Guidelines for diagnosis and treatment of HIV/AIDS in China (2005)

Acquired immunodeficiency syndrome (AIDS), caused by the human immunodeficiency virus (HIV), has become a major public health issue in China. It not only posesses formidable challenges for the health of the Chinese people, but has also influenced China's economic development and social stability. Tasked by the Ministry of Health, the Chinese Medical Association organized experts to develop these Guidelines for Diagnosis and Treatment of HIV/AIDS. Based on the latest national and international research developments, these guidelines adopt an evidence-based approach, taking into account the characteristics of China's situation. Topics include epidemiology, etiology, pathogenesis, pathological changes, clinical presentation and staging, laboratory tests, diagnosis, highly active antiretroviral therapy (HAART), diagnosis and treatment of common opportunistic infections (OIs), prevention of mother-to-child transmission (PMTCT), and postexposure prophylaxis. Special attention focuses on the antiretroviral therapy. Features of these guidelines include: 1) systematic and comprehensive coverage from basic science to the clinical, from treatment to prophylaxis; 2) evidence-based medicine that avoids recommending views and approaches yet to be proven; 3) clinically practical and innovative, building upon the consensus from Chinese experts (particularly in regard to HIV clinical staging and diagnostic criteria), epidemiology of HIV and AIDS in China and the clinical characteristics of Chinese AIDS patients; 4) recommendation of HAART regimens based on in-country drug availability. The essence of clinical medicine is the adoption of appropriate diagnosis and treatment approaches with consideration of the specific conditions of patients and available medical resources. Given the rapid development of modern medicine and the perpetual emergence new theories, views, and diagnosis/prevention/treatment approaches, these Guidelines will be regularly revised and updated based on the latest developments in clinical medicine. EPIDEMIOLOGY From the first cases of HIV/AIDS reported in the United States in 1981 to the end of 2003, approximately 69 million cases of HIV infections have been reported globally and 27 million of them were dead. The first case of AIDS in China was reported in 1985. Since that time, it is estimated that approximately 840 000 individuals were infected by the virus by the end of 2003, including 80 000 cases of AIDS. To date, the infection has been reported in all provinces, autonomous regions, and municipalities of China and it is spreading from high-risk populations such as drug users and commercial sex workers to the general population. Source of the infection People living with HIV/AIDS (PLWHA) are the sole sources of HIV infection. Routes of transmission of HIV The virus presents predominantly in the PLWHA's blood, semen, vaginal discharge, and breast milk. HIV transmission occurs through sexual contact (including homosexual, heterosexual and bi-sexual contact), blood or blood products (such as via intravenous drug use with needle sharing or invasive medical operations) and mother-to-child (including prenatal, intrapartum and postpartum transmission).1 It is not transmitted through day to day contact with PLWHAs, such as shaking hands, hugging, kissing for etiquette purposes, dining or drinking together; nor is it transmitted through sharing toilets, restrooms, offices, public transportation or recreational facilities. Vulnerable populations All populations are vulnerable to HIV infection. HIV infection is closely associated with behavior such that men who have sex with men, intravenous drug users (IDUs), those who have frequent sexual contact with HIV infected persons and those who frequently receive transfusions of blood or blood products (such as hemophiliacs) are at high risk of acquiring HIV. Case reporting Once a new infection is identified, the case should be immediately reported to the local CDC. Medical management Follow the principle of confidentiality, strengthen follow-up with the PLWHA, and provide medical and psychological counseling. Precautions Develop healthy sexual practices; use condoms correctly, and engage in safer sex. Refrain from drug use and needle and syringe sharing. Promote non-commercial blood donation and conduct HIV screening among blood donors. Reinforce hospital management; strictly follow disinfection procedures; control nosocomial cross infections, and prevent infections via occupational exposure. Control mother-to-child transmission. Provide medical examinations, HIV testing, and appropriate counseling services to PLWHA spouses, children of PLWHA, other sexual partners, men who have sex with men and anyone with whom the PLWHA may share needles and syringes.2 VIROLOGY HIV is a retrovirus belonging to a group of cytopathic lentiviruses. The virus has a diameter of 100—120 nm and is spherical in shape. It is composed of an interior viral core and an outer viral envelope. The viral core contains two single strands of HIV RNA, core structural proteins and enzymes necessary for viral replication, including reverse transcriptase (RT, P51/P66), integrase (INT, P32) and protease (PI, P10). It has a coat called HIV capsid proteins (P24, P17). The exterior coat of HIV is the viral envelope, embedding two glycoproteins: gp120 (envelope glycoprotein) and gp41 (transmembrane glycoprotein). HIV has a 9.8 kb genome, containing 3 structural genes (gag, pol, and env), 2 regulatory genes (tat— trans-activator; rev — regulator of virion protein expression) and 4 auxiliary genes (nef—negative regulatory factor; vpr — viral protein R; vpu — viral protein U; and vif—viral infectivity factor). HIV is highly variable. Various genes have different variabilities; env has the highest variability. Major causes for HIV variation include: random variation results in a dysfunctional reverse transcriptase; host's immunoselection pressure; gene recombi-nation between viral DNA and host DNA; and drug selective pressure. Nonstandard and no adherence to antiretroviral therapy is a major cause for drug resistance. HIV is classified into type HIV-1 and type HIV-2. The two viruses share a 40% — 60% amino acid sequence homology. Currently, HIV-1 is globally prevalent (unless otherwise noted, HIV refers to HIV-1 in this document). HIV-1 can be further classified into different subtypes, including subtype groups M (the major group), O and N. The group M has 11 subtypes: A, B, C, D, E, F, G, H, I, J and K. In addition, multiple recombinants have been identified in recent years. HIV-2 is biologically similar to HIV-1, but features lower infectivity, slower AIDS clinical progression and milder symptoms. HIV-2 has at least 7 subtypes: A, B, C, D, E, F and G. HIV-1 is the major epidemic strain in China. Eight subtypes have been identified in the country, including A, B (Europe and US B), B’ (Thailand B), C, D, E, F and G, in addition to different recombinants.3 A few PLWHAs with HIV-2 have been reported and confirmed since 1999 in China. Timely identification and confirmation of various HIV subtypes is important for estimation of prevalence trends, diagnosis as well as development of new reagents, medicines and vaccines. HIV enters cells via receptors on the surface of susceptible cells.4 Receptors include receptor type 1 (CD4, major receptor) and receptor type 2 (auxiliary receptors of CCR5 and CXCR4, etc).5 Based on the utilization of auxiliary receptors by HIV, HIV is classified into X4 HIV and R5 HIV. R5 usually utilizes CCR5 receptor only, while X4 often utilizes CXCR4, CCR5 and CCR3 receptors simultaneously, and sometimes utilizes CCR2b receptor. HIV is a fragile virus and is not able to survive long outside the body. It is easily destroyed by many physical and chemical factors. Therefore, antisepsis and inactivation methods effective for HBV are also applicable for HIV. Besides, 75% alcohol can inactivate HIV, while ultraviolet or γ-ray cannot. HIV is also very sensitive to temperature. It is more tolerant to low temperature than to high temperature. HIV in vitro will lose infectivity to T lymphocyte at 56°C for 30 minutes; this method, however, cannot completely inactivate HIV in serum. HIV can be completely inactivated at 100°C for 20 minutes.6 LABORATORY TESTS HIV laboratory tests include those for HIV antibody, quantative plasma HIV RNA (viral load), CD4+ T lymphocyte and P24 antigen assay, etc. HIV1/2 antibody test is the “golden standard” for diagnosis of HIV infection. Viral load assays and CD4+ T lymphocyte counts are two important predictors for disease progression, response to ART and prognosis. Infants under 18 months can be diagnosed by a nucleic acid test; one needs two positive nucleic acid tests to confirm a diagnosis of HIV infection. A positive HIV antibody test after 18 months confirms HIV infection. HIV1/2 antibody test It is a screening (including primary screening and retest) and confirmatory test. HIV1/2 antibody screening tests include enzyme linked immunosorbent assay (ELISA) and rapid tests (rapid test paper and gelatin particle agglutination test). ELISA is the commonly used antibody screening test. Along with the development of voluntary counseling and testing, however, rapid tests can be used. Western blot is commonly used as the HIV antibody confirmatory test. A negative HIV1/2 antibody screening test should be reported as indicating that there is no HIV infection. On the other hand, a positive screening test does not necessarily indicate that the person is infected. Such a result should be followed by a confirmatory test. The report should therefore read “HIV antibody to be confirmed”. If the confirmatory test is positive, the result can now be reported as “positive HIV-1 (or HIV-2) antibody” meaning that the person is infected with HIV. The giving of HIV1/2 antibody results should always be accompanied by confidential counseling. Viral load assays Plasma viral load is generally represented by the copies of HIV RNAs per milliliter of plasma (c/ml). Commercially available assay for viral load include reverse-transcription polymerase chain reaction (RT-PCR), nucleic acid sequence-based amplification (NASBA NucliSens) and branched DNA (bDNA) signal amplification system. Different viral load tests are compared in Table 1.Table 1: Comparison of assay methods for viral loadClinical significance of viral load assay: prediction of the disease progression, indications for starting antiretroviral therapy, evaluation of treatment efficacy, guidance for change of regimen, or reference indicator for early diagnosis of acute HIV infection. CD4+ T lymphocyte assays CD4+ T lymphocytes are the primary target cells of HIV infection. After HIV infects a person a progressive loss of CD4+ T lymphocytes occurs resulting in an inverted ratio of CD4+/CD8+ T cells. If HAART is provided, varying degrees of increase of CD4+ T lymphocytes may be seen at different stages. The CD4+ T lymphocyte subgroup test commonly used is flow cytometry, which can directly generate an absolute value of the CD4+ T lymphocyte count. Alternatively, the absolute number of CD4+ T lymphocytes can be derived from WBC differential count. If flowcytometry is not available, absolute number of lymphocytes can be referred to. Clinical significance of CD4+ T lymphocyte count: understanding the immune status of a person who is infected, monitoring disease progression, assisting with disease staging, and when to start therapy as well as, determining clinical efficacy and the likelihood of occurrence of complications such as OIs and malignancies. Intervals of CD4+ T lymphocyte count testing should be decided by clinicians based on the conditions of patients. Generally, it is recommended that asymptomatic HIV-infected patients with CD4+ T lymphocyte count > 350×106/L receive such test once per year; PLWHAs with (200-350) × 106/L CD4+ T lymphocyte count who are not already on ART should have a CD4 test biannually; PLWHAs on ART should have a CD4 test quarterly in the first year of treatment. Beyond one year treatment if conditions are stable, they can have the test biannually. PATHOGENESIS HIV infection process Primary infection HIV enters cells via receptors (receptor type 1 and receptor type 2) on the surface of susceptible cells. The envelope glycoprotein of HIV-1, gp120 binds first to receptor type 1, and then receptor type 2, inducing a conformational change in gp120 that exposes the fusion protein gp41, leading to viral fusion with the host cell membrane and HIV entry into body cells. After its entry into human body, HIV will reach the regional lymph node within 24—48 hours; viral particles can be detected in peripheral blood in about five days. This is followed by viremia, leading to acute infection. HIV infection process in human CD4+ cells7 Adhesion and penetration: As stated above, after infection of human body, HIV-1 selectively adheres to the CD4 receptor type 1 of the target cell, and enters the cell under the assistance of a helper receptor, i.e., receptor type 2. Cyclization and integration: Viral RNA is converted to cDNA under the action of reverse transcriptase which in turn is converted to a non-covalent binding double-stranded DNA under the action of DNA polymerase. Under the action of integrase, the newly formed non-covalent binding double-stranded DNA is integrated into the host cell's chromosome DNA. The integrated viral double-stranded DNA is also called a “provirus”. Transcription and translation: When provirus is activated to undergo self transcription, viral DNA is transcribed to form RNA; some RNAs are capped to become progeny genome RNA; some other RNAs are spliced to become viral mRNAs, and translated into structural protein and nonstructural protein of virus on a cell ribosome. The synthesized viral proteins undergo saccharification and processing on endoplasmic reticulum ribosome, and are cleaved under the action of protease, resulting in proteins and enzymes of progeny virus. Assembly, maturation and budding: Gag protein is bound and assembled with viral RNA to form nucleocapsid; the envelope of virion is obtained from the release of cytoplasmic membrane during budding, generating mature viral particles. Three clinical outcomes following HIV infection Since the immune system of human body is not able to completely clear HIV, chronic infection develops. This is manifested clinically by one of the following outcomes: typical progression, rapid progression or long-term non-progression. Major factors which influence clinical outcomes of HIV infection include viral factors, host immune status and genetic background, etc. Immune response to HIV infection Immune responses to HIV include specific immune responses and nonspecific immune responses. Specific immune responses are the major responses. Specific humoral immunity: 2 — 12 weeks after HIV enters human body, the immune system generates a variety of specific antibodies to HIV protein, among which only the neutral antibodies have antivirus effects. Specific cellular immunity: mainly includes specific CD4+ T lymphocyte immune response and specific cytotoxic T lymphocyte (CTL) response. As the central cells of the immune system, CD4+ T lymphocytes play an important role in the specific immune response. They excrete various cytokines, inducing B cells to generate antibody to HIV, promoting generation and maturation of specific CTLs against HIV, and activating macrophages and NK cells. CD8+ T lymphocytes are effector cells of specific cellular immunity, suppressing viral replication directly via various cytokines (such as tumor necrosis factor, interferon, etc) or by excreting cytokines. Immunopathology Decrease in CD4+ T lymphocyte count When the body is infected with HIV, CD4+ T lymphocyte count will continuously decrease. The acute infection stage is characterized by a transient and rapid decrease of CD4+ T lymphocyte count within a short period of time; CD4+ T lymphocyte counts in most PLWHAs can automatically recover to the normal level or near normal level even without any specific treatment. The asymptomatic infection stage is characterized by a slow and constant decrease in CD4+ T lymphocyte counts. The number of CD4+ T lymphocytes is usually between (800—350)×106/L. This period varies significantly in duration (ranging from several months to more than ten years), with the average duration of about 8 years. In the symptomatic stage, CD4+ T lymphocytes again rapidly decrease; the CD4 T-lymphocyte counts in most PLWHAs go below 350 ×106/L; in late stage, CD4+ T lymphocyte counts in some patients even go below 200 × 106/L and continue to drop rapidly. The decrease in CD4+ T lymphocyte count may be due to one or more of the following factors: CD4+ T lymphocyte destruction by the virus; reduced generation of CD4+ T lymphocytes; lymphatic tissue with holding of CD4+ T lymphocytes from peripheral blood. CD4+ T lymphocyte dysfunction This is manifested mainly by one or more of the following: T-helper cells 1 (Th1) switched to T-helper cells 2 (Th2); antigen presenting cell dysfunction; decrease in production of interleukin-2; and then loss of immune function to antigen reaction, resulting in susceptivity of PLWHA to various infections. Exceptional immune activation Another immune pathological change after HIV infection is the exceptional activation of immune system, which is manifested in the abnormal increase in proportion of CD4+ and CD8+ T lymphocytes expressing immune activation markers (CD69, CD38 and HLA-DR, etc). This proportion is positively correlated with HIV plasma viral load. In addition, along with disease progression, cell activation level is also constantly increasing. Therefore, exceptional immune activation status can not only indicate change of plasma viral load, but also predict the speed of decrease in CD4+ T lymphocytes. Immune reconstitution A major progress in the HIV/AIDS research arena in the recent years is the proven finding that HAART can lead to immune reconstitution in AIDS patients.8 Immune reconstitution in AIDS patients can be defined as the return to normal or nearly normal status of the changes in the immune system caused by HIV (and as described above) in a patient receiving HAART. Specifically: 1) the CD4+ T lymphocyte count comes back to normal; 2) CD4+ T lymphocyte function also returns to normal with the restored ability to react to memory antigen stimulation; 3) abnormal immune activation in patient recovers. As the immune system recovers, the following also happens: a decreased incidence of OIs and cancers related to HIV/AIDS, decreased mortality rate and a decreased occurrence of late stage disease PLWHA. Nevertheless, HAART also has its own limitations in terms of HIV/AIDS immune reconstitution: 1) HAART may not result in immune reconstitution in a few AIDS patients; 2) HAART cannot reconstitute CD4+ T lymphocyte specific immune response against HIV, while CD8+ T lymphocyte specific anti-HIV capacity also decreases, meaning that patients need to be on long-term maintenance medication. PATHOLOGICAL CHANGES9 AIDS can affect many organs of the body. Categories of clinical pathological changes caused by AIDS include immune system, multisystem OIs (including protozoa, virus, bacteria and fungus) and cancers (including Kaposi's sarcoma, malignant lymphoma and cervical cancer). Common OIs and cancers Pneumocystis P. carinii principally causes pneumonia (PCP). Typically, both lungs show diffuse involvement, consolidation, increased weight and dramatic loss of alveoli air spaces. After formalin fixation, the lung tissue shows a coarse and sponge-like appearance with the alveolar cavities filled with a red-colored, cell-free and foam-like exudate. This finding is characteristic and called cancellate exudate. Alveolar epithelium proliferates into a cube shape cysts. The cysts are found in clusters in the cavity exudates. Gram and Giemsa stains help to display sporozoites, and the Giemsa stain clearly reveals the cysts. [Note that P. carinii has been renamed P. jiroveci but the eponym PCP is retained (Emerg Infect Dis 2002; 8: 891-896.)] Toxoplasmosis Although disseminated toxoplasmosis may involve the eyes, lungs, heart and digestive tracts, toxoplasmic encephalitis is most common. The lesion may be localized or diffuse, causing abscesses commonly in the basal ganglia or the cerebellum cortex, and even in the subarachnoid space. The uniqueness of this kind of abscess is revealed by enhanced CT imaging and is characterized by one or many cyst-like ringed lesions in gray matter. Some parts of brain have coagulative hemorrhagic necrotic lesions inside in which a small amount of toxoplasma can be found. The area of necrosis is surrounded by a cyst-forming belt that is made from congestion and vascular endothelial proliferation. The belt is heavily infiltrated by inflammatory materials, a large amount of toxoplasma tachyzoites and bradyzoite-containing pseudocysts. Tachyzoites in the brain are different from those in other tissues, which appear round or elliptical rather than crescent in shape. Sections from tissues other than the brain have tachyzoites that can be clearly observed through HE staining in which tachyzoites are 2—3 μm crescents and cysts or pseudocysts measuring 50 μm. In addition, a rise in the serum antibody titer is indicative of toxoplasma infection. Candidiasis Recurrent candidiasis is the most common fungal opportunistic infection in AIDS patients. For those patients with stomatic infection, the surface of their tongues shows diffuse white patches due to a layer of exudates. In some cases the exudates may appear as a thick black cover. In adults oropharyngeal candidiasis indicates that the HIV infected person has entered the stage of AIDS. Any part of the digestive tract can be involved and the esophagus is the most frequently affected. A grey pseudomembrane with irregular ulcerations may appear on the mucosal surface. The pseudomembrane consists of fibrins and necrotic materials in which a net-like pseudohyphae may be present. Disseminated candidiasis may involve many organs including the kidney (80%), brain (50%) and heart (58%), forming multiple abscesses. With histological exam C. albicans is characterized by yeast-like spores or budding spores (3—4 μm in diameter, round or oval shaped) and pseudohyphae (spores on a string). Mycobacterium infections AIDS patients often suffer from mycobacterium infections including Mycobacterium tuberculosis and Mycobacterium avium infections. Tuberculosis can usually occur at any stage of HIV infection, from early to late. Extrapulmonary tuberculosis is common and is often invasive. Under the microscope, the tuberculous granuloma of AIDS patients is atypical with striking necrotic caseation. Epithelioid cells and giant cells are rare. Tuberculosis is often exudative, with consolidation of air cavities filled with fibrin, neutrophils and histiocytes. Massive necrosis and large amounts of acid-fast bacilli are often found. Mycobacterium avium infection may present in the late stages of AIDS, usually when the CD4+ T lymphocyte count is less than 100×106/L, causing disseminated infections. Sometimes, millet-seed-like granulomas may be present on sections of the spleen, liver, lymph nodes, heart and kidneys. Under the microscope, usual structures are replaced by histiocyte clusters, which are highly swollen, strip or foam-like, and cytoplasm, which is yellow or blue stained. The nucleus is heavily dyed and giant cells are rare. Necrosis is rare or does not exist. There is no calcification or fibrosis. Acid-fast stains show swollen macrophages filled with large amounts of Mycobacterium avium. Cytomegalovirus (CMV) infection CMV infection in AIDS patients may cause gastrointestinal ulcerations, interstitial pneumonitis, glomerulonephritis and retinitis. CMV infections may also involve parts of the brain and spinal cord, including the spinal nerve root and cranial nerves. Autopsies show that the adrenal gland and respiratory system are most frequently involved. Under the microscope, some giant cells are present and sharp-demarcated inclusion bodies clearly appear in the nucleus and cytoplasm. The inclusion body in CMV infection is the largest among all viruses that are able to infect humans and can be present in both the nucleus and cytoplasm. The inclusion body may be: 1) a double-stain inclusion body in the nucleus, which is surrounded by a transparent halo, mimicking an owl's eye; 2) a double-stain or eosinophilic inclusion body in the cytoplasm; 3) a universally seen inclusion body in epithelial cells, endothelial cells, macrophages and smooth muscle cells. Immunohistochemistry, DNA in situ hybridization and PCR help to confirm diagnosis. Kaposi's sarcoma Kaposi's sarcoma is a common tumor of AIDS patients. Epidemic Kaposi's sarcoma and AIDS-associated Kaposi's sarcoma are different from other sarcomas: 1) male homosexuals or bisexuals are major victims, but this kind of sarcoma is also present in IDUs; 2) lesions are concentric and spread with time, involving not only the skin but visceral organs (75%). In falling frequency the following organs are involved: lung, lymph node, digestive tract, liver, urogenital tract, adrenal gland, heart and spleen. Kaposi's sarcoma in skin is a red or purple, flat spot/patch in the early stage later developing into a raised lesion which later becomes nodular. Erosion and ulceration may occur. Kaposi's sarcoma lesions are comprised of vascular spindle cells with vessel like fissures. Red blood cells can be seen in the fissures. Cells of sarcoma have characteristics of endothelial cells and smooth muscle cells. HSV-8 may be associated with occurrence of Kaposi's sarcoma. Pathological changes in immune system HIV associated lymphadenopathy HIV associated lymphadenopathy falls into four categories: follicular hyperplasia without lysed follicles, follicular hyperplasia with lysed follicles, follicle degeneration and follicle depletion. Before the onset of AIDS, persistent generalized lymphadeno-pathy may occur. Enlarged lymph nodes are usually smaller than 3 cm, and follicular enlargement is more common before the onset of AIDS. Some AIDS patients experienced shrunken lymph nodes where lymphadenopathy manifests as follicle degeneration and depletion. Pathological changes in the spleen Spleen enlargement is common in AIDS patients. An HIV infected adult with a spleen heavier than 400 g suggests the occurrence of OIs and cancers in the spleen. The most striking change in the spleen of AIDS patients is the high depletion of lymphocytes leaving only a small amount of or even no white pulp. Splenomegaly in children is characterized by significant depletion of lymphocytes and phagocytosis of erythrocytes. About 50% of cases may present with Kaposi-like changes. Pathological changes in the thymus There are no obvious pathological changes in the thymus of adult AIDS patients, but B cell follicles may proliferate. On the other hand, pediatric AIDS patients may experience abnormal early degeneration. HIV may impair the epithelium of the thymus causing atrophy and depletion of lymph tissues. Infiltration of plasma cells and, formation of multinuclear giant cells and thymus corpuscles cysts can be seen. Pathological changes in bone marrow In the early stages, three-fourths of the cases reveal bone marrow cell proliferation primarily of granulocytes and megakaryocytes. In late stages as the disease progresses, bone marrow cells decrease, and immature, ill-developed promyecytes and lymphoid cells cluster. Other changes include atypical megakaryocytes, fine net-like sclerosis, slight proliferation of blood vessels and histiocytes, and deposits of hemosiderin. CLINICAL PRESENTATION AND STAGING HIV disease progression is a long, complex process from initial infection to end stage disease. In the various stages of disease progression, there are many different clinical presentations.10 The Diagnostic criteria and management principles of HIV/AIDS (For trial implementation, national standard of the People's Republic of China, GB 16000-1995) defines a staging system for HIV infection and disease which divides HIV disease progression into three stages: acute infection, asymptomatic infection and symptomatic infection including AIDS.11 Acute infection Acute infection usually occurs within 2—4 weeks after infection by the HIV virus. Some HIV infected persons may show clinical symptoms caused by viremia and acute damage of the immune system. Clinical symptoms are mild and improved after 1—3 weeks in most patients. Fever is the most common clinical presentation, but sore throat, night sweats, nausea, vomiting, diarrhoea, rash, arthralgia, lymphadenopathy and neurological symptoms can be present as well. During this period, HIV-RNA and P24 antigen tests can detect HIV in the blood, while the HIV antibody can only be detected several weeks after infection. Profound reductions occur in CD4+ T lymphocyte count along with inversion of the CD4/CD8 ratio. Some patients may show mild leukopenia, thrombocytopenia or liver function abnormalities. Asymptomatic infection Following the stage of acute infection, regardless of detectible or undetectable symptoms, patients enter a stage of asymptomatic infection. This stage generally lasts 6—8 years, with variation caused by the viral load, strain of the virus, individual immunological status, nutritional conditions, lifestyle and other factors. The high rate of HIV replication eventually makes the virus infectious, compromises the immune system, and leads to the gradual decline of the CD4+ T lymphocyte count. Symptomatic infection including AIDS Following the asymptomatic period, the CD4+ T lymphocyte count declines significantly and may go below 200×106/L. The plasma viral load (RNA) level elevates markedly. Major clinical presentations include HIV-rel