Emily Barr

Continuous improvement in the immune system of HIV-infected children on prolonged antiretroviral therapy

Background: The goal of HAART is to promote reconstitution of CD4+ T cells and other immune responses. We evaluated the extent and the kinetics of immune reconstitution in HIV-infected children over 144 weeks of successful HAART. Methods: Thirty-seven children receiving their first HAART regimen had plasma HIV RNA; T cells and subpopulations; T-cell rearrangement excision circles (TREC) DNA; candida, HIVCD4 and HIVCD8 enzyme-linked immunospot measured at regular intervals. Results: Plasma HIV RNA became undetectable in 81% of patients at 24 weeks and remained undetectable in 77% at 144 weeks. In contrast, CD4+% continuously increased. Distribution of T-cell subpopulations changed rapidly during the first 48 weeks of HAART and more slowly thereafter. At 144 weeks, total, naive and activated CD4+% and naive CD8+% of HIV-infected children were not significantly different from those of healthy age-matched controls, whereas total and activated CD8+% remained elevated. CD4+ and CD8+ TREC content increased only during the first 48 weeks of HAART. They positively correlated with each other and with total CD4+%, naive CD4+% and naive CD8+%. Candida and HIVCD4 enzyme-linked immunospot increased over time reaching peak values at 48 weeks and 144 weeks, respectively. HIVCD8 enzyme-linked immunospot decreased in magnitude over 144 weeks of HAART but retained its breadth. Baseline CD4+% positively correlated with CD4+% and with functional immune reconstitution at week 144, whereas baseline TREC correlated with TREC at week 144. Conclusion: HIV-infected children acquired normal distribution of CD4+ T cells and other subpopulations and recovered CD4-mediated HIV immunity after 144 weeks of HAART.

Resistance to antiretrovirals in HIV-infected pregnant women

BACKGROUND Antiretrovirals suppress HIV replication and prevent mother-to-child-transmission of HIV (PMTCT). Resistance to antiretrovirals may reduce the efficacy of PMTCT and/or complicate treatment of maternal or infant infection. OBJECTIVES To assess resistance to antiretrovirals during pregnancy. DESIGN Retrospective chart review of 44 pregnancies. RESULTS Twenty-two patients were antiretroviral treatment-naïve, 8 were on therapy, and 14 had prior therapy, but were off medication when the genotyping was performed. Major mutations were found in 10 antiretroviral-experienced women, including 5 women with major mutations to 2 classes of drugs (none to 3 classes). Major mutations were most common for lamivudine, nevirapine, zidovudine, stavudine, and abacavir. Three women had significant resistance to zidovudine/lamivudine, a combination recommended in PMTCT guidelines. Despite significant antiretroviral resistance, 6 of 8 women with plasma HIV RNA measured within 4 weeks of delivery achieved <50 copies/mL. All neonates were uninfected. Among 6 women who received antiretrovirals exclusively for PMTCT, there were no remarkable changes of the HIV genotype before and after pregnancy. CONCLUSIONS Resistance to antiretrovirals was common in antiretroviral-experienced pregnant women, but not in naïve women. The 14% prevalence of resistance to zidovudine and lamivudine in antiretroviral-experienced women suggests that alternative NRTI are desirable for this group of patients.

Maternal Lopinavir/Ritonavir Is Associated with Fewer Adverse Events in Infants than Nelfinavir or Atazanavir

Combination antiretroviral therapy (cART) is successfully used for prevention of perinatal HIV transmission. To investigate safety, we compared adverse events (AE) among infants exposed to different maternal cART regimens. We reviewed 158 HIV-uninfected infants born between 1997 and 2009, using logistic regression to model grade ≥1 AE and grade ≥3 AE as a function of maternal cART and confounding variables (preterm, C-section, illicit drug use, race, ethnicity, infant antiretrovirals, and maternal viremia). Frequently used cART regimens included zidovudine (63%), lamivudine (80%), ritonavir-boosted lopinavir (37%), nelfinavir (26%), and atazanavir (10%). At birth, anemia occurred in 13/140 infants (9%), neutropenia in 27/107 (25%), thrombocytopenia in 5/133 (4%), and liver enzyme elevation in 21/130 (16%). Corresponding rates of AE at 4 weeks were 59/141 (42%), 54/130 (42%), 3/137 (2%), and 3/104 (3%), respectively. Serious AE (grade ≥ 3) exceeded 2% only for neutropenia (13% at birth; 9% at 4 weeks). Compared with infants exposed to maternal lopinavir/ritonavir, infants exposed to nelfinavir and atazanavir had a 5-fold and 4-fold higher incidence of AE at birth, respectively. In conclusion, hematologic and hepatic AE were frequent, but rarely serious. In this predominantly protease inhibitor-treated population, lopinavir/ritonavir was associated with the lowest rate of infant AE.

Cardiac Effects of in utero Exposure to Antiretroviral Therapy in HIV-Uninfected Children Born to HIV-Infected Mothers

Objectives:We evaluated the potential cardiac effects of in-utero exposures to antiretroviral drugs in HIV-exposed but uninfected (HEU) children. Design and methods:We compared echocardiographic parameters of left ventricular function (ejection fraction, fractional shortening, and stress–velocity index) and structure (left ventricular dimension, posterior wall/septal thickness, mass, thickness-to-dimension ratio, and wall stress) (expressed as Z-scores to account for age and body surface area) between HEU and HIV-unexposed cohorts from the Pediatric HIV/AIDS Cohort Studys Surveillance Monitoring for ART Toxicities study. Within the HEU group, we investigated the associations between the echocardiographic Z-scores and in-utero exposures to maternal antiretroviral drugs. Results:There were no significant differences in echocardiographic Z-scores between 417 HEU and 98 HIV-unexposed children aged 2–7 years. Restricting the analysis to HEU children, first-trimester exposures to combination antiretroviral therapy (a regimen including at least three antiretroviral drugs) and to certain specific antiretroviral drugs were associated with significantly lower stress–velocity Z-scores (mean decreases of 0.22–0.40 SDs). Exposure to combination antiretroviral therapy was also associated with lower left ventricular dimension Z-scores (mean decrease of 0.44 SD). First-trimester exposure to combination antiretroviral therapy was associated with higher mean left ventricular posterior wall thickness and lower mean left ventricular wall stress Z-scores. Conclusion:There was no evidence of significant cardiac toxicity of perinatal combination antiretroviral therapy exposure in HEU children. Subclinical differences in left ventricular structure and function with specific in-utero antiretroviral exposures indicate the need for a longitudinal cardiac study in HEU children to assess long-term cardiac risk and cardiac monitoring recommendations.

Safety and Tolerability of Antiretrovirals during Pregnancy

Combination antiretroviral therapy (CART) dramatically decreases mother-to-child HIV-1 transmission (MTCT), but maternal adverse events are not infrequent. A review of 117 locally followed pregnancies revealed 7 grade ≥ 3 AEs possibly related to antiretrovirals, including 2 hematologic, 3 hepatic, and 2 obstetric cholestasis cases. A fetal demise was attributed to obstetric cholestasis, but no maternal deaths occurred. The drugs possibly associated with these AE were zidovudine, nelfinavir, lopinavir/ritonavir, and indinavir. AE or intolerability required discontinuation/substitution of nevirapine in 16% of the users, zidovudine in 10%, nelfinavir in 9%, lopinavir/ritonavir in 1%, but epivir and stavudine in none. In conclusion, nevirapine, zidovudine, and nelfinavir had the highest frequency of AE and/or the lowest tolerability during pregnancy. Although nevirapine and nelfinavir are infrequently used in pregnancy at present, zidovudine is included in most MTCT preventative regimens. Our data emphasize the need to revise the treatment recommendations for pregnant women to include safer and better-tolerated drugs.

Kinetics and determining factors of the virologic response to antiretrovirals during pregnancy.

HIV-infected pregnant women with undetectable plasma HIV RNA concentrations at delivery pose a minimal risk of vertical transmission. We studied the kinetics and the determinants of the virologic response to antiretroviral therapy in 117 consecutive pregnancies. Patients who initiated therapy during pregnancy had a VL decrease of 2 and 2.5 log10 after 4 and 24 weeks, respectively. Therapeutic drug monitoring (TDM) of the protease inhibitors administered in doses recommended for nonpregnant adults resulted in below-target concentrations in 29%, 35%, and 44% of 1st, 2nd, and 3rd trimester measurements, respectively, but low drug concentrations did not correlate with virologic failure. Demographic characteristics, antiretroviral experience prior to pregnancy, baseline VL, or use of specific antiretrovirals did not affect the virologic response. Adherence to ≥95% of prescribed doses and utilization of psychosocial services were associated with undetectable plasma HIV RNA at delivery. In conclusion, the virologic responses of pregnant and nonpregnant adults share similar charactersitics.

Nevirapine- Versus Lopinavir/Ritonavir-Based Antiretroviral Therapy in HIV-Infected Infants and Young Children: Long-term Follow-up of the IMPAACT P1060 Randomized Trial

BACKGROUND The International Maternal Pediatric Adolescent AIDS Clinical Trials Network (IMPAACT) P1060 study demonstrated short-term superiority of lopinavir/ritonavir (LPV/r) over nevirapine (NVP) in antiretroviral therapy (ART), regardless of prior NVP exposure. However, NVP-based ART had a marginal benefit in CD4 percentage (CD4%) and growth. We compared 5-year outcomes from this clinical trial. METHODS Human immunodeficiency virus (HIV)-infected, ART-eligible children were enrolled into 2 cohorts based on prior NVP exposure and randomized to NVP- or LPV/r-based ART. The data safety monitoring board recommended unblinding results in both cohorts due to superiority of LPV/r for the primary endpoint: stopping randomized treatment, virologic failure (VF), or death by 6 months. Participants were offered a switch in regimens (if on NVP) and continued observational follow-up. We compared time to VF or death, death, and CD4% and growth changes using intention-to-treat analyses. Additionally, inverse probability weights were used to account for treatment switching and censoring. RESULTS As of September 2014, 329 of the 451 (73%) enrolled participants were still in follow-up (median, 5.3 years; interquartile range [IQR], 4.3-6.4), with 52% on NVP and 88% on LPV/r as originally randomized. NVP arm participants had significantly higher risk of VF or death (adjusted hazard ratio [aHR], 1.90; 95% confidence interval [CI], 1.37-2.65) but not death alone (aHR, 1.65; 95% CI, .72-3.76) compared with participants randomized to LPV/r. Mean CD4% was significantly higher in the NVP arm up to 1 year after ART initiation, but not beyond. Mean weight-for-age z scores were marginally higher in the NVP arm, but height-for-age z scores did not differ. Similar trends were observed in sensitivity analyses. CONCLUSIONS These findings support the current World Health Organization recommendation of LPV/r in first-line ART regimens for HIV-infected children. CLINICAL TRIALS REGISTRATION NCT00307151.

Serious adverse events are uncommon with combination neonatal antiretroviral prophylaxis: a retrospective case review

Six weeks of zidovudine (ZDV) is recommended for postnatal prophylaxis of HIV-exposed infants, but combination antiretrovirals are indicated if HIV transmission risk is increased. We investigated the frequency and severity of adverse events (AE) in infants receiving multiple drug prophylaxis compared to ZDV alone. In this retrospective review of 148 HIV-exposed uninfected infants born between 1997–2009, we determined clinical and laboratory AE that occurred between days of life 8–42. Thirty-six infants received combination prophylaxis; among those, a three-drug regimen containing ZDV, lamivudine, and nevirapine was most common (53%). Rates of laboratory AE grade ≥1 were as follows for the combination prophylaxis and ZDV alone groups, respectively: neutropenia 55% and 39%; anemia 50% and 39%; thrombocytopenia 0 and 3%; elevated aspartate aminotransferase 3% and 3%; elevated alanine aminotransferase 0 and 1%; hyperbilirubinemia 19% and 42%. Anemia occurred more frequently in infants who received three-drug prophylaxis compared to infants who received ZDV alone (63% vs. 39%, p = 0.04); all anemia AE were grade 1 or 2 in the three-drug prophylaxis group. Overall, 75% of infants on combination prophylaxis and 66% of infants on ZDV alone developed grade ≥1 AE (p = 0.32), and 17% of infants in either group developed grade ≥3 AE. Stavudine was substituted for ZDV in 23 infants due to anemia or neutropenia. After this antiretroviral change, 50% of evaluable infants demonstrated improvement in AE grade, and 25% had no change. In conclusion, low grade anemia, neutropenia, and hyperbilirubinemia occurred frequently regardless of the prophylactic regimen, but serious AE were uncommon. Although most AE were typical of ZDV toxicity, the combination of ZDV with lamivudine and nevirapine resulted in an increased frequency of low-grade anemia. Further studies are needed to identify prophylactic regimens with less toxicity for infants born to HIV-infected mothers.

Health Outcomes of International HIV-infected Adoptees in the US.

Background: International adoption of HIV-infected children is becoming increasingly common. Their health has not yet been described. Methods: HIV-infected international adoptees or refugees in foster care aged 0–20 years followed at Seattle Children’s Hospital or Children’s Hospital Colorado between January 1, 2004 and May 31, 2013 were included. Parameters were collected through retrospective chart review of baseline (first 6 months at study site) and annual follow-up visits. Results: Africa (90%) was the primary region of origin for the 79 children who met inclusion criteria. Median follow-up was 3 years (range: 0–7). At baseline, acute malnutrition was uncommon (8%); however, stunting occurred in 32%. Most stunting resolved during the study period. The most common medical issues at baseline were dermatologic (Tinea and Molluscum contagiosum) and gastrointestinal (parasites and diarrhea). Almost half (48%) had either mental health issues or behavioral problems. Educational delays (50%) were also common. Upon adoption, only 1% was severely (CD4% < 15%) immunosuppressed. Fifty-nine (75%) were on antiretroviral therapy (ART); 45 of these (76%) had suppressed viral load (VL). Of 14 children on ART with detectable VL, 11 (79%) demonstrated non-nucleoside reverse transcriptase inhibitor resistance and 1 (7%) protease inhibitor resistance. Conclusions: In this cohort of HIV-infected international adoptees, severe immunosuppression was uncommon. Most medical issues were mild. Stunting was common at baseline but largely resolved. Mental health issues, behavioral problems, and educational delays were common. Most children were on ART at adoption and most of these showed suppressed VL. Non-nucleoside reverse transcriptase inhibitor mutations were present in most viremic children.

Human Immunodeficiency Virus Type 1 DNA Decay Dynamics With Early, Long-term Virologic Control of Perinatal Infection

Background. Early antiretroviral therapy (ART) limits proviral reservoirs, a goal for human immunodeficiency virus type 1 (HIV-1) remission strategies. Whether this is an immediate or long-term effect of virologic suppression (VS) in perinatal infection is unknown. Methods. We quantified HIV-1 DNA longitudinally for up to 14 years in peripheral blood mononuclear cells (PBMCs) among 61 perinatally HIV-1-infected youths in the Pediatric HIV/AIDS Cohort Study who achieved VS at different ages. Participants in group 1 (n = 13) were <1 year of age and in group 2 (n = 48) from 1 through 5 years of age at VS. Piecewise linear mixed-effects regression models assessed the effect of age at VS on HIV-1 DNA trajectories during VS. Results. In the first 2 years following VS, HIV-1 DNA levels decreased by -0.25 (95% confidence interval [CI], -.36 to -.13) log10 copies/million PBMCs per year and was faster with early VS by age 1 year compared with after age 1 (-0.50 and -0.15 log10 copies/million PBMCs per year, respectively). Between years 2 and 14 from VS, HIV-1 DNA decayed by -0.05 (95% CI, -.06 to -.03) log10 copies/million PBMCs per year and was no longer significantly different between groups. The estimated mean half-life of HIV-1 DNA from VS was 15.9 years and was shorter for group 1 compared to group 2 at 5.9 years and 18.8 years, respectively (P = .09). Adjusting for CD4 cell counts had no effect on decay estimates. Conclusions. Early effective, long-term ART initiated from infancy leads to decay of HIV-1-infected cells to exceedingly low concentrations desired for HIV-1 remission strategies.