Richard A. Murphy

Antiretroviral Therapy—Associated Toxicities in the Resource-Poor World: The Challenge of a Limited Formulary

Toxicities related to antiretroviral therapy make long-term adherence to therapy difficult for patients and present challenges to providers, especially those in the resource-poor world who work with a limited formulary. In resource-poor settings, where limited drug options are the rule, when and how to change therapy are especially difficult problems. Drugs such as stavudine and didanosine are associated with serious metabolic complications, such as lactic acidosis, pancreatitis, and peripheral neuropathy. Antiretroviral agents associated with fewer metabolic effects, such as tenofovir and abacavir, remain widely unavailable. Because the current formulary restrictions appear to be unlikely to change quickly, providers in resource-poor countries must be familiar with the common adverse events-including metabolic complications, hypersensitivity reactions, anemia, and liver enzyme abnormalities-and must understand how to manage them with what is locally available. Most importantly, to avoid drug toxicities, a larger formulary is needed in resource-poor settings, and this must be a high priority for policy makers and health care professionals involved in treating human immunodeficiency virus infection globally.

Outcomes after virologic failure of first-line ART in South Africa.

Objective:To determine initial 24-week outcomes among prospectively enrolled patients with failure of initial antiretroviral therapy (ART). Methods:Baseline virologic failure was defined as HIV-1 viral load greater than 1000 copies/ml. Second-line ART was informed by results of genotype testing and selected from agents in the South-African public sector. Twenty-four week endpoints included virologic suppression and mortality. Results:The cohort consisted of 141 patients (median CD4 cell count and viral load at failure of 173 cells/μl and 17 500 copies/ml). The median prior duration of initial ART was 12.0 months. At least one major resistance mutation was found in 87% of patients.After 24 weeks of follow-up, intent-to-treat virologic suppression (<50 copies/ml) was 65%, as-treated virologic suppression was 78%, the median CD4 cell count improvement was 88 cells/μl and the mortality was 6%. The median CD4 cell count at initial virologic failure among those who died was 70 cells/μl, compared to 182 cells/μl among patients who survived (P = 0.01). Patients with wild-type virus at initial failure (N = 19) had inferior outcomes after switch. The presence of nucleoside analogue resistance mutations at failure did not affect early efficacy of boosted-protease inhibitor regimens. Conclusions:Virologic monitoring linked to resistance testing helped demonstrate the efficacy of lopinavir/ritonavir-containing second-line regimens in South Africa. A switch to second-line regimens in patients with virologic failure and drug resistance has substantial and rapid immunological and clinical benefits. Resistance testing identified a high-risk group without resistance who might benefit from increased medication access and/or adherence support.

Second-line antiretroviral therapy: Long-term outcomes in South Africa

Background:Currently, boosted protease inhibitor–containing regimens are the only option after first-line regimen failure available for patients in most resource-limited settings, yet little is known about long-term adherence and outcomes. Methods:We enrolled patients with virologic failure (VF) who initiated lopinavir/ritonavir–containing second-line antiretroviral therapy (ART). Medication possession ratios were calculated using pharmacy refill dates. Factors associated with 12-month second-line virologic suppression [viral load (VL) <50 copies/mL] and adherence were determined. Results:One hundred six patients (median CD4 count and VL at failure: 153 cells/mm3 and 28,548 copies/mL, respectively) were enrolled. Adherence improved after second-line ART switch (median adherence 6 months prior, 67%; median adherence during initial 6 months of second-line ART, 100%; P = 0.001). Higher levels of adherence during second-line ART was associated with virologic suppression at month 12 of ART (odds ratio 2.5 per 10% adherence increase, 95% CI 1.3 to 4.8, P = 0.01). Time to virologic suppression was most rapid among patients with 91%–100% adherence compared with patients with 80%–90% and <80% adherence (log rank test, P = 0.01). VF during 24 months of second-line ART was moderate (month 12: 25%, n = 32/126; month 18: 21%, n = 23/112; and month 24: 25%, n = 25/99). Conclusions:The switch to second-line ART in South Africa was associated with an improvement in adherence, however, a moderate ongoing rate of VF—among approximately 25% of patients receiving second-line ART patients at each follow-up interval—was a cause for concern. Adherence level was associated with second-line ART virologic outcome, helping explain why some patients achieved virologic suppression after switch and others did not.

Antimicrobial drug-resistant bacteria isolated from Syrian war-injured patients, August 2011-March 2013.

To the Editor: Soft-tissue injuries sustained during wars are subject to environmental contamination and, thus, to a high risk for infection. Efforts to describe the epidemiology of war-associated infections are complicated by difficult access to patients, limited availability of microbiology support, and widespread empirical antimicrobial drug use. Nevertheless, identifying the relevant pathogens is critical because war-associated injuries commonly become infected and antimicrobial drug–resistant bacteria are well-described in these injuries, including those in the Middle East (1–3). n nThe Medecins Sans Frontieres (MSF) surgical project in Amman, Jordan, was initially developed for war-injured Iraqis needing surgical reconstruction or management of chronic osteomyelitis. Infection management is based on organism-directed antimicrobial agents and wide surgical resection of involved tissue. The proximity of this project to the Syrian conflict provided an opportunity to describe microbiologic features of infections caused by war-associated injuries in Syrians, who may be at increased risk for infection-associated complications because of exclusion from care in official health systems. We describe a cross-sectional series of 61 Syrian orthopedic patients who had suspected infections, as determined on the basis of surgical samples obtained intraoperatively. n nSyrian patients admitted to the MSF clinic underwent initial surgical exploration of wounds; if infection was suspected, >3 intraoperative samples (bone, fibrous tissue, fluid) were obtained for culture and transported (at 4°–8°C) within 2 h to the laboratory at Ibn al-Haytham Hospital in Amman. Patients who were treated with antimicrobial drugs within 2 weeks before admission were excluded from analysis. n nWe retrospectively reviewed data for patients admitted during August 1, 2011–March 31, 2013. Data were collected from databases and individual charts in Amman and analyzed by using Stata 12 (http://www.stata.com/stata12/). This study was deemed exempt from additional ethical approval by the MSF review board because it involved routinely collected data. n nWe defined a multidrug-resistant (MDR) isolate as 1) extended-spectrum β-lactamase–expressing Enterobacteriaceae; 2) Pseudomonas aeruginosa and Acinetobacter baumannii isolates resistant to at least 1 agent in 3 antimicrobial categories typically used for treatment; or 3) methicillin-resistant Staphylococcus aureus (MRSA). Pathogen identification was conducted by using conventional methods and the API system (bio-Merieux, Durham, NC, USA). Antimicrobial drug susceptibility testing was conducted by using the MicroScan Walk-Away System (Dade Behring, West Sacramento, CA, USA). n nDuring the study period, 870 patient consultations were conducted, of which 345 (40%) were for patients from Syria. At the initial operating room evaluation, infection was suspected in 61 (18%) Syrians. These patients had a median age of 26 years (interquartile range 22–34); 98% were male. The median time from injury to admission was 5 months (interquartile range 1.2–8.1), but for 27 (44%) patients, the time from injury to admission was >6 months. The 2 most common injuries were gunshot wounds (32 patients [52%]) and wounds from explosions (20 patients [33%]). The dominant injury was located in an upper extremity in 14 (23%) patients and a lower extremity in 47 (77%) patients. n nFor the 61 patients, a total of 67 bacterial isolates were identified from cultures of surgical specimens. Overall, 45 (74%) patients had at least 1 positive culture, and 6 (13%) patients had polymicrobial results. Gram-negative organisms represented 24 (56%) of 43 isolates; 10 (23%) were P. aeruginosa, 8 (19%) were E. coli, and 6 (14%) were A. baumannii. Gram-positive bacteria, including MRSA, represented 19 (44%) of 43 isolates (Table). Overall, 31 (69%) of 45 patients with confirmed infection were positive for MDR organisms. Within this group, MRSA represented 8 (42%) of 19 staphylococcal isolates. n n n nTable n nAntimicrobial drug resistance among frequently isolated bacterial isolates from Syrian patients with war-associated wound infections, August 2011–March 2013* n n n nPatients who had experienced delayed definitive management were frequently positive for MDR organisms, especially gram-negative pathogens and MRSA. For a humanitarian surgical project, infection with MDR organisms leads to formidable diagnostic, treatment, and control challenges. For example, treatment of MDR infections requires ongoing access to high-quality clinical microbiology support; late-generation antimicrobial drugs, which are typically given parenterally for up to 6 weeks; trained personnel; and sufficient hospital space to isolate patients with resistant strains. Our findings support the previously reported linkage between war-associated injuries and infection with antimicrobial drug–resistant organisms (1–4) and the implications for patient management. n nThe source of antimicrobial drug–resistant organisms in war-associated injuries remains uncertain; possibilities include nosocomial transmission (5), particularly through prior contact with severely compromised health systems (6). Another possibility is fecal colonization with extended-spectrum β-lactamase–producing gram-negative bacteria. (7,8). Another likely contributor in Syria is the wide availability of antimicrobial drugs without a prescription (9). n nThis study has limitations. Although measures were taken to ensure that positive cultures represented clinical infection rather than colonization, we cannot exclude colonization as a possible source of some recovered organisms. In neglected war-associated injuries, multiple pathogens are potentially present, but every strain is not necessarily clinically relevant (10). Furthermore, complete patient histories are difficult to obtain in crisis settings, limiting our ability to describe all prior interventions. Study strengths included partnership with a high-quality culture laboratory, which is uncommon in programs treating war injuries; systemic sampling of patients with suspected infection; and use of intraoperative samples for culture. Further research needed in this neglected area includes prospective studies to determine the effect of MDR isolates on patient outcomes and randomized clinical trials of antimicrobial drug strategies to inform treatment protocols.

Highly Drug-Resistant Pathogens Implicated In Burn-Associated Bacteremia in an Iraqi Burn Care Unit

Objective In low- and middle-income countries, bloodstream infections are an important cause of mortality in patients with burns. Increasingly implicated in burn-associated infections are highly drug-resistant pathogens with limited treatment options. We describe the epidemiology of bloodstream infections in patients with burns in a humanitarian surgery project in Iraq. Methods We performed a retrospective, descriptive study of blood culture isolates identified between July 2008 and September 2009 among patients with burns in a single hospital in Iraq who developed sepsis. Results In 1169 inpatients admitted to the burn unit during the study period, 212 (18%) had suspected sepsis, and 65 (6%) had confirmed bacteremia. Sepsis was considered the primary cause of death in 198 patients (65%; 95% CI 65–70) of the 304 patients that died. The most commonly isolated organisms were Pseudomonas aeruginosa (22 isolates [34%]), Staphylococcus aureus (17 [26%]), Klebsiella pneumoniae (8 [12%]), Staphylococcus epidermidis (7 [11%]), Acinetobacter baumannii (6 [9%]), and Enterobacter cloacae (5 [8%]). A high proportion of Enterobacteriaceae strains produced extended-spectrum beta-lactamase and S. aureus isolates were uniformly methicillin-resistant. For gram-negative bacteria, the most reliably active antibiotics were imipenen and amikacin. Conclusions Burn patients with sepsis in Iraq were commonly found to have bloodstream pathogens resistant to most antibiotics available locally. Effective empirical therapy of burn sepsis in this region of Iraq would consist of vancomycin or teicoplanin and a carbapenem-class antibiotic with antipseudomonal activity.

Drug resistance and viral tropism in HIV-1 subtype C-infected patients in KwaZulu-Natal, South Africa : implications for future treatment options.

BackgroundDrug resistance poses a significant challenge for the successful application of highly active antiretroviral therapy (HAART) globally. Furthermore, emergence of HIV-1 isolates that preferentially use CXCR4 as a coreceptor for cell entry, either as a consequence of natural viral evolution or HAART use, may compromise the efficacy of CCR5 antagonists as alternative antiviral therapy. MethodsWe sequenced the pol gene of viruses from 45 individuals failing at least 6 months of HAART in Durban, South Africa, to determine the prevalence and patterns of drug-resistance mutations. Coreceptor use profiles of these viruses and those from 45 HAART-naive individuals were analyzed using phenotypic and genotypic approaches. ResultsNinety-five percent of HAART-failing patients had at least one drug-resistant mutation. Thymidine analog mutations (TAMs) were present in 55% of patients with 9% of individuals possessing mutations indicative of the TAM1 pathway, 44% had TAM2, whereas 7% had mutations common to both pathways. Sixty percent of HAART-failing subjects had X4/dual//mixed-tropic viruses compared with 30% of HAART-naïve subjects (P < 0.02). Genetic coreceptor use prediction algorithms correlated with phenotypic results with 60% of samples from HAART-failing subjects predicted to possess CXCR4-using (X4/dual/mixed viruses) versus 15% of HAART-naïve patients. ConclusionsThe high proportion of TAMs and X4/dual/mixed HIV-1 viruses among patients failing therapy highlight the need for intensified monitoring of patients taking HAART and the problem of diminished drug options (including CCR5 antagonists) for patients failing therapy in resource-poor settings.

Early warning indicators for first-line virologic failure independent of adherence measures in a South African urban clinic

We sought to develop individual-level Early Warning Indicators (EWI) of virologic failure (VF) for clinicians to use during routine care complementing WHO population-level EWI. A case-control study was conducted at a Durban clinic. Patients after ≥ 5 months of first-line antiretroviral therapy (ART) were defined as cases if they had VF [HIV-1 viral load (VL)>1000 copies/mL] and controls (2:1) if they had VL ≤ 1000 copies/mL. Pharmacy refills and pill counts were used as adherence measures. Participants responded to a questionnaire including validated psychosocial and symptom scales. Data were also collected from the medical record. Multivariable logistic regression models of VF included factors associated with VF (p<0.05) in univariable analyses. We enrolled 158 cases and 300 controls. In the final multivariable model, male gender, not having an active religious faith, practicing unsafe sex, having a family member with HIV, not being pleased with the clinic experience, symptoms of depression, fatigue, or rash, low CD4 counts, family recommending HIV care, and using a TV/radio as ART reminders (compared to mobile phones) were associated with VF independent of adherence measures. In this setting, we identified several key individual-level EWI associated with VF including novel psychosocial factors independent of adherence measures.

Coadministration of Lopinavir/Ritonavir and Rifampicin in HIV and Tuberculosis Co-Infected Adults in South Africa

Background In HIV-infected patients receiving rifampicin-based treatment for tuberculosis (TB), the dosage of lopinavir/ritonavir (LPV/r) is adjusted to prevent sub-therapeutic lopinavir concentrations. In this setting, South African clinicians were advised to administer super-boosted LPV/r (400 mg/400 mg) twice daily, instead of standard dosed LPV/r (400 mg/100 mg) twice daily. We sought to determine – in routine practice – the tolerability and HIV treatment outcomes associated with super-boosted LPV/r compared to unadjusted LPV/r in combination with rifampicin-based TB treatment. Methodology/Principle Findings We conducted a retrospective review of HIV-infected patients who receiving second-line ART with a LPV/r-containing regimen who required concomitant TB treatment. We identified 29 patients; the median age was 36 years (IQR 29–40), 22 (76%) were female, the median CD4 cell count and viral load at first-line ART failure was 86 cells/mm3 (IQR 21–159) and 39,457 copies/mL (IQR 6,025–157,500), respectively. According to physician preference, 15 (52%) of 29 patients received super-boosted LPV/r (400 mg/400 mg) every 12 hours during TB treatment and 14 (48%) of 29 patients received standard dose LPV/r (400 mg/100 mg) twice daily during TB treatment. Among patients who received super-boosted LPV/r there was a trend towards a higher rate of symptomatic transaminitis (27% vs. 7%; pu200a=u200a0.3), gastrointestinal toxicity (20% vs. 0%; pu200a=u200a0.2) and a significantly increased need for treatment discontinuation (47% vs. 7%; pu200a=u200a0.035. The durability of coadministered treatment was significantly shorter in patients who received super-boosted lopinavir/ritonavir with TB treatment compared to patients who received standard lopinavir/ritonavir dosing (log rank, Pu200a=u200a0.036). The rate of virologic failure was not higher in patients with unadjusted LPV/r dosing. Conclusions/Significance We observed a high rate of toxicity and need for treatment discontinuation among patients on standard rifampicin-based TB treatment who received super-boosted LPV/r.

Multidrug-resistant Chronic Osteomyelitis Complicating War Injury in Iraqi Civilians

BACKGROUNDnWar-related orthopedic injury is frequently complicated by environmental contamination and delays in management, placing victims at increased risk for long-term infectious complications. We describe, among Iraqi civilians with war-related chronic osteomyelitis, the bacteriology of infection at the time of admission.nnnMETHODSnIn the Médecins Sans Frontières Reconstructive Surgery Project in Amman, Jordan, we retrospectively reviewed baseline demographics and results of initial intraoperative surgical cultures among Iraqi civilians with suspected osteomyelitis.nnnRESULTSnOne hundred thirty-seven patients (90% male; median age, 35 years [interquartile range {IQR}, 28-46]; median time since initial injury, 19 months [IQR, 10-35]) were admitted with suspected chronic osteomyelitis after war-related injury. One hundred seven patients had a positive intraoperative culture. Before arrival, patients had undergone a median of 4 (IQR, 2-6) surgical procedures in Iraq. Fifty-nine (55%) of 107 patients with confirmed osteomyelitis had a multidrug-resistant (MDR) organism isolated at admission: cefepime-resistant Enterobacteriaceae (n = 40), methicillin-resistant Staphylococcus aureus (n = 16), and MDR Acinetobacter baumannii (n = 3). An association of borderline significance existed between a history of more than two prior surgical procedures in Iraq and an MDR isolate at program entry (multivariate: odds ratio, 5.3; 95% confidence interval, 0.9-30.6; p = 0.064).nnnCONCLUSIONnHealth care actors, including Iraqi health facilities and humanitarian medical organizations, must be aware of the link between chronic war injury and antimicrobial drug resistance in this region and should be prepared for the management challenges involved with the treatment of chronic drug-resistant osteomyelitis.

Factors Predicting Discordant Virological and Immunological Responses to Antiretroviral Therapy in HIV-1 Clade C Infected Zulu/Xhosa in South Africa

Factors predicting suboptimal CD4 cell recovery have been studied in HIV clade-B infected US and European populations. It is, however, uncertain to what extent these results are applicable to HIV clade-C infected African populations. Multivariate analysis using logistic regression and longitudinal analyses using mixed models were employed to assess the impact of age, gender, baseline CD4 cell count, hemoglobin, body mass index (BMI), tuberculosis and other opportunistic co-infections, and frequencies of regimen change on CD4 cell recovery at 12 and 30 months and on overtime change in CD4 cells among 442 virologically suppressed South Africans. Despite adequate virological response 37% (95% CI:32%–42%) and 83% (95% CI:79%–86%) of patients on antiretroviral therapy failed to restore CD4 cell counts ≥200 cells/mm3 after 12 and ≥500 cells/mm3 after 30 months, respectively, in this South African cohort. Critical risk factors for inadequate recovery were older age (pu200a=u200a0.001) and nadir CD4 cell count at ART initiation (p<0.0001), while concurrent TB co-infection, BMI, baseline hemoglobin, gender and antiretroviral regimen were not significant risk factors. These data suggest that greater efforts are needed to identify and treat HAART-eligible patients prior to severe CD4 cell decline or achievement of advanced age.