Gregory P. Bisson

Pharmacy refill adherence compared with CD4 count changes for monitoring HIV-infected adults on antiretroviral therapy

Background World Health Organization (WHO) guidelines for monitoring HIV-infected individuals taking combination antiretroviral therapy (cART) in resource-limited settings recommend using CD4+ T cell (CD4) count changes to monitor treatment effectiveness. In practice, however, falling CD4 counts are a consequence, rather than a cause, of virologic failure. Adherence lapses precede virologic failure and, unlike CD4 counts, data on adherence are immediately available to all clinics dispensing cART. However, the accuracy of adherence assessments for predicting future or detecting current virologic failure has not been determined. The goal of this study therefore was to determine the accuracy of adherence assessments for predicting and detecting virologic failure and to compare the accuracy of adherence-based monitoring approaches with approaches monitoring CD4 count changes. Methodology and Findings We conducted an observational cohort study among 1,982 of 4,984 (40%) HIV-infected adults initiating non-nucleoside reverse transcriptase inhibitor-based cART in the Aid for AIDS Disease Management Program, which serves nine countries in southern Africa. Pharmacy refill adherence was calculated as the number of months of cART claims submitted divided by the number of complete months between cART initiation and the last refill prior to the endpoint of interest, expressed as a percentage. The main outcome measure was virologic failure defined as a viral load > 1,000 copies/ml (1) at an initial assessment either 6 or 12 mo after cART initiation and (2) after a previous undetectable (i.e., < 400 copies/ml) viral load (breakthrough viremia). Adherence levels outperformed CD4 count changes when used to detect current virologic failure in the first year after cART initiation (area under the receiver operating characteristic [ROC] curves [AUC] were 0.79 and 0.68 [difference = 0.11; 95% CI 0.06 to 0.16; χ2 = 20.1] respectively at 6 mo, and 0.85 and 0.75 [difference = 0.10; 95% CI 0.05 to 0.14; χ2 = 20.2] respectively at 12 mo; p < 0.001 for both comparisons). When used to detect current breakthrough viremia, adherence and CD4 counts were equally accurate (AUCs of 0.68 versus 0.67, respectively [difference = 0.01; 95% CI −0.06 to 0.07]; χ2 = 0.1, p > 0.5). In addition, adherence levels assessed 3 mo prior to viral load assessments were as accurate for virologic failure occurring approximately 3 mo later as were CD4 count changes calculated from cART initiation to the actual time of the viral load assessments, indicating the potential utility of adherence assessments for predicting future, rather than simply detecting current, virologic failure. Moreover, combinations of CD4 count and adherence data appeared useful in identifying patients at very low risk of virologic failure. Conclusions Pharmacy refill adherence assessments were as accurate as CD4 counts for detecting current virologic failure in this cohort of patients on cART and have the potential to predict virologic failure before it occurs. Approaches to cART scale-up in resource-limited settings should include an adherence-based monitoring approach.

Early Mortality in Adults Initiating Antiretroviral Therapy (ART) in Low- and Middle-Income Countries (LMIC): A Systematic Review and Meta-Analysis

Background We systematically reviewed observational studies of early mortality post-antiretroviral therapy (ART) initiation in low- and middle-income countries (LMIC) in Asia, Africa, and Central and South America, as defined by the World Bank, to summarize what is known. Methods and Findings Studies published in English between January 1996 and December 2010 were searched in Medline and EMBASE. Three independent reviewers examined studies of mortality within one year post-ART. An article was included if the study was conducted in a LMIC, participants were initiating ART in a non-clinical trial setting and were ≥15 years. Fifty studies were included; 38 (76%) from sub-Saharan Africa (SSA), 5 (10%) from Asia, 2 (4%) from the Americas, and 5 (10%) were multi-regional. Median follow-up time and pre-ART CD4 cell count ranged from 3–55 months and 11–192 cells/mm3, respectively. Loss-to-follow-up, reported in 40 (80%) studies, ranged from 0.3%–27%. Overall, SSA had the highest pooled 12-month mortality probability of 0.17 (95% CI 0.11–0.24) versus 0.11 (95% CI 0.10–0.13) for Asia, and 0.07 (95% CI 0.007–0.20) for the Americas. Of 14 (28%) studies reporting cause-specific mortality, tuberculosis (TB) (5%–44%), wasting (5%–53%), advanced HIV (20%–37%), and chronic diarrhea (10%–25%) were most common. Independent factors associated with early mortality in 30 (60%) studies included: low baseline CD4 cell count, male sex, advanced World Health Organization clinical stage, low body mass index, anemia, age greater than 40 years, and pre-ART quantitative HIV RNA. Conclusions Significant heterogeneity in outcomes and in methods of reporting outcomes exist among published studies evaluating mortality in the first year after ART initiation in LMIC. Early mortality rates are highest in SSA, and opportunistic illnesses such as TB and wasting syndrome are the most common reported causes of death. Strategies addressing modifiable risk factors associated with early death are urgently needed.

Overestimates of survival after HAART: implications for global scale-up efforts.

Background Monitoring the effectiveness of global antiretroviral therapy scale-up efforts in resource-limited settings is a global health priority, but is complicated by high rates of losses to follow-up after treatment initiation. Determining definitive outcomes of these lost patients, and the effects of losses to follow-up on estimates of survival and risk factors for death after HAART, are key to monitoring the effectiveness of global HAART scale-up efforts. Methodology/Principal Findings A cohort study comparing clinical outcomes and risk factors for death after HAART initiation as reported before and after tracing of patients lost to follow-up was conducted in Botswanas National Antiretroviral Therapy Program. 410 HIV-infected adults consecutively presenting for HAART were evaluated. The main outcome measures were death or loss to follow-up within the first year after HAART initiation. Of 68 patients initially categorized as lost, over half (58.8%) were confirmed dead after tracing. Patient tracing resulted in reporting of significantly lower survival rates when death was used as the outcome and losses to follow-up were censored [1-year Kaplan Meier survival estimate 0.92 (95% confidence interval, 0.88–0.94 before tracing and 0.83 (95% confidence interval, 0.79–0.86) after tracing, log rank P<0.001]. In addition, a significantly increased risk of death after HAART among men [adjusted hazard ratio 1.74 (95% confidence interval, 1.05–2.87)] would have been missed had patients not been traced [adjusted hazard ratio 1.41 (95% confidence interval, 0.65–3.05)]. Conclusions/Significance Due to high rates of death among patients lost to follow-up after HAART, survival rates may be inaccurate and important risk factors for death may be missed if patients are not actively traced. Patient tracing and uniform reporting of outcomes after HAART are needed to enable accurate monitoring of global HAART scale-up efforts.

Extended-spectrum β-lactamase-producing Escherichia coli and Klebsiella species: Risk factors for colonization and impact of antimicrobial formulary interventions on colonization prevalence

OBJECTIVE The incidence of extended-spectrum beta-lactamase (ESbetaL)-mediated resistance has increased markedly during the past decade. Risk factors for colonization with ESbetaL-producing Escherichia coli and Klebsiella species (ESbetaL-EK) remain unclear, as do methods to control their further emergence. DESIGN Case-control study. SETTING Two hospitals within a large academic health system: a 725-bed academic tertiary-care medical center and a 344-bed urban community hospital. PATIENTS Thirteen patients with ESbetaL-EK fecal colonization were compared with 46 randomly selected noncolonized controls. RESULTS Duration of hospitalization was the only independent risk factor for ESbetaL-EK colonization (odds ratio, 1.11; 95% confidence interval, 1.02 to 1.21). Of note, 8 (62%) of the patients had been admitted from another healthcare facility. In addition, there was evidence for dissemination of a single K oxytoca clone. Finally, the prevalence of ESbetaL-EK colonization decreased from 7.9% to 5.7% following restriction of third-generation cephalosporins (P = .51). CONCLUSIONS ESbetaL-EK colonization was associated only with duration of hospitalization and there was no significant reduction following antimicrobial formulary interventions. The evidence for nosocomial spread and the high percentage of patients with ESbetaL-EK admitted from other sites suggest that greater emphasis must be placed on controlling the spread of such organisms within and between institutions.

Diagnostic accuracy of CD4 cell count increase for virologic response after initiating highly active antiretroviral therapy.

Objective:To derive and internally validate a clinical prediction rule for virologic response based on CD4 cell count increase after initiation of HAART in a resource-limited setting. Design and methods:A retrospective cohort study at two HIV care clinics in Gaborone, Botswana. The participants were previously treatment-naive HIV-1-infected individuals initiating HAART. The main outcome measure was a plasma HIV-1 RNA level (viral load) ≤ 400 copies/ml (i.e. undetectable) 6 months after initiating HAART. Results:The ability of CD4 cell count increase to predict an undetectable viral load was significantly better in those with baseline CD4 cell counts ≤ 100 cells/μl [area under the ROC curve (AUC), 0.78; 95% confidence interval (CI), 0.67–0.89; versus AUC, 0.60; 95% CI, 0.48–0.71; P = 0.018]. The sensitivity, specificity, and positive and negative predictive values of a CD4 cell count increase of ≥ 50 cells/μl for an undetectable viral load in those with baseline CD4 cell counts ≤ 100 cells/μl were 93.1, 61.3, 92.5 and 63.3%, respectively. Alternatively, these values were 47.8, 87.1, 95.0 and 24.5%, respectively, if a increase in CD4 cell count of ≥ 150 cells/μl was used. Conclusions:CD4 cell count increase after initiating HAART has only moderate discriminative ability in identifying patients with an undetectable viral load, and the predictive ability is lower in patients with lower baseline CD4 cell counts. Although HIV treatment programs in resource-constrained settings could consider the use of CD4 cell count increases to triage viral load testing, more accurate approaches to monitoring virologic failure are urgently needed.

Nonclassic measles infections in an immune population exposed to measles during a college bus trip

This study investigated the frequency of mild or asymptomatic measles infections among 44 persons exposed to a student with measles during a 3‐day bus trip using two buses. Questionnaires and serum samples were obtained 26–37 days after the trip. All participants had detectable measles‐neutralizing antibodies, and none developed classic measles symptoms. Ten persons (23%) were IgM positive for measles, indicating recent infection. Among previously vaccinated IgM‐negative persons, those who rode on bus A with the index case‐patient had significantly higher microneutralization titers than those on bus B (P = .001), suggesting that some persons on bus A were infected but were IgM negative at the time of the study. Mild or asymptomatic measles infections are probably very common among measles‐immune persons exposed to measles cases and may be the most common manifestation of measles during outbreaks in highly immune populations. J. Med. Virol. 56:337–341, 1998.

Early Versus Delayed Antiretroviral Therapy and Cerebrospinal Fluid Fungal Clearance in Adults With HIV and Cryptococcal Meningitis

BACKGROUND The burden of Cryptococcus neoformans in cerebrospinal fluid (CSF) predicts clinical outcomes in human immunodeficiency virus (HIV)-associated cryptococcal meningitis (CM) and is lower in patients on antiretroviral therapy (ART). This study tested the hypothesis that initiation of ART during initial treatment of HIV/CM would improve CSF clearance of C. neoformans. METHODS A randomized treatment-strategy trial was conducted in Botswana. HIV-infected, ART-naive adults aged≥21 years initiating amphotericin B treatment for CM were randomized to ART initiation within 7 (intervention) vs after 28 days (control) of randomization, and the primary outcome of the rate of CSF clearance of C. neoformans over the subsequent 4 weeks was compared. Adverse events, including CM immune reconstitution inflammatory syndrome (CM-IRIS), and immunologic and virologic responses were compared over 24 weeks. RESULTS Among 27 subjects enrolled (13 intervention and 14 control), [corrected] the median times to ART initiation were 7 (interquartile range [IQR], 5–10) and 32days (IQR, 28–36), respectively. The estimated rate of CSF clearance did not differ significantly by treatment strategy (-0.32 log10 colony-forming units [CFU]/mL/day±0.20 intervention and -0.52 log10 CFUs/mL/day (±0.48) control, P=.4). Two of 13 (15%) and 5 of 14 (36%) subjects died in the intervention and control arms, respectively (P=0.39). Seven of 13 subjects (54%) in the intervention arm vs 0 of 14 in the control arm experienced CM-IRIS (P=.002). CONCLUSIONS Early ART was not associated with improved CSF fungal clearance, but resulted in a high risk of CM-IRIS. Further research on optimal incorporation of ART into CM care is needed. CLINICAL TRIALS REGISTRATION NCT00976040.

Antiretroviral Failure Despite High Levels of Adherence : Discordant Adherence-Response Relationship in Botswana

Background:Although adherence to antiretroviral therapy may be higher in sub-Saharan Africa, knowledge regarding the magnitude of adherence needed to maintain virological suppression in this setting is limited. Methods:A case-control study among HIV-infected individuals initiating highly active antiretroviral therapy (HAART) in Gaborone, Botswana, was performed. Cases were randomly selected from subjects on HAART ≥6 months with plasma HIV-1 RNA levels (viral loads) >1000 copies/mL. Controls were randomly selected from subjects on HAART ≥6 months with all viral loads <400 copies/mL. HAART adherence was determined using pharmacy refill records. Results:In total, 302 individuals were included; 57 cases were compared with 245 controls with respect to adherence levels on nonnucleoside reverse transcriptase inhibitor-based HAART. Median adherence levels, as measured using pharmacy refill patterns, were consistently high but differed among cases and controls (91%, interquartile range 83%-97% for cases vs 97%, interquartile range 91%-100% for controls, P < 0.001, rank-sum test). Adherence <95% was independently associated with virological failure (odds ratio 4.19, 95% confidence interval 2.2 to 8.3). Conclusions:Very high rates of adherence were present in this setting, yet virological failure occurred nonetheless. Future work should explore other factors that might explain treatment failure in the setting of high levels of adherence.

Upregulation of the Phthiocerol Dimycocerosate Biosynthetic Pathway by Rifampin-Resistant, rpoB Mutant Mycobacterium tuberculosis

Multidrug-resistant tuberculosis has emerged as a major threat to tuberculosis control. Phylogenetically related rifampin-resistant actinomycetes with mutations mapping to clinically dominant Mycobacterium tuberculosis mutations in the rpoB gene show upregulation of gene networks encoding secondary metabolites. We compared the expressed proteomes and metabolomes of two fully drug-susceptible clinical strains of M. tuberculosis (wild type) to those of their respective rifampin-resistant, rpoB mutant progeny strains with confirmed rifampin monoresistance following antitubercular therapy. Each of these strains was also used to infect gamma interferon- and lipopolysaccharide-activated murine J774A.1 macrophages to analyze transcriptional responses in a physiologically relevant model. Both rpoB mutants showed significant upregulation of the polyketide synthase genes ppsA-ppsE and drrA, which constitute an operon encoding multifunctional enzymes involved in the biosynthesis of phthiocerol dimycocerosate and other lipids in M. tuberculosis, but also of various secondary metabolites in related organisms, including antibiotics, such as erythromycin and rifamycins. ppsA (Rv2931), ppsB (Rv2932), and ppsC (Rv2933) were also found to be upregulated more than 10-fold in the Beijing rpoB mutant strain relative to its wild-type parent strain during infection of activated murine macrophages. In addition, metabolomics identified precursors of phthiocerol dimycocerosate, but not the intact molecule itself, in greater abundance in both rpoB mutant isolates. These data suggest that rpoB mutation in M. tuberculosis may trigger compensatory transcriptional changes in secondary metabolism genes analogous to those observed in related actinobacteria. These findings may assist in developing novel methods to diagnose and treat drug-resistant M. tuberculosis infections.

Dose-Dependent Activity of Pyrazinamide in Animal Models of Intracellular and Extracellular Tuberculosis Infections

ABSTRACT Recent in vitro pharmacokinetic data suggest that the currently recommended dose of pyrazinamide may be suboptimal for killing intracellular bacilli in humans. We evaluated a range of pyrazinamide doses against intracellular and extracellular Mycobacterium tuberculosis in chronically infected mice and guinea pigs, respectively. Antibiotics were given five times weekly for 4 weeks beginning 28 days after infection. Human-equivalent doses of isoniazid reduced lung bacterial counts 10-fold in each species. Pyrazinamide given at 1/4 and 1/2 the human-equivalent dose was minimally active, while human-equivalent doses reduced lung bacterial counts by ∼1.0 log10 in each species. Doubling the human-equivalent dose of pyrazinamide reduced the lung bacillary burden by 1.7 and 3.0 log10 in mice and guinea pigs, respectively. As in humans and mice, pyrazinamide showed significant synergy with rifampin in guinea pigs. Clinical studies are warranted to investigate the sterilizing activity and tolerability of higher doses of pyrazinamide in combination tuberculosis regimens.