Suspected Treatment Failure Research Articles

Improving HIV Treatment Adherence through a Public Private Partnership in Zambia

Background: Effective ART with low viral loads and absence of STIs significantly reduce chances of sexual transmission of HIV. ART is therefore a key pillar in HIV prevention. Appropriate support is however essential for optimum treatment outcome, patient safety and HIV prevention benefit. The scale-up of ART continues to strain the already overstretched human resources in public facilities, impacts on the quality of care, and contributes to loss to follow-up. Task shifting is therefore a strategy to augment the limited human resources. Methodology: In partnership with the Livingstone General Hospital (LGH) and four private pharmacists, the COH III Project through Howard University is promoting quality HIV care by engaging the pharmacists in adherence counselling and treatment monitoring. The LGH ART pharmacist allocates consenting stable ART clients to pharmacies based on willingness to be referred and patient preference. Patients are given schedule of visits to pharmacies where the pharmacists provide medication/adherence counselling and monitor side effects. Patients with medication/treatment issues are referred back to the LGH ART clinic for follow-up. Results: Between October 2012 and August 2013, 280 patients were enrolled and followed up by the four pharmacists. 69% of patients visited the pharmacy at least once, 25% at least twice and 13% at least thrice. The 33 client referrals by pharmacists to LGH were related to adverse drug reactions, suspected treatment failure, pregnancy, and treatment monitoring. The intervention has reduced workload for the ART pharmacist; improved communication of treatment challenges and identification of patients with medication related problems, and reduced travel distances and waiting times. This has resulted in improved adherence and better patient outcomes. Conclusion: Private pharmacists present an opportunity to improve quality of HIV interventions in poor human resource capacity settings. The necessary legal and regulatory framework needs to however be developed to guide the process.

Dried blood spots for HIV‐1 drug resistance genotyping in decentralized settings in Senegal

The aim of this study was to evaluate the use for HIV-1 drug resistance testing dried blood spots collected in remote areas and sent under field conditions to a reference laboratory and also to document virological failure in patients with suspected treatment failure. Samples were collected from patients receiving first line ART at 11 hospital sites around country, kept at room temperature (<37°C) and sent within 15 days maximum to the reference laboratory. Viral nucleic acids were obtained by magnetic extraction with NucliSENS (bioMérieux, Marcy l'Etoile, France). Genotyping of HIV-1 pol gene was performed using the ANRS protocol. Drug resistance mutations were analyzed according to the Stanford University HIV database version 6.0.8. Two hundred thirty one HIV-infected adults' on HAART first line regimen composed study population. The median time on ART was 18 months (range 6-68). Regardless of the treatment duration, the overall rate of virological failure (VL ≥ 3 log10 cp/ml) was 23.8% (n = 55/231). HIV genotypes were obtained successfully in 94.5% (n = 52/55). Drug resistance mutation was found in 41/52 patients in virological failure, for 17.7% (n = 41/231) an overall rate of drug resistance mutations. M184V/I was the most frequent mutation occurring, followed by K103N. Phylogenetic analysis of the 52 genotyped viral isolates showed the predominance of CRF02_AG with 62% (n = 32/52). Use of a DBS specimen is suitable to assist national programs for monitoring in remote areas HIV drug resistance in resources limited-settings.

CART prescription trends in a prospective HIV cohort in rural Tanzania from 2007 to 2011

Comprehensive information on combined antiretroviral therapy (cART) regimens in rural Sub‐Saharan Africa over time is scarce, particularly on the use of stavudine (d4T) and second‐line regimens. Since 2010, World Health Organization (WHO) guidelines discourage using stavudine in first‐line regimens due to frequent and severe side‐effects. This study examined the practical adaption of this phasing‐out and described trends in use of various cART combinations in a rural Tanzanian setting. We analyzed longitudinal, prospectively collected data of HIV‐1‐infected adults initiating cART within the Kilombero Ulanga Antiretroviral Cohort (KIULARCO) in Ifakara, Tanzania from 2007–2011. This analysis included data of 3068 patients over a 5‐year period. Of these subjects, 1997 (66.9%) were female, median age was 37 (interquartile range [IQR] 31–44) years and median CD4 cell count at enrollment was 178 cells/µl (IQR 88‐291). The percentage of prescriptions containing stavudine in initial regimens (Table 1) fell from a peak of 75% in 2008 to 12.2% in 2011 (p for trend&lt;0.001). TDF/FTC/EFV became available in 2009 and was used in 117 (41.6%) patients initiating cART in 2011. An overall on‐treatment analysis (Figure 1) revealed that d4T/3TC/NVP and AZT/3TC/EFV were the most prescribed combinations in each year, including 2011 (684 [32.5%] and 642 [30.5%] patients respectively). Of those on d4T/3TC/NVP in 2011, 632 (92.4%) were initiated in earlier years. The ratio of second‐line to total regimens remained stable over time (p for trend=0.19) with a maximum of 34 (1.2%) patients in 2011, whereof 32 (94.1%) received a combination of ABC/ddI/LPVr.Overall on‐treatment count of patients on cART combinations by year.image Initial cART combinations prescribed by year. 2007 2008 2009 2010 2011 d4T/3TC/NVP 426 (66.6%) 536 536 (71.2%) 362 (46.8%) 93 (19.4%) 52 (12.2%) d4T/3TC/EFV 25 (3.9%) 29 (3.8%) 25 (3.2%) 6 (1.2%) 0 (0%) AZT/3TC/EFV 177 (27.7%) 174 (23.1%) 324 (41.9%) 160 (33.4%) 138 (32.4%) AZT/3TC/NVP 7 (1.1%) 10 (1.3%) 5 (0.6%) 21 (4.4%) 54 (12.7%) TDF/FTC/EFV 2 (0.3%) 2 (0.2%) 57 (7.3%) 199 (41.5%) 177 (41.6%) Total 639 752 773 479 425 Initial cART with stavudine declined to low levels according to recommendations but the overall use of stavudine remains substantial. The usage of second‐line treatment is unusually low in view of expected therapeutic failure rates, indicating potential difficulties in management of suspected treatment failure cases. Monitoring of prescription trends is a simple and feasible approach to identify deficits in the implementation of treatment guidelines for optimal outcomes.

Treatment failure of pharyngeal gonorrhoea with internationally recommended first-line ceftriaxone verified in Slovenia, September 2011

We describe the second case in Europe of verified treatment failure of pharyngeal gonorrhoea, caused by an internationally occurring multidrug-resistant gonococcal clone, with recommended first-line ceftriaxone 250 mg in Slovenia. This is of grave concern since ceftriaxone is last remaining option for empirical treatment. Increased awareness of ceftriaxone failures, more frequent test-of-cure, strict adherence to regularly updated treatment guidelines, and thorough verification/falsification of suspected treatment failures are essential globally. New effective treatment options are imperative.

Histiocyte-rich Xanthomatous Pseudotumor Mimicking Relapse on Positron Emission Tomography Imaging in an Adolescent With Primary Mediastinal Diffuse Large B-cell Lymphoma

Inflammatory pseudotumors (IPTs) are rare, enigmatic lesions that may develop as a late manifestation of a reparative process. We describe the case of a teenager with primary mediastinal subtype of diffuse large B-cell lymphoma who developed an IPT at the site of the original lymphoma, mimicking relapse of disease on positron emission tomography/computed tomography imaging. This is the first report of IPT in a teenager with mediastinal lymphoma. This case is an important reminder of the limitations of positron emission tomography/computed tomography imaging in patients with lymphoma and stresses the importance of histologic confirmation of suspected treatment failure or relapse.

Human African trypanosomiasis in Angola: clinical observations, treatment, and use of PCR for stage determination of early stage of the disease

Biological and clinical observations are described for 224 patients infected by human African trypanosomiasis (HAT) in Angola in 2007 and 2008. Seven patients were initially classified in stage 1 (S1), 17 intermediate stage (IS) (WBC <20 lymphocytes/μl with absence of trypanosomes in cerebrospinal fluid (CSF) and no neurological signs), and 200 in stage 2 (S2). Out of 224 patients, 165 (73.6%) presented one or more neurological signs. During treatment with eflornithine, six deaths of S2 patients occurred, five of which were because of an encephalopathy syndrome. Nine patients were diagnosed with a relapse or suspected treatment failure during the follow-up: eight patients after treatment with eflornithine (relapse rate 4.1%) and one patient after pentamidine (6.6%). The contribution of PCR for stage determination evaluated for S1 and IS confirms the difficulty of stage determination, as one S1 patient and two IS patients were carriers of trypanosomes detected a posteriori by PCR in CSF but were treated with pentamidine while follow-up did not confirm treatment efficacy. Since 2001 in Angola, either by passive or active mode detection, approximately 80% of the new cases every year were in S2, whereas the annual number of cases has regressed, probably because the transmission of HAT is decreasing. However, stage determination and treatment remain two major issues for the chronic form of sleeping sickness.

Multilocus Genotyping of Human Giardia Isolates Suggests Limited Zoonotic Transmission and Association between Assemblage B and Flatulence in Children

Background Giardia intestinalis is one of the most common diarrhea-related parasites in humans, where infection ranges from asymptomatic to acute or chronic disease. G. intestinalis consists of eight genetically distinct genotypes or assemblages, designated A–H, and assemblages A and B can infect humans. Giardiasis has been classified as a possible zoonotic disease but the role of animals in human disease transmission still needs to be proven. We tried to link different assemblages and sub-assemblages of G. intestinalis isolates from Swedish human patients to clinical symptoms and zoonotic transmission.Methodology/Principal FindingsMultilocus sequence-based genotyping of 207 human Giardia isolates using three gene loci: ß-giardin, glutamate dehydrogenase (gdh), and triose phosphate isomerase (tpi) was combined with assemblage-specific tpi PCRs. This analysis identified 73 patients infected with assemblage A, 128 with assemblage B, and six with mixed assemblages A+B. Multilocus genotypes (MLGs) were easily determined for the assemblage A isolates, and most patients with this genotype had apparently been infected through anthroponotic transmission. However, we also found evidence of limited zoonotic transmission of Giardia in Sweden, since a few domestic human infections involved the same assemblage A MLGs previously reported in Swedish cats and ruminants. Assemblage B was detected more frequently than assemblage A and it was also more common in patients with suspected treatment failure. However, a large genetic variability made determination of assemblage B MLGs problematic. Correlation between symptoms and assemblages was found only for flatulence, which was significantly more common in children less than six years of age infected with assemblage B.Conclusions/SignificanceThis study shows that certain assemblage A subtypes are potentially zoonotic and that flatulence is connected to assemblage B infections in young children. Determination of MLGs from assemblages A and B can be a valuable tool in outbreak situations and to help identify possible zoonotic transmission.

Outpatient treatment of children with severe pneumonia with oral amoxicillin in four countries: the MASS study

A recent randomized clinical trial demonstrated home-based treatment of WHO-defined severe pneumonia with oral amoxicillin was equivalent to hospital-based therapy and parenteral antibiotics. We aimed to determine whether this finding is generalizable across four countries. Multicentre observational study in Bangladesh, Egypt, Ghana and Vietnam between November 2005 and May 2008. Children aged 3-59 months with WHO-defined severe pneumonia were enrolled at participating health centres and managed at home with oral amoxicillin (80-90 mg/kg per day) for 5 days. Children were followed up at home on days 1, 2, 3 and 6 and at a facility on day 14 to look for cumulative treatment failure through day 6 and relapse between days 6 and 14. Of 6582 children screened, 873 were included, of whom 823 had an outcome ascertained. There was substantial variation in presenting characteristics by site. Bangladesh and Ghana had fever (97%) as a more common symptom than Egypt (74%) and Vietnam (66%), while in Vietnam, audible wheeze was more common (49%) than at other sites (range 2-16%). Treatment failure by day 6 was 9.2% (95% CI: 7.3-11.2%) across all sites, varying from 6.4% (95% CI: 3.1-9.8%) in Ghana to 13.2% (95% CI: 8.4-18.0%) in Vietnam; 2.7% (95% CI: 1.5-3.9%) of the 733 children well on day 6 relapsed by day 14. The most common causes of treatment failure were persistence of lower chest wall indrawing (LCI) at day 6 (3.8%; 95% CI: 2.6-5.2%), abnormally sleepy or difficult to wake (1.3%; 95% CI: 0.7-2.3%) and central cyanosis (1.3%; 95% CI: 0.7-2.3%). All children survived and only one adverse drug reaction occurred. Treatment failure was more frequent in young infants and those presenting with rapid respiratory rates. Clinical treatment failure and adverse event rates among children with severe pneumonia treated at home with oral amoxicillin did not substantially differ across geographic areas. Thus, home-based therapy of severe pneumonia can be applied to a wide variety of settings.

Simple Adherence Assessments to Predict Virologic Failure among HIV-Infected Adults with Discordant Immunologic and Clinical Responses to Antiretroviral Therapy

We evaluated the association between two antiretroviral therapy (ART) adherence measurements--the medication possession ratio (MPR) and patient self-report--and detectable HIV viremia in the setting of rapid service scale-up in Lusaka, Zambia. Drug adherence and outcomes were assessed in a subset of patients suspected of treatment failure based on discordant clinical and immunologic responses to ART. A total of 913 patients were included in this analysis, with a median time of 744 days (Q1, Q3: 511, 919 days) from ART initiation to viral load (VL) measurement. On aggregate over the period of follow-up, 531 (58%) had optimal adherence (MPR > or =95%), 306 (34%) had suboptimal adherence (MPR 80-94%), and 76 (8%) had poor adherence (MPR <80%). Of the 913 patients, 238 (26%) had VL > or =400 copies/ml when tested. When compared to individuals with optimal adherence, there was increasing risk for virologic failure in those with suboptimal adherence [adjusted relative risk (ARR): 1.3; 95% confidence interval (CI): 1.0, 1.6] and those with poor adherence (ARR: 1.7; 95% CI: 1.3, 2.4) based on MPR. During the antiretroviral treatment course, 676 patients (74%) reported no missed doses. The proportion of patients with virologic failure did not differ significantly among those reporting any missed dose from those reporting perfect adherence (26% vs. 26%, p = 0.97). Among patients with suspected treatment failure, a lower MPR was associated with higher rates of detectable viremia. However, the suboptimal sensitivity and specificity of MPR limit its utility as a sole predictor of virologic failure.

Management of Severe Sepsis of Abdominal Origin

Severe sepsis is a life-threatening condition that may occur as a sequela of intra-abdominal infections (IAIs) of all types. Diagnosis of IAIs is predicated upon the combination of physical examination and imaging techniques. Diffuse peritonitis usually requires urgent surgical intervention. In the absence of diffuse peritonitis, abdominal computed tomography remains the most useful test for the diagnosis of IAIs, and is essential to both guide therapeutic interventions and evaluate suspected treatment failure in the critically ill patient. Parameters most consistently associated with poor outcomes in patients with IAIs include increased illness severity, failed source control, inadequate empiric antimicrobial therapy, and healthcare-acquired, as opposed to community-acquired infection. Whereas community-acquired IAI is characterized predominantly by enteric gram-negative bacilli and anaerobes that are susceptible to narrow-spectrum agents, healthcare-acquired IAI (e.g., anastomotic dehiscence, postoperative organ-space surgical site infection) frequently involves at least one multi-drug resistant pathogen, necessitating broad-spectrum therapy guided by both culture results and local antibiograms. The cornerstone of effective treatment for abdominal sepsis is early and adequate source control, which is supplemented by antibiotic therapy, restoration of a functional gastrointestinal tract (if possible), and support of organ dysfunction. Furthermore, mitigation of deranged immune and coagulation responses via therapy with recombinant human activated protein C may improve survival significantly in severe cases complicated by septic shock and multiple organ dysfunction syndrome.

Application of the ParaSight™-F dipstick test for malaria diagnosis in a district control program

A rapid test for the diagnosis of Plasmodium falciparum infections based on the detection of histidine-rich-protein II, the ParaSight™-F test, was evaluated after introduction in a district malaria control program in Uganda. Suspected treatment failures, pregnant women and infants with clinical malaria and general fever cases were tested at health facilities in malaria hypo-, meso- and holoendemic areas. A total of 1326 tests were carried out by health unit staff, cross read by experienced laboratory staff and results compared with thick film microscopy as the standard. Rater agreement in reading the dipstick result between health unit staff and laboratory staff was high, kappa index 0.94 (0.88–0.99). Sensitivity was 99.6% (99.0–100) for parasite densities above 500/μl, 98.6% (97.7–99.6) for densities above 50/μl and 22.2% (8.6–42.3) for densities below 10/μl. With the applied testing strategies no differences were found between endemicity levels or patient categories. Specificity was 86.2% (83.3–88.8) overall, but significantly higher in general fever cases (92.7%) compared to the other patient groups (84.3%, P=0.009). At the given prevalences positive predictive values (ppv) were above 80% and negative predictive values (npv) above 90% in all cases except in pregnant women (ppv: 77.8%). We conclude that in certain situations this test is an alternative to microscopy to improve diagnostic facilities for case management in malaria control programs in endemic African countries.

Partial Characterization of Chlamydia trachomatis Isolates Resistant to Multiple Antibiotics

In vitro susceptibility testing was done on urogenital isolates of Chlamydia trachomatis from five patients, four of whom were suspected treatment failures. At least one isolate from each patient was resistant to tetracycline at concentrations greater than or equal to micrograms/ml, although less than 1% of a population of organisms showed high-level resistance. Fully resistant populations selected by passage through 8 micrograms/ml tetracycline either died or lost their resistance on further passage in antibiotic-free medium. Relatively large inocula were required to demonstrate resistance, and morphology of inclusions was altered at high tetracycline concentrations. The observed resistance may be a new characteristic of the organism or merely newly recognized. Isolates resistant to tetracycline were resistant to doxycycline, erythromycin, sulfamethoxazole, and clindamycin but sensitive to rifampin, ciprofloxacin, and ofloxacin. Thus, resistance to tetracycline, erythromycin, and clindamycin occurs in C. trachomatis and may be a factor in some treatment failures.

TREATMENT OF MALARIA IN CHILDREN WITH CHLOROQUINE

Forty-nine children with 54 episodes of malaria were treated with chloroquine with four known relapses and one suspected treatment failure. A dosage scale for children is offered (Table I). Only minor toxic effects of chloroquine were observed. Chloroquine did not prevent the presence of the gametocytes of Plasmodium falciparum in peripheral blood. Nine cases severely ill with malaria responded well to this treatment.