Recommendations for the Use of Antiretroviral Drugs in Pregnant Women with HIV Infection and Interventions to Reduce Perinatal HIV Transmission in the United States
Management of Infants Born to Women with HIV Infection
Diagnosis of HIV Infection in Infants and Children
Last Updated: November 14, 2017; Last Reviewed: November 14, 2017
|Rating of Recommendations: A = Strong; B = Moderate; C = Optional
Rating of Evidence: I = One or more randomized trials in children† with clinical outcomes and/or validated endpoints; I* = One or more randomized trials in adults with clinical outcomes and/or validated laboratory endpoints with accompanying data in children† from one or more well-designed, nonrandomized trials or observational cohort studies with long-term clinical outcomes; II = One or more well-designed, nonrandomized trials or observational cohort studies in children† with long-term outcomes; II* = One or more well-designed, nonrandomized trials or observational studies in adults with long-term clinical outcomes with accompanying data in children† from one or more similar nonrandomized trials or cohort studies with clinical outcome data; III = Expert opinion
† Studies that include children or children/adolescents, but not studies limited to post-pubertal adolescents
Diagnosis of HIV Infection in Infants and Children
HIV infection can be definitively diagnosed through use of virologic assays in most non-breastfed infants with HIV exposure by age 1 to 2 months and in virtually all infants with HIV infection by age 4 to 6 months. Antibody tests, including the newer antigen-antibody combination immunoassays (sometimes referred to as fourth- and fifth-generation tests), do not establish the presence of HIV infection in infants because of transplacental transfer of maternal antibodies to HIV; therefore, a virologic test must be used.1,2 Positive virologic tests (i.e., nucleic acid tests [NAT]—a class of tests that includes HIV RNA and DNA polymerase chain reaction [PCR] assays, and related RNA qualitative or quantitative assays) indicate likely HIV infection. The first test result should be confirmed as soon as possible by a repeat virologic test on a second specimen, because false-positive results can occur with both RNA and DNA assays.3 For additional information on HIV and RNA assays and diagnosis of Group M non-subtype B and Group O HIV-1 infections and HIV-2 infections, see the Virologic Assays to Diagnose HIV Infection in Infants Younger than 18 Months with Perinatal HIV-1 Exposure section and Other Issues section below.
Antigen/antibody combination immunoassays which detect HIV-1/2 antibodies as well as HIV-1 p24 antigen are not recommended for infant diagnosis. The sensitivity of the antigen component in the first months of life is less than that of an HIV NAT, and antibody tests should not be used for diagnosis in infants and children less than 18 months of age.4-6 Children with perinatal HIV exposure aged 18 to 24 months occasionally have residual maternal HIV antibodies; definitive confirmation of HIV infection in children in this age group who are HIV antibody-positive should be based on a NAT (see Diagnostic Testing in Children with Perinatal HIV Exposure in Special Situations). Diagnosis in children aged >24 months relies primarily on HIV antibody and antigen/antibody tests (see Diagnostic Testing in Children with Non-Perinatal HIV Exposure or Children with Perinatal Exposure Aged >24 Months).1
Infants who are found to have positive HIV antibody tests but whose mothers’ HIV status is unknown (see Identification of Perinatal HIV Exposure) should be assumed to be exposed to HIV and undergo HIV diagnostic testing as described below.7
For antiretroviral (ARV) management of HIV-exposed and HIV-infected newborns, see Antiretroviral Management of Newborns with Perinatal HIV Exposure.8,9
Timing of Diagnostic Testing in Infants with Perinatal HIV Exposure
Confirmation of HIV infection is based on two positive virologic tests from separate blood samples in infants and children younger than 18 months. Figure 1 summarizes the timing of recommended virologic diagnostic testing for infants at low risk of transmission (based on maternal antiretroviral therapy [ART] and viral suppression) with additional time points to be considered for infants at higher risk and those on combination ARV prophylaxis regimens.
Figure 1. Recommended Virologic Testing Schedules for Infants Exposed to HIV by Perinatal HIV Transmission Risk
Low Risk: Infants born to mothers who received standard ART during pregnancy with sustained viral suppression (usually defined as confirmed HIV RNA level below the lower limits of detection of an ultrasensitive assay) and no concerns related to maternal adherence.
Higher Risk: Infants born to mothers living with HIV who did not receive prenatal care, did not receive antepartum or intrapartum ARVs, received intrapartum ARV drugs only, mothers who initiated ART late in pregnancy (late second or third trimester), were diagnosed with acute HIV infection during pregnancy, who had detectable HIV viral loads close to the time of delivery, including those who received combination ARV drugs and did not have sustained viral suppression.
*For higher-risk infants, additional virologic diagnostic testing should be considered at birth and 2 to 4 weeks after cessation of ARV prophylaxis (i.e., at 8–10 weeks of life).
NAT= nucleic acid test
HIV infection can be presumptively excluded in non-breastfed infants with two or more negative virologic tests (one at age ≥14 days and one at age ≥4 weeks) or one negative virologic test (i.e., negative NAT [RNA or DNA]) at age ≥8 weeks, or one negative HIV antibody test at age ≥6 months.1,7
Definitive exclusion of HIV infection in a non-breastfed infant is based on two or more negative virologic tests (i.e., negative NATs [RNA or DNA]), one at age ≥1 month and one at age ≥4 months, or two negative HIV antibody tests from separate specimens obtained at age ≥6 months.
For both presumptive and definitive exclusion of HIV infection, a child must have no other laboratory (i.e., no positive virologic test results or low CD4 T lymphocyte [CD4] cell count/percent) or clinical evidence of HIV infection and not be breastfeeding. Many experts confirm the absence of HIV infection in infants with negative virologic tests by performing an antibody test at age 12 to 18 months to document seroreversion to HIV antibody-negative status.
Pneumocystis jirovecii pneumonia (PCP) prophylaxis is recommended for infants with indeterminate HIV infection status starting at age 4 to 6 weeks until they are determined to be HIV-uninfected or presumptively uninfected.10 Thus, PCP prophylaxis can be avoided or discontinued if HIV infection is presumptively excluded (see the Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Exposed and HIV-Infected Children and Initial Postnatal Management of the Neonate Exposed to HIV section).
Virologic Testing at Birth for Newborns at Higher Risk of Perinatal HIV Transmission
Virologic testing at birth should be considered for newborns at higher risk of perinatal HIV transmission,11-16 such as infants born to mothers living with HIV who:
- Did not receive prenatal care
- Did not receive antepartum or intrapartum ARV drugs
- Received intrapartum ARV drugs only
- Initiated ART late in pregnancy (late second or third trimester)
- Were diagnosed with acute HIV infection during pregnancy
- Had detectable HIV viral load close to the time of delivery
- Received combination ARV drugs and did not have sustained viral suppression
Testing infants exposed to HIV close to the time of birth identifies 20% to 58% of infants with HIV infection; however, in one study that specifically evaluated infants born to mothers who had not received ARV drugs during pregnancy and hence were at higher risk of in utero infection, birth testing identified 66.4% of infants with HIV infection.17 Prompt diagnosis of infant HIV infection is critical to allow for discontinuing ARV prophylaxis and instituting early ART (see When to Initiate Therapy). Blood samples from the umbilical cord should not be used for diagnostic evaluations because of the potential for contamination with maternal blood. Working definitions have been proposed to differentiate acquisition of HIV infection in utero from the intrapartum period. Infants who have a positive virologic test at or before age 48 hours are considered to have early (i.e., intrauterine) infection, whereas infants who have a negative virologic test during the first week of life and subsequent positive tests are considered to have late (i.e., intrapartum) infection.11,12,18
Virologic Testing at Age 14 to 21 Days
The diagnostic sensitivity of virologic testing increases rapidly by age 2 weeks,7 and early identification of infection would permit discontinuation of neonatal ARV prophylaxis and initiation of ART (see Infants Younger than Age 12 Months and Table 5 in When to Initiate Therapy).
Virologic Testing at Age 1 to 2 Months
Testing performed at age 1 to 2 months is intended to maximize the detection of infants with HIV infection.19,20 Two studies found that although the sensitivity during prophylaxis was not associated with the type of maternal or neonatal ARV prophylaxis, the sensitivity of diagnostic HIV testing during the period of infant ARV prophylaxis was lower compared to the sensitivity during the subsequent testing interval at 3 months of age. Overall, in both studies, 89% of infants with HIV infection were identified by 4 to 6 weeks of age. Of those infants who had negative testing in the first 7 days of life, repeat testing at 4 weeks to 6 weeks of age during the period of neonatal ARV prophylaxis identified 76% of infants with HIV infection in one study,19 and 68% of infants with HIV infection in the second study.17 In both studies, infants with negative testing in the first 7 days of life were diagnosed when the next diagnostic test was performed at 3 months of age.
For infants at higher risk of perinatal HIV transmission, the Panel suggests an additional virologic test 2 to 4 weeks after cessation of ARV prophylaxis (i.e., at 8–10 weeks of age) given the increased risk of infection and concern that ARV prophylaxis, particularly combination ARV prophylaxis, may reduce the sensitivity of testing during prophylaxis.7,17,19 In these situations, many experts recommend one test at age 4 to 6 weeks to allow prompt recognition of infected infants, with an additional test at 8 weeks of life (2 weeks after cessation of prophylaxis at 6 weeks of life) to capture additional cases. For infants at low risk of transmission, a single test obtained at 1 to 2 months of age may be timed to occur 2 to 4 weeks after cessation of ARV prophylaxis.
An infant with two negative virologic tests (one at age ≥14 days and the other at age ≥4 weeks) or one negative test at age ≥8 weeks can be viewed as presumptively uninfected, assuming the child has not had a positive virologic test, CD4 immunosuppression, or clinical evidence of HIV infection.
Virologic Testing at Age 4 to 6 Months
Infants with HIV exposure who have had negative virologic assays at age 14 to 21 days and at age 1 to 2 months, have no clinical evidence of HIV infection, and are not breastfed should be retested at age 4 to 6 months for definitive exclusion of HIV infection.
Antibody Testing at Age 6 Months and Older
Two or more negative HIV antibody tests performed in non-breastfed infants at age ≥6 months can also be used to definitively exclude HIV infection in children with no clinical or virologic laboratory-documented evidence of HIV infection.21,22
Antibody Testing at Age 12 to 18 Months to Document Seroreversion
Some experts confirm the absence of HIV infection in infants and children with negative virologic tests (when there has not been prior confirmation of two negative antibody tests) by repeat serologic testing between 12 and 18 months of age to confirm that maternal HIV antibodies transferred in utero have disappeared.1 In a recent study, the median age at seroreversion was 13.9 months.23 Although the majority of infants who are HIV-uninfected will serorevert by age 15 to 18 months, there are reports of late seroreversion after 18 months (see below). Factors that might influence the time to seroreversion include maternal disease stage and assay sensitivity.23-26
Diagnostic Testing in Children with Perinatal HIV Exposure in Special Situations
Late Seroreversion (≤24 Months of Age)
Non-breastfed children with HIV exposure with no other HIV transmission risk and no clinical or virologic laboratory evidence of HIV infection may have residual HIV antibodies up to age 24 months (these children are called late seroreverters).23-26 In one study, 14% of children with HIV exposure who were uninfected seroreverted after age 18 months.23 These children may have positive immunoassay results but indeterminate supplemental antibody tests (using Western blot or IFA). In such cases, repeat antibody testing at a later time would document seroreversion. Due to the possibility of residual HIV antibodies, virologic testing (i.e., with a NAT) is necessary to definitively exclude or confirm HIV infection in children with perinatal HIV exposure who have a positive HIV antibody (or antigen/antibody) test at age 18 to 24 months.
Postnatal HIV Infection in Children with Perinatal HIV Exposure with Prior Negative Virologic Tests for Whom There Are Additional HIV Transmission Risks In contrast to late seroreverters, in rare situations postnatal HIV infections have been reported in children with HIV exposure who had prior negative HIV virologic tests. This occurs in children who become infected through an additional risk after completion of testing (see Diagnostic Testing in Children with Non-Perinatal HIV Exposure or Children with Perinatal Exposure Aged >24 Months). If an HIV antibody test is positive at age 18 to 24 months, repeated virologic testing will distinguish residual antibodies in late-seroreverting (uninfected) children from children with antibodies due to true infection.
Suspicion of HIV-2 or Non-Subtype B HIV-1 Infections with False-Negative Virologic Test Results
Children with non-subtype B HIV-1 infection and children with HIV-2 infection may have false-negative virologic tests but persistent positive immunoassay results and indeterminate HIV-1 Western blot results.27-29 The diagnostic approach in these situations is discussed below in the sections on Virologic Assays to Diagnose Group M Non-Subtype B and Group O HIV-1 Infections and on Virologic Assays to Diagnose HIV-2 Infections.
Diagnostic Testing in Children with Non-Perinatal HIV Exposure or Children with Perinatal HIV Exposure Aged >24 Months
Breastfeeding is a known route of postnatal HIV transmission. Typical scenarios in the United States include women who have not been adequately counseled about infant feeding, women who breastfeed despite being counseled not to (e.g., women from communities where breastfeeding is the norm and women who fear that not breastfeeding would be stigmatizing, including those where avoidance of breastfeeding raise suspicions about maternal HIV infection), and women who learn of their HIV diagnosis only after initiating breastfeeding (e.g., women who were HIV negative during pregnancy but who acquire HIV infection postnatally; breastfeeding during acute HIV infection is associated with an increased risk of perinatal HIV transmission).30-33 Breast milk from a donor with unrecognized HIV infection at the time of donation is an additional risk factor. Infants who are breastfed by women living with HIV should undergo immediate HIV diagnostic testing, and counseling to discontinue breastfeeding should be provided. Follow-up, age-appropriate testing should be performed at 4 to 6 weeks, 3 months, and 6 months after breastfeeding cessation if the initial tests are negative. Diagnostic testing may be influenced by factors that include the transplacental transfer of maternal antibody resulting in residual antibody in children aged up to 24 months (women who acquired HIV infection before delivery), as well as the possibility of performing the test during acute HIV infection; thus, a NAT would be the choice for initial testing. The receipt of postnatal ARV prophylaxis may delay the detection of HIV infection (see Antiretroviral Management of Newborns with Perinatal HIV Exposure).34-36
Receipt of solid food premasticated, prechewed, or prewarmed by a caregiver living with HIV has been documented to be associated with risk of HIV transmission.37-42 If this occurs in children with perinatal HIV exposure aged 24 months or younger with prior negative virologic tests, it will be necessary for such children to undergo virologic diagnostic testing, as they may have residual maternal HIV antibodies (see Diagnostic Testing in Children with Perinatal HIV Exposure in Special Situations).
Additional Routes of HIV Transmission
Additional routes of HIV transmission in children include sexual abuse or receipt of contaminated blood products. In such cases, maternal HIV status may be negative. If the maternal HIV status is unknown, age-appropriate testing should be performed as described for children with perinatal HIV exposure.
Acquisition of HIV is possible through accidental needlestick injuries, sexual transmission, or injection drug use in older children. Medical procedures performed in settings with inadequate infection control practices may pose a potential risk; although tattooing or body piercing presents a potential risk of HIV transmission, no cases of HIV transmission from these activities have been documented.43
Diagnosis of HIV-1 infection in infants and children with non-perinatal HIV exposure only or children with perinatal HIV exposure aged >24 months relies primarily on HIV antibody and antigen/antibody tests.1,44 Food and Drug Administration (FDA)-approved diagnostic tests include:
- Antigen/antibody combination immunoassays, which detect HIV-1/2 antibodies as well as HIV-1 p24 antigen (fourth and fifth generation tests [the fifth generation test differentiates between HIV-1 and HIV-2 antibodies as well as HIV-1 p24 antigen]): Recommended for initial testing to screen for established infection with HIV-1 or HIV-2 and for acute HIV-1 infection (p24 antigen from HIV-1 non-B, non-M and HIV-2 strains may not be detected).45
- HIV-1/2 immunoassays (third-generation antibody tests): Alternative for initial testing.
- HIV-1/HIV-2 antibody differentiation immunoassay, which differentiates HIV-1 antibodies from HIV-2 antibodies: Recommended for supplemental testing.
- HIV-1 NAT may be necessary as an additional test to diagnose acute HIV infection.
- HIV-1 Western blot and HIV-1 indirect IFAs (first-generation tests): Alternative for supplemental testing but will not detect acute HIV infection.
Diagnosis of HIV-2 in children with non-perinatal exposure or children with perinatal exposure aged >24 months relies on the Centers for Disease Control and Prevention (CDC)/Association of Public Health Laboratories (APHL) 2014 laboratory testing guidelines, which recommend using an HIV-1/HIV-2 antibody differentiation immunoassay that differentiates HIV-1 antibodies from HIV-2 antibodies for supplemental testing. This is not subject to the same testing ambiguity as when the HIV-1 Western blot is used as a supplemental test; more than 60% of individuals with HIV-2 infection are misclassified as having HIV-1 by the HIV-1 Western blot.1,46 All HIV-2 cases should be reported to the HIV surveillance program of the state or local health department; additional HIV-2 DNA PCR testing can be arranged by their public health laboratory or the CDC if an HIV-1/HIV-2 antibody differentiation immunoassay is not conclusive. HIV-2 DNA PCR testing may be necessary for definitive diagnosis (this assay is not commercially available).47,48
Virologic Assays to Diagnose HIV Infection in Infants Younger than 18 Months with Perinatal HIV-1 Exposure
HIV RNA Assays
HIV quantitative RNA assays detect extracellular viral RNA in plasma. Their specificity has been shown to be 100% at birth and at 1, 3, and 6 months of age and is comparable to HIV DNA PCR.19 HIV RNA levels <5,000 copies/mL may not be reproducible and should be repeated before being interpreted as documentation of HIV infection in an infant.49,50 Testing at birth will detect infants who were infected in utero and not those who become infected from exposure during or immediately prior to delivery (i.e., in the intrapartum period). Studies have shown that HIV RNA assays identify 25% to 58% of infants with HIV infection from birth through the first week of life, 89% at age 1 month, and 90% to 100% by age 2 to 3 months (similar to results of HIV DNA PCR for early diagnosis of HIV).3,7,19,51
HIV RNA undergoes reverse transcription to double-stranded DNA, which persists intracellularly within an infected cell. HIV DNA PCR assays detect intracellular DNA, and usually remain positive in individuals receiving ARV treatment. In contrast, HIV RNA assays are affected by maternal antenatal treatment or infant combination ARV prophylaxis.52 In one study, the sensitivity of HIV RNA assays were not associated with the type of maternal or infant ARV prophylaxis, but HIV RNA levels at 1 month were significantly lower in infants with HIV infection receiving multidrug prophylaxis (n = 9) compared to levels among infants receiving single-drug zidovudine prophylaxis (n = 47) (median HIV RNA 2.5 log copies/mL vs. 5.4 log copies/mL, respectively). In contrast, the median HIV RNA levels were high (median HIV RNA 5.6 log copies/mL) by age 3 months in both groups after stopping prophylaxis.19 Further studies are necessary to evaluate the sensitivity and predictive value of HIV RNA assays during and after receipt of infant ARV prophylaxis.
An HIV quantitative RNA assay can be used as a supplemental test for infants who have an initial positive HIV DNA PCR test. In addition to providing virologic confirmation of infection status, the expense of repeat HIV DNA PCR testing is spared and an HIV RNA measurement is available to assess baseline viral load. This viral load can also be used to determine HIV genotype and guide initial ARV treatment in an infected infant. HIV RNA assays may be more sensitive than HIV DNA PCR for detecting non-subtype B HIV (see Virologic Assays to Diagnose Group M Non-Subtype B and Group O HIV-1 Infections).
The HIV qualitative RNA assay (APTIMA HIV-1 RNA Qualitative Assay) is an alternative diagnostic test that can be used for infant testing. It is the only qualitative RNA test that is FDA-approved.18,53-56
HIV DNA PCR and Related Assays
HIV DNA PCR is a sensitive technique used to detect intracellular HIV viral DNA in peripheral blood mononuclear cells. The specificity of the HIV DNA PCR is 99.8% at birth and 100% at ages 1, 3, and 6 months. Studies have shown that HIV DNA PCR assays identify 20% to 55% of infants with HIV infection from birth through the first week of life, with the same caveat as for RNA testing that testing at birth will detect infants infected in utero and not those infected during the intrapartum period, but the percentage increases to more than 90% by 2 to 4 weeks of age and to 100% at ages 3 months and 6 months.7,18,19,51
Two studies provided data on diagnostic testing at different time points in infants with confirmed HIV infection including those who had negative testing at birth (i.e., infants considered to be infected during the intrapartum period). A randomized, international study of 1,684 infants evaluated the efficacy of three different regimens of neonatal prophylaxis containing 6 weeks of zidovudine either alone or with two or three other ARV drugs; none of their mothers had received prenatal ARV drugs. Infant testing was performed at birth, 10 to 14 days, 4 to 6 weeks, and 3 and 6 months (no testing was performed between 6 weeks and 3 months). Ninety-three (66.4%) of 140 infants with HIV infection were identified at birth, and by 4 to 6 weeks of age, 89% of the 140 infants were identified. Of the 47 infants with HIV infection who had negative DNA PCR tests at birth, 68% were identified during the period of neonatal ARV prophylaxis at 4 to 6 weeks; by 3 months, all 47 infants were identified.17 More recent data from Thailand showed that, in non-breastfed infants, receiving an ARV prophylaxis regimen of zidovudine/lamivudine/nevirapine for 6 weeks was associated with a delay in first HIV DNA detection. In this cohort, up to 20% of HIV-exposed infants had their first positive DNA PCR test after 2 months of age, prompting the authors to recommend infant testing at 4 months of age, having discontinued neonatal prophylaxis for at least 4 to 6 weeks.57
Although the AMPLICOR® HIV-1 DNA test has been widely used for diagnosis of infants born to mothers with HIV-1 infection since it was introduced in 1992, it is no longer commercially available in the United States. The sensitivity and specificity of non-commercial HIV-1 DNA tests (using individual laboratory reagents) may differ from the sensitivity and specificity of the FDA-approved commercial test.
The COBAS AmpliPrep/COBAS TaqMan HIV-1 qualitative test which detects both HIV-1 RNA and proviral DNA in plasma, whole blood, and dried blood spots may be used for infant diagnosis but is not FDA-approved.58
Virologic Assays to Diagnose Group M Non-Subtype B and Group O HIV-1 Infections
Although HIV-1 Group M subtype B is the predominant viral subtype found in the United States, multiple subtypes and recombinant forms are found in the United States with a widespread geographic distribution.59 In an evaluation of infants with perinatal HIV infection diagnosed in New York state in 2001 and 2002, 16.7% of infants were infected with a non-subtype B strain of HIV, compared with 4.4% of infants born in 1998 and 1999.60 Among a group of 40 children attending a pediatric HIV clinic in Rhode Island during 1991 through 2012, 14 (35%) were infected with non-B HIV-1 subtypes. All 14 children with non-B subtypes were either born outside the United States or their parents were of foreign origin.61
In an analysis of 1,277 unique sequences collected in Rhode Island from 2004 to 2011, 8.3% were non-B subtypes (including recombinant forms). Twenty-two percent of non-B subtypes formed transmission clusters, including individuals with perinatally-acquired infection.62 In an analysis of 3,895 HIV-1 sequences collected between July 2011 and June 2012 in the United States, 5.3% were determined to be non-B subtypes (including recombinant forms). Among individual states, the percentage of non-B subtypes ranged from 0% (in 12 states) to 28.6% in South Dakota, with seven states having greater than 10%.63 Evolving immigration patterns may be contributing to local and regional increases in HIV-1 subtype diversity. Non-subtype B viruses predominate in other parts of the world, such as subtype C in regions of Africa and India and subtype CRF01 in much of Southeast Asia. Group O HIV strains are seen in West-Central Africa.64 Non-subtype B and Group O strains may also be seen in countries with links to these geographical regions.65-69 Geographical distribution of HIV groups is available at https://www.hiv.lanl.gov/components/sequence/HIV/geo/geo.comp.
Currently available real-time HIV RNA PCR assays and the qualitative diagnostic RNA assay have improved sensitivity for detection of non-subtype B HIV infection and the less common Group O strains, compared to older RNA assays that did not detect or appropriately amplify many non-B subtypes and Group O HIV70-75(see HIV RNA Monitoring in Children: General Considerations in Clinical and Laboratory Monitoring).
Thus, a real-time PCR assay or qualitative RNA assay, rather than a DNA PCR assay, should be used for infant testing when evaluating an infant born to a mother whose HIV infection is linked to an area endemic for non-subtype B HIV or Group O strains, such as Africa or Southeast Asia. Another indication is when initial testing is negative using a HIV DNA PCR test and non-subtype B or Group O perinatal exposure is suspected. Two negative HIV antibody tests obtained at age ≥6 months provide further evidence to definitively rule out HIV infection. Clinicians should consult with an expert in pediatric HIV infection; state or local public health departments or the CDC may be able to assist in obtaining referrals for diagnostic testing.
Virologic Assays to Diagnose HIV-2 Infections
HIV-2 infection is endemic in Angola; Mozambique; West African countries, including Cape Verde, Ivory Coast, Gambia, Guinea-Bissau, Mali, Mauritania, Nigeria, Sierra Leone, Benin, Burkina Faso, Ghana, Guinea, Liberia, Niger, Nigeria, Sao Tome, Senegal, and Togo; and parts of India.76-78 It also occurs in countries such as France and Portugal, which have large numbers of immigrants from these regions.79,80 HIV-1 and HIV-2 coinfections may also occur, but these are rare outside areas where HIV-2 is endemic. HIV-2 is rare in the United States. Although accurate diagnosis of HIV-2 can be problematic, it is clinically important because HIV-2 strains are resistant to several ARV drugs developed to suppress HIV-1.81-83
Infant testing with HIV-2-specific DNA PCR tests should be performed at time points similar to those used for HIV-1 testing when evaluating an infant born to a mother with a known or suspected HIV-2 infection. A mother should be suspected of being infected with HIV-2 if her infection is linked to an area endemic for HIV-2 infection or if her HIV testing results are suggestive of HIV-2 infection (i.e., positive initial HIV 1/2 immunoassay test, repeatedly indeterminate results on HIV-1 Western blot, and HIV-1 RNA viral loads at or below the limit of detection; however, the current recommendation to use an HIV-1/HIV-2 antibody differentiation immunoassay for supplemental testing is not subject to the same testing ambiguity as when the HIV-1 Western blot is used as a supplemental test as described below).1,84 HIV-2 DNA PCR testing can be arranged by the HIV surveillance program of the state or local health department through their public health laboratory or the CDC, because this assay is not commercially available.47,48 Clinicians should consult with an expert in pediatric HIV infection when caring for infants with suspected or known exposure to HIV-2.76,85
- Centers for Disease Control and Prevention and Association of Public Health Laboratories. Laboratory Testing for the Diagnosis of HIV Infection: Updated Recommendations. Available at http://stacks.cdc.gov/view/cdc/23447. Published June 27, 2014. Accessed May 22, 2016. 2014.
- Donovan M, Palumbo P. Diagnosis of HIV: challenges and strategies for HIV prevention and detection among pregnant women and their infants. Clin Perinatol. 2010;37(4):751-763, viii. Available at http://www.ncbi.nlm.nih.gov/pubmed/21078448.
- Read JS, Committee on Pediatric Aids AAoP. Diagnosis of HIV-1 infection in children younger than 18 months in the United States. Pediatrics. 2007;120(6):e1547-1562. Available at http://www.ncbi.nlm.nih.gov/pubmed/18055670.
- Tamhane M, Gautney B, Shiu C, et al. Analysis of the optimal cut-point for HIV-p24 antigen testing to diagnose HIV infection in HIV-exposed children from resource-constrained settings. J Clin Virol. 2011;50(4):338-341. Available at http://www.ncbi.nlm.nih.gov/pubmed/21330193.
- Wessman MJ, Theilgaard Z, Katzenstein TL. Determination of HIV status of infants born to HIV-infected mothers: a review of the diagnostic methods with special focus on the applicability of p24 antigen testing in developing countries. Scand J Infect Dis. 2012;44(3):209-215. Available at http://www.ncbi.nlm.nih.gov/pubmed/22074445.
- Bhowan K, Sherman GG. Performance of the first fourth-generation rapid human immunodeficiency virus test in children. Pediatr Infect Dis J. 2013;32(5):486-488. Available at http://www.ncbi.nlm.nih.gov/pubmed/23190776.
- Havens PL, Mofenson LM, American Academy of Pediatrics Committee on Pediatric A. Evaluation and management of the infant exposed to HIV-1 in the United States. Pediatrics. 2009;123(1):175-187. Available at http://www.ncbi.nlm.nih.gov/pubmed/19117880.
- Ferguson W, Goode M, Walsh A, Gavin P, Butler K. Evaluation of 4 weeks' neonatal antiretroviral prophylaxis as a component of a prevention of mother-to-child transmission program in a resource-rich setting. Pediatr Infect Dis J. 2011;30(5):408-412. Available at http://www.ncbi.nlm.nih.gov/pubmed/21266939.
- Sollai S, Noguera-Julian A, Galli L, et al. Strategies for the prevention of mother to child transmission in Western countries: an update. Pediatr Infect Dis J. 2015;34(5 Suppl 1):S14-30. Available at http://www.ncbi.nlm.nih.gov/pubmed/25894973.
- Panel on Opportunistic Infections in HIV-Exposed and HIV-Infected Children. Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Exposed and HIV-Infected Children. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/oi_guidelines_pediatrics.pdf.
- Lilian RR, Kalk E, Technau KG, Sherman GG. Birth Diagnosis of HIV Infection on Infants to Reduce Infant Mortality and Monitor for Elimination of Mother-to-Child Transmission. Pediatr Infect Dis J. 2013. Available at http://www.ncbi.nlm.nih.gov/pubmed/23574775.
- Jourdain G, Mary JY, Coeur SL, et al. Risk factors for in utero or intrapartum mother-to-child transmission of human immunodeficiency virus type 1 in Thailand. J Infect Dis. 2007;196(11):1629-1636. Available at http://www.ncbi.nlm.nih.gov/pubmed/18008246.
- Tubiana R, Le Chenadec J, Rouzioux C, et al. Factors associated with mother-to-child transmission of HIV-1 despite a maternal viral load <500 copies/ml at delivery: a case-control study nested in the French perinatal cohort (EPF-ANRS CO1). Clin Infect Dis. 2010;50(4):585-596. Available at http://www.ncbi.nlm.nih.gov/pubmed/20070234.
- Katz IT, Shapiro DE, Tuomala R. Factors Associated With Lack of Viral Suppression at Delivery. Ann Intern Med. 2015;162(12):874-875. Available at http://www.ncbi.nlm.nih.gov/pubmed/26075762.
- Momplaisir FM, Brady KA, Fekete T, Thompson DR, Diez Roux A, Yehia BR. Time of HIV Diagnosis and Engagement in Prenatal Care Impact Virologic Outcomes of Pregnant Women with HIV. PLoS One. 2015;10(7):e0132262. Available at http://www.ncbi.nlm.nih.gov/pubmed/26132142.
- Mandelbrot L, Tubiana R, Le Chenadec J, et al. No perinatal HIV-1 transmission from women with effective antiretroviral therapy starting before conception. Clin Infect Dis. 2015;61(11):1715-1725. Available at https://www.ncbi.nlm.nih.gov/pubmed/26197844.
- Nielsen-Saines K, Watts DH, Veloso VG, et al. Three postpartum antiretroviral regimens to prevent intrapartum HIV infection. N Engl J Med. 2012;366(25):2368-2379. Available at http://www.ncbi.nlm.nih.gov/pubmed/22716975.
- Lilian RR, Kalk E, Bhowan K, et al. Early diagnosis of in utero and intrapartum HIV infection in infants prior to 6 weeks of age. J Clin Microbiol. 2012;50(7):2373-2377. Available at http://www.ncbi.nlm.nih.gov/pubmed/22518871.
- Burgard M, Blanche S, Jasseron C, et al. Performance of HIV-1 DNA or HIV-1 RNA tests for early diagnosis of perinatal HIV-1 infection during anti-retroviral prophylaxis. J Pediatr. 2012;160(1):60-66 e61. Available at http://www.ncbi.nlm.nih.gov/pubmed/21868029.
- Lilian RR, Johnson LF, Moolla H, Sherman GG. A mathematical model evaluating the timing of early diagnostic testing in HIV-exposed infants in South Africa. J Acquir Immune Defic Syndr. 2014;67(3):341-348. Available at http://www.ncbi.nlm.nih.gov/pubmed/25118910.
- Kuhn L, Schramm DB, Shiau S, et al. Young age at start of antiretroviral therapy and negative HIV antibody results in HIV-infected children when suppressed. AIDS. 2015;29(9):1053-1060. Available at http://www.ncbi.nlm.nih.gov/pubmed/25870988.
- Payne H, Mkhize N, Otwombe K, et al. Reactivity of routine HIV antibody tests in children who initiated antiretroviral therapy in early infancy as part of the Children with HIV Early Antiretroviral Therapy (CHER) trial: a retrospective analysis. Lancet Infect Dis. 2015;15(7):803-809. Available at http://www.ncbi.nlm.nih.gov/pubmed/26043884.
- Gutierrez M, Ludwig DA, Khan SS, et al. Has highly active antiretroviral therapy increased the time to seroreversion in HIV exposed but uninfected children? Clin Infect Dis. 2012;55(9):1255-1261. Available at http://www.ncbi.nlm.nih.gov/pubmed/22851494.
- Gulia J, Kumwenda N, Li Q, Taha TE. HIV seroreversion time in HIV-1-uninfected children born to HIV-1-infected mothers in Malawi. J Acquir Immune Defic Syndr. 2007;46(3):332-337. Available at http://www.ncbi.nlm.nih.gov/pubmed/17786126.
- Alcantara KC, Pereira GA, Albuquerque M, Stefani MM. Seroreversion in children born to HIV-positive and AIDS mothers from Central West Brazil. Trans R Soc Trop Med Hyg. 2009;103(6):620-626. Available at http://www.ncbi.nlm.nih.gov/pubmed/19339030.
- Sohn AH, Thanh TC, Thinh le Q, et al. Failure of human immunodeficiency virus enzyme immunoassay to rule out infection among polymerase chain reaction-negative Vietnamese infants at 12 months of age. Pediatr Infect Dis J. 2009;28(4):273-276. Available at http://www.ncbi.nlm.nih.gov/pubmed/19289981.
- Kline NE, Schwarzwald H, Kline MW. False negative DNA polymerase chain reaction in an infant with subtype C human immunodeficiency virus 1 infection. Pediatr Infect Dis J. 2002;21(9):885-886. Available at http://www.ncbi.nlm.nih.gov/pubmed/12380591.
- Zaman MM, Recco RA, Haag R. Infection with non-B subtype HIV type 1 complicates management of established infection in adult patients and diagnosis of infection in newborn infants. Clin Infect Dis. 2002;34(3):417-418. Available at http://www.ncbi.nlm.nih.gov/pubmed/11774090.
- Obaro SK, Losikoff P, Harwell J, Pugatch D. Failure of serial human immunodeficiency virus type 1 DNA polymerase chain reactions to identify human immunodeficiency virus type 1 clade A/G. Pediatr Infect Dis J. 2005;24(2):183-184. Available at http://www.ncbi.nlm.nih.gov/pubmed/15702052.
- Liang K, Gui X, Zhang YZ, Zhuang K, Meyers K, Ho DD. A case series of 104 women infected with HIV-1 via blood transfusion postnatally: high rate of HIV-1 transmission to infants through breast-feeding. J Infect Dis. 2009;200(5):682-686. Available at http://www.ncbi.nlm.nih.gov/pubmed/19627245.
- Nesheim S, Harris LF, Lampe M. Elimination of perinatal HIV infection in the USA and other high-income countries: achievements and challenges. Curr Opin HIV AIDS. 2013;8(5):447-456. Available at http://www.ncbi.nlm.nih.gov/pubmed/23925002.
- De Schacht C, Mabunda N, Ferreira OC, et al. High HIV incidence in the postpartum period sustains vertical transmission in settings with generalized epidemics: a cohort study in Southern Mozambique. J Int AIDS Soc. 2014;17:18808. Available at http://www.ncbi.nlm.nih.gov/pubmed/24629842.
- Blumental S, Ferster A, Van den Winjgaert S, Lepage P. HIV transmission through breastfeeding: still possible in developed countries. Pediatrics. 2014;134(3):875-879. Available at http://pediatrics.aappublications.org/content/134/3/e875.
- Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission. 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. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/PerinatalGL.pdf. Accessed on May 22, 2016.
- Committee On Pediatric AIDS. Infant feeding and transmission of human immunodeficiency virus in the United States. Pediatrics. 2013;131(2):391-396. Available at http://www.ncbi.nlm.nih.gov/pubmed/23359577.
- King CC, Kourtis AP, Persaud D, et al. Delayed HIV detection among infants exposed to postnatal antiretroviral prophylaxis during breastfeeding. AIDS. 2015;29(15):1953-1961. Available at http://www.ncbi.nlm.nih.gov/pubmed/26153671.
- Centers for Disease Control and Prevention. Premastication of food by caregivers of HIV-exposed children--nine U.S. sites, 2009-2010. MMWR Morb Mortal Wkly Rep. 2011;60(9):273-275. Available at http://www.ncbi.nlm.nih.gov/pubmed/21389930.
- Gaur AH, Freimanis-Hance L, Dominguez K, et al. Knowledge and practice of prechewing/prewarming food by HIV-infected women. Pediatrics. 2011;127(5):e1206-1211. Available at http://www.ncbi.nlm.nih.gov/pubmed/21482608.
- Hafeez S, Salami O, Alvarado M, Maldonado M, Purswani M, Hagmann S. Infant feeding practice of premastication: an anonymous survey among human immunodeficiency virus-infected mothers. Arch Pediatr Adolesc Med. 2011;165(1):92-93. Available at http://www.ncbi.nlm.nih.gov/pubmed/21199989.
- Maritz ER, Kidd M, Cotton MF. Premasticating food for weaning African infants: a possible vehicle for transmission of HIV. Pediatrics. 2011;128(3):e579-590. Available at http://www.ncbi.nlm.nih.gov/pubmed/21873699.
- Ivy W, 3rd, Dominguez KL, Rakhmanina NY, et al. Premastication as a route of pediatric HIV transmission: case-control and cross-sectional investigations. J Acquir Immune Defic Syndr. 2012;59(2):207-212. Available at http://www.ncbi.nlm.nih.gov/pubmed/22027873.
- Gaur AH, Cohen RA, Read JS, et al. Prechewing and prewarming food for HIV-exposed children: a prospective cohort experience from Latin America. AIDS Patient Care STDS. 2013;27(3):142-145. Available at http://www.ncbi.nlm.nih.gov/pubmed/23477456.
- National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention Available at http://www.cdc.gov/nchhstp/. Last updated December 7, 2015. Accessed May 22, 2016. [press release]. 2014.
- Alexander TS. Human Immunodeficiency Virus Diagnostic Testing: 30 Years of Evolution. Clin Vaccine Immunol. 2016;23(4):249-253. Available at http://www.ncbi.nlm.nih.gov/pubmed/26936099.
- Ly TD, Plantier JC, Leballais L, Gonzalo S, Lemee V, Laperche S. The variable sensitivity of HIV Ag/Ab combination assays in the detection of p24Ag according to genotype could compromise the diagnosis of early HIV infection. J Clin Virol. 2012;55(2):121-127. Available at http://www.ncbi.nlm.nih.gov/pubmed/22795598.
- 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.
- Shanmugam V, Switzer WM, Nkengasong JN, et al. Lower HIV-2 plasma viral loads may explain differences between the natural histories of HIV-1 and HIV-2 infections. J Acquir Immune Defic Syndr. 2000;24(3):257-263. Available at http://www.ncbi.nlm.nih.gov/pubmed/10969350.
- 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.
- Lilian RR, Bhowan K, Sherman GG. Early diagnosis of human immunodeficiency virus-1 infection in infants with the NucliSens EasyQ assay on dried blood spots. J Clin Virol. 2010;48(1):40-43. Available at https://www.ncbi.nlm.nih.gov/pubmed/20211580.
- Patel JA, Anderson EJ, Dong J. False Positive Ultrasensitive HIV bDNA Viral Load Results in Diagnosis of Perinatal HIV-Infection in the Era of Low Transmission. Laboratory Medicine. 2009;40(10):611-614. Available at http://labmed.oxfordjournals.org/content/40/10/611.
- American Academy of Pediatrics Committee on Pediatric AIDS. HIV testing and prophylaxis to prevent mother-to-child transmission in the United States. Pediatrics. 2008;122(5):1127-1134. Available at http://www.ncbi.nlm.nih.gov/pubmed/18977995.
- Saitoh A, Hsia K, Fenton T, et al. Persistence of human immunodeficiency virus (HIV) type 1 DNA in peripheral blood despite prolonged suppression of plasma HIV-1 RNA in children. J Infect Dis. 2002;185(10):1409-1416. Available at http://www.ncbi.nlm.nih.gov/pubmed/11992275.
- U.S. Food and Drug Administration. APTIMA HIV-1 RNA Qualitative Assay. 2009; http://www.fda.gov/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/LicensedProductsBLAs/BloodDonorScreening/InfectiousDisease/ucm149922.htm.
- Pierce VM, Neide B, Hodinka RL. Evaluation of the Gen-Probe Aptima HIV-1 RNA qualitative assay as an alternative to Western blot analysis for confirmation of HIV infection. J Clin Microbiol. 2011;49(4):1642-1645. Available at http://www.ncbi.nlm.nih.gov/pubmed/21346052.
- Fiscus SA, McMillion T, Nelson JA, Miller WC. Validation of the Gen-Probe Aptima qualitative HIV-1 RNA assay for diagnosis of human immunodeficiency virus infection in infants. J Clin Microbiol. 2013;51(12):4137-4140. Available at http://www.ncbi.nlm.nih.gov/pubmed/24088864.
- Nelson JA, Hawkins JT, Schanz M, et al. Comparison of the Gen-Probe Aptima HIV-1 and Abbott HIV-1 qualitative assays with the Roche Amplicor HIV-1 DNA assay for early infant diagnosis using dried blood spots. J Clin Virol. 2014;60(4):418-421. Available at http://www.ncbi.nlm.nih.gov/pubmed/24929752.
- Puthankit T, Rojanwiwat T. Delayed HIV DNA PCR detection among infants received combination ART prophylaxis. Conference on Retroviruses and Opportunistic Infections 2017.
- Templer SP, Seiverth B, Baum P, Stevens W, Seguin-Devaux C, Carmona S. Improved Sensitivity of a Dual-Target HIV-1 Qualitative Test for Plasma and Dried Blood Spots. J Clin Microbiol. 2016;54(7):1877-1882. Available at https://www.ncbi.nlm.nih.gov/pubmed/27194686.
- Pyne MT, Hackett J, Jr., Holzmayer V, Hillyard DR. Large-scale analysis of the prevalence and geographic distribution of HIV-1 non-B variants in the United States. J Clin Microbiol. 2013;51(8):2662-2669. Available at http://www.ncbi.nlm.nih.gov/pubmed/23761148.
- Karchava M, Pulver W, Smith L, et al. Prevalence of drug-resistance mutations and non-subtype B strains among HIV-infected infants from New York State. J Acquir Immune Defic Syndr. 2006;42(5):614-619. Available at http://www.ncbi.nlm.nih.gov/pubmed/16868498.
- Rogo T, DeLong AK, Chan P, Kantor R. Antiretroviral treatment failure, drug resistance, and subtype diversity in the only pediatric HIV clinic in Rhode Island. Clin Infect Dis. 2015;60(9):1426-1435. Available at http://www.ncbi.nlm.nih.gov/pubmed/25637585.
- Chan PA, Reitsma MB, DeLong A, et al. Phylogenetic and geospatial evaluation of HIV-1 subtype diversity at the largest HIV center in Rhode Island. Infect Genet Evol. 2014;28:358-366. Available at http://www.ncbi.nlm.nih.gov/pubmed/24721515.
- Germer JJ, Wu P, Soderberg JD, Mandrekar JN, Yao JD. HIV-1 subtype diversity among clinical specimens submitted for routine antiviral drug resistance testing in the United States. Diagn Microbiol Infect Dis. 2015;83(3):257-260. Available at http://www.ncbi.nlm.nih.gov/pubmed/26302855.
- Bush S, Tebit DM. HIV-1 Group O Origin, Evolution, Pathogenesis, and Treatment: Unraveling the Complexity of an Outlier 25 Years Later. AIDS reviews. 2015;17(3):147-158. Available at http://www.ncbi.nlm.nih.gov/pubmed/26450803.
- Auwanit W, Isarangkura-Na-Ayuthaya P, Kasornpikul D, Ikuta K, Sawanpanyalert P, Kameoka M. Detection of drug resistance-associated and background mutations in human immunodeficiency virus type 1 CRF01_AE protease and reverse transcriptase derived from drug treatment-naive patients residing in central Thailand. AIDS Res Hum Retroviruses. 2009;25(6):625-631. Available at http://www.ncbi.nlm.nih.gov/pubmed/19500016.
- Deshpande A, Jauvin V, Pinson P, Jeannot AC, Fleury HJ. Phylogenetic analysis of HIV-1 reverse transcriptase sequences from 382 patients recruited in JJ Hospital of Mumbai, India, between 2002 and 2008. AIDS Res Hum Retroviruses. 2009;25(6):633-635. Available at http://www.ncbi.nlm.nih.gov/pubmed/19534630.
- Chaix ML, Seng R, Frange P, et al. Increasing HIV-1 non-B subtype primary infections in patients in France and effect of HIV subtypes on virological and immunological responses to combined antiretroviral therapy. Clin Infect Dis. 2013;56(6):880-887. Available at http://www.ncbi.nlm.nih.gov/pubmed/23223603.
- Hemelaar J, Gouws E, Ghys PD, Osmanov S, Isolation W-UNfH, Characterisation. Global trends in molecular epidemiology of HIV-1 during 2000-2007. AIDS. 2011;25(5):679-689. Available at http://www.ncbi.nlm.nih.gov/pubmed/21297424.
- Dauwe K, Mortier V, Schauvliege M, et al. Characteristics and spread to the native population of HIV-1 non-B subtypes in two European countries with high migration rate. BMC Infect Dis. 2015;15:524. Available at http://www.ncbi.nlm.nih.gov/pubmed/26572861.
- Church D, Gregson D, Lloyd T, et al. Comparison of the RealTime HIV-1, COBAS TaqMan 48 v1.0, Easy Q v1.2, and Versant v3.0 assays for determination of HIV-1 viral loads in a cohort of Canadian patients with diverse HIV subtype infections. J Clin Microbiol. 2011;49(1):118-124. Available at http://www.ncbi.nlm.nih.gov/pubmed/21084515.
- Cobb BR, Vaks JE, Do T, Vilchez RA. Evolution in the sensitivity of quantitative HIV-1 viral load tests. J Clin Virol. 2011;52 Suppl 1:S77-82. Available at http://www.ncbi.nlm.nih.gov/pubmed/22036041.
- Katsoulidou A, Rokka C, Issaris C, et al. Comparative evaluation of the performance of the Abbott RealTime HIV-1 assay for measurement of HIV-1 plasma viral load on genetically diverse samples from Greece. Virol J. 2011;8:10. Available at http://www.ncbi.nlm.nih.gov/pubmed/21219667.
- Gueudin M, Leoz M, Lemee V, et al. A new real-time quantitative PCR for diagnosis and monitoring of HIV-1 group O infection. J Clin Microbiol. 2012;50(3):831-836. Available at http://www.ncbi.nlm.nih.gov/pubmed/22170927.
- Xu S, Song A, Nie J, et al. Comparison between the automated Roche Cobas AmpliPrep/Cobas TaqMan HIV-1 test version 2.0 assay and its version 1 and Nuclisens HIV-1 EasyQ version 2.0 assays when measuring diverse HIV-1 genotypes in China. J Clin Virol. 2012;53(1):33-37. Available at http://www.ncbi.nlm.nih.gov/pubmed/22051503.
- Muenchhoff M, Madurai S, Hempenstall AJ, et al. Evaluation of the NucliSens EasyQ v2.0 assay in comparison with the Roche Amplicor v1.5 and the Roche CAP/CTM HIV-1 Test v2.0 in quantification of C-clade HIV-1 in plasma. PLoS One. 2014;9(8):e103983. Available at http://www.ncbi.nlm.nih.gov/pubmed/25157919.
- 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.
- 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.
- 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.
- Barin F, Cazein F, Lot F, et al. Prevalence of HIV-2 and HIV-1 group O infections among new HIV diagnoses in France: 2003-2006. AIDS. 2007;21(17):2351-2353. Available at http://www.ncbi.nlm.nih.gov/pubmed/18090288.
- Thiebaut R, Matheron S, Taieb A, et al. Long-term nonprogressors and elite controllers in the ANRS CO5 HIV-2 cohort. AIDS. 2011;25(6):865-867. Available at http://www.ncbi.nlm.nih.gov/pubmed/21358376.
- Menendez-Arias L, Alvarez M. Antiretroviral therapy and drug resistance in human immunodeficiency virus type 2 infection. Antiviral Res. 2014;102:70-86. Available at http://www.ncbi.nlm.nih.gov/pubmed/24345729.
- Tchounga BK, Inwoley A, Coffie PA, et al. Re-testing and misclassification of HIV-2 and HIV-1&2 dually reactive patients among the HIV-2 cohort of the West African Database to evaluate AIDS collaboration. J Int AIDS Soc. 2014;17:19064. Available at http://www.ncbi.nlm.nih.gov/pubmed/25128907.
- Balestre E, Ekouevi DK, Tchounga B, et al. Immunologic response in treatment-naive HIV-2-infected patients: the IeDEA West Africa cohort. J Int AIDS Soc. 2016;19(1):20044. Available at http://www.ncbi.nlm.nih.gov/pubmed/26861115.
- Linley L, Ethridge SF, Oraka E, et al. Evaluation of supplemental testing with the Multispot HIV-1/HIV-2 Rapid Test and APTIMA HIV-1 RNA Qualitative Assay to resolve specimens with indeterminate or negative HIV-1 Western blots. J Clin Virol. 2013;58 Suppl 1:e108-112. Available at http://www.ncbi.nlm.nih.gov/pubmed/24342469.
- 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.