Monitoring prevention or emergence of HIV drug resistance: results of a population-based foundational survey of early warning indicators in mainland Tanzania

BACKGROUND: In Tanzania, routine individual-level testing for HIV drug resistance (HIVDR) using laboratory genotyping and phenotyping is not feasible due to resource constraints. To monitor the prevention or emergence of HIVDR at a population level, WHO developed generic strategies to be adapted by countries, which include a set of early warning indicators (EWIs). METHODS: To establish a baseline of EWIs, we conducted a retrospective longitudinal survey of 35 purposively sampled care and treatment clinics in 17 regions of mainland Tanzania. We extracted data relevant for four EWIs (ART prescribing practices, patients lost to follow-up 12 months after ART initiation, retention on first-line ART at 12 months, and ART clinic appointment keeping in the first 12 months) from the patient monitoring system on patients who initiated ART at each respective facility in 2010. We uploaded patient information into WHO HIVResNet excel-based tool to compute national and facility averages of the EWIs and tested for associations between various programmatic factors and EWI performance using Fisher’s Exact Test. RESULTS: All sampled facilities met the WHO EWI target (100%) for ART prescribing practices. However, the national averages for patients lost to follow-up 12 months after ART initiation, retention on first-line ART at 12 months, and ART clinic appointment keeping in the first 12 months fell short, at 26%, 54% and 38%, respectively, compared to the WHO targets ≤ 20%, ≥ 70%, and ≥ 80%. Clinics with fewer patients lost to follow-up 12 months after ART initiation and more patients retained on first-line-ART at 12 months were more likely to have their patients spend the longest time in the facility (including wait-time and time with providers), (p = 0.011 and 0.007, respectively). CONCLUSION: Tanzania performed very well in EWI 1a, ART prescribing practices. However, its performance in other three EWIs was far below the WHO targets. This study provides a baseline for future monitoring of EWIs in Tanzania and highlights areas for improvement in the management of ART patients in order not only to prevent emergence of HIVDR due to programmatic factors, but also to improve the quality of life for ART patients

Decline in the prevalence HIV among pregnant women attending antenatal clinics in Tanzania, 2001-2011

Background: The Tanzania National AIDS Control Programme has established HIV sentinel surveillance among antenatal clinic (ANC) attendees as one of the methods for collecting data on HIV prevalence. This article provides trends on HIV prevalence for 92 sentinel sites that have constantly been part of the surveillance system since 2001 and have participated in at least three consecutive rounds.Method: The surveillance population included all pregnant women aged 15–49 years who were attending a selected sentinel ANC site for the first time for any pregnancy between 2001 and 2011. Serial testing for HIV infection was done anonymously by detecting for the presence of IgG antibodies to HIV on dried blood spot (DBS) specimens. HIV trends were calculated taking into account random effects from sites on the following variables:  region, sites and socio-demographic characteristics defined as age, marital status, parity, education level and duration of stay at present residence.Results: Overall, there was a significant decline in HIV prevalence from 9.6% in 2001 to 5.6% in 2011 (p<0.01). Specifically, the HIV prevalence among 15-24 years’ pregnant women significantly declined from 7.8% in 2001/2002 to 4% in 2011 (p<0.01). The decline in HIV prevalence occurred irrespective of residence, marital status, education level or previous pregnancies.Conclusion: There has been a significant decline in HIV infections among young pregnant women attending ANC clinics in Tanzania since 2001. This study also indicates that ANC surveillance among pregnant women over time can provide useful estimates of HIV situation between the population surveys

Knowledge and utilization of prevention of mother-to-child transmission of HIV services among pregnant women in Tanzania

Background: Human Immunodeficiency Virus (HIV) infection among children is mainly vectored through mother-to-child transmission. Prevention of mother-to-child-transmission strategy is highly effective; however, its accessibility and utilization is affected by the lack of knowledge among other factors. Methods: A cross-sectional study was conducted among antenatal care attendees in two districts in Tanzania to determine their knowledge and utilization of the prevention of MTCT services. Results:  We interviewed 160 antenatal care attendees aged 18-45 years with a mean (SD) age of 30.4 (6.3) years; 74 (46.2 %) were HIV-infected. HIV-infected women demonstrated significantly correct knowledge of HIV (p=0.001) and AIDS (p=0.014) than uninfected individuals. HIV-infected women also significantly demonstrated correct knowledge of mother-to-child transmission during pregnancy than HIV-uninfected women (p=0.016) and during delivery (p=0.005). A significant proportion of HIV-positive women compared to HIV-negative women were aware that correct use of antiretroviral during pregnancy can reduce the risk of mother-to-child-transmission of HIV (p<0.039), but only 6 (3.75%) of all women were aware that correct use of antiretroviral during delivery can significantly reduce the risk of mother-to-child-transmission. HIV-infected women had significant comprehensive knowledge of HIV/AIDS (p=0.001) and prevention of mother-to-child transmission of HIV (p=0.006) than HIV-negative women. Comprehensive knowledge prevention of mother-to-child transmission of HIV was low among the study participants. Male partners’ involvement in maternal antenatal care was significantly higher among HIV-infected women than males from the HIV-infected women group (p<0.006). Conclusion: The study demonstrated inadequate knowledge of PMTCT among women who made ANC visits. HIV uninfected women had poorer knowledge compared to the HIV-infected ones. Routine HIV counseling and testing services were highly accepted among these women

Optimizing the efficiency and implementation of cash transfers to improve adherence to antiretroviral therapy: study protocol for a cluster randomized controlled trial.

BACKGROUND: Antiretroviral therapy (ART) for HIV, taken daily, is an effective strategy to clinically suppress the virus, providing the dual benefit of improved survival and vastly decreasing the risk of transmission. However, this highly effective intervention has not yet reached all who could benefit. Cash transfers are increasingly recognized as an effective strategy to motivate behavior change and improve HIV care and treatment outcomes, including engagement in HIV care and adherence to ART. Despite a growing evidence base and strong theoretical foundation for the cash transfer approach, key questions remain. To address these questions and begin to bridge the "know-do gap" with respect to cash transfers, our team is employing an implementation science approach to iterative development of an incentive-based intervention to promote ART uptake and adherence among people living with HIV (PLHIV) in the Lake Zone region, Tanzania. METHODS: We will conduct a type I hybrid implementation-effectiveness trial to test the effectiveness of a cash transfer intervention on the outcome of HIV viral suppression, and concurrently examine the potential for real-world implementation with a mobile health technology (mHealth) system. Specifically, our team will expand the intervention to 32 clinics and enroll 1984 PLHIV to (a) evaluate its effectiveness by conducting a cluster randomized controlled trial with clinics as the unit of randomization and 12-month viral suppression as the primary outcome and (b) evaluate the implementation challenges and successes at multiple levels (patient, provider, clinic). DISCUSSION: This trial will provide evidence not only about the real-world effectiveness of cash transfers for retention in HIV care and viral suppression, but also on the implementation challenges and successes that will facilitate or hinder wider scale-up within Tanzania and beyond. TRIAL REGISTRATION: ClinicalTrials.gov NCT04201353 . Registered on December 17, 2019

Trends in Prevalence of Advanced HIV Disease at Antiretroviral Therapy Enrollment - 10 Countries, 2004-2015.

Monitoring prevalence of advanced human immunodeficiency virus (HIV) disease (i.e., CD4+ T-cell count <200 cells/μL) among persons starting antiretroviral therapy (ART) is important to understand ART program outcomes, inform HIV prevention strategy, and forecast need for adjunctive therapies.*,†,§ To assess trends in prevalence of advanced disease at ART initiation in 10 high-burden countries during 2004-2015, records of 694,138 ART enrollees aged ≥15 years from 797 ART facilities were analyzed. Availability of national electronic medical record systems allowed up-to-date evaluation of trends in Haiti (2004-2015), Mozambique (2004-2014), and Namibia (2004-2012), where prevalence of advanced disease at ART initiation declined from 75% to 34% (p<0.001), 73% to 37% (p<0.001), and 80% to 41% (p<0.001), respectively. Significant declines in prevalence of advanced disease during 2004-2011 were observed in Nigeria, Swaziland, Uganda, Vietnam, and Zimbabwe. The encouraging declines in prevalence of advanced disease at ART enrollment are likely due to scale-up of testing and treatment services and ART-eligibility guidelines encouraging earlier ART initiation. However, in 2015, approximately a third of new ART patients still initiated ART with advanced HIV disease. To reduce prevalence of advanced disease at ART initiation, adoption of World Health Organization (WHO)-recommended "treat-all" guidelines and strategies to facilitate earlier HIV testing and treatment are needed to reduce HIV-related mortality and HIV incidence

Leave no one behind: response to new evidence and guidelines for the management of cryptococcal meningitis in low-income and middle-income countries

In 2018, WHO issued guidelines for the diagnosis, prevention, and management of HIV-related cryptococcal disease. Two strategies are recommended to reduce the high mortality associated with HIV-related cryptococcal meningitis in low-income and middle-income countries (LMICs): optimised combination therapies for confirmed meningitis cases and cryptococcal antigen screening programmes for ambulatory people living with HIV who access care. WHO's preferred therapy for the treatment of HIV-related cryptococcal meningitis in LMICs is 1 week of amphotericin B plus flucytosine, and the alternative therapy is 2 weeks of fluconazole plus flucytosine. In the ACTA trial, 1-week (short course) amphotericin B plus flucytosine resulted in a 10-week mortality of 24% (95% CI −16 to 32) and 2 weeks of fluconazole and flucytosine resulted in a 10-week mortality of 35% (95% CI −29 to 41). However, with widely used fluconazole monotherapy, mortality because of HIV-related cryptococcal meningitis is approximately 70% in many African LMIC settings. Therefore, the potential to transform the management of HIV-related cryptococcal meningitis in resource-limited settings is substantial. Sustainable access to essential medicines, including flucytosine and amphotericin B, in LMICs is paramount and the focus of this Personal View

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

SummaryBackground Azithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatoryactions. We aimed to evaluate the safety and efficacy of azithromycin in patients admitted to hospital with COVID-19.Methods In this randomised, controlled, open-label, adaptive platform trial (Randomised Evaluation of COVID-19Therapy [RECOVERY]), several possible treatments were compared with usual care in patients admitted to hospitalwith COVID-19 in the UK. The trial is underway at 176 hospitals in the UK. Eligible and consenting patients wererandomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once perday by mouth or intravenously for 10 days or until discharge (or allocation to one of the other RECOVERY treatmentgroups). Patients were assigned via web-based simple (unstratified) randomisation with allocation concealment andwere twice as likely to be randomly assigned to usual care than to any of the active treatment groups. Participants andlocal study staff were not masked to the allocated treatment, but all others involved in the trial were masked to theoutcome data during the trial. The primary outcome was 28-day all-cause mortality, assessed in the intention-to-treatpopulation. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936.Findings Between April 7 and Nov 27, 2020, of 16 442 patients enrolled in the RECOVERY trial, 9433 (57%) wereeligible and 7763 were included in the assessment of azithromycin. The mean age of these study participants was65·3 years (SD 15·7) and approximately a third were women (2944 [38%] of 7763). 2582 patients were randomlyallocated to receive azithromycin and 5181 patients were randomly allocated to usual care alone. Overall,561 (22%) patients allocated to azithromycin and 1162 (22%) patients allocated to usual care died within 28 days(rate ratio 0·97, 95% CI 0·87–1·07; p=0·50). No significant difference was seen in duration of hospital stay (median10 days [IQR 5 to >28] vs 11 days [5 to >28]) or the proportion of patients discharged from hospital alive within 28 days(rate ratio 1·04, 95% CI 0·98–1·10; p=0·19). Among those not on invasive mechanical ventilation at baseline, nosignificant difference was seen in the proportion meeting the composite endpoint of invasive mechanical ventilationor death (risk ratio 0·95, 95% CI 0·87–1·03; p=0·24).Interpretation In patients admitted to hospital with COVID-19, azithromycin did not improve survival or otherprespecified clinical outcomes. Azithromycin use in patients admitted to hospital with COVID-19 should be restrictedto patients in whom there is a clear antimicrobial indication

Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Background: In this study, we aimed to evaluate the effects of tocilizumab in adult patients admitted to hospital with COVID-19 with both hypoxia and systemic inflammation. Methods: This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. Those trial participants with hypoxia (oxygen saturation &lt;92% on air or requiring oxygen therapy) and evidence of systemic inflammation (C-reactive protein ≥75 mg/L) were eligible for random assignment in a 1:1 ratio to usual standard of care alone versus usual standard of care plus tocilizumab at a dose of 400 mg–800 mg (depending on weight) given intravenously. A second dose could be given 12–24 h later if the patient's condition had not improved. The primary outcome was 28-day mortality, assessed in the intention-to-treat population. The trial is registered with ISRCTN (50189673) and ClinicalTrials.gov (NCT04381936). Findings: Between April 23, 2020, and Jan 24, 2021, 4116 adults of 21 550 patients enrolled into the RECOVERY trial were included in the assessment of tocilizumab, including 3385 (82%) patients receiving systemic corticosteroids. Overall, 621 (31%) of the 2022 patients allocated tocilizumab and 729 (35%) of the 2094 patients allocated to usual care died within 28 days (rate ratio 0·85; 95% CI 0·76–0·94; p=0·0028). Consistent results were seen in all prespecified subgroups of patients, including those receiving systemic corticosteroids. Patients allocated to tocilizumab were more likely to be discharged from hospital within 28 days (57% vs 50%; rate ratio 1·22; 1·12–1·33; p&lt;0·0001). Among those not receiving invasive mechanical ventilation at baseline, patients allocated tocilizumab were less likely to reach the composite endpoint of invasive mechanical ventilation or death (35% vs 42%; risk ratio 0·84; 95% CI 0·77–0·92; p&lt;0·0001). Interpretation: In hospitalised COVID-19 patients with hypoxia and systemic inflammation, tocilizumab improved survival and other clinical outcomes. These benefits were seen regardless of the amount of respiratory support and were additional to the benefits of systemic corticosteroids. Funding: UK Research and Innovation (Medical Research Council) and National Institute of Health Research