Human Immunodeficiency Virus–2 (HIV-2): A Summary of the Present Standard of Care and Treatment Options for Individuals Living with HIV-2 in Western Europe

Abstract

Human immunodeficiency virus–2 (HIV-2) is endemic in some countries in West Africa. Due to the lower prevalence in industrialized countries, there is limited experience and knowledge on the management of individuals living with HIV-2 in Europe. Compared to HIV-1, there are differential characteristics of HIV-2 regarding diagnostic procedures, the clinical course, and, most importantly, antiretroviral therapy.

We integrated the published literature on HIV-2 (studies and reports on epidemiology, diagnostics, the clinical course, and treatment), as well as expert experience in diagnosing and clinical care, to provide recommendations for a present standard of medical care of those living with HIV-2 in Western European countries, including an overview of strategies for diagnosis, monitoring, and treatment, with suggestions for effective drug combinations for first- and second-line treatments, post-exposure prophylaxis, and the prevention of mother-to-child transmission, as well as listings of mutations related to HIV-2 drug resistance and C-C motif chemokine receptor type 5 and C-X-C motif chemokine receptor type 4 coreceptor tropism.

HIV-2, antiretroviral therapy, resistance, diagnosis, care

(See the Editorial Commentary by Jenny-Avital on pages 510–2 and the Major Article by Raugi et al on pages 369–78.)

The frequency of human immunodeficiency virus–2 (HIV-2) is much lower than that of HIV-1. The absolute number of individuals living with HIV-2 worldwide is unknown. Reliable and current data are missing. According to the experts, the number is estimated at 1–2 million [1].

West African countries were known for having the world’s highest prevalences of HIV-2 in parts of their populations, including Guinea-Bissau (up to 4%) [2]. HIV-2 infections have also been reported from Senegal, the Gambia, Sierra Leone, and the Ivory Coast and, to a lesser extent, from Cape Verde, Angola, Mozambique, and the Goa region in India [1, 3]. In Europe, France and Portugal report the highest prevalences (between 1000 and 2000 cases for both countries, respectively) [4, 5].

In contrast to HIV-1, there are only limited data on the value of diagnostic tools, monitoring, and treatment for patients living with HIV-2. Published HIV-2 guidelines are available from France [5], Great Britain [6], Portugal [7], Spain [8], and the United States [9] dating from 2010 to 2019. To reach a standard, we summarized current strategies and tools for the care of individuals living with HIV-2 in Western Europe.

DIAGNOSIS OF HUMAN IMMUNODEFICIENCY VIRUS–2 INFECTION

Individuals from the aforementioned countries and individuals with high-risk sexual contact with persons from these countries should be tested for a possible HIV-2 infection or dual infection when HIV antibody tests are reactive.

In general, the diagnosis of an infection with HIV-2 is more challenging than the diagnosis of HIV-1, and national HIV Expertise Centers should be contacted if difficulties arise.

For initial screening, standard HIV antibody screening tests (fourth generation) are recommended because they detect both HIV-1 and HIV-2 antibodies and antigens. Reactive HIV screening tests require confirmatory testing with antibody differentiation assays, such as immunoblot, line-immuno-assay, Western blot, or other antibody differentiation assays containing HIV-1 and HIV-2 antigens. Other confirmatory assays, such as HIV-1–mono immunoblot or Western blot assays (containing only HIV-1 antigens) may miss an HIV-2 infection due to cross-reactivity. In patients who have been diagnosed with HIV based on enzyme-linked immunosorbent assays and who have a low or undetectable HIV-1 viral plasma load in the absence of antiviral therapy (ART), we should consider the possible presence of HIV-2 or other HIV variants and perform additional testing by specific, antibody-based confirmatory assays. Patients with an HIV infection under ART with relevant and constant CD4+ cell loss and without detectable HIV-1 plasma RNA should be reevaluated for a possible HIV-2 infection or both HIV-1 and HIV-2 or (as well as other HIV variants) [10].

Commercially available HIV-1 RNA viral load (VL) tests usually do not detect or quantify HIV-2. Most laboratories use in-house assays for HIV-2 VL determination, based on primers and probes in the long terminal repeats (LTR) region [11]. For the European region, 2 commercial tests kits are available: (1) the Generic HIV-2 Charge Virale (for research use only; Biocentric, Bandol, France), which is based on TaqMan 1-step reverse transcription-quantitative polymerase chain reaction (PCR) and targets the LTR and gag regions [12]; and (2) the Real Star HIV-2 (for research use only; Altona Diagnostics, Hamburg, Germany).

An HIV-2 plasma VL analysis should not be used exclusively as a confirmation assay, as the HIV-2 VL is frequently below the detection limit even in the absence of ART [1, 13, 14]. While positive HIV-2 PCR results from plasma confirm an HIV-2 infection, a negative PCR result does not exclude the possibility of an HIV-2 infection.

If the serology shows indeterminate results and the HIV-1 and HIV-2 PCRs are both negative, proviral DNA should be used on enriched peripheral blood mononuclear cells. If the type of HIV cannot be cleared, an HIV-2 specialized laboratory should be contacted.

The determination of HIV-2 resistance-associated mutations (RAMs) can be performed by nucleic acid sequencing. Free-access, web-based interpretation rules or interpretation systems are provided by National Agency for AIDS Research (ANRS)(ANRS-AC43 resistance group genotype interpretation for HIV-2), REGA (an algorithm for the use of genotypic HIV-2 resistance data), the Stanford HIV drug resistance database, and HIV-GRADE (Genotypic Resistance-Algorithm DEutschland, HIV-GRADE [HIV Genotypic Resistance-Algorithm Deutschland]) (described in the chapter titled “Bioinformatics Tools”) [15].

In Europe, dual infections are rare and represent about 0.1% of new HIV infections in France [16]. They may remain undetected when standard antibody screening and confirmation assays based only on HIV-1 are used. If individuals living with dual infections are treated with an ART ineffective for HIV-2 (see below), they will show neither clinical improvement nor CD4⁺ cell count recovery despite HIV-1 plasma RNA undetectability. Hence, samples from such individuals should be promptly reanalyzed to exclude a possible HIV-2 infection.

CHARACTERISTICS OF HUMAN IMMUNODEFICIENCY VIRUS–2 INFECTION

HIV-2 infections are characterized by a slower rate of disease progression, compared to HIV-1 [17, 18]. Data from cohorts in West Africa indicate that up to 37% of untreated individuals living with HIV-2 have an undetectable VL [14] and exhibit long-term survival [13]. In a French study cohort, about half of the untreated patients showed undetectable VLs, while those with viremia had a mean VL of 3.0 log₁₀ copies/mL [19]. The estimated annual average decrease in CD4⁺-cells count was 4.5-fold less pronounced in ART-naive HIV-2 patients than in patients living with HIV-1, after adjusting for sex, age, and geographic origin (decline of 11 versus 49 cells/year, respectively) [20]. However, the antiretroviral treatment of an HIV-2 infection should not be started too late, since the immune reconstitution of HIV-2 patients under ART is poorer than in HIV-1 infected patients [20]. Data from the French ANRS CO5 cohort and the European ACHIeV2e network suggest that starting therapy early in the course of infection should allow for an efficient recovery of CD4⁺-cells [21, 22]. The mean observed CD4⁺ cell count recovery at 12 months after initiating a first-line ART was +105 cells/µL in patients living with HIV-2 (n = 185), in comparison to +202 cells/µl in patients living with HIV-1 (n = 30 231) in the same cohort [22]. The proportion of nonprogressor patients is higher in those living with HIV-2 than in those living with HIV-1. Data from the French ANRS CO5 HIV-2 cohort showed that, using the same definition as for an HIV-1 infection, 6% of individuals living with HIV-2 are long-term nonprogressors (ie, asymptomatic for ≥8 years while maintaining a CD4⁺ cell count ≥500 cells/µL) and 9% are elite controllers (ie, controlling HIV replication in the absence of ART for ≥10 years) [23]. Nevertheless, a notable proportion of those living with HIV-2 will finally progress to AIDS if left untreated [24].

TREATMENT

Monitoring Before Start of Treatment

CD4⁺ cell counts and plasma VLs should be monitored every 3 months (or at least twice a year) depending on the patient’s clinical status, previous CD4⁺ cell count, and the rate of the CD4⁺ cell count decline. Any detectable VL should be confirmed using a subsequent follow-up sample, with samples taken 1 month apart.

Before the treatment start, a genotypic resistance test of viral RNA for nucleoside reverse transcriptase inhibitors (NRTIs), protease inhibitors (PIs), and integrase inhibitors (INIs) is recommended in case of a detectable plasma VL. If the VL is too low to be amplified, proviral DNA could be considered. An occurrence of primary resistance was reported for 5% of patients in France [16, 25] and may dramatically impair the success of treatment. In addition, the resistance of HIV-2 develops more rapidly under suboptimal ART, and therapy options are more limited compared to HIV-1 [26–28].

Recommended Treatment Start

A systematic review of ART for persons living with HIV-2 produced no data from randomized, controlled trials guiding ART initiation, but such a trial is ongoing in West Africa (ANRS 12294 FIT2 trial). Current national European guidelines [5–8] concur that the initiation of ART should be based on the CD4⁺ cell count, viremia, and clinical status (see above, under “Characteristics of Human Immunodeficiency Virus–2 Infection”). Antiretroviral therapy of an HIV-2 infection is always indicated in symptomatic patients; that is, those with specific, HIV-related symptoms (Centers for Disease Control and Prevention category B or C, according to the revised classification system for adolescents and adults living with HIV) [5–9].

Antiretroviral treatment should be considered in asymptomatic patients with any of the following conditions:

• A CD4⁺ cell count ≤500 CD4⁺-cells/µL blood [5, 7];

• A CD4⁺ cell count decrease of more than 30 cells/µL a year over a period of more than 3 years [5, 7];

• Repeatedly detectable HIV-2 RNA in plasma [5, 7]; or

• Comorbidities, such as a chronic hepatitis B virus infection [5].

Treatment may be delayed in asymptomatic patients without any of these criteria, like long-term nonprogressors with stable CD4⁺ cell counts of more than 500 cells/µL and undetectable plasma VLs [5]. However, United States (Department of Health and Human Services) guidelines recommend treatment start at or soon after an HIV-2 diagnosis (unaffected by the CD4⁺ cell count and VL, as in HIV-1) [9]. This can be an option for HIV-2 patients, either regarding public health care aspects [1] or regarding “treatment as prevention” aspects (though the VLs in blood and genital secretions are reduced in those living with HIV-2 [28]), and should be discussed with the affected persons on a case-by-case basis.

Recommended Drugs: First-line Treatment

The selection of an appropriate antiretroviral regimen is challenging due to the limited number of drugs effective against HIV-2, compared to HIV-1.

All nucleoside and nucleotide reverse transcriptase inhibitors (NNRTIs), due to the large extent of polymorphisms, and the fusion inhibitor enfuvirtide are ineffective drugs against HIV-2. In addition, the PIs atazanavir, fosamprenavir, indinavir, nelfinavir, and tipranavir have reduced activity against HIV-2. Effective drugs against HIV-2 are all NRTIs; the (boosted) PIs darunavir, lopinavir, and saquinavir; all INIs; and the C-C motif chemokine receptor type 5 (CCR5)-inhibitor maraviroc, in case of CCR5 tropism of the virus [15, 21, 22, 26–30].

The recommended first-line treatment for HIV-2 infection should consist of a combination of 2 NRTIs plus a third partner: either an INI or a boosted, active PI (listed in Table 1).

Table 1.

Recommended Drugs for First- and Second-line Treatment of Persons Living With Human Immunodeficiency Virus–2

Backbone Drugs, 2 NRTIs	Plus	Third Drug
TAF/TDF + FTC/3TC or ABC + 3TC		1 PI (DRV/r, DRV/c, LPV/r) or 1 INI (RAL, DTGa, EVG/cb, BICc)

Abbreviations: 3TC, lamivudine; ABC, abacavir; BIC, bictegravir; c, cobicistat; DRV/r, boosted darunavir; DTG, dolutegravir; EVG/c, boosted elvitegravir; FTC, emtricitabine; HIV-2, human immunodeficiency virus–2; INI, integrase inhibitor; LPV/r, boosted lopinavir; NRTI, nucleoside reverse transcriptase inhibitors; PI, protease inhibitor; r, ritonavir; RAL, raltegravir; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate.

^aDTG: prescribers should consider the childbearing potential in women and pay attention to the current recommendations of medical agencies for drug safety.

^bEVG/c is not recommended for use during pregnancy because of substantially lower exposures of cobicistat and elvitegravir during the second and third trimesters.

^cBIC is active against HIV-2 replication, but only in vitro data are available (Smith, 2019 [31]). BIC is recommended for the treatment of HIV-2, comparable to DTG (Gottlieb, 2018 [1]). BIC is not evaluated in pregnant women and women of childbearing potential.

Data on dosing of the boosted PI darunavir (DRV/r) are still limited. For wild-type viruses without protease RAMs, DRV/r at 800/100 mg once daily is an option (Sophie Matheron, personal data from the French cohort). In the Portuguese cohort, several viral failures of first-line regimens with DRV/r at 800/100 mg once daily occurred, with detection of the I50V mutation (Perpetua Gomes, personal data). For those viruses with predicted resistance to DRV (the presence of at least 1 of the RAMs: I50V, I54M, I84V, and/or L90M; see Table 2), INIs should be considered as a first choice; if this is not possible, DRV/r at 600/100 mg should be administered twice daily. No clinical data on DRV/cobicistat are yet available, but theoretically cobicistat should work as in HIV-1.

Table 2.

Human Immunodeficiency Virus–2 Resistance

Drug	Mutations Associated With High Level of Resistance	Mutations Associated With Intermediate Level of Resistance
AZT	• Q151M • S215A/C/F/L/Y + 1 of (N69S/T, K70R, Y115F, K223R)	• S215A/C/F/L/Y
3TC/FTC	• M184VI	• K65R
ABC	• K65R • Q151M • M184V/I + 1 of (L74V, Y115F)	• 2 of (D67N, K70R/N, M184V/I, S215A/C/F/L/Y)
TDF/TAF	• K65R • Q151M + V111I
SQV	• G48V • L90M	• I84V
LPV	• V47A • I54M • 2 of (I82F, I84V, L90M)	• V62A + L99F • 1 of (I82F, I84V, L90M)
DRV	• I50V • I54M • I84V + L90M	• 1 of (I84V, L90M)
RAL	• N155H/R • Q148H/K/R • 1 of (E92Q, T97A) + Y143C/G/R • E92Q + T97A • 231ins [32]	• E92Q • Y143C/G/R
EVG	• E92Q/G • Q148H/K/R • N155H • T97A + Y143C • 231ins [32]	• Y143C
DTG	• G140S + Q148H/R • Q148K • E92Q + N155H • T97A + N155H • 231ins [32]	• E92Q • Q148H/R • N155H • T97A+ Y143C
BIC	• G140S + Q148H/R • Q148K • E92Q + N155H • T97A + N155H	• E92Q • Q148H/R • N155H • T97A+Y143C • 231ins [32]

Data are given according to the HIV-2EU expert group resistance interpretation rule set (Charpentier, 2015 [15]; updated January 2020).

Abbreviations: 3TC, lamivudine; ABC, abacavir; AZT, zidovudine; BIC, bictegravir; DRV, darunavir; DTG, dolutegravir; EVG, elvitegravir; FTC, emtricitabine; LPV, lopinavir; RAL, raltegravir; SQV, saquinavir; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate.

INIs are recommended as a first-line treatment mainly due to their in vivo efficiency and low side effect profile. There are limited data on integrase inhibitors from clinical practice [32–36]. As in HIV-1, physicians should consider the childbearing potential in women and pay attention to the current recommendations of medical agencies for drug safety.

The few available data on the treatment of coinfected patients living with HIV-1/HIV-2 suggest that ARTs active against both viruses should be chosen. The treatment start should be guided by the recommendations for the HIV-1 infection and monitoring should include VL and drug resistance testing for both HIV-1 and HIV-2 [38].

Recommended Drugs: Second-line Treatment

The definition of treatment failure in HIV-2 is more complex than in HIV-1, given the intrinsically low VLs in nontreated infections and the poor CD4⁺ cell recovery during treatment, and contains combined endpoints regarding the VL, CD4+ cell recovery, and clinical course.

Treatment failure in HIV-2 can be defined as:

• The detection of HIV-2 plasma RNA in at least 2 consecutive analyses;

• A decline in the CD4⁺ cell count, which can occur even by undetectable HIV-2 RNA plasma; and/or

• The persistence or emergence of HIV/AIDS–specific symptoms [5, 21, 26–28].

In case of therapy failure, the choice of a second-line regimen should be based on the results of genotypic resistance testing and the evaluation of the causes of failure (intolerance, lack of adherence).

Depending on the results of genotyping tests, zidovudine (AZT), maraviroc, and boosted saquinavir in combination can be considered as an option for a second-line treatment. When the CCR5 coreceptor inhibitor maraviroc is considered as a treatment option, tropism testing can be performed either phenotypically or genotypically by nucleic acid Sanger sequencing of the gp105 V3 loop region, similarly to in HIV-1 [39, 40].

HIV-2 RAMs for NRTIs and PIs differ from those for HIV-1 regarding their appearance and significance. The European Union’s HIV-2 expert group (HIV-2EU) has published a list of HIV-2 resistance mutations and a standardized HIV-2 drug resistance interpretation rule set [15]. Table 2 provides an updated table of HIV-2 RAMs and Table 3 provides an overview of features in the V3 loop that are discriminatory for viruses using CCR5 and those that are capable of using C-X-C motif chemokine receptor type 4 (CXCR4) according to geno2pheno_{[coreceptor-HIV2]}.

Table 3.

V3 Loop Amino Acids Position Features and CCR5/CXCR4 Tropism

V3 Position	R5 Feature	X4 Feature	R5 Weights	X4 Weights
18	L	H,Q,F,M	.69	-.23, -.15, -.12, -.1
19	I	R,K,V	.19	-.25, -.23, -.19
Insertion after position 22	-	H,Y	.36	-.18, -.18
24	P	NA	.17	NA
Insertion after position 24	-	I,V	.45	-.22, -.21
23	Q	R	.14	-.14
27a	Q	K	.09	-.12
13a	T	R	.11	-.07
26a	NA	N	NA	-.09
10a	A	K	.09	-.07
14a	I	L	.08	-.08
22	S	NA	.08	NA
15a	A	G	.08	-.07
8a	K	S	.07	-.07

Data are from Döring, 2016 [39]. The table shows discriminatory features of the geno2pheno_{[coreceptor-HIV2]} model in the HIV-2 V3 loop that make up >75% of the total model weights. Positions 18 and 19, insertions after position 24, and the overall charge represent major genotypic markers according to Visseaux and colleagues [40]. Entries marked with NA indicate features that did not exceed the 75% cutoff on the model weights.

Abbreviations: CCR5, C-C motif chemokine receptor type 5; CXCR4, C-X-C motif chemokine receptor type 4; HIV-2, human immunodeficiency virus–2; NA, not applicable.

^aPositions of discriminatory features that were not described previously in the literature.

If the first-line treatment contained a PI, the second-line treatment should contain an INI and vice versa, depending on the results of resistance testing.

Bioinformatic Tools for the Interpretation of Human Immunodeficiency Virus–2 Genotypic Resistance/Tropism Data

Drug resistance against HIV-2 can be determined using the HIV-2EU resistance tool (http://www.hiv-grade.de), which determines drug resistance according to the rule set of the HIV-2EU. The French rule set is available via the ANRS-AC43 website (http://www.hivfrenchresistance.org). HIV-2 coreceptor usage can be determined using the statistical model of geno2pheno_{[coreceptor-hiv2]} (http://coreceptor-hiv2.geno2pheno.org).

These tools allow the analysis of nucleotide sequences of the relevant genomic regions. To interpret the results, the input sequences are aligned to an HIV-2 reference strain. The HIV-2EU tool evaluates the impact of mutations according to the HIV-2EU rule set [11], while geno2pheno_{[coreceptor-HIV2]} uses a linear model that considers all V3 positions [39, 40].

Parameter Monitoring Under Treatment

Treatment should be closely monitored to minimize the risk of emergence of viral resistance. There is evidence that the barrier for the development of NRTI and PI resistance of HIV-2 is at least partially lower and the time window for a regimen change is narrower than in HIV-1 [26–28]. CD4 cell count monitoring is relevant, because some patients living with HIV-2 can deteriorate without a detectable HIV-2 viral load [6].

Monitoring is recommended as follows:

1. The quantification of HIV-2 VL and CD4⁺ cell counts at Months 1, 3, and 6 after the initiation or change of ART and, subsequently,

   • i. Every 3 months when the CD4⁺ cell count is <200 cells/µL;

   • ii. Every 3 to 6 months when the CD4⁺ cell count is between 200–500 cells/µL or >500 cells/µL, depending on the patient adherence, clinical status, and comorbidities;

2. Checking adherence;

3. Resistance testing in cases of treatment failure;

4. Checking plasma VL and CD4⁺ cell count immediately in cases of clinical progression; and

5. Testing VL, CD4⁺ cell count, and adherence every 1 to 3 months throughout pregnancy.

Pregnancy

Regarding maternal and fetal safety, data from HIV-1 treatment can be transferred to HIV-2. If a pregnant woman is already under ART with drugs active against HIV-2 and with no or lowest possible toxicity for the fetus, the treatment should be continued. Otherwise, the choice to continue or to switch should be made on a case-by-case decision, taking into account the mother’s HIV clinical status, including results of cumulative genotyping tests and adherence of and tolerance to ART.

Treating pregnant women or women of childbearing potential who are not able to use effective contraception throughout treatment imply that the prescriber has to consider all safety information, precautionary statements and caveats regarding ART medication, especially regarding INIs (dolutegravir, bictegravir), PIs, cobicistat, and tenofovir alafenamide. The administration of DRV/r twice daily should be considered during the third trimester or earlier, depending on the HIV-2 plasma concentration and drug history. So far, there is more clinical experience in treating pregnant women with NRTIs and PIs, compared to INIs [41].

Pregnant women fulfilling any of the criteria mentioned in the section on “Recommended Treatment Start” should start treatment with the recommended and suitable drugs for first-line HIV-2 ART from Week 12–15 onwards, selecting the safest and best-known substances in terms of potential maternal and fetal toxicity. Regarding United States (Department of Health and Human Services) guidelines [9], ART can be offered to all pregnant women living with HIV-2.

The risk of mother-to-child transmission (MTCT) in HIV-2 is lower than in HIV-1, due to the reduced average plasma VL [41]. To further reduce the MTCT risk, ART from the beginning of the third trimester of pregnancy is recommended also for women living with HIV-2 who have an undetectable plasma VL and no comorbidities.

If the VL is detectable or undetermined shortly before delivery, the addition of raltegravir (RAL) to an established ART should be considered and/or a planned caesarean section should be discussed. In these cases, as well as in cases of delivery complications and an increased risk of MTCT, intravenous AZT therapy should be applied perinatally (according to current guidelines for HIV-1).

Postexposure prophylaxis for the newborn should always be considered. All newborns who were perinatally exposed to HIV-2 (if the mother’s plasma VL was unknown or if the last VL measurement was above the detection limit) should receive appropriate antiretroviral triple therapy as soon as possible after delivery. If the maternal ultimate VL before delivery was undetectable, AZT monotherapy to the newborn can be administered according to current guidelines for HIV-1 and newborn postexposure prophylaxis, as there are no specific data for HIV-2.

Postexposure Prophylaxis

Postexposure prophylaxis with tenofovir alafenamide/tenofovir disoproxil fumarate combined with emtricitabine and either RAL, DRV/cobicistat, or DRV/r should be offered in case of high-risk contact with an ART-naive patient living with HIV-2 with a detectable or undetermined VL. Alternatively, AZT and lamivudine could be used instead.

In case of high-risk contact with an ART-experienced patient living with HIV-2 with a detectable or undetermined plasma VL, 2 NRTIs plus a third agent (an INI, DRV/r, boosted lopinavir, or boosted saquinavir) should be offered based on the history of previous ART regimens and treatment failures of the index patient, the tolerability of the drugs, and the results of genotypic resistance testing (reverse transcriptase, protease, and integrase), if available. Abacavir should only be used with a verified negative human leukocyte antigen (HLA)-B*5701) status.

Prexposure Prophylaxis

Preexposure prophylaxis is currently discussed and offered in HIV-1 settings. The sexual transmission of HIV-2 is roughly 5 times less efficient than the sexual transmission of HIV-1 [28, 42]. To date, there are no data available for the use and benefits of preexposure prophylaxis in HIV-2 settings, so that no reliable statement on this topic is currently possible.

CONCLUDING REMARKS

There are only limited data on diagnostics, monitoring, and treatment of patients living with HIV-2, and no European consensus guidelines are available for the management of these infections.

State-of-the-art diagnostics enable the discrimination between HIV-1 and HIV-2, but diagnostics should remain mainly in the hands of experienced or national reference laboratories. Commercial tests for HIV-1 RNA do not detect or quantify HIV-2 RNA. Recently, a commercial assay for the detection and quantification of HIV-2 RNA has become available.

ART is challenging due to the limited number of drugs effective for HIV-2. Remarkably few data are available to assess the efficacy and safety of treatment regimens in pregnancy, infancy, and HIV-1/HIV-2 coinfections. Existing national guidelines and recommendations for HIV-2 ART are based mainly on expert experience, in vitro data, and extrapolation from HIV-1. Bioinformatics tools for interpretations of drug resistance and viral tropism are freely available.

There is still a need for additional and increased collaborations between clinicians and researchers from both developed countries and from HIV-2–endemic settings to fill all the existing gaps.

Notes

Acknowledgments. The authors dedicate this work to Ricardo Camacho (1954–2018), who permanently stimulated the human immunodeficiency virus–2 (HIV-2) aspect in his scientific life. The authors are deeply grateful for his unique contribution to this paper.

The authors thank Sophie Matheron (Infectious Diseases Department, Bichat Claude Bernard Hospital, Universite de Paris, Institut National de la Santé et de la Recherche Médicale, Paris, France) for essential help, personal data, and discussion (especially on the Diagnostics, Treatment, and Pregnancy sections).

Financial support. This work was supported by the HIV/hepatitis (HEP) Master Project (grant number IIA5-2013-2514-AUK375), Bundesministerium für Besundheit (BMBF Federal Ministry of Health), Fund Ref 10.13039/501100003107, and Deutsche Zentrum für Infektionsforschung (DZIF, German Center for Infection Research).

Potential conflicts of interest. D. B. has received speaker fees and expenses for participation on medical meetings and conferences from Janssen-Cilag, Abbvie, and Gilead and speaker fees from Hexal, outside the submitted work. M. O. has received speaker fees from Janssen-Cilag and advisory board fees from Abbvie and Gilead, outside the submitted work. R. K. has received personal fees from Gilead, Bristol-Myers Squibb (BMS), ViiV, Merck, Sharp & Dohme (MSD), Roche, Siemens, and VELA and grants from ViiV, outside the submitted work. J. E. has received speaker fees from MSD, ViiV, and Gilead and advisory board fees from ViiV and MSD, outside the submitted work. A. W. has received institutional grants from ViiV, Gilead, Janssen, Merck, CLJI, and Virology Education; travel support from Virology Education; and nonfinancial support from ARK Diagnostics, outside the submitted work. Jean Ruelle has received grants from ViiV Healthcare and Merck Sharpe & Dohme and personal fees from Gilead. P. G. has received personal fees from ViiV Healthcare, Gilead Sciences, Merck, and Janssen, outside the submitted work. N. T. has received personal fees from GlaxoSmithKline, Gilead, and BMS, outside the submitted work. B. J. has received personal fees from ViiV, Gilead, Janssen-Cilag, Bristol-Myers Squibb, and MSD, outside the submitted work. J. R. has received speaker fees and advisory board fees from Gilead, Abbott, ViiV, Abbvie, Janssen, and Merck and meeting expenses from Gilead and Abbott, outside the submitted work. M. S. has received personal fees from Janssen, Gilead, ViiV, and MSD outside the submitted work. K. M. has received advisory board fees from Abbvie and ViiV Healthcare and grants from Janssen and MSD, outside the submitted work. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.