Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection
Diagnosis of HIV Infection in Infants and Children
(Last updated:2/12/2014; last reviewed:2/12/2014)
- Virologic assays that directly detect HIV must be used to diagnose HIV infection in infants younger than 18 months (AII).
- HIV DNA polymerase chain reaction and HIV RNA assays are recommended as preferred virologic assays (AII).
- Virologic diagnostic testing in infants with known perinatal HIV exposure is recommended at ages 14 to 21 days, 1 to 2 months, and 4 to 6 months (AII).
- Virologic diagnostic testing at birth should be considered for infants at high risk of HIV infection (BIII).
- Virologic diagnostic testing should be considered 2 to 4 weeks after cessation of antiretroviral (ARV) prophylaxis for infants receiving combination ARV infant prophylaxis, if the results of prior virologic testing were negative while the infant was receiving prophylaxis (BIII).
- A positive virologic test should be confirmed as soon as possible by a repeat virologic test on a second specimen (AII).
- Definitive exclusion of HIV infection in non-breastfed infants is based on 2 or more negative virologic tests, with one obtained at age ≥1 month and one at age ≥4 months, or 2 negative HIV antibody tests from separate specimens obtained at age ≥6 months (AII).
- Some experts confirm the absence of HIV infection at 12 to 18 months of age in infants with prior negative virologic tests by performing an antibody test to document loss of maternal HIV antibodies (BIII).
- Screening HIV antibody assays in conjunction with a confirmatory antibody test or virologic detection test can be used for diagnosis of HIV infection in children with perinatal exposure aged ≥18 months and in children with non-perinatal exposure (see text for special situations) (AII).
|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 and adolescents but not studies limited to postpubertal adolescents
Diagnostic Testing in Infants with Perinatal HIV-1 (HIV) Exposure
HIV infection can be definitively diagnosed through use of virologic assays in most non-breastfed HIV-exposed infants by age 1 month and in virtually all infected infants by age 4 months. Tests for antibodies to HIV, including newer tests, do not establish the presence of HIV infection in infants because of transplacental transfer of maternal antibodies to HIV; therefore a virologic test should be used.1,2
Positive virologic tests (i.e., nucleic acid amplification tests [NAT]—a class of tests which includes HIV DNA, RNA 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.
HIV culture is not used for routine HIV diagnostic testing, although it has sensitivity similar to that of HIV DNA PCR.3
It is more complex and expensive to perform than DNA PCR or RNA assays, requires 2 to 4 weeks for definitive results, and is generally not available outside of research laboratories. Use of the currently approved HIV p24 antigen assay is not recommended for infant diagnosis in the United States because the sensitivity and specificity of the assay in the first months of life are less than that of other HIV virologic tests.4,5
Infants who are found to have positive HIV antibody tests on screening but whose mothers’ HIV status is unknown (see Identification of Perinatal HIV Exposure
) should be assumed to be HIV-exposed and undergo the HIV diagnostic testing described here.6
HIV DNA PCR
HIV DNA PCR is a sensitive technique used to detect specific HIV viral DNA in peripheral blood mononuclear cells. The specificity of the HIV DNA PCR is 99.8% at birth and 100% at 1, 3, and 6 months. The sensitivity of the test performed at birth is 55% but increases to more than 90% by 2 to 4 weeks of age, and 100% at ages 3 months and 6 months.6-9
HIV RNA Assays
HIV quantitative RNA assays detect extracellular viral RNA in the plasma. Their specificity (for results ≥5,000 copies/mL) has been shown to be 100% at birth, 1, 3, and 6 months of age and is comparable to HIV DNA PCR.8 HIV RNA levels <5,000 copies/mL may not be reproducible and should be repeated before they are interpreted as documenting HIV infection in an infant. The sensitivity of HIV RNA assays has been shown to be 25% to 58% during the first weeks of life, 89% at age 1 month, and increases to 90% to 100% by age 2 to 3 months.6-8,10-12
In studies of infants receiving zidovudine or no prophylaxis, HIV RNA assays were found to be as sensitive as HIV DNA PCR for early diagnosis of HIV infection in HIV-exposed infants. An HIV RNA assay can be used as the confirmatory 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. HIV RNA assays may be more sensitive than HIV DNA PCR for detecting HIV non-subtype B (see HIV Subtype section below). While HIV DNA PCR remains positive in most individuals receiving antiretroviral treatment, HIV RNA assays may be affected by maternal antenatal treatment or infant combination antiretroviral (ARV) prophylaxis.8,13 In one study, the sensitivity of HIV RNA assays was not associated with the type of maternal or infant ARV prophylaxis, but HIV RNA levels at 1 month were lower in infants receiving multidrug prophylaxis (n = 9) compared to levels among infected 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. These data suggest that diagnostic sensitivity of HIV assays may be affected by the type of infant prophylaxis.8
Further studies are necessary to confirm this trend.
The HIV qualitative RNA assay (APTIMA HIV-1 RNA Qualitative Assay) is an alternative diagnostic test that can be used for infant testing.9,14-18
Issues Related to Diagnosis of 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, 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. Non-subtype B and Group O strains may also be seen in countries with links to these geographical regions.19-22
Geographical distribution of HIV groups is available at http://www.hiv.lanl.gov/components/sequence/HIV/geo/geo.comp
Currently available HIV DNA PCR tests have decreased sensitivity for detection of non-subtype B HIV, and false-negative HIV DNA PCR test results have been reported in infants infected with non-subtype B HIV.23-25
In an evaluation of perinatally infected infants diagnosed in New York State in 2001 through 2002, 16.7% of infants were infected with a non-subtype B strain of HIV, compared with 4.4% of infants diagnosed between 1998 and 1999.26
Currently available real-time HIV RNA PCR assays have improved sensitivity for detection of non-subtype B HIV infection and the more uncommon Group O strains compared to other RNA assays that do not detect or properly quantify all non-B subtypes and group O HIV27-32
(see HIV RNA Monitoring in Children: General Considerations
in Clinical and Laboratory Monitoring
When evaluating an infant whose mother or father (or both) comes from an area endemic for non-subtype B HIV or Group O strains, such as Africa and Southeast Asia, clinicians should consider conducting initial testing using one of the assays more sensitive for non-subtype B viruses, such as one of the real-time PCR assays. In addition, when non-subtype B perinatal exposure is suspected in infants with negative HIV DNA PCR results, repeat testing using one of the newer RNA assays is recommended. The child should undergo close clinical monitoring and HIV serologic testing at age 18 months to definitively rule out HIV infection. Clinicians should consult with an expert in pediatric HIV infection; state or local public health departments or the Centers for Disease Control and Prevention (CDC) may be able to assist in obtaining referrals for diagnostic testing.
Issues Related to Diagnosis of 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 in parts of India.33,34
It also occurs in countries such as France and Portugal, which have large numbers of immigrants from these regions;35,36
HIV-2 is rare in the United States. 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 and HIV-1 RNA viral loads at or below the limit of detection.37,38
This pattern of HIV testing can also be seen in patients who have a false-positive HIV-1 test. HIV-1 and HIV-2 coinfections may also occur, further complicating the diagnosis.
The majority of commercially available HIV screening antibody tests can detect both HIV-1 and HIV-2 but cannot distinguish between the two viruses. The only Food and Drug Administration (FDA)-approved antibody test that distinguishes between HIV-1 and HIV-2 is the Bio-Rad Laboratories Multispot HIV-1/HIV-2 test. If HIV-2 is suspected, infection can be confirmed using a supplemental test such as an HIV-2 immunoblot or HIV-2-specific Western blot. HIV-2 immunoblots are available through commercial labs; however, none are FDA-approved for HIV-2 diagnosis. 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 their public health laboratory or the CDC.
Infants born to HIV-2-infected mothers should be tested for HIV-2 infection with HIV-2-specific virologic assays (HIV-2 DNA PCR testing) at time points similar to those used for HIV-1 testing. HIV-2 virologic assays are not commercially available, but the National Perinatal HIV Hotline (1-888-448-8765) can provide a list of sites that perform this testing. Clinicians should consult with an expert in pediatric HIV infection when caring for infants with suspected or known exposure to HIV-2.34,39-41
Timing of Diagnostic Testing in Infants with Known Perinatal HIV Exposure
Virologic diagnostic testing of an HIV-exposed infant should be performed at age 14 to 21 days, at age 1 to 2 months, and at age 4 to 6 months. Virologic diagnostic testing should be considered at birth for infants at high risk of HIV infection and 2 to 4 weeks after discontinuation of prophylaxis for infants receiving combination neonatal ARV regimens (see below).
Confirmation of HIV infection should be based on two positive virologic tests from separate blood samples, regardless of a child’s age. A positive HIV antibody test with confirmatory Western blot (or immunofluorescent antibody [IFA] assay) at age ≥18 months confirms HIV infection, except in occasional late seroreverters (see the Diagnostic Testing in Children with Perinatal HIV Exposure in Special Situations
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 at age ≥8 weeks, or one negative HIV antibody test at age ≥6 months.1,6 Pneumocystis jiroveci
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
Thus, initiation of PCP prophylaxis can be avoided or discontinued if an infant has negative virologic tests at ages 2 weeks and ≥4 weeks, or if virologic testing is negative at age ≥8 weeks.
exclusion of HIV infection in a non-breastfed infant is based on 2 or more negative virologic tests, one at age ≥1 month and one at age ≥4 months, or 2 negative HIV antibody tests from separate specimens obtained at age ≥6 months. For both presumptive
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.
Virologic Testing at Birth (Optional)
Virologic testing at birth should be considered for newborns at high risk of perinatal HIV transmission, such as infants born to HIV-infected mothers who did not receive prenatal care or prenatal ARVs, were diagnosed with acute HIV infection during pregnancy, or who had HIV viral loads ≥1,000 copies/mL close to the time of delivery.44
As many as 30% to 40% of HIV-infected infants can be identified by age 48 hours.6
Prompt diagnosis is critical to allow for discontinuing ARV prophylaxis and instituting early ARV therapy (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 during the intrauterine period 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.45
Some researchers have proposed that infants with early infection may have more rapid disease progression than those with late infection and, therefore, should receive more aggressive therapy.45,46
However, data from prospective cohort studies have demonstrated that although early differences in HIV RNA levels were present between infants with a positive HIV culture within 48 hours of birth and those with a first positive culture after age 7 days, these differences were no longer statistically significant after age 2 months.47
HIV RNA levels after the first month of life were more predictive of rapid disease progression than the time at which HIV culture tests were positive.47,48
Virologic Testing at Age 14 to 21 Days
The diagnostic sensitivity of virologic testing increases rapidly by age 2 weeks6
and early identification of infection would permit discontinuation of neonatal ARV prophylaxis and further evaluation for initiation of ARV therapy (see Infants Younger than Age 12 Months
and Table 5
in When to Initiate
Virologic Testing at Age 1 to 2 Months
Infants with negative virologic tests before age 1 month should be retested at age 1 to 2 months. Most HIV-exposed neonates will receive 6 weeks of neonatal ARV prophylaxis. Although the use of antepartum, intrapartum, and neonatal zidovudine single-drug prophylaxis did not delay detection of HIV by culture in infants in Pediatric AIDS Clinical Trials Group (PACTG) protocol 076 or the sensitivity and predictive values of many virologic assays,6,10-12,49
this may not always apply to current combination prenatal and neonatal ARV regimens if the test is obtained while the infant is receiving combination neonatal ARV prophylaxis.8
Virologic diagnostic testing for infants receiving combination ARV infant prophylaxis should be considered 2 to 4 weeks after cessation of prophylaxis if prior negative diagnostic testing was performed during the period of prophylaxis. In such situations, the test recommended at age 1 to 2 months can be delayed until after cessation of ARV prophylaxis.
An infant with two negative virologic tests, one at age ≥14 days and one at age ≥1 month, can be viewed as presumptively
uninfected and will not need PCP prophylaxis, 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
HIV-exposed children 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 HIV-exposed children with no clinical or virologic laboratory evidence of HIV infection.
Antibody Testing at Age 12 to 18 Months to Document Seroreversion
Some experts confirm the absence of HIV infection in infants 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
In a recent study, the median age at seroreversion was 13.9 months.50
Although the majority of HIV-uninfected infants 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.50-53
Diagnostic Testing in Children with Perinatal HIV Exposure in Special Situations
- Late seroreversion up to age 24 months
- Postnatal HIV infection in HIV-exposed children with prior negative virologic tests for whom there are additional HIV transmission risks
- HIV-2 and non-subtype B HIV-1
Non-breastfed, perinatally HIV-exposed infants with no other HIV transmission risk and no clinical or virologic laboratory evidence of HIV infection may have residual HIV antibodies for up to age 24 months (these infants are called late seroreverters).52-55
In one study 14% seroreverted after age 18 months.50
These children may have positive enzyme-linked immunosorbent assay (EIA) results but indeterminate confirmatory antibody tests (Western Blot or IFA). In such cases, repeat antibody testing at a later time would document seroreversion.
In contrast to late seroreverters, in rare situations, postnatal HIV infections have been reported in HIV-exposed infants who had prior negative HIV virologic tests. This occurs in infants who become infected through an additional risk after completion of testing (see Diagnostic Testing in Children with Non-Perinatal HIV Exposure section below). If a confirmatory HIV antibody test is positive at age 18 months, repeated virologic testing will distinguish between residual antibodies in uninfected, late seroreverting children and true infection.
Postnatal HIV exposure can occur if an HIV-infected mother breastfeeds her infant. 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 do so, and women who learn of their HIV diagnosis only after initiating breastfeeding. Diagnostic testing to rule out acquisition of HIV through breast milk will only be accurate after breastfeeding has completely ceased. The timing of testing in such situations is discussed below in Diagnostic Testing in Children with Non-Perinatal HIV Exposure.
Another example where there can be postnatal HIV exposure is when an HIV-infected caregiver premasticates or prechews solid food before feeding it to an infant. This practice has been documented to result in HIV transmission.41,54-58
In such exposed children, both screening EIA and confirmatory antibody tests (EIA, Western Blot or IFA) may be positive at 18 months. Another study documented very rare cases of late postnatal infection without identified risk factors, suggesting the possibility of intrafamilial HIV transmission.59
Children with non-subtype B HIV-1 infection and children with HIV-2 infection may have persistent positive EIA tests and indeterminate confirmatory antibody tests.23-25,60
Situations in which such infections may be suspected and the diagnostic approach to them are discussed above in in Issues Related to Diagnosis of Group M Non-Subtype B and Group O HIV-1 Infections and Issues Related to Diagnosis of HIV-2 Infection.
Diagnostic Testing in Children with Non-Perinatal HIV Exposure
Breastfeeding is a known route of HIV transmission. Infants who are breastfed by HIV-infected women, including those diagnosed with acute HIV infection during breastfeeding or who breastfed before knowing their HIV diagnosis should undergo immediate HIV virologic testing and breastfeeding should be discontinued. Follow-up virologic testing should be performed at 4 to 6 weeks, 3 and 6 months after breastfeeding cessation if the initial tests are negative.61,62
HIV antibody testing of an infant to assess for HIV exposure would not be helpful if the mother acquired HIV infection after giving birth. In that situation, an infant would be HIV antibody-negative but still at risk of acquiring HIV infection through breastfeeding and counseling to cease breastfeeding should be provided.
Perinatal HIV acquisition accounts for the majority of HIV infections in children, but providers may need to evaluate children exposed to HIV through other routes, such as sexual abuse, or because they were adopted from countries in which parenteral exposure to HIV via contaminated blood products is a possibility. In such cases, maternal HIV status may be negative or unknown. Receipt of solid food premasticated or prechewed by an HIV-infected caregiver also has been documented to be associated with risk of HIV transmission.41,54-58
Finally, acquisition of HIV is possible through accidental needlesticks or behavioral risks, such as sexual activity or injection drug use in older children.
Screening HIV antibody assays in conjunction with a confirmatory antibody test or virologic detection test should be performed on children who are suspected to have HIV infection because of clinical or laboratory findings consistent with HIV. Additional virologic testing may be necessary if acute HIV infection or end-stage AIDS is suspected because antibody testing can be negative in these situations.
- Schneider E, Whitmore S, Glynn KM, et al. Revised surveillance case definitions for HIV infection among adults, adolescents, and children aged <18 months and for HIV infection and AIDS among children aged 18 months to <13 years--United States, 2008. MMWR Recomm Rep. Dec 5 2008;57(RR-10):1-12. Available at http://www.ncbi.nlm.nih.gov/pubmed/19052530.
- Donovan M, Palumbo P. Diagnosis of HIV: challenges and strategies for HIV prevention and detection among pregnant women and their infants. Clin Perinatol. Dec 2010;37(4):751-763, viii. Available at http://www.ncbi.nlm.nih.gov/pubmed/21078448.
- McIntosh K, Pitt J, Brambilla D, et al. Blood culture in the first 6 months of life for the diagnosis of vertically transmitted human immunodeficiency virus infection. The Women and Infants Transmission Study Group. J Infect Dis. Oct 1994;170(4):996-1000. Available at http://www.ncbi.nlm.nih.gov/pubmed/7930747.
- 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. Apr 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. Scandinavian journal of infectious diseases. Mar 2012;44(3):209-215. Available at http://www.ncbi.nlm.nih.gov/pubmed/22074445.
- 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. Jan 2009;123(1):175-187. Available at http://www.ncbi.nlm.nih.gov/pubmed/19117880.
- American Academy of Pediatrics Committee on Pediatric AIDS. HIV testing and prophylaxis to prevent mother-to-child transmission in the United States. Pediatrics. Nov 2008;122(5):1127-1134. Available at http://www.ncbi.nlm.nih.gov/pubmed/18977995.
- 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. Jan 2012;160(1):60-66 e61. Available at http://www.ncbi.nlm.nih.gov/pubmed/21868029.
- 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. Jul 2012;50(7):2373-2377. Available at http://www.ncbi.nlm.nih.gov/pubmed/22518871.
- Lambert JS, Harris DR, Stiehm ER, et al. Performance characteristics of HIV-1 culture and HIV-1 DNA and RNA amplification assays for early diagnosis of perinatal HIV-1 infection. J Acquir Immune Defic Syndr. Dec 15 2003;34(5):512-519. Available at http://www.ncbi.nlm.nih.gov/pubmed/14657763.
- Nesheim S, Palumbo P, Sullivan K, et al. Quantitative RNA testing for diagnosis of HIV-infected infants. J Acquir Immune Defic Syndr. Feb 1 2003;32(2):192-195. Available at http://www.ncbi.nlm.nih.gov/pubmed/12571529.
- Young NL, Shaffer N, Chaowanachan T, et al. Early diagnosis of HIV-1-infected infants in Thailand using RNA and DNA PCR assays sensitive to non-B subtypes. J Acquir Immune Defic Syndr. Aug 15 2000;24(5):401-407. Available at http://www.ncbi.nlm.nih.gov/pubmed/11035610.
- 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. May 15 2002;185(10):1409-1416. Available at http://www.ncbi.nlm.nih.gov/pubmed/11992275.
- Kerr RJ, Player G, Fiscus SA, Nelson JA. Qualitative human immunodeficiency virus RNA analysis of dried blood spots for diagnosis of infections in infants. J Clin Microbiol. Jan 2009;47(1):220-222. Available at http://www.ncbi.nlm.nih.gov/pubmed/19005148.
- Stevens WS, Noble L, Berrie L, Sarang S, Scott LE. Ultra-high-throughput, automated nucleic acid detection of human immunodeficiency virus (HIV) for infant infection diagnosis using the Gen-Probe Aptima HIV-1 screening assay. J Clin Microbiol. Aug 2009;47(8):2465-2469. Available at http://www.ncbi.nlm.nih.gov/pubmed/19474266.
- U.S. Food and Drug Administration. APTIMA HIV-1 RNA Qualitative Assay. 2009. Available at http://www.fda.gov/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/LicensedProductsBLAs/BloodDonorScreening/InfectiousDisease/ucm149922.htm.
- Walter J, Kuhn L, Semrau K, et al. Detection of low levels of human immunodeficiency virus (HIV) may be critical for early diagnosis of pediatric HIV infection by use of dried blood spots. J Clin Microbiol. Sep 2009;47(9):2989-2991. Available at http://www.ncbi.nlm.nih.gov/pubmed/19625479.
- 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. Apr 2011;49(4):1642-1645. Available at http://www.ncbi.nlm.nih.gov/pubmed/21346052.
- Osmanov S, Pattou C, Walker N, et al. Estimated global distribution and regional spread of HIV-1 genetic subtypes in the year 2000. J Acquir Immune Defic Syndr. Feb 1 2002;29(2):184-190. Available at http://www.ncbi.nlm.nih.gov/pubmed/11832690.
- 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. Jun 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. Jun 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. Mar 2013;56(6):880-887. Available at http://www.ncbi.nlm.nih.gov/pubmed/23223603.
- 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. Sep 2002;21(9):885-886. Available at http://www.ncbi.nlm.nih.gov/pubmed/12380591.
- 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. Feb 2005;24(2):183-184. Available at http://www.ncbi.nlm.nih.gov/pubmed/15702052.
- 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. Feb 1 2002;34(3):417-418. Available at http://www.ncbi.nlm.nih.gov/pubmed/11774090.
- 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. Aug 15 2006;42(5):614-619. Available at http://www.ncbi.nlm.nih.gov/pubmed/16868498.
- Swanson P, de Mendoza C, Joshi Y, et al. Impact of human immunodeficiency virus type 1 (HIV-1) genetic diversity on performance of four commercial viral load assays: LCx HIV RNA Quantitative, AMPLICOR HIV-1 MONITOR v1.5, VERSANT HIV-1 RNA 3.0, and NucliSens HIV-1 QT. J Clin Microbiol. Aug 2005;43(8):3860-3868. Available at http://www.ncbi.nlm.nih.gov/pubmed/16081923.
- 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.
- 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. Jan 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. Dec 2011;52 Suppl 1:S77-82. Available at http://www.ncbi.nlm.nih.gov/pubmed/22036041.
- 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. Jan 2012;53(1):33-37. Available at http://www.ncbi.nlm.nih.gov/pubmed/22051503.
- 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. Mar 2012;50(3):831-836. Available at http://www.ncbi.nlm.nih.gov/pubmed/22170927.
- Campbell-Yesufu OT, Gandhi RT. Update on human immunodeficiency virus (HIV)-2 infection. Clin Infect Dis. Mar 15 2011;52(6):780-787. Available at http://www.ncbi.nlm.nih.gov/pubmed/21367732.
- Torian LV, Eavey JJ, Punsalang AP, et al. HIV type 2 in New York City, 2000-2008. Clin Infect Dis. Dec 1 2010;51(11):1334-1342. Available at http://www.ncbi.nlm.nih.gov/pubmed/21039219.
- 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. Nov 12 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. Mar 27 2011;25(6):865-867. Available at http://www.ncbi.nlm.nih.gov/pubmed/21358376.
- Nasrullah M, Ethridge SF, Delaney KP, et al. Comparison of alternative interpretive criteria for the HIV-1 Western blot and results of the Multispot HIV-1/HIV-2 Rapid Test for classifying HIV-1 and HIV-2 infections. J Clin Virol. Dec 2011;52 Suppl 1:S23-27. Available at http://www.ncbi.nlm.nih.gov/pubmed/21993309.
- Wesolowski LG, Delaney KP, Hart C, et al. Performance of an alternative laboratory-based algorithm for diagnosis of HIV infection utilizing a third generation immunoassay, a rapid HIV-1/HIV-2 differentiation test and a DNA or RNA-based nucleic acid amplification test in persons with established HIV-1 infection and blood donors. J Clin Virol. Dec 2011;52 Suppl 1:S45-49. Available at http://www.ncbi.nlm.nih.gov/pubmed/21995934.
- 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. Oct 1 2010;51(7):833-843. Available at http://www.ncbi.nlm.nih.gov/pubmed/20804413.
- Centers for Disease C, Prevention. HIV-2 Infection Surveillance--United States, 1987-2009. MMWR Morb Mortal Wkly Rep. Jul 29 2011;60(29):985-988. Available at http://www.ncbi.nlm.nih.gov/pubmed/21796096.
- Centers for Disease C, Prevention. Premastication of food by caregivers of HIV-exposed children--nine U.S. sites, 2009-2010. MMWR Morb Mortal Wkly Rep. Mar 11 2011;60(9):273-275. Available at http://www.ncbi.nlm.nih.gov/pubmed/21389930.
- Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from the Centers for Disease Control and Prevention, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. 2013. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/adult_oi.pdf. Accessed May 28th, 2013.
- Robinson LG, Fernandez AD. Clinical care of the exposed infants of HIV-infected mothers. Clin Perinatol. Dec 2010;37(4):863-872, x-xi. Available at http://www.ncbi.nlm.nih.gov/pubmed/21078455.
- 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. Apr 9 2013. Available at http://www.ncbi.nlm.nih.gov/pubmed/23574775.
- Bryson YJ, Luzuriaga K, Sullivan JL, Wara DW. Proposed definitions for in utero versus intrapartum transmission of HIV-1. N Engl J Med. Oct 22 1992;327(17):1246-1247. Available at http://www.ncbi.nlm.nih.gov/pubmed/1406816.
- Mayaux MJ, Burgard M, Teglas JP, et al. Neonatal characteristics in rapidly progressive perinatally acquired HIV-1 disease. The French Pediatric HIV Infection Study Group. JAMA. Feb 28 1996;275(8):606-610. Available at http://www.ncbi.nlm.nih.gov/pubmed/8594241.
- Shearer WT, Quinn TC, LaRussa P, et al. Viral load and disease progression in infants infected with human immunodeficiency virus type 1. Women and Infants Transmission Study Group. N Engl J Med. May 8 1997;336(19):1337-1342. Available at http://www.ncbi.nlm.nih.gov/pubmed/9134873.
- Ioannidis JP, Tatsioni A, Abrams EJ, et al. Maternal viral load and rate of disease progression among vertically HIV-1-infected children: an international meta-analysis. AIDS. Jan 2 2004;18(1):99-108. Available at http://www.ncbi.nlm.nih.gov/pubmed/15090835.
- Connor EM, Sperling RS, Gelber R, et al. Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. Pediatric AIDS Clinical Trials Group Protocol 076 Study Group. N Engl J Med. Nov 3 1994;331(18):1173-1180. Available at http://www.ncbi.nlm.nih.gov/pubmed/7935654.
- 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. Nov 2012;55(9):1255-1261. Available at http://www.ncbi.nlm.nih.gov/pubmed/22851494.
- 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. Jun 2009;103(6):620-626. Available at http://www.ncbi.nlm.nih.gov/pubmed/19339030.
- 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. Nov 1 2007;46(3):332-337. Available at http://www.ncbi.nlm.nih.gov/pubmed/17786126.
- 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. Apr 2009;28(4):273-276. Available at http://www.ncbi.nlm.nih.gov/pubmed/19289981.
- Gaur AH, Freimanis-Hance L, Dominguez K, et al. Knowledge and practice of prechewing/prewarming food by HIV-infected women. Pediatrics. May 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. Jan 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. Sep 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. Feb 1 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. Mar 2013;27(3):142-145. Available at http://www.ncbi.nlm.nih.gov/pubmed/23477456.
- Frange P, Burgard M, Lachassinne E, et al. Late postnatal HIV infection in children born to HIV-1-infected mothers in a high-income country. AIDS. Jul 17 2010;24(11):1771-1776. Available at http://www.ncbi.nlm.nih.gov/pubmed/20479638.
- Haas J, Geiss M, Bohler T. False-negative polymerase chain reaction-based diagnosis of human immunodeficiency virus (HIV) type 1 in children infected with HIV strains of African origin. J Infect Dis. Jul 1996;174(1):244-245. Available at http://www.ncbi.nlm.nih.gov/pubmed/8656008.
- 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. 2012. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/PerinatalGL.pdf. Accessed on January 5, 2014.
- Committee On Pediatric AIDS. Infant feeding and transmission of human immunodeficiency virus in the United States. Pediatrics. Feb 2013;131(2):391-396. Available at http://www.ncbi.nlm.nih.gov/pubmed/23359577.