HIV-2 Infection

Andrew Kapoor; Simi Padival

HIV-2 Infection

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Free Review Questions

Continuing Education Activity

HIV-2 is an enveloped retrovirus that causes infection in humans, similar to HIV-1. It is endemic to parts of West Africa, but globalization has led to worldwide spread. It is estimated that 1 to 2 million people live with HIV-2, and without treatment, infection invariably leads to significant morbidity and mortality. Given global interconnectedness and immigration from endemic regions, clinicians should become familiar with the differences between HIV-1 and HIV-2 infection and maintain a high index of suspicion for HIV-2 in persons from high-risk regions. This activity outlines the epidemiology, evaluation, diagnostic testing, and treatment options for HIV-2 infection. It further reviews the role interprofessional teams play in improving outcomes for patients with HIV-2.

Objectives:

Identify the epidemiology and transmission dynamics of HIV-2.
Identify the common pathophysiologic differences between HIV-1 and HIV-2.
Assess the typical presentation of a patient with HIV-2 and its distinguishing features.
Determine the main treatment strategies used by interprofessional team members and identify key treatment differences between HIV-1 and HIV-2.

Introduction

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 AIDS, there are important differences between them regarding epidemiology, diagnosis, and management.[1]

Although HIV-2 is less common globally, it is an important cause of disease in many regions. It 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] It is currently estimated 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 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. Its 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.

Etiology

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 United States 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]

Epidemiology

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 1-2 million 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 United States.[17] Between 2010–2017, 198 cases of HIV-2 had been reported in the United States by the CDC.[4][18]

Of the new cases identified, 55% were diagnosed in the Northeast, with an additional 30% being diagnosed in the Southern United States.[4] The majority of US cases are acquired through heterosexual contact (61.1%), with a minority related to MSM (25.3%) or IVDU (11.6%).[4] In the United States, 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.

Several studies have demonstrated that the demographics of HIV-2 are shifting.[12] The peak global incidence likely occurred sometime in the 1970-the 1980s, at which time 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 over 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 sociobehavioral interventions.[24][10]

Pathophysiology

Compared to HIV-1, infection with HIV-2 is defined by 3 major differences:

A longer asymptomatic phase
A slower rate of CD4 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 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.[27][2]

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][27] These factors contribute to a longer asymptomatic disease phase and result in longer AIDS-free survival. A study in 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. 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] These studies done 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. It 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 co-infected.[29][34][29] 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]

History and Physical

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 TB, although these findings may not be globally generalizable. Few studies have compared the frequency of OIs 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. It remains unclear if this may be related to longer survival times or differences in neurotropism between HIV-1 and HIV-2.[38][1] In addition, HIV-associated nephropathy (HIVAN), which occurs in about 10% of patients with HIV-1, has been rarely described among patients with HIV-2.[40][41]

Evaluation

Historically, the diagnosis of HIV-2 has been challenged by several issues, including HIV antibody differentiation and the detection of plasma HIV-2 RNA levels. Before the widespread availability of the 4th 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 an HIV-1 patient on appropriate therapy, untreated HIV-positive patients 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 4th generation HIV-1/2 antigen-antibody testing, which includes a differentiation assay. Consequently, in 2014, the Centers for Disease Control (CDC) 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 ART.[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 United States.

Treatment / Management

The goals of 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 HIV-1 patients. 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 either a combination of 2 nucleoside reverse transcriptase inhibitors (NRTIs) plus an integrase strand transfer inhibitor (INSTI) or 2 nucleoside reverse transcriptase inhibitors (NRTIs) plus a boosted protease inhibitor (PI) with either darunavir or lopinavir.[51] It is important to note that HIV-2 has intrinsic drug resistance to all non-nucleoside reverse transcriptase inhibitors (NNRTI), rendering them ineffective.[52] In addition, most PIs 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 HIV-1 patients, except for baseline resistance testing. To determine treatment progress, clinicians can follow CD4 counts and HIV-2 viral loads if they are available. However, treatment failure should be suspected in patients with undetectable baseline viral loads if disease progression or continued CD4 decline occurs.

Differential Diagnosis

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.

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 (NTM)
Bartonellosis
Syphilis
Mucocutaneous candidiasis
Cryptococcosis
Histoplasmosis
Coccidioidomycosis
Aspergillosis
Cytomegalovirus
Herpes simplex virus
Varicella zoster virus
Human herpesvirus-8/Kaposi sarcoma
Progressive multifocal leukoencephalopathy (PML)

Prognosis

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]

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 HIV-2 and HIV-1 patients on antiretroviral therapy.[57]

Complications

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]

Deterrence and Patient Education

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 specifically 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 efficacy of long-acting injectable PrEP in the prevention of HIV-2, though recent in vitro studies have shown cabotegravir to have efficacy against HIV-2.[59]

Enhancing Healthcare Team Outcomes

An interprofessional team approach involving clinicians, mid-level practitioners, 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. Central to the care team is the patient, and focus should be paid to ensuring the HIV care team provides strong, unified communication, clear disease understanding, and a supportive environment. Providing an interprofessional care team has been shown among HIV-1 patients to improve important outcomes such as virologic suppression and patient retention.[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.

Details

References

[1]

Nyamweya S, Hegedus A, Jaye A, Rowland-Jones S, Flanagan KL, Macallan DC. Comparing HIV-1 and HIV-2 infection: Lessons for viral immunopathogenesis. Reviews in medical virology. 2013 Jul:23(4):221-40. doi: 10.1002/rmv.1739. Epub 2013 Feb 26 [PubMed PMID: 23444290]

[2]

Campbell-Yesufu OT, Gandhi RT. Update on human immunodeficiency virus (HIV)-2 infection. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2011 Mar 15:52(6):780-7. doi: 10.1093/cid/ciq248. Epub [PubMed PMID: 21367732]

[3]

Gottlieb GS, Raugi DN, Smith RA. 90-90-90 for HIV-2? Ending the HIV-2 epidemic by enhancing care and clinical management of patients infected with HIV-2. The lancet. HIV. 2018 Jul:5(7):e390-e399. doi: 10.1016/S2352-3018(18)30094-8. Epub [PubMed PMID: 30052509]

[4]

Peruski AH, Wesolowski LG, Delaney KP, Chavez PR, Owen SM, Granade TC, Sullivan V, Switzer WM, Dong X, Brooks JT, Joyce MP. Trends in HIV-2 Diagnoses and Use of the HIV-1/HIV-2 Differentiation Test - United States, 2010-2017. MMWR. Morbidity and mortality weekly report. 2020 Jan 24:69(3):63-66. doi: 10.15585/mmwr.mm6903a2. Epub 2020 Jan 24 [PubMed PMID: 31971928]

[5]

Visseaux B, Damond F, Matheron S, Descamps D, Charpentier C. Hiv-2 molecular epidemiology. Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases. 2016 Dec:46():233-240. doi: 10.1016/j.meegid.2016.08.010. Epub 2016 Aug 12 [PubMed PMID: 27530215]

[6]

Gottlieb GS, Sow PS, Hawes SE, Ndoye I, Coll-Seck AM, Curlin ME, Critchlow CW, Kiviat NB, Mullins JI. Molecular epidemiology of dual HIV-1/HIV-2 seropositive adults from Senegal, West Africa. AIDS research and human retroviruses. 2003 Jul:19(7):575-84 [PubMed PMID: 12908935]

[7]

Lemey P, Pybus OG, Wang B, Saksena NK, Salemi M, Vandamme AM. Tracing the origin and history of the HIV-2 epidemic. Proceedings of the National Academy of Sciences of the United States of America. 2003 May 27:100(11):6588-92 [PubMed PMID: 12743376]

[8]

Clavel F. HIV-2, the West African AIDS virus. AIDS (London, England). 1987 Sep:1(3):135-40 [PubMed PMID: 3126752]

[9]

Kloser PC, Mangia AJ, Leonard J, Lombardo JM, Michaels J, Denny TN, Sharer L, Sathe S, Weiss SH, Schable C. HIV-2-associated AIDS in the United States. The first case. Archives of internal medicine. 1989 Aug:149(8):1875-7 [PubMed PMID: 2764658]

Level 3 (low-level) evidence

[10]

de Silva TI, van Tienen C, Onyango C, Jabang A, Vincent T, Loeff MF, Coutinho RA, Jaye A, Rowland-Jones S, Whittle H, Cotten M, Hué S. Population dynamics of HIV-2 in rural West Africa: comparison with HIV-1 and ongoing transmission at the heart of the epidemic. AIDS (London, England). 2013 Jan 2:27(1):125-34. doi: 10.1097/QAD.0b013e32835ab12c. Epub [PubMed PMID: 23032414]

[11]

Mendoza C, Lozano AB, Caballero E, Cabezas T, Ramos JM, Soriano V. Antiretroviral Therapy for HIV-2 Infection in Non-Endemic Regions. AIDS reviews. 2020:22(1):44-56. doi: 10.24875/AIDSRev.M20000029. Epub [PubMed PMID: 32167506]

[12]

Gottlieb GS. Changing HIV epidemics: what HIV-2 can teach us about ending HIV-1. AIDS (London, England). 2013 Jan 2:27(1):135-7. doi: 10.1097/QAD.0b013e32835a11a4. Epub [PubMed PMID: 23221427]

[13]

Carvalho AC, Valadas E, França L, Carvalho C, Aleixo MJ, Mendez J, Marques R, Sarmento A, Doroana M, Antunes F, Branco T, Aguas M, Sarmento E Castro R, Lazarus JV, Barros H. Population mobility and the changing epidemics of HIV-2 in Portugal. HIV medicine. 2012 Apr:13(4):219-25. doi: 10.1111/j.1468-1293.2011.00963.x. Epub 2011 Dec 4 [PubMed PMID: 22136745]

[14]

García-Deltoro M. Rapid Initiation of Antiretroviral Therapy after HIV Diagnosis. AIDS reviews. 2019:21(2):55-64. doi: 10.24875/AIDSRev.M19000027. Epub [PubMed PMID: 31332395]

[15]

de Silva TI, Cotten M, Rowland-Jones SL. HIV-2: the forgotten AIDS virus. Trends in microbiology. 2008 Dec:16(12):588-95. doi: 10.1016/j.tim.2008.09.003. Epub 2008 Oct 27 [PubMed PMID: 18964021]

[16]

De Cock KM, Adjorlolo G, Ekpini E, Sibailly T, Kouadio J, Maran M, Brattegaard K, Vetter KM, Doorly R, Gayle HD. Epidemiology and transmission of HIV-2. Why there is no HIV-2 pandemic. JAMA. 1993 Nov 3:270(17):2083-6 [PubMed PMID: 8147962]

[17]

Remy G. [HIV-2 infection in the world. A geographical perspective]. Sante (Montrouge, France). 1998 Nov-Dec:8(6):440-6 [PubMed PMID: 10064918]

Level 3 (low-level) evidence

[18]

Centers for Disease Control and Prevention (CDC). HIV-2 Infection Surveillance--United States, 1987-2009. MMWR. Morbidity and mortality weekly report. 2011 Jul 29:60(29):985-8 [PubMed PMID: 21796096]

[19]

Poulsen AG, Kvinesdal B, Aaby P, Mølbak K, Frederiksen K, Dias F, Lauritzen E. Prevalence of and mortality from human immunodeficiency virus type 2 in Bissau, West Africa. Lancet (London, England). 1989 Apr 15:1(8642):827-31 [PubMed PMID: 2564911]

[20]

Wilkins A, Ricard D, Todd J, Whittle H, Dias F, Paulo Da Silva A. The epidemiology of HIV infection in a rural area of Guinea-Bissau. AIDS (London, England). 1993 Aug:7(8):1119-22 [PubMed PMID: 8397950]

[21]

Tienen Cv, van der Loeff MS, Zaman SM, Vincent T, Sarge-Njie R, Peterson I, Leligdowicz A, Jaye A, Rowland-Jones S, Aaby P, Whittle H. Two distinct epidemics: the rise of HIV-1 and decline of HIV-2 infection between 1990 and 2007 in rural Guinea-Bissau. Journal of acquired immune deficiency syndromes (1999). 2010 Apr:53(5):640-7. doi: 10.1097/QAI.0b013e3181bf1a25. Epub [PubMed PMID: 19841588]

[22]

Larsen O, da Silva Z, Sandström A, Andersen PK, Andersson S, Poulsen AG, Melbye M, Dias F, Nauclér A, Aaby P. Declining HIV-2 prevalence and incidence among men in a community study from Guinea-Bissau. AIDS (London, England). 1998 Sep 10:12(13):1707-14 [PubMed PMID: 9764792]

[23]

da Silva ZJ, Oliveira I, Andersen A, Dias F, Rodrigues A, Holmgren B, Andersson S, Aaby P. Changes in prevalence and incidence of HIV-1, HIV-2 and dual infections in urban areas of Bissau, Guinea-Bissau: is HIV-2 disappearing? AIDS (London, England). 2008 Jun 19:22(10):1195-202. doi: 10.1097/QAD.0b013e328300a33d. Epub [PubMed PMID: 18525265]

[24]

Schmidt WP, Van Der Loeff MS, Aaby P, Whittle H, Bakker R, Buckner M, Dias F, White RG. Behaviour change and competitive exclusion can explain the diverging HIV-1 and HIV-2 prevalence trends in Guinea-Bissau. Epidemiology and infection. 2008 Apr:136(4):551-61 [PubMed PMID: 17559692]

[25]

Alabi AS, Jaffar S, Ariyoshi K, Blanchard T, Schim van der Loeff M, Awasana AA, Corrah T, Sabally S, Sarge-Njie R, Cham-Jallow F, Jaye A, Berry N, Whittle H. Plasma viral load, CD4 cell percentage, HLA and survival of HIV-1, HIV-2, and dually infected Gambian patients. AIDS (London, England). 2003 Jul 4:17(10):1513-20 [PubMed PMID: 12824789]

[26]

Berry N, Ariyoshi K, Jaffar S, Sabally S, Corrah T, Tedder R, Whittle H. Low peripheral blood viral HIV-2 RNA in individuals with high CD4 percentage differentiates HIV-2 from HIV-1 infection. Journal of human virology. 1998 Nov-Dec:1(7):457-68 [PubMed PMID: 10195267]

[27]

Esbjörnsson J, Månsson F, Kvist A, da Silva ZJ, Andersson S, Fenyö EM, Isberg PE, Biague AJ, Lindman J, Palm AA, Rowland-Jones SL, Jansson M, Medstrand P, Norrgren H, Sweden and Guinea-Bissau Cohort Research Group. Long-term follow-up of HIV-2-related AIDS and mortality in Guinea-Bissau: a prospective open cohort study. The lancet. HIV. 2018 Nov 1:():. pii: S2352-3018(18)30254-6. doi: 10.1016/S2352-3018(18)30254-6. Epub 2018 Nov 1 [PubMed PMID: 30392769]

[28]

Andersson S, Norrgren H, da Silva Z, Biague A, Bamba S, Kwok S, Christopherson C, Biberfeld G, Albert J. Plasma viral load in HIV-1 and HIV-2 singly and dually infected individuals in Guinea-Bissau, West Africa: significantly lower plasma virus set point in HIV-2 infection than in HIV-1 infection. Archives of internal medicine. 2000 Nov 27:160(21):3286-93 [PubMed PMID: 11088091]

[29]

Marlink R, Kanki P, Thior I, Travers K, Eisen G, Siby T, Traore I, Hsieh CC, Dia MC, Gueye EH. Reduced rate of disease development after HIV-2 infection as compared to HIV-1. Science (New York, N.Y.). 1994 Sep 9:265(5178):1587-90 [PubMed PMID: 7915856]

[30]

Schim van der Loeff MF, Jaffar S, Aveika AA, Sabally S, Corrah T, Harding E, Alabi A, Bayang A, Ariyoshi K, Whittle HC. Mortality of HIV-1, HIV-2 and HIV-1/HIV-2 dually infected patients in a clinic-based cohort in The Gambia. AIDS (London, England). 2002 Sep 6:16(13):1775-83 [PubMed PMID: 12218389]

[31]

Adjorlolo-Johnson G, De Cock KM, Ekpini E, Vetter KM, Sibailly T, Brattegaard K, Yavo D, Doorly R, Whitaker JP, Kestens L. Prospective comparison of mother-to-child transmission of HIV-1 and HIV-2 in Abidjan, Ivory Coast. JAMA. 1994 Aug 10:272(6):462-6 [PubMed PMID: 8040982]

[32]

Burgard M, Jasseron C, Matheron S, Damond F, Hamrene K, Blanche S, Faye A, Rouzioux C, Warszawski J, Mandelbro L, ANRS French Perinatal Cohort EPF-CO1. Mother-to-child transmission of HIV-2 infection from 1986 to 2007 in the ANRS French Perinatal Cohort EPF-CO1. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2010 Oct 1:51(7):833-43. doi: 10.1086/656284. Epub [PubMed PMID: 20804413]

[33]

Ghys PD, Fransen K, Diallo MO, Ettiègne-Traoré V, Coulibaly IM, Yeboué KM, Kalish ML, Maurice C, Whitaker JP, Greenberg AE, Laga M. The associations between cervicovaginal HIV shedding, sexually transmitted diseases and immunosuppression in female sex workers in Abidjan, Côte d'Ivoire. AIDS (London, England). 1997 Oct:11(12):F85-93 [PubMed PMID: 9342059]

[34]

Esbjörnsson J, Månsson F, Kvist A, Isberg PE, Nowroozalizadeh S, Biague AJ, da Silva ZJ, Jansson M, Fenyö EM, Norrgren H, Medstrand P. Inhibition of HIV-1 disease progression by contemporaneous HIV-2 infection. The New England journal of medicine. 2012 Jul 19:367(3):224-32. doi: 10.1056/NEJMoa1113244. Epub [PubMed PMID: 22808957]

[35]

Prince PD, Matser A, van Tienen C, Whittle HC, Schim van der Loeff MF. Mortality rates in people dually infected with HIV-1/2 and those infected with either HIV-1 or HIV-2: a systematic review and meta-analysis. AIDS (London, England). 2014 Feb 20:28(4):549-58. doi: 10.1097/01.SPC.0000432532.87841.78. Epub [PubMed PMID: 23921613]

Level 1 (high-level) evidence

[36]

Sørensen A, Jespersen S, Katzenstein TL, Medina C, Té Dda S, Correira FG, Hviid CJ, Laursen AL, Wejse C. Clinical presentation and opportunistic infections in HIV-1, HIV-2 and HIV-1/2 dual seropositive patients in Guinea-Bissau. Infectious diseases (London, England). 2016 Aug:48(8):604-11. doi: 10.1080/23744235.2016.1180708. Epub 2016 May 10 [PubMed PMID: 27163507]

[37]

van der Sande MA, Schim van der Loeff MF, Bennett RC, Dowling M, Aveika AA, Togun TO, Sabally S, Jeffries D, Adegbola RA, Sarge-Njie R, Jaye A, Corrah T, McConkey S, Whittle HC. Incidence of tuberculosis and survival after its diagnosis in patients infected with HIV-1 and HIV-2. AIDS (London, England). 2004 Sep 24:18(14):1933-41 [PubMed PMID: 15353979]

[38]

Lucas SB, Hounnou A, Peacock C, Beaumel A, Djomand G, N'Gbichi JM, Yeboue K, Hondé M, Diomande M, Giordano C. The mortality and pathology of HIV infection in a west African city. AIDS (London, England). 1993 Dec:7(12):1569-79 [PubMed PMID: 7904450]

[39]

Churchill D, Waters L, Ahmed N, Angus B, Boffito M, Bower M, Dunn D, Edwards S, Emerson C, Fidler S, Fisher M, Horne R, Khoo S, Leen C, Mackie N, Marshall N, Monteiro F, Nelson M, Orkin C, Palfreeman A, Pett S, Phillips A, Post F, Pozniak A, Reeves I, Sabin C, Trevelion R, Walsh J, Wilkins E, Williams I, Winston A. British HIV Association guidelines for the treatment of HIV-1-positive adults with antiretroviral therapy 2015. HIV medicine. 2016 Aug:17 Suppl 4():s2-s104. doi: 10.1111/hiv.12426. Epub [PubMed PMID: 27568911]

[40]

Khan S, Haragsim L, Laszik ZG. HIV-associated nephropathy. Advances in chronic kidney disease. 2006 Jul:13(3):307-13 [PubMed PMID: 16815235]

Level 3 (low-level) evidence

[41]

Izzedine H, Damond F, Brocheriou I, Ghosn J, Lassal H, Deray G. HIV-2 infection and HIV-associated nephropathy. AIDS (London, England). 2006 Apr 4:20(6):949-50 [PubMed PMID: 16549986]

[42]

Centers for Disease Control and Prevention (CDC). National HIV Testing Day and new testing recommendations. MMWR. Morbidity and mortality weekly report. 2014 Jun 27:63(25):537 [PubMed PMID: 25095328]

[43]

Chang M, Wong AJ, Raugi DN, Smith RA, Seilie AM, Ortega JP, Bogusz KM, Sall F, Ba S, Seydi M, Gottlieb GS, Coombs RW. Clinical validation of a novel diagnostic HIV-2 total nucleic acid qualitative assay using the Abbott m2000 platform: Implications for complementary HIV-2 nucleic acid testing for the CDC 4th generation HIV diagnostic testing algorithm. Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology. 2017 Jan:86():56-61. doi: 10.1016/j.jcv.2016.11.011. Epub 2016 Nov 23 [PubMed PMID: 27951466]

Level 2 (mid-level) evidence

[44]

Popper SJ, Sarr AD, Travers KU, Guèye-Ndiaye A, Mboup S, Essex ME, Kanki PJ. Lower human immunodeficiency virus (HIV) type 2 viral load reflects the difference in pathogenicity of HIV-1 and HIV-2. The Journal of infectious diseases. 1999 Oct:180(4):1116-21 [PubMed PMID: 10479138]

[45]

Jones J, Sullivan PS, Curran JW. Progress in the HIV epidemic: Identifying goals and measuring success. PLoS medicine. 2019 Jan:16(1):e1002729. doi: 10.1371/journal.pmed.1002729. Epub 2019 Jan 18 [PubMed PMID: 30657770]

[46]

Gottlieb GS, Eholié SP, Nkengasong JN, Jallow S, Rowland-Jones S, Whittle HC, Sow PS. A call for randomized controlled trials of antiretroviral therapy for HIV-2 infection in West Africa. AIDS (London, England). 2008 Oct 18:22(16):2069-72; discussion 2073-4. doi: 10.1097/QAD.0b013e32830edd44. Epub [PubMed PMID: 18832869]

Level 1 (high-level) evidence

[47]

Matheron S, Descamps D, Gallien S, Besseghir A, Sellier P, Blum L, Mortier E, Charpentier C, Tubiana R, Damond F, Peytavin G, Ponscarme D, Collin F, Brun-Vezinet F, Chene G, France REcherche Nord&Sud Sida-Hiv Hépatites (ANRS) 159 HIV-2 Trial Study Group. First-line Raltegravir/Emtricitabine/Tenofovir Combination in Human Immunodeficiency Virus Type 2 (HIV-2) Infection: A Phase 2, Noncomparative Trial (ANRS 159 HIV-2). Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2018 Sep 28:67(8):1161-1167. doi: 10.1093/cid/ciy245. Epub [PubMed PMID: 29590335]

[48]

Ba S, Raugi DN, Smith RA, Sall F, Faye K, Hawes SE, Sow PS, Seydi M, Gottlieb GS, University of Washington–Dakar HIV-2 Study Group. A Trial of a Single-tablet Regimen of Elvitegravir, Cobicistat, Emtricitabine, and Tenofovir Disoproxil Fumarate for the Initial Treatment of Human Immunodeficiency Virus Type 2 Infection in a Resource-limited Setting: 48-Week Results From Senegal, West Africa. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2018 Oct 30:67(10):1588-1594. doi: 10.1093/cid/ciy324. Epub [PubMed PMID: 29672676]

[49]

Bénard A, Damond F, Campa P, Peytavin G, Descamps D, Lascoux-Combes C, Taieb A, Simon F, Autran B, Brun-Vézinet F, Chêne G, Matheron S, ANRS CO5 HIV-2 Cohort Study Group. Good response to lopinavir/ritonavir-containing antiretroviral regimens in antiretroviral-naive HIV-2-infected patients. AIDS (London, England). 2009 Jun 1:23(9):1171-3. doi: 10.1097/QAD.0b013e32832949f0. Epub [PubMed PMID: 19349850]

[50]

INSIGHT START Study Group, Lundgren JD, Babiker AG, Gordin F, Emery S, Grund B, Sharma S, Avihingsanon A, Cooper DA, Fätkenheuer G, Llibre JM, Molina JM, Munderi P, Schechter M, Wood R, Klingman KL, Collins S, Lane HC, Phillips AN, Neaton JD. Initiation of Antiretroviral Therapy in Early Asymptomatic HIV Infection. The New England journal of medicine. 2015 Aug 27:373(9):795-807. doi: 10.1056/NEJMoa1506816. Epub 2015 Jul 20 [PubMed PMID: 26192873]

[51]

Günthard HF, Saag MS, Benson CA, del Rio C, Eron JJ, Gallant JE, Hoy JF, Mugavero MJ, Sax PE, Thompson MA, Gandhi RT, Landovitz RJ, Smith DM, Jacobsen DM, Volberding PA. Antiretroviral Drugs for Treatment and Prevention of HIV Infection in Adults: 2016 Recommendations of the International Antiviral Society-USA Panel. JAMA. 2016 Jul 12:316(2):191-210. doi: 10.1001/jama.2016.8900. Epub [PubMed PMID: 27404187]

[52]

Shah SS, Fine SM, Vail RM, McGowan JP, Merrick ST, Radix AE, Hoffmann CJ, Gonzalez CJ. Diagnosis and Management of HIV-2 in Adults. 2022 Aug:(): [PubMed PMID: 32573998]

[53]

Charpentier C, Visseaux B, Bénard A, Peytavin G, Damond F, Roy C, Taieb A, Chêne G, Matheron S, Brun-Vézinet F, Descamps D, ANRS CO5 HIV-2 Cohort. Transmitted drug resistance in French HIV-2-infected patients. AIDS (London, England). 2013 Jun 19:27(10):1671-4. doi: 10.1097/QAD.0b013e32836207f3. Epub [PubMed PMID: 23595155]

[54]

Gottlieb GS, Raugi DN, Smith RA, University of Washington-Dakar HIV-2 Study Group. HIV Drug Resistance. The New England journal of medicine. 2018 Mar 1:378(9):874-5. doi: 10.1056/NEJMc1716089. Epub [PubMed PMID: 29504389]

[55]

Laville P, Fartek S, Cerisier N, Flatters D, Petitjean M, Regad L. Impacts of drug resistance mutations on the structural asymmetry of the HIV-2 protease. BMC molecular and cell biology. 2020 Jun 23:21(1):46. doi: 10.1186/s12860-020-00290-1. Epub 2020 Jun 23 [PubMed PMID: 32576133]

[56]

Martinez-Steele E, Awasana AA, Corrah T, Sabally S, van der Sande M, Jaye A, Togun T, Sarge-Njie R, McConkey SJ, Whittle H, Schim van der Loeff MF. Is HIV-2- induced AIDS different from HIV-1-associated AIDS? Data from a West African clinic. AIDS (London, England). 2007 Jan 30:21(3):317-24 [PubMed PMID: 17255738]

[57]

Tchounga B, Ekouevi DK, Balestre E, Dabis F. Mortality and survival patterns of people living with HIV-2. Current opinion in HIV and AIDS. 2016 Sep:11(5):537-544 [PubMed PMID: 27254747]

Level 3 (low-level) evidence

[58]

Witvrouw M, Pannecouque C, Switzer WM, Folks TM, De Clercq E, Heneine W. Susceptibility of HIV-2, SIV and SHIV to various anti-HIV-1 compounds: implications for treatment and postexposure prophylaxis. Antiviral therapy. 2004 Feb:9(1):57-65 [PubMed PMID: 15040537]

[59]

Smith RA, Wu VH, Zavala CG, Raugi DN, Ba S, Seydi M, Gottlieb GS, University of Washington-Dakar HIV-2 Study Group. In Vitro Antiviral Activity of Cabotegravir against HIV-2. Antimicrobial agents and chemotherapy. 2018 Oct:62(10):. doi: 10.1128/AAC.01299-18. Epub 2018 Sep 24 [PubMed PMID: 30012774]

[60]

Ojikutu B, Holman J, Kunches L, Landers S, Perlmutter D, Ward M, Fant G, Hirschhorn L. Interdisciplinary HIV care in a changing healthcare environment in the USA. AIDS care. 2014:26(6):731-5. doi: 10.1080/09540121.2013.855299. Epub 2013 Nov 6 [PubMed PMID: 24191727]

[61]

Doshi RK, Milberg J, Isenberg D, Matthews T, Malitz F, Matosky M, Trent-Adams S, Parham Hopson D, Cheever LW. High rates of retention and viral suppression in the US HIV safety net system: HIV care continuum in the Ryan White HIV/AIDS Program, 2011. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2015 Jan 1:60(1):117-25. doi: 10.1093/cid/ciu722. Epub 2014 Sep 15 [PubMed PMID: 25225233]