Claudia P. Cortes

Cross-Sectional Analysis of Late HAART Initiation in Latin America and the Caribbean: Late Testers and Late Presenters

Background Starting HAART in a very advanced stage of disease is assumed to be the most prevalent form of initiation in HIV-infected subjects in developing countries. Data from Latin America and the Caribbean is still lacking. Our main objective was to determine the frequency, risk factors and trends in time for being late HAART initiator (LHI) in this region. Methodology Cross-sectional analysis from 9817 HIV-infected treatment-naïve patients initiating HAART at 6 sites (Argentina, Chile, Haiti, Honduras, Peru and Mexico) from October 1999 to July 2010. LHI had CD4+ count ≤200cells/mm3 prior to HAART. Late testers (LT) were those LHI who initiated HAART within 6 months of HIV diagnosis. Late presenters (LP) initiated after 6 months of diagnosis. Prevalence, risk factors and trends over time were analyzed. Principal Findings Among subjects starting HAART (n = 9817) who had baseline CD4+ available (n = 8515), 76% were LHI: Argentina (56%[95%CI:52–59]), Chile (80%[95%CI:77–82]), Haiti (76%[95%CI:74–77]), Honduras (91%[95%CI:87–94]), Mexico (79%[95%CI:75–83]), Peru (86%[95%CI:84–88]). The proportion of LHI statistically changed over time (except in Honduras) (p≤0.02; Honduras p = 0.7), with a tendency towards lower rates in recent years. Males had increased risk of LHI in Chile, Haiti, Peru, and in the combined site analyses (CSA). Older patients were more likely LHI in Argentina and Peru (OR 1.21 per +10-year of age, 95%CI:1.02–1.45; OR 1.20, 95%CI:1.02–1.43; respectively), but not in CSA (OR 1.07, 95%CI:0.94–1.21). Higher education was associated with decreased risk for LHI in Chile (OR 0.92 per +1-year of education, 95%CI:0.87–0.98) (similar trends in Mexico, Peru, and CSA). LHI with date of HIV-diagnosis available, 55% were LT and 45% LP. Conclusion LHI was highly prevalent in CCASAnet sites, mostly due to LT; the main risk factors associated were being male and older age. Earlier HIV-diagnosis and earlier treatment initiation are needed to maximize benefits from HAART in the region.

Haplotype structure of CYP2B6 and association with plasma efavirenz concentrations in a Chilean HIV cohort

OBJECTIVES Efavirenz is extensively metabolized by CYP2B6, and associations between CYP2B6 polymorphisms and plasma efavirenz exposure have been reported. The objective of this study was to investigate CYP2B6 haplotype structure and functional consequences in a Latin American population. PATIENTS AND METHODS Two hundred and nineteen patients were recruited at Fundación Arriarán, Chile, between September and December 2008. Plasma efavirenz concentrations were determined using liquid chromatography with mass spectrometry. Genotyping for 30 single nucleotide polymorphisms (SNPs) with a minor allele frequency of >0.05 in the HapMap CEU population at intervals of approximately 1 kb across the CYP2B6 locus was conducted using Sequenom iPLEX MALDI-TOF. RESULTS Thirteen SNPs passed quality control and, of these, statistically significant associations (P < 0.001) with plasma efavirenz concentrations were observed for 11. Pairwise tagging SNP analysis (R(2) > 0.8) identified 3 SNPs (rs10403955, rs2279345 and rs8192719) representative of the 11 associated SNPs. A composite genetic model of these three alleles was constructed, and an association between carriers of four to six of these alleles and the risk of efavirenz plasma concentrations >4 microg/mL was identified with an odds ratio of 48.1 (95% confidence interval: 13.5-207.7). This represents a positive predictive value of 80.9% and a negative predictive value of 91.8%, with sensitivity of 57.9% and specificity of 97.2%. CONCLUSIONS A composite genetic model of CYP2B6 SNPs in a Chilean HIV-positive cohort may have value in predicting concentrations of efavirenz associated with a higher likelihood of CNS toxicity. Further investigation of the functional basis of these associations is now required.

Correlates of Efavirenz Exposure in Chilean Patients Affected With Human Immunodeficiency Virus Reveals a Novel Association With a Polymorphism in the Constitutive Androstane Receptor

Objective:To explore the effect of demographics and single-nucleotide polymorphisms in cytochrome P450 (CYP) 2B6, 2A6, UDP-glucuronosyltransferase (UGT) 2B7, and the constitutive androstane receptor (CAR) genes on efavirenz pharmacokinetics in a Chilean cohort affected with human immunodeficiency virus. Methods:Timed plasma samples obtained throughout the dosing interval were analyzed for efavirenz concentrations with liquid chromatography/tandem mass spectrometry. DNA from whole-blood samples was used for genetic analysis. Data were analyzed using a Mann–Whitney statistical test; furthermore, a Pearson or Spearman correlation was used. A multivariate analysis was then conducted using multiple linear regression by best subset analysis. Results:Overall 219 patients were included, 208 patients had measurable efavirenz levels and available genetic samples. The overall median (interquartile range) of efavirenz concentration was 2.6 (2.1–3.7) mcg/mL. In multivariate regression analysis, CYP2B6 516G>T (P < 0.0001) and CAR rs2307424 C>T (P = 0.002) were significantly related to efavirenz plasma concentrations. Conclusion:This novel association between CAR rs2307424 and efavirenz plasma concentrations now requires validation in other cohorts.

Long-term outcomes of a national expanded access program to antiretroviral therapy: the Chilean AIDS cohort.

Objective: To evaluate impact of the program after up to 6 years of follow-up in survival, virologic, and immunologic response. Methods: Prospective follow-up of patients initiating first highly active antiretroviral therapy from 2001 to 2007. Chile began in 2001 an expanded access program to antiretroviral therapy. The Chilean AIDS Cohort has enrolled >85% of patients from this program in the public health system. Statistical analysis: χ2, Fisher tests, survival, univariate and multivariate analysis. Results: Five thousand one hundred fifteen adults (16% women); median follow-up: 3.64 years (18,159 patient-years). At baseline: median age, 35.8 years; 45.6% had clinical AIDS; median CD4 cell count, 102 cells per cubic millimeter. Global mortality, 9.0%; loss to follow-up, 6.8%. Probability of survival at 1 and 5 years were 0.95 and 0.89, respectively. First regimen was maintained in 72% of those alive and in control at 1 year and 48% at end of study. Main reason for therapy change/discontinuation was drug toxicity (44.9%). At last visit, 74% of active patients had viral suppression, and median CD4 cell count had reached 301 cells per cubic millimeter. Conclusions: In this middle-income country, wide access highly active antiretroviral therapy has been successfully implemented and evaluated. Despite advanced disease at initiation, survival, clinical, virologic, and immunologic outcomes have been comparable with that of industrialized countries.

Importance of Legionella pneumophila in the Etiology of Severe Community-Acquired Pneumonia in Santiago, Chile

BACKGROUND In US and European literature, Legionella pneumophila is reported as an important etiologic agent of severe community-acquired pneumonia (CAP), but in Chile this information is lacking. The aim of this study was to determine the incidence and identify predictors of severe CAP caused by L pneumophila in Santiago, Chile. METHODS A multicenter, prospective clinical study lasting 18 months was conducted; it included all adult patients with severe CAP admitted to the ICUs of four hospitals in Santiago. We excluded patients who were immunocompromised, had been hospitalized in the previous 4 weeks, or presented with another disease during their hospitalization. All data for the diagnosis of severe CAP were registered, and urinary antigens for L pneumophila serogroup 1 were determined. RESULTS A total of 104 patients with severe CAP were included (mean ± SD age, 58.3 ± 19.3 years; men, 64.4%; APACHE (Acute Physiology and Chronic Health Evaluation) II score, 16.7 ± 6.3; Sepsis-related Organ Failure Assessment score, 6.1 ± 3.2; Pitt Bacteremia Score, 3.4 ± 2.5; Pao2/Fio2, 170.8 ± 87.1). An etiologic agent was identified in 62 patients (59.6%), with the most frequent being Streptococcus pneumoniae (27 patients [26%]) and L pneumophila (nine patients [8.6%]). Logistic regression analysis showed that a plasma sodium level of ≤ 130 mEq/L was an independent predictor for L pneumophila severe CAP (OR, 11.3; 95% CI, 2.5-50.5; P = .002). Global mortality was 26% and 33% for L pneumophila. The Pitt bacteremia score and pneumonia score index were the best predictors of mortality. CONCLUSIONS We found that in Santiago, L pneumophila was second to S pneumoniae as the etiologic agent of severe CAP. Severe hyponatremia at admission appears to be an indicator for L pneumophila etiology in severe CAP.

Tuberculosis in antiretroviral treatment programs in lower income countries: availability and use of diagnostics and screening.

Objectives In resource-constrained settings, tuberculosis (TB) is a common opportunistic infection and cause of death in HIV-infected persons. TB may be present at the start of antiretroviral therapy (ART), but it is often under-diagnosed. We describe approaches to TB diagnosis and screening of TB in ART programs in low- and middle-income countries. Methods and findings We surveyed ART programs treating HIV-infected adults in sub-Saharan Africa, Asia and Latin America in 2012 using online questionnaires to collect program-level and patient-level data. Forty-seven sites from 26 countries participated. Patient-level data were collected on 987 adult TB patients from 40 sites (median age 34.7 years; 54% female). Sputum smear microscopy and chest radiograph were available in 47 (100%) sites, TB culture in 44 (94%), and Xpert MTB/RIF in 23 (49%). Xpert MTB/RIF was rarely available in Central Africa and South America. In sites with access to these diagnostics, microscopy was used in 745 (76%) patients diagnosed with TB, culture in 220 (24%), and chest X-ray in 688 (70%) patients. When free of charge culture was done in 27% of patients, compared to 21% when there was a fee (p = 0.033). Corresponding percentages for Xpert MTB/RIF were 26% and 15% of patients (p = 0.001). Screening practices for active disease before starting ART included symptom screening (46 sites, 98%), chest X-ray (38, 81%), sputum microscopy (37, 79%), culture (16, 34%), and Xpert MTB/RIF (5, 11%). Conclusions Mycobacterial culture was infrequently used despite its availability at most sites, while Xpert MTB/RIF was not generally available. Use of available diagnostics was higher when offered free of charge.

Cancer in HIV-Infected Persons From the Caribbean, Central and South America

Background:HIV-infected individuals have heightened cancer risk. With the advent of highly active antiretroviral therapy (HAART), the frequency of some AIDS-defining cancers (ADC) has decreased although certain non-AIDS-defining cancers (NADC) are becoming more frequent. Cancers among HIV-infected individuals in Latin American and the Caribbean have not yet been carefully studied. Methods:Cancer cases among the Caribbean, Central and South American network for HIV Research (CCASAnet) cohort were identified reviewing clinical records and pre-existing databases. Results:There were 406 cancers reported: 331 ADC (224 Kaposi sarcomas and 98 non Hodgkin lymphomas). Most frequent NADC (n = 75) were Hodgkin lymphoma and skin cancers. Seventy-three percent of NADC and 45% of ADC were diagnosed >1 year after HIV diagnosis. Fifty-six percent of ADC occurred before HAART start. Median time from HAART start until cancer diagnosis was 2.5 years for NADC and 0.5 years for ADC (P = <0.001). Within 3372 HAART starters, 158 were diagnosed with 165 cancers (82.4% ADC); 85 cases were previous to or concomitant with HAART initiation. Incidence of cancer after HAART initiation in 8080 person-years of follow-up was 7.2 per 1000 person-years (95% confidence interval = 5.5 to 9.3) for ADC and 2.7 (95% confidence interval = 1.8 to 4.1) for NADC; incidence was higher in the first 2 months, particularly for ADC (47.6). A pre-HAART ADC was a predictor of mortality after adjusting for age, sex, and CD4 at HAART initiation. Conclusions:ADC were the most frequent cancers in this region and were often diagnosed close to HIV diagnosis and HAART start. Incidence of cancer was highest around HAART initiation.

Implementation of tuberculosis intensive case finding, isoniazid preventive therapy, and infection control ("Three I's") and HIV-tuberculosis service integration in lower income countries

Setting World Health Organization advocates for integration of HIV-tuberculosis (TB) services and recommends intensive case finding (ICF), isoniazid preventive therapy (IPT), and infection control (“Three I’s”) for TB prevention and control among persons living with HIV. Objective To assess the implementation of the “Three I’s” of TB-control at HIV treatment sites in lower income countries. Design Survey conducted between March-July, 2012 at 47 sites in 26 countries: 6 (13%) Asia Pacific, 7 (15%), Caribbean, Central and South America, 5 (10%) Central Africa, 8 (17%) East Africa, 14 (30%) Southern Africa, and 7 (15%) West Africa. Results ICF using symptom-based screening was performed at 38% of sites; 45% of sites used symptom-screening plus additional diagnostics. IPT at enrollment or ART initiation was implemented in only 17% of sites, with 9% of sites providing IPT to tuberculin-skin-test positive patients. Infection control measures varied: 62% of sites separated smear-positive patients, and healthcare workers used masks at 57% of sites. Only 12 (26%) sites integrated HIV-TB services. Integration was not associated with implementation of TB prevention measures except for IPT provision at enrollment (42% integrated vs. 9% non-integrated; p = 0.03). Conclusions Implementation of TB screening, IPT provision, and infection control measures was low and variable across regional HIV treatment sites, regardless of integration status.

Zika Virus Infection Presenting with Postauricular Lymphadenopathy

A 28-year-old, otherwise healthy Chilean man presented in December 2015 with fever, headache, and myalgia. He had returned, 2 days ago, from a tourist trip to Colombia, where he had visited Bogota and the northern region including Cartagena de Indias, Santa Marta, and Tayrona National Park. During his return, he suffered nonspecific symptoms including sore throat, anorexia, and myalgia. A day later, he noted high grade fever and tender nodules behind his ears (Figure 1 ). Physical examination revealed fever (39.0°C), a maculopapular rash of the trunk and extremities (Figure 2 ), mild conjunctivitis, and a generalized lymphadenopathy with palpable tender axillary, cervical, and bilateral postauricular lymph nodes. After dengue and chikungunya virus infections were excluded by molecular methods, antigen detection, and IgM antibody testing, samples were sent to the national reference laboratory (Instituto de Salud Publica de Chile, Santiago, Chile), where Zika virus (ZIKV) nucleic acids were detected by real-time reverse transcription polymerase chain reaction (RT-PCR) as previously described.1 The sample was also positive using a commercial RT-PCR assay for the detection of ZIKV (Zika Virus genesig® Advanced Kit; Primerdesign™ Ltd., Southampton, United Kingdom) in the clinical laboratory, Clinica Alemana, Santiago. The patient recovered rapidly and without complications. Figure 1. Bilateral tender postauricular lymphadenopathy in patient with Zika virus infection. Figure 2. Maculopapular rash on the patients arm. Since 2015, ZIKV is rapidly emerging within the Americas, where it is disseminated by mosquitos of the Aedes genus. However, the virus is also transmitted by blood transfusion and, as recently suggested, by contact with infectious semen.2,3 Because of its possible association with fetal malformations and neurological complications, this epidemic has been declared a global public health emergency by the World Health Organization. The clinical presentation of the infection is similar to dengue including fever, rash, joint pain, conjunctivitis, myalgia, headache, and vomiting.4–6 Although lymphadenopathy has recently been described in patients with ZIKV infection in Brazil,7,8 it is usually not listed as a typical manifestation. Our case confirms that ZIKV might cause systemic lymphadenopathy including the posterior auricular lymph nodes. Because tender bilateral postauricular lymphadenopathy is a known clinical sign of postnatal rubella, it might mislead ZIKV diagnosis especially in pediatric patients.

Use of third line antiretroviral therapy in Latin America

Background Access to highly active antiretroviral therapy (HAART) is expanding in Latin America. Many patients require second and third line therapy due to toxicity, tolerability, failure, or a combination of factors. The need for third line HAART, essential for program planning, is not known. Methods Antiretroviral-naïve patients ≥18 years who started first HAART after January 1, 2000 in Caribbean, Central and South America Network (CCASAnet) sites in Argentina, Brazil, Honduras, Mexico, and Peru were included. Clinical trials participants were excluded. Third line HAART was defined as use of darunavir, tipranavir, etravirine, enfuvirtide, maraviroc or raltegravir. Need for third line HAART was defined as virologic failure while on second line HAART. Results Of 5853 HAART initiators followed for a median of 3.5 years, 310 (5.3%) failed a second line regimen and 44 (0.8%) received a third line regimen. Cumulative incidence of failing a 2nd or starting a 3rd line regimen was 2.7% and 6.0% three and five years after HAART initiation, respectively. Predictors at HAART initiation for failing a second or starting a third line included female sex (hazard ratio [HR] = 1.54, 95% confidence interval [CI] 1.18–2.00, p = 0.001), younger age (HR = 2.76 for 20 vs. 40 years, 95% CI 1.86–4.10, p<0.001), and prior AIDS (HR = 2.17, 95% CI 1.62–2.90, p<0.001). Conclusions Third line regimens may be needed for at least 6% of patients in Latin America within 5 years of starting HAART, a substantial proportion given the large numbers of patients on HAART in the region. Improved accessibility to third line regimens is warranted.