Browse the corpus

Human immunodeficiency virus (HIV)-2 is an enveloped retrovirus causing human infection, similar to HIV-1, and is primarily endemic to West Africa. Due to globalization and increased migration, HIV-2 has now spread worldwide, with an estimated 1 to 2 million individuals affected. Without treatment, HIV-2 results in significant morbidity and mortality. Clinicians must recognize the distinctions between HIV-1 and HIV-2, particularly in individuals from high-prevalence regions, as prompt diagnosis and management are critical to improving outcomes. Comprehensive care for HIV-2 involves understanding its epidemiology, unique diagnostic challenges, and tailored treatment strategies. Participants in this course learn to differentiate between HIV-1 and HIV-2 in clinical practice, assess epidemiological and diagnostic nuances, and implement effective treatment plans. The course highlights the importance of collaboration within interprofessional teams, fostering better diagnostic accuracy and treatment adherence. This approach ultimately enhances patient outcomes by addressing the unique challenges of managing HIV-2 in diverse healthcare settings. Objectives: Apply evidence-based strategies to manage comorbidities and complications associated with human immunodeficiency virus-2 infection. Identify the epidemiology and clinical presentation of human immunodeficiency virus-2 in diverse populations. Differentiate human immunodeficiency virus (HIV)-2 infection from HIV-1 based on clinical, serological, and virological criteria. Collaborate with an interprofessional team to ensure comprehensive care for individuals with human immunodeficiency virus-2. Access free multiple choice questions on this topic.

Human immunodeficiency virus (HIV) is an enveloped retrovirus that can be categorized into 2 distinct subtypes: HIV type 1 (HIV-1) and HIV type 2 (HIV-2). Although both viruses share similar transmission routes and can cause acquired immunodeficiency syndrome, there are important differences between them regarding epidemiology, diagnosis, and management.[1] Although HIV-2 is less common globally, this virus is an important cause of disease in many regions. HIV-2 predominates in West Africa, but globalization has led to a sizeable number of cases in other parts of Africa, Europe, India, and the United States.[2] The current estimation is that about 1 to 2 million people are living with HIV-2 globally, although this is likely an underestimate.[3] The first cases of HIV-2 were detected in the United States (US) in the late 1980s, and currently, about 1% of persons living with HIV in the US are estimated to have HIV-2.[4] Clinicians are generally less familiar with HIV-2, and disease-specific data are lacking. This has limited our contemporary understanding of prevalence, treatment, and monitoring in comparison to HIV-1. To date, the approach to HIV-2 has largely been extrapolated from studies in HIV-1, though notable differences exist. The lower prevalence compared to HIV-1 has resulted in a paucity of drug trials or epidemiologic studies to address the current limitations in our understanding of HIV-2 management. However, given its global distribution, clinicians must become familiar with the differences between HIV-1 and HIV-2 while maintaining a high index of suspicion for HIV-2 in persons from endemic regions.

HIV-2 is a viral zoonosis that infects humans similarly to HIV-1. Phylogenetic studies suggest it emerged from sooty mangabey monkeys infected with simian immunodeficiency virus (SIV) in Guinea-Bissau.[5] Molecular clock analyses indicate it likely crossed species from sooty mangabey monkeys into humans between the 1940s-1950s.[6][7] However, the first case was not recognized until 1986 when a man from Guinea Bissau living in Portugal presented with severe immunodeficiency and negative HIV-1 testing.[8] Several years later, in 1989, the first case was identified in the US when a woman from Cape Verde presented with central nervous system toxoplasmosis, a common opportunistic infection seen in those with HIV-1.[9] The pandemic spread of HIV-2 was catalyzed by colonial wars being fought in Guinea and across West Africa during the 1960s-1970s.[10][11] This resulted in significant migration across West Africa and emigration to Europe. As conflicts continued, blood products were widely used to manage injuries, sexual networks emerged between military personnel and local communities, and widespread vaccination campaigns were enacted without modern sterilization techniques.[10][12] The emergence of HIV-2 in Guinea Bissau, driven by these factors, led to rapid spread into neighboring countries and eventually to distant Portuguese colonies, including Cape Verde, Angola, Mozambique, India, and Brazil. Ultimately, this also resulted in significant levels of HIV-2 transmission in Portugal, which currently maintains the highest prevalence of HIV-2 infection in Europe.[13]

Worldwide, most HIV infections are caused by HIV-1, and in 2018, an estimated 38 million people were infected globally.[14] HIV-2 infections make up the minority of cases, and it is estimated that about 1 to 2 million individuals globally have HIV-2, though estimates have been difficult to ascertain.[15] The majority of cases are concentrated in West Africa, where HIV-2 is endemic. Prevalence rates are greater than 1% in Cape Verde, Guinea-Bissau, Senegal, The Gambia, Mali, Cote d’Ivoire, Sierra Leone, and Nigeria.[3][16] Although less common, HIV-2 infection has also been reported in several other regions, including Europe, South America, Asia, and the US.[17] Between 2010 and 2017, 198 cases of HIV-2 had been reported in the US by the Centers for Disease Control and Prevention.[4][18] Of the new cases identified, 55% were diagnosed in the Northeast, with 30% being diagnosed in the Southern US.[4] The majority of US cases are acquired through heterosexual contact (61.1%), with a minority related to men who have sex with men (25.3%) or intravenous drug users (11.6%).[4] In the US, the overall prevalence of HIV-2 is thought to be approximately 0.5% to 1%, but historical limitations in HIV-2 testing suggest this is likely an underestimate. Results from several studies have demonstrated that the demographics of HIV-2 are shifting.[12] The peak global incidence likely occurred sometime in the 1970s or 1980s, when Guinea Bissau had a remarkable point prevalence of 8% to 10%.[19][20] HIV serostatus surveys in Guinea have supported this notion and found that prevalence among adults older than 40 approaches 20%, while it remains low at 1% to 2% among younger adults.[10] However, prevalence rates across West African nations have steadily declined over the past several decades. In Guinea, prevalence had decreased from 8.3% in the 1990s to 4.7% by the mid-2000s, while concurrently, HIV-1 prevalence rose from 0.5% to 3.6% over the same period.[21] The reasons for this are unclear, but several studies have identified decreasing viral fitness, lower transmission efficiency, and competitive exclusion of HIV-1 as possible mechanisms.[22][23] Phylogenetic and modeling studies have attributed up to 30% of the decline in HIV-2 prevalence to competitive exclusion, with the remaining 70% attributable to population-level socio-behavioral interventions.[24][10]

Compared to HIV-1, infection with HIV-2 is defined by 3 major differences: A longer asymptomatic phase A slower rate of cluster of differentiation (CD)4 decline lower plasma viral loads. Given these significant advantages over HIV-1, it has historically been associated with overall lower mortality.[25][26] However, more recent prospective cohort studies have shown that when left untreated, those with HIV-2 infection also progress to acquired immunodeficiency syndrome (AIDS) and death.[27] Recent data has also demonstrated that although the asymptomatic phase of HIV-2 is longer, once CD4 counts drop below 200 cells/µL, the mortality rate seen in untreated HIV-2 infection is equivalent to those with untreated HIV-1.[2][27] The pathophysiologic differences noted above result in distinctly different natural histories when comparing HIV-1 and HIV-2. Those with HIV-2 have been shown to have half the rate of CD4 decline over time (0.4% vs 0.9% per year) and, on average, have viral loads that are 28-fold lower after seroconversion.[27][28] These factors contribute to a longer asymptomatic disease phase and result in longer AIDS-free survival. Results from a study of commercial sex workers from Senegal highlighted this finding that 5-year survival among those with HIV-1 was half that of their HIV-2 infected counterparts.[29] Data from another HIV-2 cohort quantified median survival more granularly, where it was noted that those with HIV-1 had a median survival of 8.2 years compared to 15.6 years among those with HIV-2.[27] A significant difference in the time to AIDS was also seen, with a median of 6.2 years in those with HIV-1 compared to 14.3 years in those with HIV-2.[27][30] The studies completed before the widespread availability of antiretroviral therapy (ART) demonstrate the divergent natural histories seen in patients with HIV-1 and HIV-2 before marked CD4 decline.

Data from another HIV-2 cohort quantified median survival more granularly, where it was noted that those with HIV-1 had a median survival of 8.2 years compared to 15.6 years among those with HIV-2.[27] A significant difference in the time to AIDS was also seen, with a median of 6.2 years in those with HIV-1 compared to 14.3 years in those with HIV-2.[27][30] The studies completed before the widespread availability of antiretroviral therapy (ART) demonstrate the divergent natural histories seen in patients with HIV-1 and HIV-2 before marked CD4 decline. Although the natural history may differ, the transmission of HIV-2 occurs by the same routes as HIV-1, including perinatal, sexual contact, and bloodborne exposure. During the mechanisms of transmission overlap, HIV-2 is a markedly less efficient virus and, thus, significantly less infectious. Globally, this has resulted in disproportionately fewer cases of HIV-2 and a more limited spread in comparison to HIV-1. The comparatively lower efficiency of HIV-2 has been well illustrated in studies examining mother-to-child transmission from the pre-antiretroviral era. Remarkably, perinatal transmission among HIV-2 positive mothers has been notably low at 1% to 2%, whereas in mothers with HIV-1, transmission ranges from 15% to 30%.[31][32] Perinatal cohort studies from West Africa have demonstrated this is likely driven by factors specific to HIV-2, including lower pretreatment viral loads among peripartum women and decreased viral shedding in the female genital tract during delivery.[33] Interestingly, dual infection with both HIV-1 and HIV-2 can occur in regions where both viruses circulate widely. Dual infection has most commonly been reported in West Africa, where seroprevalence studies estimate dual infection in up to 5% to 10% of those infected.[30] Initially, several small cohorts and experimental studies in non-human primates suggested primary infection with HIV-2 may reduce the likelihood of subsequent HIV-1 acquisition and slow disease progression in those who were coinfected.[29][34] More recent data suggest that primary HIV-2 infection and the resulting HIV antibodies have no protective effect on HIV-1 acquisition. Long-term data has also illustrated that dually infected patients follow the expected disease trajectory of those with HIV-1 mono-infection.[35]

All patients diagnosed with HIV-2 should have a complete medical history, physical examination, and laboratory evaluation similar to that of a patient infected with HIV-1. The goal of an initial evaluation is to confirm the diagnosis of HIV-2, screen for and identify any opportunistic infections, provide patients with education and support, and discuss the benefits of antiretroviral therapy. Because of the natural history of undiagnosed HIV-2, clinicians should be aware that patients may present at older ages, represent a different demographic, or have non-traditional risk factors upon diagnosis. Thus, a low threshold should be maintained in sending HIV-2 testing, particularly in patients with epidemiologic risk. Those with HIV-2 often present with similar clinical symptoms as those with HIV-1, including developing an acute retroviral syndrome or opportunistic infection. All opportunistic infections have been seen in patients with HIV-2, including oral candidiasis, Pneumocystis pneumonia, cytomegalovirus, Kaposi sarcoma, tuberculosis, disseminated mycobacterial infection, toxoplasmosis, and progressive multifocal leukoencephalopathy, among others.[27][36][37][38] Evaluation for co-infection and concurrent opportunistic infection should be methodical and follow the guidelines outlined for HIV-1 infection.[39] Importantly, dual infection with HIV-1 should be ruled out early as part of initial laboratory testing. In a study of HIV-2 from The Gambia, the most common AIDS-defining feature at presentation was generalized wasting and pulmonary tuberculosis, although these findings may not be globally generalizable. Few studies have compared the frequency of opportunistic infections in patients with HIV-1 to those with HIV-2, but some evidence suggests that encephalitis may occur more frequently in those with HIV-2. Whether this is related to longer survival times or differences in neurotropism between HIV-1 and HIV-2 is unclear.[1][38] In addition, HIV-associated nephropathy, which occurs in about 10% of patients with HIV-1, has been rarely described among patients with HIV-2.[40][41]

Historically, the diagnosis of HIV-2 has been challenged by several issues, including HIV antibody differentiation and the detection of plasma HIV-2 ribonucleic acid levels. Before the widespread availability of the fourth-generation HIV-1/2 antigen-antibody tests, clinicians had to rely on clinical suspicion to determine when HIV-2-specific testing was appropriate. Such scenarios included declining CD4 counts in a patient with HIV-1 on appropriate therapy, untreated patients who are HIV-positive with an undetectable viral load, or those with opportunistic infection from West Africa. Previous immunoassays effectively detected HIV-1 and HIV-2 antibodies but did not differentiate between them. Confirmatory western blots were used, but cross-reactivity between HIV-1 and HIV-2 antibodies often resulted in indeterminate results or misdiagnosis as HIV-1. Many of these limitations have been mitigated by the widespread use of the fourth-generation HIV-1/2 antigen-antibody testing, which includes a differentiation assay. Consequently, in 2014, the Centers for Disease Control and Prevention revised its HIV testing algorithm to improve the diagnosis of HIV-2 by including the differentiation assay results.[42] The testing algorithm was revised in 2018 and should be used by all clinicians when interpreting diagnostic testing results for HIV.[43] Commercially available HIV-2 viral load testing remains challenging, and currently, there are only 2 labs that routinely carry out this testing in the United States. Further complicating HIV-2 plasma viral load testing is the appreciation that up to 40% of patients with HIV-2 have an undetectable viral load without antiretroviral therapy.[44] Thus, viral load testing should be considered unreliable. Though it can be useful to confirm a diagnosis of HIV-2 and monitor treatment in some cases, it cannot rule out infection. Resistance testing is also unavailable, and currently, there are no validated HIV-2 genotypic or phenotypic resistance assays approved for clinical use in the US.

The goals of antiretroviral therapy (ART) in HIV-2 are similar to those for HIV-1: prevention of transmission, immune restoration, durable viral suppression, and a reduction in morbidity and mortality.[45] However, there are very few trials in HIV-2 to specifically address when ART should be started, what agents may work best, or which regimens should be used in the setting of virologic failure.[46] Most treatment data used to guide HIV-2 management has been extrapolated from the wealth of studies performed on patients with HIV-1. Despite the lack of clinical evidence, it is clear that several combination therapies used in HIV-1 are also very effective in treating those with HIV-2.[47][48][49] Currently, it is recommended that all patients diagnosed with HIV-2 be started on ART as soon as possible after diagnosis.[50] The first line of recommended treatments includes combining 2 nucleoside reverse transcriptase inhibitors (NRTIs) plus an integrase strand transfer inhibitor or 2 NRTIs plus a boosted protease inhibitor with either darunavir or lopinavir.[51] HIV-2 has intrinsic drug resistance to all non-nucleoside reverse transcriptase inhibitors, rendering them ineffective.[52] In addition, most protease inhibitors are ineffective except for darunavir, lopinavir, and saquinavir.[53] The fusion inhibitor enfuvirtide also has no HIV-2 activity and should not be used. These drug resistance patterns result from natural polymorphisms in HIV-2 that result in ineffective or less effective binding to comparable drug target sites in HIV-1.[54] This occurs primarily through conformational variants in the wild-type HIV-2 reverse transcriptase and protease enzymes.[55] The initial monitoring of patients with HIV-2 should follow the same recommended guidelines set out for patients with HIV-1, except for baseline resistance testing. To determine treatment progress, clinicians can follow CD4 counts and HIV-2 viral loads if available. However, treatment failure should be suspected in patients with undetectable baseline viral loads if disease progression or continued CD4 decline occurs.

HIV-2 should be considered in those with epidemiologic risk factors or an opportunistic infection. As such, the differential is broad and includes a range of diseases caused by opportunistic and sexually transmitted pathogens, including: HIV-1 infection Dual infection with HIV-1 and HIV-2 Hepatitis B Hepatitis C Pneumocystis jiroveci pneumonia Toxoplasma gondii encephalitis Cryptosporidiosis Mycobacterium tuberculosis Nontuberculous mycobacterial infection Bartonellosis Syphilis Mucocutaneous candidiasis Cryptococcosis Histoplasmosis Coccidioidomycosis Aspergillosis Cytomegalovirus Herpes simplex virus Varicella zoster virus Human herpesvirus-8/Kaposi sarcoma Progressive multifocal leukoencephalopathy

There is an overall paucity of data on the prognosis and outcomes of those living with HIV-2, and existing studies have been small. However, HIV-2 cohorts have consistently shown that in patients with CD4 cell counts greater than 500 cells/µL, survival is improved compared to age-matched controls with HIV-1.[30][35] Results from further studies have demonstrated that in those with HIV-2 and advanced disease, mortality rates are similar to patients with HIV-1 when adjusted for CD4 count, age, and demographic factors.[56] Currently, there is limited data on whether long-term mortality rates or non-AIDS-related comorbidities are similar when comparing individuals with HIV-2 and HIV-1 on antiretroviral therapy.[57]

The complications from chronic infection with HIV-2 are similar to those in patients with HIV-1. Once patients with HIV-2 have developed advanced immunosuppression with CD4 cell counts less than 200 cells/µL, they are at risk of developing the same types of opportunistic infections seen in HIV-1.[2] As in those with HIV-1, the risk for these infectious complications can be minimized by initiating ART and the resultant immune reconstitution. Although there is no data specifically from HIV-2 patient cohorts, the same primary prophylaxis is recommended for those with CD4 counts below 200 cells/µL to prevent opportunistic infection with common pathogens such as Pneumocystis jiroveci and Toxoplasma gondii.[38]

Sexual contact is the primary mode of transmission for HIV-2, and patients at risk should be counseled about safe sexual practices and encouraged to get routine testing. Counseling should be culturally competent, sensitive to issues of sexual identity, and tailored to each patient's risk. If other risk factors are present, including the use of intravenous drugs, specific harm reduction strategies or interventions should be offered to mitigate transmission from contaminated equipment. Pre-exposure prophylaxis (PrEP) should be offered to patients at substantial risk of acquiring HIV infection. Although there are no data explicitly addressing PrEP in preventing HIV-2, the antiretrovirals used for PrEP are active against both HIV-1 and HIV-2, and similarly, high levels of efficacy would be expected.[58] Currently, less is known about the potential effectiveness of long-acting injectable PrEP in the prevention of HIV-2, though recent in vitro studies results have shown cabotegravir to have efficacy against HIV-2.[59]

An interprofessional team approach involving clinicians, specialists, nurses, and pharmacists is essential in managing HIV-2 infection, given it can be complex and lifelong. The clinical care team should involve an infectious disease specialist with expertise in HIV care, a social worker, a pharmacist, and other specialist care if needed. The patient is central to the care team, and focus should be paid to ensuring the HIV care team provides strong, unified communication, clear disease understanding, and a supportive environment. An interprofessional care team approach has been shown to improve important outcomes such as virologic suppression and patient retention among patients with HIV-1.[60][61] Similar outcomes could be expected for those living with HIV-2, given the significant overlap in clinical services and support required to manage patients successfully. The role of long-acting injectable agents and the uptake of telemedicine may present both new opportunities and challenges for multidisciplinary teams caring for those with HIV. However, as HIV clinical care continues to evolve, multidisciplinary teams must continue working synergistically to maximize patient engagement, retention, and virologic suppression.