 62% reported usingcombination postnatal prophylaxis in high-risk situations in the past year. Zidovudine, lamivudine, andnevirapine was the combination regimen used most often.6 The National Perinatal HIV Hotline (1-888-448-8765)
The National Perinatal HIV Hotline is a federally funded service providing free clinical consultation toproviders caring for HIV-infected pregnant women and their infants.
Recommendations for Infant Antiretroviral Prophylaxis in Specific Clinical Situations
Infants Born to Mothers Who Received Antepartum/Intrapartum Antiretroviral Drugs with
Effective Viral Suppression
The risk of HIV acquisition is small in infants born to women who received standard ARV prophylaxisregimens during pregnancy and labor and had undetectable viral loads at delivery or born by scheduledcesarean section to mothers with low viral loads at delivery. Such infants should receive the 6-week Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States zidovudine infant prophylaxis regimen. In that situation, combining zidovudine with additional ARV drugs toreduce transmission risk is not recommended because the benefit would be very limited.
Infants Born to Mothers Who Have Received Antepartum/Intrapartum Antiretroviral Drugs
But Have Suboptimal Viral Suppression Near Delivery
The risk of perinatal transmission is related to maternal antepartum viral load in women on no ARV drugs aswell as women receiving ARVs.7-9 Scheduled cesarean delivery is recommended for prevention of perinataltransmission in women who have received antepartum ARV drugs but have detectable viremia (HIV RNA>1,000 copies/mL) near the time of delivery (see Intrapartum Care and Transmission and Mode of Delivery).
In PACTG 316, transmission occurred in 0% of 17 infants when maternal HIV RNA levels at delivery were>10,000 copies/mL and delivery was by scheduled cesarean delivery.2 However, not all women withdetectable viremia near delivery will undergo cesarean delivery. The risk of acquisition of HIV will be higherin infants born to mothers with higher viral loads near delivery, particularly if delivery is vaginal. Thegradient of transmission risk is based on HIV RNA levels. In the Women and Infants Transmission Study(WITS), the risk of transmission of HIV was ≤1.8% in women who received triple-combination ARVprophylaxis and had HIV RNA levels <30,000 copies/mL at delivery; it increased to 4.8% in women withHIV RNA levels ≥30,000 copies/mL.9 All infants should receive zidovudine for 6 weeks. No specific data address whether a more intensivecombination infant prophylaxis regimen (2 or 3 drugs) provides additional protection against transmissionwhen maternal antepartum/intrapartum prophylaxis is received but viral replication near delivery issignificant. Elective cesarean section is recommended for pregnant women with HIV RNA levels >1,000copies/mL near delivery. Extrapolation of findings from the previously discussed NICHD-HPTN040/PACTG 1043 study3 suggests that combination infant prophylaxis should be considered, depending onassessment of risk based on maternal viral load and mode of delivery. That decision should be made inconsultation with a pediatric HIV specialist before delivery and accompanied by maternal counseling on thepotential risks and benefits of this approach.
Infants Born to Mothers Who Received Only Intrapartum Antiretroviral Drugs
All infants whose mothers have received only intrapartum ARV drugs should be given zidovudine for 6weeks. This infant prophylaxis regimen is a critical component of prevention when no maternal antepartumARV drugs have been received. The PETRA study demonstrated that intrapartum prophylaxis alone, withoutinfant prophylaxis, is ineffective in reducing perinatal transmission.10 A study in Thailand indicated thatlonger infant prophylaxis with zidovudine (6 weeks vs. 3 days) is required for optimal efficacy whenmaternal antenatal exposure to zidovudine is <4 weeks.11 Infant prophylaxis with zidovudine should beinitiated as soon after delivery as possible. In addition to zidovudine, three doses of nevirapine should beadministered in the first week of life (first dose at birth–48 hours, second dose 48 hours after first dose, andthird dose 96 hours after second dose). In the NICHD-HPTN 040/PACTG 043 trial previously discussed,41% of women received zidovudine during labor. Administration of intrapartum zidovudine did not affecttransmission rates.3 Infants Born to Mothers Who Did Not Receive Antepartum or Intrapartum Antiretroviral
The two-drug regimen of 6 weeks of zidovudine plus three doses of nevirapine in the first week of life (firstdose at birth–48 hours, second dose 48 hours after first dose, and third dose 96 hours after second dose) isrecommended based on the results of the NICHD-HPTN 040/PACTG 1043 study, which demonstratedincreased efficacy of combination regimens in reducing intrapartum transmission compared with use ofzidovudine alone in infants.3 Prophylaxis should be initiated as soon after delivery as possible.
Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States The interval during which infant prophylaxis can be initiated and still be of benefit is undefined. In the NewYork State study, when prophylaxis was delayed beyond 48 hours after birth, no efficacy could bedemonstrated. Data from animal studies indicate that the longer the delay in institution of prophylaxis, theless likely that infection will be prevented. In most studies of animals, ARV prophylaxis initiated 24 to 36hours after exposure usually has been ineffective in preventing infection, although a delay in administrationhas been associated with decreased viremia.12-14 In the NICHD-HPTN 040/PACTG 1043 study, infantregimens were initiated within 48 hours of life and usually within 12 hours of life.3 Initiation of infantprophylaxis after age 2 days is not likely to be efficacious in preventing transmission and, by age 14 days,infection already would be established in most infants.15 Initiating prophylaxis as soon after delivery aspossible increases its potential efficacy and minimizes potential harm, such as development of resistant virus,if infection has occurred.
Infants Born to Mothers with Antiretroviral Drug-Resistant Virus
The optimal prophylactic regimen for newborns delivered by women with ARV drug-resistant virus isunknown. ARV prophylaxis for infants born to mothers with known or suspected drug resistance should bedetermined in consultation with a pediatric HIV specialist before delivery. Data from the WITS suggest that in women who have mixed zidovudine-resistant and -sensitive viralpopulations, the zidovudine-sensitive rather than -resistant virus may be preferentially transmitted.16, 17 Thus,the 6-week infant zidovudine prophylaxis (along with maternal intravenous intrapartum zidovudineprophylaxis) continues to be recommended, even when maternal zidovudine-resistant virus with thymidine-associated mutations is identified.
Some studies have suggested that ARV drug-resistant virus may have decreased replicative capacity (reducedviral fitness) and transmissibility.17 However, transmission from mother to child of multidrug-resistant virushas been reported.18-20 For these newborns, use of zidovudine in combination with other ARV drugs, selected on the basis ofmaternal virus resistance testing, should be considered. The efficacy of this approach for prevention oftransmission, however, has not been proven in clinical trials, and for many drugs, appropriate dosingregimens for neonates have not been established. Decisions regarding use of additional drugs should be madein consultation with a pediatric HIV specialist and will depend on maternal history of past and current ARVdrug exposure, HIV RNA levels at or near delivery, current and previous maternal resistance testing, andavailability of drug formulation and dosing information in the infant. Short-Term Antiretroviral Drug Safety and Choice for Neonatal Prophylaxis
Infant prophylaxis with zidovudine has been associated with only minimal toxicity, consisting primarily oftransient hematologic toxicity (mainly anemia), which generally resolves by age 12 weeks (see InitialPostnatal Management). Data are limited on the toxicity to infants of exposure to multiple ARV drugs. The latest information on neonatal dosing for ARV drugs can be found in the Guidelines for the Use ofAntiretroviral Agents in Pediatric HIV Infection. Other than zidovudine, lamivudine is the nucleoside reversetranscriptase inhibitor (NRTI) with the most experience in use for neonatal prophylaxis. In early studies,neonatal exposure to combination zidovudine/lamivudine was generally limited to 110, 21, 22 or 2 weeks.3 Sixweeks of infant zidovudine/lamivudine exposure also has been reported; these studies suggest thathematologic toxicity may be increased over that seen with zidovudine alone, although the infants also had inutero exposure to maternal combination therapy. In a French study, more severe anemia and neutropenia were observed in infants exposed to 6 weeks ofzidovudine/lamivudine for prophylaxis plus maternal antepartum zidovudine/lamivudine than in a historical Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States cohort exposed only to maternal and infant zidovudine. Anemia was reported in 15% and neutropenia in 18%of infants exposed to zidovudine/lamivudine, with 2% of infants requiring blood transfusion and 4%requiring treatment discontinuation for toxicity.4 Similarly, in a Brazilian study of maternal antepartum and6-week infant zidovudine/lamivudine prophylaxis, neonatal hematologic toxicity was common, with anemiaseen in 69% and neutropenia in 13% of infants.23 Experience with other NRTI drugs for neonatal prophylaxis is more limited.24, 25 Hematologic andmitochondrial toxicity may be more common with exposure to multiple versus single NRTI drugs.4, 26-29 Nevirapine is the only non-nucleoside reverse transcriptase inhibitor drug with a pediatric drug formulationand neonatal dosing information (see Guidelines for the Use of Antiretroviral Agents in Pediatric HIVInfection).30 In rare cases, chronic multiple-dose nevirapine has been associated with severe and potentiallylife-threatening rash and hepatic toxicity. These toxicities have not been observed in infants receiving single-dose nevirapine, the two-drug zidovudine regimen plus three doses of nevirapine in the first week of life inNICHD-HPTN 040/PACTG 1043), or in breastfeeding infants receiving nevirapine prophylaxis daily for 6weeks to 6 months to prevent transmission of HIV via breast milk.3, 31-34 Resistance to nevirapine can occur,however, with exposure to nevirapine in infants who become infected despite prophylaxis.35, 36 ARV drug-resistance testing is recommended for all HIV-infected infants before initiation of antiretroviral therapy (seeGuidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection).
Of the protease inhibitors (PIs), although nelfinavir, lopinavir/ritonavir, ritonavir, tipranavir, andfosamprenavir have pediatric drug formulations, their use in neonates is not recommended. Pharmacokinetic(PK) studies of nelfinavir in newborn infants show highly variable plasma concentrations and no single dosethat results in safe but adequate nelfinavir concentrations in all infants has been defined.25, 37, 38 In addition,nelfinavir powder is no longer commercially available in the United States. No PK data are available for theother PIs in infants in the first 2 weeks of life. PK data are available for treatment of HIV-infected infants 2to 6 weeks of age with lopinavir/ritonavir. Although the lopinavir area under the curve (AUC) wassignificantly lower with dosing 300 mg lopinavir/75 mg ritonavir/m2 body surface area twice daily thanobserved for infants >6 weeks of age, treatment was well tolerated and 80% of 10 infants had viral control at6 months.39 Studies are ongoing but data are not yet available for infants <2 weeks of age. However, in 4premature infants (2 sets of twins) started on lopinavir/ritonavir from birth, heart block developed thatresolved after drug discontinuation.40, 41 In studies of adults, both ritonavir and lopinavir/ritonavir cause dose-dependent prolongation of the PR interval, and cases of significant heart block, including complete heartblock, have been reported. Elevation of 17-hydroxyprogesterone and dehydroepiandrosterone-sulfate hasalso been associated with administration of lopinavir/ritonavir compared with zidovudine in the neonatalperiod. Levels of 17-hydroxyprogesterone were greater in infants who were also exposed tolopinavir/ritonavir in utero compared with those exposed only in the neonatal period. Term infants wereasymptomatic but 3 premature newborns experienced life-threatening symptoms compatible with adrenalinsufficiency, including hyponatremia and hyperkalemia with, in 1 case, cardiogenic shock.42 Based on theseand other post-marketing reports of cardiac toxicity (including complete atrioventricular block, bradycardia,and cardiomyopathy), lactic acidosis, acute renal failure, adrenal dysfunction, central nervous systemdepression, respiratory complications leading to death, and metabolic toxicity,43 predominantly in pretermneonates, the Food and Drug Administration now recommends that lopinavir/ritonavir NOT be administeredto neonates before a postmenstrual age (first day of the mother’s last menstrual period to birth plus the timeelapsed after birth) of 42 weeks and a postnatal age of at least 14 days. Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States Neonatal Antiretroviral Drug Dosing
Table 9. Recommended Neonatal Dosing for Prevention of Mother-to-Child Transmission of HIV
All HIV-Exposed Infants (initiated as soon after delivery as possible)
≥35 weeks’ gestation at birth: 4 mg/kg/dose PO twice
daily, started as soon after birth as possible and preferably within 6–12 hours of delivery (or, if unable to tolerate oral agents, 3 mg/kg/dose IV, beginning within 6–12 hours of ≥30 to <35 weeks’ gestation at birth: 2 mg/kg/dose PO
(or 1.5 mg/kg/dose IV), started as soon after birth as possible, preferably within 6–12 hours of delivery, then every 12 hours, advanced to 3 mg/kg/dose PO (or 2.3 mg/kg/dose IV) every 12 hours at age 15 days <30 weeks’ gestation at birth: 2 mg/kg body weight/dose
PO (or 1.5 mg/kg/dose IV) started as soon after birth as possible, preferably within 6–12 hours of delivery, then every 12 hours, advanced to 3 mg/kg/dose PO (or 2.3 mg/kg/dose IV) every 12 hours after age 4 weeks Additional Antiretroviral Prophylaxis Agents for HIV-Exposed Infants of Women who Received No Antepartum
Antiretroviral Prophylaxis (initiated as soon after delivery as possible)
Weight Band Dosing
Birth weight 1.5-2 kg: 8 mg TOTAL for each dose
Birth weight >2 kg: 12 mg TOTAL for each dose
Key to Abbreviations: IV = intravenously; NVP = nevirapine; PO = orally; ZDV = zidovudine
The recommended dose of zidovudine for post-exposure prophylaxis in full-term neonates is 4 mg/kg bodyweight orally (PO) twice daily for the first 6 weeks of life, beginning as soon after birth as possible andpreferably within 6 to 12 hours of delivery.10, 31, 44-51 (Table 9) If the infant is unable to tolerate oralmedications, the 6-week zidovudine prophylaxis regimen can be administered intravenously (IV). Thezidovudine dosing requirements differ for premature infants and term infants (see Antiretroviral Drug Dosingfor Premature Infants).
In the United Kingdom and many other European countries, a 4-week neonatal chemoprophylaxis regimen isrecommended for infants born to mothers who have received antenatal combination ARV drug regimens.52, 53This approach also can be considered in cases where adherence to or toxicity from the 6-week zidovudineprophylaxis regimen is a concern. In an Irish observational study, a transmission rate of 1.1% was observedin 916 infants who received 4 weeks of zidovudine infant prophylaxis following antenatal maternalcombination ARV prophylaxis. That is the standard regimen in Ireland and the transmission rate was similarto that observed in the United States, where 6 weeks of infant zidovudine prophylaxis is standard.53 Aprospective, observational study reported that the 4-week zidovudine regimen allowed earlier recovery fromanemia in otherwise healthy infants compared with the 6-week zidovudine regimen.54 The optimal duration Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States of neonatal zidovudine chemoprophylaxis, however, has not been established in clinical trials, and in theUnited States, the standard 6-week infant zidovudine regimen is recommended unless there are concernsabout adherence or toxicity. Consultation with an expert in pediatric HIV infection is advised if earlydiscontinuation of prophylaxis is considered.
PKs and safety of the single-dose nevirapine regimen to mother and infant55 and chronic nevirapineadministration to infants to prevent HIV transmission during breastfeeding have been studied.56 The 3-doseextended nevirapine regimen that was used in NICHD-HPTN 040/PACTG 1043 and is recommended for HIV-exposed infants whose mothers did not receive ARV during the antepartum period has also been studied.30 Inthe NICHD-HPTN 040/PACTG 1043 study, nevirapine concentrations were measured in 14 newbornsparticipating in a PK substudy during the second week of life and in single samples from 30 more newborns onDays 10 to 14. The median nevirapine elimination half-life was 30.2 hours (range: 17.8–50.3 hours) and theconcentration remained greater than the target of 100 ng/mL in all infants through Day 10 of life.30 Antiretroviral Drug Dosing for Premature Infants
Dosing recommendations for premature infants is available for only zidovudine and nevirapine (see Table 9).
Zidovudine is primarily cleared through hepatic glucuronidation to an inactive metabolite; this metabolicpathway is immature in neonates, leading to prolonged zidovudine half-life and clearance compared witholder infants. Clearance is further prolonged in premature infants because their hepatic metabolic function iseven less mature than in term infants.57, 58 The recommended zidovudine dosage for infants less than 35weeks’ gestation at birth is 2 mg/kg body weight per dose PO every 12 hours (or 1.5 mg/kg/dose IV every 12hours), increasing to 3 mg/kg/dose PO (or 2.3 mg/kg/dose IV) every 12 hours at age 15 days. For infantsborn at less than 30 weeks’ gestation, 2 mg/kg/dose PO (or 1.5 mg/kg/dose IV) started as soon after birth aspossible, preferably within 6 to 12 hours of delivery, then every 12 hours, advanced to 3 mg/kg/dose PO (or2.3 mg/kg/dose IV) every 12 hours after age 4 weeks is recommended.
PKs in low birth weight infants receiving a single dose of nevirapine have been described. In a study of 81infants less than 37 weeks’ gestation, of which 29.6% were small for gestational age, half-lives were verylong—median 59 hours in infants whose mothers received single-dose nevirapine and 69 hours in infants whosemothers did not receive single-dose nevirapine. AUC of nevirapine was higher and clearance lower (P <.0001)in small-for-gestational-age infants.59 Use of ARV drugs other than zidovudine and nevirapine cannot be recommended at this time in prematureinfants because data on dosing and safety are lacking. Immature renal and hepatic metabolism can increasethe risk of overdosing and toxicity. However, in situations where there is a high risk of infant HIV infection,consultation with a pediatric HIV specialist is recommended to determine if the benefits of combination ARVprophylaxis other than zidovudine and nevirapine outweigh the potential risks.
Breastfeeding Infants of Mothers Diagnosed with HIV Infection Postpartum
Breastfeeding should be stopped until infection is confirmed or ruled out in women who are breastfeeding atthe time of HIV diagnosis or suspected to be HIV infected. Pumping and temporarily discarding breast milkcan be recommended to mothers who are suspected of being HIV infected but whose infection is not yetconfirmed and who want to continue to breastfeed. If HIV infection is ruled out, breastfeeding can resume.
The risk of acquisition of HIV associated with breastfeeding depends on multiple infant and maternal factors,including maternal viral load and CD4 T-lymphocyte (CD4-cell) count.60 Infants of women who developacute HIV infection while breastfeeding are at greater risk of becoming infected than are those of womenwith chronic HIV infection61 because acute HIV infection is accompanied by a rapid increase in viral loadand a corresponding decrease in CD4-cell count.62 Other than discontinuing breastfeeding, optimal strategies for managing infants born to HIV-infected mothers Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States who breastfed their infants before HIV diagnosis have yet to be defined. Some experts would consider theuse of post-exposure prophylaxis in infants for 4 to 6 weeks after cessation of breastfeeding. Post-exposureprophylaxis, however, is less likely to be effective in this circumstance compared with other nonoccupationalexposures because the exposure to breast milk is likely to have occurred over a prolonged period rather thanin a single exposure.63 Several studies of infants breastfed by women with chronic HIV infection have shown that daily infantnevirapine or nevirapine plus zidovudine can reduce the risk of postnatal infection during breastfeeding.31-33The NICHD-HPTN 040/PACTG 043 study demonstrated that combination ARV prophylaxis was moreeffective than zidovudine prophylaxis alone for preventing intrapartum transmission in mothers who havenot received antepartum ARV drugs.3 However, whether the combination regimens in this trial are effectivefor preventing transmission after cessation of breastfeeding in mothers with acute HIV infection is unknown. An alternative approach favored by some experts would be to offer a combination ARV regimen that wouldbe effective for treatment of HIV should the infant become infected. If this route is chosen, currentrecommendations for treatment should guide selection of an appropriate combination ARV regimen (seeGuidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection). Regardless of whether post-exposure prophylaxis or “preemptive therapy” is chosen, the optimal duration of the intervention isunknown. A 28-day course may be reasonable based on current recommendations for nonoccupational HIVexposure.63 As in other situations, decisions regarding administration of a prophylactic or preemptivetreatment regimen should be accompanied by consultation with a pediatric HIV specialist and maternalcounseling on the potential risks and benefits of this approach.
Infants should be tested for HIV infection at baseline and 4 to 6 weeks, 3 months, and 6 months afterrecognition of maternal infection to determine HIV status. In infants younger than age 18 months, HIV DNAor RNA polymerase chain reaction (PCR) tests should be used for diagnosis. HIV DNA PCR is preferable forinfants who are receiving combination ARV prophylaxis or preemptive treatment. HIV antibody assays canbe used in infants older than age 18 months. Post-exposure ARV prophylaxis or preemptive treatment shouldbe discontinued in infants who are found to be HIV infected while receiving one of these regimens.
Resistance testing then should be performed and an appropriate combination therapy regimen initiated (seeGuidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection). References
Connor EM, Sperling RS, Gelber R, et al. Reduction of maternal-infant transmission of human immunodeficiency virustype 1 with zidovudine treatment. Pediatric AIDS Clinical Trials Group Protocol 076 Study Group. N Engl J Med. Nov3 1994;331(18):1173-1180. Available at http://www.ncbi.nlm.nih.gov/pubmed/7935654.
Dorenbaum A, Cunningham CK, Gelber RD, et al. Two-dose intrapartum/newborn nevirapine and standardantiretroviral therapy to reduce perinatal HIV transmission: a randomized trial. JAMA. Jul 10 2002;288(2):189-198.
Available at http://www.ncbi.nlm.nih.gov/pubmed/12095383.
Nielsen-Saines K, Watts DH, Veloso VG, et al. Three postpartum antiretroviral regimens to prevent intrapartum HIVinfection. N Engl J Med. Jun 21 2012;366(25):2368-2379. Available at http://www.ncbi.nlm.nih.gov/pubmed/22716975.
Mandelbrot L, Landreau-Mascaro A, Rekacewicz C, et al. Lamivudine-zidovudine combination for prevention ofmaternal-infant transmission of HIV-1. JAMA. Apr 25 2001;285(16):2083-2093. Available athttp://www.ncbi.nlm.nih.gov/pubmed/11311097.
Haile-Selassie H, Townsend C, Tookey P. Use of neonatal post-exposure prophylaxis for prevention of mother-to-childHIV transmission in the UK and Ireland, 2001-2008. HIV Med. Aug 2011;12(7):422-427. Available athttp://www.ncbi.nlm.nih.gov/pubmed/21251184.
Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States McKeegan K, Rutstein R, Lowenthal E. Postnatal infant HIV prophylaxis: a survey of U.S. practice. AIDS Patient CareSTDS. Jan 2011;25(1):1-4. Available at http://www.ncbi.nlm.nih.gov/pubmed/21162689.
Mofenson LM, Lambert JS, Stiehm ER, et al. Risk factors for perinatal transmission of human immunodeficiency virustype 1 in women treated with zidovudine. Pediatric AIDS Clinical Trials Group Study 185 Team. N Engl J Med. Aug 51999;341(6):385-393. Available at http://www.ncbi.nlm.nih.gov/pubmed/10432323.
Garcia PM, Kalish LA, Pitt J, et al. Maternal levels of plasma human immunodeficiency virus type 1 RNA and the riskof perinatal transmission. Women and Infants Transmission Study Group. N Engl J Med. Aug 5 1999;341(6):394-402.
Available at http://www.ncbi.nlm.nih.gov/pubmed/10432324.
Cooper ER, Charurat 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 Acquir Immune Defic Syndr. Apr 152002;29(5):484-494. Available at http://www.ncbi.nlm.nih.gov/pubmed/11981365.
10. Petra Study Team. Efficacy of three short-course regimens of zidovudine and lamivudine in preventing early and late transmission of HIV-1 from mother to child in Tanzania, South Africa, and Uganda (Petra study): a randomised, double-blind, placebo-controlled trial. Lancet. Apr 6 2002;359(9313):1178-1186. Available athttp://www.ncbi.nlm.nih.gov/pubmed/11955535.
11. Lallemant M, Jourdain G, Le Coeur S, et al. A trial of shortened zidovudine regimens to prevent mother-to-child transmission of human immunodeficiency virus type 1. Perinatal HIV Prevention Trial (Thailand) Investigators. N EnglJ Med. Oct 5 2000;343(14):982-991. Available at http://www.ncbi.nlm.nih.gov/pubmed/11018164.
12. Van Rompay KK, Otsyula MG, Marthas ML, Miller CJ, McChesney MB, Pedersen NC. Immediate zidovudine treatment protects simian immunodeficiency virus-infected newborn macaques against rapid onset of AIDS. AntimicrobAgents Chemother. Jan 1995;39(1):125-131. Available at http://www.ncbi.nlm.nih.gov/pubmed/7695293.
13. Tsai CC, Follis KE, Sabo A, et al. Prevention of SIV infection in macaques by (R)-9-(2- phosphonylmethoxypropyl)adenine. Science. Nov 17 1995;270(5239):1197-1199. Available athttp://www.ncbi.nlm.nih.gov/pubmed/7502044.
14. Bottiger D, Johansson NG, Samuelsson B, et al. Prevention of simian immunodeficiency virus, SIVsm, or HIV-2 infection in cynomolgus monkeys by pre- and postexposure administration of BEA-005. AIDS. Feb 1997;11(2):157-162. Available at http://www.ncbi.nlm.nih.gov/pubmed/9030361.
15. Dunn DT, Brandt CD, Krivine A, et al. The sensitivity of HIV-1 DNA polymerase chain reaction in the neonatal period and the relative contributions of intra-uterine and intra-partum transmission. AIDS. Sep 1995;9(9):F7-11. Available athttp://www.ncbi.nlm.nih.gov/pubmed/8527070.
16. Colgrove RC, Pitt J, Chung PH, Welles SL, Japour AJ. Selective vertical transmission of HIV-1 antiretroviral resistance mutations. AIDS. Dec 3 1998;12(17):2281-2288. Available at http://www.ncbi.nlm.nih.gov/pubmed/9863870.
17. Bauer GR, Colgrove RC, Larussa PS, Pitt J, Welles SL. Antiretroviral resistance in viral isolates from HIV-1- transmitting mothers and their infants. AIDS. Aug 22 2006;20(13):1707-1712. Available athttp://www.ncbi.nlm.nih.gov/pubmed/16931934.
18. Cohan D, Feakins C, Wara D, et al. Perinatal transmission of multidrug-resistant HIV-1 despite viral suppression on an enfuvirtide-based treatment regimen. AIDS. Jun 10 2005;19(9):989-990. Available athttp://www.ncbi.nlm.nih.gov/pubmed/15905684.
19. Desai N, Mathur M. Selective transmission of multidrug resistant HIV to a newborn related to poor maternal adherence.
Sex Transm Infect. Oct 2003;79(5):419-421. Available at http://www.ncbi.nlm.nih.gov/pubmed/14573842.
20. De Jose MI, Ramos JT, Alvarez S, Jimenez JL, Munoz-Fernandez MA. Vertical transmission of HIV-1 variants resistant to reverse transcriptase and protease inhibitors. Arch Intern Med. Dec 10-24 2001;161(22):2738-2739. Available athttp://www.ncbi.nlm.nih.gov/pubmed/11732941.
21. Moodley J, Moodley D, Pillay K, et al. Pharmacokinetics and antiretroviral activity of lamivudine alone or when coadministered with zidovudine in human immunodeficiency virus type 1-infected pregnant women and their offspring.
Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States J Infect Dis. Nov 1998;178(5):1327-1333. Available at http://www.ncbi.nlm.nih.gov/pubmed/9780252.
22. Moodley D, Moodley J, Coovadia H, et al. A multicenter randomized controlled trial of nevirapine versus a combination of zidovudine and lamivudine to reduce intrapartum and early postpartum mother-to-child transmission of humanimmunodeficiency virus type 1. J Infect Dis. Mar 1 2003;187(5):725-735. Available athttp://www.ncbi.nlm.nih.gov/pubmed/12599045.
23. Lambert JS, Nogueira SA, Abreu T, et al. A pilot study to evaluate the safety and feasibility of the administration of AZT/3TC fixed dose combination to HIV infected pregnant women and their infants in Rio de Janeiro, Brazil. SexTransm Infect. Dec 2003;79(6):448-452. Available at http://www.ncbi.nlm.nih.gov/pubmed/14663118.
24. Gray G, Violari A, McIntyre J, et al. Antiviral activity of nucleoside analogues during short-course monotherapy or dual therapy: its role in preventing HIV infection in infants. J Acquir Immune Defic Syndr. Jun 2006;42(2):169-176.
Available at http://www.ncbi.nlm.nih.gov/pubmed/16639342.
25. Rongkavilit C, van Heeswijk RP, Limpongsanurak S, et al. Dose-escalating study of the safety and pharmacokinetics of nelfinavir in HIV-exposed neonates. J Acquir Immune Defic Syndr. Apr 15 2002;29(5):455-463. Available athttp://www.ncbi.nlm.nih.gov/pubmed/11981361.
26. Torres SM, Walker DM, Carter MM, et al. Mutagenicity of zidovudine, lamivudine, and abacavir following in vitro exposure of human lymphoblastoid cells or in utero exposure of CD-1 mice to single agents or drug combinations.
Environ Mol Mutagen. Apr-May 2007;48(3-4):224-238. Available at http://www.ncbi.nlm.nih.gov/pubmed/17358033.
27. Le Chenadec J, Mayaux MJ, Guihenneuc-Jouyaux C, Blanche S, Enquete Perinatale Francaise Study Group. Perinatal antiretroviral treatment and hematopoiesis in HIV-uninfected infants. AIDS. Sep 26 2003;17(14):2053-2061. Availableat http://www.ncbi.nlm.nih.gov/pubmed/14502008.
28. Pacheco SE, McIntosh K, Lu M, et al. Effect of perinatal antiretroviral drug exposure on hematologic values in HIV- uninfected children: An analysis of the women and infants transmission study. J Infect Dis. Oct 152006;194(8):1089-1097. Available at http://www.ncbi.nlm.nih.gov/pubmed/16991083.
29. Feiterna-Sperling C, Weizsaecker K, Buhrer C, et al. Hematologic effects of maternal antiretroviral therapy and transmission prophylaxis in HIV-1-exposed uninfected newborn infants. J Acquir Immune Defic Syndr. May 12007;45(1):43-51. Available at http://www.ncbi.nlm.nih.gov/pubmed/17356471.
30. Mirochnick M, Nielsen-Saines K, Pilotto JH, et al. Nevirapine concentrations in newborns receiving an extended prophylactic regimen. J Acquir Immune Defic Syndr. Mar 1 2008;47(3):334-337. Available athttp://www.ncbi.nlm.nih.gov/pubmed/18398973.
31. Kumwenda NI, Hoover DR, Mofenson LM, et al. Extended antiretroviral prophylaxis to reduce breast-milk HIV-1 transmission. N Engl J Med. Jul 10 2008;359(2):119-129. Available at http://www.ncbi.nlm.nih.gov/pubmed/18525035.
32. Six Week Extended-Dose Nevirapine Study Team, Bedri A, Gudetta B, et al. Extended-dose nevirapine to 6 weeks of age for infants to prevent HIV transmission via breastfeeding in Ethiopia, India, and Uganda: an analysis of threerandomised controlled trials. Lancet. Jul 26 2008;372(9635):300-313. Available athttp://www.ncbi.nlm.nih.gov/pubmed/18657709.
33. Chasela CS, Hudgens MG, Jamieson DJ, et al. Maternal or infant antiretroviral drugs to reduce HIV-1 transmission. N Engl J Med. Jun 17 2010;362(24):2271-2281. Available at http://www.ncbi.nlm.nih.gov/pubmed/20554982.
34. Coovadia HM, Brown ER, Fowler MG, et al. Efficacy and safety of an extended nevirapine regimen in infant children of breastfeeding mothers with HIV-1 infection for prevention of postnatal HIV-1 transmission (HPTN 046): arandomised, double-blind, placebo-controlled trial. Lancet. Jan 21 2012;379(9812):221-228. Available athttp://www.ncbi.nlm.nih.gov/pubmed/22196945.
35. Moorthy A, Gupta A, Bhosale R, et al. Nevirapine resistance and breast-milk HIV transmission: effects of single and extended-dose nevirapine prophylaxis in subtype C HIV-infected infants. PLoS One. 2009;4(1):e4096. Available athttp://www.ncbi.nlm.nih.gov/pubmed/19119321.
Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States 36. Fogel J, Hoover DR, Sun J, et al. Analysis of nevirapine resistance in HIV-infected infants who received extended nevirapine or nevirapine/zidovudine prophylaxis. AIDS. Apr 24 2011;25(7):911-917. Available athttp://www.ncbi.nlm.nih.gov/pubmed/21487249.
37. 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. Jun 1 2005;39(2):189-194.
Available at http://www.ncbi.nlm.nih.gov/pubmed/15905735.
38. Mirochnick M, Nielsen-Saines K, Pilotto JH, et al. Nelfinavir and Lamivudine pharmacokinetics during the first two weeks of life. Pediatr Infect Dis J. Sep 2011;30(9):769-772. Available athttp://www.ncbi.nlm.nih.gov/pubmed/21666540.
39. Chadwick EG, Pinto J, Yogev R, et al. Early initiation of lopinavir/ritonavir in infants less than 6 weeks of age: pharmacokinetics and 24-week safety and efficacy. Pediatr Infect Dis J. Mar 2009;28(3):215-219. Available athttp://www.ncbi.nlm.nih.gov/pubmed/19209098.
40. Lopriore E, Rozendaal L, Gelinck LB, Bokenkamp R, Boelen CC, Walther FJ. Twins with cardiomyopathy and complete heart block born to an HIV-infected mother treated with HAART. AIDS. Nov 30 2007;21(18):2564-2565.
Available at http://www.ncbi.nlm.nih.gov/pubmed/18025905.
41. McArthur MA, Kalu SU, Foulks AR, Aly AM, Jain SK, Patel JA. Twin preterm neonates with cardiac toxicity related to lopinavir/ritonavir therapy. Pediatr Infect Dis J. Dec 2009;28(12):1127-1129. Available athttp://www.ncbi.nlm.nih.gov/pubmed/19820426.
42. Simon A, Warszawski J, Kariyawasam D, et al. Association of prenatal and postnatal exposure to lopinavir-ritonavir and adrenal dysfunction among uninfected infants of HIV-infected mothers. JAMA. Jul 6 2011;306(1):70-78. Available athttp://www.ncbi.nlm.nih.gov/pubmed/21730243.
43. Boxwell D, Cao K, Lewis L, Marcus K, Nikhar B. Neonatal toxicity of Kaletra oral solution: LPV, ethanol or prophylene glycol? Paper presented at: 18th Conference on Retroviruses and Opportunistic Infections (CROI); February27-Mar 2, 2011; Boston, MA. Abstract 708.
44. Taha TE, Kumwenda NI, Hoover DR, et al. Nevirapine and zidovudine at birth to reduce perinatal transmission of HIV in an African setting: a randomized controlled trial. JAMA. Jul 14 2004;292(2):202-209. Available athttp://www.ncbi.nlm.nih.gov/pubmed/15249569.
45. Taha TE, Kumwenda NI, Gibbons A, et al. Short postexposure prophylaxis in newborn babies to reduce mother-to-child transmission of HIV-1: NVAZ randomised clinical trial. Lancet. Oct 11 2003;362(9391):1171-1177. Available athttp://www.ncbi.nlm.nih.gov/pubmed/14568737.
46. Shapiro RL, Thior I, Gilbert PB, et al. Maternal single-dose nevirapine versus placebo as part of an antiretroviral strategy to prevent mother-to-child HIV transmission in Botswana. AIDS. Jun 12 2006;20(9):1281-1288. Available athttp://www.ncbi.nlm.nih.gov/pubmed/16816557.
47. Gray GE, Urban M, Chersich MF, et al. A randomized trial of two postexposure prophylaxis regimens to reduce mother- to-child HIV-1 transmission in infants of untreated mothers. AIDS. Aug 12 2005;19(12):1289-1297. Available athttp://www.ncbi.nlm.nih.gov/pubmed/16052084.
48. Kilewo C, Karlsson K, Ngarina M, et al. Prevention of mother-to-child transmission of HIV-1 through breastfeeding by treating mothers with triple antiretroviral therapy in Dar es Salaam, Tanzania: the Mitra Plus study. J Acquir ImmuneDefic Syndr. Nov 1 2009;52(3):406-416. Available at http://www.ncbi.nlm.nih.gov/pubmed/19730269.
49. Peltier CA, Ndayisaba GF, Lepage P, et al. Breastfeeding with maternal antiretroviral therapy or formula feeding to prevent HIV postnatal mother-to-child transmission in Rwanda. AIDS. Nov 27 2009;23(18):2415-2423. Available athttp://www.ncbi.nlm.nih.gov/pubmed/19730349.
50. Shapiro RL, Hughes MD, Ogwu A, et al. Antiretroviral regimens in pregnancy and breast-feeding in Botswana. N Engl J Med. Jun 17 2010;362(24):2282-2294. Available at http://www.ncbi.nlm.nih.gov/pubmed/20554983.
Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States 51. Kesho Bora Study Group, de Vincenzi I. Triple antiretroviral compared with zidovudine and single-dose nevirapine prophylaxis during pregnancy and breastfeeding for prevention of mother-to-child transmission of HIV-1 (Kesho Borastudy): a randomised controlled trial. Lancet Infect Dis. Mar 2011;11(3):171-180. Available athttp://www.ncbi.nlm.nih.gov/pubmed/21237718.
52. de Ruiter A, Mercey D, Anderson J, et al. British HIV Association and Children's HIV Association guidelines for the management of HIV infection in pregnant women 2008. HIV Med. Aug 2008;9(7):452-502. Available athttp://www.ncbi.nlm.nih.gov/pubmed/18840151.
53. Ferguson W, Goode M, Walsh A, Gavin P, Butler K. Evaluation of 4 weeks' neonatal antiretroviral prophylaxis as a component of a prevention of mother-to-child transmission program in a resource-rich setting. Pediatr Infect Dis J. May2011;30(5):408-412. Available at http://www.ncbi.nlm.nih.gov/pubmed/21266939.
54. Lahoz R, Noguera A, Rovira N, et al. Antiretroviral-related hematologic short-term toxicity in healthy infants: implications of the new neonatal 4-week zidovudine regimen. Pediatr Infect Dis J. Apr 2010;29(4):376-379. Availableat http://www.ncbi.nlm.nih.gov/pubmed/19949355.
55. Mirochnick M, Dorenbaum A, Blanchard S, et al. Predose infant nevirapine concentration with the two-dose intrapartum neonatal nevirapine regimen: association with timing of maternal intrapartum nevirapine dose. J AcquirImmune Defic Syndr. Jun 1 2003;33(2):153-156. Available at http://www.ncbi.nlm.nih.gov/pubmed/12794547.
56. Shetty AK, Coovadia HM, Mirochnick MM, et al. Safety and trough concentrations of nevirapine prophylaxis given daily, twice weekly, or weekly in breast-feeding infants from birth to 6 months. J Acquir Immune Defic Syndr. Dec 152003;34(5):482-490. Available at http://www.ncbi.nlm.nih.gov/pubmed/14657758.
57. Capparelli EV, Mirochnick M, Dankner WM, et al. Pharmacokinetics and tolerance of zidovudine in preterm infants. J Pediatr. Jan 2003;142(1):47-52. Available at http://www.ncbi.nlm.nih.gov/pubmed/12520254.
58. Mirochnick M, Capparelli E, Connor J. Pharmacokinetics of zidovudine in infants: a population analysis across studies.
Clin Pharmacol Ther. Jul 1999;66(1):16-24. Available at http://www.ncbi.nlm.nih.gov/pubmed/10430105.
59. Mugabo P, Els I, Smith J, et al. Nevirapine plasma concentrations in premature infants exposed to single-dose nevirapine for prevention of mother-to-child transmission of HIV-1. S Afr Med J. Sep 2011;101(9):655-658. Available athttp://www.ncbi.nlm.nih.gov/pubmed/21920159.
60. Kuhn L, Reitz C, Abrams EJ. Breastfeeding and AIDS in the developing world. Curr Opin Pediatr. Feb 2009;21(1):83- 93. Available at http://www.ncbi.nlm.nih.gov/pubmed/19242244.
61. Van de Perre P, Lepage P, Homsy J, Dabis F. Mother-to-infant transmission of human immunodeficiency virus by breast milk: presumed innocent or presumed guilty? Clin Infect Dis. Sep 1992;15(3):502-507. Available athttp://www.ncbi.nlm.nih.gov/pubmed/1445596.
62. Daar ES. Virology and immunology of acute HIV type 1 infection. AIDS Res Hum Retroviruses. Oct 1998;14(Suppl 3):S229-234. Available at http://www.ncbi.nlm.nih.gov/pubmed/9814948.
63. Smith DK, Grohskopf LA, Black RJ, et al. Antiretroviral postexposure prophylaxis after sexual, injection-drug use, or other nonoccupational exposure to HIV in the United States: recommendations from the U.S. Department of Health andHuman Services. MMWR Recomm Rep. Jan 21 2005;54(RR-2):1-20. Available athttp://www.ncbi.nlm.nih.gov/pubmed/15660015.
Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States
Run-Together Sentences (RTS) Explanation Contrary to popular belief, run-together sentences are not simply sentences that are too long. Instead, run-together Connections sentences are the result of combining two or more complete sentences together without an acceptable A complete sentence , also know as an independent clause , contains a subject-verb unit; in the examp