Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents Living 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: April 8, 2015; Last Reviewed: April 8, 2015
|Summary of HIV-2 Infection|
HIV-2 infection is endemic in West Africa. Although HIV-2 has had only limited spread outside this area, it should be considered when treating persons of West African origin or in those who have had sexual contact or shared needles with persons of West African origin. The prevalence of HIV-2 infection is also disproportionately high 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).
Clinical Course of HIV-2 Infection
Compared to HIV-1 infection, the clinical course of HIV-2 infection is generally characterized by a longer asymptomatic stage, lower plasma HIV-2 viral loads, and lower mortality rate.1,2 However, HIV-2 infection can also progress to AIDS over time. Concomitant HIV-1 and HIV-2 infection may occur and should be considered in patients from areas with a high prevalence of HIV-2.
Diagnosis of HIV-2 Infection
In the appropriate epidemiologic setting, HIV-2 infection should be suspected in patients with clinical conditions suggestive of HIV infection but with atypical serologic results (e.g., a positive screening assay with an indeterminate HIV-1 Western blot.3 The possibility of HIV-2 infection should also be considered in the appropriate epidemiologic setting in patients with serologically confirmed HIV infection but low or undetectable HIV-1 RNA levels or in those with declining CD4 T lymphocyte (CD4) cell counts despite apparent virologic suppression on antiretroviral therapy (ART).
The 2014 Centers for Disease Control and Prevention guidelines for HIV diagnostic testing4 recommend initial HIV testing using an HIV-1/HIV-2 antigen/antibody combination immunoassay and subsequent testing using an HIV-1/HIV-2 antibody differentiation immunoassay. The Multispot HIV-1/HIV-2 Rapid Test (Bio-Rad Laboratories) is Food and Drug Administration-approved for differentiating HIV-1 from HIV-2 infection. Commercially available HIV-1 viral load assays do not reliably detect or quantify HIV-2.5,6 Quantitative HIV-2 plasma RNA viral load testing has recently become available for clinical care at the University of Washington (http://depts.washington.edu/labweb/AboutLM/Contact.htm)7 and the New York State Department of Health (https://www.wadsworth.org/programs/id/bloodborne-viruses/clinical-testing/hiv-2-nucleic-acid).8 However, it is important to note that approximately one-quarter to one-third of patients with HIV-2 infection who are not on ART will have HIV-2 RNA levels below the limits of detection; some of these patients will have clinical progression and CD4 cell count decline. No validated HIV-2 genotypic or phenotypic antiretroviral (ARV) resistance assays are available for clinical use.
Treatment of HIV-2 Infection
To date, no randomized trials addressing the question of when to start ART or the choice of initial or second-line therapy for HIV-2 infection have been completed;9 thus, the optimal treatment strategy has not been defined. Although the optimal CD4 cell count threshold for initiating ART in HIV-2 infection is unknown, therapy should be started before there is clinical progression.
HIV-2 is intrinsically resistant to non-nucleoside reverse transcriptase inhibitors (NNRTI)10 and to enfuvirtide (T-20).11 Data from in vitro studies suggest that HIV-2 is sensitive to the currently available nucleoside reverse transcriptase inhibitors (NRTIs), although with a lower barrier to resistance than HIV-1.12,13 Darunavir (DRV), lopinavir (LPV), and saquinavir (SQV) are more active against HIV-2 than other approved protease inhibitors (PIs);14-17 one of these boosted PIs should be used if a PI-based regimen is used. Other PIs should be avoided because of their lack of ARV activity and high failure rates. The integrase strand transfer inhibitors (INSTIs) raltegravir (RAL), elvitegravir (EVG), and dolutegravir (DTG) have potent activity against HIV-2 in vitro.18-21 The CCR5 antagonist maraviroc (MVC) appears active against some HIV-2 isolates;22 however, no approved assays to determine HIV-2 co-receptor tropism exist and HIV-2 is known to use many other minor co-receptors in addition to CCR5 and CXCR4.23
Several small studies suggest poor responses in individuals with HIV-2 infection treated with some ARV regimens, including dual-NRTI regimens; regimens containing NNRTI plus two NRTIs; and some unboosted PI-based regimens including nelfinavir (NFV) or indinavir (IDV) plus zidovudine (ZDV) and lamivudine (3TC); and atazanavir (ATV)-based regimens.9,24-27 Clinical data on the effectiveness of triple-NRTI regimens are conflicting.28,29 In general, HIV-2 active, boosted PI-containing regimens have resulted in more favorable virologic and immunologic responses than two or three-NRTI-based regimens.29-31 However, CD4 cell recovery on therapy is generally poorer than that observed for HIV-1.31-33 INSTI-based regimens may also have favorable treatment responses.34,35 A large systematic review of ART for patients with HIV-2 infection (n = 17 studies, 976 patients with HIV-2) was unable to conclude which specific regimens are preferred.36
Resistance-associated viral mutations to NRTIs, PIs, and/or INSTIs commonly develop in patients with HIV-2 while on therapy.24,29,37-41 Currently, HIV-2 transmitted drug resistance appears rare.41,42 In one small study, DTG was found to have activity as a second-line INSTI in some patients with HIV-2 who had extensive ARV experience and RAL resistance.43 Genotypic algorithms used to predict drug resistance in HIV-1 may not be applicable to HIV-2, because pathways and mutational patterns leading to resistance may differ between the HIV types.13,29,44
Some groups have recommended specific preferred and alternative regimens for initial therapy of HIV-2 infection;45-48 however, currently, there are no controlled trial data to support the effectiveness of the recommended regimens. Pending more definitive data on outcomes in an ART-naive patient who has HIV-2 mono-infection or HIV-1/HIV-2 dual infection and requires treatment, a regimen containing two NRTIs plus an HIV-2 active boosted PI or INSTI should be initiated in individuals with HIV-2 infection.
HIV-2 plasma RNA levels, CD4 cell counts, and clinical improvements can be monitored to assess treatment response, as is recommended for HIV-1. Patients who have HIV-2 RNA levels below the limits of detection before therapy should still have HIV-2 plasma RNA monitoring, in addition to CD4 cell count and clinical monitoring. In the event of virologic, immunologic, or clinical failure, second-line treatment should be instituted in consultation with an expert in HIV-2 management.
- Matheron S, Pueyo S, Damond F, et al. Factors associated with clinical progression in HIV-2 infected-patients: the French ANRS cohort. AIDS. Dec 5 2003;17(18):2593-2601. Available at https://www.ncbi.nlm.nih.gov/pubmed/14685053.
- Marlink R, Kanki P, Thior I, et al. Reduced rate of disease development after HIV-2 infection as compared to HIV-1. Science. Sep 9 1994;265(5178):1587-1590. Available at https://www.ncbi.nlm.nih.gov/pubmed/7915856.
- O'Brien TR, George JR, Epstein JS, Holmberg SD, Schochetman G. Testing for antibodies to human immunodeficiency virus type 2 in the United States. MMWR Recomm Rep. Jul 17 1992;41(RR-12):1-9. Available at https://www.ncbi.nlm.nih.gov/pubmed/1324395.
- Centers for Disease Control and Prevention and Association of Public Health Laboratories. Laboratory Testing for the Diagnosis of HIV Infection: Updated Recommendations. 2014. Available at http://stacks.cdc.gov/view/cdc/23447.
- Chan PA, Wakeman SE, Flanigan T, Cu-Uvin S, Kojic E, Kantor R. HIV-2 diagnosis and quantification in high-risk patients. AIDS Res Ther. 2008;5:18. Available at https://www.ncbi.nlm.nih.gov/pubmed/18700986.
- 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. Oct 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. Oct 2012;55(2):128-133. Available at http://www.ncbi.nlm.nih.gov/pubmed/22832059.
- Styer LM, Miller TT, Parker MM. Validation and clinical use of a sensitive HIV-2 viral load assay that uses a whole virus internal control. J Clin Virol. Dec 2013;58 Suppl 1:e127-133. Available at http://www.ncbi.nlm.nih.gov/pubmed/24342472.
- 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. Oct 18 2008;22(16):2069-2072; discussion 2073-2064. Available at https://www.ncbi.nlm.nih.gov/pubmed/18832869.
- 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. Dec 15 2004;37(5):1543-1549. Available at https://www.ncbi.nlm.nih.gov/pubmed/15577405.
- Poveda E, Rodes B, Toro C, Soriano V. Are fusion inhibitors active against all HIV variants? AIDS Res Hum Retroviruses. Mar 2004;20(3):347-348. Available at https://www.ncbi.nlm.nih.gov/pubmed/15117459.
- Boyer PL, Sarafianos SG, Clark PK, Arnold E, Hughes SH. Why do HIV-1 and HIV-2 use different pathways to develop AZT resistance? PLoS Pathog. Feb 2006;2(2):e10. Available at https://www.ncbi.nlm.nih.gov/pubmed/16485036.
- 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. May 1 2009;199(9):1323-1326. Available at https://www.ncbi.nlm.nih.gov/pubmed/19358668.
- Parkin NT, Schapiro JM. Antiretroviral drug resistance in non-subtype B HIV-1, HIV-2 and SIV. Antivir Ther. Feb 2004;9(1):3-12. Available at https://www.ncbi.nlm.nih.gov/pubmed/15040531.
- Desbois D, Roquebert B, Peytavin G, et al. In vitro phenotypic susceptibility of human immunodeficiency virus type 2 clinical isolates to protease inhibitors. Antimicrob Agents Chemother. Apr 2008;52(4):1545-1548. Available at https://www.ncbi.nlm.nih.gov/pubmed/18227188.
- Brower ET, Bacha UM, Kawasaki Y, Freire E. Inhibition of HIV-2 protease by HIV-1 protease inhibitors in clinical use. Chem Biol Drug Des. Apr 2008;71(4):298-305. Available at https://www.ncbi.nlm.nih.gov/pubmed/18312292.
- Rodes B, Sheldon J, Toro C, Jimenez V, Alvarez MA, Soriano V. Susceptibility to protease inhibitors in HIV-2 primary isolates from patients failing antiretroviral therapy. J Antimicrob Chemother. Apr 2006;57(4):709-713. Available at https://www.ncbi.nlm.nih.gov/pubmed/16464891.
- Roquebert B, Damond F, Collin G, et al. HIV-2 integrase gene polymorphism and phenotypic susceptibility of HIV-2 clinical isolates to the integrase inhibitors raltegravir and elvitegravir in vitro. J Antimicrob Chemother. Nov 2008;62(5):914-920. Available at https://www.ncbi.nlm.nih.gov/pubmed/18718922.
- Charpentier C, Larrouy L, Collin G, et al. In-vitro phenotypic susceptibility of HIV-2 clinical isolates to the integrase inhibitor S/GSK1349572. AIDS. Nov 13 2010;24(17):2753-2755. Available at http://www.ncbi.nlm.nih.gov/pubmed/20827161.
- Smith RA, Raugi DN, Pan C, et al. Three main mutational pathways in HIV-2 lead to high-level raltegravir and elvitegravir resistance: implications for emerging HIV-2 treatment regimens. PLoS One. 2012;7(9):e45372. Available at http://www.ncbi.nlm.nih.gov/pubmed/23028968.
- Smith RA, Raugi DN, Pan C, et al. In vitro activity of dolutegravir against wild-type and integrase inhibitor-resistant HIV-2. Retrovirology. Feb 05 2015;12:10. Available at http://www.ncbi.nlm.nih.gov/pubmed/25808007.
- Visseaux B, Charpentier C, Hurtado-Nedelec M, et al. In vitro phenotypic susceptibility of HIV-2 clinical isolates to CCR5 inhibitors. Antimicrob Agents Chemother. Jan 2012;56(1):137-139. Available at http://www.ncbi.nlm.nih.gov/pubmed/22064539.
- Owen SM, Ellenberger D, Rayfield M, et al. Genetically divergent strains of human immunodeficiency virus type 2 use multiple coreceptors for viral entry. J Virol. Jul 1998;72(7):5425-5432. Available at https://www.ncbi.nlm.nih.gov/pubmed/9620997.
- Gottlieb GS, Badiane NM, Hawes SE, et al. Emergence of multiclass drug-resistance in HIV-2 in antiretroviral-treated individuals in Senegal: implications for HIV-2 treatment in resouce-limited West Africa. Clin Infect Dis. Feb 15 2009;48(4):476-483. Available at https://www.ncbi.nlm.nih.gov/pubmed/19143530.
- 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. Jun 26 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. Jul 2003;17 Suppl 3:S49-54. Available at https://www.ncbi.nlm.nih.gov/pubmed/14565609.
- Cavaco-Silva J, Aleixo MJ, Van Laethem K, et al. Mutations selected in HIV-2-infected patients failing a regimen including atazanavir. J Antimicrob Chemother. Jan 2013;68(1):190-192. Available at http://www.ncbi.nlm.nih.gov/pubmed/22977160.
- Matheron S, Damond F, Benard A, et al. CD4 cell recovery in treated HIV-2-infected adults is lower than expected: results from the French ANRS CO5 HIV-2 cohort. AIDS. Feb 14 2006;20(3):459-462. Available at https://www.ncbi.nlm.nih.gov/pubmed/16439883.
- Ruelle J, Roman F, Vandenbroucke AT, et al. Transmitted drug resistance, selection of resistance mutations and moderate antiretroviral efficacy in HIV-2: analysis of the HIV-2 Belgium and Luxembourg database. BMC Infect Dis. 2008;8:21. Available at https://www.ncbi.nlm.nih.gov/pubmed/18304321.
- Benard A, Damond F, Campa P, et al. Good response to lopinavir/ritonavir-containing antiretroviral regimens in antiretroviral-naive HIV-2-infected patients. AIDS. Jun 1 2009;23(9):1171-1173. Available at https://www.ncbi.nlm.nih.gov/pubmed/19349850.
- 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.
- Drylewicz J, Matheron S, Lazaro E, et al. Comparison of viro-immunological marker changes between HIV-1 and HIV-2-infected patients in France. AIDS. Feb 19 2008;22(4):457-468. Available at https://www.ncbi.nlm.nih.gov/pubmed/18301058.
- 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. Apr 24 2010;24(7):1043-1050. Available at http://www.ncbi.nlm.nih.gov/pubmed/20397306.
- Peterson K, Ruelle J, Vekemans M, Siegal FP, Deayton JR, Colebunders R. The role of raltegravir in the treatment of HIV-2 infections: evidence from a case series. Antivir Ther. 2012;17(6):1097-1100. Available at http://www.ncbi.nlm.nih.gov/pubmed/22892365.
- Zheng Y, Lambert C, Arendt V, Seguin-Devaux C. Virological and immunological outcomes of elvitegravir-based regimen in a treatment-naive HIV-2-infected patient. AIDS. Sep 24 2014;28(15):2329-2331. Available at http://www.ncbi.nlm.nih.gov/pubmed/25313590.
- Ekouevi DK, Tchounga BK, Coffie PA, et al. Antiretroviral therapy response among HIV-2 infected patients: a systematic review. BMC Infect Dis. 2014;14:461. Available at http://www.ncbi.nlm.nih.gov/pubmed/25154616.
- Damond F, Matheron S, Peytavin G, et al. Selection of K65R mutation in HIV-2-infected patients receiving tenofovir-containing regimen. Antivir Ther. Aug 2004;9(4):635-636. Available at https://www.ncbi.nlm.nih.gov/pubmed/15456096.
- Raugi DN, Smith RA, Ba S, et al. Complex patterns of protease inhibitor resistance among antiretroviral treatment-experienced HIV-2 patients from Senegal: implications for second-line therapy. Antimicrob Agents Chemother. Jun 2013;57(6):2751-2760. Available at http://www.ncbi.nlm.nih.gov/pubmed/23571535.
- Charpentier C, Eholie S, Anglaret X, et al. Genotypic resistance profiles of HIV-2-treated patients in West Africa. AIDS. May 15 2014;28(8):1161-1169. Available at http://www.ncbi.nlm.nih.gov/pubmed/24583671.
- Charpentier C, Roquebert B, Delelis O, et al. Hot spots of integrase genotypic changes leading to HIV-2 resistance to raltegravir. Antimicrob Agents Chemother. Mar 2011;55(3):1293-1295. Available at http://www.ncbi.nlm.nih.gov/pubmed/21189351.
- Charpentier C, Camacho R, Ruelle J, et al. HIV-2EU: supporting standardized HIV-2 drug resistance interpretation in Europe. Clin Infect Dis. Jun 2013;56(11):1654-1658. Available at http://www.ncbi.nlm.nih.gov/pubmed/23429380.
- Charpentier C, Visseaux B, Benard A, et al. Transmitted drug resistance in French HIV-2-infected patients. AIDS. Jun 19 2013;27(10):1671-1674. Available at http://www.ncbi.nlm.nih.gov/pubmed/23595155.
- Descamps D, Peytavin G, Visseaux B, et al. Dolutegravir in HIV-2 infected patients with resistant virus to first-line integrase inhibitors from the French Named Patient Program. Clin Infect Dis. Feb 17 2015. Available at http://www.ncbi.nlm.nih.gov/pubmed/25690598.
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