Where Have All the "AIDS Babies" Gone? A Historical Memoir of the Pediatric AIDS Epidemic in New Haven and its Eventual Eradication.

S.L. was one of our first HIV-positive babies. He was born at Yale-New Haven Hospital (YNHH) in 1982. His mother was a sex worker who also injected drugs. He died at 3½ years following multiple episodes of opportunistic infection and metastatic lymphoma. In the years between 1986 and 1990, 163 HIV-positive mothers gave birth at YNHH. The mother-to-child transmission (MTCT) rate was 20 percent. Women represented 8 percent of all HIV cases in the US compared with 29 percent in New Haven. We had a six times greater proportion of children living with HIV. The mean number of HIV-exposed babies rose annually from 26 (1985-87) to 37 (1988-90). Our first team of caregivers comprised a nurse practitioner, a social worker, and me. We were, in time, joined by a growing number of colleagues. Enlightened and generous hospital administrators provided us with outpatient space and the promise of continued funding to support additional staff and in 1987, an independent Pediatric AIDS Care Program. We implemented the proven MTCT prevention guidelines articulated in the Pediatric AIDS Clinical Trials Group (PACTG) protocol 076 and by 1995, the MTCT rate at YNHH fell to 9 percent. Since 1996, the MTCT rate at YNHH has been zero percent. Combination antiretroviral therapy, cART, made its debut in the mid-1990s; five classes of drugs with multiple agents in each were licensed between 2003 and 2013. We designed individual treatment plans for each child and gradually entered an era when our clinic was populated with healthier long-term survivors. Our Program flourished, based on a multidisciplinary approach which honored interprofessional collaboration.

Seroepidemiology of WU polyomavirus among children exposed perinatally to HIV-1.

WU polyomavirus (WUPyV), a new member of the genus wukipolyomavirus in the family Polyomaviridae, has been detected in serum and tissues of individuals infected with HIV. However, the epidemiology of WUPyV among children exposed perinatally to HIV-1 is unknown. To investigate the epidemiology of WUPyV in children exposed to and infected perinatally with HIV, serum samples from 150 children exposed to HIV and 114 children infected with HIV were screened for IgG antibodies to WUPyV. A subset was screened for IgM antibodies to WUPyV. Both antibody detection assays were performed using a recombinant WUPyV VP1-based ELISA. The overall seroprevalence of WUPyV IgG was 76.3% in children infected with HIV and 62% in children exposed perinatally to HIV. In the group of children infected with HIV, the prevalence of WUPyV IgG antibody reached its peak in 2-3 year olds (90.9%). In children 0-5 months of age, IgG seroprevalence was lower in those children exposed to HIV compared to children infected with HIV (43.1% vs.75%, P = 0.047). However, the seroprevalence of WUPyV IgM antibody was higher in children exposed to HIV compared to infants infected with HIV (27.4% vs. 8.3%, P = 0.044). WUPyV infection is acquired in early childhood in the majority of children born to mothers infected with HIV. The implication of this infection and the specific clinical syndrome that it produces, if any, remain to be defined.

Chronic kidney disease associated with perinatal HIV infection in children and adolescents.

BACKGROUND: This study describes the incidence, clinical and demographic characteristics, and spectrum of chronic kidney disease (CKD) in youths with perinatal HIV-1 infection. METHODS: Retrospective analysis between May 1993 and December 2006 of subjects with renal disease followed in the Pediatric AIDS Clinical Trials Group 219/219C multicenter study examining the long-term consequences of perinatal HIV infection. Diagnosis confirmation was made utilizing a questionnaire mailed to research sites. Participants with CKD of other etiology than HIV were excluded. Outcome measures were biopsy-diagnosed CKD and, in the absence of biopsy, HIV-associated nephropathy (HIVAN) using established clinical criteria. RESULTS: Questionnaires on 191 out of 2,102 participants identified 27 cases of CKD: 14 biopsy-diagnosed and 6 clinical cases of HIVAN, and 7 biopsy-diagnosed cases of immune complex-mediated kidney disease (lupus-like nephritis, 3; IgA nephropathy, 2; membranous nephropathy, 2). Incidence rates for CKD associated with HIV in pre-highly active antiretroviral therapy (HAART) (1993-1997) and HAART (1998-2002, 2003-2006) eras were 0.43, 2.84, and 2.79 events per 1,000 person years respectively. In multivariate analysis, black race and viral load ≥100,000 copies/mL (rate ratios 3.28 and 5.05, p ≤ 0.02) were associated with CKD. CONCLUSIONS: A variety of immune complex-mediated glomerulonephritides and HIVAN occurs in this population. Black race and uncontrolled viral replication are risk factors for CKD associated with HIV.

Update on successes and challenges regarding mother-to-child transmission of HIV.

PURPOSE OF REVIEW: There is an unprecedented global commitment to reverse the pediatric HIV epidemic by making prevention of mother-to-child transmission (PMTCT) services accessible in all countries. This review outlines the successes made and the challenges that remain. RECENT FINDINGS: In resource-rich countries, mother-to-child transmission rates of HIV as low as 1% have been achieved. The efficacy of short-course antiretrovirals for PMTCT in Africa is estimated at 50%. Coinfections with herpes simplex virus type 2, other sexually transmitted infections resulting in genital ulcers, and endemic infectious diseases (e.g., malaria) may increase the risk of mother-to-child transmission of HIV. Vertical transmission of drug-resistant viruses has been reported; the prevalence and effect of transmitted resistant virus on treatment outcomes are under investigation. Obstacles facing PMTCT in resource-limited countries include the lack of healthcare infrastructure, limited manpower, and competing public health priorities with the limited healthcare budget. SUMMARY: Although the birth of an HIV-infected child in a resource-rich country is now a sentinel health event, in most resource-limited countries the birth of an HIV-infected child continues to be the status quo. Comprehensive PMTCT, including antiretroviral treatment for HIV-infected women and children, should be paramount in resource-limited countries.

We never thought this would happen: transitioning care of adolescents with perinatally acquired HIV infection from pediatrics to internal medicine.

PURPOSE: Transitioning the medical care of children with perinatally acquired HIV from pediatric care to internal medicine practices has become increasingly important as newer therapies prolong survival. The study aims to describe challenges to caring for these adolescents and the potential barriers to transitioning them to internal medicine-based care. METHODS: Qualitative study in which data were gathered from open-ended interviews conducted from November 2005 to April 2006 with 18 adolescents with HIV, 15 of their parents, and 9 pediatric health care providers from the Yale Pediatric AIDS Care Program, New Haven, Connecticut. RESULTS: Issues of stigma played a prominent role in both the challenges to care and barriers to transitioning care. Challenges to care were: (1) poor adherence to medication regimens; (2) adolescent sexuality; and (3) disorganized social environments. Potential barriers to transitioning care were: (1) families' negative perceptions of and experiences with stigma of HIV disease - which undermined the desire to meet new providers; (2) perceived and actual lack of autonomy - pediatric providers feared that staff in adult clinics would demand a level of independence that adolescents did not have; and (3) difficulty letting go of relationships - adolescents, guardians, and providers described a familial relationship and expressed anxiety about terminating their relationships. CONCLUSION: Understanding these challenges and barriers can inform both pediatric and adult HIV care providers and enable them to create successful transition programs, with the goal of improving retention and follow-up to care.

Absolute CD4+ T-lymphocyte count as a surrogate marker of pediatric human immunodeficiency virus disease progression.

BACKGROUND: Traditionally in pediatric HIV, the CD4+ T-lymphocyte percent is used to monitor disease progression because of the variability in absolute CD4+ T-lymphocyte numbers. Because of the high cost of equipment, sophisticated and delicate technology, most laboratories in resource-limited settings use simple protocols that enumerate only the absolute CD4+ T-lymphocyte counts. We assessed the use of absolute CD4+ T-lymphocyte count as a surrogate marker of pediatric HIV disease progression. METHODS: We analyzed the CD4+ T-lymphocytes and HIV viral load over a 10-year period (1996-2006) of 97 HIV-infected children enrolled in the Yale Prospective Longitudinal Pediatric HIV Cohort using generalized linear mixed models. Both CD4+ T-lymphocytes and HIV viral load were assessed at baseline and every 2-3 months. The modeling approach used in this study allows the intercept and the rate at which outcome variables change over time to vary across participants. RESULTS: We determined that absolute CD4+ T-lymphocytes count was just as reliable at monitoring pediatric HIV as CD4+ T-lymphocyte percentage. Antiretroviral treatment, regardless of the regimen used, was associated with higher CD+ T-lymphocytes count (P < 0.01). Race was significantly associated with CD4+ T-lymphocytes counts (with lower values for blacks compared with nonblacks; P < 0.01). The presence of other infections was associated with lower CD4+ T-lymphocyte count (P = 0.01) and higher viral load (P < 0.01), respectively. CONCLUSIONS: In situations where determination of CD4+ T-lymphocyte percentages is not readily available, the absolute count may provide an affordable and accessible laboratory surrogate marker of HIV disease progression in children.

Care and management of the infant of the HIV-1-infected mother.

Mother-to-child transmission of the human immunodeficiency virus continues to be a major global health problem. The pediatric HIV-1 epidemic is fueled by HIV-1 infection in women of childbearing age with vertical transmission in utero or at the time of birth. In resource-rich countries, the birth of an infected child is a sentinel health event signaling a chain of missed opportunities and barriers to prevention. Because the fate and ultimate HIV-infection status of the baby is inextricably linked to the infection status of the mother and her general state of well-being, we provide in this review: 1) background and state-of-the-art management guidelines for optimum maternal care; 2) strategies to minimize the risk of vertical transmission of HIV; and 3) recommendations for managing infants born to HIV-infected women. These are discussed under four case scenarios that obstetric and pediatric providers frequently encounter in their practices.

Virologic and host characteristics of human immunodeficiency virus type 1-infected pediatric long term survivors.

BACKGROUND: There are limited data concerning determinants of varying clinical progression rates in human immunodeficiency virus type 1 (HIV-1)-infected children. Therefore, we sought to determine whether viral or host factors associated with nonprogressive HIV-1 infection in adults play a role in limiting progression of infection in 5 vertically infected youths, ages 12-18 years, who have displayed no signs of advanced HIV-1 disease or acquired immunodeficiency syndrome despite having received minimal treatment with antiretroviral drugs. RESULTS: The 5 individuals, whom we characterize as long term survivors, have maintained low loads of HIV-1 RNA in plasma when compared to many of their peers, and have also maintained normal and stable CD4 T-lymphocyte numbers and percentages throughout their lives. Determination of their predominant HIV-1 sequences revealed that 4 of 5 patients harbor virus with markers of resistance to their therapy (one was never treated). Furthermore 2 harbored viral isolates that contained insertions in Gag or Vif that inhibit HIV-1 replication. Moreover, 2 were found to be heterozygous for the CCR2 polymorphism 64I, a genotype associated with slower progression to acquired immunodeficiency syndrome in adults. All 5 expressed the histocompatibility leukocyte antigen DQ1 and 2 had unusual DR/DQ1 phenotypes. CONCLUSIONS: We believe that the limited antiretroviral therapy received by the long term survivors cannot solely account for their benign clinical status. Therefore, we conclude that other factors, including gene polymorphisms that affect viral replicative capacity, account for the long term survival in some, and deduce that, as in adults, no single factor (virologic or host) can account for this clinical phenotype in all cases.

Increased replication of non-syncytium-inducing HIV type 1 isolates in monocyte-derived macrophages is linked to advanced disease in infected children.

Non-syncytium-inducing (NSI) strains of HIV-1 prevail among most infected children, including pediatric patients who develop advanced disease, severe immune suppression, and die. A study was designed to address the hypothesis that genotypic and/or phenotypic markers can distinguish NSI viruses isolated during early infection from NSI viruses found in advanced disease. Primary HIV-1 isolates, which were obtained from 43 children, adolescents, and adults who displayed a cross-section of clinical disease and immune suppression but were untreated by protease inhibitor antiretroviral therapy, were characterized for replication phenotype in different cell types. Most individuals (81%) harbored NSI viruses and almost half had progressed to advanced disease or severe immune deficiency. About 51% of NSI isolates produced low levels of p24 antigen (median, 142 pg/ml) in monocyte-derived macrophages (MDMs), 31% produced medium levels (median, 1584 pg/ml), and 17% produced high levels (median, 81,548 pg/ml) (p < 0.001). Seven of eight syncytium-inducing isolates also replicated in MDMs and displayed a dual-tropic phenotype that was associated with advanced disease. Replication of NSI viruses in MDMs varied as much as 100- to 1000-fold and was independent of replication in peripheral blood mononuclear cells. Replication in MDMs provided a clear biological feature to distinguish among viruses that were otherwise identical by NSI phenotype, V3 genotype, and CCR5 coreceptor usage. Low-level MDM replication was characteristic of viruses isolated from asymptomatic individuals, including long-term survivors. Enhanced MDM replication was related to morbidity and mortality among patients. Replication levels in MDMs provide a novel prognostic indicator of pathogenic potential by NSI viruses.

Incidence of persistent renal dysfunction in human immunodeficiency virus-infected children: associations with the use of antiretrovirals, and other nephrotoxic medications and risk factors.

BACKGROUND: Survival of HIV-infected children continues to increase and the use of antiretrovirals (ARVs) is expanding; however there are few data regarding the incidence of renal dysfunction and associated risk factors among HIV-infected children and youth. METHODS: A total of 2102 children enrolled in Pediatric AIDS Clinical Trials Group Study 219/219C, were followed and assessed prospectively for >30 months. Occurrence of clinical events and laboratory abnormalities were recorded using standardized criteria and forms. Therapeutic decisions were made by clinicians at each site. Occurrence of persistent renal laboratory abnormalities was the main outcome measure. RESULTS: Four hundred forty-six (22%) enrollees exhibited at least one persistent renal laboratory abnormality. Elevated serum creatinine (Cr) was more common than persistent proteinuria (15% vs. 8%). The incidence of new renal laboratory abnormalities was 3.7 events per 100 person-years with rates increasing between 1993 and 2005. Older age (>or=6 years vs. <6 years), Hispanic ethnicity, and Black non-Hispanic race were associated with increased risk of renal dysfunction, but CDC clinical class and plasma HIV RNA levels were not. Subjects exposed to ARV regimens containing tenofovir and/or indinavir had approximately twice the risk of developing renal dysfunction compared with persons exposed to other ARVs. The risk of renal dysfunction was also elevated for other antivirals (hazard ratio = 5.4) and amphotericin B (hazard ratio = 28). CONCLUSIONS: Persistent renal function abnormalities occur frequently in HIV-infected children. Improved survival, Black race and Hispanic ethnicity, and exposure to tenofovir, indinavir, and other antimicrobial agents increase the risk for renal dysfunction. All HIV-infected children should be monitored closely for evidence of renal disease.

Complex determinants in human immunodeficiency virus type 1 envelope gp120 mediate CXCR4-dependent infection of macrophages.

Host cell range, or tropism, combined with coreceptor usage defines viral phenotypes as macrophage tropic using CCR5 (M-R5), T-cell-line tropic using CXCR4 (T-X4), or dually lymphocyte and macrophage tropic using CXCR4 alone or in combination with CCR5 (D-X4 or D-R5X4). Although envelope gp120 V3 is necessary and sufficient for M-R5 and T-X4 phenotypes, the clarity of V3 as a dominant phenotypic determinant diminishes in the case of dualtropic viruses. We evaluated D-X4 phenotype, pathogenesis, and emergence of D-X4 viruses in vivo and mapped genetic determinants in gp120 that mediate use of CXCR4 on macrophages ex vivo. Viral quasispecies with D-X4 phenotypes were associated significantly with advanced CD4+-T-cell attrition and commingled with M-R5 or T-X4 viruses in postmortem thymic tissue and peripheral blood. A D-X4 phenotype required complex discontinuous genetic determinants in gp120, including charged and uncharged amino acids in V3, the V5 hypervariable domain, and novel V1/V2 regions distinct from prototypic M-R5 or T-X4 viruses. The D-X4 phenotype was associated with efficient use of CXCR4 and CD4 for fusion and entry but unrelated to levels of virion-associated gp120, indicating that gp120 conformation contributes to cell-specific tropism. The D-X4 phenotype describes a complex and heterogeneous class of envelopes that accumulate multiple amino acid changes along an evolutionary continuum. Unique gp120 determinants required for the use of CXCR4 on macrophages, in contrast to cells of lymphocytic lineage, can provide targets for development of novel strategies to block emergence of X4 quasispecies of human immunodeficiency virus type 1.

Transmission of HIV-1 from mother to infant.

In the developed world, antiretroviral therapy (ART) administered to the mother during pregnancy and intrapartum and to the infant in the neonatal period has resulted in a reduction of the overall risk of vertical transmission of HIV-1 to approximately 8%. In some settings, ART combined with cesarean section and a reduction in duration of ruptured membranes has resulted in a further lessening of risk to levels < or = 2 percent. A number of less expensive and greatly abbreviated ART regimens, useful for application in resource poor settings, also have resulted in reductions of mother-to-infant transmission of HIV-1 by 33 to 50% compared to baseline. A multitude of studies have shown these drugs to be safe for mothers, fetuses, and newborns. Breastfeeding seems to represent a risk factor that adds to the risk of vertical transmission, especially in infants who are fed a combination of breastmilk and other liquids and solids. Studies designed to assess the possible benefits of treating genital ulcer disease, chorioamnionitis, mastitis, and malnutrition in HIV-infected women, and of applying antiseptic washes to the cervix and vagina during labor, are in progress.

Inhibition of human immunodeficiency virus type 1 (HIV-1) replication by a two-amino-acid insertion in HIV-1 Vif from a nonprogressing mother and child.

We studied a 15-year-old girl, patient X, who has maintained consistently low plasma loads of human immunodeficiency virus type 1 (HIV-1) RNA, as well as normal and stable CD4(+) T-cell concentrations. She has presented no clinical manifestations of AIDS, despite having only received zidovudine monotherapy for a part of her life. Patient X's HIV-positive mother (patient Y) has also not progressed to AIDS and has never been treated with antiretroviral agents. HIV-1 isolated from patient X replicated poorly in human peripheral blood mononuclear cells (PBMC). In order to map the determinant of the poor growth of patient X's isolate, viral sequences from patient X were determined and examined for insertion or deletion mutations. These sequences contained a two-amino-acid insertion mutation in the Vif gene, which was also observed in uncultured PBMC acquired at different times. Furthermore, Vif sequences harbored by patient Y contained the identical mutation. These observations suggest that polymorphic HIV-1 was transmitted to patient X perinatally 15 years previously and has been maintained since that time. Recombinant HIV-1, engineered with Vif sequences from patient X, replicated in PBMC to levels approximately 20-fold lower than that of wild type. Removal of the insertion mutation from this recombinant restored replication efficiency to wild-type levels, while introduction of the insertion mutation into wild-type Vif sequences resulted in greatly decreased replication. Furthermore, Vif protein from patient X's HIV-1 was aberrantly cleaved, suggesting a mechanism for loss of Vif function. Since HIV-1 containing these sequences replicates poorly, the implication is that the two-amino-acid insertion mutation in Vif contributes significantly to the nonprogressor status of this mother and child. Further studies of these sequences might provide information regarding contributions of Vif structure and/or function to HIV-1 virulence.