Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV
The information in the brief version is excerpted directly from the full-text guidelines. The brief version is a compilation of the tables and boxed recommendations.
Considerations for Antiretroviral Use in Special Patient Populations
Last Updated: December 18, 2019; Last Reviewed: December 18, 2019
|Key Considerations and Recommendations|
|Rating of Recommendations: A = Strong; B = Moderate; C = Optional
Rating of Evidence: I = Data from randomized controlled trials; II = Data from well-designed nonrandomized trials or observational cohort studies with long-term clinical outcomes; III = Expert opinion
HIV-2 infection is endemic in West Africa, with certain countries experiencing a population prevalence of >1%. The possibility of HIV-2 infection should be considered when treating persons of West African origin, persons who have had sexual contact with or who have shared needles with persons of West African origin, and persons who reside in countries with strong socioeconomic ties to West Africa (e.g., France, Spain, Portugal, and former Portuguese colonies such as Brazil, Angola, Mozambique, and parts of India). Globally, it has been estimated that one million to two million individuals have HIV-2, a number that includes people with HIV-1/HIV-2 dual infection. However, current and accurate prevalence data are scarce, and neither the Joint United Nations Programme on HIV and AIDS nor the World Health Organization have formal surveillance systems for HIV-2.1
Clinical Course of HIV-2 Infection
The clinical course of HIV-2 infection is generally characterized by a longer asymptomatic stage, lower plasma viral loads, and a lower mortality rate than HIV-1 infection.2,3 However, without effective antiretroviral therapy (ART), HIV-2 infection will progress to AIDS and death in the majority of individuals.4 Concomitant HIV-1 and HIV-2 infection may occur, and the possibility of this coinfection should be considered when treating persons from areas with a high prevalence of HIV-2.
Diagnostic and Monitoring Assays for HIV-2 Infection
In the appropriate epidemiologic setting, HIV-2 infection should be suspected in persons who have clinical conditions that suggest HIV infection but who have atypical serologic results (e.g., a positive screening assay with an indeterminate HIV-1 Western blot).5 The possibility of HIV-2 infection should also be considered in the appropriate epidemiologic setting in persons who have serologically confirmed HIV infection but who have low or undetectable HIV-1 RNA levels, or in those who have declining CD4 T lymphocyte (CD4) cell counts despite apparent virologic suppression on ART.
The 2014 Centers for Disease Control and Prevention guidelines for HIV diagnostic testing6 recommend using an HIV-1/HIV-2 antigen/antibody combination immunoassay for initial testing and using an HIV-1/HIV-2 antibody differentiation immunoassay for subsequent testing. The Geenius HIV 1/2 Supplemental Assay (Bio-Rad Laboratories) is approved by the Food and Drug Administration (FDA) to differentiate HIV-1 infection from HIV-2 infection. The Multispot HIV-1/HIV-2 Rapid Test is no longer available. Commercially available HIV-1 RNA assays do not reliably detect or quantify HIV-2 RNA.7 Quantitative HIV-2 RNA testing is available at the University of Washington (UW)8 and the New York State Department of Health (NYSDOH).9 HIV-2 nucleic acid amplification test-based (total DNA/RNA) diagnostic testing is available for clinical care at UW.10 However, it is important to note that up to one-third of persons with untreated HIV-2 will have HIV-2 RNA levels below the limits of detection (10 copies/mL for UW testing and 7 IU/mL for NYSDOH testing); some of these persons will have clinical progression and CD4 count decline. No validated HIV-2 genotypic or phenotypic antiretroviral (ARV) resistance assays are approved by the FDA for clinical use. HIV-2 genotypic ARV resistance assays are available at UW for research use only.
Treatment of HIV-2 Infection
To date, no randomized controlled trials that address when to start ART or the choice of initial or subsequent ART regimens for HIV-2 have been completed;11 thus, the optimal treatment strategy has not been defined. Existing data on the treatment of HIV-2 and extrapolation from data on the treatment of HIV-1 suggest that ART should be started at or soon after HIV-2 diagnosis in order to prevent disease progression and transmission of HIV-2 to others (AIII). However, CD4 cell recovery in persons with HIV-2 who are on ART is generally poorer than that observed in persons with HIV-1.12,13
Data from in vitro studies suggest that HIV-2 is sensitive to the currently available nucleoside reverse transcriptase inhibitors (NRTIs); however, HIV-2 is more likely to develop resistance to NRTIs than HIV-1.14 HIV-2 is intrinsically resistant to non-nucleoside reverse transcriptase inhibitors (NNRTIs);15 thus, NNRTI-based regimens are not recommended for treatment of HIV-2 (AII). Several small studies in individuals with HIV-2 have reported poor responses to dual-NRTI regimens16,17 or regimens that contain an NNRTI plus two NRTIs.18,19 Clinical data on the effectiveness of triple-NRTI regimens are conflicting.20,21
Integrase strand transfer inhibitor (INSTI)-based regimens or protease inhibitor (PI)-based regimens are treatment options for persons with HIV-2. As discussed below, two single-arm clinical trials showed favorable outcomes in patients who received INSTI-based regimens; data regarding the efficacy of PI-based regimens primarily come from observational reports. A randomized controlled trial comparing raltegravir (RAL) plus tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) to lopinavir/ritonavir plus TDF/FTC is currently underway (FIT-2; NCT02150993).
Integrase Strand Transfer Inhibitor-Based Regimens
All FDA-approved INSTIs—RAL, elvitegravir (EVG), dolutegravir (DTG), and bictegravir—have potent activity against HIV-2 in vitro.22-26 INSTI-based regimens have shown favorable treatment responses in observational studies.27-29 Two single-arm, open-label clinical trials have assessed the effectiveness of INSTI-based regimens in ART-naive individuals with HIV-2. One study evaluated RAL plus TDF/FTC, and the other evaluated EVG/cobicistat/TDF/FTC. Both studies demonstrated favorable clinical and immuno-virologic results at 48 weeks, providing the best evidence to date for HIV-2 treatment recommendations.30,31
Protease Inhibitor-Based Regimens
In general, regimens that contain boosted PIs that are active against HIV-2 (and that also include two NRTIs) have resulted in more favorable virologic and immunologic responses than regimens that consist of only two or three NRTIs.12,13,21,32 Darunavir (DRV), lopinavir, and saquinavir are more active against HIV-2 than other approved PIs.33-35 Older, unboosted PI-based regimens, including nelfinavir or indinavir plus zidovudine and lamivudine, and atazanavir-based regimens have shown poor clinical success rates.11,16,17,36,37
Amongst the entry inhibitors, HIV-2 is intrinsically resistant to enfuvirtide.38 The CCR5 antagonist maraviroc appears to be active against some HIV-2 isolates;39 however, there are no FDA-approved assays that can determine HIV-2 co-receptor tropism, and HIV-2 is known to use many other minor co-receptors in addition to CCR5 and CXCR4.40 There are no data yet on the activity of ibalizumab against HIV-2.
Some national and international guidelines have recommended specific preferred and alternative drug regimens for initial and second-line ART for HIV-2 infection;41-44 however, there are currently no comparative randomized controlled clinical trial data that support the effectiveness of a specific recommended regimen.
Until there are more definitive data on outcomes, the Panel on Antiretroviral Guidelines for Adults and Adolescents recommends the following regimens for individuals with HIV-2 mono-infection or HIV-1/HIV-2 dual infection:
- A regimen that contains one INSTI plus two NRTIs is the recommended initial ART regimen for most individuals with HIV-2 (AII). Data from an observational study in Botswana suggest that there is an increased risk of neural tube defects in infants born to those who were receiving DTG at the time of conception; however, the risk of these defects is still low. Before initiating an INSTI-based regimen in a person of childbearing potential, clinicians should review Table 6b for information to consider when choosing an ART regimen.
- An alternative regimen is a boosted PI (DRV or LPV) that is active against HIV-2 plus two NRTIs (BII).
- NNRTI-based regimens are not recommended for persons with HIV-2 (AII).
- Patients with hepatitis B virus (HBV)/HIV-2 coinfection require ART regimens that contain drugs with activity against both HIV-2 and HBV (AIII). See Hepatitis B Virus/HIV Coinfection for more information.
- HIV-2 plasma RNA levels, CD4 cell counts, and clinical status should be monitored to assess treatment response, as is recommended for HIV-1 (AII).
- Persons who have HIV-2 RNA levels that are below the limits of detection before they initiate ART should still undergo routine HIV-2 plasma RNA monitoring in addition to CD4 cell count and clinical monitoring. Unlike HIV-1, persons with HIV-2 require continued CD4 cell count monitoring, as disease progression can occur in the setting of undetectable HIV-2 viral load (AIII).
Persons with HIV-2 who are of childbearing potential require similar considerations when choosing a regimen as those with HIV-1 (see What to Start). There are no data on HIV-2 treatment as prevention; however, both data from studies of people with HIV-1 and data on the natural history of HIV-2 transmission suggest that effective ART likely provides a reduced risk of transmission to sexual partners.
Viral mutations that are associated with resistance to NRTIs, PIs, and/or INSTIs may develop in persons with HIV-2 while they are on ART.35,45,46 Currently, transmitted drug resistance appears to be rare among people with HIV-2.47,48 In several small studies, twice-daily dosing of DTG was found to have some residual activity as a second-line INSTI in some persons with HIV-2 who had extensive ART experience and RAL resistance.49-52 Genotypic algorithms that are used to predict drug resistance in HIV-1 may not be applicable to HIV-2, because the pathways and mutational patterns that lead to resistance may differ between the HIV types (see the HIV2EU Algorithm and the Stanford University HIV Drug Resistance Database).53 In the event of virologic, immunologic, or clinical failure, a new ART regimen should be constructed in consultation with an expert in HIV-2 management.
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- 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. Available at: http://www.ncbi.nlm.nih.gov/pubmed/30392769.
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- Damond F, Benard A, Balotta C, et al. An international collaboration to standardize HIV-2 viral load assays: results from the 2009 ACHI(E)V(2E) quality control study. J Clin Microbiol. 2011;49(10):3491-3497. Available at: http://www.ncbi.nlm.nih.gov/pubmed/21813718.
- Chang M, Gottlieb GS, Dragavon JA, et al. Validation for clinical use of a novel HIV-2 plasma RNA viral load assay using the Abbott m2000 platform. J Clin Virol. 2012;55(2):128-133. Available at: http://www.ncbi.nlm.nih.gov/pubmed/22832059.
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- Chang M, Wong AJ, Raugi DN, et al. 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. J Clin Virol. 2017;86:56-61. Available at: http://www.ncbi.nlm.nih.gov/pubmed/27951466.
- Gottlieb GS, Eholie SP, Nkengasong JN, et al. A call for randomized controlled trials of antiretroviral therapy for HIV-2 infection in West Africa. AIDS. 2008;22(16):2069-2072; discussion 2073-2064. Available at: https://www.ncbi.nlm.nih.gov/pubmed/18832869.
- Drylewicz J, Eholie S, Maiga M, et al. First-year lymphocyte T CD4+ response to antiretroviral therapy according to the HIV type in the IeDEA West Africa collaboration. AIDS. 2010;24(7):1043-1050. Available at: http://www.ncbi.nlm.nih.gov/pubmed/20397306.
- Ekouevi DK, Balestre E, Coffie PA, et al. Characteristics of HIV-2 and HIV-1/HIV-2 dually seropositive adults in West Africa presenting for care and antiretroviral therapy: The IeDEA-West Africa HIV-2 Cohort Study. PLoS One. 2013;8(6):e66135. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23824279.
- Smith RA, Anderson DJ, Pyrak CL, Preston BD, Gottlieb GS. Antiretroviral drug resistance in HIV-2: three amino acid changes are sufficient for classwide nucleoside analogue resistance. J Infect Dis. 2009;199(9):1323-1326. Available at: https://www.ncbi.nlm.nih.gov/pubmed/19358668.
- Tuaillon E, Gueudin M, Lemee V, et al. Phenotypic susceptibility to nonnucleoside inhibitors of virion-associated reverse transcriptase from different HIV types and groups. J Acquir Immune Defic Syndr. 2004;37(5):1543-1549. Available at: https://www.ncbi.nlm.nih.gov/pubmed/15577405.
- Jallow S, Kaye S, Alabi A, et al. Virological and immunological response to Combivir and emergence of drug resistance mutations in a cohort of HIV-2 patients in The Gambia. AIDS. 2006;20(10):1455-1458. Available at: https://www.ncbi.nlm.nih.gov/pubmed/16791023.
- Adje-Toure CA, Cheingsong R, Garcia-Lerma JG, et al. Antiretroviral therapy in HIV-2-infected patients: changes in plasma viral load, CD4+ cell counts, and drug resistance profiles of patients treated in Abidjan, Cote d'Ivoire. AIDS. 2003;17 Suppl 3:S49-54. Available at: https://www.ncbi.nlm.nih.gov/pubmed/14565609.
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- Sarfo FS, Bibby DF, Schwab U, et al. Inadvertent non-nucleoside reverse transcriptase inhibitor (NNRTI)-based antiretroviral therapy in dual HIV-1/2 and HIV-2 seropositive West Africans: a retrospective study. J Antimicrob Chemother. 2009;64(3):667-669. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19549668.
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- 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). Available at: http://www.ncbi.nlm.nih.gov/pubmed/30803972.
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