Virus World

We did a thorough in-vitro evaluation of the drug resistance profile of HIV-1 from an observational case to show that five-class pan-resistant clinical cases do exist. We investigated a case of a highly treatment-experienced Caucasian male with HIV-1 who had a poor virological response to previous combination antiretroviral therapy (ART) and who was not responding to a dolutegravir-based regimen. For the complete panel of approved antiretrovirals, we examined genotypic resistance using the Stanford HIV Drug Resistance Database interpretation algorithm, and we examined phenotypic resistance using the PhenoSense and Trofile assays. Using viral gp160 sequence analysis, we also explored the potential susceptibility of this virus to novel therapeutic drugs targeting viral envelope binding.

The individual was diagnosed with HIV-1 on Sept 29, 1989. Since starting antiretroviral treatment in 1995, the individual had received more than 14 different antiretroviral drugs over the course of his illness. In November, 2017, a blood sample was collected from the individual and we did drug resistance analysis tests. We found that this individual was infected with a pan-resistant HIV-1 subtype B strain that showed broad genotypic and phenotypic cross-resistance to all approved antiretroviral drugs, including the newest second-generation integrase inhibitors, dolutegravir and bictegravir. With no remaining clinical options available, except for investigational drugs, this case provides evidence that new antiretroviral drugs with different mechanisms of action are needed. Our case report shows that HIV-1 multidrug cross-resistance remains an important concern, despite the extensive number of antiretroviral drugs currently available. Highly treatment-experienced patients, especially those who have been given suboptimal combination ART, can develop highly complex resistance-associated mutation patterns, conferring cross-resistance to all widely available ARTs. The identification and reporting of cases, such as the one described in this report, are needed to increase awareness of emerging trends that have the potential to affect patient management.

Original Study Available at Lancet Microbe (June 11, 2020):

https://doi.org/10.1016/S2666-5247(20)30006-9

A single dose of an antibody-based treatment can prevent HIV transmission from mother to baby, new nonhuman primate research suggests for the first time. When that single dose is given is key, however. The study found rhesus macaque newborns did not develop the monkey form of HIV, called SHIV, when they received a combination of two antibodies 30 hours after being exposed to the virus.

Delaying treatment until 48 hours, on the other hand, resulted in half of the baby macaques developing SHIV when they were given four smaller doses of the same antibody cocktail. In comparison, the study found macaques that received the current standard HIV treatment – antiretroviral drugs – remained SHIV-free when they started a three-week regimen of that therapy 48 hours after exposure. “These promising findings could mean babies born to HIV-positive mothers can still beat HIV with less treatment,” said the study’s corresponding’s author, Nancy Haigwood, Ph.D., a professor of pathobiology and immunology in the Oregon Health & Science University School of Medicine, as well as the director at the Oregon National Primate Research Center at OHSU.

This is the first time a single dose of broadly neutralizing antibodies given after viral exposure has been found to prevent SHIV infection in nonhuman primate newborns. Previous research by Haigwood, Ann Hessell, Ph.D., and others showed four doses of antibodies started 24 hours after exposure prevented SHIV infection, with all 10 of the baby primates in that study not having any SHIV virus for six months. Both studies used a combination of two antibodies called PGT121 and VRC07-523. The new study also suggests a much shorter course of antiretroviral therapy given after virus exposure could prevent HIV transmission to newborns. Human babies born from HIV-positive mothers typically take the drug cocktail – a personalized regimen of multiple drugs taken daily – for about six weeks before being re-tested. If the tests are then positive, they likely need to take HIV drugs for the rest of their lives. But this study showed nonhuman primate newborns didn’t have SHIV after undergoing antiretroviral therapy for just three weeks starting 48 hours after exposure.

Published in Nature Communications (07 January 2020):

https://doi.org/10.1038/s41467-019-13972-y

A new study published as "Editor's Choice" in The Journal of Infectious Diseases found that expansion of HIV treatment eligibility to include those under age 15 led to large and significant increases in initiation of antiretroviral therapy within 30 days of enrollment in care among 10- to 14-year-olds living with HIV. Led by Olga Tymejczyk and Ellen Brazier of the Institute for Implementation Science in Population Health (ISPH) at the CUNY Graduate School of Public Health and Health Policy, the study used real-world longitudinal service delivery data from HIV clinics in seven countries in sub-Saharan Africa, all members of the global IeDEA research consortium: Burundi, Democratic Republic of the Congo (DRC), Rwanda, Kenya, Uganda, Malawi, and Zambia. All of the countries in the study adopted general universal test and treat, or Treat All, policies in 2016--policies that made all people living with HIV eligible for immediate treatment, regardless of CD4 count or clinical symptoms. Prior to adopting general Treat All policies in 2016, Uganda and Zambia had also adopted pediatric-specific Treat All policies in 2013, which extended treatment eligibility to all children younger than 15 years.

Using a regression discontinuity design, the study found large increases in rapid ART initiation among young adolescents following the adoption of Treat All policies. In Burundi, Democratic Republic of the Congo, Kenya, Malawi, and Rwanda, where "Treat All" policies were adopted in 2016, there was a 23.4 percentage point increase in rapid ART initiation among young adolescents. In Uganda and Zambia in 2013, there was a 11.2 percentage point increase in rapid ART initiation following the adoption of pediatric Treat All policies. Given the study design, these increases in rapid ART initiation can be interpreted as the effect of expanded treatment eligibility guidelines for a population that has proven hard to reach with HIV care. The researchers emphasize, however, that as more follow-up data become available, it will be important to assess whether these young adolescent patients remain on treatment and achieve viral suppression. "We also need to do more to shorten the time from HIV infection to diagnosis and enrollment in HIV care," said Brazier. "Most of those enrolling into HIV care between the ages of 10-14 years are thought to have acquired the infection perinatally. While it is encouraging that Treat All has improved their access to HIV treatment, we need to understand and address barriers to timely diagnosis and enrollment in HIV among this age group." 

Published J. Infect. Diseases (04 November, 2019): 

https://doi.org/10.1093/infdis/jiz547

Elderly cancer patients who are HIV-positive, particularly those with prostate and breast cancers, have worse outcomes compared to cancer patients in the same age range who do not have HIV. A Moffitt Cancer Center researcher, in collaboration with investigators at the National Cancer Institute, Duke University, and Johns Hopkins Bloomberg School of Public Health, took a closer look at the disparity, factoring in whether or not cancer treatment had an impact on outcomes among this patient population. Their findings were published today in JAMA Oncology.

“Previous studies have shown that HIV-infected cancer patients are more likely to die from their cancer than HIV-uninfected cancer patients. However, those studies have not been able to take into account detailed information on the treatments patients may have received, , including the exact type or timing of treatment,” said Anna E. Coghill, Ph.D, M.P.H., assistant member of the Cancer Epidemiology Department at Moffitt. Using the Surveillance, Epidemiology, and End Results Medicare-linked data, the researchers evaluated 288 HIV-infected and 307,980 HIV-uninfected patients, ages 65 years or older, who were diagnosed with non-advanced colorectal, lung, prostate or breast cancer and received stage-appropriate cancer treatment during the year after their cancer diagnosis. 

Results showed that cancer-specific mortality was higher in HIV-infected cancer patients compared with their HIV-uninfected counterparts in breast and prostate cancers. Furthermore, they found that HIV-infected women were nearly twice as likely to experience disease relapse or death after successfully completing initial cancer therapy.

Published in JAMA Oncology:

https://doi.org/10.1001/jamaoncol.2019.1742

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 antiretroviral therapy, according to a study published in the Journal of Infectious Diseases. Called HIV-associated immune amnesia, the finding 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.

Mark K. Slifka, Ph.D., a professor of molecular microbiology and immunology at the Oregon Health & Science University School of Medicine and Oregon National Primate Research Center, led the study. Slifka 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 U.S. case was in 1949, meaning study subjects 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. Slifka and his colleagues plan to evaluate whether the same phenomenon occurs in HIV-infected men, and if people living with HIV also lose immune memory to other diseases.

Published in J. Infectious Diseases(23 December 2019):

https://doi.org/10.1093/infdis/jiz678

Summary: HIV can persist in the nervous system, even when the virus is suppressed. Even when the virus is suppressed, neurocognitive problems associated with the infection can persist.

Investigators from the University of North Carolina, the University of Pittsburgh, and Yale University studied participants enrolled in the AIDS Clinical Trials Group (ACTG) HIV Reservoirs Cohort Study. This primarily male group–aged 45 to 56–of long-term HIV survivors had infections controlled with ART for on average nine years. Researchers analyzed each participant’s CSF for HIV DNA and then compared these data to each participants’ results from standard neurocognitive evaluations. About half of participants had viral DNA in cells in the CSF, indicating the presence of latent virus, even though standard HIV RNA ‘viral load’ tests of the cell-free CSF fluid were positive in only 4% of participants. Investigators also found that 30% of individuals with persistent HIV DNA in the CSF experienced clinical neurocognitive impairment compared with 11% of individuals whose CSF did not contain viral DNA.

The new findings suggest that the presence of persistent HIV-infected cells in the central nervous system (CNS), despite long-term ART, may play a role in neurocognitive impairment. The authors note that the overall frequency of neurocognitive impairment in this group was relatively low and that the association does not confirm that HIV DNA causes HAND. Overall, the current study found that examining CSF cells revealed a higher-than-expected prevalence of persistent HIV in the CNS, which may be a significant obstacle to efforts to eradicate HIV from the body.

The study was published on July 15, 2019 in the J. Clinical Invest.:

https://doi.org/10.1172/JCI127413