Editor’s Note: The 15th National Conference on AIDS and Hepatitis C, hosted by the Chinese Medical Association and its Infectious Diseases Branch, took place in Guangzhou from November 10 to 12, 2023. Dr. Taisheng Li, the conference chair and a renowned figure from Peking Union Medical College Hospital, delivered a captivating presentation titled “A New Concept in Comprehensive Diagnosis and Treatment in the Post-ART Era of HIV/AIDS.” In an exclusive interview with Infectious Disease Frontline, he further shared insights on topics including immune reconstitution deficiency in HIV-infected individuals.
Post-ART Era: Providing Personalized Comprehensive Treatment for HIV Patients
Infectious Disease Frontline: In your presentation at the conference, you discussed a new concept called “A New Concept in Comprehensive Diagnosis and Treatment in the Post-ART Era of HIV/AIDS.” Could you provide an overview of this new concept?
Dr. Taisheng Li: As we all know, the first case of AIDS was reported globally in 1981, and over the past 42 years, there have been significant changes in the diagnosis and treatment of AIDS. Initially, before the introduction of Highly Active Antiretroviral Therapy (HAART) in 1996, AIDS posed a significant threat to human health, essentially being considered an incurable disease. The advent of HAART marked a crucial turning point in our battle against AIDS, enabling humans to gain the upper hand gradually. Subsequent research, particularly after 2010, emphasized the benefits of early diagnosis and treatment, leading to the introduction of “Rapid ART.” In 2016, China proposed the concept of “Test and Treat,” advocating for early prevention, diagnosis, and treatment of AIDS. Recent Chinese guidelines and the national free drug list underscore the importance of “Rapid ART.”
With the widespread adoption of concepts like HAART and “Rapid ART,” the prognosis of HIV patients has significantly improved. The latest data from the Chinese Center for Disease Control and Prevention (China CDC) reveals a treatment success rate of over 90% for HIV patients in China over the past two decades. These individuals, achieving sustained virological suppression, can now lead long-term lives similar to those with chronic conditions like hypertension or diabetes. However, unlike common internal medicine diseases, HIV patients, even with highly effective ART, still face challenges such as chronic inflammation activation or complications arising from long-term ART use, leading to non-AIDS-defining diseases (NAD). These include metabolic syndrome, cardiovascular diseases, chronic liver, kidney, and bone diseases, as well as inflammatory autoimmune diseases. Internationally, attention to NAD began around 2011. In 2018, the Chinese AIDS Diagnosis and Treatment Guidelines for the first time proposed the concept of comprehensive management for HIV patients. The 2021 guidelines further refined this approach, gaining recognition from the World Health Organization (WHO). The updated WHO AIDS Treatment Guidelines in the same year also proposed “patient-centered” comprehensive lifecycle management for HIV patients.
Whether it’s comprehensive management or lifecycle management, in the post-HAART era, we increasingly emphasize personalized comprehensive management for HIV patients. This involves not only providing the best ART regimen based on individual patient characteristics such as age, underlying diseases, and co-infection with HBV or HCV but also addressing NAD management. For instance, caution is required in using tenofovir in patients with impaired renal function, and ART regimens for HIV/HBV co-infected patients should include at least two drugs targeting HBV. In case of issues like renal damage, overweight/obesity, abnormal blood sugar or lipids during treatment, multidisciplinary discussions involving nephrology, cardiology, endocrinology, etc., are necessary to provide “patient-centered” comprehensive medical services.
In this concept of comprehensive management throughout the disease course, we need to pay special attention to four vulnerable groups. The first group comprises individuals aged 50 and above, focusing on the aging of HIV-infected individuals. The second group involves managing individuals with underlying diseases like cardiovascular diseases and special populations such as those co-infected with HIV and HBV or HCV. The third group includes vulnerable populations such as those facing financial difficulties, children, adolescents, and elderly individuals living alone, requiring psychological and social support. The fourth group comprises patients with immune reconstitution deficiencies or those with failed immune reconstitution. Most of these patients have received ART for at least 3-5 years but have not achieved long-term recovery of CD4+ T lymphocyte counts (WHO defines immune reconstitution deficiency as having received at least 5 years of ART, with CD4+ T lymphocyte count <500/μL; most literature defines it as successful viral suppression after 18-24 months of antiviral therapy but CD4+ T cell count <350/μL).
Immune Reconstitution Deficiency: The Achilles’ Heel of HIV Patients
Infectious Disease Frontline: As you mentioned, some patients fail to achieve immune reconstitution even with prolonged antiviral therapy. What are the significant research advancements for patients with immune reconstitution deficiency or immune reconstitution disorders?
Dr. Taisheng Li: After the advent of Highly Active Antiretroviral Therapy (HAART), the academic community raised a question: Can late-stage AIDS patients achieve immune function restoration through HAART, specifically, whether patients have a sufficient quantity and quality of CD4+ T lymphocytes to maintain or approach normal immune function. Fortunately, during the peak of medical advancements, in the best hospitals, under the guidance of the best mentors, I conducted research on these issues. Under the mentorship of Dr. Otranto at PTTIE Hospital in Paris, France, I was among the first internationally to propose the theory of immune reconstitution in AIDS patients. This theory posits that in late-stage AIDS patients receiving effective ART and achieving virological control, the quantity and function of CD4+ T lymphocytes can gradually recover. At that time, we anticipated that after 5-8 years of ART, patients’ CD4+ T lymphocyte counts could return to the levels seen in normal individuals. Studies conducted after 2001 found that about 70% of patients did indeed recover, but 30% still faced challenges with immune reconstitution.
Currently, it is believed that the causes of immune reconstitution deficiency may include reduced generation of CD4+ T lymphocytes due to aging, insufficient thymus generation, cytokine imbalances, or increased destruction of CD4+ T lymphocytes due to sustained immune activation. Since 2008, international discussions have focused on addressing these issues. Over the past decade, therapies aimed at enhancing thymus activity or lymphocyte proliferation, including recombinant human interleukin-2 (IL-2), IL-7, growth factors, and immunomodulators such as chloroquine, hydroxychloroquine, and metformin, have not been validated by prospective studies.
We noticed that the Chinese herbal medicine Tripterygium wilfordii Hook.f. (Lei Gong Teng) has anti-inflammatory and immunosuppressive effects and has been used to treat rheumatoid arthritis. After fourteen years of effort, our research found that Tripterygium wilfordii Hook.f. preparation could improve the decrease in CD4+ T lymphocytes caused by immune inflammation activation in HIV-infected individuals. Subsequently, we identified the key component inhibiting inflammation, Triptolide, and developed the chemically modified Class 1 new drug Hydroxytriptolide Alcohol (LLDT-8, Leitengshu). Starting in 2018, we conducted a nationwide multicenter, double-blind, double-simulation randomized controlled trial, enrolling 149 patients with immune reconstitution deficiency (at least 4 years of ART, viral suppression for at least 3.5 years, CD4+ T lymphocytes below 350/μL). Patients were randomized to receive LLDT-8 (including high-dose and low-dose groups) or placebo. The study results showed that the CD4+ T lymphocytes in the high-dose group were significantly higher than the placebo group (63 vs. 49 cells/μL), and some inflammatory markers also decreased to varying degrees. The research findings were accepted and published by The Lancet, and Hema Urban, the Senior Executive Editor of The Lancet, highly praised the study, stating that it is expected to provide the first prospectively validated treatment for patients with immune reconstitution deficiency. We hope to initiate Phase III clinical trials of LLDT-8 as soon as possible, allowing this gem unearthed from the traditional Chinese medicine treasury, developed into a modern chemical new drug, to benefit potentially millions of AIDS patients with immune reconstitution deficiency.
World AIDS Day Message: For a Future Without HIV
Infectious Disease Frontline: As World AIDS Day approaches (every December 1st), what message do you have for HIV-infected individuals and clinical practitioners?
Dr. Taisheng Li: This year’s World AIDS Day theme in China is “Gathering Social Forces, Collaborating to Combat AIDS,” aiming to mobilize various sectors of society to curb the spread of AIDS. AIDS is our common enemy, but HIV-infected individuals and AIDS patients are innocent. They are still our fellow human beings, deserving of our care.
Currently, treatment for HIV infection has made significant progress, with an effective treatment rate of up to 95% for newly diagnosed HIV-infected individuals. However, the prevention and treatment of HIV infection still face challenges. The primary reason for the inability to eliminate HIV is the lack of an effective vaccine, relying mainly on antiviral drugs for prevention and treatment. The key to drug treatment lies in early diagnosis and early treatment. Unfortunately, there is still a considerable proportion of patients who are late discoverers of HIV in clinical practice, leading to misdiagnosis or missed diagnosis. By the time of the initial diagnosis, AIDS symptoms may have already appeared. Hospitals of the caliber of Peking Union Medical College Hospital often receive challenging cases from all over the country. These patients often go through multiple hospitals, departments, and doctors before finally discovering HIV infection, and they may present with late-stage AIDS symptoms, such as severe opportunistic infections, resulting in a poor prognosis. Another challenge is how to eliminate social discrimination and increase acceptance of HIV-infected individuals, starting with hospitals. Many HIV-infected individuals may develop other major diseases such as cancer and cardiovascular diseases. General hospitals typically refer patients to infectious disease hospitals, and infectious disease hospitals may not be able to perform high-difficulty surgeries such as thoracotomy and coronary artery bypass surgery. The “U=U” concept has been accepted by authoritative organizations such as the WHO. We hope that various sectors of society can widely accept these new concepts and accept HIV-infected individuals.
Finally, to ensure that our descendants live in a world without the HIV virus, I also hope that with strong national support, the Chinese AIDS research team can devote themselves to research and contribute to the final battle against AIDS. In the process of climbing the “Mount Everest” of eliminating AIDS, we hope to lead globally and reach the summit soon!
Dr. Taisheng Li, MD, PhD
Director of Infectious Diseases Department, Peking Union Medical College Hospital
