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Consensus and Guideline

Chinese Guidelines for the Diagnosis and Treatment of HIV/AIDS (2021 Edition)

Editor(s): Zhao, Wei

Author Information
Infectious Diseases & Immunity: July 2022 - Volume 2 - Issue 3 - p 145-167
doi: 10.1097/ID9.0000000000000044
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Abstract

Introduction

Acquired immunodeficiency syndrome (AIDS) is an important public health problem in China. The first edition of the guidelines for the diagnosis and treatment of AIDS was formulated in 2005 by the AIDS Professional Group of Society of Infectious Diseases of the Chinese Medical Association. The guidelines were updated in 2011, 2015, and 2018.[1] The 2021 edition of the guidelines is revised on the basis of the fourth edition and updated according to the national clinical practice and the latest research results.

Epidemiology

Current status

The Joint United Nations Programme on HIV/AIDS estimated that 37.7 million people were living with HIV/AIDS (PLWHA) globally by the end of 2020, with 1.5 million new HIV infections in the same year and 27.5 million patients on ART (commonly known as the “AIDS cocktail”).[2] On June 8, 2021, the United Nations revealed its “Political Declaration toward ending the AIDS epidemic by 2030,” which included intentions to prioritize HIV prevention and to ensure that effective and comprehensive HIV prevention programs will cover 95% of people at risk of

HIV infection by 2025, that the 95-95-95 goals will be achieved by 2030 (ie, 95% diagnosed among all people living with HIV infection, 95% on antiretroviral therapy [ART] among those diagnosed, and 95% virally suppressed among those treated), that mother-to-child transmission of HIV will be eliminated by 2025, that annual new HIV infections and annual AIDS-related deaths will be reduced to under 370,000 and 250,000, respectively, and that all forms of HIV-related stigma and discrimination will be eliminated by 2025 toward the goal of ending the AIDS epidemic by 2030.[3]

Source of infection

PLWHA: HIV presents predominantly in the body fluids of PLWHA, including the blood, semen, vaginal secretions, pleural effusions, ascites, cerebrospinal fluid, amniotic fluid, breast milk, and others.

Routes of HIV infection and transmission

HIV transmission occurs through sexual contact (including unprotected homosexual, heterosexual, and bi-sexual contact), blood or blood products (such as via intravenous drug use with needle sharing, unsafe and substandard invasive medical operations, or tattoos), and mother-to-child (including intrauterine transmission, intrapartum transmission, and transmission through breastfeeding).

Vulnerable populations: Men who have sex with men (MSM), intravenous drug users, individuals who have sexual contact with those with HIV infection/AIDS, individuals with multiple sex partners, and those contracting sexually transmitted infections are at high risk of acquiring HIV.

Case reporting

HIV Voluntary Counseling and Testing has been implemented. Newly diagnosed HIV/AIDS cases should be immediately reported to the local Center for Disease Control and Prevention following the Law of the People's Republic of China on the Prevention and Treatment of Infectious Diseases. Corresponding measures should be taken to manage the reported cases under the guidelines set for class B infectious diseases.

Medical management

Follow the principle of confidentiality and take whole-course management measures, including the following: strengthening follow-up of PLWHA; providing timely, standardized, and comprehensive treatment, including ART and symptomatic supportive care; and providing necessary medical and psychological counseling (including education and measures regarding the prevention of HIV transmission from patients with HIV infection/AIDS).

Precautions

Individuals should use condoms correctly and engage in safer sex; refrain from drug use and needle and syringe sharing. Moreover, non-commercial blood donation should be promoted, with HIV screening among blood donors. Hospital management should be reinforced to strictly follow disinfection procedures and control nosocomial cross infections. Infections via occupational exposure should be prevented. Mother-to-child transmission should be controlled. Medical examinations, HIV testing, and appropriate counseling services should be provided to spouses and sex partners of PLWHA, children of PLWHA, and intravenous drug addicts with whom PLWHA share needles and syringes. People at high risk of acquiring HIV infection should receive antiviral drugs for pre-exposure prophylaxis (PrEP) and post-exposure prophylaxis (PEP) after providing written informed consent and ensuring high compliance.

Pathogenic features

HIV is a human lentivirus belonging to the lentivirus genus and Retroviridae family. The spherical virus is 100 to 120 nm in diameter. It comprises an interior viral core and outer viral envelope. The viral core is formed by the capsid protein (p24) containing two identical single positive strands of HIV RNA; nucleocapsid protein; and enzymes necessary for viral replication, including reverse transcriptase (p51/p66), integrase (p32), and protease (p10). The exterior coat of HIV is the viral envelope comprising a phospholipid bilayer originating from the cell membrane of the host cell, embedded envelope glycoprotein gp120, and transmembrane glycoprotein gp41. The viral matrix protein underlies the enveloped virion (MA, p17) to form the inner shell of the virus.

HIV is classified into two types: HIV-1 and HIV-2. The HIV genome is approximately 9.7 kb. Long terminal repeats are situated at each end of the genome and are involved in the regulation of HIV gene integration and expression, as well as viral replication. The HIV genome contains three structural genes (gag, pol, and env), two regulatory genes (tat [trans-activator of transcription] and rev [regulator of expression of virion proteins]), and four auxiliary genes (nef [negative regulatory factor], vpr [viral protein r], vpu [viral protein u], and vif [viral infectivity factor] in HIV-1) among which vpu is unique to HIV-1 and vpx is unique to HIV-2.

HIV is highly variable, with env ranking first among variable genes. The major contributors to this variability include random variation resulting from the lack of proofreading ability in reverse transcriptases, a high viral replication rate within the host body, host immunoselection, gene recombination between viral DNA and host DNA, and drug selective pressure. Nonstandard ART and poor adherence to ART are the major contributing factors for drug resistance.

HIV-1 is the major epidemic strain in China. Ten subtypes have been identified in the country, including A, B (Europe and US B), B’ (Thailand B), C, D, F, G, H, J, and K, in addition to different circulating recombinant forms (CRFs) and unique recombinant forms.[4] The results from the fourth nationwide HIV molecular epidemiologic survey in 2015 showed that CRF07_BC, CRF01_AE, CRF08_BC, and subtype B are the main HIV-1 subtypes circulating in China.[5] The HIV-2 subtype is mainly concentrated in West Africa and has not yet spread worldwide; however, several PLWHA with HIV-2 infection have been identified since 1999 in parts of China followed by reports of imported HIV-2 cases in multiple regions, which deserve closer attention.[6]

The main receptors involved in HIV-1 entry into host cells are CD4 molecules expressed on the surface of T lymphocytes, mononuclear macrophages, and dendritic cells. HIV enters cells via receptors on the surface of these susceptible cells. The receptors include receptor type 1 (CD4, major receptor) and receptor type 2 (auxiliary receptors of CCR5 and CXCR4, among others). Based on the utilization of auxiliary receptors by HIV, HIV is classified as X4 HIV and R5 HIV. R5 usually utilizes the CCR5 receptor alone, while X4 often utilizes the CXCR4, CCR5, and CCR3 receptors simultaneously. CCR5 and CXCR4 are differentially expressed in some T cell subsets: naive T lymphocytes (CD45RA) memory T lymphocytes express high levels of CXCR4, CCR5, while memory T lymphocytes (CD45RO) express high levels of CCR5. Macrophages and dendritic cells also express high levels of CCR5. In the early and late stages of HIV infection, HIV usually utilizes CCR5 and CXCR4, respectively, as auxiliary receptors.

The process of HIV infection in human cells is as follows: (1) Adsorption, membrane fusion, and penetration: After HIV-1 infects the human body, it selectively attaches to the CD4 receptor of the target cell and enters the host cell with the help of auxiliary receptors. (2) Reverse transcription, nuclear entry, and integration: In the cytoplasm, reverse transcriptase converts the viral RNA genome into complementary DNA (cDNA) molecules that are synthesized by DNA polymerase to produce linear double-stranded DNA. This DNA is then integrated into the chromosomal DNA of the host cell (a process mediated by integrase) after it enters the cell nucleus. The viral DNA integrated into the host DNA is referred to as a “provirus.” (3) Transcription and translation: The activation and transcription of provirus mediated by cellular RNA polymerase produce RNA transcripts. Some of these RNA transcripts are subject to cap and tail additions to form the progeny viral RNA genomes; others are subject to splicing to form viral mRNAs that are translated by the nuclear proteasome into viral structural (Gag, Gag-Pol, and Env precursor protein) and various non-structural proteins. The synthesized viral proteins are then glycated and processed on ribosomes attached to the endoplasmic reticulum and cleaved under the action of protease, resulting in proteins and enzymes of progeny viruses. (4) Assembly, budding, and maturation: The process of virus assembly is complex and highly ordered. Gag and Gag-Pol precursor proteins and the virus's progeny RNA genomes are packaged on the inner surface of the cellular membrane, while gp120 and gp41 transported to the surface of the cellular membrane bind to the Gag and matrix protein as they bud from the membrane. Hence, the virions acquire their envelopes from the cellular membrane via budding to become independent virus particles. In the middle or late stage of budding, the viral protease cleaves the Gag and Gag-Pol precursor proteins in the virus particle into smaller viral proteins, including p17, p24, p7, and p6 (Gag) and reverse transcriptase, integrase, and protease (Pol). These viral proteins are then further combined with the viral progeny RNA genomes to produce mature infectious viral particles.

HIV is a fragile virus and is not able to survive long outside the host. It is easily destroyed by many physical and chemical factors. General-purpose disinfectants effective against the hepatitis B virus (HBV), including iodine tincture, peroxyacetic acid, glutaraldehyde, and sodium hypochlorite, also effectively inactivate HIV. While 70% alcohol can inactivate HIV, ultraviolet light and γ-rays cannot. HIV is also very sensitive to temperature, although it is more tolerant of low than high temperatures. HIV in vitro loses T lymphocyte infectivity within 20 min at 56°C; however, this method cannot completely inactivate HIV in serum. HIV can be completely inactivated at 100°C for 20 min.

Laboratory tests[7]

The laboratory tests for HIV/AIDS mainly include HIV antibody tests, HIV RNA nucleic acid tests (qualitative and quantitative), CD4+ T lymphocyte count, HIV drug resistance tests, and others. The HIV-1/2 antibody test is the “golden standard” for the diagnosis of HIV infection; HIV RNA nucleic acid testing (qualitative and quantitative) is also used to diagnose HIV infection. The HIV antibody tests include screening tests and antibody confirmatory tests (intended to confirm the presence of antibodies). The HIV confirmatory tests detect antibodies and nucleic acids (qualitative and quantitative nucleic acid testing). HIV RNA nucleic acid quantitation and CD4+ T lymphocyte count are two important indicators of disease progression, clinical use of medications, efficacy, and prognosis. Finally, HIV drug resistance testing can provide references for the selection and changes in ART regimens.

HIV-1/2 antibody tests

The HIV-1/2 antibody tests include screening and confirmatory tests. The HIV-1/2 antibody screening tests include enzymelinked immunosorbent assay (ELISA), chemiluminescent or immunofluorescence assays, rapid tests (Dot-ELISA and dot immunocolloidal gold technique or electroselenium method, immunochromatography, and others), simple tests (gelatin particle agglutination test), and others. The HIV antibody confirmatory tests, including immunoblotting, line/linear immunoassays, and rapid tests, are intended to confirm the presence of antibodies.

Negative screening test Results: are reported as “negative for HIV-1/2 antibody,” meaning that the person is not infected with HIV; however, during the window period, patients with HIV infection might also receive negative screening test results. If the screening test is positive, two copies (rapid) /two spots of the original reagent (chemiluminescent assay or enzyme-linked immunoassay) or two different reagents should be used for repeated tests. If both tests are negative, the report should read “negative for HIV antibody”; if the two tests produce a negative result and a positive result or if both tests are positive, a confirmatory test should be performed.

Confirmatory test of antibodies: Antibody confirmatory tests without HIV-specific bands are reported as “negative for HIV-1/ 2 antibody.” If HIV-specific bands appear but the diagnostic criteria are not satisfied, the results are reported as “HIV antibody to be confirmed”, followed by nucleic acid testing or follow-up visits in 2 to 4 weeks to determine the presence of HIV antibodies based on the results of nucleic acid or follow-up tests. Confirmatory tests of HIV-1/2 antibodies with positive results are reported as “positive HIV-1/2 antibody confirmed”.

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 lymphocytes and impaired cellular immune function.

Flow cytometry is commonly used to assess CD4+ T lymphocyte subgroups. This method can directly provide an absolute value of the CD4+ T lymphocyte count. Alternatively, the absolute number of CD4+ T lymphocytes can be derived from white blood cell differential counts. The clinical significance of CD4+ T lymphocyte count includes determining the immune status, monitoring disease progression, assisting with disease staging, and determining treatment efficacy and the occurrence of clinical complications in individuals with HIV infection.

Frequency of CD4+ T lymphocyte count testing: The intervals at which CD4+ T lymphocyte counts are assessed should be decided by clinicians based on the specific conditions of patients. CD4+ T lymphocyte counts should be performed once before treatment, once 3 months after treatment initiation, and every 3 to 6 months within the first 2 years after treatment (patients with HIV infection with CD4+ T lymphocyte counts of <200–300/μL at baseline are recommended to be tested once every 3 months, while those with counts >300/μL at baseline should undergo testing once every 6 months). Beyond 2 years of treatment, patients with CD4+ T lymphocyte count of 300 to 500/μL whose HIV infections are fully suppressed by ART are recommended to undergo testing once every 12 months, while those with counts > 500/μL can undergo testing depending on their choice. In cases with delayed ART initiation, changes in drug regimen due to ART failure and viral loads >200 copies/mL in repeated tests in the treatment process are recommended to be tested once every 3 to 6 months. Testing should be performed at regular intervals in patients experiencing virological breakthrough, AIDS-related clinical symptoms, or receiving therapies that may reduce CD4+ T lymphocyte counts, based on the patient's clinical condition.

The inverted CD4+/CD8+ T lymphocyte ratio can be improved to varying degrees with the prolonged use of ART. Changes in the inverted ratio are closely associated with the timing of treatment initiation and basal CD4+T lymphocyte counts, suggesting the treatment efficacy and patient's immune-inflammatory status.[8]

HIV nucleic acid testing

After a person is infected with HIV, the virus quickly replicates in the body and HIV RNA viral load can be quantitatively detected in the host plasma. Plasma viral load is generally represented by the copies of HIV RNAs per milliliter of plasma (copies/mL) or international units (IU/mL). A viral load below the lower limit of detection suggests that the virus was not detected by the test, a finding that occurs in persons not infected with HIV, patients experiencing ART success, or some individuals infected with HIV who can effectively suppress viral replication without treatment.

A viral load above the lower limit of detection indicates that the virus has been detected by the test. Further diagnosis can be established based on the patient's epidemiologic history, clinical symptoms, and the results of preliminary HIV antibody screening.

The commonly used assays for viral load include reverse transcription-polymerase chain reaction (PCR), nucleic acid sequence-based amplification, and real-time fluorescence-based quantitative PCR amplification (real-time PCR). The clinical significance of viral load assay includes the prediction of disease progression, evaluation of ART efficacy, and guidance on changes of ART regimen; moreover, the results can be used as a reference indicator for the diagnosis of HIV infection, including patients in the acute phase/window period or late-stage of HIV infection and infants aged <18 months.

Nucleic acid testing methods (qualitative and quantitative)

As a type of HIV test, nucleic acid testing is a confirmatory test of the presence of viral nucleic acids. A positive qualitative nucleic acid test should be reported as “positive for HIV-1 nucleic acid,” while a negative result should be reported as “negative for HIV-1 nucleic acid.” A viral load result below the lower limit of detection should be reported as “below the lower limit of detection”; if the viral load result is >5000 copies/mL, the detected level of viral load should be reported. If the viral load is above the lower limit of detection but ≤5000 copies/mL, resampling and retesting are recommended. Clinicians can confirm or rule out HIV infection based on the patient's epidemiologic history, clinical manifestations, CD4+ and CD8+T lymphocyte counts, or the results of follow-up HIV antibody tests.

Frequency of viral load assays

Viral load testing should be performed once before ART initiation. If ART is not initiated promptly, regular testing of viral loads is recommended. After initial treatment, the first viral load testing is recommended to occur approximately 4 weeks after treatment initiation, followed by repeated testing once every 3 months until full viral suppression is achieved. Within the first 2 years after treatment initiation, viral load testing is recommended to be performed once every 3 to 4 months. Beyond 2 years of treatment, the testing should be performed once every 6 months in cases with stable viral suppression. If the treatment regimen is changed due to ART failure, the first testing is suggested to be conducted in the fourth week after regimen change, followed by repeated testing once every 3 months until the virus is suppressed. For virally suppressed patients who switch their ART regimen due to drug toxicity or medication regimen simplification, viral load assays should be performed in the fourth week after regimen change to confirm viral suppression. If the viral load is >200 copies/mL during treatment, repeated testing once every 3 months is recommended. For patients with newly developed AIDS-related clinical symptoms or patients receiving glucocorticoid or antitumor chemotherapeutic agents, nucleic acid testing should be performed once every 3 months.

HIV genotypic resistance testing

The results of HIV drug resistance testing can provide a reference for ART regimen prescription and adjustment. The occurrence of HIV drug resistance suggests the presence of a drug-resistant HIV strain. Comprehensive and adequate consideration should be given to drug resistance test results, clinical conditions, and patient compliance to evaluate factors, including drug tolerance, drug absorption, and drug metabolism. Changes to the ART regimen should be made under the guidance of experienced physicians. A negative HIV drug resistance test indicates that drug resistance is not detected in the tested specimen, but does not necessarily indicate that the tested person is not infected with drug-resistant strains.

Drug resistance testing includes genotypic and phenotypic assays. Globally, the most predominantly used methods are genotypic assays. Compared with phenotypic assays, genotypic assays feature lower cost, more rapid turnaround time, and greater sensitivity for detecting mixtures of wild-type and resistant viruses. HIV genotypic resistance testing is performed before ART initiation and when the treatment regimen needs to be changed due to unsatisfactory reduction in viral load or virologic failure after treatment. For patients experiencing ART failure, drug-resistance testing should be performed when the patient is still receiving antiviral medications; if antiviral medications have been discontinued, the test should be performed within 4 weeks after discontinuation.

Pathogenesis

HIV primarily invades the human body's immune system, including CD4+T lymphocytes, mononuclear macrophages, and dendritic cells, and is manifested primarily by a constant decrease in CD4+ T lymphocyte counts. The disease eventually leads to cellular immune defects in the human body, which contributes to the occurrence of various opportunistic infections and tumors. HIV infection also increases the risk of cardiovascular diseases (CVDs), bone diseases, nephropathy, hepatic insufficiency, and others.

After HIV enters the human body, it reaches regional lymph nodes within 24 to 48 hours and viral components can be detected in the peripheral blood in approximately 5 to 10 days. This is followed by viremia, leading to acute infection characterized by a transient and rapid drop in CD4+T lymphocyte count within a short time. CD4+ T lymphocyte counts in most PLWHA can automatically recover to normal or near-normal levels even without specific treatment. Since the host immune system cannot completely clear HIV due to the presence of viral reservoirs, chronic infection, including asymptomatic and symptomatic stages of infection, develops. Globally, the asymptomatic phase has an average duration of approximately 8 years; however, in China, HIV infection progresses faster in male homosexuals, with a mean time from initial infection to the development of AIDS of 4.8 years.[9] The asymptomatic infection stage is mainly characterized by a slow and constant decrease in CD4+ T lymphocyte counts; in the symptomatic stage, CD4+ T lymphocytes again rapidly decrease. The CD4+ T lymphocyte counts in most PLWHA go below 350/μL and may drop to below 200/μL in some patients with late-stage disease. HIV infection induces decreases in CD4+ T lymphocyte count due to apoptosis and pyroptosis of CD4+T lymphocytes by HIV; direct destruction of CD4+ T lymphocytes caused by HIV replication, including changes in cellular membrane integrity during HIV budding; indirect destruction of CD4+ T lymphocytes caused by HIV replication, including the release of inflammatory factors or destruction by the immune system; and thymic atrophy and thymocyte death induced by HIV infection. Apart from a decrease in CD4+T lymphocyte count, the immunological abnormalities induced by HIV include dysfunction and abnormal immune activation of CD4+T lymphocytes, B lymphocytes, mononuclear macrophages, natural killer (NK) cells, and dendritic cells.

HIV infection manifests clinically by one of the following three outcomes: typical, rapid, or long-term slow progression. The major factors influencing the clinical outcomes of HIV infection include viral factors, host immune status, and genetic background.

The human body fights HIV infection via innate and adaptive immune responses. The mucous membranes are the main portals of invasion for HIV, sites of HIV replication, and important routes of sexual HIV transmission. HIV can also enter the body through damaged mucous membranes. Local innate immune cells, including mononuclear macrophages, dendritic cells, NK cells, and γδT cells, recognize, phagocytize, and kill invading HIV and present the viral antigens to the adaptive immune system. Within 2 to 12 weeks, the human body produces various specific antibodies against HIV proteins, of which broad-spectrum neutralizing antibodies play an important role in controlling viral replication.[10] Specific cellular immunity mainly includes HIV-specific CD4+ T lymphocyte immune response to HIV and specific cytotoxic T lymphocyte response to HIV.

In most patients with HIV infection/AIDS on ART, abnormal changes in the immune system caused by HIV can be restored to normal or nearly normal status; that is, immune reconstitution, including the recovery of CD4+ T lymphocyte count and immunologic functions. However, 10% to 40% of patients with HIV infection/AIDS do not achieve complete immune reconstitution despite prolonged and sustained suppression of viral replication. These patients are referred to as patients with poor immune reconstitution or immunological non-responders and show higher mortality rates and incidence of AIDS-related and non-AIDS-related illnesses[11] than patients achieving complete immune reconstitution.

Clinical presentation and staging

HIV disease progression is a long, complex process from initial infection to end-stage disease. The various stages of disease progression show different clinical presentations associated with HIV. HIV disease progression can be divided into three stages— acute infection, asymptomatic infection, and AIDS—based on the post-infection clinical manifestations.

Acute infection

Acute infection usually occurs within 6 months after infection by HIV. Some people with HIV infection show clinical symptoms caused by viremia and acute damage of the immune system during the acute phase. Fever is the most common clinical presentation, although sore throat, night sweats, nausea, vomiting, diarrhea, rash, arthralgia, lymphadenopathy, and neurological symptoms may also be present. The clinical symptoms are mild and improved after 1 to 3 weeks in most patients.

During this period, HIV-RNA and p24 antigen can be detected in the blood, with a transient drop in CD4+T lymphocyte count and inverted CD4+/CD8+ T lymphocyte ratio. Some patients show mild leukopenia, thrombocytopenia, or liver function abnormalities.

Asymptomatic infection

Following acute infection, regardless of detectable or undetectable symptoms, patients enter the asymptomatic infection stage. This stage generally lasts 4 to 8 years, with variation caused by the viral load; viral strain; infection routes; and individual patient differences in immunological status, nutritional conditions, lifestyle, and other factors. During this stage, persistent HIV replication compromises the immune system, leading to the gradual decline of CD4+T lymphocyte count. Symptoms or signs, such as lymphadenectasis, can also appear.

AIDS

AIDS is the final stage of HIV infection. The CD4+T lymphocyte count falls below 200/μL in most patients with AIDS. The major clinical presentations during this stage include HIV-related symptoms, HIV-related signs, and various opportunistic infections and tumors.

Diagnostic criteria[12]

Diagnostic principles

The diagnosis of HIV infection/AIDS should be based on a comprehensive and careful analysis of patient epidemiologic history (including unsafe sex, intravenous drug use, transfusion of blood or blood products not tested for HIV antibodies, children of HIV-positive women, or workers with occupational exposure to HIV), clinical presentation, and laboratory findings. HIV antibody tests and pathogenic assays help to confirm the diagnosis of HIV infection. Epidemiologic history is an important diagnostic criterion for acute infection and HIV infection in infants. CD4+T lymphocyte count and clinical presentation are the major criteria for HIV infection diagnosis and staging. AIDS-indicative diseases are also important references for the diagnosis of AIDS. “ HIV-infected” refers to individuals whose HIV infection has not progressed to AIDS, while “AIDS patients” refers to individuals whose HIV infection has progressed to AIDS.

HIV infection in adults, adolescents, and children aged >18 months can be diagnosed if one of the following criteria is satisfied: (1) positive HIV antibody screening test and positive HIV confirmatory test (positive confirmatory antibody test, positive qualitative nucleic acid test, or quantitative nucleic acid testing >5000 copies/mL); (2) recent epidemiologic history or AIDS-related clinical presentations and positive reaction to two HIV nucleic acid tests; and (3) HIV seropositivity.

For children aged ≤18 months, HIV infection can be diagnosed if one of the following criteria is met: (1) children of HIV-positive women and positive reaction to two HIV nucleic acid tests (the second sampling and test need to be performed 4 weeks after birth); (2) history of iatrogenic exposure, HIV seropositivity, or positive reaction to two HIV nucleic acid tests; and (3) children of HIV-positive women and HIV seropositivity.

Diagnostic criteria for early-stage (phase I) HIV infection

Phase I HIV infection in HIV-infected adults and adolescents aged ≥15years can be diagnosed if one of the following criteria is satisfied: (1) epidemiologic history in the past 3 to 6 months, acute HIV infection syndrome, and/or persistent generalized lymphadenopathy; (2) negative antibody screening results and positive reaction to two nucleic acid tests; and (3) occurrence of HIV seroconversion within 1 year. The diagnosis of phase I HIV infection for HIV-infected children aged <15 years should be based on CD4+T lymphocyte counts and associated clinical presentations.[12]

Diagnostic criteria for mid-stage (phase II) HIV infection

Phase II HIV infection in HIV-infected adults and adolescents aged ≥15 years can be diagnosed if one of the following criteria is satisfied: CD4+T lymphocyte count 200 to 500/μL and absence of symptoms or presentation of clinical symptoms associated with the asymptomatic infection stage. The diagnosis of phase II HIV infection for HIV-infected children aged <15 years should be based on CD4+T lymphocyte counts and associated clinical presentations.[12]

Diagnostic criteria for AIDS (phase III)

HIV-infected adults and adolescents aged ≥15 years can be diagnosed with AIDS if one of the following criteria is met: (1) Prolonged irregular fever (>38°C) of unknown etiology, >1 month; (2) Diarrhea (>3 times per day) for >1 month; (3) Weight loss >10% of body weight within 6months; (4) Recurrent oral fungal infection; (5) Recurrent herpes simplex virus or zoster virus infections; (6) Pneumocystis jirovecii pneumonia (PCP); (7) Recurrent bacterial pneumonia; (8) Active tuberculosis or nontuberculous mycobacteria (NTM) infection; (9) Non-superficial fungal infection; (10) Space occupying lesion in the central nervous system; (11) Dementia in young and middle-aged adults; (12) Active cytomegalovirus (CMV) infection; (13) Cerebral toxoplasmosis; (14) Talaromyces marneffei infection; (15) Recurrent septicemia; and (16). Kaposi's sarcoma, lymphoma.

These individuals can also be diagnosed with AIDS if HIV infection is confirmed and the CD4+T lymphocyte count is <200/μL.

Children aged <15 years can be diagnosed with AIDS if one of the following criteria is met: HIV infection and CD4+T lymphocyte percentage <25% (aged <12months), <20% (aged 12–36months), or <15% (aged 37–60months) or CD4+T lymphocyte count <200/μL (5–l4years of age); or HIV infection accompanied by at least one AIDS-indicative disease in cases in children.

Common opportunistic infections[13,14]

Pneumocystis jirovecii pneumonia

Diagnosis

  • A. This disease develops subacutely, presenting as gradually deteriorating dyspnea with fever, dry cough, and chest tightness. The symptoms gradually worsen over time, and respiratory distress may occur in severe cases.
  • B. Lung examinations may reveal few positive signs, such as sporadic dry or wet rales. These signs are usually disproportionateto the symptom severity.
  • C. Chest radiographs show diffuse net-nodule-like interstitial infiltration in both lungs starting from the hilus. Lung computed tomography (CT) scans show ground-glass-like shadows in both lungs. Concurrent bacterial or mycobacterial infections are present in 13% to 18% of patients and can manifest with corresponding pulmonary imaging findings.
  • D. Blood-gas analysis shows hypoxemia and significantly decreased arterial partial pressure of oxygen (PaO2) in severe cases, often <60 mmHg (1 mmHg = 0.133 kPa).
  • E. Blood lactate dehydrogenase levels >500 mg/dL and plasma (1, 3)-β-D-glucan (BDG) levels notably higher than normal.[15]
  • F. Confirmed diagnosis depends on the identification of the pathogen in sputum or bronchovesicular lavage/lung biopsy specimens, in which Pneumocystis cysts or trophozoites may be found. PCR is also an alternative diagnostic method.[16]

Treatment

  • A. Symptomatic treatment: bed rest, supplemental oxygen, and balanced intake of water and electrolytes.
  • B. Pathogen treatment: The first-line regimen of choice is oral cotrimoxazole (SMZ-TMP) for mild-moderate cases (TMP 15–20 mg kg−1·d−1, SMZ 75–100 mg kg−1·d−1, 3–4 times daily). A course lasts 21 days and can be prolonged when necessary. Severe cases should be administered intravenous co-trimoxazole at the same dose as for oral administration. For patients with allergies to SMZ-TMP, desensitization therapy can be attempted. Alternative treatments include: (i) clindamycin (600–900 mg, IV, every 8 hours) or oral clindamycin (450 mg, every 6 hours) combined with oral primaquine (15–30 mg, qd for 21 days); (ii) oral dapsone (100 mg once daily) combined with oral trimethoprim (TMP) (200–400 mg, 2–3 times daily) for 21 days; and (iii) pentamidine (3–4 mg/kg, once daily, slow IV drip [longer than 60 min]) for 21 days.
  • C. Hormonotherapy: For patients with moderate or severe PCP (PaO2<70mmHg or alveolar-arterial PO2 difference >35 mmHg), hormonotherapy can be adopted in the early stage (within 72 hours). Oral prednisone (40 mg bid × 5days, then 20 mg bid × 5 days, and then 20 mg once a day to completion of treatment) should be administered. If intravenous methylprednisolone is used, it should contain 75% prednisone (dosage as above).
  • D. Assisted ventilation: Assisted ventilation can be administered in patients with obvious progressive dyspnea.
  • E. ART: ART should be initiated as soon as possible, usually within 2 weeks after initiation of anti-PCP treatment.

Prophylaxis

  • A. Prophylaxis indications: CD4+T lymphocyte count <200/μL (adults, adolescents, pregnant women, and patients on ART).
  • B. Medications: The first-line regimen choice is SMZ-TMP (1 and 2 tablets/d for primary and secondary prophylaxis, respectively). In patients who cannot tolerate or have an allergy to the medication, the alternative is dapsone. Patients with PCP receiving ART treatment can discontinue medications for PCP prophylaxis when their CD4+T lymphocyte count is >200/μL for ≥6 months. Patients with PCP receiving ART treatment can also consider discontinuing the medications for PCP prophylaxis when their CD4+T lymphocyte count is 100 to 200/μL with viral load persistently below the lower limit of detection for 3 to 6 months. If CD4+ T lymphocyte counts relapse to <200/μL, prophylaxis should be reinitiated.

Tuberculosis

Diagnosis[17]

Tuberculosis can occur in patients with HIV infection/AIDS with any level of CD4+T lymphocyte counts. The diagnosis of HIV/ AIDS and tuberculosis co-infection should be based on a comprehensive analysis of clinical presentations and the results of auxiliary, pathological, and imaging examinations. The clinical manifestations of tuberculosis and its diagnostic methods in patients with HIV infection/AIDS are characteristic of this condition; hence, the diagnostic methods for general tuberculosis cases should not be applied indiscriminately in the diagnosis of HIV/AIDS and tuberculosis co-infection. When making the diagnosis, special attention should be paid to the patient immune status: patients with high CD4+T lymphocyte counts exhibit clinical manifestations similar to those of general tuberculosis cases, while patients with lower CD4+T lymphocyte counts usually present with extrapulmonary tuberculosis or disseminated tuberculosis. In terms of tuberculosis diagnosis, the World Health Organization (WHO) guidelines[18] recommend the use of rapid molecular assays, including Xpert MTB/RIF and Xpert MTB/RIF Ultra as the initial test for tuberculosis diagnosis. Some studies showed that the Xpert MTB/RIF assay offers higher sensitivity and specificity for the diagnosis of pulmonary tuberculosis in patients with HIV infection/AIDS and can be used to quickly differentiate tuberculous mycobacteria (MTB) from NTM, demonstrating its good diagnostic value.[19] Acid-fast staining, culture, rapid molecular assays, such as Xpert MTB/ RIF, and histopathologic examinations are the major methods for confirming tuberculosis.

Treatment

Patients with HIV infection/AIDS with tuberculosis complications should undergo routine treatment regimens for tuberculosis; however, drug interactions and incompatibility between anti-tuberculosis and antiviral medications should be considered.

The anti-tuberculosis medications mainly include isoniazid, rifampicin, rifabutin, ethambutol, and pyrazinamide. If the mycobacterium tuberculosis infection is susceptible to first-line antituberculous agents, then isoniazid + rifampicin (or rifabutin) + ethambutol + pyrazinamide should be used for 2 months of intensive therapy, followed by the use of isoniazid + rifampicin (or rifabutin) for 4 months of consolidation therapy. For patients slow to respond to antituberculous treatment (ie, with persisting tuberculosis-associated clinical presentations or positive cultures for Mycobacterium tuberculosis after 2 months of antituberculous treatment) or those with tuberculosis of bones and joints, the course of antituberculous treatment should be prolonged to 9 months. For patients with central nervous system tuberculosis, the therapy course should be lengthened to 9 to 12 months.

All patients with HIV/AIDS co-infected with tuberculosis should receive ART regardless of CD4+T lymphocyte counts. As immune reconstitution inflammatory syndrome (IRIS) barely leads to death, current recommendations indicate that patients with HIV co-infected with tuberculosis should start ART as early as possible (ART initiation within 2 weeks after antituberculous treatment initiation is recommended).[13,20–22] Early ART initiation (within 2 weeks after antituberculous treatment initiation) for children co-infected with active tuberculosis is recommended regardless of CD4+T lymphocyte counts. Pregnant women co-infected with HIV and active tuberculosis should also initiate ART as early as possible to improve maternal health and to prevent mother-to-child HIV transmission. For patients co-infected with HIV and drug-resistant tuberculosis, including multidrug-resistant tuberculosis or extensively drug-resistant tuberculosis, ART should be started within 8 weeks after the initiation of second-line anti-tuberculosis drugs. For patients with central nervous system tuberculosis, early initiation of ART incurs a higher risk of developing IRIS. The optimal timing of ART initiation for these patients remains unclear, and it is generally recommended that ART should be started after 4 to 8 weeks of antituberculous treatment.

Patients co-infected with HIV and tuberculosis need to be closely monitored for adverse drug reactions and drug-drug interactions. If necessary, the dose of antiviral or anti-tuberculosis agents should be adjusted or therapeutic drug monitoring (TDM) performed to guide treatment interventions.

Prophylaxis[13,17,23]

Regardless of the degree of immunosuppression and even if tests for latent tuberculosis infection have not been performed (eg, interferon-gamma release assay), patients with HIV infection/ AIDS (including patients who have already received ART, pregnant women, and patients who previously received anti-tuberculosis treatment) should receive tuberculosis preventive treatment (TPT) if active tuberculosis is excluded; however, active tuberculosis needs to be excluded before TPT initiation. The preferred TPT regimen is oral isoniazid (5 mg·kg−1·d−1 once daily for 9 months). The concomitant use of vitamin B6 (25 mg/d, oral, administered until the end of prophylactic treatment) can reduce the incidence of peripheral neuritis. An alternative regimen is oral rifampicin (10 mg·kg−1·d−1 once daily for 4 months).

NTM infection

HIV/AIDS can be complicated by NTM infection, with Mycobacterium avium (MAC) infection being the most common.

Diagnosis

MAC infection has similar clinical symptoms as active tuberculosis except for a high frequency of systemic dissemination that involves multiple organs, which manifests as anemia, hepatosplenomegaly, and generalized lymphadenopathy. Confirmed diagnosis depends on the detection of NTM in blood culture, lymph node culture, bone marrow culture, or culture of other sterile tissues or body fluid culture. Bacterial strains can also be identified through DNA probe tests, high-performance liquid chromatography, mass spectrometry techniques, or biochemical reactions. The colloidal gold method may be useful for the preliminary identification of NTM and PCR plus gene sequencing can be used to identify clinically isolated common mycobacteria. Acid-fast staining, culture of stool or biopsy specimens, and imaging examinations are also helpful for diagnosis.

Treatment

The first-line treatment regimen for MAC infection[24] is: clarithromycin (500 mg twice daily [or azithromycin 500 mg/ d)] + ethambutol (15 mg·kg−1·d−1) combined with rifabutin (300–600 mg/d)). For patients with severe infection and severe immunosuppression (CD4+T lymphocyte count <50/μL), amikacin (10 mg·kg−1·d−1, intramuscularly, qd) or quinolone antibacterial drugs, such as levofloxacin or moxifloxacin, may be concomitantly administered. The therapy course usually lasts for at least 12months. Treatment of other NTM infections should be adapted based on the identification of bacterial species and results of drug susceptibility testing.[21] ART should be started as soon as possible, usually 2 weeks after the initiation of anti-MAC therapy.

Prophylaxis

Primary prophylaxis: Primary prophylaxis is not recommended for patients with immediate ART initiation. For patients with CD4+T lymphocyte counts <50/μL regardless of ART status, if HIV RNA is not completely suppressed and no effective ART is currently available, primary prophylaxis may be prescribed by physicians to avoid disseminated MAC infection.[13] The regimen for primary prophylaxis is clarithromycin (500 mg bid) or azithromycin (1200 mg/week). In patients who cannot tolerate clarithromycin and azithromycin, rifabutin can be used for prophylaxis therapy (routine dosage 300 mg, qd) after active tuberculosis is excluded. For patients who have not initiated ART, the medications for prophylaxis can be discontinued once effective ART is initiated. Secondary prophylaxis: After standardized treatment is completed for individuals with MAC infection, long-term therapy (secondary prophylaxis) must be maintained until the patient's CD4+T lymphocyte count is >100/ μL for >6 months. The secondary prophylactic regimen is consistent with the primary regimen.

CMV infection

As the most common herpes virus infection in patients with HIV/ AIDS, CMV infection can be categorized as CMV viremia or CMV with organ involvement. CMV infection can involve multiple organ systems, including the eyes, lungs, digestive systems, central nervous system, and others, among which CMV retinochoroiditis is the most common in patients with HIV infection/AIDS.

Diagnosis and treatment of CMV retinitis

Diagnosis

The typical symptoms include muscae volitantes, floating objects in vision, blind spots, and peripheral vision impairment. Patients with CMV retinitis usually present with rapid vision deterioration, lesions with a scrambled-eggs-with-tomatoes appearance in fundus examinations, and dense and yellowish-white retinal lesions along the blood vessels with or without intraretinal hemorrhage. CMV DNA can be detected in the vitreous humor of 80% of patients with CMV retinitis. The confirmed diagnosis depends on the funduscopic exam.

Treatment

Recommended systemic therapy regimen: (a) ganciclovir (5 mg/ kg, IV drip, q12 h for 14–21 days), then 5 mg/kg IV drip, qd; (b) ganciclovir (5 mg/kg IV drip, q12 h for 14–21 days), then oral ganciclovir (900 mg, qd or 1.0, tid); and (c) oral ganciclovir (900 mg, q12 h for 14–21 days), then 900 mg, qd or oral ganciclovir 1.0, tid. Alternative treatment regimen: foscarnet sodium (60 mg/ kg IV drip, q8 h or 90 mg/kg IV drip, q12 h, 14–21 days), then 90 to 120 mg/kg IV drip, qd, or oral ganciclovir (1.0, tid).

Topical treatment: Topical treatment requires the involvement of ophthalmologists for the administration of intravitreal injection of ganciclovir (2 mg per injection) or foscarnet (2.4 mg per injection) once weekly until the retinal lesions are controlled or inactive.

Diagnosis and treatment of CMV infections in other sites

The clinical presentations of CMV pneumonia include fever, cough, dyspnea, and interstitial changes on chest radiographs. The diagnosis of CMV pneumonia is challenging and mainly depends on clinical symptoms, radiographic changes, and pathologic findings (CMV inclusion bodies observed in pulmonary tissues or cells). Meanwhile, other common pathogens associated with pneumonia must be excluded. Intravenous infusions of ganciclovir, foscarnet sodium, or ganciclovir combined with foscarnet sodium are recommended as treatment regimens; however, the therapy course is yet to be confirmed.

CMV esophagitis or enteritidis: presents as fever, dysphagia or odynophagia, diarrhea, watery stools, or watery stools mixed with blood, accompanied by abdominal pain. Ulceration of the mucous membrane can be observed on gastroscopy or enteroscopy, and CMV inclusion bodies can be observed in histopathological examinations. Treatment: medications as above. The therapy course lasts for 3 to 4 weeks or until after symptoms or signs disappear.

CMV encephalitis: presents as neuropsychiatric alterations, trance, insanity, confusion, dullness, aphasia, visual impairment, inertia, epileptic seizure, facial paralysis, and others. The diagnosis of CMV encephalitis depends on the detection of CMV DNA in the cerebrospinal fluid or brain tissue by PCR, with a sensitivity of 80% and a specificity of 90%. Treatment regimen: Ganciclovir is used in combination with foscarnet sodium for 3 to 6 weeks (dosage same as above), followed by maintenance therapy until the results of quantitative CMV assay of cerebrospinal fluid are negative. Therapy regimens should be personalized based on specific conditions.

Antiretroviral therapy

ART should be started as early as possible (within 2 weeks after initiation of anti-CMV treatment).

Prophylaxis

Primary prophylaxis is not recommended for CMV infection. Funduscopic examinations should be regularly performed for patients with CD4+T lymphocyte counts <200/μL. Once CMV infection occurs, it should be actively treated. The prophylaxis regimen should be continued even after CMV retinitis lesions become inactive. Ganciclovir (1.0, tid, oral) is usually used to prevent the reactivation of the CMV infection. Discontinuation of prophylaxis can be considered if CD4+T lymphocyte count is > 100/μL for > 3 to 6 months in response to ART. Secondary prophylaxis is not recommended for CMV enteritis, CMV pneumonia, and CMV neuropathy.

Herpes simplex virus or varicella zoster virus infections[25]

Diagnosis

Herpes simplex and herpes zoster infections can usually be diagnosed based on their typical clinical presentations. Diagnosis can also be confirmed by PCR and viral culture of the collected blister fluids.

Treatment

The main medications are acyclovir, famciclovir, valaciclovir, and foscarnet sodium. Acyclovir or foscarnet sodium are recommended for the treatment of HIV infection complicated by varicella zoster virus infection. (1) The treatment courses for oral herpes simplex and genital herpes simplex last for 5 to 10 and 5 to 14 days, respectively. The treatment regimen is oral acyclovir (400 mg, tid). (2) Severe mucosal herpes simplex: acyclovir (5 mg/ kg IV drip, q8 h), then oral acyclovir (400 mg tid) once the damaged mucosa begins to heal. The medications should be discontinued after the damage completely heals. (3) For patients with herpes simplex resistant to acyclovir, foscarnet sodium (40 mg/kg IV drip, q8 h or q12 h) is recommended until the disease is cured. (4) Localized herpes zoster: acyclovir (5–10 mg/kg IV drip, q8 h for 7 days). (5) Severe mucocutaneous herpes zoster: foscarnet sodium (40 mg/kg IV drip q8 h or q12 h) or acyclovir (10 mg/kg IV drip, q8 h), then oral valaciclovir (1.0 tid) after the patient is medically stable and until the lesions disappear. (6) Acute retinal necrosis: acyclovir (10 mg/kg, q8 h, IV drip), then oral valaciclovir (1.0 tid) after the patient is medically stable.

Cerebral toxoplasmosis

Diagnosis

The clinical presentations of cerebral toxoplasmosis include fever and localized or diffuse damage to the central nervous system. Cranial CT scans show one or more low-density sites appearing as rings or nodules in contrast enhancement, frequently surrounded by edema belts. Cranial magnetic resonance imaging shows multiple long T1 and long T2 signals. Positron emission tomography is helpful for clinical diagnosis. Immunological-based techniques adopted to detect Toxoplasma antibodies in serum or interstitial fluid specimens are auxiliary methods of diagnosing toxoplasmosis. Diagnosis may be confirmed by brain biopsy.

Treatment

Pathogen treatment

The first-line regimen of choice is pyrimethamine (loading dose 100 mg, oral, bid, 50–75 mg/d for subsequent maintenance) + sulfadiazine (1–1.5 g orally, 4 times/d).

Alternative treatment

SMZ-TMP (3 tablets, orally, tid) combined with clindamycin (600 mg, IV, administered every 6 hours) or azithromycin (0.5 g/d). The therapy course lasts for at least 6 weeks.

Symptomatic treatment

Reduction of intracranial pressure (ICP), anticonvulsant therapy, antiepileptic therapy, and others.

Prophylaxis

For patients with AIDS without a history of cerebral toxoplasmosis but with CD4+ T lymphocyte counts <200/μL and positive Toxoplasma immunoglobulin G results, a prescription of SMZ-TMP (2 tablets/d, qd) for prophylaxis purposes is generally indicated. After ART initiation, prophylaxis can be stopped when the CD4+T lymphocyte count reaches 100 to 200/μL and the viral load is persistently below the lower limit of detection for 3 to 6 months. For patients who have had cerebral toxoplasmosis, the long-term use of pyrimethamine (25–50 mg/d) + sulfadiazine (2–4 g/d) for prophylaxis is needed until the CD4+T lymphocyte count increases to >200/μL for ≥6 months. Prophylaxis should be restarted if the CD4+T lymphocyte count drops to <200/μL.

Fungal infection

Diagnosis

Candida and Cryptococcus neoformans infections are the more common fungal infections occurring in clinical practice. T. marneffei infection is also common in Southern China or damp and rainy regions. The diagnosis of fungal infection depends on the clinical presentation, pathogens found in cultures of infected site biopsy specimens, or the results of pathological examinations. C. neoformans infection predominantly occurs in patients with CD4+T lymphocyte counts <100/μL. Cryptococcus antigen latex agglutination tests of blood or cerebrospinal fluid specimens can assist with the diagnosis of C. neoformans infection. Meningitis or meningoencephalitis due to Cryptococcus mainly manifests in clinical practice as fever, progressive headache, psychiatric symptoms, and neurological symptoms. Increased ICP with severe headache, nausea, and vomiting is also a common clinical presentation. T. marneffei infection predominantly occurs in patients with CD4+T lymphocyte counts < 50/μL, manifesting as fever, anemia, cough, rash, generalized lymphadenopathy, hepatosplenomegaly. and umbilicated rash. Tests for T. marneffei-specific mannoprotein and galactomannan can assist with rapid diagnosis.[26] A confirmed diagnosis depends on the detection of T. marneffei in blood culture, bone marrow culture, and culture of other sterile body fluids.

Treatment

Candida infection[27]

Oral Candida infections The first-line regimen is oral fluconazole (100–200 mg/d for 7–14days). An alternative treatment regimen is the administration of an itraconazole oral solution (200 mg, qd for 7–14 days) or topical nystatin and a mouthwash containing sodium bicarbonate.

Esophageal Candida infection Oral or intravenous fluconazole (100–400 mg/d), itraconazole oral solution (200 mg qd), or oral voriconazole (200 mg) bid; the therapy course lasts for 14–21 days. For patients with oropharyngeal or esophageal fungal infections, ART should be initiated as soon as possible and antifungal therapy can be concomitantly administered with ART.

C. neoformans infection

Meningitis or meningoencephalitis due to Cryptococcus[13,28] Principles of pathogen treatment: The treatment regimen is divided into the induction, consolidation, and maintenance phases (reference: “ Expert consensus on the diagnosis and treatment of cryptococcal meningitis”[28]) [Table 1]. The classical regimen for the induction phase is amphotericin B + 5-flucytosine. The amphotericin B dose starts at 0.02 to 0.1 mg kg−1·d−1 and is gradually raised to 0.5 to 0.7 mg kg−1·d−1. Amphotericin B frequently leads to adverse reactions; therefore, close patient observation is necessary. The induction phase lasts for at least 4 weeks, followed by consolidation with fluconazole (600–800 mg/ d) for at least 6 weeks after improvement of clinical symptoms and conversion of cerebrospinal fluid culture from positive to negative. Subsequently, patients are switched to maintenance with fluconazole (200 mg/d) for at least 1 year, until those on ART show CD4+T lymphocyte counts of >100/μL for at least 6 months.

Table 1 - Antifungal drug regimens for meningitis or meningoencephalitis due to Cryptococcus
Anti-fungal medications

Treatment phase First-line Second-line Course of treatment
Induction Amphotericin B (0.5–0.7 mg·kg−1·d−1) + flucytosine (100 mg·kg−1·d−1) Amphotericin B (0.5–0.7 mg·kg−1·d−1) + fluconazole (600–800 mg/d)Amphotericin B (0.5–0.7 mg·kg−1·d−1)Fluconazole (600–800 mg/d) ± Flucytosine (100 mg·kg−1·d−1)Itraconazole injection (days 1–2, loading dose 200 mg, q12h; starting from day 3, 200 mg, qd) ± flucytosine (100 mg·kg−1·d−1)Voriconazole (day 1 loading dose 6 mg/kg, q12h; starting from day 2, 4 mg/kg, q12h) ± flucytosine (100 mg·kg−1·d−1) ≥4 weeks
Consolidation Fluconazole (600–800 mg/d) ± flucytosine (100 mg·kg−1·d−1)Amphotericin B (0.5–0.7 mg·kg−1·d−1) ±flucytosine (100 mg·kg−1·d−1) Itraconazole oral solution (200 mg, q12h) ± flucytosine (100 mg·kg−1·d−1)Voriconazole tablets (200 mg, q12h) ± flucytosine (100 mg·kg−1·d−1) ≥6 weeks
Maintenance Fluconazole 200 mg/d Itraconazole 400 mg/d ≥1 year

Lower ICP: Patients with elevated ICP must receive aggressive antihypertensive treatment. The commonly used ICP-lowering methods include antihypertensive drugs, lumbar puncture drainage, lumbar cistern drainage, external drainage via lateral ventricle, ventriculoperitoneal shunt, placement of Ommaya sacs (reservoir sacs), and others. Aseptic techniques should be strictly adhered to in continuous external drainage for ICP reduction. Intensive care is required to prevent secondary infections.

Pulmonary cryptococcosis The recommended treatment regimen for diffuse pulmonary cryptococcal infection is consistent with that for central nervous system infections. Localized pulmonary cryptococcal infection: oral fluconazole (400–800 mg/d for 10 weeks), followed by maintenance with oral fluconazole (200 mg/ d). The antifungal therapy course lasts for 6 months in total.

Cryptococcal antigenemia[13,22] For patients positive for qualitative serum cryptococcal antigen, oral fluconazole (400–800 mg/ d for 10 weeks) is recommended, followed by maintenance oral fluconazole (200 mg/d). The therapy course lasts for 6 to 12 months in total.

Antiretroviral therapy Patients infected with HIV with cryptococcal pneumonia should receive ART after 2 weeks of anti-cryptococcal therapy. For HIV patients with cryptococcal meningitis, premature ART might be associated with a higher mortality rate; thus, properly deferred ART can be considered (ART is generally initiated after 4–6 weeks of standard anti-cryptococcal therapy).[22,29] For some individuals, ART needs to be started in advance, although it is best to ensure that ART is initiated after negative cerebrospinal fluid culture tests are obtained.[30]

T. marneffei infection

Antifungal therapy Induction phase: Regardless of disease severity, the first-line regimen is amphotericin B (0.5–0.7 mg·kg−1·d−1) or liposomal amphotericin B (3–5 mg·kg−1·d−1 IV drip) for 2 weeks, with patients being closely monitored for adverse reactions.[31–33] Patients who cannot tolerate amphotericin B can receive an alternative regimen comprising voriconazole IV drip or oral voriconazole as follows: 6 mg/kg (loading dose) q12 h on day 1, then 4 mg/kg, q12 h for >2 weeks.[31] Consolidation phase: oral itraconazole or voriconazole 200 mg, q12 h for 10weeks in total.[32] Subsequently, secondary prophylaxis is conducted: oral itraconazole (200 mg, qd). The discontinuation of prophylaxis can be considered for patients on ART treatment with CD4+ T lymphocyte counts >100/μL for at least 6 consecutive months.[34] Once the CD4+ T lymphocyte count is <100/μL, prophylaxis therapy must be restarted.[32] ART can be started within 1 to 2 weeks after the initiation of effective antifungal therapy. Special attention must be paid to avoid drug interactions between antifungal and antiviral medications and to monitor, prevent, and treat IRIS.

Antiretroviral therapy

Treatment objectives

To minimize HIV replication, decrease the viral load to the lower limit of detection, reduce HIV mutation, restore immune function, reduce abnormal immune activation, contain HIV spread and prevent mother-to-child transmission, and reduce the incidence and fatality rate of HIV infection and non-AIDS-related illnesses such that PLWHA can achieve normal life expectancy and improve their quality of life.

Introduction to antiretroviral drugs currently available in China [Table 2]

Globally, over 30 antiretroviral drugs in six classes are currently available: nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), integrase inhibitors (INSTIs), fusion inhibitors (FIs), and CCR5 inhibitors. As shown in Table 2, the antiretroviral drugs available in China are divided into five categories: NRTIs, NNRTIs, PIs, INSTIs, and FIs (including compounded preparations).

Table 2 - Introduction to the major antiretroviral drugs currently available in China
Drug name Acronym Class Administration and dosage Major adverse reactions ARV interactions and considerations Remarks
Zidovudine AZT NRTIs Adults: 300 mg bid; Newborns/infants: 2 mg/kg, 4 times/d; Children: 160 mg/m2 surface area tid 1. Bone marrow suppression, severe anemia, or neutropenia; 2. GI discomfort: nausea, vomiting, diarrhea, and others; 3. Elevated CPK and ALT, lactic acidosis, and/ or hepatic steatosis Chinese generic drugs available
Lamividine 3TC NRTIs Adults: 150 mg bid, or 300 mg qd; Newborns: 2 mg/kg, bid; Children: 4 mg/kg, bid Few and mild. Rare headache, nausea, diarrhea, and others Imported and Chinese generic drugs available
Azvudine NRTIs auxiliary vif protein inhibitor 3 mg qd on an empty stomach at bedtime, do not crush the tablet Fever, dizziness, nausea, diarrhea, hepatorenal impairment, and others; may lead to neutropenia and elevated levels of serum total bilirubin, glutamic-oxalacetic transaminase, and blood glucose Combined with NRTIs and NNRTIs, recommended for adult patients with viral load ≥105copies/mL Conditionally approved Chinese generic drugs
Abacavir ABC NRTIs Adults: 300 mg bid;Newborns/infants: not recommended;Children: 8 mg/kg bid, maximum close 300 mg bid 1. Hypersensitivity. ABC should be stopped for life in case of such reactions; 2. Nausea, vomiting, diarrhea, and others Screening for HLA-B5701 before starting ABC, not recommended for patients positive for HLA-B5701. Not recommended for patients with viral load ≥105copies/mL Imported and Chinese generic drugs available
Tenofovir disoproxil TDF NRTIs Adults: 300 mg qd, take TDF with food 1. Osteoporosis; 2. Nephrotoxicity; 3. Mild-to-moderate GI discomfort; for example, nausea, vomiting, diarrhea, and others; 4. Metabolic disorder such as hypophosphatemia and abnormal fat distribution, may lead to acidosis and/or hepatic steatosis Imported and Chinese generic drugs available
Zidovudine/lamivudine AZT/3TC NRTIs 1 tab bid See AZT and 3TC See AZT Imported and Chinese generic drugs available
Emtricitabine/tenofovir FTC/TDF NRTIs 1 tab qd See TDF Imported and Chinese generic drugs available
Emtricitabine/tenofovir alafenamide FTC/TAF NRTIs Adults and adolescents (aged ≥12 years and weight ≥35 kg): 1 tab qd(1) 200 mg/10 mg; (combined with PIs or EVG/c containing enhancers)(2) 200 mg/25 mg (combined with NNRTIs or INSTIs) 1. Diarrhea; 2. Nausea; 3. Headache Rifampicin and rifabutin can reduce TAF exposure and lead to a lower level of plasma TAF. Concomitant use not recommended Imported drugs available
Lamivudine/tenofovir disoproxil fumarate 3TC/TDF NRTIs 1 tab qd See 3TC and TDF Chinese generic drugs available
Nevirapine NVP NNRTIs Adults: 200 mg bid;Newborns/infants: 5mg/kg bid;Children: aged <8 years, 4mg/kg bid; aged >8 years, 7 mg/kg bidCaution: only half-doses (ie, qd) can be administered during the lead-in period (the first 2 weeks). Then, the full dose (ie, bid) is administered if no severe side effect occurs 1. Rash. NVP should be stopped for life in case of severe or life-threatening rash; 2. Hepatic toxicity. NVP should be stopped for life in case of severe hepatitis or hepatic insufficiency May lead to decreased blood concentrations of PIs Chinese generic drugs available
Nevirapine/zidovudine/ lamivudine NVP/AZT/3TC NNRTIs+NRTIs 1 tab bid (recommended for patients able to tolerate NVP 200 mg qd during the 2-week lead-in period) See NVP/AZT/3TC Chinese generic drugs available
Efavirenz EFV NNRTIs Adults: 400 mg qd;Children: weight 15–25 kg: 200–300 mg qd; 25–40 kg: 300–100 mg qd; >40kg: 400 mg qd at bedtime 1. CNS toxicity; for example, dizziness, headache, insomnia, depression, abnormal thinking, etc. May produce long-term neuropsychiatric consequences. May be associated with suicidal intent; 2. Rash; 3. Hepatic toxicity; 4. Hyperlipemia and hypertriglyceridemia Chinese generic drugs available
Rilpivirine RPV NNRTIs 25 mg qd, with meals Mainly depression, insomnia, headache, and rash Classification of drug safety during pregnancy: category B; not recommended for patients with viral load ≥105 copies/ mL Imported drugs available
Ainuovirine NNRTIs Adults: 150 mg/d (2 tablets, 75 mg/ tab) on an empty stomach Mainly hepatic toxicity, dreaminess, insomnia, and others Not yet evaluated in pregnant women and children Chinese generic drugs available
Doravirine DOR NNRTIs Adults: 100 mg qd with or without food Few adverse reactions, rare nausea, dizziness, abnormal dreams Imported drugs available
Doravirine/lamivudine/ tenofovir disoproxil fumarate DOR/3TC/TDF NRTIs + NNRTIs Adults: 1 tab qd (active ingredients in each tablet: DOR 100 mg/3TC 300 mg/TDF 300 mg); take with or without food See TDF, 3TC, and DOR Imported drugs available
Lopinavir/ritonavir LPV/r PIs Adults: 2 tabs bid (active ingredients in each tablet: LPV/r, 200 mg/50 mg)Children: 7–15 kg, LPV 12 mg/kg and RTV 3 mg/kg, bid: LPV 15–40 kg, 10 mg/kg and RTV 2.5 mg/kg, bid Mainly diarrhea, nausea, dyslipidemia, headache, and elevated serum transaminase level Imported drugs available
Darunavir/cobicistat DRV/c PIs Adults: 1 tab qd (active ingredients in each tablet: DRV/COBI 800mg/ 150mg). Take with meals, do not break or crush the tablets Diarrhea, nausea, and rash Not yet evaluated in pregnant women Imported drugs available
Raltegravir RAL INSTIs Adults: 400 mg bid Common adverse reactions include diarrhea, nausea, headache, fever, and others; rare abdominal pain, fatigue, hepatorenal damage, and others Imported drugs available
Dolutegravir DTG INSTIs Adults and adolescents aged ≥12 years: 50 mg qd, in the presence of INSTIs resistance, DTG should preferably be taken after meals to enhance exposureFor children aged 6–12 years: 15–20 kg, 20 mg qd; 20–30 kg, 25 mg qd; 30–40 kg, 35 mg qd; >40 kg, 50 mg qd Common adverse reactions include psychiatric and neurological symptoms, such as insomnia, headache, dizziness, abnormal dreaming and depression, as well as nausea, diarrhea, vomiting, rash, pruritus, fatigue, and others; rare hypersensitivity reactions including rash, systemic symptoms, organ dysfunction (including hepatic impairment), and reduced renal tubular secretion of creatinine When combined with EFV or NVP, administer the medication twice daily Imported drugs available
Dolutegravir/lamivudine DTG/3TC INSTIs + NRTIs 1 tab qd See DTG and 3TC Imported drugs available
Dolutegravir/abacavir/ lamivudine DTG/ABC/3TC INSTIs + NRTIs Adults and adolescents (aged ≥12 years and weight ≥40 kg): 1 tab qd (active ingredients in each tablet: DTG 50 mg/ABC 600 mg/ 3TC 300 mg) See ABC, DTG, and 3TC Screening for HLA-B5701 before treatment initiation; ABC-containing ART regimens not recommended for patients positive for HLA-B5701 Imported drugs available
Elvitegravir/cobicistat/ emtricitabine/tenofovir Alafenamide EVG/c/FTC/TAF INSTIs+NRTIs Adults and adolescents (aged ≥12 years and weight ≥35kg): 1 tab qd (active ingredients in each tablet: B/G/c/FTC/TAF 150 mg/ 150 mg/200 mg/10 mg), take with meals 1. Diarrhea; 2. Nausea; 3. Headache Concomitant use of rifampicin or rifabutin not recommended; not recommended for pregnant women Imported drugs available
Bictegravir/emtricitabine/ tenofovir alafenamide BIC/FTC/TAF INSTIs + NRTIs Adults: 1 tab qd (active ingredients in each tablet: BIC/FTC/TAF 50 mg/ 200 mg/25 mg) 1. Headache; 2. Diarrhea; 3. Nausea Concomitant use of rifampicin or rifabutin not recommended; no data currently available for the use of BIC/FTC/TAF by pregnant women Imported drugs available
Albuvirtide ABT FIs Adults and adolescents aged >16 years: 320 mg qd on days 1, 2, 3, and 8, then once per week, IV drip Allergic dermatitis, fever, dizziness, and diarrhea Since the metabolism of ABT is not catalyzed by cytochrome P450 enzymes, ABT has fewer interactions with other medications Chinese generic drugs available
NRTIs: Nucleoside reverse transcriptase inhibitors; NNRTIs: Non-nucleoside reverse transcriptase inhibitors; PIs: Protease inhibitors; INSTIs: Integrase inhibitors; FIs: Fusion inhibitors; CPK: Creatine phosphate kinase; ALT: Alanine transaminase; AST: Aspartate aminotransferase; “–”: No relevant data; bid: Once every 12 h; tid: Once every 8 h.

Optimal timing to start ART and ART regimens for adults and adolescents[20–22,35]

Optimal timing for ART initiation in adults and adolescents

Once the diagnosis of HIV infection is confirmed, immediate ART initiation is recommended regardless of CD4+T lymphocyte levels. ART initiation must be accelerated for patients who are pregnant and those with AIDS, acute opportunistic infections, CD4+T lymphocyte count <200/μL, HIV-associated nephropathy, and acute and co-infection with active HBV/HCV. Before ART initiation, patient adherence and consent must be obtained and the patient must be well-educated on medication compliance. For eligible patients, rapid ART initiation or ART initiation on the same day as HIV diagnosis can be considered. If the patient has severe opportunistic infections and previous acute episodes of chronic illnesses, ART should be initiated after the patient is medically stable, using the aforementioned regimens for opportunistic infections used as reference. After ART initiation, lifelong ART is required.

First-line ART regimens for adults and adolescents

The recommended first-line regimens comprise two NRTIs (backbone medications) combined with a third class of drugs. The third class of drugs includes NNRTIs or enhanced PIs (containing ritonavir or cobicistat) or INSTIs; a single-tablet regimen (STR) can also be adopted. Table 3 lists the recommended first-line ART regimens and alternative regimens for adults and adolescents based on antiviral medications available in China.

Table 3 - Recommended first-line ART regimens for adults and adolescents
Recommended regimens
2 NRTIs Third class of drugs
 TDF + 3TC (FTC) + NNRTIs: EFVa, RPVb
 TAF/FTC Or + PIs: LPV/r
Or + INSTIs: DTG; RAL
Single-tablet regimen
 TAF/FTC/BIC
 TAF/FTC/EVG/c
 ABCc/3TC/DTG
 DOR/3TC/TDF
1 NRTI + 1 INSTI
 DTG/3TCd or DTG + 3TCd
Alternative regimens
2 NRTIs Third class of drugs
 AZT (ABC) + 3TC + NNRTIs: EFV or NVPe or RPV or DOR or ainuovirine
Or + PIs: LPV/r, DRV/c
Or + INSTIs: DTG, RAL
 TDF +3TC (FTC) + NNRTIs: ainuovirine
 TDF+ Azvudinef + NNRTIs: EFV
ART: Antiretroviral therapy; NRTIs: Nucleoside reverse transcriptase inhibitors; NNRTIs: Nonnucleoside reverse transcriptase inhibitors; PIs: Protease inhibitors; INSTIs: Integrase inhibitors; TDF: Tenofovir; 3TC: Lamivudine; FTC: Emtricitabine; TAF: Tenofovir alafenamide; EFV: Efavirenz; RPV: Rilpivirine; LPV/r: Lopinavir/ritonavir; DRV/c: Darunavir/cobicistat; DTG: Dolutegravir; RAL: Raltegravir; BIC: Bictegravir; EVG/c: Elvitegravir/cobicistat; ABC: Abacavir; DOR: Doravirine; AZT: Zidovudine; NVP: Nevirapine.
aEFV not recommended for patients with viral loads >5 × 105copies/mL.
bRPV only used in patients with viral load <105copies/mLand CD4+T lymphocyte count >200/μL.
cUsed in patients negative for HLA-B5701.
dDTG+3TC and DTG/3TC are used in patients tested negative for HBsAg with viral load <5 × 105 copies/mL.
eFor patients with baseline CD4+T lymphocyte counts >250/μL regimens containing NVP should be avoided where possible; for patients co-infected with HCV, regimens containing NVP should be avoided.
fConditionally approved Chinese generic drugs used in combination with NRTIs and NNRTIs for adult patients with high viral load (≥105copies/mL).

ART for special populations

Children[22,36]

ART should be initiated as soon as possible in HIV-infected children. Without timely ART initiation, AIDS-related mortality rates can reach 20% to 30% in the first year after birth and over 50% in the second year.

Optimal timing of ART initiation and regimens for HIV-infected children

Once HIV diagnosis is confirmed for children, immediate ART initiation is recommended regardless of CD4+T lymphocyte levels. If ART cannot be initiated, the patient's immunologic, virologic, and clinical status must be closely monitored at a recommended frequency of 3 to 4 months.

The recommended first-line regimens for children comprise two NRTIs (backbone medications) combined with a third class of drugs, which include INSTIs or NNRTIs or enhanced PIs (containing ritonavir or cobicistat). Table 4 lists the recommended regimens in detail based on China's current clinical practices.

Table 4 - ART regimens for children
Age Recommended regimen Alternative regimen Descriptions
Children aged <3 years ABC (or AZT) + 3TC + LPV/r (or DTG) ABC (or AZT) + 3TC + NVP (or RAL) 1. Due to rapid drug metabolism in very young infants and their high viral load correlated with the immaturity of their immune system, highly potent regimens are required for ART in infants;2. LPV/r is chosen for NNRTIs-exposed infants;3. TDF cannot be used for children in this age range
Children aged 3–10 years ABC + 3TC + EFV (or DTG) AZT (or TDF) + 3TC + NVP (or EFV, or LPV/r, or RAL)
Children aged >10 years and adolescents TDF (or ABC) + 3TC + EFV (or DTG) AZT + 3TC + NVP (or EFV, or LPV/r, or RAL)
ART: Antiretroviral therapy; ABC: Abacavir; AZT: Zidovudine; 3TC: Lamivudine; LPV/r: Lopinavir/ritonavir; DTG: Dolutegravir; NVP: Nevirapine; RAL: Raltegravir; EFV: Efavirenz; TDF: Tenofovir; NNRTIs: Non-nucleoside reverse transcriptase inhibitors.

Monitoring of ART efficacy in children infected with HIV

  • a. Viral load is the primary measure of ART efficacy. After 6 months of ART, viral load testing should be performed once annually or when ART failure is suspected.
  • b. CD4+T lymphocyte count is another useful indicator of ART efficacy. CD4+T lymphocyte counts should be performed once every 3 to 6 months; however, these results cannot determine ART success or failure.
  • c. Clinical monitoring is an essential component of monitoring in children infected with HIV. Height, weight, growth markers, and compliance must be monitored during each follow-up visit.

Management of first-line ART failure in children

After first-line ART failure, the regimen should be adjusted based on the results of drug resistance testing. (1) For children experiencing failure of first-line NNRTI-based regimens, the treatment should be switched to DTG or enhanced PIs + 2 NRTIs (preferred PIs: LPV/r). (2) Failure on a first-line LPV/r-based regimen does not generally occur due to resistance to LPV/r. Medication adherence can be improved, and the viral load can be tested after 3 months. If HIV infection is still not suppressed, the treatment should be switched to DTG + 2 NRTIs. If DTG is unavailable, RAL + 2 NRTIs should be used. If both DTG and RAL are unavailable, children aged <3 years can be maintained on their initial treatment regimen and educated on compliance while children aged >3 years can be switched to NNTRIs + 2 NRTIs (preferred NNTRIs: EFV). (3) Substitution of NRTIs in case of treatment failure: ABC or TDF can be substituted with AZT, while AZT can be substituted with TDF or ABC.

Pregnant women with HIV/AIDS

Please refer to the section on “Prevention of mother-to-child (or vertical) HIV transmission and reproductive options for HIV-serodiscordant couples”.

Lactating women

Breastfeeding involves the risk of HIVtransmission; thus, women infected with HIV should avoid breastfeeding where possible. In particular, breastfeeding is not recommended for women whose viral load remains detectable. If the mother insists on breastfeeding, the ART regimen must be continued during the entire lactation period (consistent with the ART regimen used during pregnancy) and breastfeeding should not be continued beyond 6 months.

Patients with HIV/AIDS co-infected with Mycobacterium tuberculosis

For details on the timing of ART initiation, please refer to the part on “tuberculosis” in “Diagnosis and prophylaxis of common opportunistic infections.” The recommended first-line ART regimens for HIV/AIDS patients co-infected with tuberculosis are AZT (TDF) + 3TC (FTC) +EFV or INSTIs-containing ART regimens.[20–22] Previous studies[37] showed that while DTG-containing ART regimens can be used in patients with HIV co-infected with tuberculosis, the dose of DTG needed to be increased (50 mg, bid) when co-administered with rifampicin. Since clinical studies on patients with HIV co-infected with tuberculosis did not indicate the non-inferiority of RAL-containing ART regimens to EFV-containing regimens in terms of antiviral efficacy, RAL is generally only used in some HIV patients co-infected with tuberculosis.[38,39] An increase in the dose of RAL (800 mg, BID) is recommended when it is co-administered with rifampicin. Since rifabutin is a weaker inducer of liver enzymes, substitution of rifampicin with rifabutin can be considered in patients with HIV on DTG or RAL who are co-infected with tuberculosis, with no need for dose adjustment. If the abovementioned ART regimens are not available, FI-containing ART regimens can be used. Co-administration of new-generation integrase inhibitors (BIC or EVG/c) and rifamycins is not recommended. If rifabutin is used for antituberculous treatment, PI-containing ART regimens can also be used.

Maintenance with methadone in intravenous drug users

The timing of ART initiation for intravenous drug-dependent patients is the same as that for other patients; however, drug addiction may affect patient adherence to medications. Thus, before initiating ART, patients must be adequately informed that medication adherence is a primary determinant of treatment success. STRs or fixed-dose combination regimens should be used where possible and preference of RAL or DTG or BIC-containing ART regimens can be considered for eligible patients. Medication adherence can be effectively improved by continuous monitoring of drug distributions. Moreover, drug interactions between antiviral medications and methadone should be considered.

Patients with HIV/AIDS co-infected with HBV

In individuals with no indication for the deferred initiation of anti-HIV therapy, ART should be started as soon as possible regardless of CD4 level. (A) HIV patients co-infected with HBV require the administration of HIV/HBV co-treatment. Treatment regimen: Two agents with anti-HBV activity and TDF (or TAF) + 3TC (or FTC) are recommended as the preferred nucleoside drugs in ART regimens (TDF + FTC, TDF + 3TC, and TAF + FTC all contain mixtures); however, TAF is associated with a lower incidence of renal toxicity and osteoporosis compared to TDF.[40] (B) HBV-associated indicators should be monitored during treatment, including HBV DNA, hepatic biochemical indicators, hepatic imaging, and HBV drug resistance. Clinicians should be aware of the potential for the occurrence of hepatic cirrhosis and hepatocellular carcinoma. (C) Regimens containing only one nucleoside drug with anti-HBV activity (TDF, 3TC, entecavir, telbivudine, and adefovir) are not recommended for HIV patients co-infected with HBV in case HIV resistance to nucleoside drugs is induced.

The following should be noted[41]: (A) Patients with renal insufficiency: If the estimated glomerular filtration rate (eGFR) is <60 mL·min−1·1.73m−2, TDF should not be selected or the dose of TDF needs to be adjusted. If the eGFR is <60 mL·min−1·1.73 m−2 and >30 mL·min−1·1.73 m−2, regimens containing TAF + FTC/3TC can be considered. The use of TAF in patients with eGFR <30 mL·min−1·1.73 m−2 has yet to be approved. When TDF/TAF is not accessible, entecavir should be added to the ART regimen. (B) If the HIV/HBV co-infected patient is a pregnant woman, regimens containing 3TC (FTC) + TDF are recommended. Some studies have demonstrated the efficacy and safety of TAF in pregnant women.[42] For more details on the use of TAF in pregnant women, please refer to the section on “Prevention of mother-to-child (or vertical) HIV transmission” and reproductive options for HIV-serodiscordant couples.

Patients with HIV/AIDS co-infected with HCV

ART regimens for patients infected with HIV alone can serve as a reference for ART regimens in patients with HIV/HCV coinfections. However, the following points should be considered: (A) ART medications with less hepatic toxicity are recommended. The preference of INSTIs or FIs-containing ART regimens can be considered for eligible patients. (B) Anti-HCV therapies are recommended for HIV patients co-infected with HCV. The guidelines on HCV treatment can be used as a reference for regimens against HIV/HCV co-infection. The accumulation of drug toxicities and metabolism-based drug-drug interactions must be considered in the choice of medications, including switching to ART regimens with no interactions with anti-HCV drugs, as well as the consideration of short-term substitution with INSTIs or FIs. To avoid interactions between drugs with long half-lives, delaying anti-HCV treatment initiation for 2 weeks is recommended after changes in ART regimen. If a switch back to the original ART regimen is required upon completion of anti-HCV treatment, the switch should also be delayed by 2 weeks. If the original ART regimen needs to be changed due to treatment of HCV infection, monitoring of HIV RNA levels for 2 to 8 weeks is recommended to evaluate if the new regimen can effectively suppress HIV. (C) ART initiation before anti-HCV treatment is recommended for patients with CD4+T lymphocyte counts < 200/μL. Anti-HCV treatment can be started when the immune function has been restored to a certain level.

The anti-HCV regimen and course of anti-HCV therapy for patients with HIV/HCV co-infections are consistent with those for patients infected with HCV alone, with equivalent overall efficacy. Direct-acting antivirals (DAAs) are recommended and interactions between the selected DAAs and ART medications should be considered. As EFV and LPV/r interact with some DAAs, these interactions must be carefully evaluated before DAAs are used. If DAAs need to be used concomitantly with ART medications, it is recommended that relevant drug interactions be consulted for a more rational choice of medications.

Some studies have reported HBV reactivation induced by DAA administration and resulting in hepatic failure in patients tri-infected with HIV/HBV/HCV. Hence, for patients with HIV/ HBV/HCV tri-infection, anti-HCV regimens with DAAs must be initiated after the patient is medically stable on an ART regimen containing agents with anti-HBV activity. HIV patients coinfected with HCV need to be routinely screened for HBV markers before using DAAs.[43]

Monitoring of ART

Clinical assessments and laboratory tests need to be regularly performed during ART to evaluate its efficacy and to promptly identify the adverse effects of antiviral medications, as well as drug resistance. Medications should be promptly substituted based on these results to ensure ART success.

Evaluation of treatment efficacy

The effectiveness of ART can be evaluated according to virologic indicators, immunologic indicators, and clinical symptoms. Virologic changes are the most important indicators.

Virologic indicators

HIV plasma viral load should decrease by more than 1 log in most patients within 4 weeks after ART initiation and become undetectable after 3 to 6 months.

Immunologic indicators

Within 1 year after ART initiation, the CD4+ T lymphocyte count should increase by 30% or 100/μL compared with the pretherapy baseline count, suggesting treatment effectiveness.

Clinical symptoms

After ART initiation, the incidence of opportunistic infections and the mortality rate due to HIV/AIDS are reduced significantly. Children show improved height, nutritional conditions, and physical development.

Antiretroviral drug resistance testing

Antiretroviral drug resistance is one of the major causes of ART failure. Drug resistance testing can be performed in patients experiencing poor efficacy of ART or ART failure.

Monitoring of adverse drug effects

The adverse effects of antiviral medications comprise short-term and long-term adverse effects. In particular, adverse reactions caused by the administration of some antiviral medications, including metabolic disorders, weight gain, osteoporosis, and hepatorenal damage, need to be closely monitored, promptly identified, and properly managed. When necessary, ART regimens must be changed. The adverse effects of antiviral medications and their tolerance affect patient medication adherence and, thus, ART efficacy; therefore, close monitoring and timely management of adverse reactions are vital for the improvement of treatment efficacy.

Monitoring of drug concentrations

TDM can be performed for special populations (such as children, pregnant women, and patients with renal insufficiency) when conditions allow.

Principles of drug substitution and ART for patients experiencing treatment failure[20–22,35]

ART for virologically-suppressed patients

Definition of virological suppression: HIV viral load below the lower limit of detection (<20 or 50 copies/mL) after over 24 weeks of regular ART. In patients experiencing persistent virological suppression, ART regimens can be adjusted or optimized to specific needs. For more details, please refer to the section on “Whole-course management of HIV infection.”

ART for patients experiencing treatment failure

Definition of virological failure: For patients receiving continuous ART with plasma viral loads persistently >200 copies/mL 24 weeks after treatment initiation (initiation or adjustment) or virological rebound, defined as the reoccurrence of viral load >200 copies/mL after full virological suppression is achieved.

When virological failure occurs, the patient's adherence to treatment, drug-drug interactions, and drug-food interactions should be evaluated first, especially medication adherence, which is the determinant of treatment success. ART regimens must be adjusted for patients experiencing ART failure based on the results of HIV drug resistance testing. The principles of regimen substitution include the substitution of at least two ART medications, and it is best to choose three drugs with antiviral activity (medications with antiviral activity can be selected from among previously used drugs; eg, 3TC). The new ART regimens usually include a drug with full antiviral activity (enhanced PIs or INSTs) or a drug that has never been used with new mechanisms of action (eg, FIs) or a combination of the abovementioned medications.

Drug-drug interactions

Common ART medications interact with many other classes of drugs due to their metabolic pathways and toxicity. Concomitant medication use must be closely watched in clinical practice and the medication regimen or dosage promptly adjusted based on relevant guidelines or medicine instructions.

Immune reconstitution inflammatory syndrome

Diagnosis

IRIS refers to a collection of clinical syndromes that occur during the recovery of immune function following ART initiation in patients with AIDS. This condition predominantly manifests as fever, emergence of latent infection, and aggravation or exacerbation of the initial infection. IRIS associated with a variety of latent or active opportunistic infections, such as tuberculosis and NTM infection, PCP or CMV infection, Varicella-zoster virus infection, toxoplasmosis, and cryptococcal infection, can occur after ART initiation. In patients tri-infected with HIV/HBV/HCV, IRIS can manifest as viral hepatitis activity or exacerbation. IRIS generally occurs within 3 months after ART initiation and must be differentiated from primary or new opportunistic infections. Apart from opportunistic infections, IRIS can also manifest as other diseases, such as sarcoidosis and Kaposi's sarcoma. The diagnostic criteria for IRIS[13,17] are as follows: (1) The clinical symptoms of opportunistic infections, including tuberculosis or cryptococcal meningitis, are exacerbated after the administration of ART. As the patient responds to ART, an exaggerated inflammatory response is accompanied by an exacerbation of tuberculosis and enlargement of pre-existing lesions or the appearance of new lesions. Symptoms, such as aggravated headache and increased ICP, can manifest in patients with cryptococcal meningitis. (2) Exacerbation of clinical symptoms not associated with new opportunistic infections, HIV-associated tumors, adverse drug reactions, drug resistance, or treatment failure. (3) The viral load decreases and (or) the CD4 + T lymphocyte count increases after ART initiation.

Treatment[13]

Patients who develop IRIS should continue ART. IRIS manifesting as worsening of pre-existing infections is usually self-limiting and self-healing and, thus, does not require special treatment. IRIS manifesting as the reactivation of latent infections requires targeted antipathogenic treatment; in this context, corticosteroids or non-steroidal anti-inflammatory drugs can be used for the short-term treatment of IRIS in severe cases. Corticosteroids should be avoided in patients with Kaposi's sarcoma, as well as those with suspected tuberculosis-IRIS (ie, cases in which treatment failure cannot be excluded). Corticosteroids should be used with caution in patients with CMV infection and short-course oral corticosteroid therapy is recommended if needed.

Risk factors associated with IRIS

The risk factors associated with the appearance of IRIS include[13] the first-time initiation of ART, high baseline viral load, and low baseline CD4+T lymphocyte count. The incidence of IRIS can be lowered by effectively controlling acute opportunistic infections before ART initiation or by actively identifying and treating latent opportunistic infections before ART initiation.

AIDS-associated tumors[21,44]

AIDS-associated tumors mainly include non-Hodgkin's lymphoma and Kaposi's sarcoma. Screening for non-HIV-defining cancers, including liver cancer, lung cancer, and perianal cancer, as well as their diagnosis, treatment, and management, also deserves attention. The confirmed diagnosis of cancer depends on pathology biopsies. Personalized comprehensive treatment, including surgery, chemotherapy, interventional therapy, and radiotherapy, should be offered based on the patient's disease state (for more details, please refer to relevant guidelines). ART is recommended to be initiated as soon as possible for all HIV-infected patients with cancer. Interactions between antiviral and anticancer medications need to be considered, and ART regimens with less bone marrow suppression and fewer drug-drug interactions should be selected where possible (eg, INSTs or FI-containing regimens). The standards for the diagnosis and treatment of cancer should not be lowered due to HIV infection; rather, a multidisciplinary team (MDT) model should be promoted. Diagnosis and treatment plans should be developed together with experts from the departments of oncology, interventional radiology, pathology, and surgery. During treatment, special attention should be given to the prevention of various complications, especially infections.

Prevention of mother-to-child (or vertical) HIV transmission and reproductive options for HIV-serodiscordant couples

Three principles need to be considered in the prevention of mother-to-child AIDS transmission: (1) lower the rate of mother-to-child transmission of HIV; (2) improve the health and the survival rate of infants; and (3) pay attention to the health of HIV-infected women and their children. Effective specific interventions to reduce the risk of mother-to-child AIDS transmission include the early administration of antiretroviral drugs + obstetrical management + counseling on postnatal feeding.

Prophylaxis with antiretroviral drugs

All HIV-infected pregnant women should receive lifelong ART as soon as possible, regardless of their CD4+T lymphocyte count or clinical staging.

Preferred regimen

TDF/FTC (or TDF+3TC or ABC/3TC or ABC+3TC) +RAL (or DTG).

DTG is recommended as the preferred regimen for women of child-bearing age with pregnancy intentions and women at different stages of pregnancy, although the patient needs to be informed of potential risks involved in DTG-based regimens. RAL can also be safely used during the preparation for pregnancy or during pregnancy. BIC is not recommended for pregnant women at present due to insufficient data on the use of BIC during pregnancy. EVG/c is not recommended for use in pregnancy because of inadequate drug levels in the second and third trimesters of pregnancy.[20]

Alternative regimens

TDF/FTC (or TDF+3TC, or ABC/3TC, or ABC+3TC, or AZT/ 3TC, or AZT+3TC, or TAF/FTC) +EFV (or RPV, or LPV/r).

EFV can be used in all stages of pregnancy. There exists substantial clinical experience with the use of LPV/r, although LPV/r may induce pronounced reactions in the gastrointestinal tract and increase the risk of premature delivery and low birth weight.[45] TAF/FTC can be used after 14weeks of pregnancy as an alternative regimen.

Antiviral medications should be prophylactically administered to infants of HIV-infected women as soon as possible (within 6 hours after delivery), and specific dosing regimens should be determined based on the risk of exposure.[46] Children at average risk of exposure: for children of women on ART with a high level of adherence and long-term virological suppression, AZT or NVP can be prophylactically administered for 4 weeks; NVP is preferred if breastfeeding is chosen. In children at high risk of exposure, a triple-drug combination of AZT + 3TC + NVP (or LPV/r) should be administered for 6 weeks after delivery to infants of women who have been on ART during pregnancy but have not achieved long-term virological suppression, women with <12 weeks of ART, or women found to be HIV-positive during delivery. AZT + 3TC + NVP is recommended in the first two weeks after delivery, while AZT + 3TC + LPV/r is recommended in weeks 3 to 6 after delivery. When conditions allow, AZT + 3TC + RAL can be used for 6 weeks after delivery.[45]

To prevent PCP, all infants of HIV-infected women should receive PCP prophylaxis upon completion of 4 to 6 weeks of HIV prophylaxis, unless HIV infection has been ruled out.

Obstetrical management

Voluntary counseling on the prevention of mother-to-child AIDS transmission and relevant testing should be provided to pregnant women with a confirmed diagnosis of HIV infection. The decision to terminate or to continue pregnancy should be made by the pregnant patient and her family after their informed consent is obtained.

For HIV-infected pregnant women who choose to terminate the pregnancy, prompt and safe surgical abortion should be performed to reduce the incidence of complications. For pregnant women who choose to continue the pregnancy, high-quality counseling on antenatal care and postpartum breastfeeding should be provided and appropriate interventions should be implemented.

HIV-infected pregnant women and their families should be provided adequate counseling and informed of the important role of institutional delivery in protecting maternal and child safety and preventing mother-to-child HIV transmission. Moreover, they should be offered assistance regarding an early confirmation of the delivery hospital and arrive at the designated hospital for delivery as soon as possible. HIV infection is not an indication for cesarean section. Moreover, cesarean section is not recommended and urgent cesarean sections should be avoided in pregnant women who have been on ART during the first and second trimesters of pregnancy, pregnant women regularly taking medications, pregnant women who do not present with clinical symptoms of AIDS, women with viral loads <1000 copies/mL during the third trimester of pregnancy, and women approaching childbirth.[46] For women with viral loads >1000 copies/mL or whose viral load is unknown at the time of delivery, a planned cesarean section at week 38 of pregnancy is recommended to reduce perinatal HIV transmission as much as possible.[21] Healthcare facilities should provide pregnant women infected with HIV with safe obstetric services and, when possible, avoid invasive operations that may increase the risk of mother-to-child HIV transmissions during delivery where possible (including lateral episiotomy, amniotomy, vacuum-assisted delivery with ventouse or forceps delivery, and intrauterine fetal scalp monitoring).

Counseling on postnatal infant feeding

Artificial feeding is recommended for children of HIV-infected pregnant women. Breastfeeding should be avoided, and mixed feeding should be prohibited. Medical professionals should evaluate pregnant women infected with HIV and their families regarding the acceptability of artificial feeding; their knowledge and skills; cost burden; whether sufficient, nutritious, and safe milk substitutes can be continuously obtained; and whether timely comprehensive counseling and support from medical professionals can be provided. When possible, guidance and support regarding artificial feeding should be provided to patients eligible for artificial feeding. For HIV-infected pregnant women who are not eligible for artificial feeding and, hence, choose breastfeeding, adequate counseling on the correct practices of exclusive breastfeeding should be offered to these women and their families. ART must be sustained during the entire lactation period and breastfeeding preferably should not be continued beyond 6 months. Meanwhile, the children of pregnant women infected with HIV should be provided services, including conventional healthcare services, child growth monitoring, monitoring of infection status, guidance on preventing malnutrition, vaccination, and AIDS testing services (including antibody assays and early nucleic acid testing).

Follow-up of children of HIV-positive pregnant women

HIV nucleic acid testing should be performed for the early diagnosis of HIV infection within 48 hours, after birth as well as 6 weeks and 3 months after birth. HIV antibody assays should be performed 12 and 18 months after birth.[46] HIV antibody tests should be repeated once 24 months after birth for HIV-exposed children who test positive for HIV antibody 18 months after birth and negative for HIV nucleic acid. To monitor the safety of administering medications for infection prophylaxis, routine blood and liver function tests should be performed after birth as a reference for baseline evaluation. The intervals of subsequent monitoring depend on the results of the baseline liver function and routine blood tests, gestational age, clinical status of the newborn infants, the dose of AZT or NVP, and the administration of other drugs.

Reproductive options for HIV-serodiscordant couples

For consistently virally-suppressed HIV-positive women on ART with an HIV-negative male partner, natural conception during ovulation or in vitro fertilization are recommended. For consistently virally-suppressed HIV-positive men on ART with an HIV-negative female partner, natural conception during ovulation is also recommended as it is currently believed that no HIV transmission occurs between spouses under these circumstances.[45] Under certain circumstances, if the HIV-positive male partner attempts natural conception when viral suppression has not been achieved, the HIV-negative female partner should continuously take TDF/FTC (or TDF+3TC) for exposure prophylaxis from 20 days before condomless sexual intercourse during ovulation until 1 month after intercourse. If natural conception is attempted, the HIV-negative partner should be tested for HIV antibodies after unprotected sexual intercourse to prevent spousal HIV transmission.

Achieving persistent viral suppression in the HIV-positive partner on ART is the key to preparing for pregnancy in HIV-serodiscordant couples. In addition, the accurate calculation of the ovulation period is vital for improving the success rate of conception. Couples should seek professional help from a gynecologist if necessary.

In case of limited or no access to viral load testing, ART is recommended to be sustained for over 6 months before conception. In such instances, it is good practice to seek advice from an HIV specialist and the HIV-negative partner needs to take medications for exposure prophylaxis.

HIV exposure management and prophylaxis[22,47–49]

Post-exposure prophylaxis

PEP refers to a biological method of taking specific anti-HIV drugs as soon as possible (within 72 hours) to reduce the risk of acquiring HIV infection after a previously uninfected person is exposed to a high risk of HIV infection (eg, explicit exchange of bodily fluids with HIV-infected persons or persons with suspected HIV infection).

HIV exposure is divided into occupational and non-occupational exposures.

Occupational exposure

HIV occupational exposure refers to healthcare workers, policemen, or other personnel at risk of acquiring HIV infection at work through contact with the blood, tissue, or other bodily fluids of HIV-infected persons.[50,51]

Routes of HIV exposure and their risk levels

The routes of occupational exposure include contact with damaged skin (needlestick, cut, and others) and contact with non-intact skin or mucous membranes. If the exposure source is the blood of HIV-infected persons, the risks of acquiring HIV via exposure to damaged skin and mucous membrane are 0.3% and 0.09%, respectively. The risk of HIV infection via exposure to non-intact skin is still unclear but is generally considered to be <0.1%.

Grading of exposure risks: (a) low transmission risk: low viral load level, exposure source is on ART and has achieved persistent virological success; (b) high transmission risk: high viral load level, end stage of HIV disease progression (AIDS), exposure source is not on ART or does not take medications regularly; and (c) the exposure source is unknown: lack of information on the disease stage and HIV status of the source, as well as the viral load of the contaminated medical devices or items.

Principles of occupational HIV post-exposure management

(a) Contaminated sites should be washed with liquid soap and running water. (b) Contaminated mucous membranes, such as conjunctiva, should be flushed repeatedly with a massive amount of isotonic sodium chloride solution. (c) If a wound is involved, express contaminated blood from the lesion as much as possible by gently squeezing the wound from proximal towards distal pressure points, and then rinse the wound with liquid soap and running water. (d) Local wound disinfection can be performed with 75% alcohol or 0.5% iodophor.

Principles of medication regimens for HIV prophylaxis after occupational exposure

PEP regimens: The preferred and recommended PEP regimens are TDF/FTC + RAL (or DTG); BIC/FTC/TAF can also be considered. If INSTIs are not available, PIs, such as LPV/r and DRV/c, can be used. AZT/3TC can be used in individuals with decreased renal function and no HBV infection. A study has shown that PEP regimen containing ABT (ABT + DTG, or ABT + TDF + 3TC) had high treatment completion rate, compliance, and good safety, but more researches needed on this regimen.[52]

Timing of PEP initiation and recommended duration: PEP should be initiated as soon as possible after HIV exposure (within 2 hours where possible). It is best to start PEP within 24 hours after exposure, but no later than 72 hours. PEP should be continuously administered for 28 days.

HIV monitoring after occupational exposure

HIV antibody testing should be performed immediately and at 4, 8, 12, and 24weeks after occupational exposure to HIV. For HIV-exposed and HBV-infected individuals, HBV-related indicators should be monitored after the discontinuation of prophylaxis.

Prevention of occupational exposure

The measures to prevent occupational exposure mainly include standardized procedures and prophylaxis.

Non-occupational exposure to HIV

Non-occupational exposure to HIV refers to HIV exposure resulting from other personal behaviors besides occupations. The principles of non-occupational exposure evaluation and management, especially medications for prophylaxis, are the same as those for occupational exposure. In particular, prophylactic drug administration after exposure evaluation should be voluntary, and standardized follow-up procedures are needed to identify individuals infected with HIV as soon as possible.

Precautions

  • A. All PEPs should be implemented voluntarily, and the informed consent form needs to be signed. Emphasis should be placed on following standardized follow-up procedures.
  • B. Pre-prophylaxis baseline tests, including routine blood tests, hepatorenal function tests, and tests for HBV infection status, should be considered.

Pre-exposure prophylaxis

PrEP is defined as a biological prophylactic method of lowering the risk of infection via drug administration in individuals at high risk of acquiring HIV infection.[49]

Target population

Individuals, including MSM; men who have sex with men and women; men who do not use condoms; transgender individuals’ commercial sex workers; individuals with multiple sex partners; patients with STIs; and individuals who share needles, syringes, or other devices with others.

Principles of drug administration

Daily drug administration[49]

Daily oral PrEP with TDF/FTC is recommended for all populations at high risk for HIV infection, including pregnant or breastfeeding women at high risk of HIV acquisition. If PrEP withdrawal or discontinuation is intended, PrEP should be used continuously for 7 days after the last risky exposure.

On-demand dosing (2-1-1 regimen)

On-demand dosing is only recommended for MSM. 2-1-1 regimen: 2 tablets of TDF/FTC taken orally 2 to 24 hours before expected sexual activity. After sexual intercourse, 1 tablet should be taken 24 hours after the last administration and another tab should be taken 48 hours after the previous dosing.

Follow-up visits and monitoring

Follow-ups and HIV antigen/antibody testing should be performed 1 month after PrEP initiation. Subsequently, follow-up visits are conducted once every 3 months, at which changes in renal functions are monitored. Testing for markers of HBV infection and syphilis serology testing are also recommended during each follow-up visit. HCV antibody tests should be performed annually.

Precautions

Baseline tests, standardized follow-ups, and behavioral assessments must be performed.

Whole-course management of HIV infection

The introduction and application of ART have significantly lowered the incidence of AIDS-related opportunistic infections and tumors, turning AIDS into a chronic but manageable disease that is difficult to completely cure at present. As the length of survival in patients with HIV infection/AIDS increases, the incidence of a variety of non-AIDS-defining diseases (NADs), including metabolic syndrome; cardiovascular and cerebrovascular diseases; chronic liver, kidney, and bone diseases; and non-AIDS-defining tumors has also been increasing. These diseases have become the major factors affecting the quality of life and prognosis of patients with HIV infection/AIDS in the post-ART era.[21–22,53] Changes in the disease spectrum caused by ART are also changing the model of diagnosis, treatment, and care for patients with HIV infection/AIDS. Whole-course management of HIV infection refers to a management model facilitating comprehensive diagnosis, treatment, services, and care offered by a MDT throughout the whole course of treatment for patients diagnosed with HIV infection. Whole-course management mainly focuses on (1) prophylaxis and early diagnosis of HIV infection; (2) diagnosis, treatment. and prophylaxis of opportunistic infections; (3) initiation of personalized antiviral therapies and follow-ups on these therapies, as well as education and monitoring of medication compliance; (4) screening and management of NADs; and (5) comprehensive psychosocial care. The diagnosis and treatment model adopted in the whole-course management of HIV infection features multidisciplinary cooperation by doctors from the division of infectious diseases.

Prophylaxis and early diagnosis of HIV infection

Counseling on the prophylaxis against HIV infection should be offered to high-risk populations, including guidance on safer sexual practices, the use of PrEP and PEP, prevention of HIV mother-to-child transmission, and early ART initiation for patients with HIV infection/AIDS. Early testing and counseling on testing services (including nucleic acid testing) are recommended.

Opportunistic infection diagnosis, treatment, and prophylaxis

See “Opportunistic infections.”

Initiation and follow-up of personalized antiviral therapies

The early initiation of ART is recommended for all patients with HIV infection/AIDS regardless of their CD4+T lymphocyte counts. In clinical practice, ART regimens should be developed based on a comprehensive analysis of the patient's disease status, presence of complications including co-infections and tumors, status of underlying diseases, drug-drug interactions, patient adherence, viral load, features of HIV drug resistance (especially the features of HIV drug resistance in local populations), drug accessibility, barrier to drug resistance, and adverse reactions (especially long-term adverse reactions). Medication adherence is the most vital determinant of ART success; thus, patients must be well-educated on medication adherence before ART is initiated. During follow-up visits, long-term adverse drug reactions need to be monitored and ART regimens must be adjusted or measures taken accordingly. The case management model is recommended in standardized patient follow-ups and management.

In recent years, the concept of personalized antiviral treatment has been proposed. Some drugs are not suitable for some patient groups; for example, EFV is not suitable for patients with viral loads >5 × 105 copies/mL.[54] Some studies showed that the blood EFV concentrations remained outside the therapeutic window in 22% of patients at a dose of 600 mg daily. Moreover, these patients had higher risks of ART failure or adverse reactions.[55] Some studies have suggested that patients with AIDS in China can achieve therapeutic effects on ART regimens containing 400 mg EFV, with fewer adverse reactions.[56,57] The WHO ART guidelines already list 300 mg TDF + 300 mg 3TC + 400 mg EFV as one ART option.[22] In recent years, an increasing number of studies have assessed the effects of lowering routine doses of antiviral medications. These studies showed that lowering the dosage in ART regimens can help retain antiviral efficacy while lowering the incidence of adverse reactions.[58,59] Personalized antiviral therapies usually perform TDM, that is, adjust the drug doses based on blood drug concentrations. Although routine TDM is currently not recommended in clinical practice, TDM is recommended for patients on regimens with clinically significant drug-drug interactions; patients with clinically apparent hepatic and renal dysfunctions; patients experiencing dose-related adverse reactions; patients experiencing changes in dosage; patients having good adherence to therapies but achieving poor ART efficacy; and pregnant women who are on ART and at higher risks.[20]

The arbitrary adjustment of regimens is not recommended for patients showing effective viral suppression after ART. The optimization of ART regimens can be considered under the following circumstances[20]: (A) simplification of the medication regimen by reducing the number of tablets and dose frequency; (B) improving drug tolerance by reducing short-term or long-term toxicity; (C) preventing or alleviating drug-drug interactions; (D) optimization of ART for pregnant women or patients who might get pregnant; (E) reduction of treatment costs; and (F) switching to long-acting injectable formulations to reduce drug burden. Therapy optimization should be based on maintaining viral suppression without posing threats to the future selection of medications. When optimizing ART regimens, special attention should be paid to a patient history of HIV drug resistance and HBV or HCV co-infections. Viral suppression status should be monitored after therapy regimens are adjusted.

Switches between antiviral medications of the same class are usually safe and effective. The results of multiple studies have suggested that antiviral efficacy can be maintained following the substitution of NNRTI- or PI-based regimens for INSTIs-based regimens (eg, DTG, RAL, BIC, or EVG/c). For some patients, simplified two-drug regimens can be adopted based on their disease status. The efficacy and safety of the two-drug regimen ART DTG+3TC in primary and secondary treatments have been confirmed, and it is currently listed as a preferred ART regimen in international guidelines; however, this regimen is not suitable for patients co-infected with HBV.[20,21] The simplified INSTI- or PI-containing regimens currently supported by research data or clinical experience include[20]: (A) DTG + RPV; (B) DTG + 3TC (or FTC); (C) DRV/r + DTG; (D) PIs (ATV/r, LPV/r, DRV/r) + 3TC; and (E) ABT + LPV/r. Single-drug therapies are not allowed in ART optimization.

Screening and management of NADs

The application of ART has turned AIDS into a chronic illness that should be followed up and managed using models for chronic disease management. During follow-up visits, the evaluation and screening for NADS should be performed and prophylactic or treatment measures should be taken according to the evaluation results. A study in China showed that patients with AIDS who had not initiated ART were exposed to more risk factors for CVD and showed a high incidence of CVD within 10 years, while ART showed a lower rate of intervention on hyperlipemia. Patients aged ≥50 years with CD4+T lymphocyte counts <200/μL had higher risks of developing CVD. Thus, routine clinical management practices for patients with HIV infection/AIDS who have not started ART should incorporate the screening and evaluation of CVD risk factors.[60] During follow-up visits, CVD risk assessment should be performed and prophylactic measures should be taken accordingly. For patients with HIV infection with chronic illnesses, including hypertension, diabetes mellitus, dyslipidemia, coronary heart disease, cerebrovascular disease, non-HIV-related tumors (especially liver, lung, breast, prostate, and colorectal cancer, and others), chronic obstructive pulmonary disease, non-alcoholic fatty liver disease, and bone disease, chronic disease management archives should be built according to the standards of archive establishment for HIV-negative patients, and screening and prophylaxis should be performed based on relevant guidelines.[21,22] With the increasing length of survival in patients with HIV infection, special attention is needed regarding the impact of age on the care of patients with HIV infection. Moreover, the evaluation of geriatric syndromes should be incorporated into comprehensive HIV care.[61] Diagnosis and treatment should be provided based on the characteristics of these chronic illnesses and the requirements for tiered diagnosis and treatment. Patients should be encouraged to receive diagnosis and treatment in the specialist outpatient clinics of general hospitals.

Comprehensive psychosocial care

Patients should be offered comprehensive care and services,[21] including screening for mental health screening, counseling on healthy lifestyles (eg, smoking cessation), Routes of HIV infection and transmission screening and management, counseling on procreation, screening for HIV-associated neurocognitive disorder, counseling on travel and health, and palliative medical care. These services should be provided based on relevant guidelines or standards.

Counseling on vaccinations for patients with HIV infection/ AIDS should be considered. HIV-infected populations negative for HBV surface antigen and HBV surface antibody should be vaccinated against HBV as soon as possible, regardless of their HBV core antibody counts. While the vaccination success rate in populations with CD4+T lymphocyte counts <200/μL is lower than that in HIV-negative populations and HIV-infected persons with higher CD4+T lymphocyte counts, HBV vaccination is still recommended. Patients with HIV/AIDS infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have a higher fatality rate due to a higher incidence of severe cases.[62] Thus, patients with HIV infection/AIDS should receive inactivated SARS-CoV-2 vaccines. Recombinant subunit vaccines can also be considered.[63]

The coronavirus disease 2019 pandemic has had varying impacts on medical services for patients with HIV infection/ AIDS. Hence, based on these impacts, efforts are needed to create favorable conditions to minimize the negative impacts and to guarantee the sustainability of medical services.

Consultants: Fu Gao, Fu-Sheng Wang

Academic secretaries: Yinzhong Shen, Wei Lyu, Yun He, Xiejie Chen

Writing experts (Arranged in order by the number of strokes in last name): Ping Ma (The Second Department of Infectious Diseases, Tianjin Second People's Hospital), Min Wang (Center of Infectious Diseases, The First Hospital of Changsha), Hui Wang (The First Department of Infectious Diseases, The Third People's Hospital of Shenzhen), Fuxiang Wang (The Third Department of Infectious Diseases, The Third People's Hospital of Shenzhen), Li Shi (Department of Infection Diseases, Tibet Autonomous Region People's Hospital), Hongzhou Lu (The Third People's Hospital of Shenzhen/Shanghai Public Health Clinical Center), Hanhui Ye (Department of Infectious Diseases, Mengchao Hepatobiliary Hospital of Fujian Medical University), Lang Bai (Department of Infectious Diseases, West China Hospital Sichuan University), Wei Lyu (Department of Infectious Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences), Biao Zhu (Department of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University), Shuiqing Liu (The First Department of Infection, Guiyang Public Health Clinical Center), Yanfen Liu (Department of Infectious Diseases, The Fourth People's Hospital of Nanning), Jianning Jiang (Department of Infectious Diseases, The First Affiliated Hospital of Guangxi Medical University), Yongtao Sun (Department of Infection, Tangdu Hospital, Air Force Medical University), Lijun Sun (Outpatient of Infection Center, Beijing Youan Hospital, Capital Medical University), Taisheng Li (Department of Infectious Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences), Linghua Li (Infectious Diseases Center, Guangzhou Eighth People's Hospital, Guangzhou Medical University), Huiqin Li (Department of Infectious Diseases, Yunnan Provincial Infectious Disease Hospital), Hao Wu (Clinical Research Center for Infectious Diseases, Beijing Youan Hospital, Capital Medical University), Yun He (The First Department of Infectious Diseases, The Third People's Hospital of Shenzhen), Yan He (Department of Infectious Diseases, The Second Xiangya Hospital of Central South University), Shenghua He (The First Department of Infectious Diseases, The Public Health Clinical Center of Chengdu), Ning Wang (National Center for AIDS/STD Control and Prevention, Chinese Center for Disease Control and Prevention), Yinzhong Shen (Department of Infection and Immunology, Shanghai Public Health Clinical Center, Fudan University), Yuxia Song (Department of Infectious Diseases, The Eighth Affiliated Hospital of Xinjiang Medical University), Tong Zhang (Clinical Research Center for Infectious Diseases, Beijing Youan Hospital, Capital Medical University), Fujie Zhang (Center of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University), Xiejie Chen (Infectious Diseases Center, Guangzhou Eighth People's Hospital, Guangzhou Medical University), Yahong Chen (Department of Infectious Diseases, Mengchao Hepatobiliary Hospital of Fujian Medical University), Yaokai Chen (Department of Infectious Diseases, Chongqing Public Health Medical Center), Feng Lin (Department of Infectious Diseases, Hainan General Hospital), Cong Jin (Reference Laboratory, National Center for AIDS/STD Control and Prevention, Chinese Center for Disease Control and Prevention), Hongxin Zhao (Infectious Diseases Center, Beijing Ditan Hospital, Capital Medical University), Qingxia Zhao (Department of Infectious Diseases, Henan Infectious Disease Hospital), Xiaoyuan Xu (Department of Infectious Diseases, Peking University First Hospital), Zhe Xu (Department of Biological damage Treatment, The Fifth Medical Center of Chinese PLA General Hospital), Xiaoping Tang (Guangzhou Medical University), Wei Guo (Department of Infectious Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology), Bin Su (Clinical Research Center for Infectious Diseases, Beijing Youan Hospital, Capital Medical University), Weimin Jiang (Department of Infectious Diseases, Huashan Hospital, Fudan University), Yan Jiang (Reference Laboratory, National Center for AIDS/ STD Control and Prevention, Chinese Center for Disease Control and Prevention), Jianhua Yu (Affiliated Hangzhou Xixi Hospital, Zhejiang University School of Medicine), Jingdong Xie (Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine), Weiping Cai (Infectious Diseases Center, Guangzhou Eighth People's Hospital, Guangzhou Medical University), Hongxia Wei [Department of Infectious Diseases, Nanjing Hospital Affiliated to Nanjing University of Traditional Chinese Medicine (The Second Hospital of Nanjing)].

Funding

This work was supported by the Major National Science and Technology Projects during the 13th Five-Year Plan Period (2017ZX10202101).

Conflicts of Interest

None.

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Keywords:

Acquired immunodeficiency syndrome; Diagnosis; Guideline; HIV; Treatment

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