High mortality in HIV-infected children diagnosed in hospital underscores need for faster diagnostic turnaround time in prevention of mother-to-child transmission of HIV (PMTCT) programs.

BACKGROUND: Despite expanded programs for prevention of mother-to-child HIV transmission (PMTCT), HIV-infected infants may not be diagnosed until they are ill. Comparing HIV prevalence and outcomes in infants diagnosed in PMTCT programs to those in hospital settings may improve pediatric HIV diagnosis strategies. METHODS: HIV-exposed infants <12 months old were recruited from 9 PMTCT sites in public maternal child health (MCH) clinics or from an inpatient setting in Nairobi, Kenya and tested for HIV using HIV DNA assays. A subset of HIV-infected infants <4.5 months of age was enrolled in a research study and followed for 2 years. HIV prevalence, number needed to test, infant age at testing, and turnaround time for tests were compared between PMTCT programs and hospital sites. Among the enrolled cohort, baseline characteristics, survival, and timing of antiretroviral therapy (ART) initiation were compared between infants diagnosed in PMTCT programs versus hospital. RESULTS: Among 1,923 HIV-exposed infants, HIV prevalence was higher among infants tested in hospital than PMTCT early infant diagnosis (EID) sites (41% vs. 11%, p < 0.001); the number of HIV-exposed infants needed to test to diagnose one infection was 2.4 in the hospital vs. 9.1 in PMTCT. Receipt of HIV test results was faster among hospitalized infants (7 vs. 25 days, p < 0.001). Infants diagnosed in hospital were older at the time of testing than PMTCT diagnosed infants (5.0 vs. 1.6 months, respectively, p < 0.001). In the subset of 99 HIV-infected infants <4.5 months old followed longitudinally, hospital-diagnosed infants did not differ from PMTCT-diagnosed infants in time to ART initiation; however, hospital-diagnosed infants were >3 times as likely to die (HR = 3.1, 95% CI = 1.3-7.6). CONCLUSIONS: Among HIV-exposed infants, hospital-based testing was more likely to detect an HIV-infected infant than PMTCT testing. Because young symptomatic infants diagnosed with HIV during hospitalization have very high mortality, every effort should be made to diagnose HIV infections before symptom onset. Systems to expedite turnaround time at PMTCT EID sites and to routinize inpatient pediatric HIV testing are necessary to improve pediatric HIV outcomes.

Correlates of age at attainment of developmental milestones in HIV-infected infants receiving early antiretroviral therapy.

BACKGROUND: Infant HIV-1 infection is associated with impaired neurologic and motor development. Antiretroviral therapy (ART) has the potential to improve developmental outcomes but the relative contributions of pre-ART disease status, growth, treatment regimen and ART response during infancy are unknown. METHODS: Kenyan ART-naive infants <5-months old initiated ART and had monthly assessment of age of full neck control, unsupported walking and monosyllabic speech during 24 months of follow-up. Pre-ART and post-ART correlates of age at milestone attainment were evaluated using t tests or multivariate linear regression. RESULTS: Among 99 infants, pre-ART correlates of later milestone attainment included: underweight and stunted (neck control, walking and speech, all P values <0.05), missed prevention of mother-to-child transmission (P = 0.04) (neck control), previous hospitalization, World Health Organization (WHO) Stage III/IV, low CD4 count, and wasting (speech and walking, all P values <0.05), and low maternal CD4 (speech, P = 0.04). Infants initiated ART at a median of 14 days following enrollment. Infants receiving nevirapinevs lopinavir/ritonavir-based ART attained later speech (18.1 vs. 15.5 months, P = 0.003) [corrected]. Adjusting for pre-ART level, lower 6-month gain in CD4% was associated with later walking (0.18 months earlier per unit increase in CD4%; P = 0.004) and speech (0.12 months earlier per unit increase in CD4%; P = 0.05), and lower 6-month gains in weight-for-age (P = 0.009), height-for-age (P = 0.03) and weight-for-height (P = 0.02) were associated with later walking. CONCLUSION: In HIV-infected infants, compromised pre-ART immune and growth status, poor post-ART immune and growth responses, and use of nevirapine- vs. lopinavir/ritonavir-based ART were each associated with later milestone attainment [corrected]. The long-term consequences of these delays are unknown.

Lipid changes in Kenyan HIV-1-infected infants initiating highly active antiretroviral therapy by 1 year of age.

BACKGROUND: Early highly active antiretroviral therapy (HAART) is recommended for HIV-1-infected infants. There are limited data on lipid changes during infant HAART. METHODS: Nonfasting total (TC), low density lipoprotein (LDL) and high density lipoprotein (HDL) cholesterol and triglycerides (TG) were measured at 0, 6 and 12 months. Correlates of lipid levels and changes post-HAART were assessed using linear regression. RESULTS: Among 115 infants, pre-HAART median age was 3.8 months, CD4% was 19% and weight-for-age Z score was -2.42. Pre-HAART median lipid levels were: TC, 108.7 mg/dL; LDL, 42.5 mg/dL; HDL, 29.4 mg/dL and TG, 186.9 mg/dL. Few infants had abnormally high TC (6.2%) or LDL (5.6%), but many had low HDL (76.5%) or high TG (69.6%). Higher pre-HAART weight-for-age and height-for-age Z scores were each associated with higher pre-HAART TC (P = 0.04 and P = 0.01) and LDL (P = 0.02 and P = 0.008). From 0 to 6 months post-HAART, TC (P < 0.0001), LDL (P < 0.0001) and HDL (P < 0.0001) increased significantly, and 23.1% (P = 0.002), 14.0% (P = 0.2), 31.3% (P < 0.0001) and 50.8% (P = 0.2) of infants had abnormally high TC, high LDL, low HDL and high TG, respectively. Changes in TC and HDL were each associated with higher gain in weight-for-age Z score (P = 0.03 and P = 0.01) and height-for-age Z score (P = 0.01 and P = 0.007). Increased change in LDL was associated with higher gain in height-for-age Z score (P = 0.03). Infants on protease inhibitor-HAART had smaller HDL increase (P = 0.004). CONCLUSIONS: Infants had substantive increases in lipids, which correlated with growth. Increases in HDL were attenuated by protease inhibitor-HAART. It is important to determine clinical implications of these changes.

An increasing proportion of monotypic HIV-1 DNA sequences during antiretroviral treatment suggests proliferation of HIV-infected cells.

Understanding how HIV-1 persists during effective antiretroviral therapy (ART) should inform strategies to cure HIV-1 infection. We hypothesize that proliferation of HIV-1-infected cells contributes to persistence of HIV-1 infection during suppressive ART. This predicts that identical or monotypic HIV-1 DNA sequences will increase over time during ART. We analyzed 1,656 env and pol sequences generated following single-genome amplification from the blood and sputum of six individuals during long-term suppressive ART. The median proportion of monotypic sequences increased from 25.0% prior to ART to 43.2% after a median of 9.8 years of suppressive ART. The proportion of monotypic sequences was estimated to increase 3.3% per year (95% confidence interval, 2.3 to 4.4%; P < 0.001). Drug resistance mutations were not more common in the monotypic sequences, arguing against viral replication during times with lower antiretroviral concentrations. Bioinformatic analysis found equivalent genetic distances of monotypic and nonmonotypic sequences from the predicted founder virus sequence, suggesting that the relative increase in monotypic variants over time is not due to selective survival of cells with viruses from the time of acute infection or from just prior to ART initiation. Furthermore, while the total HIV-1 DNA load decreased during ART, the calculated concentration of monotypic sequences was stable in children, despite growth over nearly a decade of observation, consistent with proliferation of infected CD4(+) T cells and slower decay of monotypic sequences. Our findings suggest that proliferation of cells with proviruses is a likely mechanism of HIV-1 DNA persistence, which should be considered when designing strategies to eradicate HIV-1 infection.

Survival benefit of early infant antiretroviral therapy is compromised when diagnosis is delayed.

Late presentation is common among African HIV-1-infected infants. Incidence and correlates of mortality were examined in 99 infants with HIV-1 diagnosis by 5 months of age. Twelve-month survival was 66.8% (95% confidence interval: 55.9-75.6%). World Health Organization stage 3 or 4, underweight, wasting, microcephaly, low hemoglobin, pneumonia and gastroenteritis predicted mortality. Early HIV-1 diagnosis with antiretroviral therapy before symptomatic disease is critical for infant survival.

HTLV-2 infection in injection drug users in King County, Washington.

Human T-cell lymphotropic virus type 2 (HTLV-2) is endemic in injection drug users (IDU), and native American populations in the Americas. Transmission is associated with high-risk injection and sexual practices. A cohort of 2561 IDU in King County, Washington completed 2 study visits over 1 y. HTLV-2 infection was detected in 190 (7.4%) of 2561 IDU, and 13 (7.8 cases per 1000 person-y) incident infections occurred during the study. Prevalent infection was associated with female gender, non-white race, longer duration as IDU, having a tattoo, combined injection of heroin and cocaine, and with serologic evidence of hepatitis B and C infection. Seroconversion was more common in women, and was associated with African American race, heterosexual identity and longer duration as IDU. In conclusion, increased risk of HTLV-2 infection was associated with non-white race, and injection drug of choice, suggesting injection networks may play an important role in transmission of HTLV-2. The high correlation of HTLV-2 infection with HCV infection suggests the major route of transmission in IDU is via injection practices. Additional studies are needed to examine the clinical manifestations of HTLV-2 infection, as well as the clinical and virological manifestations of HTLV-2/HCV coinfection.