In June 2021, the United Nations General Assembly voted to adopt a political declaration on ending the AIDS epidemic by 2030. Over the years, countries have continued to work towards this goal. Recently, the 9th National AIDS Academic Conference, sponsored by the China Association for the Prevention and Treatment of STDs and AIDS, was held in Qingdao, Shandong Province. At the meeting, scientists focused on key areas such as HIV testing and antiretroviral treatment, contributed new ideas, new technologies and new models of prevention and treatment, and worked together to promote the mainland towards a future of "ending AIDS".
Promote the high-quality development of HIV testing
Early detection of infected people, timely initiation of antiretroviral therapy, and effective viral suppression are important measures proposed by UNAIDS to end the global AIDS epidemic. Strengthening testing is the main strategy for the future global AIDS prevention and control, and it has also been an important part of the mainland's prevention and control measures for many years.
"Human immunodeficiency virus (HIV) serology and nucleic acid detection technologies continue to advance, and early and rapid testing products are emerging, but countries are still far from the first 95% target set by the World Health Organization (WHO) where 95% of infected people know their infection status through testing. Shang Hong, academician of the Chinese Academy of Engineering, president of the First Affiliated Hospital of China Medical University, and vice president of the China Association for the Prevention and Treatment of STDs and AIDS, pointed out. According to reports, the window period for HIV testing has been shortened to 7~10 days, but it is estimated that about 15% of HIV-infected people still do not participate in testing, and the proportion of late detection of HIV infection in mainland China is relatively high, reaching 38.7%.
To this end, the mainland has applied a multi-test joint testing strategy based on testing sites, community services, partner services and home self-testing to some areas and high-risk groups. In particular, in terms of self-testing, in 2019, the mainland independently developed and approved the world's first urine antibody self-testing agent, and in the same year, it issued the "AIDS Self-testing Guidance Manual", providing important support for promoting HIV self-testing.
Thanks to the efforts of all sectors of society, the scale of HIV testing in mainland China has been further expanded, and the diagnosis and detection rate has increased year by year. By 2022, it is estimated that 84% of the mainland will have an HIV diagnosis detection rate, about twice that of 2011.
In addition to the diagnostic discovery of HIV, the mainland has also continued to innovate in the detection technology and application strategies of HIV treatment monitoring and functional cure. According to Shang Hong, CD4+ T cells are the key indicators to assess the progression of HIV infection, and HIV load is the preferred indicator for monitoring the efficacy of antiviral therapy. The mainland issued the Guidelines for the Diagnosis and Treatment of HIV/AIDS in China (2021 Edition), which clarified the time distribution and frequency requirements of the two tests. In addition, the state implements the policy of "four frees and one care", provides a free CD4 test and a viral load test once a year, and includes CD4 testing in medical insurance.
Viral reservoirs of latent infection are a major obstacle to HIV cure. Shang Hong's team discovered for the first time the key molecule that regulates the release of viruses from reservoir cells, TRABD2A, and established a new method for reservoir detection. "At present, it has been validated in more than 300 patients on antiretroviral therapy, and multi-center clinical validation is underway. Shang Hong said.
In addition, domestic scholars have constructed a new dual-fluorescent reporter virus model, DFV-B, which can directly label latent infection of primary CD4+ T cells, and innovated the detection method of repositories. Some scholars have also used DFV-B to obtain a new HIV-1 latent promoter (LPA), which effectively inhibits latent reactivation by targeting the AKT/mTOR signaling pathway, providing a new idea of functional cure.
"The 2030 public health goals include not only ending the AIDS epidemic, WHO also proposes to eliminate viral hepatitis by 2030. Jin Cong, director of the reference laboratory of the Chinese Center for Disease Control and Prevention, proposed that "the scope of AIDS testing should be further expanded, and multiple diseases and prevention should be achieved through the same testing of multiple diseases." ”
According to Jin Cong, studies have found that HIV-infected people have a higher probability of co-infection with other menstrual blood or sexually transmitted diseases. The multi-disease co-detection strategy based on HIV testing can help to detect multiple pathogens co-infection in a timely manner, adjust the treatment regimen for a single pathogen, reduce the risk of accelerated disease progression and death caused by the interaction between diseases, and improve the quality of life of co-infected people by combining antiviral therapy and prevention and treatment of co-infection.
"At present, there are combined detection reagents for HIV, viral hepatitis, syphilis and other co-infected diseases in clinical practice, and only one sample can be used to detect a variety of infectious diseases. Jin Cong said, "The strategy of multi-disease co-examination is conducive to building a people-centered integrated health service system, which is one of the directions worth exploring in the future." ”
Identifying the path to success with antiviral therapy
Antiretroviral therapy is currently one of the most effective ways to control the HIV epidemic. "The study found that the improvement of the success rate of antiviral therapy is closely related to the use of integrase chain transfer inhibitors (INSTIs) treatment regimens. Zhang Fujie, chief physician of the AIDS Clinical Center of Beijing Ditan Hospital affiliated to Capital Medical University, said.
Zhang Fujie introduced that China's HIV antiretroviral treatment can be divided into three stages. The first phase began in 1985 when the first case of AIDS was identified on the mainland, but between 1985 and 2002, the choice of antiretroviral treatment drugs was limited. The second phase began in 2003, when the mainland introduced the "four frees and one care" policy, and officially began to provide free antiviral drug treatment to patients, when the mainland only had four domestic generic drugs. In 2009, the mainland AIDS treatment programme added free drugs for second-line treatment. The third phase began in 2016, when the mainland began to implement a "detect and treat" strategy, recommending antiretroviral treatment for all people living with HIV. By deleting obsolete drugs, introducing imported drugs, and accelerating the research and development of domestic original antiviral drugs, the mainland AIDS treatment drug market has formed a "troika", that is, free drugs, medical insurance drugs, and self-financed drugs coexist, and antiviral drugs have entered the era of integrase.
"As a lifelong treatment, the key and difficulty in the success of antiviral therapy lies in improving the maintenance rate of treatment. Zhang Fujie introduced that once the infected person stops antiviral drugs during treatment, it is easy to cause the virus to rebound, destroy the immune system, and cause various serious opportunistic infections and tumors during the onset period, so that the survival rate of patients is greatly reduced.
A German study found significant differences in treatment maintenance rates among different first-line antiviral regimens. At 24 months of antiviral therapy in treatment-naïve HIV patients, first-line regimen maintenance rates were 64 percent in the INSTIs, non-nucleoside reverse transcriptase inhibitors (NNRTIs) group, and 22 percent in the protease inhibitor (PI) group, respectively. After statistical adjustments for virologic failure and adverse drug reactions, the cohort retention rate in the INSTIs group was still better than that of other regimens.
"Beijing Ditan Hospital was the first to carry out antiviral treatment in China, and the hospital's exploration process can be regarded as a microcosm of China's 20 years of antiviral treatment. In order to further explore the risk factors affecting the maintenance rate of antiretroviral therapy, Zhang Fujie led the team to conduct a retrospective longitudinal cohort study of 10,498 HIV-naïve patients treated in Beijing Ditan Hospital from 2003 to 2022. Based on the background and situation of the hospital's application of different first-line treatment regimens to treat HIV-naïve patients, the research team analyzed factors such as gender, transmission route, and duration of HIV infection from diagnosis to antiretroviral therapy, and found that integrase regimens were a protective factor for improving the treatment maintenance rate.
"Statistical analysis shows that with the change of treatment regimen and the application of integrase regimen, the success rate of antiviral therapy has increased significantly. This conclusion also gives us the confidence to tell everyone and the world that long-term antiviral therapy can be successful. "This also reminds us that we need to continue to find better drug solutions for the scientific prevention and treatment of HIV/AIDS to improve the success rate of long-term treatment." ”
"Although the mainland has made great achievements in antiviral treatment, there is still a long way to go. Zhang Fujie reminded that "at present, the proportion of long-term treatment interruption in mainland China is high, the incidence of drug resistance is high, the incidence of adverse drug reactions is high, and the risk of non-AIDS comorbidities and death is increased." This is also a common challenge facing the whole world, which requires great attention. ”
The molecular monitoring platform helps precise prevention and control
It is understood that for a long time, the mainland has lacked a unified intelligent analysis platform at the molecular level for HIV/AIDS prevention and control, and data analysis is highly dependent on international databases, which has great limitations. This gap was filled with the official launch of the China HIV Gene Sequence Data Platform in December 2022.
Xing Hui, director of the Virus and Immunology Research Office of the Chinese Center for Disease Control and Prevention, introduced that the Chinese HIV gene sequence data platform was jointly developed by the Chinese Center for Disease Control and Prevention, the National Center for Microbial Science of the Institute of Microbiology of the Chinese Academy of Sciences, and the Institute of Microbial Epidemiology, Academy of Military Sciences.
"The massive amount of genetic data generated in HIV prevention and research can be used for HIV molecular surveillance, which can quickly identify risk networks and potential outbreaks by comparing viral sequences to determine whether they are genetically linked. However, even if people with a medical background are not familiar with bioinformatics, it is difficult to master the analysis methods of gene sequences, which may lead to data waste. Xing Hui introduced that on the China HIV gene sequence data platform, molecular network analysis results can be generated with one click only by uploading the sequence file in FASTA format and the corresponding information file of the sequence, which greatly reduces the difficulty of genetic data analysis.
Xing Hui pointed out that the practical application of HIV molecular surveillance in public health is very extensive. Some people living with HIV are diagnosed in areas other than where they are infected, and molecular surveillance can be used to link infected people in different areas and identify the growing transmission network in the population. On this basis, precise intervention can be carried out for high-risk infection sources, and real-time spatio-temporal dynamic early warning can be provided to prevent the spread of HIV, so as to control the increase of HIV infection.
"The realization of the above work is inseparable from the tracing of the strain, and the application of the China HIV gene sequence data platform can help improve the accuracy of tracing the source. Xing Hui said. According to reports, the HIV gene database of Los Alamos National Laboratory in the United States is currently the most widely used HIV database in the world, but the database is not precise enough to classify the epidemic strains in the mainland, and cannot identify the subclusters of the main circulating CRF01_AE and CRF07_BC recombinant strains in the mainland, which is solved in the sequence analysis module of the Chinese HIV gene sequence data platform.
In addition, the use of HIV gene sequences to identify HIV drug resistance is also the mainstream method for judging drug-resistant strains, which has the significant advantage of being fast and efficient. The HIV drug resistance analysis tool in the China HIV gene sequence data platform uses a convolutional neural network model to train the HIV phenotype drug resistance data, and the model is fine-tuned to improve the accuracy of the prediction results of drug resistance to non-B subtypes. It was found that the analysis tool was better than the Stanford HIV resistance analysis tool in terms of non-B subtypes.
"Since its launch, the platform has received a total of 375,000 visits, with users covering more than 20 countries, and has been applied to the research and efficient handling of key epidemics in mainland China, strongly supporting the precise prevention and control of HIV at the molecular level. In the next step, the platform will play a role in HIV prediction and early warning, as well as the surveillance and detection of drug-resistant strains. Xing Hui introduced.
Text: Health News reporter Liu Jiyue Editor: Li Shiyao Proofreader: Yang Zhenyu Review: Qin Mingrui Xu Bingnan