Breaking the drug-resistant TB transmission cycle important

GeneXpert

Nearly two months after the Health Ministry set a highly ambitious target of working towards elimination of tuberculosis by 2025, a study published in The Lancet Infectious Diseases indicates that India’s TB crisis is all set to snowball by 2040 when one in 10 cases could be drug-resistant. What is even more alarming is that the increased number of drug-resistant cases — both multidrug-resistant TB (resistant to more than one of the first-line drugs) and extensively drug-resistant TB (additionally resistant to fluoroquinolones and at least one of the second-line injectable drugs) — will come from direct transmission from infected people to others rather than by strains acquiring resistance to TB drugs during treatment due to inappropriate treatment or discontinuation of treatment midway. The study found that “most incident” MDR cases are “not caused” by acquired drug resistance, and that acquired drug resistance will become a “decreasing cause” of drug-resistant TB. The increased availability of drugs to fight drug-sensitive TB has led to the emergence of MDR-TB strains. With increasing number of MDR-TB cases, there has been a shift in the way people get infected with drug-resistant TB — from strains acquiring drug resistance during treatment to direct transmission of MDR-TB strains from an infected person. The same trend is seen in the case of XDR-TB too. As a result, in high MDR-TB burden countries such as India, improved treatment outcomes in people might only reduce and not eliminate drug-resistant TB. Till 2015, only about 93,000 people with MDR-TB have been diagnosed and put on treatment.

The study, based on a mathematical model to forecast how TB is likely to progress in the four most-affected countries (Russia, the Philippines and South Africa, India), suggests that the number of new MDR-TB cases in a year in India will touch 12.4% by 2040, up from 7.9% in 2000. In the case of XDR-TB, the incident cases will rise to 8.9%, up from 0.9% in 2000. In 2015, the four countries accounted for about 40% (more than 230,000) of all drug-resistant TB cases in the world. Besides increasing the number of people who are diagnosed early and successfully treated, India’s TB control programme has come up with enhanced interventions to break the transmission cycle of the bacteria in the community. One of the ways this can be achieved is by carrying out immediate screening of all family members of a patient who has been diagnosed with the disease. Contact screening of family members and preventive treatment of all children below the age of five years who have not developed TB disease are already a part of the Revised National Tuberculosis Control Program (RNTCP) but is rarely done. Another important strategy that has to be adopted is making drug susceptibility testing universal and mandatory. Developing more accurate, cheaper and effective diagnostic tests and improved treatment regimens that are less expensive and of shorter duration will also go a long way in winning the war against the disease.

Published in The Hindu on May 12, 2017

The big test for malaria vaccine RTS,S

anopheles-gambiae-mosquito-james-gathany-cdc

In 2015, Africa accounted for 92% of global deaths and 90% of all malaria cases.

Beginning next year, the World Health Organisation will begin pilot tests of the injectable malaria vaccine RTS,S (or Mosquirix) on 750,000 children aged 5-17 months in Ghana, Kenya and Malawi. The vaccine has been successfully put through a Phase III trial, in which the drug is tested for safety and efficacy. Any decision on wider use will be taken based on the results of the pilot tests in the three countries. If the vaccine does indeed prove to be ready for large-scale use, it will be a milestone in the fight against malaria. Although the number of cases globally and in the African region came down by 21% between 2010 and 2015, in 2015 itself the number of deaths worldwide on account of the disease was as high as 429,000. According to WHO estimates, Africa accounted for 92% of these deaths, and 90% of the 212 million new cases that year. In such a scenario, even a vaccine with limited benefits could yield a substantial improvement. The vaccine, given in four doses, protects against Plasmodium falciparum, which is the most prevalent malaria parasite in Africa. The three countries have been chosen as they have settings with moderate-to-high transmission of malaria and already have in place malaria control programmes such as the use of bed-nets, rapid diagnostic tests and combination therapy. Each country is to decide where precisely to run the pilots.

The first three doses of the vaccine will be administered with a minimum interval of one month between each dose, followed by the fourth dose 15 to 18 months after the third dose. The first dose will be administered at about five months of age and the third dose has to be completed by nine months of age. While the drop-out rate increases as the number of doses increases, the biggest challenge is the fourth dose, which warrants a new immunisation contact to be made 15 to 18 months after the last dose. In Phase III trials, the efficacy of the vaccine was around 30% when children received all the four doses; the vaccine also reduced the most severe cases by a third. But there was a significant drop in these benefits when children did not receive the fourth dose. Given the low protection efficacy of the vaccine even in tightly controlled clinical settings, the pilot tests will be useful in evaluating the likelihood of replicating the immunisation schedule in the context of routine health-care settings. Also, the extent to which the vaccine reduces the all-cause mortality has to be evaluated as this was not “adequately addressed” during the trial. There is, specifically, a need to ascertain if excess cases of meningitis and cerebral malaria seen during the trials are causally related to the vaccination. Unlike other vaccines, the less-than-optimum protection offered by this vaccine would mean that existing malaria intervention measures will have to be used in conjunction to reduce the incidence of the disease.

Published in The Hindu on April 28, 2017

The self-test option for HIV

OraquickWith the World Health Organisation releasing guidelines on HIV self-testing, a major obstacle in improving access to diagnosis has been cleared. Though much progress has been achieved in India in making HIV testing accessible and free of cost, many infected persons remain unaware of their status. Across the world, nearly 40 per cent of people with HIV are unaware of their infection and run the risk of unknowingly transmitting it. Besides going a long way in preventing new infections, early diagnosis will help in a prompt start to treatment and enable the infected to live longer and healthier. Though there has been a 66 per cent drop in incidence in 2015 in India compared with 2000, the number of new HIV infections last year was 86,000; children below 15 years of age alone account for 12 per cent of this number. In 2015, the total number of people with HIV in India was estimated to be 2.1 million. Of this, 1.5 million were detected and tested at integrated counselling and testing centres (ICTC) and about a million people are on treatment. This leaves about half a million who are unaware of their HIV status. The government has approved in principle the proposal to take HIV testing closer to those in need by starting community-based testing. This will soon become operational and will be in addition to institutional testing. India is also weighing the option of self-testing.

The WHO-approved OraQuick HIV self-testing is based on HIV antibodies present in oral and blood samples. The test can detect antibodies developed within three months of getting infected. It is a screening test, and a positive result should be reconfirmed though a blood-based test. Despite greater awareness, people with HIV still face stigma and discrimination. As a result, getting everyone at risk of HIV infection tested has been a challenge. The OraQuick self-testing makes diagnosis easier and faster, besides ensuring privacy and confidentiality, thus encouraging more people to get tested. But there are challenges in terms of counselling and sensitivity, with the accuracy of the tests pegged at around 93 per cent. Counselling has to be done through innovative ways, such as over the telephone, as in the case of the U.S. Unlike the conventional method of getting tested at ICTCs, people self-testing should be more aware about the possibility of false negatives. But the risk of not getting tested far outweighs the limitations posed by self-testing. Twenty-three countries have in place policies that support HIV self-testing. It is time India adopted it quickly to enable more people to test themselves and help break the transmission cycle.

Published in The Hindu on December 2, 2016

No complacency on Zika

zika-microcephaly - Photo WHO

There have been 2,300 confirmed cases of microcephaly since May 2015. Photo: WHO

The World Health Organisation has declared that the Zika virus no longer constitutes a public health emergency of international concern. This brings to an end the heightened global focus on the virus that has caused about 2,300 confirmed cases of microcephaly (a birth defect manifesting in a smaller head size) since May 2015. The WHO had declared the Zika virus a public health emergency on February 1, considering the high number of neurological disorders reported in Brazil and a similar cluster in French Polynesia in 2014. Among the reasons cited were the unknown causal link between the virus and microcephaly and neurological complications, the possibility of its global spread, lack of vaccines and diagnostic tools, and the lack of immunity to the virus in newly affected countries. The link between Zika and microcephaly was established in May, the hunt for a potent vaccine and reliable diagnostic tool has begun, and scientists have been able to find the routes of transmission. However, the global risk assessment has not changed. The spread of Zika to 67 countries and territories is a grim reminder of the lack of immunity against the virus and the abundance of mosquito vectors. A dozen countries have reported local transmission.

Despite the link between the Zika virus infection and microcephaly being well established, the entire spectrum of challenges posed by the disease is not known. The WHO Emergency Committee has called for sustained research and dedicated resources to address the long-term challenges posed by babies born with microcephaly, but signalling the end of the global emergency may lead to lowering of the global alert. There should be no setback to funding, the global search for effective vaccines and diagnostic tests, and creating awareness about the risk of sexual transmission. For instance, it is not clear why more babies were born with microcephaly in northeast Brazil compared to the rest of the country or why the country had a higher caseload than others. This information is crucial to understanding the link between Zika infection and microcephaly, and thereby to containing incidence where the mosquito vector is predominant. Medical journals should continue to provide free and immediate access to papers on the Zika virus, which played a crucial role in information-sharing. The WHO has said it is “not downgrading the importance of Zika” and that its “response is here to stay”. It now needs to ensure that vigilance remains high despite the decline in incidence.

Published in The Hindu on November 23, 2016

Time India got serious about fighting TB

GeneXpert

The number of estimated TB deaths in India shot up from 220,000 in 2014 to 483,000 in 2015

Pushed to a corner owing to lack of political will on the part of countries with a high burden of tuberculosis, the World Health Organisation has called for the first United Nations General Assembly session on the disease. The fight against TB cannot be won as long as the high-burden countries, particularly India which has the highest TB burden in the world, do not galvanise their government machinery effectively. While the number of deaths caused by TB and the incidence rate had been consistently dropping from the historical highs globally, there has been a recent uptick that is much larger than previously estimated. The primary reason is the sharp increase in the incidence estimate from India — from 2.2 million cases in 2014 to 2.8 million in 2015. Ironically, the revised disease burden estimate for India is an “interim” one; the actual burden, which could be much higher, will be known only when the national TB prevalence survey that is scheduled to begin next year is completed. The number of estimated deaths caused by TB more than doubled from 220,000 in 2014 to 483,000 in 2015. As in the case of incidence, the revised estimate for deaths could also be an underestimation.

The increase in incidence owes to a 34 per cent rise in case notifications by health-care providers in the private sector between 2013 and 2015. Yet, in 2015 notifications by doctors in the private sector comprised only 16 per cent of the total. Though notification was made mandatory in 2012, only 1.7 million incident TB cases in the public and private sectors were notified in 2015. Thus the fate of 1.1 million patients is simply not known: they have fallen off the radar. For an effective fight against TB, the control programme needs to be aware of every single patient diagnosed, and offer treatment to all. If there are only about 50 per cent of the patients approaching the private sector who successfully complete treatment, a recent study has shown that in 2013 only about 65 per cent of the 1.9 million who approached the public sector completed the treatment regime. The crisis has been aggravated with the disease becoming more expensive and difficult to treat and the number of people with drug-resistant forms increasing. The national TB control programme is behind schedule with respect to critical programmes including the expansion of the GeneXpert pilot programme, scaling up of drug sensitivity testing, and the introduction of a child-friendly paediatric TB drug. Only sustained action on several fronts can help bring TB under check. The global war will not be successful till India wins the battle within its own boundaries first.

Nobel Prizes – The lure of the exotic and esoteric

imageIf “wonderful discoveries happening in biology” had acted as a trigger for Nobel Laureate Venkatraman Ramakrishnan to switch from physics to chemistry, the nearly matured and well-established field of chemistry failed to enthuse Yoshinori Ohsumi, and he shifted to biology. Autophagy — a fundamental process for degrading and recycling cellular components — was known long before he ventured into the field, but it was his paradigm-shifting research that revealed the importance of this fundamental process that comes into play every other minute. His seminal work helped reveal that vacuoles in yeast and lysosomes in human cells are not just garbage bins but recyclers and fuel producers. Right from the stage of embryo development to countering the negative effects of ageing, autophagy plays an important role. As in the case of many Laureates, Dr. Ohsumi’s initial years were more than frustrating, but he prevailed. His approach to science is an antithesis to what is generally seen in today’s young researchers, and that precisely is what helped him break new ground and bag the Nobel Prize this year — only the third Laureate since 2010 to not share the Prize for Physiology or Medicine with others.

But lysosomes and other cellular bodies would be severely impacted if molecular machines in our body failed to work synchronously to carry materials around in a cell and for several other functions. Though not as elegant as the molecular machines at work inside us, the work done by Jean-Pierre Sauvage, J. Fraser Stoddart and Bernard L. Feringa, the winners of the Nobel Prize in Chemistry, has set the ball rolling in the endeavour to realise Nobel Laureate Richard Feynman’s dream more than 50 years ago of building very small machines. Though very primitive at this point in time, science will see one of the biggest revolutions when the cogs and cranks of their work are finally put together to build machines on a nanoscale; nanomachines will find applications in diverse fields, from medicine to electronics. Much like the nanomachines of tomorrow, David J. Thouless, F. Duncan M. Haldane and J. Michael Kosterlitz’s theoretical explanations for exotic states of materials by using topological concepts will give birth to a completely different class of products. This year’s Nobel-winning physicists, they predicted the exotic behaviour that other scientists later found at the surface of materials and inside very thin layers, such as superconductivity and magnetism in extremely thin materials. Physicists are now looking beyond the ordinary to find new and exotic phases of matter that change in a stepwise fashion.

Published in The Hindu on October 8, 2016

ISRO makes India proud again

optimized-insat-3dr-isro-2

INSAT-3DR was launched on September 8, 2016. – Photo: ISRO

The Indian Space Research Organisation (ISRO) crossed an important milestone with the successful launch of weather satellite INSAT-3DR using a Geosynchronous Satellite Launch Vehicle equipped with the indigenous cryogenic upper stage. The successful launch marks a departure from the long history of failures with the GSLV; except for the first, every launch of the Polar Satellite Launch Vehicle (PSLV), the workhorse of ISRO, has been a success. That September 8 launch marks the third consecutive success; the fact that it is the first operational flight by the GSLV carrying the indigenous cryogenic upper stage is confirmation that India now belongs to the elite club of countries that have mastered the cryogenic technology. Maintaining structural and thermal integrity of the engine at very high temperatures during combustion just a few centimetres away from – 250° C, a temperature at which materials behave very differently, is a huge challenge. Likewise, igniting a cryogenic fuel and sustaining the combustion for a prolonged period is a daunting task. The Thursday launch had fully utilised the maximum payload carrying capacity of the GSLV-Mk II by carrying the heaviest satellite (2,211 kg) ever from Indian soil. This became possible only because the cryogenic upper stage was used. Unlike solid and liquid propellants, the specific impulse or thrust provided by a cryogenic rocket stage is much higher and is therefore more efficient to carry heavier payloads.

Unlike in the case of the PSLV where industry participation is around 80 per cent, it is only about half in the case of the GSLV. ISRO is a research and development organisation and not a production organisation, but the lack of greater industry participation has resulted in it being unable to launch more satellites in a year using the GSLV. However, efforts are under way to change this and ISRO has set a target of two GSLV launches in a year by 2018-2019. Even as the GSLV-Mk II has completed its first operational flight, ISRO is busy preparing for a ground qualification test of a more powerful GSLV-Mk III launch vehicle in about two months. The first experimental flight using the GSLV-Mk III is scheduled to take place by the end of this year and will use a new cryogenic engine. With an ability to provide double the thrust compared with the current cryogenic technology, the vehicle would be able to carry payloads up to four tonnes. This would mean that the GSLV-Mk III, when fully operational after three-four launches, will make ISRO truly independent by not having to rely on facilities abroad for launching heavier payloads. Besides independence, the country would stand to gain tremendously through cheaper launches.