Diagnosis and Management of HIV-2 in Adults

Purpose and Development of This Guideline

Lead author: Sanjiv S. Shah, MD, MPH, AAHIVS, with the Medical Care Criteria Committee, July 2019

The New York State Department of Health (NYSDOH) AIDS Institute (AI) developed this guideline for primary care providers and other clinicians who may diagnose and treat patients with HIV-2 infection. The guideline is designed to achieve the following goals:

• Inform clinicians about when to suspect and how to diagnose and manage the care of adults with HIV-2.
• Identify the similarities and differences in treatment for individuals with HIV-1 and HIV-2.
• Recommend preferred antiretroviral (ARV) regimens for treatment and identify ARVs to avoid.
• Encourage clinicians to use the services of the NYSDOH Wadsworth Center, the NYS public health laboratory, for testing used in monitoring HIV-2.
• Integrate current evidence-based clinical recommendations into the healthcare-related implementation strategies of the Ending the Epidemic (ETE) initiative, which seeks to end the AIDS epidemic in NYS by the end of 2020.

Guideline development: This guideline was developed by the NYSDOH AI Clinical Guidelines Program, which is a collaborative effort between the NYSDOH AI Office of the Medical Director and the Johns Hopkins University School of Medicine, Division of Infectious Diseases.

Established in 1986, the goal of the Clinical Guidelines Program is to develop and disseminate evidence-based, state-of-the-art clinical practice guidelines to improve the quality of care provided to people who have HIV, hepatitis C virus, or sexually transmitted infections; people with substance use issues; and members of the LGBTQ community. NYSDOH AI guidelines are developed by committees of clinical experts through a consensus-driven process.

The NYSDOH AI charged the Medical Care Criteria Committee (Adult HIV and related guidelines) with developing evidence-based clinical recommendations for identifying and treating HIV-2. The resulting recommendations are based on an extensive review of the medical literature and reflect consensus among this panel of experts. Each recommendation is rated for strength and for quality of the evidence (see below). If recommendations are based on expert opinion, the rationale for the opinion is included.

HIV-2 Overview

Lead author: Sanjiv S. Shah, MD, MPH, AAHIVS, with the Medical Care Criteria Committee, July 2019

The HIV-2 virus was first isolated in West Africa in the mid-1980s among individuals living with AIDS [Clavel, et al. 1986]. HIV-2 infection is endemic in West Africa, with the highest prevalence in Cape Verde, the Ivory Coast, Gambia, Guinea-Bissau, Mali, Mauritania, Nigeria, and Sierra Leone [Gottlieb, et al. 2018]. Although rare, HIV-2 infection has also been reported in several countries in Europe, South America, and Asia, and in the United States [Gottlieb 2018]. As of June 2010, 166 cases of HIV-2 had been reported in the United States and 46% of those were from New York City [CDC 2011]. The majority of individuals with HIV-2 are from West Africa or have had sexual contact or shared injection drug equipment with someone from this region [Torian, et al. 2010].

HIV-2 infection is associated with slower disease progression than HIV-1 infection because of lower plasma viral load levels of HIV-2 [Simon, et al. 1993; Popper, et al. 1999; Gottlieb, et al. 2002; MacNeil, et al. 2007; van der Loeff, et al. 2010]. With lower levels of virus, HIV-2 is transmitted less efficiently than HIV-1 through sexual behavior and from mother to child [Adjorlolo-Johnson, et al. 1994; O’Donovan, et al. 2000; Burgard, et al. 2010]. Similar to HIV-1, HIV-2 disease progression correlates with increasing plasma HIV-2 viral load [Gottlieb, et al. 2002]. Although HIV-2 is less virulent than HIV-1, individuals with HIV-2 manifest clinical signs, symptoms, and opportunistic infections (OIs) similar to those seen with HIV-1. In addition, the majority of individuals with HIV-2, if untreated, will eventually progress to AIDS and death [Esbjornsson, et al. 2018].

There are many similarities in the management of patients with HIV-1 and those with HIV-2, including prophylaxis for and treatment of OIs and timing of antiretroviral therapy (ART) initiation. As noted in the section on treatment, below, ART should be recommended for all patients diagnosed with HIV-2 [Ba, et al. 2018]. As with HIV-1, the patient should make the final decision of whether and when to initiate ART.

A key difference in the clinical management of HIV-2 compared with HIV-1 is that resistance testing is not commercially available in the United States and guidance in interpreting mutations is not readily available for HIV-2. Another important difference in management is that the nonnucleoside reverse transcriptase inhibitor (NNRTI) class of ARV medications is not effective against HIV-2. Furthermore, unlike in HIV-1, there are no randomized clinical trials of ARV treatment for HIV-2 that indicate the optimal time to initiate treatment or the preferred initial regimen. Therefore, treatment recommendations for HIV-2 are in large part derived from clinical studies conducted in HIV-1. Because HIV-1 and HIV-2 share the same pathogenic process, extrapolating to HIV-2 from HIV-1 is a clinically valid approach.

References

Adjorlolo-Johnson G, De Cock KM, Ekpini E, et al. Prospective comparison of mother-to-child transmission of HIV-1 and HIV-2 in Abidjan, Ivory Coast. JAMA 1994;272(6):462-466. [PMID: 8040982]

Ba S, Raugi DN, Smith RA, et al. A trial of a single tablet regimen of elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate for the initial treatment of HIV-2 infection in a resource-limited setting: 48 week results from Senegal, West Africa. Clin Infect Dis 2018. [PMID: 29672676]

Burgard M, Jasseron C, Matheron S, et al. Mother-to-child transmission of HIV-2 infection from 1986 to 2007 in the ANRS French Perinatal Cohort EPF-CO1. Clin Infect Dis 2010;51(7):833-843. [PMID: 20804413]

CDC. HIV-2 infection surveillance–United States, 1987-2009. MMWR Morb Mortal Wkly Rep 2011;60(29):985-988. [PMID: 21796096]

Clavel F, Guyader M, Guetard D, et al. Molecular cloning and polymorphism of the human immune deficiency virus type 2. Nature 1986;324(6098):691-695. [PMID: 3025743]

Esbjornsson J, Mansson F, Kvist A, et al. Long-term follow-up of HIV-2-related AIDS and mortality in Guinea-Bissau: a prospective open cohort study. Lancet HIV 2018. [PMID: 30392769]

Gottlieb G. Treatment of HIV-2 infection. 2018 May 25. https://www.uptodate.com/contents/treatment-of-hiv-2-infection [accessed 2019 Jun 6]

Gottlieb G, 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. Lancet HIV 2018;5(7):e390-e399. [PMID: 30052509]

Gottlieb G, Sow PS, Hawes SE, et al. Equal plasma viral loads predict a similar rate of CD4+ T cell decline in human immunodeficiency virus (HIV) type 1- and HIV-2-infected individuals from Senegal, West Africa. J Infect Dis 2002;185(7):905-914. [PMID: 11920314]

MacNeil A, Sarr AD, Sankale JL, et al. Direct evidence of lower viral replication rates in vivo in human immunodeficiency virus type 2 (HIV-2) infection than in HIV-1 infection. J Virol 2007;81(10):5325-5330. [PMID: 17329334]

O’Donovan D, Ariyoshi K, Milligan P, et al. Maternal plasma viral RNA levels determine marked differences in mother-to-child transmission rates of HIV-1 and HIV-2 in The Gambia. MRC/Gambia Government/University College London Medical School working group on mother-child transmission of HIV. AIDS 2000;14(4):441-448. [PMID: 10770548]

Popper SJ, Sarr AD, Travers KU, et al. Lower human immunodeficiency virus (HIV) type 2 viral load reflects the difference in pathogenicity of HIV-1 and HIV-2. J Infect Dis 1999;180(4):1116-1121. [PMID: 10479138]

Simon F, Matheron S, Tamalet C, et al. Cellular and plasma viral load in patients infected with HIV-2. AIDS 1993;7(11):1411-1417. [PMID: 7904166]

Torian LV, Eavey JJ, Punsalang AP, et al. HIV type 2 in New York City, 2000-2008. Clin Infect Dis 2010;51(11):1334-1342. [PMID: 21039219]

van der Loeff MF, Larke N, Kaye S, et al. Undetectable plasma viral load predicts normal survival in HIV-2-infected people in a West African village. Retrovirology 2010;7:46. [PMID: 20482865]

Diagnosis of HIV-2

Lead author: Sanjiv S. Shah, MD, MPH, AAHIVS, with the Medical Care Criteria Committee, July 2019

Before the 4th-generation HIV-1/2 Ag/Ab and HIV-1/2 Ab differentiation immunoassays for HIV testing became widely available, clinicians suspected chronic HIV-2 infection in certain clinical scenarios, such as a declining CD4 cell count in an HIV-1–seropositive, untreated individual with an undetectable HIV-1 plasma viral load, or an opportunistic infection in an individual from West Africa who is not HIV-1 seropositive.

Currently, all HIV testing performed according to the CDC/APHL algorithm begins with an FDA-approved 4th-generation HIV-1/2 Ag/Ab combination immunoassay [CDC 2018], which detects HIV-1 p24 antigen and HIV-1 and HIV-2 antibodies but not HIV-2 antigen. If the combination immunoassay is reactive, a supplemental HIV-1/2 Ab differentiation assay is performed. There are 4 scenarios, described below, in which clinicians should consider HIV-2 infection.

• HIV-1/HIV-2 differentiation assay is reactive for HIV-2 antibody: The individual is considered HIV-2 antibody positive, and a clinical evaluation for HIV-2 infection should be performed (see Monitoring ART in Individuals With HIV-2 in this guideline).
• HIV-1/HIV-2 differentiation assay is reactive for HIV-1 and HIV-2 antibody: The individual is considered HIV positive, undifferentiated, and HIV-1 RNA and HIV-2 RNA or DNA testing should be performed to confirm or exclude HIV-1/HIV-2 coinfection. A minority of individuals with HIV-2 are coinfected with HIV-1. Qualitative and quantitative HIV-2 viral load testing is available by contacting the Bloodborne Viruses Laboratory at the Wadsworth Center (see Box 1: Wadsworth Center Bloodborne Viruses Laboratory Services, below).
• HIV-1/HIV-2 differentiation assay is nonreactive or indeterminate for HIV-1 and/or HIV-2 antibody: Plasma HIV-1 RNA testing should be performed to confirm or exclude acute HIV-1 infection [CDC 2018].
  • If the Ab differentiation assay is nonreactive or HIV-1 indeterminate and HIV-1 RNA is not detected, the individual is considered negative for HIV-1 and HIV-2.
  • If the antibody differentiation assay is either HIV-2 indeterminate or HIV indeterminate and HIV-1 RNA is not detected, then HIV-2 RNA testing may be used to confirm HIV-2 infection. However, because HIV-2 RNA levels can be low or undetectable in a person with HIV-2 infection, the absence of HIV-2 RNA does not exclude HIV-2 infection. Therefore, in a person at high risk for HIV-2 infection who has undetectable HIV-2 RNA, clinicians should consider testing for HIV-2 DNA or repeating the HIV testing algorithm in 2 to 4 weeks, starting with the HIV-1/2 Ag/Ab combination immunoassay. If results remain unclear, clinicians may consider obtaining other HIV-2–specific tests through public health or commercial laboratories or the CDC.
• Nonreactive 4th-generation HIV-1/2 Ag/Ab immunoassay and suspected recent exposure to HIV-2 (e.g., exposure from a sex partner from an HIV-2 endemic area): HIV-2 RNA testing may be required or the HIV testing algorithm may be repeated, beginning with the 4th-generation HIV-1/2 Ag/Ab immunoassay, 4 weeks (and not later than 12 weeks) after the first test.

Reference

CDC. 2018 Quick reference guide: Recommended laboratory HIV testing algorithm for serum or plasma specimens. 2018 Jan. https://stacks.cdc.gov/view/cdc/50872 [accessed 2019 Jun 6]

Treatment of HIV-2

Lead author: Sanjiv S. Shah, MD, MPH, AAHIVS, with the Medical Care Criteria Committee, July 2019

All FDA-approved NRTIs effectively inhibit HIV-2 reverse transcriptase [Menendez-Arias and Alvarez 2014]. Three HIV protease inhibitors effectively inhibit HIV-2, but given the availability of darunavir, use of lopinavir and saquinavir should be limited. Atazanavir, fosamprenavir, tipranavir, and nelfinavir have no or greatly reduced in vitro inhibitory activity against HIV-2. As a class, NNRTIs are not active against HIV-2 [Menendez-Arias and Alvarez 2014].

Based on limited clinical trial data using the INSTIs elvitegravir and raltegravir, and in vitro data, it is expected that a DTG- or BIC-based regimen with 2 NRTIs can be used to treat treatment-naive patients with HIV-2. In one study of a single-tablet regimen (EVG/COBI/TDF/FTC), 93.3% of subjects had viral suppression at 48 weeks [Ba, et al. 2018]. A study of a multi-tablet regimen (TDF/FTC and RAL) demonstrated that 96% of participants with HIV-2 completing the 48-week follow-up had an HIV-2 viral load <40 copies/mL [Matheron, et al. 2018]. It is important to involve patients in the decision-making process regarding initiation of ART, and clinicians should work to remove barriers to treatment initiation, such as lack of access to combination therapy.

In treatment-experienced patients with HIV-2, the ARVs listed in Table 1 can be considered if their potency has not been compromised by prior treatment failure and the likely emergence of drug resistance/cross-resistance. There are no commercially available genotypic or phenotypic drug resistance assays for HIV-2 available in the United States that can be used to guide the selection of an alternative ART regimen in the setting of virologic failure.

Bictegravir is highly potent against HIV-2 in vitro [Tsiang, et al. 2016; Le Hingrat, et al. 2018; Smith, et al. 2019]; however, there are no published data on the use of TAF/FTC/BIC in patients with HIV-2. If no drug resistance testing is available, DTG and BIC should be used with caution in ART-experienced patients with HIV-2 who have virologic failure on a RAL- or EVG- based ART regimen. The chemokine receptor antagonist maraviroc (MVC) is active against HIV-2 strains that exclusively use CCR5 for viral entry [Borrego, et al. 2012]. However, its use in the treatment of HIV-2 is limited because there is no commercially available tropism assay for HIV-2 to predict susceptibility to MVC. The fusion inhibitor enfuvirtide has no in vitro activity against HIV-2 [Menendez-Arias and Alvarez 2014]. There are no data at this time to determine if ibalizumab, a humanized monoclonal IgG-4 antibody that prevents HIV cell entry by binding to the host CD4 receptor, can be used to treat HIV-2.

In the setting of HIV-1/HIV-2 coinfection, HIV-1 drug resistance testing should be performed to guide the choice of an initial regimen or to modify a regimen if virologic failure develops. If HIV-1 drug-resistant virus has been identified, ARV agents that are active only against HIV-1 (such as an NNRTI) can be used to treat individuals with HIV-1/HIV-2 coinfection, as long as a combination of anti–HIV-2 active agents is also used to fully suppress both viruses.

References

Ba S, Raugi DN, Smith RA, et al. A trial of a single tablet regimen of elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate for the initial treatment of HIV-2 infection in a resource-limited setting: 48 week results from Senegal, West Africa. Clin Infect Dis 2018. [PMID: 29672676]

Borrego P, Calado R, Marcelino JM, et al. Baseline susceptibility of primary HIV-2 to entry inhibitors. Antivir Ther 2012;17(3):565-570. [PMID: 22293827]

Eron JJ, Orkin C, Gallant J, et al. A week-48 randomized phase-3 trial of darunavir/cobicistat/emtricitabine/tenofovir alafenamide in treatment-naive HIV-1 patients. AIDS 2018;32(11):1431-1442. [PMID: 29683855]

Le Hingrat Q, Collin G, Le M, et al. A new mechanism of resistance of HIV-2 to integrase inhibitors: a 5 amino-acids insertion in the integrase C-terminal domain. Clin Infect Dis 2018. [PMID: 30383215]

Matheron S, Descamps D, Gallien S, et al. First-line raltegravir/emtricitabine/tenofovir combination in human immunodeficiency virus type 2 (HIV-2) infection: A phase 2, noncomparative trial (ANRS 159 HIV-2). Clin Infect Dis 2018;67(8):1161-1167. [PMID: 29590335]

Menendez-Arias L, Alvarez M. Antiretroviral therapy and drug resistance in human immunodeficiency virus type 2 infection. Antiviral Res 2014;102:70-86. [PMID: 24345729]

Smith RA, Raugi DN, Wu VH, et al. Comparison of the antiviral activity of bictegravir against HIV-1 and HIV-2 isolates and integrase inhibitor-resistant HIV-2 mutants. Antimicrob Agents Chemother 2019;63(5). [PMID: 30803972]

Tsiang M, Jones GS, Goldsmith J, et al. Antiviral activity of bictegravir (GS-9883), a novel potent HIV-1 integrase strand transfer inhibitor with an improved resistance profile. Antimicrob Agents Chemother 2016;60(12):7086-7097. [PMID: 27645238]

Monitoring ART in Individuals With HIV-2

Lead author: Sanjiv S. Shah, MD, MPH, AAHIVS, with the Medical Care Criteria Committee, July 2019

There is no FDA-approved, HIV-2 quantitative viral load assay commercially available. However, an HIV-2 quantitative viral load test is available by contacting the Bloodborne Viruses Laboratory at the Wadsworth Center (see Diagnosis of HIV-2 > Box 1: Wadsworth Center Bloodborne Viruses Laboratory Services in this guideline). In New York State, HIV-2 viral load testing should be used to determine the effectiveness of an ART regimen in patients with HIV-2 [Ba, et al. 2018; Matheron, et al. 2018]. If clinicians outside of New York State do not have access to HIV-2 viral load testing, they should suspect treatment failure if an individual with HIV-2 has a sustained or progressive decline in CD4 cell count or experiences clinical disease progression on therapy. Data from a multi-cohort study indicate that patients with HIV-2 who were initiated on a first-line combination ART regimen had less robust CD4 cell count increases than individuals with HIV-1, even after adjustment for plasma viral load levels [Wittkop, et al. 2017]. In HIV-2, a muted CD4 cell count increase from baseline after treatment initiation may not necessarily imply that the regimen is ineffective. If patients with HIV-2 have either immunologic or virologic treatment failure, clinicians are strongly urged to refer them to or consult with experienced HIV-2 clinical management specialists.

In addition to monitoring ART, patients with HIV-2 require the same laboratory and diagnostic testing, use and appropriate discontinuation of prophylaxis for OIs, and use of immunizations as patients with HIV-1 (see NYSDOH AI guidelines Primary Care Approach > Preventive Medicine and Immunizations for Adults with HIV).

References

Ba S, Raugi DN, Smith RA, et al. A trial of a single tablet regimen of elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate for the initial treatment of HIV-2 infection in a resource-limited setting: 48 week results from Senegal, West Africa. Clin Infect Dis 2018. [PMID: 29672676]

Matheron S, Descamps D, Gallien S, et al. First-line raltegravir/emtricitabine/tenofovir combination in human immunodeficiency virus type 2 (HIV-2) infection: A phase 2, noncomparative trial (ANRS 159 HIV-2). Clin Infect Dis 2018;67(8):1161-1167. [PMID: 29590335]

Wittkop L, Arsandaux J, Trevino A, et al. CD4 cell count response to first-line combination ART in HIV-2+ patients compared with HIV-1+ patients: a multinational, multicohort European study. J Antimicrob Chemother 2017;72(10):2869-2878. [PMID: 29091198]

Pregnancy and HIV-2

Lead author: Sanjiv S. Shah, MD, MPH, AAHIVS, with the Medical Care Criteria Committee, July 2019

A combination of either TDF/FTC or ABC/3TC (if HLA-B*5701 is negative) plus either twice-daily RAL or twice-daily DRV/r is recommended during pregnancy. For individuals with HIV-2, viral load monitoring during pregnancy and prophylactic ART for the HIV-2–exposed infant should follow the recommendations for pregnancy and infant exposure in the setting of HIV-1 (see the NYSDOH AI guidance NYS Good Practices to Prevent Perinatal HIV Transmission). During the early part of pregnancy, it is important that healthcare providers follow the Wadsworth Center protocol for accurate and timely submission of specimens and know the amount of time needed to return the results of HIV-2 viral load testing. For example, the Wadsworth Center Bloodborne Viruses Laboratory is not open on weekends, so if a patient’s blood is drawn on a Thursday or Friday, the separated plasma should be stored at the drawing facility in a freezer and shipped on Monday, Tuesday, or Wednesday of the following week to ensure weekday delivery to the laboratory.

Serial HIV-2 diagnostic testing in HIV-2–exposed infants to confirm or exclude HIV-2 infection is available free of charge from the Wadsworth Center (see Diagnosis of HIV-2 > Box 1: Wadsworth Center Bloodborne Viruses Laboratory Services in this guideline). For diagnostic testing of infants exposed to HIV-2, whole blood collected in an EDTA tube (purple top, prevents blood clotting) must be received in the laboratory within 3 days of collection. Collection kits for pediatric HIV diagnostic testing may be requested from the Wadsworth Center Order Desk at (518) 474-4175.

Pre- and Post-Exposure Prophylaxis for HIV-2

Lead author: Sanjiv S. Shah, MD, MPH, AAHIVS, with the Medical Care Criteria Committee, July 2019

As with HIV-1, TDF/FTC is active against HIV-2 [Menendez-Arias and Alvarez 2014] and could be used as a pre-exposure prophylaxis (PrEP) regimen to prevent infection with HIV-2. For more information on evaluating patients for PrEP see NYSDOH AI guideline PrEP to Prevent HIV and Promote Sexual Health.

Reference

Menendez-Arias L, Alvarez M. Antiretroviral therapy and drug resistance in human immunodeficiency virus type 2 infection. Antiviral Res 2014;102:70-86. [PMID: 24345729]

All Recommendations

Lead author: Sanjiv S. Shah, MD, MPH, AAHIVS, with the Medical Care Criteria Committee, July 2019