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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
HIV-2 Infection and Pregnancy
(Last updated: August 6, 2015; last reviewed: August 6, 2015)
HIV-2 infection should be considered in pregnant women who are from—or have partners from—countries in which the disease is endemic and who have positive results on an HIV-1/HIV-2 antibody or HIV-1/HIV-2 antigen/antibody immunoassay. They should be tested with a supplemental HIV-1/HIV-2 antibody differentiation assay. If they are indeed HIV-2 infected it would show negative HIV-1 antibodies and positive HIV-2 antibodies (AII).
A regimen with two nucleoside reverse transcriptase inhibitors and a boosted protease inhibitor 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 cell (CD4) counts <500 cells/mm3(AIII).
Lopinavir/ritonavir plus zidovudine/lamivudine or abacavir/lamivudine or tenofovir disoproxil fumarate/emtricitabine is the preferred combination antiretroviral therapy regimen for HIV-2-infected pregnant women who require treatment (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 counts >500 cells/mm3 and no significant clinical disease). Experts have recommended the following approaches:
A boosted protease inhibitor-based regimen (two nucleoside reverse transcriptase inhibitors plus lopinavir/ritonavir) 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, 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 have positive results on an HIV-1/HIV-2 antibody or HIV-1/HIV-2 antigen/antibody immunoassay. They should be tested with a supplemental HIV-1/HIV-2 antibody differentiation immunoassay. If they are indeed HIV-2 infected it would show negative HIV-1 antibodies and positive HIV-2 antibodies. In rare instances, a woman may have dual infection with HIV-1 and HIV-2 and both tests will be positive. Before the CDC implemented a new HIV testing algorithm in 2014, such individuals typically would have tested positive for HIV-1 antibody on an initial enzyme-linked immunoassay screening test and had 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.
In 2014, the CDC released a new HIV Testing Algorithm, which may enhance the diagnosis of HIV-2. The first step in that algorithm is performance on serum or plasma of an HIV-1/HIV-2 antigen/antibody combination assay (e.g., Abbott Architect HIV Ag/Ab combo assay, BioRad GS Combo Ag/Ab EIA, Alere Determine).10 This test does not distinguish between antibodies to HIV-1 and HIV-2. Specimens which are reactive on this test must be tested with a Food and Drug Administration (FDA)-approved second-generation antibody assay to distinguish HIV-1 from HIV-2 antibodies. There are two HIV-2 antibody supplemental tests now approved by FDA that can be used as part of the CDC recommended HIV laboratory testing algorithm: Multispot HIV-1/HIV-2 Rapid Test (Bio-Rad Laboratories) and GeeniuS (Bio-Rad Laboratories). Viral load assays for HIV-2 are not commercially available, but may be available under research protocols. The University of Washington (http://depts.washington.edu/labweb/AboutLM/Contact.htm)11 and the New York State Department of Health (http://www.hivguidelines.org/wp-content/uploads/2014/04/human-immunodeficiency-virus-type-2-hiv-2.pdf)12 offer HIV-2 viral load assays. 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.13 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).14
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.3,15,16 Several studies confirm that rates of perinatal transmission of HIV-2 are low with and without interventions (0% to 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.17-20 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.21
Few data exist on which to base treatment decisions or strategies for prevention of perinatal transmission in patients infected with HIV-2. In a systematic review of non-pregnant, HIV-2-infected patients from 1996–2012, Ekouevi, et al. noted a heterogeneity of treatment outcomes among HIV-2-infected patients initiating combination antiretroviral therapy, especially in resource-limited settings.22 Non-nucleoside reverse transcriptase inhibitors (NNRTIs) and enfuvirtide are not active against HIV-2 and should not be used for treatment or prophylaxis.23,24 HIV-2 has variable sensitivity to protease inhibitors (PIs), with lopinavir, saquinavir, and darunavir having the most activity.25 The integrase inhibitors raltegravir and elvitegravir also appear to be effective against HIV-2.3,26-29 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.30,31 HIV-2 drug resistance has been documented with various antiretroviral (ARV) drugs.32,33
The care of HIV-2-infected pregnant women has been based on expert opinion. A regimen with two nucleoside reverse transcriptase inhibitors 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/mm3.34 Based on efficacy and available data on safety in HIV-1-infected pregnant women, lopinavir/ritonavir plus zidovudine/lamivudine or abacavir/lamivudine or tenofovir disoproxil fumarate/emtricitabine or lamivudine is preferred.35,36 NNRTIs should not be used because they are not active against HIV-2.
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.18 Single-drug prophylaxis with zidovudine alone has also been considered by other experts for prevention of perinatal transmission because HIV-2 has a significantly lower risk of perinatal transmission than HIV-1.18 However, this may not be an optimal choice as there seems to be a low genetic barrier to resistance in HIV-2, with as few as two mutations conferring full zidovudine resistance.35,37 All infants born to mothers infected with HIV-2 should receive the standard 6-week zidovudine prophylactic regimen.36 The possible risks and benefits of 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 obstetric 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.18
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.38 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.36
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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.
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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.
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. 2013;58 Suppl 1:e127-133. Available at http://www.ncbi.nlm.nih.gov/pubmed/24342472.
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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.
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.
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.
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.
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.
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.
Prince PD, Matser A, van Tienen C, Whittle HC, Schim van der Loeff MF. Mortality rates in people dually infected with HIV-1/2 and those infected with either HIV-1 or HIV-2: a systematic review and meta-analysis. AIDS. 2014;28(4):549-558. Available at http://www.ncbi.nlm.nih.gov/pubmed/23921613.
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.
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