Controling HIV-like virus in monkeys by early intervention

HIV photo-Optimized

The paper was published in Nature on March 13.

In an interesting study, the immune system of monkeys was found capable of controlling HIV-like virus (simian-human immunodeficiency virus (SHIV)) when treatment with a combination of two broadly neutralising antibodies was started three days after infection. The immune system of the animals was found to control the virus even after the anti-HIV antibodies were no longer present in the monkeys.

In a paper published on March 13 in the journal Nature, researchers from the National Institutes of Health and other institutes infected 13 macaque monkeys with SHIV virus. Unlike earlier studies where intervention began late, the researchers started treating the monkeys with two broadly neutralizing HIV antibodies from the third day of infection. The monkeys were infused with the two drugs three times over a two-week period.

Compared with controls, six monkeys were able to suppress the virus for 56 days to as long as six months; in one monkey the virus was below detectable level for 150 days. Once the antibodies level dropped to a very low in the animals, the virus resurfaced. The time taken to rebound was directly related to the concentration of the neutralising antibodies in the plasma.

Quite unexpectedly, five to 22 months after the virus resurfaced, the immune system of the six monkeys spontaneously regained control of the virus and brought it down to undetectable levels for another five to 13 months. Four other monkeys could never fully regain complete control of the virus but the viral load was “very low level” for more than two years. Of the 13 monkeys studied, 10 were able to benefit from two neutralising antibodies administered.

A particular kind of immune cells called CD8+ T cells were found to be higher in all the animals that were infected with SHIV virus. To ascertain if CD8+ T cells were responsible for mediating sustained suppression of virus replication, the researchers purposely depleted the CD8+ T cells in the six monkeys. What followed was a sharp increase in the viral load in all the animals. This helped the researchers conclude that the CD8+ T cells controlled the virus multiplication following the administration of the neutralising antibodies.

The study shows that a combination therapy of two neutralising antibodies given early after infection can control SHIV viral load for nearly six months and facilitate the emergence of potent CD8+ T cells that “durably suppress virus replication”.

Though SHIV infection in macaque monkeys differs from HIV-1 infection in humans in many ways, based on the study, the researchers suggest that immunotherapy should be explored to control the spread of virus, contain the damage to CD8+ T cells, mobilise a robust immune response and control HIV infection in humans.

Published in The Hindu on March 14, 2017

Top health stories of 2016

On the health front, the year 2016 witnessed a few setbacks and but also a few positive developments. Here are the most important health developments of 2016

1. Trial results confirm Ebola vaccine provides high protection

who-ebola-optimizedThe Ebola virus that killed more than 11,300 people in three West African countries — Guinea, Liberia and Sierra Leone has finally met its match.

In December, an Ebola vaccine trial carried out in 2015 in nearly 12,000 people in Guinea was found to be safe and highly protective against the deadly virus.

No Ebola cases were recorded in nearly 6,000 people who received the vaccine, while there were 23 cases in the arm that received the vaccine after a 3-week delay. The trial used an innovative design called a “ring vaccination” approach — the same method that was used to eradicate small pox. In the ring vaccination strategy, whenever a new Ebola case was diagnosed, all the people who may have been in contact with that person were traced and included in the trial.

The vaccine was found to have high efficacy even when the interim results were announced. So everyone included in the trial was offered the vaccine immediately, including children older than 6 years.

A total of 28,616 Ebola cases and 11,310 deaths have been reported in three countries, as on June 2016.

Oraquick2. HIV self-testing gets a shot in the arm

Access to and uptake of HIV diagnosis got a shot in the arm when the WHO in November released new guidelines on HIV self-testing. Lack of an HIV diagnosis has been a major obstacle in the war against HIV.

Today, 40 per cent of all people with HIV (over 14 million) are simply unaware of their status. While more than 18 million people with HIV are currently taking anti-retroviral treatment (ART), and a similar number is still unable to access treatment as many are not aware of their HIV positive status.

Only 30 per cent of men have tested for HIV. As a result, men with HIV are less likely to be diagnosed and more likely to die of HIV-related causes than women.

Testing also remains low among high-risk population such as men who have sex with men, sex workers, transgender people, injection drug users, and people in prisons.  These people comprise nearly 44 per cent of the 1.9 million new adult HIV infections that occur each year.

People can use oral fluid or blood- finger-pricks to discover their status in the comfort of their house with no fear of being subjected to stigma and discrimination. This is bound to encourage more people to get tested.

Results are ready within 20 minutes or less. Those with positive results are advised to seek confirmatory tests at health clinics. Twenty three countries currently have national policies that support HIV self-testing. India is yet to approve HIV self-testing.

zika-microcephaly - Photo WHO3. Zika virus and public health emergency of international concern

On November 18, the World Health Organisation declared that Zika virus is no longer a public health emergency of international concern. It was in February that the WHO declared the Zika outbreak and congenital malformations and neurological disorders in newborns believed to be caused by the virus as a global public health emergency. Brazil has been the worst affected by the virus.

A distinct pattern of birth defects caused by Zika infection during pregnancy is now officially known as congenital Zika syndrome.

In November, a study showed that a small group of Zika-infected babies in Brazil who were born with normal-size heads had developed microcephaly five months to a year after birth.

The virus that has caused about 2,300 confirmed cases of microcephaly (a congenital disorder where babies are born with a small head) since May 2015. The link between Zika virus and microcephaly was established in May this year. After the initial spread to 67 countries, including countries in Southeast Asia, the spread has since slowed down.

While Aedes species of mosquitoes is the primary vector that transmits the virus, it can also be transmitted though semen, blood, tears and other blood fluids. Unlike in the case Ebola, scientists are yet to find an efficacious vaccine against Zika virus. And we are yet to fully understand the entire spectrum of neurological problems that may show up in children born with microcephaly. Meanwhile, the WHO has advised that pregnant women refrain from travelling to countries where local transmission of Zika virus is still prevalent.

GeneXpert4. Incidence of TB in India increases sharply

Although global TB deaths dropped by 22 per cent between 2000 and 2015, TB is still one of the top 10 causes of death worldwide. It kills more people than HIV and malaria.

Of the estimated 10.4 million new cases worldwide, the estimated number of new cases in India alone has increased sharply from 2.2 in 2014 to 2.8 million in 2015. The true incidence in India will be known once the national TB prevalence survey scheduled to begin next year is completed. Besides the uptick in incidence, the number of estimated deaths caused by TB has also more than doubled from 220,000 in 2014 to 483,000 in 2015.

The sudden increase in TB incidence in India is due to 34 per cent increase in case notification between 2013 and 2015 by doctors in the private sector. Yet, in 2015, notification by private-sector doctors was only 16 per cent of the total case notification. Of the 2.8 million estimated cases each year in India, only 1.7 million cases both in the public and private sector were notified in 2015. So the remaining 1.1 million cases are simply not known.

anopheles-gambiae-mosquito-james-gathany-cdc5. Sri Lanka becomes malaria-free

In September, Sri Lanka achieved a huge public health success when the WHO declared it as malaria-free. There has been no local transmission nation-wide in Sri Lanka since October 2012. The WHO certifies a country as malaria-free when the chain of local transmission has been interrupted nationwide for at least three years. With this, Sri Lanka joins the ranks of 34 countries that have been certified as malaria-free since 1960s.

With no local transmission currently, Sri Lanka’s focus is on preventing the re-introduction of malaria from outside, particularly countries such as India, which are malaria-endemic. There were 95 re-introduced cased in 2013, 49 cases in 2014 and 36 cases in 2015.

Sri Lanka was able to win the war against malaria by targeting both the vector and the parasite. This was achieved by active detection of cases and targeting parasite carriers by screening people whether they had malaria symptoms or not.

It came to eliminating malaria in 1963 when it reported just 17 cases including six that were due to local transmission.

Zika - antenatal-care. Photo WHO6. Thailand ends vertical transmission of HIV

In June, Thailand became the first country in the Asia-Pacific region to end vertical transmission of HIV from mother to child.

In 2000, an estimated 1,000 children in Thailand were infected with HIV due to vertical transmission. But in 2015, the numbers dropped dramatically to just 85, a decline of more than 90 per cent. The rate of mother-to-child transmission of HIV has been reduced to less than 2 per cent.

Thailand achieved this feat by ensuring that 98 per cent of all pregnant women with HIV had access to antiretroviral therapy. Women with HIV have a 15-45 per cent chance of transmitting the virus to their children during pregnancy, labour, delivery or breastfeeding if they are not on treatment during pregnancy. But the risk drops to just over 1 per cent if antiretroviral medicines are given to both mothers and children throughout the stages when infection can occur.

Treatment to prevent vertical transmission is not 100 per cent certain.  So vertical transmission is considered to be eliminated when a country successfully achieves a reduction in transmission to such a low level that it no longer constitutes a public health problem.

Besides treating pregnant women with HIV with antiretroviral medicines, Thailand witnessed a sharp drop in the number of women in the child-bearing age becoming infected with HIV. Between 2000 and 2014, the annual number of women newly infected with HIV fell from 15,000 to 1,900 — an 87 per cent reduction.

polio7. Polio end game starts across the world

In April, 155 countries including India switch from using a trivalent oral polio vaccine that contains type 1, type 2 and type 3 strains to a bivalent oral polio vaccine that contains only type 1 and type 3 strains. The global vaccine switch took place between April 17 and May 1.

The reason for removing the type 2 strain from the vaccine was to confer better protection against polio. The oral polio vaccine contains live, weakened virus, which on rare occasions can turn virulent and cause vaccine-derived poliovirus. Though wild poliovirus type 2 was eradicated in 1999, all type 2 polio cases have been caused only by vaccine-derived polioviruses.  The type 2 strain in the trivalent OPV had caused over 90 per cent of vaccine-derived poliovirus cases in the world in the last 10 years.

Polio, including vaccine-derived polio, can be eradicated only when oral polio vaccine is eventually withdrawn after wild polio transmission has been stopped. Removing type 2 strain from the vaccine and switching over to a bivalent vaccine is the “first major step” of this withdrawal process.

Published in The Hindu on December 28, 2016

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

First CRISPR trial on humans set to begin

HIV - Researchers   successfully modified the T cells of 12 HIV patients to resist infection. - Photo Penn Medicine

Researchers from the Perelman School of Medicine successfully used a genome-editing technology to modify the T cells of 12 HIV patients to resist infection. – Photo: Penn Medicine

On June 21, the National Institutes of Health gave permission for starting the first ever clinical trial using CRISPR genome-editing technology, Nature news notes. The trial, which  will begin before the end of the year, will be carried out on 18 cancer patients to “help augment cancer therapies that rely on enlisting a patient’s T cells, a type of immune cell”.

The goal of the trial is not to cure cancer but to test the safety of CRISPR-Cas9 technology. According to Nature, the T cells from the patients suffering from melanoma, sarcoma or myeloma will be removed and three edits will be performed using CRISPR.

The first one will be to insert a gene for a protein engineered to detect cancer cells and instruct the T cells to target them, the second edit will be clean up the T cells so they don’t interfere with the process and finally the third edit will be to “remove the gene for a protein that identifies the T cells as immune cells and prevent the cancer cells from disabling them”. The cells will be returned to the patients once all the three edits are completed.

CRISPR is not the only genome-editing technology around.  However, CRISPR is far better than other technologies as editing is far easier and more efficient. But it does have some inherent problems.  According to the journal, CRISPR has a propensity for going in off-target edits. “These are instances in which the system cuts or mutates unintended parts of the genome. And despite precautions, the immune system could still attack the edited cells,” it says.

Though this is the first time that permission has been granted for a human clinical trial involving CRISPR, another genome-editing technology was used in the past.  The enzymes called zinc-finger nucleases (ZFNs) were used to genetically engineer the immune cells of 12 people with HIV, to resist infection, and decrease the viral load of some patients taken off antiretroviral therapy. The results published in The New England Journal of Medicine on March 5, 2014 was the first time gene editing approach was used in a trial on humans.

After four weeks of infusing the edited immune cells back into the patients, six subjects were taken off HIV medications for 12 weeks. While two were put back on treatment, the viral load decreased on average by 10 fold at the end of the 12-weeks treatment interruption.

Also, one week after the initial infusion, the decrease in the modified T cells was significantly less than the unmodified T cells during the period of treatment interruption. “The modified cells were also observed in the gut-associated lymphoid tissue, which is a major reservoir of immune cells and a critical reservoir of HIV infection, suggesting that the modified cells are functioning and trafficking normally in the body,” a release notes.

“This study shows that we can safely and effectively engineer an HIV patient’s own T cells to mimic a naturally occurring resistance to the virus, infuse those engineered cells, have them persist in the body, and potentially keep viral loads at bay without the use of drugs,” corresponding author Carl H. June from Perelman School of Medicine, University of Pennsylvania said in the release.

A smartphone dongle to diagnose HIV, syphilis

Dongle

The device was recently field-tested on 96 patients in Rwanda. – Photo: Tassaneewan Laksanasopin

A palm-sized dongle connected to a smartphone will soon be able to diagnose HIV and syphilis with good accuracy. The device, which was recently field-tested on 96 patients in Rwanda, had high sensitivity and specificity for both HIV and syphilis. The results are published today (February 5) in the journal Science Translational Medicine.

Sensitivity and specificity for both the infections are comparable to the lab-based ELISA. In the case of HIV, the sensitivity was 100 per cent and specificity was 87 per cent. For syphilis, the sensitivity was 92-100 per cent and specificity was 79-92 per cent. “Two types of syphilis antibodies are looked for to confirm infection and prevent over-treatment,” Dr. Tiffany W. Guo of the Department of Biomedical Engineering, Columbia University said in an email to this Correspondent. He is one of the authors of the paper.

“By increasing detection of syphilis infections, we might be able to reduce deaths by 10-fold. And for large-scale screening where the dongle’s high sensitivity with few false negatives is critical, we might be able to scale up HIV testing at the community level with immediate antiretroviral therapy that could nearly stop HIV transmissions and approach elimination of this devastating disease,” Dr. Tassaneewan Laksanasopin of the Department of Biomedical Engineering, Columbia University and the corresponding author noted in a release.

The device has several highlights. For instance, both HIV and syphilis can be diagnosed in about 15 minutes and at a fraction of the cost of a lab-based ELISA test. The dongle cost under $34 compared with an astronomical $18,450 for ELISA equipment. Also, the material and reagent required for testing HIV and syphilis cost no more than $1.44; in the case of conventional lab-based equipment the cost for testing these infections is $8.50.

What makes the device particularly interesting is the very low power consumed to run it. This would be of immense value when the device is used in the field where power may not be available 24×7.

This became possible as the device does not use a power-consuming electrical pump to generate vacuum but a rubber bulb (as in the case of the manual blood pressure measuring instrument — sphygmomanometer) which when pressed creates a negative pressure. The negative pressure, in turn, moves a sequence of reagents that are already stored in a cassette. Other electrical components used consume very little power.

The total power consumed by the device for a test is 1.6 mW. By comparison, a smartphone uses 751 mW on a 3G network; even in a standby mode, a smartphone consumes as much as 17.5 mW.

The researchers came out with a second innovation to power the device using a smartphone. The audio jack of iPhone sends a 19-kHz audio signal that is converted into a stable DC 3 volt. This innovation made the use of a battery redundant. Since audio jacks are standardized among smartphones, the dongle can be attached to any compatible smart device.

“We designed our device to minimize power consumption (e.g. get rid of the electrical pump) and the only component that requires power (which is very little) is the optics. So the power converted from the audio signal is sufficient to run the device,”said Dr. Guo.

It is very easy to operate the dongle. Health workers needed all of 30 minutes of training before they started using the device.

Fingerprick whole-blood specimen was sufficient to diagnose both the infections. During the trial, the freshly collected whole-blood was diluted before testing the sample. “This field testing was a first time performance on freshly collected whole blood, which our cassettes [where the reagents are preloaded] were not best optimised for. Subsequent to the trial, we changed the amount of antigens coated on plastic cassettes which can detect undiluted whole blood,” Dr. Guo said.

There are five detection zones on the microfluidic cassette. Each zone is coated with antigens/antibodies specific to diseases plus internal negative and positive controls. Blood sample is flowed through the microfluidic channel, passing through each detection zone in sequence.

The dongle detects the presence of antibodies against HIV and syphilis from blood samples by capturing these antibodies using specific antigens in the microfluidic channel.

“The dongle is used as an analyser to quantify the amount of antibodies from blood samples and display results as positive or negative,” said Dr. Guo.

Published in the Hindu on February 5, 2015

Editorial: Irrational prejudice against HIV

That India still has no anti-discrimination law to protect the interests of HIV positive people shows how little the nation as a whole cares about them and how callous society is to their plight. As a result, discrimination against HIV positive people, including children, rears its ugly head time and again. The latest example is the case of 13 HIV positive orphans studying in a school in Rivona, Goa, being forced to leave school because of pressure from parents of other students; these children join the ranks of a couple of hundred others in India who have faced the same fate. Stigma and discrimination have affected and gravely impeded the battle against HIV. Besides anxiety and denial, the mortal fear of being stigmatised and discriminated against prevents many from seeking early testing and treatment. As a result, they not only fail to get timely intervention but also go about infecting others. Only about half of the 2.1 million people in India who are HIV positive are currently on antiretroviral treatment. It’s a shame that this situation prevails even 28 years after the first person with HIV was diagnosed in Chennai. Besides doing nothing to end discrimination, this incident amply demonstrates that the state has failed to raise awareness and dispel the myths and misconceptions about the routes of HIV transmission. The sexual route, transfusion of HIV infected blood, being pricked by a needle used on an HIV positive person, and from infected mother to child are the only modes of HIV transmission. Also, the fact that young children are infected with the virus turns the spotlight on our failing to eliminate transmission from pregnant mother to child. Preventing vertical transmission is one of the easiest ways to cut the incidence rate.

Refusal of school admission and expulsion from school are but only the beginning of a long journey of discrimination and negative social response that HIV positive people encounter. Eviction of HIV positive tenants from houses, refusal to employ such people and even ostracism from villages are not uncommon. But most alarming is the refusal by most private hospitals to admit HIV positive people, and the fear among many doctors and paramedics to treat them. These individuals who are supposed to be best informed seem to suffer from the same paranoia that has seized the common man. In stark contrast, doctors have no hesitation in treating those with hepatitis B and C, which are much more easily transmissible than HIV by the same routes. Hence, the compulsion to broad-base the Health Minister’s initiative to “mainstream AIDS awareness to reduce HIV infection rate” to also address the issue of discrimination cannot be overemphasised.

Published in The Hindu on August 1, 2014

India scores by battling HIV/AIDS but falls short fighting TB and malaria

The global burden and mortality from HIV/AIDS, TB and malaria across the world, and in the developing countries in particular, have dropped significantly since 2000, a report published today (July 24) in The Lancet points out.

According to the report, the HIV epidemic appears “smaller than previously estimated,” while in the case of malaria, the global burden is far higher than the WHO estimates.

On a finer scale, the reductions have been significant in the case of the global incidence of HIV, and child mortality from malaria in sub-Saharan Africa during the period 2000-2013. While globally HIV incidence dropped by one-third from its peak, child mortality from malaria in sub-Saharan Africa declined by 31.5 per cent.

The main reason for these reductions is the increased focus on the three diseases across the world brought about by the Millennium Declaration in 2000 through the formulation of Millennium Development Goal 6 (MDG 6). If MDG 4 aimed at reducing child mortality and MDG 5 targeted maternal mortality reduction, the formulation of MDG 6 focussed on stopping the spread of the three diseases by 2015.

In 2013, HIV incidence stood at 1.8 million compared with 2.8 million in 1997 when the incidence had peaked. Similarly, mortality from HIV/AIDS in 2013 was 1.3 million compared with 1.7 million in 2005, which was the year when the epidemic was at its peak.

Of the three diseases, India has had the most success battling HIV/AIDS. Since 2000, the annual rate of reduction in new cases was more than four times that of the worldwide rate — a decrease of 16.3 per cent per year compared with the global drop of 3.9 per cent.

In 2013, nearly 79,000 Indian died of HIV/AIDS and the number of new HIV infections was about 31,000.

Tuberculosis

Globally, concerted efforts to stem the HIV/AIDS epidemic have benefited TB control during the period 2000-2013. Globally, in 2013, there were 7.5 million new TB cases, and the disease caused 1.4 million deaths. The mortality figure in 2000 was 1.6 million.

Despite TB prevalence rates reducing since 2000, the number of people living with TB worldwide increased from around 8.5 million in 1990 to about 12 million in 2013.

In South Asia, where half of global TB deaths take place, mortality rate reduction per year was 4.2 per cent. In East Asia, death rates fell annually by 7.5 per cent.

But the TB scenario in India is grim. While globally the prevalence of TB in people who are not infected with HIV was 160.2 for 100,000, it was 275.3 per 100,000 people in India. Mortality figure last year in India in those who are HIV negative was more than 545,500.

“In India, success at reducing the prevalence of TB has fallen behind global progress, despite significant gains against HIV/AIDS,” a release states.

But the authors of the study have warned that with increased longevity, higher number of TB cases and deaths would occur globally.

Malaria

In the case of malaria, the epidemic peaked in the early 2000s — with 232 million cases in 2003 and 1.2 million deaths in 2004. Last year, 164.9 million malaria cases and 854,568 deaths due to malaria were reported from across the world. The Lancet study reveals that malaria is killing more people than previously estimated.

Though sub-Saharan Africa has higher malaria burden, about 50 per cent of global deaths from malaria last year were in just three countries — India, Nigeria and Democratic Republic of Congo. The mortality rate in India was 11 deaths per 100,000. Countries neighbouring India had death rates between 1 and 2 per 100,000.

India has halved the number of malaria deaths per 100,000 during the period 1990-2013. But malaria still remains a “tremendous health burden for Indians.” About 61 million cases were reported last year and it killed more than 116,000 people. The other three countries where over five million new cases are seen every year are Nigeria (30 million), Democratic Republic of Congo (six million) and Mozambique (six million).

Published in The Hindu on July 22, 2014