Alternative antiretroviral monitoring strategies for HIV-infected patients in east Africa: opportunities to save more lives?

<p>Abstract</p> <p>Background</p> <p>Updated World Health Organization guidelines have amplified debate about how resource constraints should impact monitoring strategies for HIV-infected persons on combination antiretroviral therapy (cART). We estimated the incremental benefit and cost effectiveness of alternative monitoring strategies for east Africans with known HIV infection.</p> <p>Methods</p> <p>Using a validated HIV computer simulation based on resource-limited data (USAID and AMPATH) and circumstances (east Africa), we compared alternative monitoring strategies for HIV-infected persons newly started on cART. We evaluated clinical, immunologic and virologic monitoring strategies, including combinations and conditional logic (e.g., only perform virologic testing if immunologic testing is positive). We calculated incremental cost-effectiveness ratios (ICER) in units of cost per quality-adjusted life year (QALY), using a societal perspective and a lifetime horizon. Costs were measured in 2008 US dollars, and costs and benefits were discounted at 3%. We compared the ICER of monitoring strategies with those of other resource-constrained decisions, in particular earlier cART initiation (at CD4 counts of 350 cells/mm³rather than 200 cells/mm³).</p> <p>Results</p> <p>Monitoring strategies employing routine CD4 testing without virologic testing never maximized health benefits, regardless of budget or societal willingness to pay for additional health benefits. Monitoring strategies employing virologic testing conditional upon particular CD4 results delivered the most benefit at willingness-to-pay levels similar to the cost of earlier cART initiation (approximately $2600/QALY). Monitoring strategies employing routine virologic testing alone only maximized health benefits at willingness-to-pay levels (>$4400/QALY) that greatly exceeded the ICER of earlier cART initiation.</p> <p>Conclusions</p> <p>CD4 testing alone never maximized health benefits regardless of resource limitations. Programmes routinely performing virologic testing but deferring cART initiation may increase health benefits by reallocating monitoring resources towards earlier cART initiation.</p

Adherence to antiretroviral therapy in a clinical cohort of HIV-infected children in East Africa

Objective To describe antiretroviral therapy (ART) adherence and associated factors for a large HIVinfected pediatric cohort followed by sites of the East Africa International Epidemiologic Databases to Evaluate AIDS (IeDEA) consortium. Methods This study utilized prospectively collected clinical data from HIV-infected children less than 13 years of age who initiated ART within 4 clinical care programs (with 26 clinical sites) in Kenya, Uganda, and Tanzania and were followed for up to 6 years. Programs used one of 3 adherence measures, including 7-day quantitative recall, 7-day categorical recall, and clinician pill assessments. We fit a hierarchical, three-level, logistic-regression model to examine adherence, with observations nested within patient, and patients within the 26 sites providing pediatric HIV data to this analysis. Results In East Africa, 3,304 children, 52.0% male, were enrolled in care and were subsequently observed for a median of 92 weeks (inter-quartile range [IQR] 50.3±145.0 weeks). Median age at ART initiation was 5.5 years ([IQR] 3.0±8.5 years). ªGoodº adherence, as reported by each clinic\u27s measures, was extremely high, remaining on average above 90% throughout all years of follow-up. Longer time on ART was associated with higher adherence (adjusted Odds Ratio±aOR±per log-transformed week on ART: 1.095, 95% Confidence Interval±CI± [1.052±1.150].) Patients enrolled in higher-volume programs exhibited higher rates of clinician- assessed adherence (aOR per log-500 patients: 1.174, 95% CI [1.108±1.245]).Significant site-level variability in reported adherence was observed (0.28), with even higher variability among patients (0.71). In a sub-analysis, being an orphan at the start of ART was strongly associated with lower ART adherence rates (aOR: 0.919, 95% CI [0.864±0.976]). Conclusions Self-reported adherence remained high over a median of 1.8 years in HIV care, but varied according to patient-level and site-level factors. Consistent adherence monitoring with validated measures and attention to vulnerable groups is recommended

Frequency and impact of suboptimal immune recovery on first-line antiretroviral therapy within the International Epidemiologic Databases to Evaluate AIDS in East Africa

OBJECTIVE: To describe patterns of suboptimal immune recovery (SO-IR) and associated HIV-related-illnesses during the first 5 years following first-line antiretroviral therapy (ART) initiation across seven ART sites in East Africa. DESIGN: Retrospective analysis of data from seven ART clinical sites (three Uganda, two Kenya and two Tanzania). METHODS: SO-IR was described by proportions of ART-treated adults with CD4 cell counts less than 200, less than 350 and less than 500 cells/μl. Kaplan-Meier survival analysis techniques were used to assess predictors of SO-IR, and incident rates of HIV-related illnesses at CD4 cell counts less than 200, 200-350, 351-499, and >500 cells/μl, respectively. RESULTS: Overall 80 843 adults initiated non-nucleoside reverse transcriptase inhibitor-based first-line ART; 65% were women and median CD4 cell count was 126 [interquartile range (IQR), 52-202] cells/μl. Cumulative probability of SO-IR <200 cells/μl, <350 cells/μl and <500 cells/μl, after 5 years, was 11, 38 and 63%, respectively. Incidence of HIV-related illnesses was higher among those with CD4 cell counts less than 200 and 200-350 cells/μl, than those who achieved CD4 counts above these thresholds. The most common events, at CD4 < 200 cells/μl, were pulmonary tuberculosis [incident rate 15.98 (15.47-16.51)/100 person-years at risk (PYAR), oral candidiasis [incident rate 12.5 (12.03-12.94)] and herpes zoster [incident rate 6.30 (5.99-6.64)] events/100 PYAR. With attainment of a CD4 cell count level 200-350 cells/μl, there was a substantial reduction in events/100 PYAR - by 91% to 1.45 (1.29-1.63) for TB, by 94% to 0.75 (0.64-0.89) for oral candidiasis, by 84% to 0.99 (0.86-1.14) for Herpes Zoster, and by 78% to 1.22 (1.07-1.39) for chronic diarrhea. The incidence of all events decreased further with CD4 counts above these thresholds. CONCLUSION: Around 40% of adults initiated on ART have suboptimal immune recovery with CD4 counts <350 cells/μl after five years. Such patients will require closer monitoring for both HIV-related and non-HIV-related clinical events

Estimated mortality of adult HIV-infected patients starting treatment with combination antiretroviral therapy

To provide estimates of mortality among HIV-infected patients starting combination antiretroviral therapy

Adjusting Mortality for Loss to Follow-Up: Analysis of Five ART Programmes in Sub-Saharan Africa

Evaluation of antiretroviral treatment (ART) programmes in sub-Saharan Africa is difficult because many patients are lost to follow-up. Outcomes in these patients are generally unknown but studies tracing patients have shown mortality to be high. We adjusted programme-level mortality in the first year of antiretroviral treatment (ART) for excess mortality in patients lost to follow-up

Pancreatic Fistula Following Pancreaticoduodenectomy: Clinical Predictors and Patient Outcomes

Pancreatic fistula continues to be a common complication following PD. This study seeks to identify clinical factors which may predict pancreatic fistula (PF) and evaluate the effect of PF on outcomes following pancreaticoduodenectomy (PD). We performed a retrospective analysis of a clinical database at an academic tertiary care hospital with a high volume of pancreatic surgery. Five hundred ten consecutive patients underwent PD, and PF occurred in 46 patients (9%). Perioperative mortality of patients with PF was 0%. Forty-five of 46 PF (98%) closed without reoperation with a mean time to closure of 34 days. Patients who developed PF showed a higher incidence of wound infection, intra-abdominal abscess, need for reoperation, and hospital length of stay. Multivariate analysis demonstrated an invaginated pancreatic anastomosis and closed suction intraperitoneal drainage were associated with PF whereas a diagnosis of chronic pancreatitis and endoscopic stenting conferred protection. Development of PF following PD in this series was predicted by gender, preoperative stenting, pancreatic anastomotic technique, and pancreas pathology. Outcomes in patients with PF are remarkable for a higher rate of septic complications, longer hospital stays, but in this study, no increased mortality

Predictors of CNS Injury as Measured by Proton Magnetic Resonance Spectroscopy in the Setting of Chronic HIV infection and CART

The reasons for persistent brain dysfunction in chronically HIV-infected persons on stable combined antiretroviral therapies (CART) remain unclear. Host and viral factors along with their interactions were examined in 260 HIV-infected subjects who underwent magnetic resonance spectroscopy (MRS) Metabolite concentrations (NAA/Cr, Cho/Cr, MI/Cr and Glx/Cr) were measured in the basal ganglia, the frontal white matter and grey matter and the best predictive models were selected using a bootstrap-enhanced Akaike Information Criterion (AIC). Depending on the metabolite and brain region, age, race, HIV RNA concentration, ADC stage, duration of HIV infection, nadir CD4, and/or their interactions were predictive of metabolite concentrations, particularly the basal ganglia NAA/Cr and the mid-frontal NAA/Cr and Glx/Cr whereas current CD4 and the CPE index rarely or did not predict these changes. These results show for the first time that host and viral factors related to both current and past HIV status contribute to persisting cerebral metabolite abnormalities and provide a framework for further understanding neurological injury in the setting of chronic and stable disease

Chemokines in cerebrospinal fluid correlate with cerebral metabolite patterns in HIV-infected individuals

Chemokines influence HIV neuropathogenesis by affecting the HIV life cycle, trafficking of macrophages into the nervous system, glial activation, and neuronal signaling and repair processes; however, knowledge of their relationship to in vivo measures of cerebral injury is limited. The primary objective of this study was to determine the relationship between a panel of chemokines in cerebrospinal fluid (CSF) and cerebral metabolites measured by proton magnetic resonance spectroscopy (MRS) in a cohort of HIV-infected individuals. One hundred seventy-one stored CSF specimens were assayed from HIV-infected individuals who were enrolled in two ACTG studies that evaluated the relationship between neuropsychological performance and cerebral metabolites. Concentrations of six chemokines (fractalkine, IL-8, IP-10, MCP-1, MIP-1β, and SDF-1) were measured and compared with cerebral metabolites individually and as composite neuronal, basal ganglia, and inflammatory patterns. IP-10 and MCP-1 were the chemokines most strongly associated with individual cerebral metabolites. Specifically, (1) higher IP-10 levels correlated with lower N-acetyl aspartate (NAA)/creatine (Cr) ratios in the frontal white matter and higher MI/Cr ratios in all three brain regions considered and (2) higher MCP-1 levels correlated with lower NAA/Cr ratios in frontal white matter and the parietal cortex. IP-10, MCP-1, and IL-8 had the strongest associations with patterns of cerebral metabolites. In particular, higher levels of IP-10 correlated with lower neuronal pattern scores and higher basal ganglia and inflammatory pattern scores, the same pattern which has been associated with HIV-associated neurocognitive disorders (HAND). Subgroup analysis indicated that the effects of IP-10 and IL-8 were influenced by effective antiretroviral therapy and that memantine treatment may mitigate the neuronal effects of IP-10. This study supports the role of chemokines in HAND and the validity of MRS as an assessment tool. In particular, the findings identify relationships between the immune response—particularly an interferon-inducible chemokine, IP-10—and cerebral metabolites and suggest that antiretroviral therapy and memantine modify the impact of the immune response on neurons

BMC Res Notes

Objective Pediatric antiretroviral therapy (ART) for children with HIV (CHIV) must be dosed appropriately for children’s changing weights as they grow. To inform accurate estimates of ART formulations and doses needed, we described weight-for-age distributions among CHIV on ART in the IeDEA global pediatric collaboration between 2004 and 2016, using data from six regions (East, West, Central, and Southern Africa, Asia–Pacific, and Central/South America and the Caribbean). Results Overall, 59,862 children contributed to the analysis. Age and weight data were available from 530,080 clinical encounters for girls and 537,894 for boys. For each one-year age stratum from 0 to 15 years, we calculated the proportion of children in each of the weight bands designated by the World Health Organization as relevant to pediatric ART formulations: 0 to  < 3 kg, 3 to  < 6 kg, 6 to  < 10 kg, 10 to  < 14 kg, 14 to  < 20 kg, 20 to  < 25 kg, 25 to  < 30 kg, 30 to  < 35 kg, 35 to  < 40 kg, 40 to  < 45 kg, 45 to  < 50 kg, 50 to  < 55 kg, 55 to  < 60 kg, and ≥ 60 kg. Data are reported for the entire cohort, as well as stratified by sex and IeDEA region, calendar year of ART use, and duration on ART at time of assessment (< 12 or ≥ 12 months), provided in data tables. These data are critical to improve the accuracy of forecasting and procurement of pediatric ART formulations as the pediatric HIV epidemic and pediatric HIV treatment strategies evolve