Earlier treatment and higher CD4 counts linked to smaller HIV reservoir

People who start antiretroviral treatment early, before they develop extensive immune system damage, have a smaller HIV viral reservoir, which may improve prospects for a functional cure, according to studies presented this week at the 11th International AIDS Society Conference on HIV Science (IAS 2021).

Very soon after initial infection, HIV establishes a lasting reservoir of inactive virus in long-lived resting T-cells. While antiretroviral drugs can control viral replication, they do not eliminate these latent viral blueprints, which can resume virus production when treatment stops – the key barrier to a cure for HIV.

CD4 count at treatment initiation

Professor Edwina Wright of the University of Melbourne and an international team of colleagues looked at the association between CD4 T-cell count and viral reservoir size in people who began early antiretroviral therapy (ART) in the START (Strategic Timing of Antiretroviral Treatment) trial.

As reported at the 2015 IAS conference, START showed that people who initiate treatment with a CD4 count above 500 cells/mm 3 have a significantly lower risk of illness and death than those who wait until it falls below 350. These findings led to a change in global treatment guidelines to recommend ART for everyone diagnosed with HIV, regardless of CD4 count.

In this substudy, Wright and colleagues compared the size of the viral reservoir in people who started treatment with a CD4 count of 500-599 (36 participants), 600-799 (60 participants) or more than 800 (50 participants) at the time of enrolment. A majority of these participants (60%) were women, most were Black and the median age was approximately 40 years.

Looking at samples collected after about three years on ART, they measured total HIV DNA, a specific type of HIV DNA (2-long terminal repeat DNA) and cell-associated unspliced HIV RNA in CD4 cells, as well as plasma HIV RNA using a single-copy assay. They also assessed markers of T-cell activation (HLA-DR, PD-1 and pSTAT5 expression).

The researchers found that total HIV DNA was lower in people who started treatment with a CD4 count above 800 compared with those who started with 600-799 or 500-599 cells/mm3 (16, 30 and 68 copies per million cells, respectively). While total DNA and plasma HIV RNA were significantly reduced in people who started treatment at the highest CD4 level, this was not the case for 2-long terminal repeat DNA or cell-associated unspliced RNA. T-cell activation as measured by HLA-DR was significantly lower in people who started ART with a CD4 count above 800, but PD-1 and pSTAT5 expression did not differ.

The researchers also noted that older people and women had lower total HIV DNA levels than younger people and men, but the association between lower total DNA and higher CD4 count at ART initiation remained after adjusting for these and other factors. However, when looking at women and men separately, the association was no longer significant for the men.

"Collectively our findings indicate people with HIV who maintain CD4 T cells ≥800 cells/mm3before ART initiation are endowed with an enhanced capacity to eliminate latently infected cells and may constitute a subgroup that could potentially benefit from interventional cure studies," they concluded.

Reservoir size and bNAb susceptibility

In another study, Dr Brian Moldt of Gilead Sciences and colleagues compared viral reservoir size and diversity, as well as HIV's susceptibility to broadly neutralising antibodies (bNAbs), in people who started ART at different stages of infection. Currently being studied in HIV treatment,prevention and cure research, bNAbs are able to recognise conserved parts of the virus that change little across strains.

The study enrolled people in four cohorts based on when they started ART: Fiebig stage I or II (when HIV RNA and the p24 antigen can be detected), Fiebig III or IV (when HIV antibodies are first detectable), late acute infection (three months or less) and chronic infection (over six months). The cohorts included 16, 17, 14 and 17 people, respectively. More than 90% were men, they had been on ART for three to five years and CD4 counts were high (approximately 700 to 900).

The participants underwent leukapheresis, a procedure in which blood is drawn, white blood cells are removed, and the rest of the blood is returned to the body. Through this, the researchers collected a sample of peripheral blood mononuclear cells (T cells and other immune cells). The viral reservoir was measured in these cells using the intact proviral DNA assay, total HIV DNA assay and quantitative viral outgrowth assay. Susceptibility to Gilead's investigational bNAb elipovimab was determined by genotyping of the HIV envelope gene.

The researchers found that total DNA was lower in the Fiebig I-II and Fiebig III-IV groups. The late acute infection cohort had a lower level than the chronic infection cohort, but the difference did not reach statistical significance. What's more, viral diversity was lower in people who started treatment during acute infection compared with chronic infection. People who started ART earlier also generally had greater susceptibility to elipovimab.

"Individuals initiating ART during Fiebig I-IV would be an optimal target population for proof-of-concept cure trials due to smaller, less diverse HIV reservoirs," the researchers concluded.

Post-treatment control in monkeys

Finally, Dr Caroline Passaes of Institut Pasteur in Paris presented results from a study of early antiretroviral therapy and post-treatment control – the ability to maintain viral suppression after stopping therapy – in macaque monkeys.

Dubbed pVISCONTI ('p' for primate), the study used a non-human primate model to assess the impact of early versus late ART initiation on immune responses and outcomes after treatment interruption. The aim is to learn more, under standardised conditions, about the factors underlying viral control seen in people in the French VISCONTI cohort and in other post-treatment controllers.

The researchers looked at monkeys infected with SIV – HIV's simian cousin – comparing 12 animals that started combination ART during primary infection (28 days after exposure), 12 that started during chronic infection (six months post-infection) and 17 that remained untreated. ART continued for two years, then the monkeys were monitored for another six months to a year after treatment interruption. Plasma viral load, CD4 T-cells levels and CD8 T-cell responses were measured throughout the study.

Viral rebound (defined as more than 1000 copies/ml) occurred sooner in those that started treatment during chronic infection compared with primary infection. What's more, 82% of the monkeys in the primary infection group achieved post-treatment control (defined as a viral load below 400 copies/ml) at the end of the study period, compared with 25% in the chronic infection group and 12% in the untreated group.

The researchers also noted that anti-SIV CD8 T-cell activity, which was weak at the time of infection, increased after treatment interruption – particularly in monkeys that started ART during primary infection – and was stronger in post-treatment controllers.

"Early combination ART initiation favoured a delayed viral rebound and a higher frequency of post-treatment control," the researchers concluded. "Post-treatment control was associated with the promotion of a robust secondary SIV-specific CD8 T-cell response, in blood and lymphoid tissues, that efficiently counteracted viral rebound after analytic treatment interruption."

Source: https://www.aidsmap.com/news/jul-2021/earlier-treatment-and-higher-cd4-counts-linked-smaller-hiv-reservoir

Stigma and discrimination are one of the factors in the spread of HIV / AIDS

On August 6, the International NGO "International Institute of HIV / AIDS and Tuberculosis" with the assistance of the Department of Civil-Military Cooperation of the Land Forces of the Armed Forces of Ukraine for servicemen of the Land Forces of the Armed Forces of Ukraine in Mariupol held a training on "HIV/AIDS, the rights and responsibilities of people living with HIV, stigma and discrimination".

The main objectives of such trainings remain unchanged - to raise the level of awareness of servicemen on HIV / AIDS and reduce the risk of spreading the disease among the personnel of the Armed Forces of Ukraine.

Experts who have been working for many years in the field of combating the spread of HIV / AIDS in Ukraine, including Natalia Kozhan, a lecturer at the PL Shupik National University of Health of Ukraine, and Serhiy Dmytriyev, a military chaplain, were involved in the training.

The issues of the HIV / AIDS epidemic situation in Ukraine and among servicemen were considered during the classes; ways of HIV / AIDS transmission; rights and responsibilities of HIV-infected people; stigma and discrimination, as well as their prevention; spiritual support for HIV-infected servicemen and more.

For reference: the event was implemented within the PEPFAR project "HIV / AIDS Prevention in the Armed Forces of Ukraine: testing and counseling, reducing the risk of infection on the battlefield."

A new HIV vaccine has been tested in Oxford

Researchers at Oxford University have launched the first phase of clinical trials of a new HIV vaccine called HIVconsvX. Scientists hope that the drug will be effective against all strains of the virus. The vaccine is being developed as part of the European HIV Vaccine Initiative, which aims to study how inducing T-cell antibodies and targeting them to vulnerable clusters of HIV can help fight infection. Previously, HIV vaccines were developed to induce antibodies to B cells. Scientists plan to report the results by April 2022.

The developers used bioinformatics to find out which parts of HIV proteins are less prone to mutations (and, consequently, to escape from immunity) and incorporated them into the vaccine. T-cells, "feeling" these areas, "remember" them and when they encounter a real virus, they will quickly destroy the infected cells.

In the course of research, scientists will evaluate the safety, tolerability and immunogenicity of the vaccine. At the initial stage of the experiment, the first dose of HIV vaccine will be given to 13 HIV-negative participants aged 18 to 65 years who are not at high risk of HIV infection. An additional dose will be given in four weeks. At later stages, scientists plan to involve people living with HIV to participate in the experiment. Similar tests will be conducted in Europe, Africa and the United States.

According to the University of Oxford, the developed vaccine will be the "best solution" to eradicate the AIDS epidemic. "Even in the context of enhanced antiretroviral treatment and prevention, the HIV vaccine remains the best option and is likely to be a key element of the AIDS eradication program," said Tomasz Hanke, a professor of immunology at the Jenner Institute and lead researcher.

"An effective HIV vaccine has been elusive for 40 years. This is the first trial in a series of evaluations of this new vaccination strategy in both HIV-negative people for prevention and in people living with HIV for treatment, ”said Paola Chiccone, a senior fellow at the Jenner Institute at Oxford University.

The study authors explained that other potential HIV vaccines have tried to boost a patient's antibodies through B cells, but HIVconsvX activates the body's T cells, which have a powerful ability to kill pathogens. They are aimed at attacking the weak points of the virus.

The University of Oxford also participated in the development of a vaccine against coronavirus, together with AstraZeneca. The success of the COVID-19 vaccine also inspired them to develop an HIV vaccine.

Source: https://www.pharmalive.com/oxford-researchers-commence-trials-for-potential-wide-spectrum-hiv-vaccine

Training on counseling and testing for HIV with the use of rapid multitests was conducted for doctors of hospitals of the Armed Forces of Ukraine

On July 28-30, a training for doctors of hospitals of the Armed Forces of Ukraine was held in Kharkiv by representatives of the International Institute for HIV / AIDS and Tuberculosis. 17 medical workers from Kharkiv, Vinnytsia, Zhytomyr, Chasovy Yar and Lysychansk took part in the training. The main purpose of the event was to improve skills in HIV counseling and testing using rapid multitests.

Experts who have been working in the field of combating the spread of HIV / AIDS in Ukraine for many years were involved in the training, including Natalia Kozhan, a lecturer at the Shupik's National University of Health of Ukraine, a microbiologist in the laboratory department of the National Military Laboratory. -Medical Clinical Center "Main Military Clinical Hospital" Olga Stas, doctor of the highest category of the Kharkiv Regional Council "Regional Clinical Center for AIDS Prevention and Control" Kozhevnikova Irina and military chaplain Sergei Dmitriev.

Participants of theoretical and practical classes discussed the epidemiology of HIV infection; counseling on HIV treatment; a comprehensive package of services provided to HIV-positive people; dispensary supervision of HIV-infected persons, methods and algorithms of treatment of HIV / AIDS and opportunistic diseases. In addition, all participants trained in practice to conduct pre- and post-test counseling.

For reference: the event was implemented within the PEPFAR project "HIV / AIDS Prevention in the Armed Forces of Ukraine: testing and counseling, reducing the risk of infection on the battlefield."



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