• Antiretroviral therapy for HIV prevention: many concerns and challenges, but are there ways forward in sub-Saharan Africa?

      Zachariah, R; Harries, A D; Philips, M; Arnould, L; Sabapathy, K; O'Brien, D P; Ferreyra, C; Balkan, S; Médecins Sans Frontières, Medical Department (Operational Research), Brussels Operational Centre, Belgium. (2010-01-28)
      Scientists from the WHO have presented a theoretical mathematical model of the potential impact of universal voluntary HIV testing and counselling followed by immediate antiretroviral therapy (ART). The results of the model suggests that, in a generalised epidemic as severe as that in sub-Saharan Africa (SSA), HIV incidence may be reduced by 95% in 10 years and that this approach may be cost effective in the medium term. This offers a 'ray of hope' to those who have thus far only dreamed of curbing the HIV/AIDS epidemic in SSA, as until now the glaring truth has been pessimistic. When it comes to ART, approximately 7 of 10 people who clinically need ART still do not receive it. From an epidemic point of view, for every person placed on ART an estimated four to six others acquire HIV. The likelihood of achieving the targets of the Millennium Development Goals for 2015 and universal ART access by 2010 are thus extremely low. A new window of opportunity may have now opened, but there are many unanswered feasibility and acceptability issues. In this paper, we highlight four key operational challenges linked to acceptability and feasibility and discuss possible ways forward to address them.
    • Antiretroviral therapy outcomes in resource-limited settings for HIV-infected children <5 years of age.

      Sauvageot, D; Schaefer, M; Olson, D; Pujades-Rodriguez, M; O'Brien, D P; Epicentre, Paris, France. delphsauvageot@hotmail.com (2010-05)
      OBJECTIVE: We describe medium-term outcomes for young children receiving antiretroviral therapy (ART) in resource-limited countries. METHODS: Analyses were conducted on surveillance data for children <5 years of age receiving ART (initiated April 2002 to January 2008) in 48 HIV/AIDS treatment programs in Africa and Asia. Primary outcome measures were probability of remaining in care, probability of developing World Health Organization stage 4 clinical events, rate of switching to second-line ART, and drug toxicity, compared at 6, 12, 24, and 36 months of ART. RESULTS: Of 3936 children (90% in Africa) initiating ART, 9% were <12 months, 50% were 12 to 35 months, and 41% were 36 to 59 months of age. The median time of ART was 10.5 months. Probabilities of remaining in care after 12, 24, and 36 months of ART were 0.85, 0.80, and 0.75, respectively. Compared with children 36 to 59 months of age at ART initiation, probabilities of remaining in care were significantly lower for children <12 months of age. Overall, 55% and 69% of deaths and losses to follow-up occurred in the first 3 and 6 months of ART, respectively. Probabilities of developing stage 4 clinical events after 12, 24, and 36 months of ART were 0.03, 0.06, and 0.09, respectively. Only 33 subjects (0.8%) switched to second-line regimens, and 151 (3.8%) experienced severe drug toxicities. CONCLUSIONS: Large-scale ART for children <5 years of age in resource-limited settings is feasible, with encouraging clinical outcomes, but efforts should be increased to improve early HIV diagnosis and treatment.
    • The evaluation of a rapid in situ HIV confirmation test in a programme with a high failure rate of the WHO HIV two-test diagnostic algorithm.

      Klarkowski, D; Wazome, J M; Lokuge, K M; Shanks, L; Mills, C; O'Brien, D P; Public Health Department, Médecins Sans Frontières, Amsterdam, The Netherlands. derryck.klarkowski@amsterdam.msf.org (2009-02)
      BACKGROUND: Concerns about false-positive HIV results led to a review of testing procedures used in a Médecins Sans Frontières (MSF) HIV programme in Bukavu, eastern Democratic Republic of Congo. In addition to the WHO HIV rapid diagnostic test algorithm (RDT) (two positive RDTs alone for HIV diagnosis) used in voluntary counselling and testing (VCT) sites we evaluated in situ a practical field-based confirmation test against western blot WB. In addition, we aimed to determine the false-positive rate of the WHO two-test algorithm compared with our adapted protocol including confirmation testing, and whether weakly reactive compared with strongly reactive rapid test results were more likely to be false positives. METHODOLOGY/PRINCIPAL FINDINGS: 2864 clients presenting to MSF VCT centres in Bukavu during January to May 2006 were tested using Determine HIV-1/2 and UniGold HIV rapid tests in parallel by nurse counsellors. Plasma samples on 229 clients confirmed as double RDT positive by laboratory retesting were further tested using both WB and the Orgenics Immunocomb Combfirm HIV confirmation test (OIC-HIV). Of these, 24 samples were negative or indeterminate by WB representing a false-positive rate of the WHO two-test algorithm of 10.5% (95%CI 6.6-15.2). 17 of the 229 samples were weakly positive on rapid testing and all were negative or indeterminate by WB. The false-positive rate fell to 3.3% (95%CI 1.3-6.7) when only strong-positive rapid test results were considered. Agreement between OIC-HIV and WB was 99.1% (95%CI 96.9-99.9%) with no false OIC-HIV positives if stringent criteria for positive OIC-HIV diagnoses were used. CONCLUSIONS: The WHO HIV two-test diagnostic algorithm produced an unacceptably high level of false-positive diagnoses in our setting, especially if results were weakly positive. The most probable causes of the false-positive results were serological cross-reactivity or non-specific immune reactivity. Our findings show that the OIC-HIV confirmation test is practical and effective in field contexts. We propose that all double-positive HIV RDT samples should undergo further testing to confirm HIV seropositivity until the accuracy of the RDT testing algorithm has been established at programme level.
    • Illness in Returned Travelers and Immigrants/Refugees: The 6-Year Experience of Two Australian Infectious Diseases Units.

      O'Brien, D P; Leder, K; Matchett, E; Brown, G V; Torresi, J; Victorian Infectious Diseases Service, Centre for Clinical Research Excellence, Royal Melbourne Hospital, Victoria, Australia. obrien@amsterdam.msf.org (2008-02-21)
      BACKGROUND: Data comparing returned travelers and immigrants/refugees managed in a hospital setting is lacking. METHODS: We prospectively collected data on 1,106 patients with an illness likely acquired overseas who presented to two hospital-based Australian infectious diseases units over a 6-year period. RESULTS: Eighty-three percent of patients were travelers and 17% immigrants/refugees. In travelers, malaria (19%), gastroenteritis/diarrhea (15%), and upper respiratory tract infection (URTI) (7%) were the most common diagnoses. When compared with immigrants/refugees, travelers were significantly more likely to be diagnosed with gastroenteritis/diarrhea [odds ratio (OR) 8], malaria (OR 7), pneumonia (OR 6), URTI (OR 3), skin infection, dengue fever, typhoid/paratyphoid fever, influenza, and rickettsial disease. They were significantly less likely to be diagnosed with leprosy (OR 0.03), chronic hepatitis (OR 0.04), tuberculosis (OR 0.05), schistosomiasis (OR 0.3), and helminthic infection (OR 0.3). In addition, travelers were more likely to present within 1 month of entry into Australia (OR 96), and have fever (OR 8), skin (OR 6), gastrointestinal (OR 5), or neurological symptoms (OR 5) but were less likely to be asymptomatic (OR 0.1) or have anaemia (OR 0.4) or eosinophilia (OR 0.3). Diseases in travelers were more likely to have been acquired via a vector (OR 13) or food and water (OR 4), and less likely to have been acquired via the respiratory (OR 0.2) or skin (OR 0.6) routes. We also found that travel destination and classification of traveler can significantly influence the likelihood of a specific diagnosis in travelers. Six percent of travelers developed a potentially vaccine-preventable disease, with failure to vaccinate occurring in 31% of these cases in the pretravel medical consultation. CONCLUSIONS: There are important differences in the spectrum of illness, clinical features, and mode of disease transmission between returned travelers and immigrants/refugees presenting to hospital-based Australian infectious diseases units with an illness acquired overseas.
    • Management of BU-HIV co-infection

      O'Brien, D P; Ford, N; Vitoria, M; Christinet, V; Comte, E; Calmy, A; Stienstra, Y; Eholie, S; Asiedu, K (2014-06-20)
      Buruli Ulcer (BU)-HIV co-infection is an important emerging management challenge for BU disease. Limited by paucity of scientific studies, guidance for management of this co-infection has been lacking.
    • Outcomes for Mycobacterium ulcerans infection with combined surgery and antibiotic therapy: findings from a south-eastern Australian case series.

      O'Brien, D P; Hughes, A; Cheng, A C; Henry, M J; Callan, P; McDonald, A; Holten, I; Birrell, M; Sowerby, J M; Johnson, P D; et al. (Medical Society of Australia, 2007-01-15)
      OBJECTIVE: To describe the effect of antibiotics on outcomes of treatment for Buruli or Bairnsdale ulcer (BU) in patients on the Bellarine Peninsula in south-eastern Australia. DESIGN: Observational, non-randomised study with data collected prospectively or through medical record review. PATIENTS AND SETTING: All 40 patients with BU managed by staff of Barwon Health's Geelong Hospital (a public, secondary-level hospital) between 1 January 1998 and 31 December 2004. MAIN OUTCOME MEASURES: Epidemiology, clinical presentation, diagnosis, treatment and clinical outcomes. RESULTS: There were 59 treatment episodes; 29 involved surgery alone, 26 surgery plus antibiotics, and four antibiotics alone. Of 55 episodes where surgery was performed, minor surgery was required in 22, and major surgery in 33. Failure rates were 28% for surgery alone, and 19% for surgery plus antibiotics. Adjunctive antibiotic therapy was associated with increased treatment success for lesions with positive histological margins (P < 0.01), and lesions requiring major surgery for treatment of a first episode (P < 0.01). The combination of rifampicin and ciprofloxacin resulted in treatment success in eight of eight episodes, and no patients ceased therapy because of side effects with this regimen. CONCLUSIONS: Adjunctive antibiotic therapy may increase the effectiveness of BU surgical treatment, and this should be further assessed by larger randomised controlled trials. The combination of rifampicin and ciprofloxacin appears the most promising.
    • Outcomes of a remote, decentralized health center-based HIV/AIDS antiretroviral program in Zambia, 2003 to 2007

      Elema, R; Mills, C; Yun, O; Lokuge, K; Ssonko, C; Nyirongo, N; Mtonga, V; Zulu, H; Tu, D; Verputten, M; et al. (2009-02-11)
      A cross-sectional study of patients living with HIV/ AIDS treated during 2003 to 2007 in decentralized, rural health centers in Zambia was performed to measure virological outcomes after 12 months of antiretroviral therapy and identify factors associated with virological failure. Data from 228 patients who started antiretroviral therapy >12 months prior were analyzed. In all, 93% received stavudine + lamivudine + nevirapine regimens, and median antiretroviral therapy duration was 23.5 months (interquartile range 20-28). Of the 205 patients tested for viral load, 177 (86%) had viral load <1000 copies/mL. Probability of developing virological failure (viral load >1000 copies/mL) was 8.9% at 24 months and 19.6% at 32 months. Predictors for virological failure were <100% adherence, body mass index <18.5 kg/m(2), and women <40 years old. Of those with virological failure who underwent 3 to 6 months of intensive adherence counseling, 45% obtained virological success. In a remote, resource-limited setting in decentralized health centers, virological and immunological assessments of patients on antiretroviral therapy >12 months showed that positive health outcomes are achievable.
    • "Paradoxical" immune-mediated reactions to Mycobacterium ulcerans during antibiotic treatment: a result of treatment success, not failure.

      O'Brien, D P; Robson, M E; Callan, P P; McDonald, A H; Barwon Health, Geelong, VIC, Australia. daniel.obrien@amsterdam.msf.org. (2009-11-16)
      We present the first clinical descriptions of immune-mediated paradoxical reactions to effective antibiotic treatment for Mycobacterium ulcerans infection, which result in clinical deterioration after initial improvement. Recognition of this phenomenon could prevent unnecessary changes to antibiotic regimens, and might obviate the need for, or reduce the extent of, further surgery. (MJA 2009; 191: 564-566).
    • Successful treatment of Mycobacterium ulcerans osteomyelitis with minor surgical debridement and prolonged rifampicin and ciprofloxacin therapy: a case report.

      O'Brien, D P; Athan, E; Hughes, A; Johnson, P D; Department of Infectious Diseases, The Geelong Hospital, Ryrie Street, Geelong, Australia. daniel.obrien@amsterdam.msf.org. (BioMed Central, 2008-06)
      ABSTRACT: INTRODUCTION: Treatment for osteomyelitis-complicating Mycobacterium ulcerans infection typically requires extensive surgery and even amputation, with no reported benefit from adjunctive antibiotics. CASE PRESENTATION: We report a case of an 87-year-old woman with M. ulcerans osteomyelitis that resolved following limited surgical debridement and 6 months of therapy with rifampicin and ciprofloxacin. CONCLUSION: M. ulcerans osteomyelitis can be successfully treated with limited surgical debridement and adjunctive oral antibiotics.
    • Treatment Outcomes Stratified by Baseline Immunological Status Among Young Children Receiving Nonnucleoside Reverse-Transcriptase Inhibitor-Based Antiretroviral Therapy in Resource-Limited Settings.

      O'Brien, D P; Sauvageot, D; Olson, D; Schaeffer, M; Humblet, P; Pudjades, M; Ellman, T; Zachariah, R; Szumilin, E; Arnould, L; et al. (Published by: Infectious Diseases Society of America, 2007-05-01)
      A study of 568 children aged <5 years who commenced nonnucleoside reverse-transcriptase inhibitor-based antiretroviral therapy in resource-limited settings revealed good early outcomes. After 12 months of antiretroviral therapy, survival probability was 0.89 (95% confidence interval, 0.86-0.92), with no significant difference among children stratified on the basis of baseline immunological levels; 62% attained a CD4 cell percentage >25%, and 7% continued to have a CD4 cell percentage <15%.
    • Tuberculosis After HAART Initiation in HIV-Positive Patients from Five Countries with a High Tuberculosis Burden.

      Bonnet, M; Pinoges, L; Varaine, F; Oberhauser, B O; O'Brien, D P; Kebede, Y; Hewison, C; Zachariah, R; Ferradini, L; MSF Epicentre, Médecins Sans Frontieres, Paris, France. maryline.bonnet@geneva.msf.org (2006-06-12)
      BACKGROUND: HAART reduces tuberculosis (TB) incidence in people living with HIV/AIDS but those starting HAART may develop active TB or subclinical TB may become apparent in the immune reconstitution inflammatory syndrome. OBJECTIVE: To measure the incidence rate of notified TB in people receiving HAART in five HIV programmes occurring in low-resource countries with a high TB/HIV burden. METHODS: A retrospective review in five Médecins Sans Frontières programmes (Cambodia, Thailand, Kenya, Malawi and Cameroon) allowed incidence rates of notified TB to be calculated based on follow-up time after HAART initiation. RESULT: Among 3151 patients analysed, 90% had a CD4 cell count of < 200 cells/mul. Median follow-up time ranged from 3.7 months in Thailand or Kenya to 11.1 months in Cambodia. Incidence rates were 7.6, 10.4, 17.6, 14.3 and 4.8/100 person-years for pulmonary TB and 12.7, 4.3, 6.9, 2.1 and 0/100 person-years for extra-pulmonary TB in the programmes in Cambodia, Thailand, Kenya, Malawi and Cameroon, respectively. Overall, 62.3% of pulmonary TB and 54.9% of extra-pulmonary TB were diagnosed within 3 months after HAART initiation. CONCLUSION: High incidence rates of notified TB under HAART in programmes held in poor-resource countries were observed; these were likely to include both undiagnosed prevalent TB at HAART initiation and subclinical TB developing during the immune reconstitution inflammatory syndrome. This raises operational issues concerning TB diagnosis and treatment of TB/HIV-coinfected patients and prompts for urgent TB and HIV care integration.