Clinical manifestations and diagnosis of HIV-2 infection

INTRODUCTION — Although HIV-1 infection is associated with most of the global AIDS pandemic, HIV-2 is an important cause of disease in West Africa, where it is endemic. HIV-2 infection has also been described in locales with cultural and socioeconomic ties to West Africa, including the United States. It is an important consideration in patients with an AIDS-like illness or among persons with epidemiologic risk factors for infection [1]. Epidemiologic risk factors are similar to HIV-1 infection and include a past history of blood transfusion or having a sex partner or needle-sharing partner with HIV-2 infection or perinatal transmission from an HIV-2-infected mother.

This topic will address the clinical manifestations and diagnosis of HIV-2 infection. The epidemiology, transmission, natural history, pathogenesis and treatment of HIV-2 are discussed elsewhere. (See "Epidemiology, transmission, natural history, and pathogenesis of HIV-2 infection" and "Treatment of HIV-2 infection".)

STAGING OF DISEASE — In persons living with HIV-1, two important laboratory determinants of the rate of progression are the CD4 cell count and the plasma viral load [2,3]. In untreated patients, the average rate of decline of CD4 cells ("CD4 slope") is about 50/mm³ per year and the average plasma RNA viral load (without therapy) is 30,000 to 50,000 copies/mL [2-4]. Patients with a CD4 cell count <200 cells/mm³ are considered to have AIDS; such patients are at significantly increased risk for opportunistic infections and AIDS-related malignancies. (See "The natural history and clinical features of HIV infection in adults and adolescents".)

There are far fewer data on the CD4 threshold that is associated with an increased risk of AIDS and opportunistic infections among HIV-2 infected patients. Most experts apply the same CD4 cell count threshold (<200 cells/mm³) as a laboratory parameter indicating AIDS in persons living with HIV-2.

Laboratory monitoring for HIV-2 RNA viral load is problematic since testing availability is more limited. Most commercial laboratories do not offer testing for HIV-2 RNA viral load and the few that do offer only qualitative testing (eg, Quest Diagnostics laboratories). Quantitative HIV-2 RNA viral load testing may be obtained from the following laboratories [5-8]:

●University of Washington Lab Medicine Community Services: (phone 1-800-713-5198 or [email protected]) https://dlmp.uw.edu/site/contact

●New York State Department of Health Lab: (phone 518-473-6007) http://www.wadsworth.org/programs/id/bloodborne-viruses/clinical-testing/hiv-2-nucleic-acid

Laboratories that perform HIV-2 RNA quantitative testing report generally lower levels of HIV-2 viremia compared with patients with HIV-1 [5-13].

RISK FACTORS FOR CLINICAL PROGRESSION — Several factors contribute to HIV-1 disease progression including viral fitness, genetic factors, HIV coreceptor usage, nutritional status, as well as other comorbidities. However, the cofactors that lead to progression of HIV-2 infection are not as well understood.

CLINICAL MANIFESTATIONS

Primary HIV-2 infection — There are scant data on the clinical presentation of acute HIV-2 infection [14,15].

Chronic infection — Compared with HIV-1, HIV-2 infection is characterized by a longer asymptomatic stage of infection and slower declines of CD4+ T-cell counts [9-13,16-25]. (See "Epidemiology, transmission, natural history, and pathogenesis of HIV-2 infection".)

However, the clinical manifestations of advanced HIV-2 infection are generally similar to those reported for HIV-1 [26]. Once advanced immunosuppression has occurred (eg, CD4 cell count <200 cells/mm³), persons living with HIV-2 are at risk for similar types of opportunistic infections, such as tuberculosis, pneumocystis, toxoplasmosis, and cryptococcal disease. Although some studies have suggested that there may be some subtle differences in the frequencies of reported opportunistic infections in persons living with HIV-2, these observational data are limited by small numbers of patients [27-33].

The history and physical examination for persons living with HIV-2 should be detailed and extensive, similar to that of the HIV-1, as discussed elsewhere. (See "Primary care of adults with HIV".)

TESTING FOR HIV-2 INFECTION — As in HIV-1 infection, patients should have serologic testing for HIV-2 infection with confirmatory testing. (See "Screening and diagnostic testing for HIV infection", section on 'Testing algorithm'.)

Screening antibody tests approved by the US Food and Drug Administration to detect and differentiate HIV-2 infection from HIV-1 include the BioPlex 2200 HIV Ag-Ab assay (Bio-Rad Laboratories) and the Geenius HIV 1/2 Supplemental Assay [34].

A reactive result may be confirmed with a supplemental HIV-2 antibody test or an HIV-2 specific nucleic acid test. These tests include:

●An HIV-2 specific immunoblot assay (eg, Western blot)

●An HIV-2 specific enzyme immunoassay

●Real-time polymerase chain reaction (RT-PCR) testing for the viral isolate itself (DNA/RNA)

Supplemental HIV-2 testing is available through the United States Centers for Disease Control and Prevention, or may be obtained through commercial testing laboratories, such as Pathology Associates Medical Laboratories (PAML) or Quest Diagnostics in the United States [35,36]. Qualitative HIV-2 DNA/RNA testing through RT-PCR testing can be obtained through Quest Diagnostics [36] and the University of Washington Clinical Labs [37]. Quantitative HIV-2 RNA testing may be obtained as described above. (See 'Staging of disease' above.)

Outside of the United States, supplemental HIV-2 antibody assays that are commercially available include: SD Bioline (Standard Diagnostics), INNO-LIA HIV I/II Score (Innogenetics NV), and HIV-2 Blot (MP Biomedials, LLC). Point-of-care HIV-2 nucleic acid (DNA/RNA) qualitative detection and differentiation (from HIV-1) can be performed using the Alere Detect Assay [38-40].

DIAGNOSTIC ISSUES RELATED TO HIV-1 WESTERN BLOT TESTING

General background — Clinicians need to be aware that all commercially available HIV-1 Western Blot assays may fully or partially cross-react with HIV-2, giving positive, indeterminate, or negative results that could lead to an incorrect diagnosis of HIV-1 infection or a missed diagnosis of HIV-2 [41].

These diagnostic issues were well illustrated by results of an HIV-2 surveillance survey performed by the CDC in 2009, where the vast majority of cases were suspected because of inconsistent clinical or laboratory data [42]. Of 166 cases with HIV-2 infection, 56 percent of patients had an indeterminate HIV-1 immunoblot despite a positive HIV-1 or HIV-1/HIV-2 antibody screening test; 41 percent had an undetectable HIV viral load despite a positive HIV-1 immunoblot; and less than 1 percent had a negative HIV-1 immunoblot despite a positive HIV-1 or HIV-1/HIV-2 antibody screening test.

The Centers for Disease Control and Prevention has issued recommendations for a new HIV testing algorithm that includes initial screening with a fourth generation Ag/Ab HIV-1/2 immunoassay and confirmatory testing with a HIV-1/HIV-2 antibody differentiation immunoassay [43]. In addition to improving early HIV-1 detection and diagnosis, this new algorithm will likely increase HIV-2 diagnoses, and eliminate misclassification of HIV-2 resulting from a cross-reactive western blot. A detailed discussion on HIV testing is found elsewhere. (See "Screening and diagnostic testing for HIV infection", section on 'Testing algorithm'.)

Interpretation of Western blot test results — Previously recommended antibody testing included a screening enzyme immunoassay (EIA, which can also be referred to as a third generation antibody test) followed by a confirmatory Western blot if the EIA is positive. If such testing was performed in a patient with suspected HIV-2 infection, the interpretation and evaluation of various possible HIV immunoblot results are as follows:

A reactive HIV-1 Western blot — A confirmatory Western blot for HIV-1 can be reactive due to true infection with HIV-1 or cross-reactivity to HIV-2 proteins [44]. Thus, this laboratory profile can represent three possible scenarios: monoinfection with HIV-1, monoinfection with HIV-2, or dual infection with both viruses.

If HIV-2 infection is suspected (eg, the patient is from West Africa), further testing with a specific HIV-2 Western blot is recommended. If the HIV-2 Western blot is negative, the patient can be assumed to have HIV-1 monoinfection. If the HIV-2 Western blot is reactive, the patient may have monoinfection with HIV-2 or dual infection with both HIV-1 and HIV-2. Further testing for HIV-1 RNA/DNA and HIV-2 RNA/DNA should be performed.

An indeterminate HIV-1 Western blot — An indeterminate Western blot can infer acute HIV-1 infection or chronic HIV-2 infection. Further testing for HIV-1 RNA is indicated for the possibility of acute HIV-1 infection; if HIV-1 RNA is not detected, then HIV-2 Western blot testing and HIV-2 RNA/DNA should be performed [41].

A negative HIV-1 Western blot — A patient with a reactive HIV serology, but a negative confirmatory HIV-1 Western blot, may have HIV-2 infection. Thus, further testing with a specific HIV-2 Western blot test and HIV-2 RNA/DNA should be performed, particularly in persons with epidemiologic risk factors [41].

WHEN TO SUSPECT HIV-2 INFECTION — Clinicians must have a high index of suspicion for the diagnosis of HIV-2 infection since laboratory testing results can lead to diagnostic confusion, as discussed above [41]. Patients with a diagnosis of HIV-1 infection may actually be infected with HIV-2 or may be dually infected with both viruses. Certain clinical or laboratory clues should lead to further patient evaluation and testing, as discussed below [45].

Clinical clues to possible HIV-2 infection — HIV-2 diagnostic testing should be considered when clinical or laboratory data are incongruent. As examples:

●A patient from an HIV-2 endemic area, who presents with an opportunistic infection (eg, pneumocystis) or an AIDS-related clinical condition, and is found to be HIV-1 seronegative

●An HIV-1 seropositive patient with no detectable plasma HIV-1 RNA on ART who has a declining CD4 cell count

Laboratory clues for possible HIV-2 infection — HIV-2 infection may also be suspected in the following scenarios:

●An untreated HIV-1 seropositive patient who has a low or undetectable viral load

●An HIV-1 seropositive patient with a virus that cannot be genotyped on routine HIV-1 drug resistance testing

●An HIV seropositive patient with a Western blot test that is reported as "indeterminate". An indeterminate Western blot is characterized by an unusual pattern of HIV proteins (such as HIV "gag" plus "pol" without "env"). (See 'An indeterminate HIV-1 Western blot' above.)

WHO SHOULD BE SCREENED? — The Centers for Disease Control (CDC) also recommends screening for HIV-2 infection in asymptomatic persons who are at risk for HIV-2 infection, including [1,41]:

●Persons from endemic areas

●Sex partners and needle-sharing partners of persons with a diagnosis of HIV-2 infection

●Sex partners and needle-sharing partners of persons from endemic areas

●Children of women with a diagnosis of HIV-2 or risk factors for HIV-2 infection

●Persons with a history of a blood transfusion in an endemic area

Locales where the prevalence of HIV-2 infection is considered "endemic" include all countries in West Africa: Benin, Burkina-Faso, Cape Verde, Cote d’Ivoire (Ivory Coast), Gambia, Ghana, Guinea, Guinea-Bissau, Liberia, Mali, Mauritania, Niger, Nigeria, Senegal, Sierra Leone, and Togo.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Sexually transmitted infections".)

SUMMARY AND RECOMMENDATIONS

●Clinical manifestations – The clinical manifestations of advanced HIV-2 infection are generally similar to those reported for HIV-1. Once advanced immunosuppression has occurred (eg, CD4 cell count <200 cells/mm³), patients with HIV-2 are at risk for similar types of opportunistic infections, such as pneumocystis and cryptococcal disease. (See 'Clinical manifestations' above.)

●Types of tests – The HIV antibody tests approved by the US Food and Drug Administration to detect and differentiate HIV-2 infection from HIV-1 include the Geenius HIV 1/2 Supplemental Assay and the BioPlex 2200 HIV Ag-Ab assay. A reactive result may be confirmed with a supplemental HIV-2 antibody test or a DNA/RNA test. (See 'Testing for HIV-2 infection' above.)

●When to suspect HIV-2 infection – The possibility of HIV-2 infection should be considered in: a) persons from an endemic area who present with an AIDS-like illness, b) an untreated HIV-1 seropositive patient with a low or non-detectable viral load, or c) an HIV-1 seropositive patient with no detectable HIV-1 RNA with declining immunity despite antiretroviral therapy. (See 'When to suspect HIV-2 infection' above.)

●Screening for HIV-2 infection – HIV-2 screening should be considered among asymptomatic persons who are at risk of infection. Such persons include those who have lived in endemic areas or who are sexual partners or needle-sharing partners of persons at risk for HIV-2 infection. (See 'Who should be screened?' above.)