2016, Issue 12

Three updated reviews are available in Issue 12 of the Cochrane Database of Systematic Reviews

Updated Reviews

Marzia Lazzerini and her co-authors have updated this review, from January 2013. The author team has been amended, the 'Summary of findings' tables have been updated according to the GRADE approach, and a PRISMA study flow diagram has been added.  The review now includes 33 trials with 10,841 children aged one month to five years with acute or persistent diarrhoea, including dysentery, who received oral zinc supplements or placebo. The majority of the data is from Asia, from countries at high risk of zinc deficiency. In children older than six months, zinc supplementation may shorten the average duration of diarrhoea by around ½ day, and probably reduces the number of children whose diarrhoea persists until day seven. These effects are not present in children aged less than six months, but they are greater in children with malnutrition.  In children with persistent diarrhoea, zinc supplementation probably shortens the average duration of diarrhoea by around 16 hours.  Zinc administration can induce vomit (because of a metallic aftertaste), but development of a more palatable formulation may minimize this problem. The author conclude that In areas where diarrhoea is an important cause of child mortality, and the prevalence of zinc deficiency or mild/moderate malnutrition is high, zinc may be of benefit in children with diarrhoea aged six months or more.  Further research is necessary to justify continued supplementation in children less than six months of age and in children with low risk of zinc deficiency. 

This review was last published in 2009, and this update includes 'Summary of findings' tables prepared according to the GRADE approach. Germana Gregorio and her team have identified one new trial and the review now includes 35 trials with 4284 participants (2304 using polymer-based ORS and 1980 using glucose-based ORS). Polymer-based ORS are in fact “food-based” rehydration solutions made of water mixed with cooked rice, wheat, or maize, and children may like them more than salt and sugar solution, which is the standard medical treatment. Most trials compared polymer-based ORS with a sugar–salt ORS with a particular strength (ORS ≥ 310), which is slightly more salty than the currently agreed best formula (≤ 270 mOsm/L). Results showed that polymer-based ORS has advantages compared to glucose-based ORS (at ≥ 310 mOsm/L); comparisons also favoured polymer -based ORS over ORS ≤ 270, but the quality of evidence was poor.  No difference was observed between the groups regarding the number of people who needed a drip to be rehydrated, and adverse events were similar. More trials are needed comparing polymer-based ORS versus sugar-salt ORS ≤ 270 mOsm/L. 

This review  by Lawrence Mbuagbaw and colleagues updates the original, first published in 2010, with the aim to determine which non-nucleoside reverse transcriptase inhibitor(NNRTI) , either efavirenz (EFV) or nevirapine (NVP), is more effective in suppressing viral load when given in combination with two nucleoside reverse transcriptase inhibitors (NRTI) as part of initial antiretroviral therapy for HIV infection. Five new studies have been added and the review now includes 12 RCTs with 3278 participants, all adults – no trials in children were identified. Four trials included people who were also receiving treatment for tuberculosis. There was little or no difference in suppression of HIV infection, probably little or no difference in mortality, progression to AIDS, stopping treatment early and changes in blood cells affected by HIV, and there may be little or no difference in treatment failure. NVP given at the once daily dose of 400 mg led to higher mortality rates than EFV. Both drugs can cause severe adverse effects, affecting different systems:  EFV is more likely to affect mental function, while NVP is more likely to cause signs of liver damage, reduced white blood cells and rash. The authors conclude that EFV and NVP have similar clinical efficacies, and clinicians need to determine which is the more appropriate for their patients by weighing other factors like availability, cost, and concomitant medication. They must also consider individual tolerability and watch carefully for side-effects. 

2016, Issue 11

Three new reviews are available in Issue 11 of the Cochrane Database of Systematic Reviews

New Reviews

Vitamin D in its two forms (D2 and D3), is essential for bone growth and is therefore especially important in children.

Both vitamin D2 and D3 are obtained from food such as fish liver oils, eggs, and milk; however, we obtain most of our vitamin D (as vitamin D3) by synthesizing it directly when the skin is exposed to sunlight. Childhood vitamin D deficiency is common both in LMIC and high income countries, for several reasons such as lack of sunlight in the winter months, vegetarian diets, a dark pigmented skin (as melanin acts as a natural sunscreen), increased pollution, and wearing clothes covering most of the body. Vitamin D deficiency can lead to rickets, characterized by weak and deformed bones, and it has also been associated with other infections such as tuberculosis, gastroenteritis and malaria. This review, by Mohammad Yakoob and colleagues, analyses vitamin D supplementation to prevent infections, in 4 trials with a total of 3198 children under five years of age, conducted in Afghanistan, Spain, and the USA, countries with wide differences in the prevalence of vitamin D deficiency.  Evidence from the largest trial (in Afghanistan) did not demonstrate any benefit of vitamin D supplementation on the incidence of pneumonia or diarrhoea, and the authors did not find any trial that reported on the incidence of TB, malaria or febrile illness, duration of pneumonia, duration of diarrhoea, severity of infection, and cause-specific mortality. The authors conclude that whether further trials are worthwhile in areas with low baseline vitamin D deficiency is a judgement that needs to be made carefully against other competing resources for research.

The school environment plays an important role in the development of children and young people, and school-based sexuality education programmes have become popular in many regions of the world. Most of these programs are based on behavioural science theories, and aim to improve knowledge, change attitudes, intentions, behaviours, and social norms around sexual and reproductive health. There have been a large number of systematic reviews that evaluated the effectiveness of these programmes, but most of them have used self-reported sexual behaviours as their main outcomes, which have been found to be prone to bias and unreliable. In this new review, Amanda Mason-Jones and her colleagues have used biological outcome measures i.e. incidence of HIV or other STIs, or pregnancy. The review includes 8 cluster-RCTs with 55,157 participants: 5 trials were conducted in sub-Saharan Africa, one in Latin America and two in Europe.  Sexual and reproductive health education programmes alone showed no effect on the number of young people infected with HIV or other STIs during adolescence, or the number of adolescent pregnancies. Giving monthly cash, or free school uniforms, to encourage students to stay in school probably has no effect on the number of young people infected with HIV during adolescence, and may reduce the number of adolescent pregnancies (low certainty evidence). One trial assessed combined educational and incentive-based programmes showing that they  may reduce STIs (low certainty evidence) in young women, but no effect was detected for HIV or pregnancy.

Abdominal tuberculosis (TB) affects the gut, the peritoneum, abdominal lymph nodes, and, more rarely, the solid organs in the abdomen (liver, pancreas, and spleen), and leads to severe illness in adults and children, with possible complications, such as bowel rupture, which can cause death. Most current guidelines recommend treating people that have abdominal TB with antituberculous treatment (ATT) for six months, but some clinicians treat for longer periods due to concerns that six months is not adequate to achieve cure and prevent relapses.  Longer ATT, however, is associated with poor adherence, higher risk of side effects, and higher cost to health systems and to patients.   In this new review, Sophie Jullien and colleagues analyse data from three RCTs, with 328 participants, comparing six-month regimens with nine-month regimens to treat adults with intestinal and peritoneal TB. All trials were conducted in Asia, and excluded people with HIV, those with co-morbidities and those who had received ATT in the previous five years. Antituberculous regimens were based on isoniazid, rifampicin, pyrazinamide, and ethambutol. Relapse was uncommon in both shorter and longer treatment groups, and the proportion of participants who achieved clinical cure or defaulted from treatment was small in both groups.  There were 2/150 deaths (1.3%) in the six-month group and 4/144 (2.8%) in the nine-month group, but they all occurred in the first four months of treatment, so were not linked to the duration of treatment.  Six-month regimens are probably as good as nine-month regimens in terms of numbers of people cured, but more trials may be needed about treating abdominal TB in children and in people with HIV.

2016, Issue 9

One new review ,one updated review and one new protocol are available in Issue 9 of the Cochrane Database of Systematic Reviews

New Review

Tuberculous meningitis (TBM) is the main form of tuberculosis that affects the central nervous system and is associated with high rates of death and disability. Longer antituberculous treatment (ATT) regimens for TBM than for pulmonary tuberculosis are recommended to prevent relapse, but the longer regimens are associated with poor adherence.  In this new review, Sophie Jullien and colleagues analyse data from randomized controlled trials (RCTs) and prospective cohort studies of adults and children with TBM, treated with ATT regimens that included rifampicin for six months or longer than six months. Four RCTs and 12 prospective cohort studies with a total of 1881 participants are included in the review: 7 studies with 458 participants that evaluated six months of treatment, and 12 studies with 1423 participants that evaluated longer treatment.   TB relapse was an uncommon event across all studies; few participants defaulted from treatment, but adherence was not clearly documented. There was a higher death rate in participants treated for longer than six months, probably reflecting differences between the participants in the two groups of studies. The authors conclude that, as this was observational data, and most participants were HIV negative, there is the need for well-designed RCTs, or large prospective cohort studies, to resolve the uncertainty regarding the safety and efficacy of six months regimens for TBM.

Updated Review

Genotype® MTBDRsl (MTBDRsl) is a rapid DNA-based test for detecting specific mutations associated with resistance to fluoroquinolones and second-line injectable drugs (SLIDs) in Mycobacterium tuberculosis complex. This is an update from the 2014 review, performed as part of a World Health Organization process to develop updated guidelines for using MTBDRsl.  Grant Theron and colleagues have summarized evidence from 27 studies – 16 of them evaluated version 1.0 of the test, and one study version 2.0, released in 2015. The analysis shows that in people with rifampicin-resistant or MDR-TB, MTBDRsl performed on a culture isolate or smear-positive specimen may be useful in detecting second-line drug resistance. MTBDRsl (smear-positive specimen) correctly classified around six in seven people as having fluoroquinolone or SLID resistance, although the sensitivity estimates for SLID resistance varied. The test rarely gave a positive result for people without drug resistance. However, when second-line drug resistance is not detected (MTBDRsl result is negative), conventional DST can still be used to evaluate patients for resistance to the fluoroquinolones or SLIDs. The authors recommend that future work evaluate MTBDRsl version 2.0, in particular on smear-negative specimens and in different settings to account for different resistance-causing mutations that may vary by strain.

New Protocol

2016, Issue 6

One review update and two new protocols are available in Issue 6 of the Cochrane Database of Systematic Reviews

Updated Reviews

Liesl Grobler and colleagues completed this Cochrane review update on the effects of nutritional supplements for people being treated for tuberculosis. Tuberculosis is a bacterial infection which most commonly affects the lungs. People with tuberculosis are often malnourished, and malnourished people are at higher risk of developing tuberculosis as their immune system is weakened. Nutritional supplements could help people recover from the illness by strengthening their immune system, and by improving weight gain and muscle strength, allowing them to return to an active life. The review authors searched for relevant studies up to 4 February 2016, and included 35 studies with 8283 participants. Food or energy supplements may improve weight gain during recovery from tuberculosis in some settings, but there is currently no evidence that they improve tuberculosis treatment outcomes. There is also currently no reliable evidence that routinely supplementing above the recommmended daily amounts has clinical benefits.

New Protocols

2016, Issue 5

Two  new reviews and one new protocol are available in Issue 5, 2016 of the Cochrane Database of Systematic Reviews

New reviews

Maunank Shah, Karen Steingart and their team have completed this new review, which assesses the accuracy of the lateral flow urine lipoarabinomannan assay (LF-LAM) for active TB diagnosis or screening in HIV+ adults. LF-LAM is a commercially available point-of-care test, which is performed by placing urine on one end of a test strip, with positive results appearing as a coloured line. The test is simple, requires no special equipment, and shows results in 25 minutes. The review includes 12 studies: 6 evaluated LF-LAM for TB diagnosis and 6 for TB screening; all studies were conducted in low- or middle-income countries. LF-LAM was found to have low sensitivity to detect TB in adults living with HIV, whether it was used for diagnosis or screening. For TB diagnosis, the combination of LF-LAM with sputum microscopy suggests an increase in sensitivity for TB compared to either test alone, but with a decrease in specificity. However, in HIV-positive people with low CD4 counts who are seriously ill, LF-LAM may help with the diagnosis of TB.  The results of the review should be interpreted with caution as there are small number of studies and participants included in the analyses.

This new review was prepared by a team led by Carmen Gallardo, and it analysed data from trials comparing oral treatment for pulmonary TB in new patients, given as fixed-dose combinations (FDCs) that are combined in one tablet, or taken separately as single-drug formulations. FDCs are recommended by the WHO as they reduce the number of tablets that people take - this might reduce prescribing errors, and improve drug supply efficiency and patients’ adherence. The review includes 13 randomized controlled trials that enrolled 5824 people. Overall there was little or no difference between FDCs and single-drug formulations for most outcomes (treatment failure, relapse, death). There was no relevant difference for sputum smear or culture conversion at the end of treatment, for serious adverse events, and for adverse events that led to discontinuation of therapy. The authors conclude that, although there were no differences in clinical outcomes between the 2 regimens, FDCs may be more advisable than single-drug formulations in settings where there is no directly observed therapy (DOT), in order to ensure treatment compliance and avoid resistance.

New protocol

2016, Issue 4

Two  updated reviews and one new protocol are available in Issue 4, 2016 of the Cochrane Database of Systematic Reviews

Updated  reviews

This review was first published in 2008, and this update includes results from a new search, as well as an assessment of the quality of the evidence using GRADE, and 'Summary of findings' tables. There were also changes in the authors’ team, led by Arianna Rubin Means; the title has been amended, and outcomes now include also anaemia and adverse events. Helminth infections affect the human immune system, and in people with HIV they may compromise a person's ability to control HIV viral replication. Thus, treatment of helminth infections could have important benefits for people living with HIV. The review now includes 8 trials (7 from sub-Saharan Africa and one from Thailand) with 1612 participants. Treating  HIV-positive adults with deworming drugs (either without knowledge of their helminth infection status, or with diagnosed helminth infections)  may have a small suppressive effect on viral load at six weeks , but repeated dosing over two years appears to have little or no effect on either viral load  or CD4+ cells. There was no additional risk for HIV+ people in taking antihelminthic drugs, but adverse events were generally not well reported. Further long-term studies are required to make confident conclusions.

Kameshwar Prasad, Mamta B Singh and Hannah Ryan are the authors of this review, last updated in 2008, and now extensively revised: the search was updated, and  Hannah Ryan re-extracted and analysed the data, revised the 'Risk of bias' assessment, constructed a 'Summary of findings' table with GRADE assessment, and revised the Background, Results, and Discussion sections. Corticosteroids are commonly used in addition to antituberculous drugs for treating people with TB meningitis, a serious form of TB that causes headache, coma and death. Dexamethasone, methylprednisolone, or prednisolone helps reduce inflammation of the surface of the brain and blood vessels, probably decreasing pressure inside the brain, and reducing the risk of death. However, some clinicians are concerned that corticosteroids may improve survival, but result in more severely disabled survivors. Nine trials with 1337 participants are included in the review. Corticosteroids were found to reduce mortality from tuberculous meningitis, at least in the short term, but may have no effect on the number of people who survive tuberculous meningitis with disabling neurological deficit.

New protocol

2016, Issue 3

One  new protocol is available in Issue 3, 2016 of the Cochrane Database of Systematic Reviews

New protocol

2016, Issue 2

One updated review and one new protocol are available in Issue 2, 2016 of the Cochrane Database of Systematic Reviews

Updated  review

 This review was first published in 2009 and it has been now updated, with changes in the author’s team, still led by Mical Paul, and with a focus on areas with hyperendemic or holoendemic transmission of malaria (but also including trials conducted in other areas which report malaria-related outcomes). In areas where anaemia is common, health providers may give children iron tablets, with or without folic acid, in order to prevent anaemia. There is a concern amongst researchers that this may increase the risk of malaria because increased iron levels in the blood may promote the growth of the Plasmodium parasite. Results from 35 trials with 31,955 children show that iron did not cause an excess of clinical malaria in children, whether they were living in areas where anaemia is common or in those where it’s uncommon. Iron supplements may reduce clinical malaria in areas where there are prevention and management services for malaria, but increase the incidence of malaria in areas where such services are unavailable.  Iron supplementation did not cause an excess of severe malaria, and there were no differences for deaths. In conclusion, routine iron supplementation should not be withheld from children living in countries where malaria is prevalent and malaria management services are available.

New protocol

2016, Issue 1

One new review and one new protocol are available in Issue 1, 2016 of the Cochrane Database of Systematic Reviews

New review

 This new review, prepared by Cesar Henriques-Camacho and colleagues from Peru, the US and Spain, assesses the effects of ivermectin versus benzimidazoles (albendazole and thiabendazole), which are used for treating chronic strongyloides infection. Strongyloidiasis is caused by the intestinal parasitic worm Strongyloides stercoralis, found in tropical and subtropical regions. Most people remain asymptomatic but chronic infection can cause skin rash, gastrointestinal symptoms, and respiratory problems, and can be fatal in people with immune deficiency. This review includes 7  randomized controlled trials, enrolling 1147 adults with chronic strongyloides infection, conducted between 1994 and 2011 in different locations.   Parasitological cure was higher with ivermectin than with albendazole; there was little or no difference in parasitological cure between ivermectin and thiabendazole.  There were more adverse events with thiabendazole than with ivermectin. However, there were no serious adverse events or death. Further trials may help investigate the effect of different doses of ivermectin in different group of patients, and identify the optimal  treatment for vulnerable populations.

New protocol