Huang Hui Zhao, Wu Bin

(Huang Hui Zhao, Wu Bin) Chapter Twenty: AIDS – Overview AIDS, also known as Acquired Immune Deficiency Syndrome (AIDS), is caused by the Human Immunodeficiency Virus (HIV). The first report of AIDS in the United States was made in 1981, and since then, reports have emerged worldwide, with widespread outbreaks in many African countries. Since China reported its first case of AIDS in 1985, the number of cases has increased year after year. The primary modes of HIV transmission include sexual contact and intravenous drug use; other routes include blood transfusions and other blood product transmissions, as well as sexual encounters with multiple partners. The main populations susceptible to AIDS include intravenous drug users, hemophiliacs, male homosexuals, individuals who have received blood transfusions or other blood products, and those engaged in promiscuous sexual relationships. The mortality rate of AIDS is nearly 100%. HIV belongs to the Retroviridae family, subfamily Lentivirus, and is a positive-sense single-stranded RNA virus, divided into two subtypes: HIV-1 and HIV-2. The majority of cases worldwide are caused by HIV-1. HIV appears as a spherical, bag-shaped virus with a diameter of approximately 150 μm, its envelope composed of a thin lipid layer and possessing antigenic properties. HIV has 10% sequence variation. It is a single-stranded RNA virus, surrounded by a nucleocapsid protein, and features a special reverse transcriptase enzyme that can take single-stranded RNA as a template to transcribe it into double-stranded DNA. This double-stranded DNA can bind to the host cell’s DNA and then be reverse-transcribed into single-stranded viral DNA. Thus, after infection with HIV, the virus’s nucleic acid remains permanently bound to the host cell, preventing the infection from disappearing and enabling the body to fail to eliminate the virus. HIV is a virus that preferentially infects T-lymphocytes and neurons. HIV enters the human bloodstream through breaks in the skin or mucous membranes; rapid viral replication leads to high concentrations of virus in the blood and lymphatic organs. The primary target cells attacked and destroyed are Ta lymphocytes bearing CD receptors—CD4 molecules act as receptors with strong affinity for the virus’s surface glycoproteins, allowing HIV to enter cells. Once inside the cell, HIV releases its RNA and, under the action of reverse transcriptase, transcribes it into DNA, forming pre-viral DNA, which integrates with the host cell’s chromosomal DNA. Subsequently, the viral DNA is transcribed into mRNA by the host cell’s RNA, and the required structural proteins for viral replication are synthesized. RNA and structural proteins are reassembled on the cell membrane to form new viral particles, which are released through budding. While the virus rapidly replicates, the immune system also begins to develop a specific immune response against HIV. Once the body produces specific cytotoxic lymphocytes capable of targeting HIV, the viral load in the body starts to decline. Although this immune response cannot completely eliminate HIV infection, it creates a relatively balanced and stable state between viral replication and clearance. The average latency period for HIV in the human body is 12–13 years. HIV has a strong affinity for nerve cells, capable of invading the nervous system and causing damage to brain tissue, or leading to secondary opportunistic infections that result in various central nervous system disorders. When HIV DNA integrates into the host cell’s DNA, the oncogenic genes carried by HIV can cause cellular transformation into cancerous cells—especially when cellular immunity is compromised, losing its role in immune surveillance, making cancerous changes in cells more likely to occur. From HIV infection to the onset of disease, there is a complete natural process. Clinically, this process is divided into four stages: acute infection, latent period, pre-AIDS stage, and typical AIDS stage. The different clinical manifestations of these four stages represent a gradual and continuous progression of the disease.

1. Acute Infection Stage This stage occurs after HIV invades the body, triggering a series of responses. Patients may experience fever, rash, swollen lymph nodes, as well as fatigue, sweating, nausea, vomiting, diarrhea, and pharyngitis. Some patients may also develop acute aseptic meningitis, characterized by headache, neurological symptoms, and meningeal irritation. Around five weeks after the onset of these systemic symptoms such as fever, serum HIV antibodies may become positive. Following this, a relatively healthy, symptom-free latent period—often lasting for varying lengths of time—may begin to appear.

2. Latent Period: During this stage, patients may exhibit no clinical symptoms, yet the virus continues to replicate, exerting a powerful destructive impact on the body. It remains highly contagious. The average latency period for AIDS is now estimated to be 2–10 years.

3. Pre-AIDS Stage: This stage follows the latent period and marks the beginning of symptoms and signs associated with AIDS, eventually progressing to the typical AIDS stage. At this point, patients already exhibit the most fundamental characteristics of AIDS—cellular immune deficiency—but the symptoms are relatively mild. The primary clinical manifestations include swollen lymph nodes, general discomfort, muscle pain, fatigue, periodic low-grade fever, night sweats, weight loss, headaches, depression, or anxiety, and splenomegaly. Patients often develop foot fungus, bullous pustules, and genital warts, as well as common warts around the anus, genitals, weight-bearing areas, and oral mucosa. Oral herpes simplex, shingles, and oral mucosal erosion, congestion, and cheesy coatings are common. Oral lesions may also present as hairy leukoplakia, a precursor to early AIDS.

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Input: It is a new virus that was first discovered internationally in the latter half of 1995. HGV is a positive-sense single-stranded RNA virus measuring 50–100 nm in size, transmitted through blood and causing chronic infection in the population with a relatively high prevalence rate. Currently, our understanding of HGV’s biological characteristics remains limited, particularly regarding its relationship with liver diseases, which are still subject to considerable debate.

7. TT Virus (TTV) – Hepatitis: In 1987, Japanese scholars first discovered that TTV could cause hepatitis. In June 1998, the Academy of Military Medical Sciences in China successfully isolated the Chinese strain of TTV for the first time. In September of the same year, Hunan Medical University identified the first case of TTV infection, followed by the cloning of partial TTV genome sequences. TTV is a 3.7 kb, non-enveloped, single-stranded DNA virus, potentially belonging to the Parvoviridae family. TTV infections are widespread; according to epidemiological surveys conducted across various countries among different populations, the positive rate of TTV DNA in the general population often exceeds 10%.

TTV is primarily transmitted through blood, and individuals exposed to blood—such as professional blood donors, intravenous drug users, patients undergoing hemodialysis or receiving blood transfusions—have significantly higher TTV DNA positivity rates compared to the general population. TTV can also be transmitted vertically from mother to child; domestic reports have confirmed that TTV can be transmitted from mother to child during intrauterine transmission. While sexual transmission may not play a major role, TTV infection rates are not high, and most infected individuals remain asymptomatic carriers without obvious liver inflammation-related biochemical abnormalities. Some reports suggest a possible association between TTV infection and acute hepatitis, post-hepatitis cirrhosis, chronic hepatitis with prolonged ALT fluctuations. However, there is still considerable debate regarding whether TTV infection can trigger liver inflammatory responses.

(2) Pathology

The pathological characteristics of chronic hepatitis B include prominent portal area inflammation, with lymphocytes being the primary inflammatory cells, accompanied by a small number of plasma cells and macrophages. The clustering of inflammatory cells often leads to portal enlargement and can disrupt the septa, resulting in interface hepatitis, also known as piecemeal necrosis. Portal area inflammation and interface hepatitis are characteristic lesions associated with the activity and progression of chronic hepatitis B lesions. Hepatocellular degeneration and necrosis within lobules, including fusion necrosis and bridge necrosis, become increasingly pronounced as the disease progresses. Hepatocellular inflammation and necrosis, along with portal area and interface hepatitis, can lead to excessive collagen deposition within the liver, resulting in hepatic fibrosis and the formation of fibrous septa. If the condition continues to worsen, it may cause disruption of the lobular architecture, leading to pseudo-lobules and ultimately progressing to cirrhosis.

Immunohistochemical staining can reveal whether hepatocytes express HBsAg and HBcAg. Diffuse cytoplasmic and membrane-bound HBsAg expression, as well as cytoplasmic and membrane-bound HBcAg expression, indicate active HBV replication; while inclusion body-type and perinuclear HBsAg expression suggest HBV presence within hepatocytes.

Hepatitis C pathology is crucial for diagnosis, assessing the degree of inflammation and fibrosis, evaluating drug efficacy, and determining prognosis. Acute hepatitis C may exhibit portal area inflammation and various lesions in the portal region similar to those seen in hepatitis A and B. However, other histological features can also be observed, such as: ① mononuclear cell infiltration, where mononuclear cells invade the hepatic sinus and form string-like structures; ② hepatocellular ballooning degeneration; ③ bile duct damage accompanied by extensive lymphocyte infiltration in the portal area, even forming lymphoid follicles. Bile duct cells are damaged, the number of interlobular bile ducts decreases, resembling autoimmune hepatitis; ④ common interface inflammation. In chronic hepatitis C, portal area lymphoid follicles, bile duct damage, hepatocellular fatty degeneration within lobules, and aggregation of Kupffer cells or lymphocytes within lobules are often observed—these are relatively distinctive histological findings that provide valuable reference for the diagnosis of chronic hepatitis C.

(3) Symptoms and Signs

The incubation period for hepatitis ranges from 1 to 3 months. The main symptoms and signs include fatigue, loss of appetite, pain in the liver region, hepatosplenomegaly, or jaundice. Each type—acute, chronic, severe, or cholestatic—has its own distinct characteristics. Types A, B, C, D, and E all exhibit acute and severe cases; types B, C, and D can develop into chronic hepatitis, potentially progressing to cirrhosis or liver cancer. Acute jaundice hepatitis often presents with chills, fever, fatigue, loss of appetite, aversion to oily foods, diarrhea, or constipation in the pre-jaundice phase, with pain in the liver region and darkening of urine color. During the jaundice phase, fever subsides, digestive symptoms may be mild or severe, jaundice becomes more pronounced, liver enlargement is present with tenderness upon palpation, or mild splenomegaly may occur. In the recovery phase, jaundice and symptoms subside, liver and spleen return to normal, and the course of the disease lasts 2–4 months. Acute non-jaundice hepatitis is more common than jaundice-type hepatitis, with milder illness, often without jaundice, and some patients may experience no obvious symptoms or signs. Chronic hepatitis typically has a history of six months or more, often without jaundice, but with recurrent fatigue, dizziness, gastrointestinal symptoms, and discomfort in the liver region, sometimes accompanied by mild hepatosplenomegaly. Over six months of chronic hepatitis, fatigue and gastrointestinal symptoms become more pronounced, liver and spleen progressively enlarge, with liver tissue ranging from moderate to severe, possibly accompanied by spider angiomas and a “liver face.” A small number of patients may also experience extrahepatic manifestations such as arthritis, nephritis, vasculitis, or Sjögren’s syndrome. Severe hepatitis is classified into three types: acute, subacute, and chronic. Acute severe hepatitis involves rapid worsening of jaundice within 10 days after the onset of acute hepatitis, with liver shrinkage, bleeding, ascites, toxic bowel obstruction, renal failure, and varying degrees of hepatic encephalopathy. Subacute severe hepatitis occurs more than 10 days after the onset of acute hepatitis but within 8 weeks, exhibiting the aforementioned severe symptoms. Chronic severe hepatitis refers to cases where chronic hepatitis or post-hepatitis cirrhosis develops these severe symptoms. Cholestatic hepatitis begins similarly to acute jaundice hepatitis, with symptoms often milder, but liver and spleen enlargement is more pronounced, skin itching appears, and intrahepatic obstructive jaundice persists for more than 3 weeks.

(4) Laboratory Tests

1. Pathogen Detection With the rapid advancement of virology, various types of hepatitis now have specific pathogen detection methods. Typically, enzyme-linked immunosorbent assays (ELISA) are used to detect hepatitis virus markers in patient serum, such as anti-HAV IgM and HAV RNA for hepatitis A; qualitative or quantitative testing of the three systems for hepatitis B—HBsAg, anti-HBs, HBeAg, anti-HBe, and anti-HBc; anti-HCV for hepatitis C; anti-HDV IgM, HDV Ag, and HDV RNA for hepatitis D; and anti-HEV IgM for hepatitis E. TTV infection can also be detected using anti-TTV antibodies for pathogen diagnosis. The most sensitive method is polymerase chain reaction (PCR), an in vitro gene amplification technique used to detect hepatitis virus DNA or RNA; when necessary, immunoelectron microscopy can be employed to examine hepatitis virus particles or markers in feces or liver tissue.

For hepatitis B, HBV-DNA genotyping and mutation detection are also available, using methods such as: (1) qualitative and quantitative HBV-DNA testing to assess viral replication levels, primarily used for diagnosing chronic HBV infection, monitoring serum HBV-DNA levels, and evaluating antiviral treatment efficacy. (2) HBV genotype classification: commonly used methods include: ① genotype-specific primer PCR; ② restriction fragment length polymorphism analysis (RFLP); ③ linear probe reverse hybridization (INNO-LiPA); ④ PCR microplate nucleic acid hybridization enzyme-linked immunosorbent assay; ⑤ gene sequencing methods. However, currently, no HBV genotype kits have been officially approved by the State Food and Drug Administration (SFDA) in China.

(3) HBV drug resistance mutation detection: Common methods include: (1) HBV polymerase region gene sequence analysis; (2) restriction fragment length polymorphism analysis (RFLP); (3) fluorescent real-time PCR; (4) linear probe reverse hybridization, among others.

2. Biochemical Tests (1) Serum ALT and AST levels generally reflect the extent of hepatocellular injury and are the most commonly used indicators. (2) Serum bilirubin levels correlate with the degree of hepatocellular necrosis; elevated levels often appear in severe hepatitis, but it is important to differentiate them from bilirubin elevation caused by intrahepatic or extrahepatic cholestasis. In patients with liver failure, serum bilirubin levels are often high and increase progressively, with daily increases exceeding 10 µmol/L; bilirubin may also show a separation from ALT and AST, indicating severe liver disease.

(3) Prothrombin time (PT) and prothrombin activity (PTA): PT is an important indicator of liver synthetic function, while PTA is a common way to express PT values, offering significant value for assessing disease progression and prognosis. A recent decline in PTA below 40% is one of the key diagnostic criteria for liver failure; values below 20% suggest a poor prognosis.

(4) Cholinesterase levels can reflect liver synthetic function and provide valuable insights into the severity of the disease and the monitoring of liver disease progression.

(5) Serum albumin reflects liver synthetic function; in patients with chronic hepatitis B, cirrhosis, or liver failure, serum albumin levels may decrease or globulin levels may increase, resulting in a reduced albumin-to-globulin ratio.

(6) Elevated alpha-fetoprotein (AFP) often suggests hepatocellular carcinoma (HCC), making it useful for monitoring HCC development; AFP elevation may also indicate hepatocellular regeneration following extensive hepatocellular necrosis, potentially aiding in prognosis assessment. However, it is important to consider the magnitude of AFP elevation, its duration, dynamic changes, and its relationship with ALT and AST, while combining these findings with the patient’s clinical presentation and imaging results such as ultrasound for comprehensive analysis. Liver biopsy is of great importance in differentiating chronic hepatitis and evaluating treatment efficacy, and is considered a gold standard.

(5) Pathological Examination