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Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States

Special Populations

HIV-2 Infection and Pregnancy

(Last updated:March 28, 2014; last reviewed:March 28, 2014)

Panel's Recommendations

Panel's Recommendations

  • HIV-2 infection should be suspected in pregnant women who are from—or have partners from—countries in which the disease is endemic, who are HIV antibody-positive on an initial enzyme-linked immunoassay screening test, and who have repeatedly indeterminate results on HIV-1 Western blot along with HIV-1 RNA viral loads at or below the limit of detection (BII).
  • A regimen with two nucleoside reverse transcriptase inhibitors (NRTIs) and a boosted protease inhibitor (PI) currently is recommended for HIV-2-infected pregnant women who require treatment for their own health because they have significant clinical disease or CD4 T-lymphocyte (CD4-cell) counts <500 cells/mm3 (AIII).
  • Lopinavir/ritonavir plus zidovudine/lamivudine or abacavir/lamivudine or tenofovir/emtricitabine is the preferred ART regimen for HIV-2-infected pregnant women who require treatment, based on safety data on use of these drugs in HIV-1-infected pregnant women (AIII).
  • Optimal prophylactic regimens have not been defined for HIV-2-infected pregnant women who do not require treatment for their own health (i.e., CD4 cell counts >500 cells/mm3 and no significant clinical disease). Experts have recommended the following approaches:
    • A boosted PI-based regimen (two NRTIs plus ritonavir-boosted lopinavir) for prophylaxis, with the drugs stopped postpartum (BIII); or
    • Zidovudine prophylaxis alone during pregnancy and intrapartum (BIII).
  • Non-nucleoside reverse transcriptase inhibitors and enfuvirtide are not active against HIV-2 and should not be used for treatment or prophylaxis (AIII).
  • All infants born to HIV-2-infected mothers should receive the standard 6-week zidovudine prophylactic regimen (BIII).
  • In the United States, where safe infant formula is readily available, breastfeeding is not recommended for infants of HIV-2-infected mothers (AIII).
Rating of Recommendations: A = Strong; B = Moderate; C = Optional
Rating of Evidence: I = One or more randomized trials with clinical outcomes and/or validated laboratory endpoints; II = One or more well-designed, nonrandomized trials or observational cohort studies with long-term clinical outcomes; III = Expert opinion

HIV-2 infection is endemic in West African countries including Ivory Coast, Ghana, Cape Verde, Gambia, Mali, Senegal, Liberia, Guinea, Burkina Faso, Nigeria, Mauritania, Sierra Leone, Guinea Bissau, Niger, Sao Tome, and Togo; Angola; Mozambique; and in parts of India.1-4 It also occurs in countries such as France and Portugal, which have large numbers of immigrants from these regions.5 HIV-2 remains rare in the United States. Between 1998 and 2010, a total of 242 HIV-2 cases were reported to the Centers for Disease Control and Prevention (CDC), with 166 cases meeting criteria for HIV-2 diagnosis. These 166 cases constituted only 0.01% of the more than 1.4 million U.S. cases of HIV infection.6 Of the 50 women aged 15 to 44 years at diagnosis, 24 (48%) were pregnant at or after HIV-2 diagnosis.6 HIV-2 infection should be suspected in pregnant women who are from—or who have partners from—countries in which the disease is endemic, who are HIV-1 antibody positive on an initial enzyme-linked immunoassay screening test, and who have repeatedly indeterminate results on HIV-1 Western blot along with HIV-1 RNA viral loads at or below the limit of detection.7-9 Note that this pattern of HIV testing can also be seen in patients who have a false-positive HIV-1 test. 

The FDA has approved the first rapid diagnostic test that detects HIV-1 and HIV-2 antibodies and HIV-1 p24 antigen, the Alere Determine HIV-1/2 Ag/Ab Combo, which can be used on human serum, plasma, and venous or fingerstick whole-blood specimens. However, this test does not distinguish between antibodies to HIV-1 and HIV-2. Specimens which are reactive on the rapid test must be tested with an FDA-approved 2nd generation antibody assay to distinguish HIV-1 from HIV-2 antibodies. The Multispot HIV-1/HIV-2 Rapid Test (Bio-Rad Laboratories) is FDA-approved for differentiating HIV-1 from HIV-2 infections. In some commercial and public health laboratories, HIV-2 supplemental tests, such as HIV-2 immunoblot or HIV-2-specific Western blot, are available. However, none of these tests has been FDA approved for diagnosis or clinical management of HIV-2. Commercially available HIV-1 viral load assays do not reliably detect or quantify HIV-2 and no HIV-2 commercial viral load assays are currently available. All HIV-2 cases should be reported to the HIV surveillance program of the state or local health department, which can arrange for additional confirmatory testing for HIV-2 by the CDC.10 No validated HIV-2 genotype or phenotype resistance assays are available in the United States. Recently, European experts developed a rule set and an automated tool for HIV-2 drug resistance analyses that is freely available on the Internet (see http://www.hiv-grade.de).11

HIV-2 has a longer asymptomatic phase than HIV-1, with a slower progression to AIDS. The most common mode of HIV-2 transmission is through heterosexual sex. HIV-2 is less infectious than HIV-1, with a 5-fold lower rate of sexual transmission and 20- to 30-fold lower rate of vertical transmission.3,12,13 Several studies confirm that rates of perinatal transmission of HIV-2 are low with and without interventions (0%–4%), which may be a result of reduced plasma viral loads and less cervical viral shedding, compared with that seen in HIV-1-infected women.14-17 HIV-2 also can be transmitted through breastfeeding. HIV-2 infection does not protect against HIV-1 and dual infection, which carries the same prognosis as HIV-1 mono-infection, can occur.

Few data exist on which to base treatment decisions or strategies for prevention of perinatal transmission in patients infected with HIV-2. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) and enfuvirtide are not active against HIV-2 and should not be used for treatment or prophylaxis.18,19 HIV-2 has variable sensitivity to protease inhibitors (PIs), with lopinavir, saquinavir, and darunavir having the most activity against the virus.20 The integrase inhibitors raltegravir and elvitegravir also appear to be effective against HIV-2.3,21-24 The CCR5 antagonist maraviroc appears active against some strains of HIV-2, although there are no approved assays to determine HIV-2 co-receptor tropism.25,26

The care of HIV-2-infected pregnant women has been based on expert opinion. A regimen with two nucleoside reverse transcriptase inhibitors (NRTIs) and a boosted PI currently is recommended for HIV-2-infected pregnant women who require treatment for their own health because they have significant clinical disease or CD4 T lymphocyte (CD4) cell counts <500 cells/mm3.27 Based on efficacy and available data on safety in HIV-1-infected pregnant women, ritonavir-boosted lopinavir plus zidovudine/lamivudine or abacavir/lamivudine or tenofovir disoproxil fumarate/emtricitabine or lamivudine would be preferred.28,29 NNRTIs should not be used because they are not active against HIV-2. All infants born to mothers infected with HIV-2 should receive the standard 6-week zidovudine prophylactic regimen.

For HIV-2-infected pregnant women with CD4 cell counts >500 cells/mm3 and no significant clinical disease, who do not require treatment for their own health, some experts would use a boosted PI-based regimen for prophylaxis and stop the drugs postpartum. Other experts would consider zidovudine prophylaxis alone during pregnancy and intrapartum.15 Because HIV-2 has a significantly lower risk of perinatal transmission than does HIV-1, single-drug prophylaxis with zidovudine alone can be considered for prevention of perinatal transmission. All infants born to mothers infected with HIV-2 should receive the standard 6-week zidovudine prophylactic regimen.29 The possible risks and benefits of antiretroviral (ARV) prophylaxis should be discussed with the mothers.

Pregnant women who have HIV-1/HIV-2 coinfection should be treated according to the guidelines for HIV-1-monoinfected patients, making sure that the ARV regimen chosen is also appropriate for HIV-2.

Other than the standard obstetrical indications, no data exist regarding the role of elective cesarean delivery in women who are infected with HIV-2. The risk to infants from breastfeeding is lower for HIV-2 than for HIV-1, but breastfeeding should be avoided in the United States and other resource-rich countries where safe infant formula is readily available.15

Infants born to HIV-2-infected mothers should be tested for HIV-2 infection with HIV-2-specific virologic assays at time points similar to those used for HIV-1 testing.30 HIV-2 virologic assays are not commercially available, but the National Perinatal HIV Hotline (888-448-8765) can provide a list of sites that perform this testing.

Testing of infants at age 18 months (e.g., with the Bio-Rad Laboratories Multispot HIV-1/HIV-2 test) also is recommended to confirm clearance of HIV-2 antibodies.29

References

  1. De Cock KM, Brun-Vezinet F. Epidemiology of HIV-2 infection. AIDS. 1989;3 Suppl 1:S89-95. Available at http://www.ncbi.nlm.nih.gov/pubmed/2514761.
  2. De Cock KM, Adjorlolo G, Ekpini E, et al. Epidemiology and transmission of HIV-2. Why there is no HIV-2 pandemic. JAMA. 1993;270(17):2083-2086. Available at http://www.ncbi.nlm.nih.gov/pubmed/8147962.
  3. Campbell-Yesufu OT, Gandhi RT. Update on human immunodeficiency virus (HIV)-2 infection. Clin Infect Dis. 2011;52(6):780-787. Available at http://www.ncbi.nlm.nih.gov/pubmed/21367732.
  4. Heitzinger K, Sow PS, Dia Badiane NM, et al. Trends of HIV-1, HIV-2 and dual infection in women attending outpatient clinics in Senegal, 1990-2009. Int J STD AIDS. 2012;23(10):710-716. Available at http://www.ncbi.nlm.nih.gov/pubmed/23104745.
  5. Cazein F, Lot F, Pillonel J, al e. HIV and AIDS surveillance in France, 2006. Bull Epidemiol Hebd. 2007(46-47):386-393. 
  6. Centers for Disease Control and Prevention. HIV-2 infection surveillance—United States, 1987-2009. MMWR Morb Mortal Wkly Rep. 2011;60(29):985-988. Available at http://www.ncbi.nlm.nih.gov/pubmed/21796096.
  7. 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. 1992;41(RR-12):1-9. Available at http://www.ncbi.nlm.nih.gov/pubmed/1324395.
  8. 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. Available at http://www.ncbi.nlm.nih.gov/pubmed/21039219.
  9. Hollenbeck BL, Beckwith CG. HIV-2 infection in Providence, Rhode Island from 2002 to 2011. HIV Med. 2013;14(2):115-119. Available at http://www.ncbi.nlm.nih.gov/pubmed/22574645.
  10. Branson BM, Pandori M. 2012 HIV Diagnostics Conference: the molecular diagnostics perspective. Expert Rev Mol Diagn. 2013;13(3):243-245. Available at http://www.ncbi.nlm.nih.gov/pubmed/23570401.
  11. Charpentier C, Camacho R, Ruelle J, et al. HIV-2EU: supporting standardized HIV-2 drug resistance interpretation in Europe. Clin Infect Dis. 2013;56(11):1654-1658. Available at http://www.ncbi.nlm.nih.gov/pubmed/23429380.
  12. Kanki PJ, Travers KU, S MB, et al. Slower heterosexual spread of HIV-2 than HIV-1. Lancet. 1994;343(8903):943-946. Available at http://www.ncbi.nlm.nih.gov/pubmed/7909009.
  13. Matheron S, Courpotin C, Simon F, et al. Vertical transmission of HIV-2. Lancet. 1990;335(8697):1103-1104. Available at http://www.ncbi.nlm.nih.gov/pubmed/1970407.
  14. 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. Available at http://www.ncbi.nlm.nih.gov/pubmed/10770548.
  15. 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. Available at http://www.ncbi.nlm.nih.gov/pubmed/20804413.
  16. 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. Available at http://www.ncbi.nlm.nih.gov/pubmed/8040982.
  17. Andreasson PA, Dias F, Naucler A, Andersson S, Biberfeld G. A prospective study of vertical transmission of HIV-2 in Bissau, Guinea-Bissau. AIDS. 1993;7(7):989-993. Available at http://www.ncbi.nlm.nih.gov/pubmed/8357558.
  18. 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 http://www.ncbi.nlm.nih.gov/pubmed/15577405.
  19. Poveda E, Rodes B, Toro C, Soriano V. Are fusion inhibitors active against all HIV variants? AIDS Res Hum Retroviruses. 2004;20(3):347-348. Available at http://www.ncbi.nlm.nih.gov/pubmed/15117459.
  20. 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. 2008;52(4):1545-1548. Available at http://www.ncbi.nlm.nih.gov/pubmed/18227188.
  21. 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. 2008;62(5):914-920. Available at http://www.ncbi.nlm.nih.gov/pubmed/18718922.
  22. Bercoff DP, Triqueneaux P, Lambert C, et al. Polymorphisms of HIV-2 integrase and selection of resistance to raltegravir. Retrovirology. 2010;7:98. Available at http://www.ncbi.nlm.nih.gov/pubmed/21114823.
  23. Andreatta K, Miller MD, White KL. HIV-2 antiviral potency and selection of drug resistance mutations by the integrase strand transfer inhibitor elvitegravir and NRTIs emtricitabine and tenofovir in vitro. J Acquir Immune Defic Syndr. 2012. Available at http://www.ncbi.nlm.nih.gov/pubmed/23187937.
  24. 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.
  25. Borrego P, Taveira N. HIV-2 susceptibility to entry inhibitors. AIDS Rev. 2013;15(1):49-61. Available at http://www.ncbi.nlm.nih.gov/pubmed/23449229.
  26. Visseaux B, Charpentier C, Hurtado-Nedelec M, et al. In vitro phenotypic susceptibility of HIV-2 clinical isolates to CCR5 inhibitors. Antimicrob Agents Chemother. 2012;56(1):137-139. Available at http://www.ncbi.nlm.nih.gov/pubmed/22064539
  27. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Available at http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf
  28. Gilleece Y, Chadwick DR, Breuer J, et al. British HIV Association guidelines for antiretroviral treatment of HIV-2-positive individuals 2010. HIV Med.2010;11(10):611-619. Available at http://www.ncbi.nlm.nih.gov/pubmed/20961377
  29. de Ruiter A, Mercey D, Anderson J, et al. British HIV Association and Children's HIV Association guidelines for the management of HIV infection in pregnant women 2008. HIV Med. 2008;9(7):452-502. Available at http://www.ncbi.nlm.nih.gov/pubmed/18840151
  30. Panel on Antiretroviral Therapy and Medical Management of HIV-Infected Children. Guidelines for the use of antiretroviral agents in pediatric HIV infection. Available at http://aidsinfo.nih.gov/ContentFiles/PediatricGuidelines.pdf

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