New York: HIV patients lose immunity to smallpox even though they were vaccinated against the disease as children and have had much of their immune system restored with anti-retroviral therapy, says a new study.

Antiretroviral therapy (ART) is the use of HIV medicines to treat HIV infection. It helps people with HIV live longer, healthier lives and reduces the risk of HIV transmission.

The study, published in the Journal of Infectious Diseases on HIV-associated immune amnesia could explain why people living with HIV still tend to have shorter lives on average than their HIV-negative counterparts despite being on antiretroviral therapy.

The study follows other research recently published in the journals Science and Science Immunology that found the immune systems of children who contracted measles similarly ‘forgot’ their immunity against other illnesses such as influenza.

For the study, lead researcher Mark K. Slifka from Oregon Health and Science University in US, and his colleagues compared the T-cell and antibody responses of a total of 100 HIV-positive and HIV-negative women who were vaccinated against smallpox in their youth.

The research team chose smallpox because its last known US case was in 1949, meaning study participants haven’t recently been exposed to its virus, which would have triggered new T-cell and antibody responses.

They found the immune systems of HIV-positive women who were on antiretroviral therapy had a limited response when their blood was exposed to the vaccina virus, which is used in the smallpox vaccine.

Normally, those vaccinated against smallpox have CD4 T cells that remember the virus and respond in large numbers when they’re exposed again.

Previous research has shown smallpox virus-specific CD4 T cells are maintained for up to 75 years after vaccination.

This finding happened despite the fact that antiretroviral therapy works by boosting CD4 T cell counts in HIV-positive patients.

This indicates that while antiretroviral therapy may boost total T cell counts overall, it can’t recover virus-specific T cells generated from prior childhood vaccinations.

The research team plans to evaluate whether the same phenomenon occurs in HIV-infected men, and if people living with HIV also lose immune memory to other diseases.

Researchers from SUNY Downstate, Georgetown University, Cornell University, University of Southern California and John Hopkins University, also contributed to this study.

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The Joint United Nations Programme on HIV/AIDS (UNAIDS) and its partners launched the 90–90–90 targets in 2014 with the aim of diagnosing 90% of all HIV-positive people, provide antiretroviral therapy (ART) for 90% of those diagnosed, and achieve viral suppression for 90% of those treated by 2020. Despite considerable scaling up of ART across the world, 1.7 million people newly infected with HIV were detected in 2018. Eamonn Murphy, UNAIDS regional director for Asia and the Pacific, tells Sanchita Sharma why countries must retool programmes and focus on prevention, including scaling up pre-exposure prophylaxis (PrEP) for HIV-free persons at high risk of infection, and self-testing, to end AIDS. Edited excerpts:

Do you see the world meeting the 90-90-90 targets by 2020?

The simple answer is no. Some countries are doing extremely well, particularly in eastern and southern Africa. In Asia Pacific, we have a mixed but slowing response. A couple of big countries are holding us back with big epidemics; there are also some new epidemics. In the last nine years, there’s been only a 9% decline in new infections. Our progress is going backwards, that’s the real challenge.

Which are the countries doing well, and which are not?

Thailand is doing extremely well, as are Cambodia, Australia and Vietnam. But then we have the Philippines with a 200% increase in new infections in nine years, with a particularly steep rise in the last three or four years. Pakistan has had a 57% increase in the same period.

What led to the HIV outbreak in Larkana, Pakistan, this year, when at least 800 people were diagnosed with HIV, 80% of them children?

It was infection control procedures, mainly among general practitioners and local medical facilities. There were injection safety issues, including reuse of intravenous (IV) drips for saline to treat dehydration and diarrhoea in children, principally in the private sector and private blood banks. We’ve seen similar situations, but not in that scale, for example in Cambodia in the region, and globally. Pakistan quickly ordered a full investigation and scaled up testing to map it, which in a political world is a bold step.

How would you rank India on a scale of 10?

At seven, there’s been some slippage. In the Asia Pacific region [48 countries], Thailand is number one. Philippines was up there with Thailand; there was complacency and infection is back among the young in super high numbers. That’s the worry, it can happen elsewhere.

India has done a number of amazing things for the world and for its own population. Generic drugs have had the biggest impact globally to get people into treatment. Its focus on key populations (that spread infection), social contracting and putting the community first and equal in the response has been significant, but it needs to be rejuvenated. This is partly because of the lack of political will globally, regionally and at the country level, because AIDS is far from over. And at the rate we’re going, it’s going to start re-emerging in new geographic areas and new populations.

What are the new tools to stop new infection?

PrEP [pre-exposure prophylaxis] and self-testing are the two tools that really need to be scaled up. We’ve got to get prevention moving because we have a new generation that’s taking new and higher risks than the older generation that knew more about HIV. PrEP is an area India could seriously put in place; Australia saw 25% reduction (in new infection) after PrEP was rolled out there.

Should social media be used more actively for prevention messaging?

Yes. Programmes in all countries, including India, need to go through a prevention revolution. We need to retool and re-gear the programmes to target young people.

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Although adding ibalizumab to an optimized background regimen of antiretroviral therapy (ART) is not cost-effective, ibalizumab substantially increased survival for individuals with multidrug-resistant HIV, a group lacking other treatment options, and the small size of this population in the United States makes the effects on budget relatively minor, according to research presented at the 10th IAS Conference on HIV Science, held July 21 to 24, in Mexico City, Mexico.

Ibalizumab is the first FDA-approved monoclonal antibody for the treatment of multidrug-resistant HIV. The current study projected cost effectiveness and budget effects of ibalizumab and background ART for participants with multidrug-resistant HIV compared with background ART alone, using the Cost-Effectiveness of Preventing AIDS Complications model. Long-term clinical outcomes were determined using ibalizumab efficacy and patient characteristic data from the phase 3 trial. Endpoints included life expectancy in quality-adjusted life years, 5-year survival, lifetime care costs, and transmissions/100 person-years. Quality-adjusted life years and costs and discounted 3% per year were used to calculate the incremental cost-effectiveness ratio, with a value < $100,000/quality-adjusted life years considered to be cost-effective. Sensitivity analyses were performed on key parameters, and the US health sector budget impact for an estimated 5,000 individuals with multidrug-resistant HIV were also examined.

Mean initial CD4 count for participants was 150/µl. At 24 weeks, viral suppression for ibalizumab and background ART was 50%, and participants incurred a one-time cost of $10,500 for the ibalizumab loading dose and a monthly cost of $13,700 for background ART and subsequent ibalizumab injections. Participants in background ART only group did not achieve viral suppression but incurred a medication cost of $4,500 a month.

The 5-year survival with background ART only increased from 38% to 47% with the addition of ibalizumab, and quality-adjusted life years also increased from 3.74 to 5.12, respectively. Lifetime costs with background ART only were $299,600 per person compared with $660,700 per person with the addition of ibalizumab.

Researchers noted that ibalizumab and background ART only became cost-effective if the cost of IBA was reduced by over 88%, and there was no threshold of efficacy at which this combination treatment became cost-effective.

Rates of 5-year transmission decreased from 4.81/100 person-years with background ART only to 3.51/100 person-years with the addition of ibalizumab. The addition of ibalizumab  also increased costs by $708 million over 5 years for the estimated 5,000 people with multidrug-resistant HIV in the United States, which is approximately 0.6% of HIV treatment costs over that time.

Study investigators concluded, “Ibalizumab will substantially increase survival for patients with multidrug-resistant HIV, a group currently lacking other treatment options. While [adding ibalizumab to optimized background ART] is not cost-effective, the small number of eligible patients makes the budget impact of adding ibalizumab to OBR relatively small in the US.”

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HIV may persist in the central nervous system (CNS) despite treatment with antiretroviral therapy (ART), which could lead to cognitive impairment, according to a new study published in the Journal of Clinical Investigation. 

Most HIV research has focused on blood CD4+ memory T cells as the major viral reservoir; however, HIV persists in other sites, such as mucosal lymphoid tissue, bone marrow, and the brain, where infection can lead to CNS manifestations. 

According to the study authors, large studies of cerebrospinal fluid (CSF) cells in participants on ART who have suppressed plasma HIV RNA levels have not been previously performed. 

For the study, the researchers assessed HIV persistence in CSF and the associations with inflammation and cognitive performance during long-term ART. The study included mostly men aged 45 to 66 years who have had their infections controlled with ART for an average of 9 years. To assess HIV persistence, the researchers analyzed each individual’s CSF for HIV DNA and then compared the data to each of their results from standard neurocognitive evaluations. 

Overall, approximately half of the study participants had viral DNA in cells in the CSF, suggesting the presence of latent virus. However, only 4% of participants had detectable HIV RNA in cell-free CSF fluid, according to the findings. Additionally, 30% of those with persistent HIV DNA in the CSF experienced clinical neurocognitive impairment compared with 11% of individuals whose CSF did not contain viral DNA. The researchers did not correlate CSF inflammatory biomarkers with HIV persistence. 

“The striking observation that almost half of participants harbored HIV-infected cells in the CSF demonstrates that the CNS compartment is a site of viral persistence despite many years of viremia suppression on ART,” the authors wrote in the study. 

Although the findings indicate that persistent HIV-infected cells in the CNS may contribute to neurocognitive impairment, the authors noted that the overall frequency of cognitive impairment in this group was relatively low. Still, the study demonstrated a higher-than-expected prevalence of persistent HIV in the CNS, pointing to continued obstacles in the complete eradication of HIV from the body. 

“Our study indicates that examination of CSF cells is important in assessing residual HIV in compartments during ART,” the researchers wrote. 

Furthermore, sensitive methods of HIV detection combined with more research of CSF cells can help provide more insight into the CNS reservoir of HIV, the authors concluded. 

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HIV – the Aids causing virus – has been wiped out for the first time in living animals, with researchers saying a cure for humans is on the horizon. A clinical trial could start within a year, scientists predict. Current HIV treatment focuses on the use of antiretroviral therapy (ART) that suppresses HIV replication but does not eliminate the virus from the body. It requires life-long use and if the therapy is stopped, HIV could rebound and cause the development of Aids. But scientists at Temple University in Philadelphia carried out gene testing that saw mice infected with HIV have it completely eliminated from their DNA. Senior investigator Professor Kamel Khalili said: ‘Our study shows treatment to suppress HIV replication and gene editing therapy, when given sequentially, can eliminate HIV from cells and organs of infected animals.’ Dr Kamel Khalili led the team who discovered the gene editing tool (Picture: SWNS) His team used a technique called CRISPR-Cas9 that can snip faulty DNA infected with the harmless virus. It has been likened to a pair of ‘molecular scissors’. It combines this with a recently developed therapeutic strategy known as long-acting slow-effective release (LASER) ART. Currently, the HIV virus is able to rebound because it integrates its DNA sequence into the genomes of cells in an infected person’s immune system and lies beyond the reach of antiretroviral drugs. But in the new study, published in Nature Communications, the modified drug was packaged into nanocrystals which can reach tissues where HIV is likely to be lying dormant. From there, the nanocrystals – stored within cells for weeks – slowly release the drug to wipe out HIV. Dr Khalili said: ‘We wanted to see whether LASER ART could suppress HIV replication long enough for CRISPR-Cas9 to completely rid cells of viral DNA.’ Researchers infected mice engineered to produce human cells susceptible to HIV and then treated the animals with LASER ART and CRISPR-Cas9. Analysis of the mice at the end of their treatment revealed the HIV DNA had been completely eliminated in one-third of the infected mice. Dr Khalili said: ‘The big message of this work is that it takes both CRISPR-Cas9 and virus suppression through a method such as LASER ART, administered together, to produce a cure for HIV infection. ‘We now have a clear path to move ahead to trials in non-human primates and possibly clinical trials in human patients within the year.’ Current medication suppresses the HIV virus but does not eliminate it and relies on long-term use (Picture: Getty) Earlier this year, health secretary Matt Hancock promised there would be no new cases of HIV in England by 2030. Donald Trump has made a similar pledge for the US. Co senior investigator Dr Howard Gendelman, of Nebraska University, who developed LASER ART, said: ‘This achievement could not have been possible without an extraordinary team effort that included virologists, immunologists, molecular biologists, pharmacologists, and pharmaceutical experts. ‘Only by pooling our resources together were we able to make this groundbreaking discovery.’

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Thanks to antiretroviral therapy, children living with HIV are likely to live much longer than they would without treatment. They will go to school like other children and develop in much the same way. But how much do their teachers and peers need to know about their HIV-positive status? And what is the best way of managing their particular health needs at preschool level?

It’s a subject that affects the lives of millions. There are more children affected by HIV in sub-Saharan Africa than anywhere else in the world. Around 53% of people living with HIV are in eastern and southern Africa. Over 800,000 new HIV infections were reported in this region in 2018.

Fortunately, 59% of children living with HIV in eastern and southern Africa are receiving antiretroviral therapy. In the past, they would not have lived past the age of five. Even now, they face certain health challenges including stunted growth, under development of their vital organs, frequent opportunistic infections, and neurological problems. This is why it might be important for others to know about their status. And school is one of the places where they will learn how to cope with that. Preschools are children’s points of entry into society.

Little research exists about this. We carried out a study in a low-resource area of Nairobi, Kenya focusing on preschoolers aged four to seven years. Our main informants were their class teachers. We wanted to know what kind of support they had, how much they and their teachers knew about illnesses, what information their caregivers shared, and what sort of care they received at school.

The findings indicated that these children were at risk of not getting the support they needed for numerous reasons. We concluded that there should be more disclosure of children’s HIV status because it creates awareness of the challenges they face and activates the necessary support systems throughout their developmental progression in schools.

Social and cultural factors

Our study looked into whether children’s HIV status was disclosed when they were enrolled in preschool. It appeared that social stigma was at play. Parents were worried about devaluing their social status and exposing their children to negative experiences at school if their HIV status was known. Fathers did not want to be associated with HIV-positive children, and mothers or other female caregivers needed to develop trust in the teachers before they would reveal a child’s HIV status.

Some older siblings supported the preschoolers by making sure they had food and medication out of the view of the teachers. But this only added to the atmosphere of secrecy around care and management of children with HIV at school.

As a result, nobody could be sure exactly how many children in first grade were living with HIV. This meant they were denied the care and support they required for a good head start and school adjustment.

On top of this teachers reported that there were few policy guidelines about screening for children at risk during admission processes. This meant they could not identify children at risk. In any case, they didn’t have enough medical knowledge to handle all the health concerns of the children they did know about. It would have been helpful to have a health professional working with them in a screening process, so they could identify which children would need monitoring.

We also found that some parents or primary caregivers did not communicate clearly with their children on how to ask for help when they felt ill and what that meant. This communication was equally unclear to their teachers.

This sometimes led to poor management of illnesses or accidental disclosure of HIV status.

But some children were able to communicate their needs more freely, in ways that resulted in faster attention to emergencies and better management of risks. This is something we can learn from them.

Some classroom walls displayed materials to inform children about various aspects of health. They included sick people, hospitals, health professionals, medicines, hygiene topics and others. These were used to make children aware of illness, safety and how to ask for help. Materials like this could also help people in the wider community to understand more about HIV, and reduce the stigma.

Way forward

We believe that information about children’s health should be shared more widely at all levels of society so that HIV is seen to be manageable, like any other chronic illness, for the children’s benefit.

Modern digital technologies and mobile clinics can be helpful resources to locate and monitor these children in schools.

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