Epidemiology and Prevention of HIV Infection in Children and Adolescents

Epidemiology and Prevention of HIV Infection in Children and Adolescents

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SECTION S: Human Immunodeficiency Virus and the Acquired Immunodeficiency Syndrome

and Prevention of HIV Infection in Children 109 Epidemiology and Adolescents Jennifer S. Read

The epidemiology of infection with human immunodeficiency virus type 1 (HIV) in children and adolescents has evolved dramatically since the first case of pediatric HIV infection was described in 1983.1 This evolution is due in part to improvements in the management of HIV infection, with resultant increased survival of infected individuals. This chapter addresses the epidemiology of HIV infection among children and adolescents, clinical manifestations and progression of disease, and prevention of HIV infection in children and adolescents.

EPIDEMIOLOGY The epidemiology of HIV infection varies dramatically between resourcepoor and resource-rich settings around the world. Estimates of the extent of the HIV epidemic, globally and in the United States, are updated regularly by the Joint United Nations Programme on HIV/AIDS (UNAIDS)2 and by the US Centers for Disease Control and Prevention (CDC),3 respectively. In the US, black and other minority infants, children, and adolescents are disproportionately affected by HIV infection.3 HIV transmission to infants, children, and adolescents can occur through sexual contact (vaginal, anal, or orogenital), percutaneous blood exposure (from contaminated needles or other sharp instruments), mucous membrane exposure to contaminated blood or other body fluids, and transfusion with contaminated blood products.4 Children also can acquire HIV infection through mother-to-child transmission.4 Of the estimated 36.7 million people living with HIV infection in 2015, 17.8 million were women and 1.8 million were children younger than 15 years, and most HIV-infected people (25.5 million) resided in sub-Saharan Africa.2 An estimated 2.4 million HIV-infected individuals were in western and central Europe and North America. Of the estimated 2.1 million new infections in 2015 (91,000 in western and central Europe and North America), 1.9 million were among adults and 150,000 among children.2 Finally, there were an estimated 1.1 million AIDS-related deaths in 2015 (22,000 in western and central Europe and North America).2 In 2014, the number of persons living with a diagnosis of HIV infection in the US and dependent areas with confidential name-based HIV infection reporting included 2494 children (<13 years of age).3 Both in the US and globally, mother-to-child transmission is the most common means of acquisition of HIV infection by children (Table 109.1). For example, of the 2494 children reported to be living with HIV infection in the US in 2014,3 2012 (81%) were classified as having acquired infection through mother-to-child transmission.3 Although there has been a dramatic decrease in the rate of mother-to-child transmission of HIV and in the number of pediatric HIV infections and AIDS cases in the US, mother-to-child transmission has not been eliminated in the US. In 2006, there were an estimated 171,400 HIV-infected women aged 13 to 44 years in the US and five dependent areas, with an estimated 8700 births to these women.5 The estimated number of cases of motherto-child transmission of HIV in the US peaked in 1991 (1650 cases).6 By 2005, the number of cases of mother-to-child transmission in the US had decreased to an estimated 215 to 370, representing a transmission rate of approximately 2.8%.7 Mother-to-child transmission of HIV can occur during pregnancy, around the time of labor and delivery, and postnatally (through breastfeeding).8 Most transmission occurs during the intrapartum period (both in breastfeeding and nonbreastfeeding populations).9 Rates of motherto-child transmission of HIV were calculated in studies conducted in

various countries before the development and implementation of interventions to decrease transmission.10 Usually a transmission rate in the range of 25% to 30% was reported. Higher transmission rates were observed in resource-poor settings (13%−42%) compared with rates in resource-rich settings (14%−25%), in part attributed to the greater proportion of breastfeeding women in resource-poor settings. Various risk factors for mother-to-child transmission of HIV have been identified or are under investigation and can be categorized as follows: (1) the amount of virus to which the child is exposed (e.g., maternal viral load,11–15 expressed as copies/mL of HIV RNA); (2) the duration of such exposure (e.g., the duration of ruptured membranes16 or of breastfeeding,17 vaginal versus cesarean delivery before labor and before ruptured membranes18,19); and (3) other factors, including those facilitating the transfer of virus from mother to child (e.g., mixed breastfeeding,20,21 maternal breast pathology,13,22–24 and infant oral candidiasis23,24). In addition to these risk factors, characteristics of the virus and the child’s susceptibility to infection are important. Improved estimation of HIV incidence is now possible with newer assays that differentiate between recent and chronic HIV infections.25 Many cases of HIV infection in young adults represent infections that actually were acquired during adolescence, but were not recognized until several years later. In 2014, the number of persons living with a diagnosis of HIV infection in US and dependent areas with confidential namebased HIV infection reporting included 6161 adolescents (13–19 years of age) and 32,195 young adults (20–24 years of age).3 Among the estimated 734,506 male adults and adolescents living with HIV infection in 2014, 513,045 (70%) of these infections were acquired through male-to-male

TABLE 109.1  Modes of Acquisition of HIV Infection in Children and Adolescents Children

Adolescents

MOST COMMON Mother-to-child transmission

Sexual transmission • Males: male-to-male sexual transmission • Females: heterosexual transmission • Injection drug use

OTHER Transfusion of contaminated blood or blood products if effective screening not available (e.g., among patients with hemophilia early in the HIV epidemic in the US) Mucous membrane exposure to contaminated blood or other body fluids (e.g., through receipt of food that has been prechewed by an HIV-infected caregiver with bleeding gums or open sores in the mouth) Sexual abuse

Percutaneous blood exposure (from contaminated needles or other sharp instruments, e.g., with tattooing)

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PART II  Clinical Syndromes and Cardinal Features of Infectious Diseases: Approach to Diagnosis and Initial Management SECTION S  Human Immunodeficiency Virus and the Acquired Immunodeficiency Syndrome

sexual contact, 83,020 (11%) were due to injection drug use, 53,166 (7%) were due to male-to-male sexual contact and injection drug use, and 77,479 (10%) were due to heterosexual contact3 (see Table 109.1). In contrast, among the estimated 235,613 female adults and adolescents living with HIV infection in 2014, 175,581 (74%) were acquired through heterosexual contact and 53,222 (23%) from injection drug use3 (see Table 109.1). Aside from mother-to-child transmission, sexual transmission, and transmission related to intravenous drug use, other means of acquisition of HIV infection include transfusion of contaminated blood or blood products in settings in which routine and effective screening of blood is not available, percutaneous blood exposure (from contaminated needles or other sharp instruments), and mucous membrane exposure to contaminated blood or other body fluids (see Table 109.1).4 The first case of pediatric HIV infection in the US was an infant who acquired HIV infection through a transfusion of contaminated blood.1 Thousands of patients with hemophilia and other recipients of contaminated blood and blood products acquired HIV infection before screening of blood and blood products for HIV. Now, in the US and many other countries, blood, blood components, and clotting factors undergo effective screening procedures. As a result, transmission of HIV through transfusion of blood or blood products in the US has decreased substantially.26–29 The risk for transmission of HIV through blood transfusions in the US in 2010 was estimated at 1 per 1,467,000.29 In addition to intravenous drug use, other exposure to contaminated needles (e.g., with tattooing)30 can result in HIV transmission. Possible transmission of HIV through receipt of food that has been prechewed by an HIVinfected caregiver with bleeding gums or open sores in the mouth has been reported.31,32 There have been rare cases of household transmission of HIV between siblings,33 but in these cases, there were opportunities for skin or mucous membrane exposure to HIV-infected blood. Thus all caregivers of HIV-infected children should receive education regarding universal precautions.34,35 Transmission of HIV has not been described as a result of routine outpatient or inpatient care or in schools or childcare settings in the US.4,36–38 Cases of HIV transmission to children through sexual abuse have been reported.39–41

CLINICAL MANIFESTATIONS AND PROGRESSION Infection with HIV can result in a myriad of clinical manifestations. Acquired immunodeficiency syndrome, or AIDS, refers to the most advanced disease stage of HIV infection. AIDS is defined by the development of life-threatening manifestations, including opportunistic infections and neoplasms, due to progressive immunosuppression induced by HIV infection. Previously, the CDC had classified HIV-infected children (below 13 years of age) according to their clinical status (ranging from N [not symptomatic], through A and B, to C [severely symptomatic; AIDS]) and immunologic status (category 1 [CD4+ T-lymphocyte count or percentage indicating no evidence of immune suppression] to category 3 [severe suppression]).42 Thus, combining both the clinical and immunologic staging of children resulted in categories of N1 through C3. This classification system took into account the age-related changes (<1 year, 1−5 years, 6−12 years) in the normal ranges of CD4+ lymphocyte counts. The classification system for adolescents and adults similarly classified HIVinfected individuals according to their clinical and immunologic status, except that the clinical staging ranged from A to C (no category N).43 In 2014, the CDC revised the surveillance case definition for HIV infection.44 According to this new case definition, a confirmed case of HIV infection (whether in children [<13 years of age] or in adolescents and adults) can be classified into one of five HIV infection stages (stages 0, 1, 2, 3, or unknown).44 Early infection is classified as stage 0, and AIDS is classified as stage 3.44 The natural history of HIV infection in infants who acquired HIV infection through mother-to-child transmission differs from that in adults. Plasma viral loads among untreated, infected infants increase rapidly after birth,45 peaking at 1 to 2 months of age (median values of 318,000 and 256,000 copies/mL, respectively).45 Untreated, viral loads decline slowly during the first 2 years of life,46 reaching values observed in HIV-infected adults only at approximately 5 years of age.47 Studies of HIV-infected infants who acquired infection through mother-to-child transmission48,49 that were published in the late 1990s,

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at a time when pediatric antiretroviral treatment was limited, described rapid progression of disease. For example, in a study of 128 HIV-infected children in North America,48 the median ages of progression to clinical classes A, B, and C were 5, 11, and 48 months, respectively. In another study of 392 HIV-infected children in Europe, about 20% progressed to class C disease or death during the first year of life, and approximately 5% progressed per year thereafter.49 The mortality rate at 6 years was 26%.49 Early onset of clinical manifestations of HIV infection (lymphadenopathy, hepatomegaly, splenomegaly at 3 months of age or earlier) and positive HIV diagnostic testing within the first week of life were associated with more rapid disease progression.48 In subsequent studies of HIV-infected children in Africa, more than one third of untreated, HIV-infected infants died by 12 months of age,50 and approximately one half died by 24 months of age.51 After the introduction of more effective antiretroviral regimens, the morbidity and mortality associated with HIV infection among infants, children, adolescents, and adults has decreased substantially.52–64 Opportunistic and other infections were uncommon among HIV-infected children in 2000 to 2004,65 and infection rates were lower than those reported in earlier years.66 Similarly, the incidence of certain noninfectious conditions (encephalopathy, pancreatitis, cardiac disorders) decreased between 2001 and 2006 among HIV-infected children and adolescents.67 In a randomized clinical trial conducted in South Africa, infants with early time-limited antiretroviral therapy had better clinical and immunologic outcomes than infants with deferred therapy. Also, infants with early antiretroviral therapy did not have excess disease progression during subsequent treatment interruption.68,69 Based on these data and the high risk for rapid progression of HIV infection in infants, urgent antiretroviral therapy for all HIV-infected infants is recommended, regardless of clinical, immunologic (CD4+ lymphocyte percentage), or viral load status.70 For children aged 1 to <6 years, urgent treatment is recommended for those with CDC stage 3-defining opportunistic infections or stage 3 immunodeficiency (CD4+ cell count <500 cells/mm3).70 Antiretroviral treatment is recommended for children aged 1 to <6 years with moderate HIV-related symptoms, those with a CD4+ cell count of 500 to 999 cells/mm3, and those who are asymptomatic or mildly symptomatic and who have a CD4 cell count ≥1000 cells/mm3.70 For children ≥6 years of age, urgent antiretroviral treatment is recommended for those with CDC stage 3-defining opportunistic infections or stage 3 immunodeficiency (CD4+ cell count <200 cells/mm3).70 Antiretroviral treatment is recommended for children ≥6 years of age with moderate HIV-related symptoms, those with a CD4+ cell count of 200 to 499 cells/mm3, and those who are asymptomatic or mildly symptomatic and with a CD4 cell count ≥500 cells/mm3.70 There is substantial variation in HIV disease progression among adolescents and adults; some individuals progress to AIDS in less than 5 years,71 but some untreated individuals (so-called long-term nonprogressors) do not deteriorate clinically or immunologically for many years.72,73 Current guidelines for initiation of antiretroviral therapy in HIV-infected adolescents and adults74 recommend the initiation of antiretroviral therapy in all HIV-infected individuals, regardless of CD4+ count, to decrease morbidity and mortality related to HIV infection. Antiretroviral therapy should be initiated as soon as possible after diagnosis of HIV infection, although in certain circumstances (i.e., related to clinical and/ or psychosocial factors), therapy may be deferred.74

PREVENTION Mother-to-child transmission represents the means by which virtually all infants and young children acquire HIV infection. Most adults and adolescents acquire HIV infection through sexual transmission or percutaneous exposure (e.g., intravenous drug use). Discussion of prevention of HIV transmission to children and adolescents focuses on these routes of transmission.

Prevention of Mother-to-Child Transmission Prevention of mother-to-child transmission of HIV is just one component of the overall management of HIV-infected women and their children (Box 109.1). The World Health Organization (WHO) Strategic Approach to Prevention of Pediatric HIV Infection75 includes four

Epidemiology and Prevention of HIV Infection in Children and Adolescents

BOX 109.1  Prevention of Mother-to-Child Transmission of HIV Antiretroviral agent(s) ■ For the mother (for treatment of the mother’s own HIV infection, for prevention of mother-to-child transmission of HIV) ■ For the nonbreastfeeding infant (early postnatal period) Cesarean delivery before labor and before rupture of membranes Interventions to prevent breast milk transmission of HIV ■ Complete avoidance of breastfeeding ■ Exclusive breastfeeding when complete avoidance of breastfeeding is not feasible or safe ■ Antiretroviral prophylaxis for the breastfeeding infant

components: primary prevention of HIV infection; prevention of unintended pregnancies among HIV-infected women; prevention of transmission of HIV infection from mothers to children; and provision of ongoing support, care, and treatment to HIV-infected women and their families. Ideally, primary prevention of HIV infection occurs (e.g., an HIV-uninfected woman does not acquire HIV infection either before or during pregnancy). To facilitate prevention of acquisition of HIV infection, individuals should know their own and their sexual partners’ HIV infection status. This is accomplished through provision of and access to HIV counseling and testing. Prevention of unintended pregnancies is crucial for women who acquire HIV infection. Antiretroviral therapy for HIV-infected women, for their own health and for prevention of mother-to-child transmission of HIV, as well as other interventions to prevent mother-to-child transmission, should be available. Finally, HIV-infected women and their children need ongoing support, care, and treatment, including infant feeding counseling and support. Although different interventions to prevent mother-to-child transmission of HIV have been and are being investigated, efficacy has been demonstrated to date for only the following: antiretroviral use during pregnancy by HIV-infected women,76–83 cesarean delivery before labor and before ruptured membranes,18 complete avoidance of breastfeeding,84 and (in settings where complete avoidance of breastfeeding is not feasible) exclusive breastfeeding,85 antiretroviral prophylaxis administered to the infant while breastfeeding,86–89 and antiretroviral use by breastfeeding mothers.88,90

Antiretroviral Agents Maternal use of antiretroviral agents during the antepartum and intrapartum periods, and during the postpartum period if breastfeeding, as well as infant antiretroviral prophylaxis while breastfeeding, are associated with significant reduction in the rates of mother-to-child transmission of HIV. In the first efficacy trial of antiretroviral prophylaxis, zidovudine alone was given to mothers during pregnancy and the intrapartum period and to their infants.76 Subsequently, the US Public Health Service issued guidelines regarding the use of zidovudine prophylaxis,91 and such prophylaxis played a central role in the prevention of motherto-child transmission in the US92 and other resource-rich settings. More recently, an increasing number of HIV-infected women have been using combination antiretroviral therapy (cART) during pregnancy.93 In 2015, results from a randomized trial demonstrated lower rates of mother-tochild transmission with cART regimens including three drugs (zidovudine, lamivudine, and lopinavir/ritonavir [0.5%] or tenofovir, emtricitabine, and lopinavir/ritonavir [0.6%]) compared with zidovudine, with a single dose of nevirapine at delivery, plus tenofovir and emtricitabine (1.8%).83 Antiretroviral agents prevent mother-to-child transmission of HIV by decreasing the viral load in maternal blood and genital secretions,12,94 an important risk factor for vertical transmission.94–96 In addition to decreasing viral load, other mechanisms of action of antiretroviral therapy in reducing vertical transmission are suggested by several observations. First, there is no threshold maternal plasma viral load below which transmission does not occur; transmission has been observed at all levels

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of maternal viral load.94,96,97 Second, among women with lower plasma viral loads (<1000 copies/mL), more intensive maternal antiretroviral regimens are associated with lower risks for transmission.98 Also, maternal plasma load at delivery and antepartum antiretroviral use are each independent risk factors for transmission.93 Pre-exposure infant prophylaxis can be accomplished through the maternal use of antiretroviral agents that cross the placenta and result in adequate systemic drug concentrations in the infant. Postexposure infant prophylaxis can be achieved through administration of antiretroviral agents to the infant after birth. In this situation, the antiretroviral agents can protect the infant from acquiring infection through maternal microtransfusions of blood during labor or from virus swallowed by the infant during delivery. The efficacy and effectiveness of intrapartum or neonatal antiretroviral regimens for prevention of mother-to-child transmission (i.e., initiated too late to prevent transmission by decreasing maternal viral load)81,99–104 lend further support to the benefit of infant pre-exposure and postexposure prophylaxis. Guidelines addressing the use of antiretroviral therapy during pregnancy have been developed by the US Department of Health and Human Services (DHHS) Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission,105 the WHO,107 and other groups. Guidelines for the use of antiretroviral agents in HIV-infected pregnant women in the US have evolved over the years.105 Current recommendations are for all pregnant, HIV-infected women to use cART to prevent mother-to-child transmission of the virus, irrespective of the woman’s plasma CD4+ count or viral load (copies/mL), and such therapy should be initiated as early in pregnancy as possible.105 In general, indications for initiation of antiretroviral therapy in women of reproductive age, pregnant women, or postpartum women are the same as those for other HIV-infected adults and adolescents.74 British guidelines for the management of HIV-infected women include zidovudine alone as a valid option for women with higher CD4+ counts and lower pretreatment plasma viral loads (<10,000 copies/mL) who do not want to use cART during pregnancy and who are willing to give birth by planned cesarean delivery.108 Antiretroviral resistance testing should be performed in all HIVinfected, antiretroviral-naïve pregnant women before initiation of antiretroviral treatment (if the pretreatment viral load is above the threshold for resistance testing [i.e., >500−1000 copies/mL]).105 For women with viral loads above the threshold for resistance testing while using antiretroviral agents and for those who have suboptimal viral suppression after initiating antiretroviral therapy during pregnancy, resistance testing should be performed before modifying antiretroviral regimens.105 Of note, for women who come to attention late in pregnancy, empiric antiretroviral therapy should be initiated without waiting for resistance testing results. After results become available, the antiretroviral regimen can be modified if necessary.105 Women using cART during pregnancy should continue this regimen as much as possible around the time of delivery, and intrapartum (intravenous) zidovudine is not required for women with good adherence to cART who have viral loads ≤1000 copies/mL.105 However, intravenous zidovudine should be administered to other HIV-infected women, especially those with a viral load of >1000 copies/mL or an unknown viral load near delivery.105 For women of unknown HIV infection status who present in labor, expedited antigen/antibody testing should be performed. If this testing is positive, maternal intravenous zidovudine and infant cART should be initiated immediately, without waiting for the results of an HIV-1/HIV-2 antibody differentiation assay.105 All newborn infants of HIV-infected women should receive antiretroviral postexposure prophylaxis, irrespective of whether the mother used antiretroviral agents during pregnancy.105 A 4-week regimen of zidovudine is recommended for transmission prophylaxis for full-term infants whose mothers adhered to a cART regimen during pregnancy (with sustained viral suppression).105 A longer (6-week) regimen of antiretroviral prophylaxis (with a combination ARV regimen) is recommended for all high-risk infants (i.e., those whose mothers did not use antepartum or intrapartum ARVs or whose mothers used only intrapartum ARVs, and those whose mothers used cART but without sustained viral suppression).105 In the United Kingdom, a 4-week infant antiretroviral prophylaxis regimen is recommended.108 Antiretroviral prophylaxis for infants should begin as soon as possible (preferably within 6–12 hours) after birth.105

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Clinical trials are planned to address the question of whether using cART for HIV-exposed, high-risk infants will affect the establishment and persistence of HIV infection, as well as to assess the safety of such an approach. The effectiveness of antiretroviral therapy in improving maternal CD4+ lymphocyte counts and decreasing plasma viral load should be monitored carefully in any HIV-treated patient population, including infected pregnant women.105 Laboratory monitoring to assess antiretroviral drug-related toxicities is based on the known adverse events related to the drugs being used.105 In addition, the benefits of antiretroviral agents for HIV-infected women and their infants (treatment of the mother’s own HIV infection, prevention of mother-to-child transmission of HIV) must be weighed against adverse events associated with these drugs. Potential adverse events related to in utero exposure to antiretroviral agents include congenital anomalies, malignancies, mitochondrial toxicity, and preterm birth. Studies evaluating in utero exposure to antiretroviral agents, especially first-trimester exposure, generally have not demonstrated significant associations between exposure and infant congenital anomalies.111–116 Some studies116,117 have reported a higher risk for congenital anomalies among infants with first-trimester exposure to efavirenz, but more research regarding first-trimester exposure to the drug is necessary to evaluate potential risks more conclusively. However, because of potential central nervous system abnormalities with first-trimester exposure to efavirenz and similar findings in primates, the use of efavirenz during the first trimester of pregnancy should be avoided.105 Findings to date regarding the short-term (e.g., within the first 2−4 years of life) risk for malignancies among infants with in utero antiretroviral exposure are reassuring.118–121 Nonetheless, the possibility that children with in utero exposure are at increased risk for cancer at older ages remains. Children with exposure to antiretroviral agents should have follow-up into adulthood because of the potential for carcinogenicity of antiretroviral agents.105 In utero exposure to nucleoside and nucleotide analogue reverse transcriptase inhibitors has been linked to mitochondrial dysfunction in French infants.122,123 However, results of other studies from the US and Europe124–129 have not corroborated these results. Further research in this area is needed. Even if a clear association between in utero antiretroviral exposure and mitochondrial dysfunction is delineated, the absolute risk for severe mitochondrial dysfunction appears to be low and outweighed by the benefit of antiretroviral agents in reducing the risk for mother-tochild transmission of HIV. The possibility of an association between use of cART, especially those regimens containing protease inhibitors, during pregnancy and infant preterm birth should be considered, although currently available data are conflicting.130–150 In general, however, the benefits of antiretroviral use during pregnancy are considered to outweigh the small possible risk for preterm birth. Neonatal anemia has been associated with in utero or early postnatal exposure to antiretroviral agents; therefore treated babies should have routine hematologic evaluation. Based on studies suggesting other laboratory abnormalities among infants with in utero or early postnatal exposure to antiretroviral agents,151–157 some experts recommend more extensive laboratory assessments, such as a complete blood count with differential of white cells and hepatic transaminase assays. WHO guidelines regarding the use of antiretroviral agents107 recommend initiation in all HIV-infected pregnant or breastfeeding women regardless of WHO clinical stage or CD4+ count and continuation lifelong. All infants born to HIV-infected mothers should receive antiretroviral prophylaxis. For infants of women who are using ART and are breastfeeding, 6 weeks of infant prophylaxis with daily nevirapine is recommended.107 For infants receiving replacement feeding, 4 to 6 weeks of infant prophylaxis is recommended (with daily nevirapine or twicedaily zidovudine).107 High-risk infants (infants who are at high risk of acquiring HIV infection because they are [1] born to mothers with chronic HIV infection who received less than 4 weeks of antiretroviral therapy by the time of delivery; [2] born to mothers with chronic HIV infection and a viral load above 1000 copies/mL in the 4 weeks prior to delivery; [3] born to mothers with acute HIV infection during pregnancy or during breastfeeding; or [4] born to mothers identified for the first time as HIV-infected during the postpartum period) should receive

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prophylaxis with twice-daily zidovudine and once-daily nevirapine for the first 6 weeks of life (irrespective of whether breastfed or formula fed).107 Such breastfed infants should continue prophylaxis for an additional 6 weeks (for a total of 12 weeks of infant prophylaxis).107 The WHO guidelines recommend initiation of antiretroviral therapy in all HIVinfected children younger than 10 years of age, regardless of WHO clinical stage or CD4+ cell count.

Cesarean Delivery Before Labor and Before Ruptured Membranes In the late 1990s, results from both a multicenter, randomized clinical trial conducted in Europe and a meta-analysis of prospective cohort studies conducted in North America and Europe demonstrated the effectiveness of cesarean delivery before labor and before ruptured membranes in reducing mother-to-child transmission of HIV.18,19 In the clinical trial, the risk for mother-to-child transmission of HIV was 80% lower among women allocated to the group who underwent cesarean delivery before labor and before rupture of membranes; the risk for transmission was highest among women who delivered vaginally (10.2%), followed by those who had a cesarean delivery after onset of labor or ruptured membranes (8.8%), with the lowest risk among those who underwent cesarean delivery before labor and before rupture of membranes (2.4%).18 The individual patient meta-analysis of data from 15 prospective cohort studies found that, after controlling for maternal age, use of antiretroviral agents during pregnancy (mostly zidovudine alone), and infant birth weight, cesarean delivery before labor and before ruptured membranes was associated with a lower risk for transmission of HIV (adjusted odds ratio [OR], 0.43; 95% confidence interval [CI], 0.33−0.56) compared with other modes of delivery.19 A large proportion of mother-to-child transmission of HIV occurs during the intrapartum period.8,9 One potential mechanism of intrapartum HIV transmission is fetal exposure to infected maternal blood and cervicovaginal secretions. An early study of twins born to HIVinfected women found that the first-born twin was at higher risk for HIV transmission compared with the second twin,158 suggesting that time spent with exposure to infected blood and secretions in the vagina increased risk. In addition, a longer duration of ruptured membranes is associated with a greater risk for mother-to-child transmission of HIV.159 For each hour increase in the duration of ruptured membranes, there is an approximate 2% increase in the risk for mother-to-child transmission of HIV.158 This association suggests that intrapartum transmission results from ascending infection from the lower genital tract, after the integrity of the amniotic membranes is disrupted. Another potential mechanism for mother-to-child transmission of HIV is microtransfusions of maternal blood during uterine contractions. Placental microtransfusions occur when a small amount of maternal blood crosses the placenta to the fetus. Two studies assessing the levels of placental alkaline phosphatase found that the lowest cord placental alkaline phosphatase levels, and thus the lowest volumes of maternal-fetal transfusion, were among those undergoing cesarean delivery before labor and before rupture of membranes.160,161 Based on these studies, the American College of Obstetricians and Gynecologists (ACOG) recommended that: (1) HIV-infected women with plasma viral loads >1000 copies/mL should be counseled on the benefits of cesarean delivery before labor and before rupture of membranes to prevent mother-to-child transmission; (2) cesarean delivery should be performed at 38 completed gestational weeks, based on the best clinical estimate, to minimize the odds for onset of labor and rupture of the membranes; (3) HIV-infected women should receive antiretroviral agents during pregnancy and without interruption before the cesarean delivery; and (4) women should receive intravenous zidovudine 3 hours before the cesarean delivery, before labor and before rupture of membranes.161 After the release of data regarding mode of delivery and mother-to-child transmission of HIV,18,19 cesarean delivery for HIVinfected women was performed with increasing frequency in clinical centers in the US.163 However, HIV-preventive cesarean delivery generally is not feasible in resource-poor settings because of the lack of a skilled attendant during labor and for other reasons. Scheduled cesarean delivery at 38 weeks’ gestation is recommended for HIV-infected women in the US with plasma viral loads above 1000 copies/mL or unknown plasma

Epidemiology and Prevention of HIV Infection in Children and Adolescents

viral loads near the time of delivery, irrespective of use of antepartum antiretroviral agents.105 Because cesarean delivery is a major operative procedure, there are concerns about potential risks to the mothers and infants. Compared with vaginal delivery among HIV-uninfected women, cesarean delivery is associated with increased risk for intraoperative and postoperative complications, particularly after emergency cesarean delivery.164–167 Several studies have compared postpartum morbidity according to mode of delivery among HIV-infected women.18,168–171 The results of these studies, summarized in a Cochrane review,172 indicate that the risk for postpartum morbidity, primarily infectious (i.e., urinary tract infection, pneumonia, wound infection, septicemia, and episiotomy infection), was highest with nonelective cesarean delivery, intermediate with elective cesarean delivery, and lowest with vaginal delivery. The DHHS Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission105 has concluded that the observed postpartum morbidity associated with cesarean delivery before labor and before ruptured membranes among HIV-infected women is not of sufficient frequency or severity to outweigh the benefit of decreased transmission of HIV to the infant. Studies among HIV-uninfected women have demonstrated that infants who are delivered before 39 weeks’ gestation are at an increased risk for neonatal respiratory morbidity and other complications. In two recent analyses of data from prospective cohort studies,173,174 respiratory morbidity among neonates of HIV-infected pregnant women was assessed according to mode of delivery. In an analysis of more than 1000 mother-infant pairs in North America, the authors concluded that there was minimal neonatal respiratory morbidity risk in near-term infants born by cesarean delivery before labor and rupture of membranes.173 In an analysis of more than 1400 HIV-infected women and their infants in Latin America, few children born by cesarean delivery before labor and before ruptured membranes for prevention of mother-to-child transmission of HIV had respiratory distress syndrome or transient tachypnea of the newborn, and only a minority required ventilator support.174 It therefore appears that the benefits of cesarean delivery for prevention of mother-to-child transmission of HIV outweigh the small risk for respiratory morbidity among near-term infants.173,174 To strike a balance between minimizing the risks for iatrogenic prematurity and ensuring that the cesarean delivery before labor and before rupture of membranes is performed before the onset of labor, the ACOG recommends that infants of HIV-infected women should be delivered a week earlier (at 38 completed weeks of gestation) than is customary among uninfected women (39 completed weeks of gestation).162 Although the ACOG generally recommends testing amniotic fluid if elective delivery is being considered before 39 week to determine fetal pulmonary maturity,175 amniocentesis should not be performed routinely in HIV-infected women. Therefore clinicians should depend on the best clinical estimate of gestational age to determine when to deliver.176 Unresolved questions regarding mode of delivery and prevention of mother-to-child transmission of HIV include whether cesarean delivery before labor and before ruptured membranes is beneficial among HIVinfected, pregnant women with low plasma viral loads (<1000 copies/ mL) and whether there is a benefit of cesarean delivery before labor and before rupture of membranes among women who are using cART. In one recent study, the mother-to-child transmission rate in term births (including all modes of delivery) according to maternal viral load at delivery was 0.6% (<400 copies/mL).177 A similarly low rate of transmission (0.8%) has been observed among women using cART for at least the last 14 days of pregnancy, regardless of mode of delivery.178 However, analyses of data from the European Collaborative Study179 demonstrated an 80% lower risk for transmission with cesarean delivery before labor and before rupture of membranes when adjusting for use of cART and preterm birth (adjusted OR, 0.20; 95% CI, 0.05−0.65). Similarly, among 560 women with undetectable viral loads, cesarean delivery before labor and before rupture of membranes was associated with a 90% lower risk for transmission (OR, 0.10; 95% CI, 0.03−0.33).180 More recent data from the UK and Ireland regarding HIV-infected women with plasma viral loads of 50 to 399 copies/mL suggest the risk for mother-to-child transmission among women with a scheduled cesarean delivery is less than one half that in women intending to delivery vaginally.181

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Interventions to Prevent Breast Milk Transmission of HIV Both the CDC182 and the American Academy of Pediatrics (AAP)183,184 recommend that HIV-infected women in the US not breastfeed their children. These recommendations are based in large part on the results of a randomized clinical trial conducted in Kenya, where the observed rate of mother-to-child transmission of HIV among mothers randomized to not breastfeed was significantly lower than among mothers randomized to breastfeed (20.5% vs. 36.7% at 2 years, P < 0.001).84 The evidence for breast milk transmission of HIV and risk factors for such transmission have been summarized185; these include longer duration of breastfeeding, more advanced HIV disease in the mother, the child’s susceptibility to infection, and factors that may facilitate transfer of HIV from mother to child or are otherwise associated with an increased risk for breast milk transmission. A meta-analysis incorporating data from thousands of breastfeeding children of HIV-infected women in sub-Saharan Africa17 demonstrated that breast milk transmission of HIV contributes substantially to overall mother-to-child transmission. The longer breastfeeding continues, the greater the cumulative risk for HIV transmission. More advanced maternal disease stage, as manifested by lower CD4+ lymphocyte counts, is a risk factor for breast milk transmission of HIV,13,24 along with higher maternal peripheral blood or human milk viral load.13–15 Factors that facilitate the transfer of the virus from mother to child and other factors, including maternal breast abnormalities, infant candidiasis, and mixed feeding, are associated with breast milk transmission of HIV.13–15,20,22–24 If complete avoidance of breastfeeding is not safe or feasible, specific interventions to prevent breast milk transmission of HIV can be implemented. Some of these interventions have been evaluated in clinical trials, whereas others are currently under study. Because a longer duration of breastfeeding is associated with a greater risk for transmission,17,84 early weaning was thought to be a reasonable intervention to decrease the risk for transmission. However, the morbidity associated with complete avoidance of breastfeeding and with early weaning, owing to contaminated water used in the preparation of replacement feeds, serves to counterbalance the benefits of such interventions to prevent mother-to-child transmission of HIV. For example, in the clinical trial of formula feeding versus breastfeeding, the two groups of children experienced similar mortality and malnutrition rates during the first 2 years of life.186 Similarly, studies in Malawi and Uganda documented increased risks for severe gastroenteritis187,188 and gastroenteritisassociated mortality187 among HIV-exposed infants. In a randomized trial evaluating the safety and efficacy of early weaning,189 there was no statistically significant difference in HIV-free survival between those children who ceased breastfeeding at about 4 months of age and those who continued breastfeeding (P = 0.27). Because more advanced maternal disease (e.g., as manifested by a higher maternal viral load in breast milk) is associated with a greater risk for mother-to-child transmission of HIV, two types of interventions have been proposed to decrease the infectiousness of the breast milk of HIVinfected mothers: maternal use of antiretroviral agents while breastfeeding, and treatment (chemical or heat) of breast milk. Two randomized clinical trials conducted in sub-Saharan Africa evaluated the use of antiretroviral prophylaxis by breastfeeding women in the reduction of mother-to-child transmission of HIV.88,90 In the BAN trial, HIV-infected, breastfeeding mothers with a CD4+ lymphocyte count of ≥250 cells/mm3 and their infants were randomized at 1 week after delivery to receive maternal antiretroviral regimen for 28 weeks, infant nevirapine for 28 weeks, or no prophylaxis beyond the first week of age. Before randomization, all mothers and infants had received standard perinatal prophylaxis, which included a single dose of oral nevirapine given to mothers in labor and to their infants immediately after birth. In addition, all mothers had received zidovudine and lamivudine as a single tablet every 12 hours from the onset of labor to 7 days after birth, and all infants received zidovudine until 7 days of age. Of 2369 mother-infant pairs who were randomized, 5% of infants were HIV-infected at 2 weeks of life. The estimated risk for mother-to-child transmission of HIV between 2 and 28 weeks was higher in the control group (5.7%) than in the other groups (maternal regimen group: 2.9%, P = 0.009; infant regimen group: 1.7%, P < 0.001). The estimated risks for infant HIV infection or death between 2 and 28 weeks were 7% in the control group, 4.1% in the maternal regimen group (P = 0.02), and 2.6% in the infant regimen group (P < 0.001).88 In the Kesho

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Bora study, women with CD4+ lymphocyte counts between 200 and 500 cells/mm3 were randomized to either (1) zidovudine with lamivudine and lopinavir/ritonavir (triple-ARV) at 28 to 36 weeks’ gestation until 6 months postpartum; or (2) zidovudine at 28 to 36 weeks’ gestation until the onset of labor, and then zidovudine with lamivudine and one dose of nevirapine at the onset of labor, followed by (in a later version of the protocol) zidovudine with lamivudine until 1 week after delivery (ZDV/ sdNVP). All infants received one dose of nevirapine within 72 hours of birth along with 1 week of zidovudine. Among 882 enrolled women, 824 were randomized and delivered 805 singleton or first, live-born infants. The cumulative risk for HIV transmission at 12 months was 5.4% in the triple-ARV arm and 9.5% in the ZDV/sdNVP arm (P = 0.03), a 43% risk reduction.90 Heat and chemical (e.g., sodium dodecyl sulfate) treatments of breast milk to decrease the amount of cell-free and cell-associated HIV have been evaluated in several studies.190,191 In addition, a method of “flash heating” of breast milk102 may be evaluated further in East Africa. Because various factors facilitate the transfer of the virus from mother to child or are otherwise associated with a greater risk for mother-tochild transmission (e.g., maternal breast abnormalities, infant candidiasis, mixed breastfeeding), interventions to prevent or treat such factors have been developed. For example, programs have been developed to educate HIV-infected women who choose to breastfeed, addressing proper positioning during breastfeeding, promptly seeking medical care if breast abnormalities develop or if the infant develops oral candidiasis or other lesions, and avoiding breastfeeding from a breast with mastitis or other abnormalities. Studies conducted in Brazil and South Africa suggest a lower risk for transmission with exclusive breastfeeding compared with mixed breastfeeding.20,193 Additional studies in Zimbabwe,21 South Africa,85 and Zambia189 support the association of exclusive breastfeeding with a lower risk for mother-to-child transmission of HIV. For example, the transmission rate among infants who were still exclusively breastfeeding at 6 months of age was 15%, but the rate was higher among those with mixed feeding at 6 months of age (27% among those who initiated mixed feeding before 14 weeks and 26% for those who initiated mixed breastfeeding after 14 weeks).85 It is noteworthy that although mixed feeding has been hypothesized to damage the intestinal mucosa, thus facilitating HIV infection of the infant through increased permeability or intestinal immune activation, the evidence to date do not support this hypothesis.194 The exact mechanism by which mixed feeding is associated with a higher risk for transmission of HIV remains controversial. Finally, interventions to decrease infant susceptibility to infection while breastfeeding (e.g., active and passive immunization of the infant, administration of antiretroviral prophylaxis to the infant while breastfeeding) have been or are being evaluated. Studies of the safety and immunogenicity of active immunization for prevention of mother-tochild transmission of HIV have been initiated.195,196 Similarly, passive immunization with polyclonal immune globulin has been evaluated in clinical trials in the US (formula-fed infants) and Uganda (predominantly breastfed infants).195,196 Several major studies have evaluated the efficacy of extended administration of antiretroviral prophylaxis to breastfeeding infants.86–89,197 In a clinical trial in Botswana, infants were randomized to 6 months of breastfeeding along with zidovudine prophylaxis, or to formula feeding with 1 month of zidovudine prophylaxis. HIV-free survival at 18 months was similar with both strategies.197 Other studies evaluating extended antiretroviral prophylaxis to breastfeeding infants (with nevirapine alone or with nevirapine and zidovudine)86–89 indicated that extended prophylaxis is efficacious in preventing breast milk transmission of HIV, with a longer duration of prophylaxis associated with a lower risk for motherto-child transmission. Durations of extended infant antiretroviral prophylaxis ranged from 6 weeks to 6 months. The results of these studies led to the concept that, if infant antiretroviral prophylaxis will be used to prevent breast milk transmission of HIV, it should be used for the duration of breastfeeding. This idea is being evaluated in an ongoing clinical trial (PROMISE), which is being conducted at multiple sites around the world.

Prevention of HIV Transmission in Adolescents Adolescents may have acquired HIV infection through mother-to-child transmission (already discussed) or can acquire through behaviors (e.g.,

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BOX 109.2  Prevention of HIV Transmission in Adolescents Counseling and education regarding behaviors that put them at risk for acquisition of HIV infection and interventions to decrease that risk ■ Counseling and education regarding safer sexual practices and about sexually transmitted infections ■ Counseling and education regarding prevention of initiation of substance abuse and prevention of HIV acquisition among those with an existing substance abuse problem Screening for sexually transmitted infections HIV testing Pre-exposure prophylaxis Postexposure prophylaxis

sexual transmission or injection drug use). Prevention of behaviorally acquired HIV infection in adolescents is the focus of this section. Essential components of the care of adolescents (Box 109.2) are counseling regarding behaviors that may put them at risk for acquisition of HIV and interventions to decrease the risk for transmission of HIV. In addition, adolescents should be educated regarding testing for HIV, pre-exposure prophylaxis, and postexposure prophylaxis. The most effective strategy for prevention of transmission of HIV in adolescents and adults will likely be to combine various types of interventions (behavioral and biological). Sexual transmission accounts for most cases of HIV infection among adolescents and adults.3 Although abstinence from sexual activity is the most effective means of avoiding acquisition of sexually transmitted infections (STIs), it is not possible to predict which adolescents will abstain. The AAP views provision of information regarding sex and STIs as an essential part of anticipatory guidance that pediatricians provide to their adolescent patients.198 The AAP recommends that this information explicitly underscores the potential consequences of STIs, including HIV.198 Adolescents with STIs, especially ulcerative diseases such as herpes simplex virus infection or syphilis, should be made aware of the association between such infections and transmission of HIV.198 Screening for STIs in both public and private clinical settings represents an important component of prevention of HIV infection among adolescents and adults.199 Injection drug use or other percutaneous exposure to HIV is another important means of acquisition of HIV infection by adolescents and adults.3 Adolescents should be informed about the dangers of injection drug use as well as precautions to decrease the risk for transmission of HIV and other bloodborne viral pathogens due to contact with blood or open wounds (e.g., during contact sports).198,200 In addition to injection drug use or other percutaneous exposures, the use of noninjection drugs (e.g., alcohol, cocaine, marijuana) is associated with an increased risk for acquisition of HIV infection due to impaired judgment associated with the use of these substances, which in turn may increase the likelihood of unsafe sexual practices.198 Efforts to reduce the risk for adolescents initiating substance abuse and to prevent acquisition of HIV infection among adolescents with a substance abuse problem should be encouraged.201 The CDC recommends at least annual testing for sexually active men who have sex with men between the ages of 13 and 64 years.202 HIV testing is treated as part of routine care, and it is performed unless the patient objects (“opts out”). General consent for medical care is considered to encompass consent for HIV testing, and no specific consent for HIV testing would be required.202 Testing for HIV infection is important in the prevention of HIV transmission because it provides the individual with knowledge of his or her HIV infection status, and, with this knowledge, most individuals reduce high-risk sexual behaviors.203 In addition, testing is the first step in linking an HIV-infected person to appropriate care and treatment. Antiretroviral therapy can be used to decrease the transmission of HIV. Lower plasma viral loads are associated with lower viral loads in genital secretions.204–207 However, the concentrations of most antiretroviral agents vary among different fluids.205–208 Associations between lower serum or genital viral loads and lower transmission rates among HIV

serodiscordant heterosexual couples have been observed.204,209,210 Ecologic studies of communities with high concentrations of injection drug users and of men who have sex with men suggest that increased use of antiretrovirals is associated with a decreased community viral load and a lower rate of new HIV infections.211–213 In a trial of HIV-discordant couples, almost all heterosexual, HIV-infected sexual partners who were antiretroviral naïve and had CD4+ counts between 350 and 550 cells/mm3 were randomized to initiate or delay antiretroviral therapy.214 Those who initiated antiretroviral therapy had a 96% decrease in transmission of HIV to uninfected partners. Suppression of viral load in blood and genital secretions with antiretroviral therapy should protect against transmission in other patient populations (e.g., men who have sex with men, injection drug users), but the effectiveness of such an intervention for groups other than heterosexual couples has not yet been established. The effectiveness of antiretroviral therapy in the prevention of transmission of HIV is predicated on the following: agents can effectively suppress viral loads in blood and genital fluids; adherence to therapy is high; and there is not a concomitant STI. Of note, when cART is available, rates of HIV risk behaviors may increase, sometimes substantially.215 Recommendations for postexposure prophylaxis in children and adolescents for nonoccupational exposure to HIV have been developed.216 If postexposure prophylaxis is used, it should be initiated as soon as possible after exposure (no later than 72 hours) and continued for 28 days. Close follow-up is necessary to monitor adherence to and toxicity related to the prophylaxis, to provide psychological support, and to complete serial HIV testing.

SUMMARY HIV infection among children and adolescents in the US disproportionately affects minorities. Effective antiretroviral treatment and other care and support for HIV-infected children and adolescents have resulted in significantly decreased morbidity and mortality. Major successes have been achieved in prevention of mother-to-child transmission of HIV, but such transmission has not been eliminated. In addition, acquisition of HIV infection among adolescents and adults continues at an alarming rate. Essential components of the care of adolescents

include HIV testing, counseling and education regarding behaviors that put them at risk for acquisition of HIV infection, and interventions to reduce that risk. All references are available online at www.expertconsult.com.

KEY REFERENCES 2. Joint United Nations Programme on HIV/AIDS (UNAIDS). AIDS by the numbers. http://www.unaids.org/sites/default/files/media_asset/AIDS-by-the-numbers-2016 _en.pdf. 17. The Breastfeeding and HIV International Transmission Study (BHITS) Group. Late postnatal transmission of HIV-1 in breastfed children: an individual patient data meta-analysis. J Infect Dis 2004;189:2154–2166. 19. The International Perinatal HIV Group. The mode of delivery and the risk of vertical transmission of human immunodeficiency virus type 1: a meta-analysis of 15 prospective cohort studies. N Engl J Med 1999;340:977–987. 44. Centers for Disease Control and Infection. Revised surveillance case definition for HIV infection—United States, 2014. MMWR Morb Mortal Wkly Rep 2014;63(RR-3):1–10. 69. Cotton MF, Violari A, Otwombe K, et al. Early time-limited antiretroviral therapy versus deferred therapy in South African infants infected with HIV: results from the children with HIV early antiretroviral (CHER) randomised trial. Lancet 2013;382:1555–1563. 70. Panel on Antiretroviral Therapy and Medical Management of HIV-Infected Children. Guidelines for the use of antiretroviral agents in pediatric HIV infection. http://aidsinfo.nih.gov/contentfiles/lvguidelines/pediatricguidelines.pdf. 74. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. http://aidsinfo.nih.gov/contentfiles/lvguidelines/ adultandadolescentgl.pdf. 105. Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission. 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. https://aidsinfo.nih.gov/contentfiles/ lvguidelines/PerinatalGL.pdf. 172. Read JS, Newell M-L. Efficacy and safety of cesarean delivery for prevention of mother-to-child transmission of HIV-1. Cochrane Database Syst Rev 2005;(4):CD005479. 185. Read JS, and the Committee on Pediatric AIDS. Human milk, breastfeeding, and transmission of human immunodeficiency virus type 1 in the United States. Pediatrics 2003;112:1196–1205.

Epidemiology and Prevention of HIV Infection in Children and Adolescents

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