Sarah Benki-Nugent

A Randomized Controlled Trial Comparing the Effects of Counseling and Alarm Device on HAART Adherence and Virologic Outcomes

Michael Chung and colleagues show that intensive early adherence counseling at HAART initiation resulted in sustained, significant impact on adherence and virologic treatment failure, whereas use of an alarm device had no effect.

Implementation of free cotrimoxazole prophylaxis improves clinic retention among antiretroviral therapy-ineligible clients in Kenya.

Objective:To determine whether implementation of free cotrimoxazole (CTX) provision was associated with improved retention among clients ineligible for antiretroviral therapy (ART) enrolled in an HIV treatment program in Kenya. Design:Data were obtained from a clinical cohort for program evaluation purposes. Twelve-month clinic retention was compared among ART-ineligible clients enrolled in the time period before free CTX versus the time period after. Methods:Statistical comparisons were made using Kaplan–Meier survival curves, log-rank tests, and multivariate Cox proportional hazards models. To exclude potential temporal program changes that may have influenced retention, ART clients before and after the same cut-off date were compared. Findings:Among adult clients enrolled between 2005 and 2007, 3234 began ART within 1 year of enrollment, and 1024 of those who did not start treatment were defined as ART-ineligible. ART-ineligible clients enrolled in the period following free CTX provision had higher 12-month retention (84%) than those who enrolled prior to free CTX (63%; P < 0.001). Retention did not change significantly during these periods among ART clients (P = 0.55). In multivariate analysis, ART-ineligible clients enrolled prior to free CTX were more than twice as likely to be lost to follow-up compared to those following free CTX [adjusted hazard ratio (aHR) = 2.64, 95% confidence interval 1.95–3.57, P < 0.001]. Conclusion:Provision of free CTX was associated with significantly improved retention among ART-ineligible clients. Retention and CD4-monitoring of ART-ineligible clients are essential to promptly identify ART eligibility and provide treatment. Implementation of free CTX may improve retention in sub-Saharan Africa and, via increasing timely ART initiation, provide survival benefit.

Younger age at HAART initiation is associated with more rapid growth reconstitution

Objectives:Patterns of growth following highly active antiretroviral therapy (HAART) administration among children are not well defined. The objective of this study was to determine rates and predictors of growth reconstitution among children on HAART. Methods:A study was conducted among HIV-1-infected children initiating HAART at an HIV treatment clinic in Kenya. Kaplan–Meier survival curves and Cox proportional hazards regression models compared catch-up growth (Z-score ≥0) at 12 months post-HAART. Multivariate linear mixed-effects models determined rates and predictors of growth following HAART. Results:One hundred and seventy-three HIV-1-infected children initiated HAART with a median age of 4.7 years [interquartile range (IQR) 2.4, 7.0]. At baseline, children below 3 years had lower weight-for-age (WAZ) and weight-for-height (WHZ) Z-scores than children 3–5 and 6–10 years (WAZ: P = 0.03; WHZ: P = 0.006). Adjusting for baseline growth, children below 3 years were two to three-fold more likely to attain population age-norms (Z-score = 0) than 6–10 years (WAZ: P = 0.055; WHZ: P = 0.005) at 12 months post-HAART. After adjustment, children below 3 years had higher increases in WAZ and WHZ following HAART than 6–10 years (WAZ: P = 0.006; WHZ: P = 0.005). Children at WHO stage at least 3 at baseline experienced more rapid WHZ reconstitution (P = 0.002). Food supplementation while on HAART was associated with increased monthly gains in weight indices (WAZ: P = 0.001; WHZ: P = 0.005), and multivitamins were associated with greater increases in height (P < 0.01). Conclusion:Following HAART initiation, younger children had more rapid catch-up to the population-average weight of their peers than older children, demonstrating growth benefit of earlier HAART. In addition to HAART, food supplementation and multivitamins may also accelerate growth reconstitution.

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.

Long-term virologic response and genotypic resistance mutations in HIV-1 infected Kenyan children on combination antiretroviral therapy.

Background:HIV-infected children may require the use of combination antiretroviral treatment (cART) into adulthood. However, regimens are limited to first line and second line in many African settings. Therefore, understanding the long-term rate of virologic failure and drug resistance during prolonged antiretroviral treatment is important for establishing treatment strategies in African pediatric cohorts. Methods:Children aged 18 months to 12 years initiated first-line cART and were followed every 1–3 months, for up to 5.5 years. Treatment was switched to second-line cART based on clinical and immunologic criteria according to national guidelines. Virologic failure was determined retrospectively as defined by ≥2 viral loads >5000 copies per milliliter. Drug resistance was assessed during viral failure by population-based sequencing. Results:Among 100 children on first-line cART followed for a median of 49 months, 34% children experienced virologic failure. Twenty-three (68%) of the 34 children with viral failure had detectable resistance mutations, of whom 14 (61%) had multiclass resistance. Fourteen (14%) children were switched to second-line regimens and followed for a median of 28 months. Retrospective analysis revealed that virologic failure had occurred at a median of 12 months before switching to second line. During prolonged first-line treatment in the presence of viral failure, additional resistance mutations accumulated; however, only 1 (7%) of 14 children had persistent viremia during second-line treatment. Discussion:Virologic suppression was maintained on first-line cART in two-thirds of HIV-infected children for up to 5 years. Switch to second line based on clinical/immunologic criteria occurred ∼1 year after viral failure, but the delay did not consistently compromise second-line treatment.

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.

Knowing a sexual partner is HIV-1-uninfected is associated with higher condom use among HIV-1-infected adults in Kenya

The relation between awareness of sexual partners HIV serostatus and unprotected sex was examined in HIV clinic enrollees. Increased condom use was associated with knowing that a partner was HIV-negative (adjusted odds ratio = 5.99; P < 0.001) versus not knowing partners status. Partner testing may increase condom use in discordant couples.

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.

Urgent versus post-stabilisation antiretroviral treatment in hospitalised HIV-infected children in Kenya (PUSH): a randomised controlled trial

SUMMARY Background Urgent antiretroviral therapy (ART) among hospitalized HIV-infected children may accelerate recovery or worsen outcomes due to immune reconstitution. In an unblinded randomized controlled trial, we compared urgent versus post-stabilization ART among hospitalized HIV-infected children. Methods We randomized HIV-infected, ART-naïve children age 0 – 12 years who were eligible for ART in a 1:1 ratio to receive ART within 48 hours (urgent arm) or seven to 14 days (post-stabilization arm). We excluded children with suspected or confirmed central nervous system (CNS) infection. Block randomization, with variable block sizes, was generated by a statistician not involved in study procedures. We followed children for six months for primary outcomes: mortality, drug toxicity, and immune reconstitution inflammatory syndrome (IRIS). Registered in Clinical Trials.gov (NCT02063880). Trial status: complete. Findings We began enrollment on 24th April, 2013 and completed follow-up on 17th November, 2015. Of 250 HIV infected children, we enrolled 191/250 (76%) and randomized 183/191 (96%). We included 181/183 (99%) of randomized hospitalized HIV infected children age 0–12 who had no CNS infection in a modified intent-to-treat analysis. Median age was 1·9 years (IQR 0·8–4·8). Baseline sociodemographic, clinical, and virologic characteristics did not differ between arms except median CD4%, which was lower in the urgent arm (13% [IQR 9, 18] versus 17% [IQR 9, 24], p=0·05). Pneumonia, malnutrition, and suspected tuberculosis (TB) contributed to 118/181 (65%), 58/181 (32%), and 27/181 (15%) of admission diagnoses, respectively. Median time to ART was one day (IQR 1, 1) and eight days (IQR 7, 11) in the urgent and post-stabilization arms, respectively. Overall, mortality risk was 61 per 100 person-years. Mortality risk did not differ by arm (70 versus 54 per 100 person-years in urgent versus post-stabilization arms, respectively [HR 1.26 95% CI 0.67, 2.37 p=0.47]), even after adjusting for baseline CD4% (aHR 1·30 [95% CI 0·69, 2·45, p=0·41]). There was no statistical difference in incidence of IRIS or drug toxicity between trial arms. We discontinued randomization at interim review when the futility boundary was crossed. Interpretation Early mortality risk was extremely high among hospitalized HIV-infected children. Urgent ART did not improve survival.