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ItemThe wide utility of rabbits as models of human diseases(Nature, 2018)Studies using the European rabbit Oryctolagus cuniculus contributed to elucidating numerous fundamental aspects of antibody structure and diversification mechanisms and continue to be valuable for the development and testing of therapeutic humanized polyclonal and monoclonal antibodies. Additionally, during the last two decades, the use of the European rabbit as an animal model has been increasingly extended to many human diseases. This review documents the continuing wide utility of the rabbit as a reliable disease model for development of therapeutics and vaccines and studies of the cellular and molecular mechanisms underlying many human diseases. Examples include syphilis, tuberculosis, HIV-AIDS, acute hepatic failure and diseases caused by noroviruses, ocular herpes, and papillomaviruses. The use of rabbits for vaccine development studies, which began with Louis Pasteur’s rabies vaccine in 1881, continues today with targets that include the potentially blinding HSV-1 virus infection and HIV-AIDS. Additionally, two highly fatal viral diseases, rabbit hemorrhagic disease and myxomatosis, affect the European rabbit and provide unique models to understand co-evolution between a vertebrate host and viral pathogens.
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ItemA portable device for nucleic acid quantification powered by sunlight, a flame or electricity(Nature, 2018)A decentralized approach to diagnostics can decrease the time to treatment of infectious diseases in resource-limited settings. Yet most modern diagnostic tools require stable electricity and are not portable. Here, we describe a portable device for isothermal nucleic-acid quantification that can operate with power from electricity, sunlight or a flame, and that can store heat from intermittent energy sources, for operation when electrical power is not available or reliable. We deployed the device in two Ugandan health clinics, where it successfully operated through multiple power outages, with equivalent performance when powered via sunlight or electricity. A direct comparison between the portable device and commercial qPCR (quantitative polymerase chain reaction) machines for samples from 71 Ugandan patients (29 of which were tested in Uganda) for the presence of Kaposi’s sarcoma-associated herpesvirus DNA showed 94% agreement, with the four discordant samples having the lowest concentration of the herpesvirus DNA. The device’s flexibility in power supply provides a needed solution for on-field diagnostics.
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ItemDoes U=U for breastfeeding mothers and infants? Breastfeeding by mothers on effective treatment for HIV infection in high-income settings(Elsevier, 2018)Can the campaign Undetectable=Untransmittable (U=U), established for the sexual transmission of HIV, be applied to the transmission of HIV through breastfeeding? European AIDS Clinical Society and, to some extent, American guidelines now state that mothers with HIV who wish to breastfeed should be supported, with increased clinical and virological monitoring. This Viewpoint summarises existing evidence on transmission of HIV through breastfeeding, differences in HIV dynamics and viral load between breastmilk and plasma, and the effects of antiretroviral therapy on infants. At present, insufficient evidence exists to make clear recommendations for the required frequency of clinical and virological monitoring for mother and infant in a breastfeeding relationship or for the action to be taken in the event of viral rebound. We propose a roadmap for collaborative research to provide the missing evidence required to enable mothers who wish to breastfeed to make a fully informed choice.
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ItemLopinavir plus nucleoside reverse-transcriptase inhibitors, lopinavir plus raltegravir, or lopinavir monotherapy for second-line treatment of HIV (EARNEST): 144-week follow-up results from a randomised controlled trial(The Lancet, 2018)Background Millions of HIV-infected people worldwide receive antiretroviral therapy (ART) in programmes using WHO-recommended standardised regimens. Recent WHO guidelines recommend a boosted protease inhibitor plus raltegravir as an alternative second-line combination. We assessed whether this treatment option offers any advantage over the standard protease inhibitor plus two nucleoside reverse-transcriptase inhibitors (NRTIs) second-line combination after 144 weeks of follow-up in typical programme settings. Methods We analysed the 144-week outcomes at the completion of the EARNEST trial, a randomised controlled trial done in HIV-infected adults or adolescents in 14 sites in five sub-Saharan African countries (Uganda, Zimbabwe, Malawi, Kenya, Zambia). Participants were those who were no longer responding to non-NRTI-based first-line ART, as assessed with WHO criteria, confirmed by viral-load testing. Participants were randomly assigned to receive a ritonavir-boosted protease inhibitor (lopinavir 400 mg with ritonavir 100 mg, twice per day) plus two or three clinician-selected NRTIs (protease inhibitor plus NRTI group), protease inhibitor plus raltegravir (400 mg twice per day; protease inhibitor plus raltegravir group), or protease inhibitor monotherapy (plus raltegravir induction for first 12 weeks, re-intensified to combination therapy after week 96; protease inhibitor monotherapy group). Randomisation was by computer-generated randomisation sequence, with variable block size. The primary outcome was viral load of less than 400 copies per mL at week 144, for which we assessed non-inferiority with a one-sided α of 0·025, and superiority with a two-sided α of 0·025. The EARNEST trial is registered with ISRCTN, number 37737787. Findings Between April 12, 2010, and April 29, 2011, 1837 patients were screened for eligibility, of whom 1277 patients were randomly assigned to an intervention group. In the primary (complete-case) analysis at 144 weeks, 317 (86%) of 367 in the protease inhibitor plus NRTI group had viral loads of less than 400 copies per mL compared with 312 (81%) of 383 in the protease inhibitor plus raltegravir group (p=0·07; lower 95% confidence limit for difference 10·2% vs specified non-inferiority margin 10%). In the protease inhibitor monotherapy group, 292 (78%) of 375 had viral loads of less than 400 copies per mL; p=0·003 versus the protease inhibitor plus NRTI group at 144 weeks. There was no difference between groups in serious adverse events, grade 3 or 4 adverse events (total or ART-related), or events that resulted in treatment modification. Interpretation Protease inhibitor plus raltegravir offered no advantage over protease inhibitor plus NRTI in virological efficacy or safety. In the primary analysis, protease inhibitor plus raltegravir did not meet non-inferiority criteria. A regimen of protease inhibitor with NRTIs remains the best standardised second-line regimen for use in programmes in resource-limited settings. Funding
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ItemTuberculous meningitis diagnosis and outcomes during the Xpert MTB/Rif era: a 6.5-year cohort study in Uganda(LSHTM, 2018)Background: Tuberculous meningitis (TBM) is the second most common cause of meningitis in sub-Saharan Africa and is notoriously difficult to diagnose. We describe the impact of improved TBM diagnostics over 6.5 years at two Ugandan referral hospitals. Methods: Cohort one received cerebrospinal fluid (CSF) smear microscopy only (2010-2013). Cohort two received smear microscopy and Xpert MTB/Rif (Xpert) on 1ml unprocessed CSF at physician discretion (2011-2013). Cohort three received smear microscopy, routine liquid-media culture and Xpert on large volume centrifuged CSF (2013-2017) for all meningitis suspects with a negative CSF cryptococcal antigen. We compared rates of microbiologically confirmed TBM and hospital outcomes over time. Results: 1672 HIV-infected adults presenting with suspected meningitis underwent lumbar puncture, of which 33% (558/1672) had negative CSF cryptococcal antigen and 12% (195/1672) were treated for TB meningitis. Over the study period, microbiological confirmation of TBM increased from 3% to 41% (P<0.01) and there was a decline in in-hospital mortality from 57% to 41% (P=0.27) amongst those with a known outcome. Adjusting for definite TBM diagnosis and antiretroviral therapy use, and using imputed data, assuming 50% of those with an unknown outcome died, the odds of dying were nearly twice as high in cohort one (adjusted odds ratio 1.7, 95% CI 0.7 to 4.4) compared to cohort three. Sensitivity of Xpert was 63% (38/60) and culture was 65% (39/60) against a composite reference standard. Conclusions: As TBM diagnostics have improved, microbiologically-confirmed TBM diagnoses have increased and in-hospital mortality has declined. Yet, mortality due to TB meningitis remains unacceptably high and further measures are needed to improve outcomes from TBM in Uganda.