Efficacy and safety of COVID-19 vaccines.

BACKGROUND: Different forms of vaccines have been developed to prevent the SARS-CoV-2 virus and subsequent COVID-19 disease. Several are in widespread use globally.  OBJECTIVES: To assess the efficacy and safety of COVID-19 vaccines (as a full primary vaccination series or a booster dose) against SARS-CoV-2. SEARCH METHODS: We searched the Cochrane COVID-19 Study Register and the COVID-19 L·OVE platform (last search date 5 November 2021). We also searched the WHO International Clinical Trials Registry Platform, regulatory agency websites, and Retraction Watch. SELECTION CRITERIA: We included randomized controlled trials (RCTs) comparing COVID-19 vaccines to placebo, no vaccine, other active vaccines, or other vaccine schedules. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. We used GRADE to assess the certainty of evidence for all except immunogenicity outcomes.  We synthesized data for each vaccine separately and presented summary effect estimates with 95% confidence intervals (CIs).  MAIN RESULTS: We included and analyzed 41 RCTs assessing 12 different vaccines, including homologous and heterologous vaccine schedules and the effect of booster doses. Thirty-two RCTs were multicentre and five were multinational. The sample sizes of RCTs were 60 to 44,325 participants. Participants were aged: 18 years or older in 36 RCTs; 12 years or older in one RCT; 12 to 17 years in two RCTs; and three to 17 years in two RCTs. Twenty-nine RCTs provided results for individuals aged over 60 years, and three RCTs included immunocompromized patients. No trials included pregnant women. Sixteen RCTs had two-month follow-up or less, 20 RCTs had two to six months, and five RCTs had greater than six to 12 months or less. Eighteen reports were based on preplanned interim analyses. Overall risk of bias was low for all outcomes in eight RCTs, while 33 had concerns for at least one outcome. We identified 343 registered RCTs with results not yet available.  This abstract reports results for the critical outcomes of confirmed symptomatic COVID-19, severe and critical COVID-19, and serious adverse events only for the 10 WHO-approved vaccines. For remaining outcomes and vaccines, see main text. The evidence for mortality was generally sparse and of low or very low certainty for all WHO-approved vaccines, except AD26.COV2.S (Janssen), which probably reduces the risk of all-cause mortality (risk ratio (RR) 0.25, 95% CI 0.09 to 0.67; 1 RCT, 43,783 participants; high-certainty evidence). Confirmed symptomatic COVID-19 High-certainty evidence found that BNT162b2 (BioNtech/Fosun Pharma/Pfizer), mRNA-1273 (ModernaTx), ChAdOx1 (Oxford/AstraZeneca), Ad26.COV2.S, BBIBP-CorV (Sinopharm-Beijing), and BBV152 (Bharat Biotect) reduce the incidence of symptomatic COVID-19 compared to placebo (vaccine efficacy (VE): BNT162b2: 97.84%, 95% CI 44.25% to 99.92%; 2 RCTs, 44,077 participants; mRNA-1273: 93.20%, 95% CI 91.06% to 94.83%; 2 RCTs, 31,632 participants; ChAdOx1: 70.23%, 95% CI 62.10% to 76.62%; 2 RCTs, 43,390 participants; Ad26.COV2.S: 66.90%, 95% CI 59.10% to 73.40%; 1 RCT, 39,058 participants; BBIBP-CorV: 78.10%, 95% CI 64.80% to 86.30%; 1 RCT, 25,463 participants; BBV152: 77.80%, 95% CI 65.20% to 86.40%; 1 RCT, 16,973 participants). Moderate-certainty evidence found that NVX-CoV2373 (Novavax) probably reduces the incidence of symptomatic COVID-19 compared to placebo (VE 82.91%, 95% CI 50.49% to 94.10%; 3 RCTs, 42,175 participants). There is low-certainty evidence for CoronaVac (Sinovac) for this outcome (VE 69.81%, 95% CI 12.27% to 89.61%; 2 RCTs, 19,852 participants). Severe or critical COVID-19 High-certainty evidence found that BNT162b2, mRNA-1273, Ad26.COV2.S, and BBV152 result in a large reduction in incidence of severe or critical disease due to COVID-19 compared to placebo (VE: BNT162b2: 95.70%, 95% CI 73.90% to 99.90%; 1 RCT, 46,077 participants; mRNA-1273: 98.20%, 95% CI 92.80% to 99.60%; 1 RCT, 28,451 participants; AD26.COV2.S: 76.30%, 95% CI 57.90% to 87.50%; 1 RCT, 39,058 participants; BBV152: 93.40%, 95% CI 57.10% to 99.80%; 1 RCT, 16,976 participants). Moderate-certainty evidence found that NVX-CoV2373 probably reduces the incidence of severe or critical COVID-19 (VE 100.00%, 95% CI 86.99% to 100.00%; 1 RCT, 25,452 participants). Two trials reported high efficacy of CoronaVac for severe or critical disease with wide CIs, but these results could not be pooled. Serious adverse events (SAEs) mRNA-1273, ChAdOx1 (Oxford-AstraZeneca)/SII-ChAdOx1 (Serum Institute of India), Ad26.COV2.S, and BBV152 probably result in little or no difference in SAEs compared to placebo (RR: mRNA-1273: 0.92, 95% CI 0.78 to 1.08; 2 RCTs, 34,072 participants; ChAdOx1/SII-ChAdOx1: 0.88, 95% CI 0.72 to 1.07; 7 RCTs, 58,182 participants; Ad26.COV2.S: 0.92, 95% CI 0.69 to 1.22; 1 RCT, 43,783 participants); BBV152: 0.65, 95% CI 0.43 to 0.97; 1 RCT, 25,928 participants). In each of these, the likely absolute difference in effects was fewer than 5/1000 participants. Evidence for SAEs is uncertain for BNT162b2, CoronaVac, BBIBP-CorV, and NVX-CoV2373 compared to placebo (RR: BNT162b2: 1.30, 95% CI 0.55 to 3.07; 2 RCTs, 46,107 participants; CoronaVac: 0.97, 95% CI 0.62 to 1.51; 4 RCTs, 23,139 participants; BBIBP-CorV: 0.76, 95% CI 0.54 to 1.06; 1 RCT, 26,924 participants; NVX-CoV2373: 0.92, 95% CI 0.74 to 1.14; 4 RCTs, 38,802 participants). For the evaluation of heterologous schedules, booster doses, and efficacy against variants of concern, see main text of review. AUTHORS' CONCLUSIONS: Compared to placebo, most vaccines reduce, or likely reduce, the proportion of participants with confirmed symptomatic COVID-19, and for some, there is high-certainty evidence that they reduce severe or critical disease. There is probably little or no difference between most vaccines and placebo for serious adverse events. Over 300 registered RCTs are evaluating the efficacy of COVID-19 vaccines, and this review is updated regularly on the COVID-NMA platform (covid-nma.com). Implications for practice Due to the trial exclusions, these results cannot be generalized to pregnant women, individuals with a history of SARS-CoV-2 infection, or immunocompromized people. Most trials had a short follow-up and were conducted before the emergence of variants of concern. Implications for research Future research should evaluate the long-term effect of vaccines, compare different vaccines and vaccine schedules, assess vaccine efficacy and safety in specific populations, and include outcomes such as preventing long COVID-19. Ongoing evaluation of vaccine efficacy and effectiveness against emerging variants of concern is also vital.

Antibody tests for identification of current and past infection with SARS-CoV-2.

BACKGROUND: The diagnostic challenges associated with the COVID-19 pandemic resulted in rapid development of diagnostic test methods for detecting SARS-CoV-2 infection. Serology tests to detect the presence of antibodies to SARS-CoV-2 enable detection of past infection and may detect cases of SARS-CoV-2 infection that were missed by earlier diagnostic tests. Understanding the diagnostic accuracy of serology tests for SARS-CoV-2 infection may enable development of effective diagnostic and management pathways, inform public health management decisions and understanding of SARS-CoV-2 epidemiology. OBJECTIVES: To assess the accuracy of antibody tests, firstly, to determine if a person presenting in the community, or in primary or secondary care has current SARS-CoV-2 infection according to time after onset of infection and, secondly, to determine if a person has previously been infected with SARS-CoV-2. Sources of heterogeneity investigated included: timing of test, test method, SARS-CoV-2 antigen used, test brand, and reference standard for non-SARS-CoV-2 cases. SEARCH METHODS: The COVID-19 Open Access Project living evidence database from the University of Bern (which includes daily updates from PubMed and Embase and preprints from medRxiv and bioRxiv) was searched on 30 September 2020. We included additional publications from the Evidence for Policy and Practice Information and Co-ordinating Centre (EPPI-Centre) 'COVID-19: Living map of the evidence' and the Norwegian Institute of Public Health 'NIPH systematic and living map on COVID-19 evidence'. We did not apply language restrictions. SELECTION CRITERIA: We included test accuracy studies of any design that evaluated commercially produced serology tests, targeting IgG, IgM, IgA alone, or in combination. Studies must have provided data for sensitivity, that could be allocated to a predefined time period after onset of symptoms, or after a positive RT-PCR test. Small studies with fewer than 25 SARS-CoV-2 infection cases were excluded. We included any reference standard to define the presence or absence of SARS-CoV-2 (including reverse transcription polymerase chain reaction tests (RT-PCR), clinical diagnostic criteria, and pre-pandemic samples). DATA COLLECTION AND ANALYSIS: We use standard screening procedures with three reviewers. Quality assessment (using the QUADAS-2 tool) and numeric study results were extracted independently by two people. Other study characteristics were extracted by one reviewer and checked by a second. We present sensitivity and specificity with 95% confidence intervals (CIs) for each test and, for meta-analysis, we fitted univariate random-effects logistic regression models for sensitivity by eligible time period and for specificity by reference standard group. Heterogeneity was investigated by including indicator variables in the random-effects logistic regression models. We tabulated results by test manufacturer and summarised results for tests that were evaluated in 200 or more samples and that met a modification of UK Medicines and Healthcare products Regulatory Agency (MHRA) target performance criteria. MAIN RESULTS: We included 178 separate studies (described in 177 study reports, with 45 as pre-prints) providing 527 test evaluations. The studies included 64,688 samples including 25,724 from people with confirmed SARS-CoV-2; most compared the accuracy of two or more assays (102/178, 57%). Participants with confirmed SARS-CoV-2 infection were most commonly hospital inpatients (78/178, 44%), and pre-pandemic samples were used by 45% (81/178) to estimate specificity. Over two-thirds of studies recruited participants based on known SARS-CoV-2 infection status (123/178, 69%). All studies were conducted prior to the introduction of SARS-CoV-2 vaccines and present data for naturally acquired antibody responses. Seventy-nine percent (141/178) of studies reported sensitivity by week after symptom onset and 66% (117/178) for convalescent phase infection. Studies evaluated enzyme-linked immunosorbent assays (ELISA) (165/527; 31%), chemiluminescent assays (CLIA) (167/527; 32%) or lateral flow assays (LFA) (188/527; 36%). Risk of bias was high because of participant selection (172, 97%); application and interpretation of the index test (35, 20%); weaknesses in the reference standard (38, 21%); and issues related to participant flow and timing (148, 82%). We judged that there were high concerns about the applicability of the evidence related to participants in 170 (96%) studies, and about the applicability of the reference standard in 162 (91%) studies. Average sensitivities for current SARS-CoV-2 infection increased by week after onset for all target antibodies. Average sensitivity for the combination of either IgG or IgM was 41.1% in week one (95% CI 38.1 to 44.2; 103 evaluations; 3881 samples, 1593 cases), 74.9% in week two (95% CI 72.4 to 77.3; 96 evaluations, 3948 samples, 2904 cases) and 88.0% by week three after onset of symptoms (95% CI 86.3 to 89.5; 103 evaluations, 2929 samples, 2571 cases). Average sensitivity during the convalescent phase of infection (up to a maximum of 100 days since onset of symptoms, where reported) was 89.8% for IgG (95% CI 88.5 to 90.9; 253 evaluations, 16,846 samples, 14,183 cases), 92.9% for IgG or IgM combined (95% CI 91.0 to 94.4; 108 evaluations, 3571 samples, 3206 cases) and 94.3% for total antibodies (95% CI 92.8 to 95.5; 58 evaluations, 7063 samples, 6652 cases). Average sensitivities for IgM alone followed a similar pattern but were of a lower test accuracy in every time slot. Average specificities were consistently high and precise, particularly for pre-pandemic samples which provide the least biased estimates of specificity (ranging from 98.6% for IgM to 99.8% for total antibodies). Subgroup analyses suggested small differences in sensitivity and specificity by test technology however heterogeneity in study results, timing of sample collection, and smaller sample numbers in some groups made comparisons difficult. For IgG, CLIAs were the most sensitive (convalescent-phase infection) and specific (pre-pandemic samples) compared to both ELISAs and LFAs (P < 0.001 for differences across test methods). The antigen(s) used (whether from the Spike-protein or nucleocapsid) appeared to have some effect on average sensitivity in the first weeks after onset but there was no clear evidence of an effect during convalescent-phase infection. Investigations of test performance by brand showed considerable variation in sensitivity between tests, and in results between studies evaluating the same test. For tests that were evaluated in 200 or more samples, the lower bound of the 95% CI for sensitivity was 90% or more for only a small number of tests (IgG, n = 5; IgG or IgM, n = 1; total antibodies, n = 4). More test brands met the MHRA minimum criteria for specificity of 98% or above (IgG, n = 16; IgG or IgM, n = 5; total antibodies, n = 7). Seven assays met the specified criteria for both sensitivity and specificity. In a low-prevalence (2%) setting, where antibody testing is used to diagnose COVID-19 in people with symptoms but who have had a negative PCR test, we would anticipate that 1 (1 to 2) case would be missed and 8 (5 to 15) would be falsely positive in 1000 people undergoing IgG or IgM testing in week three after onset of SARS-CoV-2 infection. In a seroprevalence survey, where prevalence of prior infection is 50%, we would anticipate that 51 (46 to 58) cases would be missed and 6 (5 to 7) would be falsely positive in 1000 people having IgG tests during the convalescent phase (21 to 100 days post-symptom onset or post-positive PCR) of SARS-CoV-2 infection. AUTHORS' CONCLUSIONS: Some antibody tests could be a useful diagnostic tool for those in whom molecular- or antigen-based tests have failed to detect the SARS-CoV-2 virus, including in those with ongoing symptoms of acute infection (from week three onwards) or those presenting with post-acute sequelae of COVID-19. However, antibody tests have an increasing likelihood of detecting an immune response to infection as time since onset of infection progresses and have demonstrated adequate performance for detection of prior infection for sero-epidemiological purposes. The applicability of results for detection of vaccination-induced antibodies is uncertain.

Chemotherapy for second-stage human African trypanosomiasis: drugs in use.

BACKGROUND: Human African trypanosomiasis, or sleeping sickness, is a severe disease affecting people in the poorest parts of Africa. It is usually fatal without treatment. Conventional treatments require days of intravenous infusion, but a recently developed drug, fexinidazole, can be given orally. Another oral drug candidate, acoziborole, is undergoing clinical development and will be considered in subsequent editions.   OBJECTIVES: To evaluate the effectiveness and safety of currently used drugs for treating second-stage Trypanosoma brucei gambiense trypanosomiasis (gambiense human African trypanosomiasis, g-HAT). SEARCH METHODS: On 14 May 2021, we searched the Cochrane Infectious Diseases Group Specialized Register, the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, Latin American and Caribbean Health Science Information database, BIOSIS, ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform. We also searched reference lists of included studies, contacted researchers working in the field, and contacted relevant organizations. SELECTION CRITERIA: Eligible studies were randomized controlled trials that included adults and children with second-stage g-HAT, treated with anti-trypanosomal drugs currently in use. DATA COLLECTION AND ANALYSIS: Two review authors extracted data and assessed risk of bias; a third review author acted as an arbitrator if needed. The included trial only reported dichotomous outcomes, which we presented as risk ratio (RR) or risk difference (RD) with 95% confidence intervals (CI).   MAIN RESULTS: We included one trial comparing fexinidazole to nifurtimox combined with eflornithine (NECT). This trial was conducted between October 2012 and November 2016 in the Democratic Republic of the Congo and the Central African Republic, and included 394 participants. The study reported on efficacy and safety, with up to 24 months' follow-up.  We judged the study to be at low risk of bias in all domains except blinding;  as the route of administration and dosing regimens differed between treatment groups,  participants and personnel were not blinded, resulting in a high risk of performance bias.   Mortality with fexinidazole may be higher at 24 months compared to NECT. There were 9/264 deaths in the fexinidazole group and 2/130 deaths in the NECT group (RR 2.22, 95% CI 0.49 to 10.11; 394 participants; low-certainty evidence). None of the deaths were related to treatment. Fexinidazole likely results in an increase in the number of people relapsing during follow-up, with 14 participants in the fexinidazole group (14/264) and none in the NECT group (0/130) relapsing at 24 months (RD 0.05, 95% CI 0.02 to 0.08; 394 participants; moderate-certainty evidence).   We are uncertain whether there is any difference between the drugs regarding the incidence of serious adverse events at 24 months. (31/264 with fexinidazole and 13/130 with NECT group at 24 months). Adverse events were common with both drugs (247/264 with fexinidazole versus 121/130 with NECT), with no difference between groups (RR 1.01, 95% CI 0.95 to 1.06; 394 participants; moderate-certainty evidence).  AUTHORS' CONCLUSIONS: Oral treatment with fexinidazole is much easier to administer than conventional treatment, but deaths and relapse appear to be more common. However, the advantages or an oral option are considerable, in terms of convenience, avoiding hospitalisation and multiple intravenous infusions, thus increasing adherence.

Vaccines for preventing rotavirus diarrhoea: vaccines in use.

BACKGROUND: Rotavirus is a common cause of diarrhoea, diarrhoea-related hospital admissions, and diarrhoea-related deaths worldwide. Rotavirus vaccines prequalified by the World Health Organization (WHO) include Rotarix (GlaxoSmithKline), RotaTeq (Merck), and, more recently, Rotasiil (Serum Institute of India Ltd.), and Rotavac (Bharat Biotech Ltd.). OBJECTIVES: To evaluate rotavirus vaccines prequalified by the WHO for their efficacy and safety in children. SEARCH METHODS: On 30 November 2020, we searched PubMed, the Cochrane Infectious Diseases Group Specialized Register, CENTRAL (published in the Cochrane Library), Embase, LILACS, Science Citation Index Expanded, Social Sciences Citation Index, Conference Proceedings Citation Index-Science, Conference Proceedings Citation Index-Social Science & Humanities. We also searched the WHO ICTRP, ClinicalTrials.gov, clinical trial reports from manufacturers' websites, and reference lists of included studies, and relevant systematic reviews. SELECTION CRITERIA: We selected randomized controlled trials (RCTs) conducted in children that compared rotavirus vaccines prequalified for use by the WHO with either placebo or no intervention. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial eligibility and assessed risk of bias. One author extracted data and a second author cross-checked them. We combined dichotomous data using the risk ratio (RR) and 95% confidence interval (CI). We stratified the analyses by under-five country mortality rate and used GRADE to evaluate evidence certainty. MAIN RESULTS: Sixty trials met the inclusion criteria and enrolled a total of 228,233 participants. Thirty-six trials (119,114 participants) assessed Rotarix, 15 trials RotaTeq (88,934 participants), five trials Rotasiil (11,753 participants), and four trials Rotavac (8432 participants). Rotarix Infants vaccinated and followed up for the first year of life In low-mortality countries, Rotarix prevented 93% of severe rotavirus diarrhoea cases (14,976 participants, 4 trials; high-certainty evidence), and 52% of severe all-cause diarrhoea cases (3874 participants, 1 trial; moderate-certainty evidence).  In medium-mortality countries, Rotarix prevented 79% of severe rotavirus diarrhoea cases (31,671 participants, 4 trials; high-certainty evidence), and 36% of severe all-cause diarrhoea cases (26,479 participants, 2 trials; high-certainty evidence).  In high-mortality countries, Rotarix prevented 58% of severe rotavirus diarrhoea cases (15,882 participants, 4 trials; high-certainty evidence), and 27% of severe all-cause diarrhoea cases (5639 participants, 2 trials; high-certainty evidence). Children vaccinated and followed up for two years In low-mortality countries, Rotarix prevented 90% of severe rotavirus diarrhoea cases (18,145 participants, 6 trials; high-certainty evidence), and 51% of severe all-cause diarrhoea episodes (6269 participants, 2 trials; moderate-certainty evidence).   In medium-mortality countries, Rotarix prevented 77% of severe rotavirus diarrhoea cases (28,834 participants, 3 trials; high-certainty evidence), and 26% of severe all-cause diarrhoea cases (23,317 participants, 2 trials; moderate-certainty evidence).  In high-mortality countries, Rotarix prevented 35% of severe rotavirus diarrhoea cases (13,768 participants, 2 trials; moderate-certainty evidence), and 17% of severe all-cause diarrhoea cases (2764 participants, 1 trial; high-certainty evidence). RotaTeq Infants vaccinated and followed up for the first year of life In low-mortality countries, RotaTeq prevented 97% of severe rotavirus diarrhoea cases (5442 participants, 2 trials; high-certainty evidence).  In medium-mortality countries, RotaTeq prevented 79% of severe rotavirus diarrhoea cases (3863 participants, 1 trial; low-certainty evidence).  In high-mortality countries, RotaTeq prevented 57% of severe rotavirus diarrhoea cases (6775 participants, 2 trials; high-certainty evidence), but there is probably little or no difference between vaccine and placebo for severe all-cause diarrhoea (1 trial, 4085 participants; moderate-certainty evidence).  Children vaccinated and followed up for two years In low-mortality countries, RotaTeq prevented 96% of severe rotavirus diarrhoea cases (5442 participants, 2 trials; high-certainty evidence).  In medium-mortality countries, RotaTeq prevented 79% of severe rotavirus diarrhoea cases (3863 participants, 1 trial; low-certainty evidence).  In high-mortality countries, RotaTeq prevented 44% of severe rotavirus diarrhoea cases (6744 participants, 2 trials; high-certainty evidence), and 15% of severe all-cause diarrhoea cases (5977 participants, 2 trials; high-certainty evidence).  We did not identify RotaTeq studies reporting on severe all-cause diarrhoea in low- or medium-mortality countries. Rotasiil Rotasiil has not been assessed in any RCT in countries with low or medium child mortality. Infants vaccinated and followed up for the first year of life In high-mortality countries, Rotasiil prevented 48% of severe rotavirus diarrhoea cases (11,008 participants, 2 trials; high-certainty evidence), and resulted in little to no difference in severe all-cause diarrhoea cases (11,008 participants, 2 trials; high-certainty evidence). Children vaccinated and followed up for two years In high-mortality countries, Rotasiil prevented 44% of severe rotavirus diarrhoea cases (11,008 participants, 2 trials; high-certainty evidence), and resulted in little to no difference in severe all-cause diarrhoea cases (11,008 participants, 2 trials; high-certainty evidence). Rotavac Rotavac has not been assessed in any RCT in countries with low or medium child mortality.  Infants vaccinated and followed up for the first year of life In high-mortality countries, Rotavac prevented 57% of severe rotavirus diarrhoea cases (6799 participants, 1 trial; moderate-certainty evidence), and 16% of severe all-cause diarrhoea cases (6799 participants, 1 trial; moderate-certainty evidence). Children vaccinated and followed up for two years In high-mortality countries, Rotavac prevented 54% of severe rotavirus diarrhoea cases (6541 participants, 1 trial; moderate-certainty evidence); no Rotavac studies have reported on severe all-cause diarrhoea at two-years follow-up. Safety No increased risk of serious adverse events (SAEs) was detected with Rotarix (103,714 participants, 31 trials; high-certainty evidence), RotaTeq (82,502 participants, 14 trials; moderate to high-certainty evidence), Rotasiil (11,646 participants, 3 trials; high-certainty evidence), or Rotavac (8210 participants, 3 trials; moderate-certainty evidence). Deaths were infrequent and the analysis had insufficient evidence to show an effect on all-cause mortality. Intussusception was rare.  AUTHORS' CONCLUSIONS: Rotarix, RotaTeq, Rotasiil, and Rotavac prevent episodes of rotavirus diarrhoea. The relative effect estimate is smaller in high-mortality than in low-mortality countries, but more episodes are prevented in high-mortality settings as the baseline risk is higher. In high-mortality countries some results suggest lower efficacy in the second year. We found no increased risk of serious adverse events, including intussusception, from any of the prequalified rotavirus vaccines.

Targeted client communication via mobile devices for improving sexual and reproductive health.

BACKGROUND: The burden of poor sexual and reproductive health (SRH) worldwide is substantial, disproportionately affecting those living in low- and middle-income countries. Targeted client communication (TCC) delivered via mobile devices (MD) (TCCMD) may improve the health behaviours and service use important for sexual and reproductive health. OBJECTIVES: To assess the effects of TCC via MD on adolescents' knowledge, and on adolescents' and adults' sexual and reproductive health behaviour, health service use, and health and well-being. SEARCH METHODS: In July/August 2017, we searched five databases including The Cochrane Central Register of Controlled Trials, MEDLINE and Embase. We also searched two trial registries. A search update was carried out in July 2019 and potentially relevant studies are awaiting classification. SELECTION CRITERIA: We included randomised controlled trials of TCC via MD to improve sexual and reproductive health behaviour, health service use, and health and well-being. Eligible comparators were standard care or no intervention, non-digital TCC, and digital non-targeted communication. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures recommended by Cochrane, although data extraction and risk of bias assessments were carried out by one person only and cross-checked by a second. We have presented results separately for adult and adolescent populations, and for each comparison. MAIN RESULTS: We included 40 trials (27 among adult populations and 13 among adolescent populations) with a total of 26,854 participants. All but one of the trials among adolescent populations were conducted in high-income countries. Trials among adult populations were conducted in a range of high- to low-income countries. Among adolescents, nine interventions were delivered solely through text messages; four interventions tested text messages in combination with another communication channel, such as emails, multimedia messaging, or voice calls; and one intervention used voice calls alone. Among adults, 20 interventions were delivered through text messages; two through a combination of text messages and voice calls; and the rest were delivered through other channels such as voice calls, multimedia messaging, interactive voice response, and instant messaging services. Adolescent populations TCCMD versus standard care TCCMD may increase sexual health knowledge (risk ratio (RR) 1.45, 95% confidence interval (CI) 1.23 to 1.71; low-certainty evidence). TCCMD may modestly increase contraception use (RR 1.19, 95% CI 1.05 to 1.35; low-certainty evidence). The effects on condom use, antiretroviral therapy (ART) adherence, and health service use are uncertain due to very low-certainty evidence. The effects on abortion and STI rates are unknown due to lack of studies. TCCMD versus non-digital TCC (e.g. pamphlets) The effects of TCCMD on behaviour (contraception use, condom use, ART adherence), service use, health and wellbeing (abortion and STI rates) are unknown due to lack of studies for this comparison. TCCMD versus digital non-targeted communication The effects on sexual health knowledge, condom and contraceptive use are uncertain due to very low-certainty evidence. Interventions may increase health service use (attendance for STI/HIV testing, RR 1.61, 95% CI 1.08 to 2.40; low-certainty evidence). The intervention may be beneficial for reducing STI rates (RR 0.61, 95% CI 0.28 to 1.33; low-certainty evidence), but the confidence interval encompasses both benefit and harm. The effects on abortion rates and on ART adherence are unknown due to lack of studies. We are uncertain whether TCCMD results in unintended consequences due to lack of evidence. Adult populations TCCMD versus standard care For health behaviours, TCCMD may modestly increase contraception use at 12 months (RR 1.17, 95% CI 0.92 to 1.48) and may reduce repeat abortion (RR 0.68 95% CI 0.28 to 1.66), though the confidence interval encompasses benefit and harm (low-certainty evidence). The effect on condom use is uncertain. No study measured the impact of this intervention on STI rates. TCCMD may modestly increase ART adherence (RR 1.13, 95% CI 0.97 to 1.32, low-certainty evidence, and standardised mean difference 0.44, 95% CI -0.14 to 1.02, low-certainty evidence). TCCMD may modestly increase health service utilisation (RR 1.17, 95% CI 1.04 to 1.31; low-certainty evidence), but there was substantial heterogeneity (I2 = 85%), with mixed results according to type of service utilisation (i.e. attendance for STI testing; HIV treatment; voluntary male medical circumcision (VMMC); VMMC post-operative visit; post-abortion care). For health and well-being outcomes, there may be little or no effect on CD4 count (mean difference 13.99, 95% CI -8.65 to 36.63; low-certainty evidence) and a slight reduction in virological failure (RR 0.86, 95% CI 0.73 to 1.01; low-certainty evidence). TCCMD versus non-digital TCC No studies reported STI rates, condom use, ART adherence, abortion rates, or contraceptive use as outcomes for this comparison. TCCMD may modestly increase in service attendance overall (RR: 1.12, 95% CI 0.92-1.35, low certainty evidence), however the confidence interval encompasses benefit and harm. TCCMD versus digital non-targeted communication No studies reported STI rates, condom use, ART adherence, abortion rates, or contraceptive use as outcomes for this comparison. TCCMD may increase service utilisation overall (RR: 1.71, 95% CI 0.67-4.38, low certainty evidence), however the confidence interval encompasses benefit and harm and there was considerable heterogeneity (I2 = 72%), with mixed results according to type of service utilisation (STI/HIV testing, and VMMC). Few studies reported on unintended consequences. One study reported that a participant withdrew from the intervention as they felt it compromised their undisclosed HIV status. AUTHORS' CONCLUSIONS: TCCMD may improve some outcomes but the evidence is of low certainty. The effect on most outcomes is uncertain/unknown due to very low certainty evidence or lack of evidence. High quality, adequately powered trials and cost effectiveness analyses are required to reliably ascertain the effects and relative benefits of TCC delivered by mobile devices. Given the sensitivity and stigma associated with sexual and reproductive health future studies should measure unintended consequences, such as partner violence or breaches of confidentiality.

Targeted client communication via mobile devices for improving maternal, neonatal, and child health.

BACKGROUND: The global burden of poor maternal, neonatal, and child health (MNCH) accounts for more than a quarter of healthy years of life lost worldwide. Targeted client communication (TCC) via mobile devices (MD) (TCCMD) may be a useful strategy to improve MNCH. OBJECTIVES: To assess the effects of TCC via MD on health behaviour, service use, health, and well-being for MNCH. SEARCH METHODS: In July/August 2017, we searched five databases including The Cochrane Central Register of Controlled Trials, MEDLINE and Embase. We also searched two trial registries. A search update was carried out in July 2019 and potentially relevant studies are awaiting classification. SELECTION CRITERIA: We included randomised controlled trials that assessed TCC via MD to improve MNCH behaviour, service use, health, and well-being. Eligible comparators were usual care/no intervention, non-digital TCC, and digital non-targeted client communication. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures recommended by Cochrane, although data extraction and risk of bias assessments were carried out by one person only and cross-checked by a second. MAIN RESULTS: We included 27 trials (17,463 participants). Trial populations were: pregnant and postpartum women (11 trials conducted in low-, middle- or high-income countries (LMHIC); pregnant and postpartum women living with HIV (three trials carried out in one lower middle-income country); and parents of children under the age of five years (13 trials conducted in LMHIC). Most interventions (18) were delivered via text messages alone, one was delivered through voice calls only, and the rest were delivered through combinations of different communication channels, such as multimedia messages and voice calls. Pregnant and postpartum women TCCMD versus standard care For behaviours, TCCMD may increase exclusive breastfeeding in settings where rates of exclusive breastfeeding are less common (risk ratio (RR) 1.30, 95% confidence intervals (CI) 1.06 to 1.59; low-certainty evidence), but have little or no effect in settings where almost all women breastfeed (low-certainty evidence). For use of health services, TCCMD may increase antenatal appointment attendance (odds ratio (OR) 1.54, 95% CI 0.80 to 2.96; low-certainty evidence); however, the CI encompasses both benefit and harm. The intervention may increase skilled attendants at birth in settings where a lack of skilled attendants at birth is common (though this differed by urban/rural residence), but may make no difference in settings where almost all women already have a skilled attendant at birth (OR 1.00, 95% CI 0.34 to 2.94; low-certainty evidence). There were uncertain effects on maternal and neonatal mortality and morbidity because the certainty of the evidence was assessed as very low. TCCMD versus non-digital TCC (e.g. pamphlets) TCCMD may have little or no effect on exclusive breastfeeding (RR 0.92, 95% CI 0.79 to 1.07; low-certainty evidence). TCCMD may reduce 'any maternal health problem' (RR 0.19, 95% CI 0.04 to 0.79) and 'any newborn health problem' (RR 0.52, 95% CI 0.25 to 1.06) reported up to 10 days postpartum (low-certainty evidence), though the CI for the latter includes benefit and harm. The effect on health service use is unknown due to a lack of studies. TCCMD versus digital non-targeted communication No studies reported behavioural, health, or well-being outcomes for this comparison. For use of health services, there are uncertain effects for the presence of a skilled attendant at birth due to very low-certainty evidence, and the intervention may make little or no difference to attendance for antenatal influenza vaccination (RR 1.05, 95% CI 0.71 to 1.58), though the CI encompasses both benefit and harm (low-certainty evidence). Pregnant and postpartum women living with HIV TCCMD versus standard care For behaviours, TCCMD may make little or no difference to maternal and infant adherence to antiretroviral (ARV) therapy (low-certainty evidence). For health service use, TCC mobile telephone reminders may increase use of antenatal care slightly (mean difference (MD) 1.5, 95% CI -0.36 to 3.36; low-certainty evidence). The effect on the proportion of births occurring in a health facility is uncertain due to very low-certainty evidence. For health and well-being outcomes, there was an uncertain intervention effect on neonatal death or stillbirth, and infant HIV due to very low-certainty evidence. No studies reported on maternal mortality or morbidity. TCCMD versus non-digital TCC The effect is unknown due to lack of studies reporting this comparison. TCCMD versus digital non-targeted communication TCCMD may increase infant ARV/prevention of mother-to-child transmission treatment adherence (RR 1.26, 95% CI 1.07 to 1.48; low-certainty evidence). The effect on other outcomes is unknown due to lack of studies. Parents of children aged less than five years No studies reported on correct treatment, nutritional, or health outcomes. TCCMD versus standard care Based on 10 trials, TCCMD may modestly increase health service use (vaccinations and HIV care) (RR 1.21, 95% CI 1.08 to 1.34; low-certainty evidence); however, the effect estimates varied widely between studies. TCCMD versus non-digital TCC TCCMD may increase attendance for vaccinations (RR 1.13, 95% CI 1.00 to 1.28; low-certainty evidence), and may make little or no difference to oral hygiene practices (low-certainty evidence). TCCMD versus digital non-targeted communication TCCMD may reduce attendance for vaccinations, but the CI encompasses both benefit and harm (RR 0.63, 95% CI 0.33 to 1.20; low-certainty evidence). No trials in any population reported data on unintended consequences. AUTHORS' CONCLUSIONS: The effect of TCCMD for most outcomes is uncertain. There may be improvements for some outcomes using targeted communication but these findings were of low certainty. High-quality, adequately powered trials and cost-effectiveness analyses are required to reliably ascertain the effects and relative benefits of TCCMD. Future studies should measure potential unintended consequences, such as partner violence or breaches of confidentiality.

Primaquine alternative dosing schedules for preventing malaria relapse in people with Plasmodium vivax.

BACKGROUND: Plasmodium vivax liver stages (hypnozoites) may cause relapses, prolonging morbidity, and impeding malaria control and elimination. The World Health Organization (WHO) recommends three schedules for primaquine: 0.25 mg/kg/day (standard), or 0.5 mg/kg/day (high standard) for 14 days, or 0.75 mg/kg once weekly for eight weeks, all of which can be difficult to complete. Since primaquine can cause haemolysis in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency, clinicians may be reluctant to prescribe primaquine without G6PD testing, and recommendations when G6PD status is unknown must be based on an assessment of the risks and benefits of prescribing primaquine. Alternative safe and efficacious regimens are needed. OBJECTIVES: To assess the efficacy and safety of alternative primaquine regimens for radical cure of P vivax malaria compared to the standard or high-standard 14-day courses. SEARCH METHODS: We searched the Cochrane Infectious Diseases Group Specialized Register; the Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE (PubMed); Embase (Ovid); LILACS (BIREME); WHO International Clinical Trials Registry Platform and ClinicalTrials.gov up to 2 September 2019, and checked the reference lists of all identified studies. SELECTION CRITERIA: Randomized controlled trials (RCTs) of adults and children with P vivax malaria using either chloroquine or artemisinin-based combination therapy plus primaquine at a total adult dose of at least 210 mg, compared with the WHO-recommended regimens of 0.25 or 0.5 mg/kg/day for 14 days. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial eligibility and quality, and extracted data. We calculated risk ratios (RRs) with 95% confidence intervals (CIs) for dichotomous data. We grouped efficacy data according to length of follow-up, partner drug, and trial location. We analysed safety data where included. MAIN RESULTS: 0.5 mg/kg/day for seven days versus standard 0.25 mg/kg/day for 14 days There may be little or no difference in P vivax recurrences at six to seven months when using the same total dose (210 mg adult dose) over seven days compared to 14 days (RR 0.96, 95% CI 0.66 to 1.39; 4 RCTs, 1211 participants; low-certainty evidence). No serious adverse events were reported. We do not know if there is any difference in the number of adverse events resulting in discontinuation of primaquine (RR 1.04, 95% CI 0.15 to 7.38; 5 RCTs, 1427 participants) or in the frequency of anaemia (RR 3.00, 95% CI 0.12 to 72.91, 1 RCT, 240 participants) between the shorter and longer regimens (very low-certainty evidence). Three trials excluded people with G6PD deficiency; two did not provide this information. Pregnant and lactating women were either excluded or no details were provided. High-standard 0.5 mg/kg/day for 14 days versus standard 0.25 mg/kg/day for 14 days There may be little or no difference in P vivax recurrences at six months with 0.5 mg/kg/day primaquine for 14 days compared to 0.25 mg/kg/day for 14 days (RR 0.84 (95% CI 0.49 to 1.43; 2 RCTs, 677 participants, low-certainty evidence). No serious adverse events were reported. We do not know whether there is a difference in adverse events resulting in discontinuation of treatment with the high-standard dosage (RR 4.19, 95% CI 0.90 to 19.60; 1 RCT, 778 participants, very low-certainty evidence). People with G6PD deficiency and pregnant or lactating women were excluded. 0.75 mg/kg/week for eight weeks versus high-standard 0.5 mg/kg/day for 14 days We do not know whether weekly primaquine increases or decreases recurrences of P vivax compared to high-standard 0.5 mg/kg/day for 14 days, at 11 months' follow-up (RR 3.18, 95% CI 0.37 to 27.60; 1 RCT, 122 participants; very low-certainty evidence). No serious adverse events and no episodes of anaemia were reported. G6PD-deficient patients were not randomized but included in the weekly primaquine group (only one patient detected). 1 mg/kg/day for seven days versus high standard 0.5 mg/kg/day for 14 days There is probably little or no difference in P vivax recurrences at 12 months between 1.0 mg/kg/day primaquine for seven days and the high-standard 0.5 mg/kg/day for 14 days (RR 1.03, 95% CI 0.82 to 1.30; 2 RCTs, 2526 participants; moderate-certainty evidence). There may be moderate to large increase in serious adverse events in the 1.0 mg/kg/day primaquine for seven days compared with the high-standard 0.5 mg/kg/day for 14 days, during 42 days follow-up (RR 12.03, 95% CI 1.57 to 92.30; 1 RCT, 1872 participants, low-certainty evidence). We do not know if there is a difference between 1.0 mg/kg/day primaquine for seven days and high-standard 0.5 mg/kg/day for 14 days in adverse events that resulted in discontinuation of treatment (RR 2.50, 95% CI 0.49 to 12.87; 1 RCT, 2526 participants, very low-certainty evidence), nor if there is difference in frequency of anaemia by 42 days (RR 0.93, 95% CI 0.62 to 1.41; 2 RCTs, 2440 participants, very low-certainty evidence). People with G6PD deficiency were excluded. Other regimens Two RCTs evaluated other rarely-used doses of primaquine, one of which had very high loss to follow-up. Adverse events were not reported. People with G6PD deficiency and pregnant or lactating women were excluded. AUTHORS' CONCLUSIONS: Trials available to date do not detect a difference in recurrence between the following regimens: 1) 0.5 mg/kg/day for seven days versus standard 0.25 mg/kg/day for 14 days; 2) high-standard 0.5 mg/kg/day for 14 days versus standard 0.25 mg/kg/day for 14 days; 3) 0.75 mg/kg/week for eight weeks versus high-standard 0.5 mg/kg/day for 14 days; 4) 1 mg/kg/day for seven days versus high-standard 0.5 mg/kg/day for 14 days. There were no differences detected in adverse events for Comparisons 1, 2 or 3, but there may be more serious adverse events with the high seven-day course in Comparison 4. The shorter regimen of 0.5 mg/kg/day for seven days versus standard 0.25 mg/kg/day for 14 days may suit G6PD-normal patients. Further research will help increase the certainty of the findings and applicability in different settings.

Screening efficiency of the Mood and Feelings Questionnaire (MFQ) and Short Mood and Feelings Questionnaire (SMFQ) in Swedish help seeking outpatients.

BACKGROUND: To evaluate screening efficiency and suggest cut-offs for parent and child Mood and Feelings Questionnaire (MFQ) and the short version (SMFQ) in unselected help seeking child- and adolescent psychiatric outpatients for subgroups of 6-12 versus 13-17 year olds and boys versus girls. METHOD: Eligible for inclusion were newly admitted outpatients age 6-17 years (n = 5908) in four Swedish child- and adolescent psychiatry clinics. They were prompted consecutively and n = 307 accepted a specific day for assessment until time slots randomly were filled. We prospectively validated the MFQ (33 items) and SMFQ (13 items) in patients (n = 186) using receiver operating characteristics against a reference test of Longitudinal Expert All Data DSM-IV depression based on a Kiddie-Schedule for Affective Disorders and Schizophrenia and 1.2 (sd .6) years of follow-up. RESULTS: A depressive disorder was confirmed in 59 (31.7%) patients ranging from 14.0% for girls 6-12 years to 53.3% for girls 13-17 years. SMFQ performed roughly equivalent to MFQ. Adolescent score on SMFQ discriminated fairly for boys with Area Under Curve .77 (95% confidence interval .59-.81) and good (.82, .69-.91) for girls and parent ratings for adolescent girls (.85, .73-.93), but not for boys. Depression in children below age 13 could not be discriminated by MFQ or SMFQ whether filled in by child and mostly also when filled in by parent. Favouring maximum kappa value, the optimal cut-off was for MFQ self-report girls ≥32 versus boys ≥11 and for SMFQ self-report girls ≥17 versus boys ≥ 6. Suggested clinical SMFQ cut-offs for girls were ≥12 and for boys ≥ 6. CONCLUSIONS: MFQ and SMFQ can, with gender-based cut-offs, be used for screening in clinical populations of adolescents but not in children. Parent MFQ and SMFQ can be used for adolescent girls but not boys. SMFQ is sufficient for screening.

New WHO guidelines for treatment of gambiense human African trypanosomiasis including fexinidazole: substantial changes for clinical practice

Human African trypanosomiasis caused by Trypanosoma brucei gambiense is a parasitic infection that usually progresses to coma and death unless treated. WHO has updated its guidelines for the treatment of this infection on the basis of independent literature reviews and using the Grading of Recommendations Assessment, Development and Evaluation methodology. The first-line treatment options, pentamidine and nifurtimox­eflornithine combination therapy, have been expanded to include fexinidazole, an oral monotherapy given a positive opinion from the European Medicines Agency. Fexinidazole is recommended for individuals who are aged 6 years and older with a bodyweight of 20 kg or more, who have first-stage or second-stage gambiense human African trypanosomiasis and a cerebrospinal fluid leucocyte count less than 100 per µL. Nifurtimox­eflornithine combination therapy remains recommended for patients with 100 leucocytes per µL or more. Without clinical suspicion of severe second-stage disease, lumbar puncture can be avoided and fexinidazole can be given. Fexinidazole should only be administered under supervision of trained health staff. Because these recommendations are expected to change clinical practice considerably, health professionals should consult the detailed WHO guidelines. These guidelines will be updated as evidence accrues.

Tracking health commodity inventory and notifying stock levels via mobile devices: a mixed methods systematic review.

BACKGROUND: Health systems need timely and reliable access to essential medicines and health commodities, but problems with access are common in many settings. Mobile technologies offer potential low-cost solutions to the challenge of drug distribution and commodity availability in primary healthcare settings. However, the evidence on the use of mobile devices to address commodity shortages is sparse, and offers no clear way forward. OBJECTIVES: Primary objective To assess the effects of strategies for notifying stock levels and digital tracking of healthcare-related commodities and inventory via mobile devices across the primary healthcare system Secondary objectives To describe what mobile device strategies are currently being used to improve reporting and digital tracking of health commodities To identify factors influencing the implementation of mobile device interventions targeted at reducing stockouts of health commodities SEARCH METHODS: We searched CENTRAL, MEDLINE Ovid, Embase Ovid, Global Index Medicus WHO, POPLINE K4Health, and two trials registries in August 2019. We also searched Epistemonikos for related systematic reviews and potentially eligible primary studies. We conducted a grey literature search using mHealthevidence.org, and issued a call for papers through popular digital health communities of practice. Finally, we conducted citation searches of included studies. We searched for studies published after 2000, in any language. SELECTION CRITERIA: For the primary objective, we included individual and cluster-randomised trials, controlled before-after studies, and interrupted time series studies. For the secondary objectives, we included any study design, which could be quantitative, qualitative, or descriptive, that aimed to describe current strategies for commodity tracking or stock notification via mobile devices; or aimed to explore factors that influenced the implementation of these strategies, including studies of acceptability or feasibility. We included studies of all cadres of healthcare providers, including lay health workers, and others involved in the distribution of health commodities (administrative staff, managerial and supervisory staff, dispensary staff); and all other individuals involved in stock notification, who may be based in a facility or a community setting, and involved with the delivery of primary healthcare services. We included interventions aimed at improving the availability of health commodities using mobile devices in primary healthcare settings. For the primary objective, we included studies that compared health commodity tracking or stock notification via mobile devices with standard practice. For the secondary objectives, we included studies of health commodity tracking and stock notification via mobile device, if we could extract data relevant to our secondary objectives. DATA COLLECTION AND ANALYSIS: For the primary objective, two authors independently screened all records, extracted data from the included studies, and assessed the risk of bias. For the analyses of the primary objectives, we reported means and proportions where appropriate. We used the GRADE approach to assess the certainty of the evidence, and prepared a 'Summary of findings' table. For the secondary objective, two authors independently screened all records, extracted data from the included studies, and applied a thematic synthesis approach to synthesise the data. We assessed methodological limitation using the Ways of Evaluating Important and Relevant Data (WEIRD) tool. We used the GRADE-CERQual approach to assess our confidence in the evidence, and prepared a 'Summary of qualitative findings' table. MAIN RESULTS: Primary objective For the primary objective, we included one controlled before-after study conducted in Malawi. We are uncertain of the effect of cStock plus enhanced management, or cStock plus effective product transport on the availability of commodities, quality and timeliness of stock management, and satisfaction and acceptability, because we assessed the evidence as very low-certainty. The study did not report on resource use or unintended consequences. Secondary objective For the secondary objectives, we included 16 studies, using a range of study designs, which described a total of eleven interventions. All studies were conducted in African (Tanzania, Kenya, Malawi, Ghana, Ethiopia, Cameroon, Zambia, Liberia, Uganda, South Africa, and Rwanda) and Asian (Pakistan and India) countries. Most of the interventions aimed to make data about stock levels and potential stockouts visible to managers, who could then take corrective action to address them. We identified several factors that may influence the implementation of stock notification and tracking via mobile device. These include challenges tied to infrastructural issues, such as poor access to electricity or internet, and broader health systems issues, such as drug shortages at the national level which cannot be mitigated by interventions at the primary healthcare level (low confidence). Several factors were identified as important, including strong partnerships with local authorities, telecommunication companies, technical system providers, and non-governmental organizations (very low confidence); availability of stock-level data at all levels of the health system (low confidence); the role of supportive supervision and responsive management (moderate confidence); familiarity and training of health workers in the use of the digital devices (moderate confidence); availability of technical programming expertise for the initial development and ongoing maintenance of the digital systems (low confidence); incentives, such as phone credit for personal use, to support regular use of the system (low confidence); easy-to-use systems built with user participation (moderate confidence); use of basic or personal mobile phones to support easier adoption (low confidence); consideration for software features, such as two-way communication (low confidence); and data availability in an easy-to-use format, such as an interactive dashboard (moderate confidence). AUTHORS' CONCLUSIONS: We need more, well-designed, controlled studies comparing stock notification and commodity management via mobile devices with paper-based commodity management systems. Further studies are needed to understand the factors that may influence the implementation of such interventions, and how implementation considerations differ by variations in the intervention.

New WHO guidelines for treatment of gambiense human African trypanosomiasis including fexinidazole: substantial changes for clinical practice.

Human African trypanosomiasis caused by Trypanosoma brucei gambiense is a parasitic infection that usually progresses to coma and death unless treated. WHO has updated its guidelines for the treatment of this infection on the basis of independent literature reviews and using the Grading of Recommendations Assessment, Development and Evaluation methodology. The first-line treatment options, pentamidine and nifurtimox-eflornithine combination therapy, have been expanded to include fexinidazole, an oral monotherapy given a positive opinion from the European Medicines Agency. Fexinidazole is recommended for individuals who are aged 6 years and older with a bodyweight of 20 kg or more, who have first-stage or second-stage gambiense human African trypanosomiasis and a cerebrospinal fluid leucocyte count less than 100 per µL. Nifurtimox-eflornithine combination therapy remains recommended for patients with 100 leucocytes per µL or more. Without clinical suspicion of severe second-stage disease, lumbar puncture can be avoided and fexinidazole can be given. Fexinidazole should only be administered under supervision of trained health staff. Because these recommendations are expected to change clinical practice considerably, health professionals should consult the detailed WHO guidelines. These guidelines will be updated as evidence accrues.

Vaccines for preventing rotavirus diarrhoea: vaccines in use.

BACKGROUND: Rotavirus results in more diarrhoea-related deaths in children under five years than any other single agent in countries with high childhood mortality. It is also a common cause of diarrhoea-related hospital admissions in countries with low childhood mortality. Rotavirus vaccines that have been prequalified by the World Health Organization (WHO) include a monovalent vaccine (RV1; Rotarix, GlaxoSmithKline), a pentavalent vaccine (RV5; RotaTeq, Merck), and, more recently, another monovalent vaccine (Rotavac, Bharat Biotech). OBJECTIVES: To evaluate rotavirus vaccines prequalified by the WHO (RV1, RV5, and Rotavac) for their efficacy and safety in children. SEARCH METHODS: On 4 April 2018 we searched MEDLINE (via PubMed), the Cochrane Infectious Diseases Group Specialized Register, CENTRAL (published in the Cochrane Library), Embase, LILACS, and BIOSIS. We also searched the WHO ICTRP, ClinicalTrials.gov, clinical trial reports from manufacturers' websites, and reference lists of included studies and relevant systematic reviews. SELECTION CRITERIA: We selected randomized controlled trials (RCTs) in children comparing rotavirus vaccines prequalified for use by the WHO versus placebo or no intervention. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial eligibility and assessed risks of bias. One review author extracted data and a second author cross-checked them. We combined dichotomous data using the risk ratio (RR) and 95% confidence interval (CI). We stratified the analysis by country mortality rate and used GRADE to evaluate evidence certainty. MAIN RESULTS: Fifty-five trials met the inclusion criteria and enrolled a total of 216,480 participants. Thirty-six trials (119,114 participants) assessed RV1, 15 trials (88,934 participants) RV5, and four trials (8432 participants) Rotavac. RV1 Children vaccinated and followed up the first year of life In low-mortality countries, RV1 prevents 84% of severe rotavirus diarrhoea cases (RR 0.16, 95% CI 0.09 to 0.26; 43,779 participants, 7 trials; high-certainty evidence), and probably prevents 41% of cases of severe all-cause diarrhoea (RR 0.59, 95% CI 0.47 to 0.74; 28,051 participants, 3 trials; moderate-certainty evidence). In high-mortality countries, RV1 prevents 63% of severe rotavirus diarrhoea cases (RR 0.37, 95% CI 0.23 to 0.60; 6114 participants, 3 trials; high-certainty evidence), and 27% of severe all-cause diarrhoea cases (RR 0.73, 95% CI 0.56 to 0.95; 5639 participants, 2 trials; high-certainty evidence). Children vaccinated and followed up for two years In low-mortality countries, RV1 prevents 82% of severe rotavirus diarrhoea cases (RR 0.18, 95% CI 0.14 to 0.23; 36,002 participants, 9 trials; high-certainty evidence), and probably prevents 37% of severe all-cause diarrhoea episodes (rate ratio 0.63, 95% CI 0.56 to 0.71; 39,091 participants, 2 trials; moderate-certainty evidence). In high-mortality countries RV1 probably prevents 35% of severe rotavirus diarrhoea cases (RR 0.65, 95% CI 0.51 to 0.83; 13,768 participants, 2 trials; high-certainty evidence), and 17% of severe all-cause diarrhoea cases (RR 0.83, 95% CI 0.72 to 0.96; 2764 participants, 1 trial; moderate-certainty evidence). No increased risk of serious adverse events (SAE) was detected (RR 0.88 95% CI 0.83 to 0.93; high-certainty evidence). There were 30 cases of intussusception reported in 53,032 children after RV1 vaccination and 28 cases in 44,214 children after placebo or no intervention (RR 0.70, 95% CI 0.46 to 1.05; low-certainty evidence). RV5 Children vaccinated and followed up the first year of life In low-mortality countries, RV5 probably prevents 92% of severe rotavirus diarrhoea cases (RR 0.08, 95% CI 0.03 to 0.22; 4132 participants, 5 trials; moderate-certainty evidence). We did not identify studies reporting on severe all-cause diarrhoea in low-mortality countries. In high-mortality countries, RV5 prevents 57% of severe rotavirus diarrhoea (RR 0.43, 95% CI 0.29 to 0.62; 5916 participants, 2 trials; high-certainty evidence), but there is probably little or no difference between vaccine and placebo for severe all-cause diarrhoea (RR 0.80, 95% CI 0.58 to 1.11; 1 trial, 4085 participants; moderate-certainty evidence). Children vaccinated and followed up for two years In low-mortality countries, RV5 prevents 82% of severe rotavirus diarrhoea cases (RR 0.18, 95% CI 0.08 to 0.39; 7318 participants, 4 trials; moderate-certainty evidence). We did not identify studies reporting on severe all-cause diarrhoea in low-mortality countries. In high-mortality countries, RV5 prevents 41% of severe rotavirus diarrhoea cases (RR 0.59, 95% CI 0.43 to 0.82; 5885 participants, 2 trials; high-certainty evidence), and 15% of severe all-cause diarrhoea cases (RR 0.85, 95% CI 0.75 to 0.98; 5977 participants, 2 trials; high-certainty evidence). No increased risk of serious adverse events (SAE) was detected (RR 0.93 95% CI 0.86 to 1.01; moderate to high-certainty evidence). There were 16 cases of intussusception in 43,629 children after RV5 vaccination and 20 cases in 41,866 children after placebo (RR 0.77, 95% CI 0.41 to 1.45; low-certainty evidence). Rotavac Children vaccinated and followed up the first year of life Rotavac has not been assessed in any RCT in countries with low child mortality. In India, a high-mortality country, Rotavac probably prevents 57% of severe rotavirus diarrhoea cases (RR 0.43, 95% CI 0.30 to 0.60; 6799 participants, moderate-certainty evidence); the trial did not report on severe all-cause diarrhoea at one-year follow-up. Children vaccinated and followed up for two years Rotavac probably prevents 54% of severe rotavirus diarrhoea cases in India (RR 0.46, 95% CI 0.35 to 0.60; 6541 participants, 1 trial; moderate-certainty evidence), and 16% of severe all-cause diarrhoea cases (RR 0.84, 95% CI 0.71 to 0.98; 6799 participants, 1 trial; moderate-certainty evidence). No increased risk of serious adverse events (SAE) was detected (RR 0.93 95% CI 0.85 to 1.02; moderate-certainty evidence). There were eight cases of intussusception in 5764 children after Rotavac vaccination and three cases in 2818 children after placebo (RR 1.33, 95% CI 0.35 to 5.02; very low-certainty evidence). There was insufficient evidence of an effect on mortality from any rotavirus vaccine (198,381 participants, 44 trials; low- to very low-certainty evidence), as the trials were not powered to detect an effect at this endpoint. AUTHORS' CONCLUSIONS: RV1, RV5, and Rotavac prevent episodes of rotavirus diarrhoea. Whilst the relative effect estimate is smaller in high-mortality than in low-mortality countries, there is a greater number of episodes prevented in these settings as the baseline risk is much higher. We found no increased risk of serious adverse events. 21 October 2019 Up to date All studies incorporated from most recent search All published trials found in the last search (4 Apr, 2018) were included and 15 ongoing studies are currently awaiting completion (see 'Characteristics of ongoing studies').

CONTEXTE: Le rotavirus entraîne plus de décès liés à la diarrhée chez les enfants de moins de cinq ans que tout autre agent unique dans les pays où la mortalité infantile est élevée. C'est également une cause fréquente d'hospitalisations liées à la diarrhée dans les pays où la mortalité infantile est faible. Les vaccins antirotavirus préqualifiés par l'Organisation mondiale de la santé (OMS) comprennent un vaccin monovalent (RV1 ; Rotarix, GlaxoSmithKline), un vaccin pentavalent (RV5 ; RotaTeq, Merck) et plus récemment un autre vaccin monovalent (Rotavac, Bharat Biotech). OBJECTIFS: Évaluer les vaccins antirotavirus préqualifiés par l'OMS (RV1, RV5 et Rotavac) pour leur efficacité et leur innocuité chez les enfants. STRATÉGIE DE RECHERCHE DOCUMENTAIRE: Le 4 avril 2018, nous avons effectué une recherche dans MEDLINE (via PubMed), le registre spécialisé du groupe de travail Cochrane sur les maladies infectieuses (the Cochrane Infectious Diseases Group), CENTRAL (publié dans la Bibliothèque Cochrane), Embase, LILACS, et BIOSIS. Nous avons également effectué des recherches dans le système d'enregistrement international des essais cliniques (ICTRP) de l'OMS, ClinicalTrials.gov, les rapports d'essais cliniques trouvés sur les sites Web des fabricants, les références des études incluses et les revues systématiques pertinentes. CRITÈRES DE SÉLECTION: Nous avons sélectionné des essais cliniques contrôlés randomisés (ECR) chez des enfants comparant des vaccins antirotavirus préqualifiés pour utilisation par l'OMS à un placebo ou à aucune intervention. RECUEIL ET ANALYSE DES DONNÉES: Deux auteurs de la revue ont évalué de façon indépendante l'éligibilité à l'essai et évalué les risques de biais. Un auteur de la revue a extrait les données et un deuxième auteur les a vérifiées par recoupement. Nous avons combiné des données dichotomiques en utilisant le risque relatif (RR) et l'intervalle de confiance à 95 % (IC). Nous avons stratifié l'analyse par taux de mortalité par pays et utilisé GRADE pour évaluer la valeur probante des données. RÉSULTATS PRINCIPAUX: Cinquante­cinq essais ont satisfait aux critères d'inclusion et enrôlé 216 480 participants au total. Trente­six essais cliniques (119 114 participants) ont évalué le RV1, 15 essais cliniques (88 934 participants) le RV5 et quatre essais cliniques (8432 participants) le Rotavac. RV1 Enfants vaccinés et suivis au cours de leur première année de vie Dans les pays à faible mortalité, le RV1 prévient 84 % des cas graves de diarrhée à rotavirus (RR 0,16, IC à 95 % : 0,09 à 0,26 ; 43 779 participants, 7 essais ; données de bonne valeur probante) et probablement 41 % des cas de diarrhée sévère toutes causes confondues (RR 0,59, IC à 95 % : 0,47 à 0,74 ; 28 051 participants, 3 essais ; données de valeur probante moyenne). Dans les pays à forte mortalité, le RV1 prévient 63 % des cas graves de diarrhée à rotavirus (RR 0,37, IC à 95 % : 0,23 à 0,60 ; 6114 participants, 3 essais ; données de bonne valeur probante) et 27 % des cas graves de diarrhée toutes causes confondues (RR 0,73, IC à 95 % : 0,56 à 0,95 ; 5639 participants, 2 essais ; données de bonne valeur probante). Enfants vaccinés et suivis pendant deux ans Dans les pays à faible mortalité, le RV1 prévient 82 % des cas graves de diarrhée à rotavirus (RR 0,18, IC à 95 % : 0,14 à 0,23 ; 36 002 participants, 9 essais ; données de bonne valeur probante) et probablement 37 % des épisodes graves de diarrhée toutes causes confondues (rapport des taux 0,63, IC à 95 % : 0,56 à 0,71 ; 39 091 participants, 2 essais ; données de valeur probante moyenne). Dans les pays à forte mortalité, le RV1 prévient probablement 35 % des cas graves de diarrhée à rotavirus (RR 0,65, IC à 95 % : 0,51 à 0,83 ; 13 768 participants, 2 essais ; données de bonne valeur probante) et 17 % des cas graves de diarrhée toutes causes confondues (RR 0,83, IC à 95 % : 0,72 à 0,96 ; 2764 participants, 1 essai ; données de valeur probante moyenne). Aucune augmentation du risque d'événements indésirables graves (EIG) n'a été décelée (RR 0,88 IC à 95 % 0,83 à 0,93 ; données de bonne valeur probante). On a signalé 30 cas d'invagination (intussusception) intestinale chez 53 032 enfants après la vaccination RV1 et 28 cas chez 44 214 enfants après l'administration d'un placebo ou l'absence d'intervention (RR 0,70, IC à 95 % : 0,46 à 1,05 ; données de faible valeur probante). RV5 Enfants vaccinés et suivis au cours de leur première année de vie Dans les pays à faible mortalité, le RV5 prévient probablement 92 % des cas graves de diarrhée à rotavirus (RR 0,08, IC à 95 % : 0,03 à 0,22 ; 4 132 participants, 5 essais ; données de valeur probante moyenne). Nous n'avons pas identifié d'études sur les diarrhées graves toutes causes confondues dans les pays à faible mortalité. Dans les pays à forte mortalité, le RV5 prévient 57 % des cas de diarrhée à rotavirus grave (RR 0,43, IC à 95 % : 0,29 à 0,62 ; 5916 participants, 2 essais ; données de bonne valeur probante), mais il n'y a probablement que peu voire pas de différence entre vaccin et placebo pour la diarrhée grave toutes causes confondues (RR 0,80, IC à 95 % : 0,58 à 1,11 ; 1 essai, 4085 participants ; données de valeur probante moyenne). Enfants vaccinés et suivis pendant deux ans Dans les pays à faible mortalité, le RV5 prévient 82 % des cas graves de diarrhée à rotavirus (RR 0,18, IC à 95 % : 0,08 à 0,39 ; 7318 participants, 4 essais ; données de valeur probante moyenne). Nous n'avons pas identifié d'études sur les diarrhées graves toutes causes confondues dans les pays à faible mortalité. Dans les pays à forte mortalité, le RV5 prévient 41 % des cas graves de diarrhée à rotavirus (RR 0,59, IC à 95 % : 0,43 à 0,82 ; 5 885 participants, 2 essais ; données de bonne valeur probante) et 15 % des cas graves de diarrhée toutes causes confondues (RR 0,85, IC à 95 % : 0,75 à 0,98 ; 5977 participants, 2 essais ; données de bonne valeur probante). Aucune augmentation du risque d'évènements indésirables graves (EIG) n'a été décelée (RR 0,93 IC à 95 % 0,86 à 1,01 ; données de valeur probante moyenne à bonne). Il y a eu 16 cas d'invagination chez 43 629 enfants après la vaccination RV5 et 20 cas chez 41 866 enfants après le placebo (RR 0,77, IC à 95 % : 0,41 à 1,45 ; données de faible valeur probante). Rotavac Enfants vaccinés et suivis au cours de leur première année de vie Le Rotavac n'a fait l'objet d'aucun ECR dans les pays à faible mortalité infantile. En Inde, pays à forte mortalité, le Rotavac prévient probablement 57 % des cas graves de diarrhée à rotavirus (RR 0,43, IC à 95 % : 0,30 à 0,60 ; 6799 participants, données de valeur probante moyenne) ; l'essai n'a pas fait état de diarrhée grave toutes causes confondues à un an de suivi. Enfants vaccinés et suivis pendant deux ans Le Rotavac prévient probablement 54 % des cas graves de diarrhée à rotavirus en Inde (RR 0,46, IC à 95 % : 0,35 à 0,60 ; 6541 participants, 1 essai ; données de valeur probante moyenne) et 16 % des cas graves de diarrhée toutes causes confondues (RR 0,84, IC à 95 % : 0,71 à 0,98 ; 6799 participants, 1 essai ; données de valeur probante moyenne). Aucune augmentation du risque d'évènements indésirables graves (EIG) n'a été décelée (RR 0,93 95 % IC 0,85 à 1,02 ; données de valeur probante moyenne). Il y a eu huit cas d'invagination intestinale chez 5 764 enfants après la vaccination par Rotavac et trois cas chez 2 818 enfants après le placebo (RR 1,33, IC à 95 % : 0,35 à 5,02 ; données de très faible valeur probante). Il n'y avait pas suffisamment de données probante indiquant un effet sur la mortalité attribuable à un vaccin antirotavirus (198 381 participants, 44 essais ; données de valeur probante faible à très faible), car les essais n'étaient pas assez puissants pour détecter un effet à ce paramètre. CONCLUSIONS DES AUTEURS: Les vaccins RV1, RV5 et Rotavac préviennent les épisodes de diarrhée à rotavirus. Bien que l'estimation de l'effet relatif soit plus faible dans les pays à forte mortalité que dans les pays à faible mortalité, le nombre d'épisodes évités est plus élevé dans ces pays car le risque de base est beaucoup plus élevé. Nous n'avons trouvé aucun risque accru d'événements indésirables graves.

Comparison of different human papillomavirus (HPV) vaccine types and dose schedules for prevention of HPV-related disease in females and males.

BACKGROUND: Uptake of human papillomavirus (HPV) vaccine remains low in many countries, although the bivalent and quadrivalent HPV vaccines given as a three-dose schedule are effective in the prevention of precancerous lesions of the cervix in women. Simpler immunisation schedules, such as those with fewer doses, might reduce barriers to vaccination, as may programmes that include males. OBJECTIVES: To evaluate the efficacy, immunogenicity, and harms of different dose schedules and different types of HPV vaccines in females and males. SEARCH METHODS: We conducted electronic searches on 27 September 2018 in Ovid MEDLINE, the Cochrane Central Register of Controlled Trials (CENTRAL) (in the Cochrane Library), and Ovid Embase. We also searched the WHO International Clinical Trials Registry Platform, and ClinicalTrials.gov (both 27 September 2018), vaccine manufacturer websites, and checked reference lists from an index of HPV studies and other relevant systematic reviews. SELECTION CRITERIA: We included randomised controlled trials (RCTs) with no language restriction. We considered studies if they enrolled HIV-negative males or females aged 9 to 26 years, or HIV-positive males or females of any age. DATA COLLECTION AND ANALYSIS: We used methods recommended by Cochrane. We use the term 'control' to refer to comparator products containing an adjuvant or active vaccine and 'placebo' to refer to products that contain no adjuvant or active vaccine. Most primary outcomes in this review were clinical outcomes. However, for comparisons comparing dose schedules, the included RCTs were designed to measure antibody responses (i.e. immunogenicity) as the primary outcome, rather than clinical outcomes, since it is unethical to collect cervical samples from girls under 16 years of age. We analysed immunogenicity outcomes (i.e. geometric mean titres) with ratios of means, clinical outcomes (e.g. cancer and intraepithelial neoplasia) with risk ratios or rate ratios and, for serious adverse events and deaths, we calculated odds ratios. We rated the certainty of evidence with GRADE. MAIN RESULTS: We included 20 RCTs with 31,940 participants. The length of follow-up in the included studies ranged from seven months to five years. Two doses versus three doses of HPV vaccine in 9- to 15-year-old females Antibody responses after two-dose and three-dose HPV vaccine schedules were similar after up to five years of follow-up (4 RCTs, moderate- to high-certainty evidence). No RCTs collected clinical outcome data. Evidence about serious adverse events in studies comparing dose schedules was of very low-certainty owing to imprecision and indirectness (three doses 35/1159; two doses 36/1158; 4 RCTs). One death was reported in the three-dose group (1/898) and none in the two-dose group (0/899) (low-certainty evidence). Interval between doses of HPV vaccine in 9- to 14-year-old females and males Antibody responses were stronger with a longer interval (6 or 12 months) between the first two doses of HPV vaccine than a shorter interval (2 or 6 months) at up to three years of follow-up (4 RCTs, moderate- to high-certainty evidence). No RCTs collected data about clinical outcomes. Evidence about serious adverse events in studies comparing intervals was of very low-certainty, owing to imprecision and indirectness. No deaths were reported in any of the studies (0/1898, 3 RCTs, low-certainty evidence). HPV vaccination of 10- to 26-year-old males In one RCT there was moderate-certainty evidence that quadrivalent HPV vaccine, compared with control, reduced the incidence of external genital lesions (control 36 per 3081 person-years; quadrivalent 6 per 3173 person-years; rate ratio 0.16, 95% CI 0.07 to 0.38; 6254 person-years) and anogenital warts (control 28 per 2814 person-years; quadrivalent 3 per 2831 person-years; rate ratio 0.11, 95% CI 0.03 to 0.38; 5645 person-years). The quadrivalent vaccine resulted in more injection-site adverse events, such as pain or redness, than control (537 versus 601 per 1000; risk ratio (RR) 1.12, 95% CI 1.06 to 1.18, 3895 participants, high-certainty evidence). There was very low-certainty evidence from two RCTs about serious adverse events with quadrivalent vaccine (control 12/2588; quadrivalent 8/2574), and about deaths (control 11/2591; quadrivalent 3/2582), owing to imprecision and indirectness. Nonavalent versus quadrivalent vaccine in 9- to 26-year-old females and males Three RCTs were included; one in females aged 9- to 15-years (n = 600), one in females aged 16- to 26-years (n = 14,215), and one in males aged 16- to 26-years (n = 500). The RCT in 16- to 26-year-old females reported clinical outcomes. There was little to no difference in the incidence of the combined outcome of high-grade cervical epithelial neoplasia, adenocarcinoma in situ, or cervical cancer between the HPV vaccines (quadrivalent 325/6882, nonavalent 326/6871; OR 1.00, 95% CI 0.85 to 1.16; 13,753 participants; high-certainty evidence). The other two RCTs did not collect data about clinical outcomes. There were slightly more local adverse events with the nonavalent vaccine (905 per 1000) than the quadrivalent vaccine (846 per 1000) (RR 1.07, 95% CI 1.05 to 1.08; 3 RCTs, 15,863 participants; high-certainty evidence). Comparative evidence about serious adverse events in the three RCTs (nonavalent 243/8234, quadrivalent 192/7629; OR 0.60, 95% CI 0.14 to 2.61) was of low certainty, owing to imprecision and indirectness. HPV vaccination for people living with HIV Seven RCTs reported on HPV vaccines in people with HIV, with two small trials that collected data about clinical outcomes. Antibody responses were higher following vaccination with either bivalent or quadrivalent HPV vaccine than with control, and these responses could be demonstrated to have been maintained for up to 24 months in children living with HIV (low-certainty evidence). The evidence about clinical outcomes and harms for HPV vaccines in people with HIV is very uncertain (low- to very low-certainty evidence), owing to imprecision and indirectness. AUTHORS' CONCLUSIONS: The immunogenicity of two-dose and three-dose HPV vaccine schedules, measured using antibody responses in young females, is comparable. The quadrivalent vaccine probably reduces external genital lesions and anogenital warts in males compared with control. The nonavalent and quadrivalent vaccines offer similar protection against a combined outcome of cervical, vaginal, and vulval precancer lesions or cancer. In people living with HIV, both the bivalent and quadrivalent HPV vaccines result in high antibody responses. For all comparisons of alternative HPV vaccine schedules, the certainty of the body of evidence about serious adverse events reported during the study periods was low or very low, either because the number of events was low, or the evidence was indirect, or both. Post-marketing surveillance is needed to continue monitoring harms that might be associated with HPV vaccines in the population, and this evidence will be incorporated in future updates of this review. Long-term observational studies are needed to determine the effectiveness of reduced-dose schedules against HPV-related cancer endpoints, and whether adopting these schedules improves vaccine coverage rates.

ANTECEDENTES: La aceptación de la vacuna contra el virus del papiloma humano (VPH) sigue siendo baja en muchos países, aunque las vacunas bivalentes y cuadrivalentes contra el VPH administradas en un calendario de tres dosis son efectivas para prevenir las lesiones precancerosas del cuello uterino en las mujeres. Los calendarios de vacunación más sencillos, como los que incluyen menos dosis, podrían reducir las barreras a la vacunación, al igual que los calendarios que incluyen a los hombres. OBJETIVOS: Evaluar la eficacia, la inmunogenicidad y los efectos perjudiciales de diferentes calendarios de dosis y diferentes tipos de vacunas contra el VPH en mujeres y hombres. MÉTODOS DE BÚSQUEDA: Se realizaron búsquedas electrónicas el 27 de septiembre 2018 en Ovid MEDLINE, el Registro Cochrane Central de Ensayos Controlados (CENTRAL) (en la Biblioteca Cochrane) y Ovid Embase. También se realizaron búsquedas en la International Clinical Trials Registry Platform de la OMS y en ClinicalTrials.gov (ambas el 27 de septiembre 2018), en sitios web de fabricantes de vacunas y se verificaron las listas de referencias de un índice de estudios sobre el VPH y otras revisiones sistemáticas pertinentes. CRITERIOS DE SELECCIÓN: Se incluyeron ensayos controlados aleatorizados (ECA) sin restricciones de idioma. Se consideraron los estudios cuando habían reclutado a hombres o mujeres con pruebas negativas para el VIH de 9 a 26 años de edad, o a hombres o mujeres con pruebas positivas para el VIH de cualquier edad. OBTENCIÓN Y ANÁLISIS DE LOS DATOS: Se siguieron los métodos recomendados por Cochrane. Se utilizó el término "control" para hacer referencia a los productos de comparación que contienen un adyuvante o vacuna activa y "placebo" para hacer referencia a los productos que no contienen un adyuvante ni vacuna activa. La mayoría de los resultados primarios de esta revisión fueron resultados clínicos. Sin embargo, para las comparaciones de los calendarios de dosis, los ECA incluidos se diseñaron para medir las respuestas de los anticuerpos (es decir, la inmunogenicidad) como resultado primario, en lugar de los resultados clínicos, debido a que no es ético recoger muestras del cuello uterino de niñas menores de 16 años de edad. Se analizaron los resultados de inmunogenicidad (es decir, títulos de la media geométrica) con los cocientes de medias, los resultados clínicos (p.ej. cáncer y neoplasia intraepitelial) con los cocientes de riesgos o los cocientes de tasas y, para los eventos adversos graves y las muertes, se calcularon los odds­ratios. La certeza de la evidencia se evaluó con los criterios GRADE. RESULTADOS PRINCIPALES: Se incluyeron 20 ECA con 31 940 participantes. La duración del seguimiento en los estudios incluidos varió de siete meses a cinco años. Dos dosis frente a tres dosis de la vacuna contra el VPH en mujeres de 9 a 15 años de edad Las respuestas de los anticuerpos después de los calendarios de dos y tres dosis de la vacuna contra el VPH fueron similares después de hasta cinco años de seguimiento (4 ECA, evidencia de certeza moderada a alta). Ningún ECA recopiló datos de los resultados clínicos. La evidencia acerca de los eventos adversos graves en los estudios que compararon los calendarios de dosis fue de certeza muy baja debido a la imprecisión y a la falta de direccionalidad (tres dosis 35/1159; dos dosis 36/1158; 4 ECA). Se informó una muerte en el grupo de tres dosis (1/898) y ninguna en el grupo de dos dosis (0/899) (evidencia de certeza baja). Intervalo entre las dosis de la vacuna contra el VPH en mujeres y hombres de 9 a 14 años de edad Las respuestas de los anticuerpos fueron más significativas con un intervalo más largo (6 o 12 meses) entre las dos primeras dosis de la vacuna contra el VPH que con un intervalo más corto (2 o 6 meses) al momento del seguimiento de hasta tres años (4 ECA, evidencia de certeza moderada a alta). Ningún ECA recopiló datos sobre los resultados clínicos. La evidencia acerca de los eventos adversos graves en los estudios que compararon los intervalos fue de certeza muy baja, debido a la imprecisión y a la falta de direccionalidad. No se informaron muertes en ninguno de los estudios (0/1898, 3 ECA, evidencia de certeza baja). Vacunación contra el VPH en hombres de 10 a 26 años de edad En un ECA hubo evidencia de certeza moderada de que la vacuna cuadrivalente contra el VPH, en comparación con el control, redujo la incidencia de lesiones genitales externas (control 36 por 3081 personas­año; cuadrivalente 6 por 3173 personas­año; cociente de tasas 0,16; IC del 95%: 0,07 a 0,38; 6254 personas­año) y verrugas anogenitales (control 28 por 2814 personas­año; cuadrivalente 3 por 2831 años­persona; cociente de tasas 0,11; IC del 95%: 0,03 a 0,38; 5645 años­persona). La vacuna cuadrivalente produjo más eventos adversos relacionados con el sitio de la inyección, como dolor o enrojecimiento, que el control (537 frente a 601 por 1000; cociente de riesgos [CR] 1,12; IC del 95%: 1,06 a 1,18; 3895 participantes, evidencia de certeza alta). Hubo evidencia de certeza muy baja de dos ECA acerca de eventos adversos graves con la vacuna cuadrivalente (control 12/2588; cuadrivalente 8/2574), y acerca de las muertes (control 11/2591; cuadrivalente 3/2582), debido a la imprecisión y la falta de direccionalidad. Vacuna nonavalente frente a cuadrivalente en mujeres y hombres de 9 a 26 años de edad Se incluyeron tres ECA; uno en mujeres de 9 a 15 años de edad (n = 600), uno en mujeres de 16 a 26 años de edad (n = 14 215) y uno en hombres de 16 a 26 años de edad (n = 500). El ECA en mujeres de 16 a 26 años informó de los resultados clínicos. Hubo poca o ninguna diferencia en la incidencia del resultado combinado de neoplasia epitelial de cuello de útero de grado alto, adenocarcinoma in situ o cáncer de cuello de útero entre las vacunas contra el VPH (cuadrivalente 325/6882, nonavalente 326/6871; OR 1,00; IC del 95%: 0,85 a 1,16; 13 753 participantes; evidencia de certeza alta). Los otros dos ECA no recopilaron datos sobre los resultados clínicos. Hubo un número ligeramente mayor de eventos adversos locales con la vacuna nonavalente (905 por 1000) que con la vacuna cuadrivalente (846 por 1000) (CR 1,07; IC del 95%: 1,05 a 1,08; 3 ECA, 15 863 participantes; evidencia de certeza alta). La evidencia comparativa acerca de los eventos adversos graves en los tres ECA (nonavalente 243/8234, cuadrivalente 192/7629; OR 0,60; IC del 95%: 0,14 a 2,61) fue de certeza baja, debido a la imprecisión y a la falta de direccionalidad. Vacunación contra el VPH para las personas que conviven con el VIH Siete ECA informaron sobre las vacunas contra el VPH en personas con VIH, y dos ensayos pequeños recopilaron datos sobre los resultados clínicos. Las respuestas de los anticuerpos fueron más altas después de la vacunación con la vacuna bivalente o cuadrivalente contra el VPH que con el control, y se pudo demostrar que estas respuestas se mantuvieron hasta 24 meses en niños que convivían con el VIH (evidencia de certeza baja). La evidencia acerca de los resultados clínicos y los efectos perjudiciales de las vacunas contra el VPH en las personas con VIH es muy incierta (evidencia de certeza baja a muy baja), debido a la imprecisión y a la falta de direccionalidad. CONCLUSIONES DE LOS AUTORES: Es similar la inmunogenicidad de los calendarios de dos y tres dosis de la vacuna contra el VPH, medida con las respuestas de los anticuerpos en mujeres jóvenes. La vacuna cuadrivalente probablemente reduce las lesiones genitales externas y las verrugas anogenitales en los hombres en comparación con el control. Las vacunas nonavalentes y cuadrivalentes ofrecen una protección similar en cuanto a un resultado combinado de lesiones precancerosas o cáncer de cuello de útero, vaginal y vulvar. En los individuos que conviven con el VIH, tanto las vacunas bivalentes como las cuadrivalentes contra el VPH producen respuestas altas de los anticuerpos. Para todas las comparaciones de los calendarios alternativos de la vacuna contra el VPH, la certeza del conjunto de evidencia sobre los eventos adversos graves notificados durante los períodos de estudio fue baja o muy baja, debido a que el número de eventos fue escaso, o a que la evidencia fue indirecta, o ambos. La vigilancia posterior a la comercialización es necesaria para continuar con el control de los efectos perjudiciales que podrían estar asociados con las vacunas contra el VPH en la población, y esta evidencia se incorporará en las actualizaciones futuras de esta revisión. Se necesitan estudios observacionales a largo plazo para determinar la efectividad de los calendarios de dosis reducidas con respecto a las variables de evaluación del cáncer relacionado con el VPH, y si la adopción de estos calendarios mejora las tasas de cobertura de la vacuna.

Vaccines for preventing rotavirus diarrhoea: vaccines in use.

BACKGROUND: Rotavirus results in more diarrhoea-related deaths in children under five years than any other single agent in countries with high childhood mortality. It is also a common cause of diarrhoea-related hospital admissions in countries with low childhood mortality. Rotavirus vaccines that have been prequalified by the World Health Organization (WHO) include a monovalent vaccine (RV1; Rotarix, GlaxoSmithKline), a pentavalent vaccine (RV5; RotaTeq, Merck), and, more recently, another monovalent vaccine (Rotavac, Bharat Biotech). OBJECTIVES: To evaluate rotavirus vaccines prequalified by the WHO (RV1, RV5, and Rotavac) for their efficacy and safety in children. SEARCH METHODS: On 4 April 2018 we searched MEDLINE (via PubMed), the Cochrane Infectious Diseases Group Specialized Register, CENTRAL (published in the Cochrane Library), Embase, LILACS, and BIOSIS. We also searched the WHO ICTRP, ClinicalTrials.gov, clinical trial reports from manufacturers' websites, and reference lists of included studies and relevant systematic reviews. SELECTION CRITERIA: We selected randomized controlled trials (RCTs) in children comparing rotavirus vaccines prequalified for use by the WHO versus placebo or no intervention. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial eligibility and assessed risks of bias. One review author extracted data and a second author cross-checked them. We combined dichotomous data using the risk ratio (RR) and 95% confidence interval (CI). We stratified the analysis by country mortality rate and used GRADE to evaluate evidence certainty. MAIN RESULTS: Fifty-five trials met the inclusion criteria and enrolled a total of 216,480 participants. Thirty-six trials (119,114 participants) assessed RV1, 15 trials (88,934 participants) RV5, and four trials (8432 participants) Rotavac.RV1 Children vaccinated and followed up the first year of life In low-mortality countries, RV1 prevents 84% of severe rotavirus diarrhoea cases (RR 0.16, 95% CI 0.09 to 0.26; 43,779 participants, 7 trials; high-certainty evidence), and probably prevents 41% of cases of severe all-cause diarrhoea (RR 0.59, 95% CI 0.47 to 0.74; 28,051 participants, 3 trials; moderate-certainty evidence). In high-mortality countries, RV1 prevents 63% of severe rotavirus diarrhoea cases (RR 0.37, 95% CI 0.23 to 0.60; 6114 participants, 3 trials; high-certainty evidence), and 27% of severe all-cause diarrhoea cases (RR 0.73, 95% CI 0.56 to 0.95; 5639 participants, 2 trials; high-certainty evidence).Children vaccinated and followed up for two yearsIn low-mortality countries, RV1 prevents 82% of severe rotavirus diarrhoea cases (RR 0.18, 95% CI 0.14 to 0.23; 36,002 participants, 9 trials; high-certainty evidence), and probably prevents 37% of severe all-cause diarrhoea episodes (rate ratio 0.63, 95% CI 0.56 to 0.71; 39,091 participants, 2 trials; moderate-certainty evidence). In high-mortality countries RV1 probably prevents 35% of severe rotavirus diarrhoea cases (RR 0.65, 95% CI 0.51 to 0.83; 13,768 participants, 2 trials; high-certainty evidence), and 17% of severe all-cause diarrhoea cases (RR 0.83, 95% CI 0.72 to 0.96; 2764 participants, 1 trial; moderate-certainty evidence).No increased risk of serious adverse events (SAE) was detected (RR 0.88 95% CI 0.83 to 0.93; high-certainty evidence). There were 30 cases of intussusception reported in 53,032 children after RV1 vaccination and 28 cases in 44,214 children after placebo or no intervention (RR 0.70, 95% CI 0.46 to 1.05; low-certainty evidence).RV5 Children vaccinated and followed up the first year of life In low-mortality countries, RV5 probably prevents 92% of severe rotavirus diarrhoea cases (RR 0.08, 95% CI 0.03 to 0.22; 4132 participants, 5 trials; moderate-certainty evidence). We did not identify studies reporting on severe all-cause diarrhoea in low-mortality countries. In high-mortality countries, RV5 prevents 57% of severe rotavirus diarrhoea (RR 0.43, 95% CI 0.29 to 0.62; 5916 participants, 2 trials; high-certainty evidence), but there is probably little or no difference between vaccine and placebo for severe all-cause diarrhoea (RR 0.80, 95% CI 0.58 to 1.11; 1 trial, 4085 participants; moderate-certainty evidence).Children vaccinated and followed up for two yearsIn low-mortality countries, RV5 prevents 82% of severe rotavirus diarrhoea cases (RR 0.18, 95% CI 0.08 to 0.39; 7318 participants, 4 trials; moderate-certainty evidence). We did not identify studies reporting on severe all-cause diarrhoea in low-mortality countries. In high-mortality countries, RV5 prevents 41% of severe rotavirus diarrhoea cases (RR 0.59, 95% CI 0.43 to 0.82; 5885 participants, 2 trials; high-certainty evidence), and 15% of severe all-cause diarrhoea cases (RR 0.85, 95% CI 0.75 to 0.98; 5977 participants, 2 trials; high-certainty evidence).No increased risk of serious adverse events (SAE) was detected (RR 0.93 95% CI 0.86 to 1.01; moderate to high-certainty evidence). There were 16 cases of intussusception in 43,629 children after RV5 vaccination and 20 cases in 41,866 children after placebo (RR 0.77, 95% CI 0.41 to 1.45; low-certainty evidence).Rotavac Children vaccinated and followed up the first year of life Rotavac has not been assessed in any RCT in countries with low child mortality. In India, a high-mortality country, Rotavac probably prevents 57% of severe rotavirus diarrhoea cases (RR 0.43, 95% CI 0.30 to 0.60; 6799 participants, moderate-certainty evidence); the trial did not report on severe all-cause diarrhoea at one-year follow-up.Children vaccinated and followed up for two yearsRotavac probably prevents 54% of severe rotavirus diarrhoea cases in India (RR 0.46, 95% CI 0.35 to 0.60; 6541 participants, 1 trial; moderate-certainty evidence), and 16% of severe all-cause diarrhoea cases (RR 0.84, 95% CI 0.71 to 0.98; 6799 participants, 1 trial; moderate-certainty evidence).No increased risk of serious adverse events (SAE) was detected (RR 0.93 95% CI 0.85 to 1.02; moderate-certainty evidence). There were eight cases of intussusception in 5764 children after Rotavac vaccination and three cases in 2818 children after placebo (RR 1.33, 95% CI 0.35 to 5.02; very low-certainty evidence).There was insufficient evidence of an effect on mortality from any rotavirus vaccine (198,381 participants, 44 trials; low- to very low-certainty evidence), as the trials were not powered to detect an effect at this endpoint. AUTHORS' CONCLUSIONS: RV1, RV5, and Rotavac prevent episodes of rotavirus diarrhoea. Whilst the relative effect estimate is smaller in high-mortality than in low-mortality countries, there is a greater number of episodes prevented in these settings as the baseline risk is much higher. We found no increased risk of serious adverse events.

Client feedback in psychological therapy for children and adolescents with mental health problems.

BACKGROUND: Childhood and adolescent mental health problems are a serious and growing concern worldwide. Research suggests that psychotherapy can have a significant and positive impact on children and adolescents with mental health problems, such as anxiety disorders, depression and conduct disorders. Client feedback tools serve as a method of monitoring clients' progress and providing feedback from clients to therapists during the therapeutic process. These tools may help to enhance clinicians' decision-making by allowing them to adapt their treatment plans as the therapy progresses, resulting in a reduction of treatment failures. Research has shown that client feedback tools have a positive effect on adults' psychotherapy. This review addresses whether feedback tools in child and adolescent therapy could help therapists to better treat their young clients. OBJECTIVES: To assess the effects of client feedback in psychological therapy on child and adolescent mental health outcomes. SEARCH METHODS: We searched the Cochrane Common Mental Disorders Controlled Trials Register (CCMDCTR, Studies and References), the Cochrane Central Register of Controlled Trials (CENTRAL), Ovid MEDLINE (1946-), Embase (1974-) and PsycINFO (1967-) to 3 April 2018. We did not apply any restriction on date, language or publication status to the search. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that compared client feedback to no client feedback in psychological therapies for children and adolescents. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed references for inclusion eligibility and extracted outcome, risk of bias and study characteristics data into customised forms. We contacted study authors to obtain missing data. We analysed dichotomous data using risk ratios (RRs) and calculated their 95% confidence intervals (CIs). For continuous data, we calculated mean differences (MDs), or standardised mean differences (SMDs) if different scales were used to measure the same outcome. We used a random-effects model for all analyses. MAIN RESULTS: We included six published RCTs, conducted in the USA (5 RCTs) and Israel (1 RCT), with 1097 children and adolescents (11 to 18 years old), in the review.We are very uncertain about the effect of client feedback on improvement of symptoms, as reported by youth in the short term because we considered evidence to be of very low-certainty due to high risk of bias and very serious inconsistency in the effect estimates from the different studies. Similarly, we are very uncertain about the effect of client feedback on treatment acceptability, due to high risk of bias, imprecision in the results, and indirectness of measuring the outcome (RR 1.08, 95% CI 0.73 to 1.61; 2 studies, 237 participants; very low-certainty).Overall, most studies reported and carried out randomisation and allocation concealment adequately. None of the studies were blinded or attempted to blind participants and personnel and were at high risk of performance bias, and only one study had blind outcome assessors. All of the studies were at high or unclear risk of attrition bias mainly due to poor, non-transparent reporting of participants' flow through the studies. AUTHORS' CONCLUSIONS: Due to the paucity of high-quality data and considerable inconsistency in results from different studies, there is currently insufficient evidence to reach any firm conclusions regarding the role of client feedback in psychological therapies for children and adolescents with mental health problems, and further research on this important topic is needed.Future studies should avoid risks of performance, detection and attrition biases, as seen in the studies included in this review. Studies from countries other than the USA are needed, as well as studies including children younger than 10 years.

Gamma-aminobutyric acid agonists for antipsychotic-induced tardive dyskinesia.

BACKGROUND: Chronic antipsychotic drug treatment may cause tardive dyskinesia (TD), a long-term movement disorder. Gamma-aminobutyric acid (GABA) agonist drugs, which have intense sedative properties and may exacerbate psychotic symptoms, have been used to treat TD. OBJECTIVES: 1. Primary objectiveThe primary objective was to determine whether using non-benzodiazepine GABA agonist drugs for at least six weeks was clinically effective for the treatment of antipsychotic-induced TD in people with schizophrenia, schizoaffective disorder or other chronic mental illnesses.2. Secondary objectivesThe secondary objectives were as follows.To examine whether any improvement occurred with short periods of intervention (less than six weeks) and, if this did occur, whether this effect was maintained at longer periods of follow-up.To examine whether there was a differential effect between the various compounds.To test the hypothesis that GABA agonist drugs are most effective for a younger age group (less than 40 years old). SEARCH METHODS: We searched the Cochrane Schizophrenia Group Trials Register (last searched April 2017), inspected references of all identified studies for further trials, and, when necessary, contacted authors of trials for additional information. SELECTION CRITERIA: We included randomised controlled trials of non-benzodiazepine GABA agonist drugs in people with antipsychotic-induced TD and schizophrenia or other chronic mental illness. DATA COLLECTION AND ANALYSIS: Two review authors independently selected and critically appraised studies, extracted and analysed data on an intention-to-treat basis. Where possible and appropriate we calculated risk ratios (RRs) and their 95% confidence intervals (CIs). For continuous data we calculated mean differences (MD). We assumed that people who left early had no improvement. We contacted investigators to obtain missing information. We assessed risk of bias for included studies and created a 'Summary of findings' table using GRADE. MAIN RESULTS: We included 11 studies that randomised 343 people. Overall, the risk of bias in the included studies was unclear, mainly due to poor reporting; allocation concealment was not described, generation of the sequence was not explicit, participants and outcome assessors were not clearly blinded. For some studies we were unsure if data were complete, and data were often poorly or selectively reported.Data from six trials showed that there may be a clinically important improvement in TD symptoms after GABA agonist treatment compared with placebo at six to eight weeks follow-up (6 RCTs, n = 258, RR 0.83, CI 0.74 to 0.92; low-quality evidence). Data from five studies showed no difference between GABA agonist treatment and placebo for deterioration of TD symptoms (5 RCTs, n = 136, RR 1.90, CI 0.70 to 5.16; very low-quality evidence). Studies reporting adverse events found a significant effect favouring placebo compared with baclofen, sodium valproate or progabide for dizziness/confusion (3 RCTs, n = 62 RR 4.54, CI 1.14 to 18.11; very low-quality evidence) and sedation/drowsiness (4 RCTS, n = 144, RR 2.29, CI 1.08 to 4.86; very low-quality evidence). Studies reporting on akathisia (RR 1.05, CI 0.32 to 3.49, 2 RCTs, 80 participants), ataxia (RR 3.25, CI 0.36 to 29.73, 2 RCTs, 95 participants), nausea/vomiting (RR 2.61, CI 0.79 to 8.67, 2 RCTs, 64 participants), loss of muscle tone (RR 3.00, CI 0.15 to 59.89, 1 RCT, 10 participants), seizures (RR 3.00, CI 0.24 to 37.67, 1 RCT, 2 participants), hypotension (RR 3.04, CI 0.33 to 28.31, 2 RCTs, 119 participants) found no significant difference between GABA drug and placebo (very low-quality evidence). Evidence on mental state also showed no effect between treatment groups (6 RCTS, n = 121, RR 2.65, CI 0.71 to 9.86; very low-quality evidence) as did data for leaving the study early (around 10% in both groups, 6 RCTS, n = 218, RR 1.47, CI 0.69 to 3.15; very low-quality evidence). No study reported on social confidence, social inclusion, social networks, or personalised quality of life, a group of outcomes selected as being of particular importance to patients. AUTHORS' CONCLUSIONS: We are uncertain about the evidence of the effects of baclofen, progabide, sodium valproate or tetrahydroisoxazolopyridinol (THIP) for people with antipsychotic-induced TD. Evidence is inconclusive and unconvincing. The quality of data available for main outcomes ranges from very low to low. Any possible benefits are likely to be outweighed by the adverse effects associated with their use.

Miscellaneous treatments for antipsychotic-induced tardive dyskinesia.

BACKGROUND: Antipsychotic (neuroleptic) medication is used extensively to treat people with chronic mental illnesses. Its use, however, is associated with adverse effects, including movement disorders such as tardive dyskinesia (TD) - a problem often seen as repetitive involuntary movements around the mouth and face. This review, one in a series examining the treatment of TD, covers miscellaneous treatments not covered elsewhere. OBJECTIVES: To determine whether drugs, hormone-, dietary-, or herb-supplements not covered in other Cochrane reviews on TD treatments, surgical interventions, electroconvulsive therapy, and mind-body therapies were effective and safe for people with antipsychotic-induced TD. SEARCH METHODS: We searched the Cochrane Schizophrenia Group's Study-Based Register of Trials including trial registers (16 July 2015 and 26 April 2017), inspected references of all identified studies for further trials and contacted authors of trials for additional information. SELECTION CRITERIA: We included reports if they were randomised controlled trials (RCTs) dealing with people with antipsychotic-induced TD and schizophrenia or other chronic mental illnesses who remained on their antipsychotic medication and had been randomly allocated to the interventions listed above versus placebo, no intervention, or any other intervention. DATA COLLECTION AND ANALYSIS: We independently extracted data from these trials and we estimated risk ratios (RR) or mean differences (MD), with 95% confidence intervals (CIs). We assumed that people who left early had no improvement. We assessed risk of bias and created 'Summary of findings' tables using GRADE. MAIN RESULTS: We included 31 RCTs of 24 interventions with 1278 participants; 22 of these trials were newly included in this 2017 update. Five trials are awaiting classification and seven trials are ongoing. All participants were adults with chronic psychiatric disorders, mostly schizophrenia, and antipsychotic-induced TD. Studies were primarily of short (three to six6 weeks) duration with small samples size (10 to 157 participants), and most (61%) were published more than 20 years ago. The overall risk of bias in these studies was unclear, mainly due to poor reporting of allocation concealment, generation of the sequence, and blinding.Nineteen of the 31 included studies reported on the primary outcome 'No clinically important improvement in TD symptoms'. Two studies found moderate-quality evidence of a benefit of the intervention compared with placebo: valbenazine (RR 0.63, 95% CI 0.46 to 0.86, 1 RCT, n = 92) and extract of Ginkgo biloba (RR 0.88, 95% CI 0.81 to 0.96, 1 RCT, n = 157), respectively. However, due to small sample sizes we cannot be certain of these effects.We consider the results for the remaining interventions to be inconclusive: Low- to very low-quality evidence of a benefit was found for buspirone (RR 0.53, 95% CI 0.33 to 0.84, 1 RCT, n = 42), dihydrogenated ergot alkaloids (RR 0.45, 95% CI 0.21 to 0.97, 1 RCT, n = 28), hypnosis or relaxation, (RR 0.45, 95% CI 0.21 to 0.94, 1 study, n = 15), pemoline (RR 0.48, 95% CI 0.29 to 0.77, 1 RCT, n = 46), promethazine (RR 0.24, 95% CI 0.11 to 0.55, 1 RCT, n = 34), insulin (RR 0.52, 95% CI 0.29 to 0.96, 1 RCT, n = 20), branched chain amino acids (RR 0.79, 95% CI 0.63 to 1.00, 1 RCT, n = 52), and isocarboxazid (RR 0.24, 95% CI 0.08 to 0.71, 1 RCT, n = 20). There was low- to very low-certainty evidence of no difference between intervention and placebo or no treatment for the following interventions: melatonin (RR 0.89, 95% CI 0.71 to 1.12, 2 RCTs, n = 32), lithium (RR 1.59, 95% CI 0.79 to 3.23, 1 RCT, n = 11), ritanserin (RR 1.00, 95% CI 0.70 to 1.43, 1 RCT, n = 10), selegiline (RR 1.37, 95% CI 0.96 to 1.94, 1 RCT, n = 33), oestrogen (RR 1.18, 95% CI 0.76 to 1.83, 1 RCT, n = 12), and gamma-linolenic acid (RR 1.00, 95% CI 0.69 to 1.45, 1 RCT, n = 16).None of the included studies reported on the other primary outcome, 'no clinically significant extrapyramidal adverse effects'. AUTHORS' CONCLUSIONS: This review has found that the use of valbenazine or extract of Ginkgo biloba may be effective in relieving the symptoms of tardive dyskinesia. However, since only one RCT has investigated each one of these compounds, we are awaiting results from ongoing trials to confirm these results. Results for the remaining interventions covered in this review must be considered inconclusive and these compounds probably should only be used within the context of a well-designed evaluative study.

Cholinergic medication for antipsychotic-induced tardive dyskinesia.

BACKGROUND: Tardive dyskinesia (TD) remains a troublesome adverse effect of conventional antipsychotic (neuroleptic) medication. It has been proposed that TD could have a component of central cholinergic deficiency. Cholinergic drugs have been used to treat TD. OBJECTIVES: To determine the effects of cholinergic drugs (arecoline, choline, deanol, lecithin, meclofenoxate, physostigmine, RS 86, tacrine, metoxytacrine, galantamine, ipidacrine, donepezil, rivastigmine, eptastigmine, metrifonate, xanomeline, cevimeline) for treating antipsychotic-induced TD in people with schizophrenia or other chronic mental illness. SEARCH METHODS: An electronic search of the Cochrane Schizophrenia Group's Study-Based Register of Trials (16 July 2015 and April 2017) was undertaken. This register is assembled by extensive searches for randomised controlled trials in many electronic databases, registers of trials, conference proceedings and dissertations. References of all identified studies were searched for further trial citations. SELECTION CRITERIA: We included reports identified by the search if they were of controlled trials involving people with antipsychotic-induced TD and chronic mental illness, who had been randomly allocated to either a cholinergic agent or to a placebo or no intervention. Two review authors independently assessed the methodological quality of the trials. DATA COLLECTION AND ANALYSIS: Two review authors extracted data and, where possible, estimated risk ratios (RR) or mean differences (MD), with 95% confidence intervals (CI). We analysed data on an intention-to-treat basis, with the assumption that people who left early had no improvement. We assessed risk of bias and created a 'Summary of findings' table using GRADE. MAIN RESULTS: We included 14 studies investigating the use of cholinergic drugs compared with placebo published between 1976 and 2014. All studies involved small numbers of participants (five to 60 people). Three studies that investigated the new cholinergic Alzheimer drugs for the treatment of TD are new to this update. Overall, the risk of bias in the included studies was unclear, mainly due to poor reporting; allocation concealment was not described, generation of the sequence was not explicit, studies were not clearly blinded, we are unsure if data are incomplete, and data were often poorly or selectively reported.We are uncertain about the effect of new or old cholinergic drugs on no clinically important improvement in TD symptoms when compared with placebo; the quality of evidence was very low (RR 0.89, 95% CI 0.65 to 1.23; 27 people, 4 RCTs). Eight trials found that cholinergic drugs may make little or no difference to deterioration of TD symptoms (low-quality evidence, RR 1.11, 95% CI 0.55 to 2.24; 147 people). Again, due to very low-quality evidence, we are uncertain about the effects on mental state (RR 0.50, 95% CI 0.10 to 2.61; 77 people, 5 RCTs), adverse events (RR 0.56, 95% CI 0.15 to 2.14; 106 people, 4 RCTs), and leaving the study early (RR 1.09,95% CI 0.56 to 2.10; 288 people 12 RCTs). No study reported on social confidence, social inclusion, social networks, or personalised quality of life. AUTHORS' CONCLUSIONS: TD remains a major public health problem. The clinical effects of both older cholinergic drugs and new cholinergic agents, now used for treating Alzheimer's disease, are unclear, as too few, too small studies leave many questions unanswered. Cholinergic drugs should remain of interest to researchers and currently have little place in routine clinical work. However, with the advent of new cholinergic agents now used for treating Alzheimer's disease, scope exists for more informative trials. If these new cholinergic agents are to be investigated for treating people with TD, their effects should be demonstrated in large well-designed, conducted and reported randomised trials.

Calcium channel blockers for antipsychotic-induced tardive dyskinesia.

BACKGROUND: Schizophrenia and related disorders affect a sizable proportion of any population. Antipsychotic medications are the primary treatment for these disorders. Antipsychotic medications are associated with a variety of adverse effects including tardive dyskinesia. Dyskinesia is a disfiguring movement disorder of the orofacial region that can be tardive (having a slow or belated onset). Tardive dyskinesia is difficult to treat, despite experimentation with several treatments. Calcium channel blockers (diltiazem, nifedipine, nimodipine, verapamil, flunarizine) have been among these experimental treatments. OBJECTIVES: To determine the effects of calcium channel blocker drugs (diltiazem, nifedipine, nimodipine, verapamil) for treatment of neuroleptic-induced tardive dyskinesia in people with schizophrenia, schizoaffective disorder or other chronic mental illnesses. SEARCH METHODS: We searched the Cochrane Schizophrenia Group Trials Register (July 2015 and April 2017), inspected references of all identified studies for further trials and contacted authors of trials for additional information. SELECTION CRITERIA: We selected randomised controlled trials comparing calcium channel blockers with placebo, no intervention or any other intervention for people with both tardive dyskinesia and schizophrenia or serious mental illness who remained on their antipsychotic medication. DATA COLLECTION AND ANALYSIS: We independently extracted data and estimated risk ratios of dichotomous data or mean differences (MD) of continuous data, with 95% confidence intervals (CI). We assumed that people who left the trials early had no improvement. We also created a 'Summary of findings' table using GRADE. MAIN RESULTS: Previous versions of this review included no trials. From the 2015 search, we identified three cross-over trials that could be included. The 2017 search found no new studies relevant to this review. The included trials randomised 47 inpatients with chronic mental illnesses in the USA and China. Trials were published in the 1990s and were of short duration (six to 10 weeks). Overall, the risk of bias was unclear, mainly due to poor reporting; allocation concealment was not described, generation of the sequence was not explicit, studies were not clearly blinded, and attrition and outcome data were not fully reported. Findings were sparse, no study reported on the primary outcome 'no clinically important improvement in tardive dyskinesia symptoms,' but two small studies (37 participants) found no difference on the tardive dyskinesia symptoms scale Abnormal Involuntary Movement Scale (AIMS) scores between diltiazem or flunarizine and placebo after three to four weeks' treatment (MD -0.71, 95% CI -2.68 to 1.26, very low quality evidence). Only one study randomising 20 participants reported on adverse events, and reported that there were no adverse events with flunarizine or with placebo (very low quality evidence). One study with 18 participants reported no events of deterioration in mental state with diltiazem or with placebo (very low quality evidence). No studies reported on acceptability of treatment or on social confidence, social inclusion, social networks or personalised quality of life outcomes designated important to patients. AUTHORS' CONCLUSIONS: Available evidence from randomised controlled trials is extremely limited and very low quality, conclusions cannot be drawn. The effects of calcium channel blockers for antipsychotic-induced tardive dyskinesia are unknown. Their use is experimental and should only be given in the context of well-designed randomised trials.

Antipsychotic reduction and/or cessation and antipsychotics as specific treatments for tardive dyskinesia.

BACKGROUND: Since the 1950s antipsychotic medication has been extensively used to treat people with chronic mental illnesses such as schizophrenia. These drugs, however, have also been associated with a wide range of adverse effects, including movement disorders such as tardive dyskinesia (TD) - a problem often seen as repetitive involuntary movements around the mouth and face. Various strategies have been examined to reduce a person's cumulative exposure to antipsychotics. These strategies include dose reduction, intermittent dosing strategies such as drug holidays, and antipsychotic cessation. OBJECTIVES: To determine whether a reduction or cessation of antipsychotic drugs is associated with a reduction in TD for people with schizophrenia (or other chronic mental illnesses) who have existing TD. Our secondary objective was to determine whether the use of specific antipsychotics for similar groups of people could be a treatment for TD that was already established. SEARCH METHODS: We updated previous searches of Cochrane Schizophrenia's study-based Register of Trials including the registers of clinical trials (16 July 2015 and 26 April 2017). We searched references of all identified studies for further trial citations. We also contacted authors of trials for additional information. SELECTION CRITERIA: We included reports if they assessed people with schizophrenia or other chronic mental illnesses who had established antipsychotic-induced TD, and had been randomly allocated to (a) antipsychotic maintenance versus antipsychotic cessation (placebo or no intervention), (b) antipsychotic maintenance versus antipsychotic reduction (including intermittent strategies), (c) specific antipsychotics for the treatment of TD versus placebo or no intervention, and (d) specific antipsychotics versus other antipsychotics or versus any other drugs for the treatment of TD. DATA COLLECTION AND ANALYSIS: We independently extracted data from these trials and estimated risk ratios (RR) or mean differences (MD), with 95% confidence intervals (CI). We assumed that people who dropped out had no improvement. MAIN RESULTS: We included 13 RCTs with 711 participants; eight of these studies were newly included in this 2017 update. One trial is ongoing.There was low-quality evidence of a clear difference on no clinically important improvement in TD favouring switch to risperidone compared with antipsychotic cessation (with placebo) (1 RCT, 42 people, RR 0.45 CI 0.23 to 0.89, low-quality evidence). Because evidence was of very low quality for antipsychotic dose reduction versus antipsychotic maintenance (2 RCTs, 17 people, RR 0.42 95% CI 0.17 to 1.04, very low-quality evidence), and for switch to a new antipsychotic versus switch to another new antipsychotic (5 comparisons, 5 RCTs, 140 people, no meta-analysis, effects for all comparisons equivocal), we are uncertain about these effects. There was low-quality evidence of a significant difference on extrapyramidal symptoms: use of antiparkinsonism medication favouring switch to quetiapine compared with switch to haloperidol (1 RCT, 45 people, RR 0.45 CI 0.21 to 0.96, low-quality evidence). There was no evidence of a difference for switch to risperidone or haloperidol compared with antipsychotic cessation (with placebo) (RR 1 RCT, 48 people, RR 2.08 95% CI 0.74 to 5.86, low-quality evidence) and switch to risperidone compared with switch to haloperidol (RR 1 RCT, 37 people, RR 0.68 95% CI 0.34 to 1.35, very low-quality evidence).Trials also reported on secondary outcomes such as other TD symptom outcomes, other adverse events outcomes, mental state, and leaving the study early, but the quality of the evidence for all these outcomes was very low due mainly to small sample sizes, very wide 95% CIs, and risk of bias. No trials reported on social confidence, social inclusion, social networks, or personalised quality of life, outcomes that we designated as being important to patients. AUTHORS' CONCLUSIONS: Limited data from small studies using antipsychotic reduction or specific antipsychotic drugs as treatments for TD did not provide any convincing evidence of the value of these approaches. There is a need for larger trials of a longer duration to fully investigate this area.