*AIDS

Chapter: AIDS
McMaster Section Editor(s): Mark Loeb
Section Editor(s) in Interna Szczeklika: Piotr Zaborowski, Jerzy Stefaniak, Miłosz Parczewski, Weronika Rymer, Agnieszka Wroczyńska
McMaster Author(s): Philippe El-Helou
Author(s) in Interna Szczeklika: Jacek Gąsiorowski, Brygida Knysz, Andrzej Gładysz
Additional Information

Etiology and Pathogenesis Top

1. Etiologic agent: Human immunodeficiency virus (HIV), a retrovirus that infects CD4-positive cells (T-helper cells, macrophages, monocytes, dendritic cells).

2. Reservoir and transmission: The reservoir of HIV is humans (however, the virus originated in nonhuman primates and was later transmitted to humans). The source of infection is another HIV-infected individual. Principal virus transmission routes include sexual contacts, blood, and mother-to-child transmission, that is, transmission to infants during pregnancy, birth, and breastfeeding.

3. EpidemiologyHIV is present worldwide, with the majority of the epidemic principally affecting sub-Saharan Africa. A significant proportion of infected individuals remain undiagnosed until clinically apparent immunodeficiency develops.

4. Risk factors: Sexual intercourse (estimated median risk of HIV transmission per exposure ranges from 1.1% for receptive anal to 0.082% for insertive vaginal intercourse; receptive oral sex, 0.02%); IV drug use (0.67% per needle-sharing event); needlestick injury (0.3% risk); transmission to a newborn from the HIV-positive mother (risk of ~30% without prophylaxis; this may be reduced to <1% if prophylactic treatment is provided to mother and child).

5. Incubation and contagious period: Primary HIV infection, 1 to 8 weeks; development of acquired immunodeficiency syndrome (AIDS) in individuals not receiving antiretroviral therapy (ART), 1.5 to 15 years (on average 8-10 years) from the time of infection. An HIV-infected individual becomes contagious within a few days of contracting the virus.

Clinical Features and Natural History Top

HIV infection progresses through various stages, which are characterized by distinctive clinical features and immunologic parameters and may be classified as one of 5 HIV infection stages (0, 1, 2, 3, or unknown) based on the CD4+ T-cell count or diagnosis of an opportunistic infection (Table 1 and Table 2). Irrespective of infection stages, clinical presentations may include the following:

1. Primary HIV infection [clinical stage 0]): Infection within prior 6 months with a documented sequence of negative/indeterminate results prior to the confirmed HIV positive test. Clinically, a primary HIV infection may manifest as acute retroviral syndrome (ARS) with clinical features of a mononucleosis-like illness. The symptoms may be minor and resolve spontaneously within 2 weeks; the most common ARS symptoms include fever, generalized lymphadenopathy, pharyngitis, rash, and myalgia/arthralgia. HIV infection is commonly associated with the history of other sexually transmitted infections, especially syphilis. Primary HIV infection may be suspected in the following cases:

1) The patient has a history of high-risk sexual exposure or has been exposed to infected blood in the previous few weeks (currently blood products are rarely a source of infection, as they are screened for HIV).

2) An adult patient has a recent episode of “mononucleosis.”

3) The patient has signs and symptoms or history of other sexually transmitted diseases (syphilis, gonorrhea).

2. Chronic HIV infection may manifest as the following conditions:

1) Asymptomatic HIV infection occurs after the primary infection and results from establishing a relative balance between HIV replication and the antiviral immune response. Patients not receiving ART may remain asymptomatic for 1.5 to 15 years.

2) Persistent generalized lymphadenopathy (PGL) is observed in the asymptomatic stage and includes enlarged lymph nodes (>1 cm in diameter) in ≥2 regions (except for inguinal nodes) persisting >3 months (key diagnostic criterion).

3) Chronic fatigue; headache; splenomegaly (~30%); increased incidence of nonopportunistic skin, respiratory, and gastrointestinal infections.

4) Symptomatic infection with clinical features not fulfilling the criteria for the AIDS-defining condition; these include infections resulting from decreased CD4+ T-cell counts (Table 2): herpes zoster (shingles) involving >1 dermatome or recurrent bacillary angiomatosis (red papillary skin lesions caused by Bartonella henselae infection with features resembling Kaposi sarcoma); oral hairy leukoplakia (lesions similar to oral candidiasis, located mainly on the lateral aspects of the tongue); oropharyngeal (thrush) candidiasis or vulvovaginal candidiasis (persistent, recurrent, or resistant to treatment); cervical dysplasia and cervical carcinoma in situ (human papillomavirus [HPV] infection); fever lasting >1 month; persistent diarrhea lasting >1 month; clinical manifestations of thrombocytopenia; listeriosis; peripheral neuropathy; pelvic inflammatory disease.

3. Clinical features of AIDS: Conditions and opportunistic infections indicative of the stage 3 disease as listed in the AIDS surveillance case definition (opportunistic infections and neoplasms: Table 2). AIDS diagnosis usually requires prompt ART, as the patient may die of opportunistic infections or neoplasms.

Diagnosis Top

The patient must give his/her informed consent prior to HIV testing. The patient has the right to anonymous testing.

HIV testing should be considered part of differential diagnosis in patients with a condition of unknown etiology that has an atypical course, is resistant to treatment, or recurs, and is potentially related to a known clinical presentation. HIV testing is particularly recommended in the case of a confirmed AIDS-indicator disease (Table 2), syphilis, molluscum contagiosum, genital herpes simplex, anogenital warts, lymphogranuloma venereum, hepatitis B or C, pneumonia not responding to antimicrobial treatment, aseptic meningitis, Guillain-Barré syndrome, transverse myelitis, encephalopathy of unknown etiology, progressive dementia in patients <60 years, vaginal dysplasia, recurrent vulvovaginal candidiasis, HPV infection and other sexually transmitted diseases, pregnancy (including partners of the pregnant women), lung cancer, seminoma, head and neck cancer, Hodgkin lymphoma, Castleman disease, thrombocytopenia, neutropenia or lymphopenia of unclear etiology, loss of body weight for unknown reasons, esophageal or oral candidiasis, persistent diarrhea of unclear etiology, colitis of unclear etiology, cachexia of unclear etiology, herpes simplex virus retinitis, varicella-zoster virus infection, Toxoplasma gondii infection, retinopathy of unclear etiology, glomerular and tubular nephropathies of unclear etiology, seborrheic dermatitis, psoriasis without a positive family history, herpes zoster (recurrent, involving large areas of the skin).

Diagnostic Tests

1. Serology (the basis of screening) (Figure 1): Serum anti-HIV antibodies (enzyme-linked immunosorbent assay [ELISA] or enzyme immunoassay [EIA]). Anti-HIV antibodies appear within 2 to 9 weeks of infection (after 8 days at the earliest) and are usually detectable within 12 weeks. A positive result must be confirmed by a Western blot assay (performed exclusively by reference centers). In the case of inconclusive results, fourth-generation tests detecting p24 antigen and anti-HIV antibodies may be used (these allow for the detection of HIV already at the stage of primary HIV infection).

2. Decreased CD4+ T-cell counts; a CD4+/CD8+ T-cell ratio <1.

3. Virology (detection of HIV RNA in serum using molecular biology methods, including DNA and RNA detection, viral culture, or HIV sequence): Diagnostics of seronegative/indeterminate individuals suspected of primary HIV infection, newborns of HIV-positive mothers. Quantitative assays (number of HIV RNA copies/mL) are used to determine viral load and to monitor the effectiveness of ART.

Diagnostic Criteria

Confirmed HIV infection (Figure 1) and fulfillment of the clinical and immunologic criteria that determine the stage of the disease (Table 1 and Table 2). Pretest and posttest counseling is necessary. In patients with primary HIV infection, the screening and confirmatory serologic tests detecting anti-HIV antibodies may be negative or inconclusive. Therefore, the diagnosis may be established solely on the basis of serum HIV RNA detection, or serum p24 antigen if the assays detecting the virus are not available (negative p24 antigen test results do not exclude acute infection).

It is highly recommended to test sexual partners of the individuals who test positive for HIV, are diagnosed with primary HIV infection, or both.

Treatment Top

1. Combined antiretroviral therapy (cART) is a combination of three drugs acting synergistically to inhibit HIV replication, which allows for at least partial functional restoration of the immune system (increase in CD4+ T-cell counts, sometimes even up to normal values) and elimination of active HIV replication (serum/plasma HIV RNA levels below the limit of detection using the molecular assay), but it does not eradicate the virus nor achieve a total virologic clearance. cART significantly reduces the risk of HIV transmission and improves survival and quality of life. It is used as a long-term treatment option to suppress HIV replication for as long as possible.

2. Indications for cART: The latest North American guidelines recommend that all HIV-positive individuals be treated regardless of their CD4+ T-cell counts, with the strength of this recommendation depending on the pretreatment CD4+ count (strong recommendation for counts <350, conditional for >500, and moderate for counts in-between). European guidelines strongly recommend treatment if CD4+ counts are <350 cells/microL. Evidence 1 Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). High Quality of Evidence (high confidence that we know true effects of the intervention). Severe P, Juste MA, Ambroise A, et al. Early versus standard antiretroviral therapy for HIV-infected adults in Haiti. N Engl J Med. 2010 Jul 15;363(3):257-65. doi: 10.1056/NEJMoa0910370. PubMed PMID: 20647201; PubMed Central PMCID: PMC3676927. Cohen MS, Chen YQ, McCauley M, et al; HPTN 052 Study Team. Prevention of HIV-1 infection with early antiretroviral therapy. N Engl J Med. 2011 Aug 11;365(6):493-505. doi:10.1056/NEJMoa1105243. Epub 2011 Jul 18. PubMed PMID: 21767103; PubMed Central PMCID: PMC3200068. Grinsztejn B, Hosseinipour MC, Ribaudo HJ, et al; HPTN 052-ACTG Study Team. Effects of early versus delayed initiation of antiretroviral treatment on clinical outcomes of HIV-1 infection: results from the phase 3 HPTN 052 randomised controlled trial. Lancet Infect Dis. 2014 Apr;14(4):281-90. doi: 10.1016/S1473-3099(13)70692-3. Epub 2014 Mar 4. Erratum in: Lancet Infect Dis. 2014 Apr;14(4):269. PubMed PMID: 24602844; PubMed Central PMCID: PMC4144040. Treatment is also recommended for higher counts (even >500 cells/microL). Evidence 2 Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). A weak rather than strong recommendation related to a smaller size of benefit in comparison to a population with a lower CD4+ count and unclear consequences of a lifelong combined antiretroviral therapy. Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to the relatively low number of events (imprecision of size of benefit) and some indirectness (lifelong treatment tested in a 3-year study). INSIGHT START Study Group, Lundgren JD, Babiker AG, Gordin F, et al. Initiation of Antiretroviral Therapy in Early Asymptomatic HIV Infection. N Engl J Med. 2015 Aug 27;373(9):795-807. doi: 10.1056/NEJMoa1506816. Epub 2015 Jul 20. PubMed PMID: 26192873; PubMed Central PMCID: PMC4569751. TEMPRANO ANRS 12136 Study Group, Danel C, Moh R, Gabillard D, et al. A Trial of Early Antiretrovirals and Isoniazid Preventive Therapy in Africa. N Engl J Med. 2015 Aug 27;373(9):808-22. doi: 10.1056/NEJMoa1507198. Epub 2015 Jul 20. PubMed PMID: 26193126. cART should be initiated regardless of the CD4+ count in the following patients:

1) Pregnant women.

2) Patients with chronic hepatitis B and/or hepatitis C (in patients with HIV/HCV coinfection and CD4+ T-cell count >500 cells/microL, cART may be delayed until HCV treatment is completed).

3) Patients >60 years of age.

4) Patients with HIV-related nephropathy.

5) Patients with acute primary HIV infection, regardless of the symptoms.

6) Patients with an AIDS-indicator disease.

7) Patients with neurocognitive disorders.

8) Serodiscordant couples (one of the partners is HIV-negative, the other is HIV-positive; the treatment is initiated in HIV positive partner).

3. Classes of drugs used in cART:

1) Nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs): Abacavir, emtricitabine, lamivudine, tenofovir, zidovudine.

2) Nonnucleoside reverse transcriptase inhibitors (NNRTIs): Efavirenz, etravirine, nevirapine, rilpivirine.

3) Protease inhibitors (PIs): Darunavir, fosamprenavir, indinavir, lopinavir, nelfinavir, saquinavir, tipranavir, atazanavir.

4) Integrase inhibitors (integrase strand transfer inhibitors [INSTIs]): Raltegravir, elvitegravir/cobicistat, dolutegravir.

5) Entry inhibitors: Enfuvirtide.

6) CCR5 inhibitors: Maraviroc.

Recommended combinations of drugs in ART-naive patients: 2 NRTIs + NNRTI; 2 NRTIs + PI (+ low-dose ritonavir); 2 NRTIs + INSTI (most current preferred regimens are INSTI-based).

Prognosis Top

The implementation of cART in HIV-infected individuals results in the restoration of immune function (lymphocyte CD4+ counts, proportions, and function), suppression of HIV replication, decrease in the risk of AIDS-related and non–AIDS-related conditions, as well as improvement in survival rates (life expectancy of an HIV-positive patient receiving cART in whom stable lymphocyte CD4+ counts >500 cells/microL have been restored is similar to individuals who are HIV-negative).Evidence 3 Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to indirectness (high-risk and older patients possibly underrepresented). Samji H, Cescon A, Hogg RS, et al; North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) of IeDEA. Closing the gap: increases in life expectancy among treated HIV-positive individuals in the United States and Canada. PLoS One. 2013 Dec 18;8(12):e81355. doi: 10.1371/journal.pone.0081355. eCollection 2013. PubMed PMID: 24367482; PubMed Central PMCID: PMC3867319.

Prevention Top

1. Avoiding exposure to HIV. No vaccine is available.

2. Postexposure prophylaxis: see Management of Occupational Exposures to Blood-Borne Viral Infections.

3. Preexposure prophylaxis provides close to a 50% decrease in the transmission rate in persons with high risk of sexual transmission (male to male), in whom we recommend its use,Evidence 4Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). High Quality of Evidence (high confidence that we know true effects of the intervention). Grant RM, Lama JR, Anderson PL, et al; iPrEx Study Team. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med. 2010 Dec 30;363(27):2587-99. doi: 10.1056/NEJMoa1011205. Epub 2010 Nov 23. PubMed PMID: 21091279; PubMed Central PMCID: PMC3079639. Volk JE, Marcus JL, Phengrasamy T, et al. No New HIV Infections With Increasing Use of HIV Preexposure Prophylaxis in a Clinical Practice Setting. Clin Infect Dis. 2015 Nov 15;61(10):1601-3. doi: 10.1093/cid/civ778. Epub 2015 Sep 1. PubMed PMID: 26334052. McCormack S, Dunn DT, Desai M, et al. Pre-exposure prophylaxis to prevent the acquisition of HIV-1 infection (PROUD): effectiveness results from the pilot phase of a pragmatic open-label randomised trial. Lancet. 2015 Sep 9. pii:S0140-6736(15)00056-2. doi: 10.1016/S0140-6736(15)00056-2. [Epub ahead of print] PubMed PMID: 26364263. and in injecting drug users, in whom we suggest its use.Evidence 5Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). A weak rather than strong recommendation due to a smaller absolute benefit and indirectness to the North American population. Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to indirectness to the North American population. Choopanya K, Martin M, Suntharasamai P, et al; Bangkok Tenofovir Study Group. Antiretroviral prophylaxis for HIV infection in injecting drug users in Bangkok, Thailand (the Bangkok Tenofovir Study): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2013 Jun 15;381(9883):2083-90. doi: 10.1016/S0140-6736(13)61127-7. Epub 2013 Jun 13. PubMed PMID: 23769234. On-demand preexposure prophylaxis is being investigated.

Tables and FiguresTop

Table 1. Stages of HIV infection based on the CD4+ T-cell counts in adults and children ≥6 yearsa

Immunologic categories (CD4+ T-cell count)

Clinical categories

CD4+ T-cell count

CD4+ T-cell %b

Stage 0

Sequence of discordant test results indicative of early HIV infection in which a negative or indeterminate result was obtained within 180 days of a positive result, regardless of CD4 T-lymphocyte test results and opportunistic illness diagnoses

Stage 1

≥500/microL

≥26

Stage 2

200-499/microL

14-25

Stage 3

<200/microL

<14

a If the criteria for stage 0 are not met and information on the criteria for other stages is missing, the stage is classified as unknown.

b CD4+ T-cell percentage is taken into consideration only if the CD4+ T-cell count is missing.

If the criteria for stage 0 are not met and an opportunistic illness defining stage-3 disease has been diagnosed (see Table 2 in AIDS), the patient is classified as stage 3 regardless of CD4+ T-cell test results.

Based on: Centers for Disease Control and Prevention (CDC). 1993 Revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. MMWR Recomm Rep. 1992 Dec 18;41(RR-17):1-19.

HIV, human immunodeficiency virus.

Table 2. AIDS-indicator diseases

Stage-3 defining opportunistic infections

Bacterial infections, multiple or recurrenta
Candidiasis of bronchi, trachea, or lungs
Candidiasis of esophagus
Cervical cancer, invasiveb
Coccidioidomycosis, disseminated or extrapulmonary
Cryptococcosis, extrapulmonary
Cryptosporidiosis, chronic intestinal (>1 month’s duration)
Cytomegalovirus disease (other than liver, spleen, or nodes), onset at age >1 month
Cytomegalovirus retinitis (with loss of vision)
Encephalopathy attributed to HIV
Herpes simplex: chronic ulcers (>1 month’s duration) or bronchitis, pneumonitis, or esophagitis (onset at age >1 month)
Histoplasmosis, disseminated or extrapulmonary
Isosporiasis, chronic intestinal (>1 month’s duration)
Kaposi sarcoma
Lymphoma, Burkitt (or equivalent term)
Lymphoma, immunoblastic (or equivalent term)
Lymphoma, primary, of brain
Mycobacterium avium complex or Mycobacterium kansasii, disseminated or extrapulmonary
Mycobacterium tuberculosis of any site, pulmonary,b disseminated, or extrapulmonary
Mycobacterium, other species or unidentified species, disseminated or extrapulmonary
Pneumocystis jirovecii (previously known as Pneumocystis carinii) pneumonia
Pneumonia, recurrentb
Progressive multifocal leukoencephalopathy
Salmonella septicemia, recurrent
Toxoplasmosis of brain, onset at age >1 month
Wasting syndrome attributed to HIV

Neoplastic diseases

Kaposi sarcoma
Lymphoma (Burkitt, primary lymphoma of brain, immunoblastic)
Invasive cervical carcinoma

Clinical syndromes

HIV-related encephalopathy
HIV-related wasting

a Only among children aged <6 years.

b Only among adults, adolescents, and children aged ≥6 years.

Adapted from: Centers for Disease Control and Prevention (CDC). Revised surveillance case definition for HIV infection--United States, 2014. MMWR Recomm Rep. 2014 Apr 11;63(RR-03):1-10.

AIDS, acquired immunodeficiency syndrome; HIV, human immunodeficiency virus.

Figure 1. Recommended laboratory HIV testing algorithm for serum or plasma specimens. Based on: Centers for Disease Control and Prevention. Laboratory Testing for the Diagnosis of HIV Infection: Updated Recommendations. Published June 27, 2014. Accessed November 23, 2015.

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