Agnes Langat

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.

Low-frequency nevirapine resistance at multiple sites may predict treatment failure in infants on nevirapine-based treatment

Background:Resistance commonly arises in infants exposed to single-dose nevirapine (sdNVP) for prevention of mother to child transmission. Although K103N and Y181C are common following sdNVP, multiple other mutations also confer NVP resistance. It remains unclear whether specific NVP resistance mutations or combinations of mutations predict virologic failure in infants when present at low frequencies before NVP-based treatment. Methods:Twenty sdNVP-exposed infants who were subsequently treated with NVP-based highly active antiretroviral therapy were examined. Pretreatment plasma samples were tested for the presence of NVP resistance mutations by allele-specific polymerase chain reaction for K103N and Y181C and ultradeep pyrosequencing (UDPS) for all primary NVP mutations. Viral levels were determined every 3 months for up to 24 months on NVP–highly active antiretroviral therapy. Cox proportional hazard models were used to determine correlates of viral failure. Results:The NVP resistance mutations K103N or Y181C were detected in pretreatment plasma samples in 6 infants by allele-specific polymerase chain reaction. NVP resistance at these or other sites was detectable by UDPS in 10 of 20 infants tested. Virologic failure occurred in 50% of infants with any NVP resistance mutations detected, whereas only 20% of infants without resistance experienced viral failure, but the difference was not significant (P = 0.19). An increase in the number of NVP resistance mutations detectable by UDPS in an infant was significantly associated with an increased risk of virologic failure [HR = 1.79 (95% confidence interval: 1.07 to 2.99), P = 0.027]. Conclusions:Low frequencies of multiple NVP resistance mutations, in addition to K103N and Y181C, present in infants before NVP-based treatment may predict treatment outcome.

Treatment interruption after 2-year antiretroviral treatment initiated during acute/early HIV in infancy.

Objective:Treatment interruption has been well tolerated and durable in some pediatric studies but none have compared treatment interruption with continued antiretroviral treatment (ART) following ART initiation in early HIV. The objective of this study was to compare outcomes in treatment interruption versus continued ART among early-treated infants. Design:Randomized trial (OPH-03; NCT00428116). Methods:The trial included HIV-infected infants who initiated ART at less than 13 months of age, received ART for 24 months, and, if eligible (CD4% >25%, normal growth), were randomized to treatment interruption versus continued ART. Children in the treatment interruption group restarted ART if they met WHO ART-eligibility criteria. During 18-months postrandomization, primary outcomes were incidence of serious adverse events and growth. CD4%, viral load, morbidity, and growth were compared. Results:Of 140 infants enrolled, 121 started ART, of whom 75 completed at least 24 months ART and 42 were randomized (21 per arm). ART was initiated at median age 5 months and randomization at 30 months. Among 21 treatment interruption children, 14 met ART restart criteria within 3 months. Randomization was discontinued by Data and Safety Monitoring Board due to low treatment interruption durability. At 18 months postrandomization, growth and serious adverse events were comparable between arms; hypercholesteremia incidence was higher in the continued arm (P = 0.03). CD4% and viral load did not differ between arms [CD4% 35% and median viral load undetectable (<150 copies/ml) in both arms, P = 0.9 for each comparison]. No infants had post-treatment viral control. Conclusion:Short treatment interruption did not compromise 18-month CD4%, viral control, growth, or morbidity compared with continued ART among infants who started ART in early HIV infection.

Gaps in Adolescent Engagement in Antenatal Care and Prevention of Mother-to-Child HIV Transmission Services in Kenya

Background: Rates of pregnancy and HIV infection are high among adolescents. However, their engagement in prevention of mother-to-child HIV transmission (PMTCT) services is poorly characterized. We compared engagement in the PMTCT cascade between adult and adolescent mothers in Kenya. Methods: We conducted a nationally representative cross-sectional survey of mother–infant pairs attending 120 maternal child health clinics selected by probability proportionate to size sampling, with a secondary survey oversampling HIV-positive mothers in 30 clinics. Antenatal care (ANC) attendance, HIV testing, and antiretroviral (ARV) use were compared between adolescent (age ⩽19 years) and adult mothers using &khgr;2 tests and logistic regression. Results: Among 2521 mothers, 278 (12.8%) were adolescents. Adolescents were less likely than adults to be employed (16.5% vs. 37.9%), married (66.1% vs. 88.3%), have intended pregnancy (40.5% vs. 58.6%), or have disclosed their HIV status (77.5% vs. 90.7%) (P < 0.01 for all). Adolescents were less likely than adults to attend ≥4 ANC visits (35.2% vs. 45.6%, P = 0.002). This effect remained significant when adjusting for employment, household crowding, pregnancy intention, gravidity, and HIV status [adjusted odds ratio (95% confidence interval) = 0.54 (0.37 to 0.97), P = 0.001]. Among 2359 women without previous HIV testing, 96.1% received testing during pregnancy; testing levels did not differ between adolescents and adults. Among 288 HIV-positive women not on antiretroviral therapy before pregnancy, adolescents were less likely than adults to be on ARVs (65.0% vs. 85.8%, P = 0.01) or to have infants on ARVs (85.7% vs. 97.7%, P = 0.005). Conclusions: Adolescent mothers had poorer ANC attendance and uptake of ARVs for PMTCT. Targeted interventions are needed to improve retention of this vulnerable population in the PMTCT cascade.

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.

Differences in virologic and immunologic response to antiretroviral therapy among HIV-1-infected infants and children.

Background:Virologic and immunologic responses to antiretroviral treatment (ART) in infants may differ from older children due to immunologic, clinical, or epidemiologic characteristics. Methods:Longitudinal ART responses were modeled and compared in HIV-infected infants and children enrolled in cohorts in Nairobi, Kenya. Participants were enrolled soon after HIV diagnosis, started on ART, and followed for 2 years. Viral load decline was compared between infant and child cohorts using a nonlinear mixed effects model and CD4% reconstitution using a linear mixed effects model. Results:Among 121 infants, median age at ART was 3.9 months; among 124 children, median age was 4.8 years. At baseline, viral load was higher among infants than children (6.47 vs. 5.91 log10 copies/ml, P < 0.001). Infants were less likely than children to suppress viral load to less than 250 copies/ml following 6 months of ART (32% infants vs. 73% children, P < 0.0001). CD4% was higher at baseline in infants than children (19 vs. 7.3%, P < 0.001). Older children had more rapid CD4% reconstitution than infants, but failed to catch up to infant CD4%. Conclusion:Despite substantially higher CD4% at ART initiation, viral suppression was significantly slower among infants than older children. New strategies are needed to optimize infant outcomes on ART.

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 lopinavir/ritonavir-based versus nevirapine-based ART attained later speech (18.1 vs. 15.5 months, P = 0.003). 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 lopinavir/ritonavir-based versus nevirapine-based ART were each associated with later milestone attainment. The long-term consequences of these delays are unknown.

Decay of HIV DNA in the Reservoir and the Impact of Short Treatment Interruption in Kenyan Infants

Abstract We compared change in HIV reservoir DNA following continued antiretroviral therapy (ART) vs short treatment interruption (TI) in early ART-treated Kenyan infants. While HIV DNA in the reservoir decayed with continued ART, HIV DNA levels were similar to pre-TI HIV DNA reservoir levels in most children after short TI.

4th National Anti-tuberculosis Drug Resistance Survey in Kenya

Introduction: Recently rapid development of drug resistant TB, particularly MDR TB (Multi Drug Resistant TB) and XDRTB (Extensively Drug-Resistant TB) possess a major threat to control of tuberculosis globally. Information on the extent of MDR-TB from Kenya is largely limited due to several factors. Monitoring of development of resistance is a vital tool in providing critical information for effective planning for TB control and in management of patients infected with TB. Methods: Cross-sectional with cluster design. Results: A total of 2,171 participants recruited into the study from 50 selected clusters. Prevalence of rifampicin resistance for new cases was 1.3% [95% CI, 0.8-2.0] and INH resistance was 5.5% [95% CI, 4.5-6.7]. MDR TB was found in 0.67% of new cases and 2.1% amongst previously treated TB cases. Discussion: Resistance to isoniazid in Kenya has been on the decline due to introduction of rifampicin in combined therapy. There was increase of MDR TB among new cases by 24% and decline in previously treated cases due to lethal impact of HIV. Conclusions: Although drug resistance TB is a growing problem in Kenya, resistance to isoniazid and rifampicin MDR TB is less than previously estimated. The country should continue to monitor drug resistance and ensure effective use of anti TB medicines.

High Viremia and Wasting Before Antiretroviral Therapy Are Associated With Pneumonia in Early-Treated HIV-Infected Kenyan Infants.

Background Human immunodeficiency virus (HIV)-infected children are particularly susceptible to acute respiratory infections (ARIs). We determined incidence and cofactors for ARIs in HIV-infected infants receiving antiretroviral therapy (ART). Methods Human immunodeficiency virus-infected infants initiated ART at ≤12 months of age and were observed monthly for 2 years in Nairobi. Acute respiratory infection rates and cofactors were determined using Andersen-Gill models, allowing for multiple events per infant. Results Among 111 HIV-infected infants, median age at ART initiation was 4.5 months. Pre-ART median CD4% was 19%, and 29% had wasting. During 24-months follow-up while on ART, upper respiratory infection (URI) and pneumonia rates were 122.6 and 34.7 per 100 person-years (py), respectively. Infants with higher pre-ART viral load (VL) (plasma HIV ribonucleic acid [RNA] ≥7 log10 copies/mL) had 4.12-fold increased risk of pneumonia (95% confidence interval [CI], 2.17-7.80), and infants with wasting (weight-for-height z-score < -2) had 2.87-fold increased risk (95% CI, 1.56-5.28). Infants with both high pre-ART VL and wasting had a higher pneumonia rate (166.8 per 100 py) than those with only 1 of these risk factors (44.4 per 100 py) or neither (17.0 per 100 py). Infants with exposure to wood fuel had significantly higher risk of URI (hazard ratio [HR] = 1.82; 95% CI, 1.44-2.28) and pneumonia (HR = 3.31; 95% CI, 1.76-6.21). Conclusions In early ART-treated HIV-infected infants, higher HIV RNA and wasting before ART were independent risk factors for pneumonia. Wood fuel use was associated with URI and pneumonia. Additional data on air pollution and respiratory outcomes in HIV-infected children may help optimize interventions to improve their lung health.