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SAMJ: South African Medical Journal

On-line version ISSN 2078-5135
Print version ISSN 0256-9574

SAMJ, S. Afr. med. j. vol.104 n.11 Pretoria Nov. 2014

 

HIV infection is confirmed and monitored by means of viral load (VL) testing, which is currently performed on either the Abbott RealTime HIV-1 assay (Abbott Molecular, USA) (limit of detection <40 RNA copies/ml) or the COBAS AmpliPrep/ COBAS TaqMan HIV-1 test, v2.0 (Roche Molecular Systems, USA) (limit of detection <20 copies/ml). Both are tested on plasma.

An alternative HIV-1 RNA test was used in case 3 at 10 weeks of age. A SANAS-accredited private laboratory performed an HIV-1 RNA VL on plasma using the VERSANT HIV-1 RNA 3.0 assay (branched DNA) (Siemens Healthcare Diagnostics, USA).

 

Results

Case 1

An infant given up for adoption at birth was diagnosed with in utero HIV infection on the basis of a positive HIV-1 PCR result within 48 hours of birth and a confirmatory HIV-1 VL of 92 920 copies/ml. The birth mother had been on and off cART for 2 years. A cART regimen of abacavir, lamivudine and ritonavir-boosted lopinavir was initiated at 16 days of age. On routine follow-up at 31 weeks of age the child was found to be virologically suppressed with normal growth and development. At 36 weeks, the social workers responsible for placement of the child requested repeat HIV testing prior to adoption. HIV-1 DNA PCR testing performed on PBMCs was negative. At 40 weeks of age, the HIV-1 PCR and VL were repeated and tested negative and less than detectable, respectively.

Case 2

Case 2 documents the HIV-1 PCR results of an exclusively formula-fed infant who received nevirapine syrup as part of the PMTCT programme (the mother, who was on cART, died shortly after delivery). At 6 weeks of age the infant tested HIV-1 PCR-positive and was subsequently referred to paediatric HIV services for confirmatory testing and cART initiation. At 8 weeks of age, cART was initiated and a specimen sent for confirmatory HIV-1 qualitative PCR testing. The patient was still being given daily nevirapine syrup at the time of testing. An indeterminate HIV-1 PCR result led to an HIV-1 VL being performed at 10 weeks, which was reported as less than detectable. A repeat HIV-1 PCR and VL were then performed at 12 weeks, with negative and less than detectable results, respectively. At 18 weeks further specimens were taken and HIV-1 PCR testing was performed at two different laboratories, both yielding indeterminate results.

Case 3

A breastfed infant whose mother had been initiated on a cART regimen of tenofovir, lamivudine and efavirenz during late pregnancy presented at 4 weeks of age with a lower respiratory tract infection complicated by empyema. HIV-1 qualitative PCR testing was performed four times between 4 and 6 weeks of age on account of repeatedly indeterminate results. Initiation of cART was further delayed because of a low baseline HIV-1 VL result of 270 copies/ml. This was repeated the following week, with a similarly low VL of 255 copies/ml. At the time, national guidelines for the initiation of ART in infants required a confirmatory HIV VL of >10 000 RNA copies/ ml. Concerns about possible laboratory contamination or suboptimal amplification prompted the decision to perform branched DNA testing, which although yielding a higher VL (2 504 copies/ml) was not considered significant for diagnostic purposes. An additional HIV-1 qualitative test performed at 12 weeks yielded another indeterminate result. The HIV diagnosis was finally confirmed at 18 weeks with a VL of 268 840 copies/ml. This was performed on the same assay as the initial HIV VL testing that had yielded low RNA titres. Internal control suppression was not noted with any of these results.

 

Discussion

The cases described above demonstrate that cART in infants can be associated with loss of detectability of HIV, leading to 'false-negative' HIV-1 PCR results. Similarly, current PMTCT practices may lead to repeatedly indeterminate results, probably because of ART suppressing the HIV VL below diagnostic threshold values, with subsequent delays in initiation of cART.

Case 1 is a complex case, with the prospect of adoption complicating counselling to caregivers, social services and future adoptive parents. Although a clear diagnosis of HIV was made at birth on the basis of a positive HIV-1 PCR result and a confirmatory VL of 92 920 copies/ml, social services requested further HIV testing at 36 weeks as part of a medical evaluation prior to adoption. Repeat HIV-1 PCR testing once cART has been initiated can, however, result in a loss of detectability of HIV-1 on account of supressed target DNA and RNA.[6] The subsequent inability to detect HIV early in the course of treatment can prove challenging as far as counselling and retention in care are concerned. The problem has become even more complex now that the possibility of a functional cure has entered the equation.[14]

Diverse practices in adoption services, especially with regard to the diagnosis of HIV and the interpretation of HIV results in the context of cART, may potentially have devastating consequences for both the infant and the adoptive parents. Although SA has approximately 3.8 million orphans[15] and the current legislative framework supports adoption as the preferred form of alternative care, no national guidelines regarding the appropriate medical evaluation of children prior to adoption have yet been developed.[16]

Similar difficulties to those in case 1 can be experienced when trying to confirm HIV status in infants already initiated on cART where the results of baseline testing are either uncertain or not available. The second case highlights the difficulties of confirmatory testing in the context of 'fast-track' entry into the treatment programme. According to the current national testing algorithm, infants who test positive with an HIV-1 PCR assay require a detectable HIV VL to confirm infection. However, these guidelines state that cART initiation should not be delayed by waiting for the VL result and that it should be commenced within 7 days of receiving a positive HIV-1 PCR result.[2,3] This can cause diagnostic difficulties if initial confirmatory testing yields indeterminate results or was performed some time after initiation of cART.

Although the potential for cART to compromise the sensitivity of HIV-1 PCR assays has been described in the medical literature,[6] it appears to be under-appreciated by both clinicians and the lay public. Of similar concern is the effect PMTCT regimens may have on the sensitivity of HIV-1 PCR assays. Both case 2 and case 3 suggest that diagnostic difficulties can be associated with different types of prophylactic infant ART exposure. Both direct exposure in the form of infant nevirapine syrup (case 2) and passively ingested ART in breastmilk when a mother is taking cART (case 3) are associated with indeterminate HIV-1 PCR results. Although these cases do not amount to incontrovertible proof of PMTCT regimens compromising PCR assay sensitivity, they are supported by similar reports in the medical literature.[17] Furthermore, a recent publication suggests that HIV-1 PCR testing with the CAP/CTM assay 2 weeks after single-dose nevirapine exposure resulted in a markedly reduced sensitivity of 83%, well below WHO standards.[18,19] Of particular concern is the possibility that combination infant ART exposure (i.e. simultaneous ART ingestion in breastmilk and in the form of nevirapine syrup, as per current guidelines) may be sufficient to suppress HIV-1 replication below the limit of detection of the CAP/CTM assay. This is of further relevance in health settings such as SA that utilise DBS specimens, as a lower specimen volume (approximately 60 µl) than for whole EDTA blood (100 µl) is tested.

Case 3 also demonstrates how repeatedly indeterminate HIV-1 PCR results can delay cART initiation, potentially resulting in a poor clinical outcome. HIV-1 PCR testing at 6 weeks has already been found to delay cART initiation in SA's public health sector beyond the time of peak HIV-related infant mortality.[20] Further delays may therefore have fatal consequences, or other serious implications including failure to follow up, the development of drug resistance, negative psychosocial consequences for the caregiver, and considerable cost implications for the public health sector. Although ART levels in untreated breastfed infants have not been sufficiently studied, it has been demonstrated that ART taken by nursing mothers is expressed in significant concentrations in breastmilk.[21] During weaning the decreased intake of breastmilk implies subsequent reduction of ART exposure. This could have led to the significantly elevated VL in case 3, supporting the possibility that ART secretion in breastmilk may compromise the sensitivity of the HIV-1 PCR assay.

Essentially, all three cases raise concerns regarding the sensitivity of HIV-1 PCR assays in the context of ART exposure. They also alert us to the possibility of overestimation of the efficacy of SA's PMTCT programme, as the data available are for children '[22] Importantly, earlier validation studies of the CAP/CTM assay were performed at a time when less ART-intensive PMTCT regimens were provided to infants. Although improvements in the sensitivity of the assay may address these challenges effectively, validation studies are needed to assess performance in the context of SA's PMTCT programme. This is of particular relevance as SA embarks on rolling out a new version of the current PCR assay, the CAP/CTM v2.0, which has a reportedly more sensitive limit of detection than the previous assay.'[23]

 

Conclusion

We have described a case series of infants with different ART exposures in whom the diagnosis of HIV or the confirmation thereof led to uncertainty. These cases suggest that children exposed to ART can have false-negative and repeatedly indeterminate HIV-1 PCR results, posing significant challenges to the current PMTCT and early infant diagnostic programmes in SA. Further studies are needed to re-evaluate the sensitivity of HIV-1 PCR assays in the context of ART exposure, and infant diagnostic algorithms need to be reviewed accordingly.

Acknowledgments. We thank the diagnostic staff at the Department of Medical Virology, Tshwane Academic Division of the National Health Laboratory Service, for their valuable contribution, Drs Sergio Carmona and Michelle Bronze for their kind assistance with testing samples of one of the cases described, and Denis Dionysiou for assistance with Fig. 1. We also thank Prof. Gayle Sherman for reviewing the manuscript.

 

References

1. Violari A, Cotton MF, Gibb DM, et al. Early antiretroviral therapy and mortality among HIV-infected infants. N Engl J Med 2008;359(21):2233-2244. [http://dx.doi.org/10.1056/NEJMoa0800971]        [ Links ]

2. South African National Department of Health. The South African Antiretroviral Treatment Guidelines 2013: PMTCT Guidelines. Pretoria: Department of Health, 2013. at http://web.up.acza/sitefiles/file/45/1335/877/PMTCT%20guidelines_March%202013_DoH.pdf (accessed 13 May 2013).         [ Links ]

3. South African National Department of Health. The South African Antiretroviral Treatment Guidelines 2013. Pretoria: Department of Health, 2013.http://www.doh.gov.za/docs/policy/2013/ART_Treatment_GuidelinesFinal_25March2013.pdf(accessed 11 October 2013).         [ Links ]

4. World Health Organization. Guidelines on HIV and Infant Feeding 2010. Principles and Recommendations for Infant Feeding in the Context of HIV and a Summary of Evidence. Geneva: World Health Organization, 2010. http://www.who.int/maternal_child_adolescent/documents/9789241599535/en/ (accessed 23 December 2013).         [ Links ]

5. The Tshwane declaration of support for breastfeeding in South Africa. South African Journal of Clinical Nutrition 2011;24(4):214.         [ Links ]

6. Persaud D, Ray SC, Kajdas J, et al. Slow human immunodeficiency virus type 1 evolution in viral eservoirs in infants treated with effective antiretroviral therapy. AIDS Res Hum Retroviruses 2007;23(3):381-390. 'http://dx.doi.org/10.1089/aid.2006.01751        [ Links ]

7. Dunn DT, Simonds RJ, Bulterys M, et al. Interventions to prevent vertical transmission of HIV-1: Effect on viral rate in early infant samples. AIDS 2000;14(10):1421-1428. [http://dx.doi.org/10.1097/00002030-200007070-00016]        [ Links ]

8. Prasitwattanaseree S, Lallemant M, Costagliola D, Jourdain G, Mary JY. Influence of mother and infant zidovudine treatment duration on the age at which HIV infection can be detected by polymerase chain reaction in infants. Antivir Ther 2004;9(2):179-185.         [ Links ]

9. Burgard M, Blanch 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. [http://dx.doi.org/10.1016/j.jpeds.2011.06.0531        [ Links ]

10. Roche® COBAS® AmpliPrep/COBAS® TaqMan HIV-1 Qual Test 'package insert!. Branchburg NJ: Roche, 2010.         [ Links ]

11. Stevens W, Erasmus L, Moloi M, et al. Performance of a novel human immunodeficiency virus (HIV) type 1 total nucleic acid-based real-time PCR assay using whole blood and dried blood spots for diagnosis of HIV ininfants. J Clin Microbiol 2008;46(12):3941-3945. [http://dx.doi.org/10.1128/JCM.00727-09]        [ Links ]

12. Maritz J, Preiser W, van Zyl GU. Establishing diagnostic cut-off criteria for the COBAS mpliPrep/COBAS TaqMan HIV-1 qualitative test through validation against the Amplicor DNA testv1.5 for infant diagnosis using dried blood spots. J Clin Virol 2012:53(2):106-109. [http://dx.doi.org.10.1016/j.jcv.2011.12.002]        [ Links ]

13. Maritz J, van Zyl GU, Preiser W. Irreproducible positive results on the Cobas Ampliprep/Cobas TaqMan HIV- 1 Qual Test are different qualitatively from confirmed positive results. J Med Virol 2014:86(1):82-87. [http://dx.doi.org/10.1002/jmv.23811]        [ Links ]

14. Persaud D, Gay H, Ziemniak C, et al. Absence of detectable HIV-1 viremia after treatment cessation in an infant. N Engl J Med 2013:369(19):1828-1835. [http://dx.doi.org/10.1056/NEJMoa1302976]        [ Links ]

15. Meintjes H, Hall K. Demography of South Afiicas children. In: Hall K, Woolard I, Lake L, et al., eds. South African Child Gauge 2012. Cape Town: Children's Institute, University of Cape Town, 2012:82-85. http://www.ci.org.za/index.php?option=com_content&view=article&id=997&Itemid=399 (accessed 12 June 2013).         [ Links ]

16. Haeri Mazanderani AF, du Plessis NM, Lumb J, et al. Recommendations for the medical evaluation of children prior to adoption in South Africa. S Afr Med J 2014:104(8):544-549. [http://dx.doi.org/10.7196/SAMJ.7958]        [ Links ]

17. Connolly MD, Rutstein RM, Lowenthal ED. Virologic testing in infants with perinatal exposure to HIV receiving multidrug prophylaxis. Pediatr Infect Dis J 2013:32(2):196-197. [http://dx.doi.org/10.1097/INF.0b013e3182787c29]zvh        [ Links ]

18. 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):2373-7237. [http://dx.doi.org.10.1128/JCM.00431-12]        [ Links ]

19. World Health Organization. WHO Recommendations on the Diagnosis of HIV Infection in Infants and Children. Geneva: WHO, 2010. http://whqlibdoc.who.int/publications/2010/9789241599085_eng.pdf(accessed 23 December 2013).         [ Links ]

20. Lilian RR, Kalk E, Technau K-G, 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 2013:32(10):1080- 1085. [http://dx.doi.org/10.1097/INF.0b013e318290622e]        [ Links ]

21. Shapiro RL, Holland DT, Capparelli E, et al. Antiretroviral concentrations in breast-feeding infants of women in Botswana receiving antiretroviral treatment. J Infect Dis 2005:192(5):720-727. [http://dx.doi.org/10.1086/432483]        [ Links ]

22. Goga AE, Dinh T-H, Jackson DJ, for the SAPMTCTE study group. Evaluation of the effectiveness of the national prevention of mother-to-child transmission (PMTCT) programme measured at six weeks postpartum in South Africa, 2010. South African Medical Research Council, National Department of Health of South Africa and PEPFAR/US Centers for Disease Control and Prevention, 2012.http://www.hst.org.za/publications/evaluation-effectiveness-national-prevention-mother-child-transmission-pmtct-programme- (accessed 24 June 2013).         [ Links ]

23. Roche® COBAS® AmpliPrep/COBAS® TaqMan HIV-1 Qualitative Test, version 2.0 'package insert1. Branchburg, NJ: Roche, 2013.         [ Links ]

 

 

Correspondence:
A F Haeri Mazanderani
ahmad.haerimazanderani@up.ac.za

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CONTINUING MEDICAL EDUCATION
GUEST EDITORIAL

 

Climate change: One of the greatest threats to public health in the 21st century

 

 

The impact of climate change on human health and well-being has already been observed. Direct effects such as those related to heat, cold, floods, storms and solar ultraviolet radiation have been documented.[1] Some vector-, food- and water-borne diseases and other infectious diseases influenced by ecosystems are likely to increase in incidence. Respiratory health is affected by near-surface ozone exposures, episodes of acute air pollution, and aero-allergens. Indirect health impacts also exist. For example, changes in agricultural production, and loss of crop yield and the nutritional value of food have detrimental effects on nutrition. Increasing ambient temperatures can lead to loss of work capacity and occupational health concerns. The impact on mental health, mass migration, conflict and violence associated with changes in climate should not be underestimated.

South Africa (SA) may be considered as one of the countries facing the greatest challenges regarding climate change and health from threats of rising sea levels to drought and flooding. Current projections suggest a higher rise in temperature in SA than the global average.[2-4] This may lead to direct effects, including increased headaches, nausea, exhaustion, heat stroke and even mortality. In addition, atmospheric changes in air pollution may also be affected, which aggravate existing conditions of asthma and allergic rhinitis. Changes in health-support needs and services may be required, e.g. reduced availability and quality of water, and food security risks decreasing an individual's ability to cope with existing and emerging diseases. The increasing occurrence of extreme weather events, together with loss of property and family support, may cause anxiety, depression and stress. Such events may also cause damage to traffic infrastructure, leading to an increase in the incidence and severity of road traffic accidents, currently among the top five causes of premature death in the SA.

The deterioration of environmental conditions may lead to population displacement and immigration into SA from neighbouring southern African countries, resulting in increased pressure on services and local environmental conditions. Violence and interpersonal crime, already a major cause of morbidity and mortality in SA, may increase. Occupational climate health-related risks are a serious concern. The mining and farming sectors are particularly susceptible to the threat of warmer temperatures, leading to heat exhaustion, inability to work, and loss of productivity.

This month's CME aims to highlight some of the impacts of climate change on human health in SA. A collaborative review article[6] gives an overview of the Fifth Assessment Report of Working Group II on Human health: Impacts, adaptation and co-benefits[1] and considers the issues pertinent to SA. The complex HIV/AIDS disease burden and its vulnerability to a changing climate are outlined by Prof. Akin Abayomi and Maureen Cowan.[7] In light of these expected health impacts, Dr Rebecca Garland[8] discusses the steps taken by SA to address the threats and risks of a changing climate on public health. Her article emphasises the need for action by all key stakeholders, including government agencies, healthcare professionals, researchers and community members to address effectively the challenges posed by climate change on public health. An article by Devin Bowles and Prof. Colin Butler[9] considers the so-called 'tertiary' health effects of climate change, which are socially, politically and economically mediated. Examples include increased under-nutrition, migration, conflict and health system strain. Prof. Tord Kjellstrom and colleagues[10] describe climate conditions in the workplace as occupational health hazards threatened by climate change.

 

 

C Y Wright

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