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Article

Viral Suppression and Resistance in a Cohort of Perinatally-HIV Infected (PHIV+) Pregnant Women

1
Hospital Federal dos Servidores do Estado, Rio de Janeiro 20221-161, Brazil
2
School of Medicine, David Geffen University of California, 10833 Le Conte Avenue, Los Angeles, CA 90095, USA
*
Author to whom correspondence should be addressed.
Int. J. Environ. Res. Public Health 2016, 13(6), 568; https://0-doi-org.brum.beds.ac.uk/10.3390/ijerph13060568
Submission received: 19 April 2016 / Revised: 25 May 2016 / Accepted: 26 May 2016 / Published: 7 June 2016
(This article belongs to the Special Issue Pediatric Infectious Diseases)

Abstract

:
Our objective was to describe viral suppression and antiretroviral (ARV) resistance mutations in an ongoing cohort of perinatally-infected HIV+ (PHIV+) pregnant women. Descriptive analysis was performed using SPSS 18.0. From 2011 to 2014, we followed 22 PHIV+ pregnant women. Median age at prenatal entry was 19 years (Interquartile range (IQR) 17.6–21.0); 86% had an AIDS diagnosis; 81% had disclosed their HIV status to partner 11. The median age at HIV diagnosis was 8.3 y (IQR 4.0–13.6), the median age at sexual debut was 16 years (IQR 14–18). At the time of prenatal care initiation, four (18%) were on their first antiretroviral treatment (ART), eight (36%) in their second regimen and nine (41%) in their third regimen or beyond, and one had no data. Seventeen of 22 (77%) had HIV-viral load (VL) > 50 copies/mL at prenatal care entry, 16 had a genotyping exam performed. Seventeen of 22 PHIV+ had VL results near delivery: 7/17 (41%) had VL < 50 copies/mL. Among those who had genotyping at prenatal entry, 11/16 (69%) had mutations associated with ARV resistance. The most frequent major mutations were K103N, M184V, T215, M41L, D67N at reverse transcriptase gene and M46, I54V and V82A at protease gene. No vertical transmissions occurred. Management of pregnancy among PHIV+ is challenging. Individualized ART are needed to achieve viral suppression in a highly ART-exposed subpopulation.

1. Introduction

Individuals with perinatally-acquired human immunodeficiency virus type 1 (HIV) infection (PHIV+) are frequently diagnosed and started on antiretroviral therapy (ART) during the first months or years of life. The global expansion in the use of pediatric ART has resulted in a significant decrease in mortality rates among PHIV+, many of whom are now sexually active adolescents or young adults [1,2,3,4]. Very high viral loads during childhood and frequent family difficulties with sustaining high adherence to complex therapeutic regimens represent barriers to achieving and maintaining viral suppression in this population. An important consequence of this conjunction is the selection of resistant virus while successive changes in ART regimens occur during childhood [3,5,6,7,8]. When reaching adolescence, the need for a third line or salvage ART regimen is not rare among PHIV+. On the other hand, it has been observed that these adolescents have reproductive expectations similar to those of HIV-uninfected individuals [9,10], and limited therapeutic options for multi-drug resistant virus may affect the management of their treatment during pregnancy [11].
A resistance mutation is a mutation in a virus gene that allows the virus to become resistant to treatment with a particular antiviral drug. The term was first used in the management of HIV, the first virus in which genome sequencing was routinely used to look for drug resistance. Most antiretroviral drugs target HIV enzymes encoded by specific genes, reverse transcriptase, protease, or integrase. These enzymes are processed protein products of the HIV pol gene, a viral structural protein [12].
Our main objective was to describe viral suppression and ARV resistance mutations in an ongoing cohort of PHIV+ pregnant adolescents and women in Rio de Janeiro, Brazil.

2. Materials and Methods

We analyzed pregnancy data among confirmed PHIV+ women followed at a referral unit for prevention of mother-to-child transmission (PMTCT). Sociodemographic and clinical data, including treatment data, were collected routinely upon enrollment and during follow-up. Women with viral load (VL) > 1000 copies/mL at enrollment underwent HIV genotyping testing using the TRUGENE HIV-1 DNA sequencing platform. This platform detects HIV genomic mutations in the protease and reverse transcriptase regions of HIV, that are the most common mutations found among antiretroviral experienced individuals in our clinical settings [13]. The genotyping kit is a sequence-based assay target at codons 1–99 at the protease region and codons 40–247 at the reverse transcriptase region. Relevant ARV genotypic mutations were determined using the Stanford database. Descriptive analyses were performed using SPSS 18.0. This study was approved by the local Institutional Review Board (Approval Code 46937015.8.0000.5252).

3. Results

From February 2011 to August 2014, 630 HIV-infected pregnant women were enrolled in the PMTCT program. Among these, 22 (3.5%) were PHIV+. The median age at enrollment for the 22 PHIV+ was 18.5 years (Interquartile Range (IQR): 17.6–21.0), 71% were non-white, 86% had an AIDS-defining diagnosis according to CDC criteria, and 81% had disclosed their HIV status to the current sexual partner. The median number of years of formal education was nine years (IQR: 6.5–11).
The median age at HIV diagnosis was 8.3 years (IQR: 4.0–13.6), the median age at sexual debut was 16 years (IQR: 14–18), and 71% conceived while using antiretrovirals (ARV). At enrollment, 4/22 (18%) were on their first ART regimen, 8/22 (36%) on their second regimen, and 9/22 (41%) on at least their third ART regimen (1/22 had no ARV data available). Prenatal care was initiated at a median gestational age of 14 weeks (IQR: 9.0–20). At enrollment, 17/22 (77%) had a viral load (VL) > 50 copies/mL, and 17/22 (77%) had a VL assay result near delivery with 7/17 (41%) having a VL < 50 copies/mL at that time. Sixteen women had viral genotype testing at prenatal entry, and all received highly active antiretroviral therapy (HAART) during pregnancy. Table 1 shows the resistance profiles for these 16 PHIV+ subjects. Among those who had genotyping testing at enrollment, 11/16 (69%) had mutations associated with ARV resistance. The most frequent major mutations found among PHIV+ at enrollment were K103N (8/16, 50%) for NNRTIs; M184V (6/16, 38%), T215 (4/16, 25% ), M41L (3/16, 19%), and D67 (3/16, 19%) for NRTIs, and M46 (3/16, 19%), I54V (2/16, 13%) and V82A (2/16, 13%) for PIs.
All patients with VL > 50 copies/mL near delivery had a cesarean section. Among those with VL < 50 copies/mL, three had a vaginal delivery and four had a cesarean section for obstetric indications. There was one spontaneous abortion.
Infants’ mean gestational age was 38 weeks (IQR: 37–39), there were four preterm infants (18%). Mean birth weight was 2814 gr (IQR: 2.43–3.17) and mean birth length was 47 cm (IQR = 46–49). None of the infants were HIV-infected.

4. Discussion

A small proportion of pregnant women followed at our PMTCT unit acquired their HIV infection perinatally, and this analysis updates information available regarding this specific population. The main limitation of our study is the small sample, due to the rarity of this event, however this is a population of significant interest as more perinatally infected individuals have children of their own.
The median age of pregnant PHIV+ was similar to what was recently observed in the United States and Italy [11,14]. The median age of 8.3 years at HIV diagnosis was very close to 7.7 years reported for Italian pregnant PHIV+ [12], but slightly younger than age 10 years which we had observed in 2010 [4], pointing to a longer exposure time of ART use in the present population.
Among this group of PHIV+, we found a higher prevalence of diagnosis disclosure to sexual partners, as compared to PHIV+ in Africa and the UK/Ireland [10,15]. This is a very positive finding, which will likely positively impact the quality of life and outlook for these patients and newly established families.
At enrollment, only 5/22 (23%) of PHIV+ had a VL below 50 copies/mL, but close to delivery this percentage increased to 41%. Our results are comparable to those from a US cohort that found 60% of pregnant PHIV+ with a VL below 400 copies/mL [11] and worse than a cohort from the United Kingdom where only 33% of PHIV+ pregnant had a viral load above 50 copies/mL near delivery [14].
Most of our patients have been exposed to at least two ART regimens and the observed suboptimal viral suppression among PHIV+ at enrollment is probably associated with non-adherence to ART and the presence of viral resistance. In a systematic review that included studies published from 1990 to 2011 with 1980 PHIV+ on ART from 26 countries, Sánchez et al. [16] found drug resistance mutations in 78% of PHIV+, higher than the 69% noted in our study. These observations among perinatally-infected populations differ significantly from data in the general population of HIV-infected women. Our own group has reported ART resistance mutations in 15.6% of 231 HIV-infected women during pregnancy [13]. In our cohort, 8/16 (50%) and 3/16 (19%) had NNRTI and PI resistance mutations, respectively. Data from 211 adolescents in the United Kingdom exposed to ART showed 65% had mutations for NNRTIs, mainly K103N and Y181C, and 26% with mutations for PIs [3]. K103N mutation is in the reverse transcriptase gene region of HIV-1. It causes the hydrophobic pocket in which the NNRTI binds to inhibit enzyme activity in reverse transcriptase to close by means of a hydrogen bond. K103N is a nonpolymorphic mutation selected in patients receiving NVP and EFV. It reduces NVP and EFV susceptibility by about 50 and 20-fold, respectively [17]. Similarly, M184V confers high-level resistance to lamivudine, and is a discriminatory mutation. It occurs at or near the binding site of the reverse transcriptase gene, a common feature of mutations that confer resistance to NRTIs [12]. T215 confers resistance to zidovudine, and is also in the reverse transcriptase gene. It is one of the Thymidine Analog Mutations (TAMs), similarly to M41L, which is also a mutation conferring high level resistance to zidovudine, stavudine and some resistance to didanosine, abacavir and tenofovir. D67 is also an NRTI mutation in the RT gene, which confers resistance to zidovudine and stavudine. M46 is a protease inhibitor mutation associated with resistance to lopinavir/ritonavir and atazanavir/ritonavir. It is an HIV protease gene mutation [18]. 154 V is a mutation associated with protease inhibitor resistance, particularly nelfinavir [19]. Like the others, is located in the HIV pol gene. V82A is a mutation also associated with protease inhibitor resistance in the HIV protease region [20].
The gestational age of infants born to PHIV+ are similar to that described in cohorts in Italy and New York [12,21] where the proportions of preterm infants were 38% and 29%, higher than what we observed. Mean birth weight among our patients was higher than in these groups probably due to the smaller proportion of preterm infants.

5. Conclusions

Despite advances in HIV treatment, ART management during the pregnancies of PHIV+ is especially challenging. New drugs, effective counseling, strategies and interventions targeting patient retention and individualized ART regimens are needed and may be crucial to achieve viral suppression in a highly ART-exposed subpopulation with expected adherence difficulties.

Acknowledgments

The authors thank Jennifer Read from the National Institutes of Health for the review of English language.

Author Contributions

Maria Letícia Cruz elaborated the study, developed the project, supervised the data analysis and interpretation, and coordinated the writing committee of the article. Edwiges Santos worked on study elaboration, data collection and approved the final version of this article. Maria de Lourdes Benamor Teixeira was responsible for quantitative analysis and approved the final version of this article. Monica Poletti and Carolina de Sousa worked on the writing committee and approved the final version of this article. Maria Isabel Gouvea and Karin Nielsen-Saines worked on data analysis and approved the final version of this article. Esaú João worked on study development, data analysis, writing committee and approved the final version of this article.

Conflicts of Interest

The authors declare no conflict of interest.

Abbreviations

The following abbreviations are used in this manuscript:
PHIV+perinatally-HIV infected
ARVAntiretroviral
ARTAntiretroviral therapy
AIDSAcquired Immunodeficiency Syndrome
HIVHuman Immunodeficiency Virus
VLViral load
CDCCenters for Disease Control and Prevention
IQRInterquartile range
NNRTINon-nucleoside reverse transcriptase inhibitor
PIProtease inhibitor
TDFTenofovir
NFVNelfinavir
DDIDidanosine
RPVRilpivirine
ABCAbacavir
ZVDZidovudine
D4TEstavudine
3TCLamivudine
FTCEmtricitabine
DRVDarunavir
TPVTripanavir
ETVEtravirine
EFZEfavirenz
ATVAtazanavir
IDVIndinavir
SQVSaquinavir
NVPNevirapine
FSPFosamprenavir
LPVLopinavir

References

  1. Matida, L.H.; Ramos, N.A., Jr.; Moncau, J.E.C.; Marcopito, L.F.; Marques, H.H.S.; Succi, R.C.M.; Negra, D.N.; Hearst, N. Grupo Brasileiro de Estudo da Sobrevida em Crianças com AIDSAIDS por transmissão vertical: Análise de sobrevivência dos casos acompanhados entre 1983 e 2002 nas diferentes regiões do Brasil. Cad. Saúde Pública 2007, 23, S435–S444. [Google Scholar] [CrossRef] [PubMed]
  2. Judd, A.; Doerholt, K.; Tookey, P.A.; Sharland, M.; Riordan, A.; Esse Menson, E.; Novelli, V.; Lyall, E.G.H.; Masters, J.; Tudor-Williams, G.; et al. For the Collaborative HIV Paediatric Study (CHIPS) and the National Study of HIV in Pregnancy and Childhood (NSHPC). Morbidity, mortality, and response to treatment by children in the united kingdom and ireland with perinatally acquired HIV Infection during 1996–2006: Planning for teenage and adult care. Clin. Infect. Dis. 2007, 45, 918–924. [Google Scholar] [PubMed]
  3. Foster, C.; Judd, A.; Tookey, P.; Tudor-Williams, G.; Dunn, D.; Shingadia, D.; Butler, K.; Sharland, M.; Gibb, D.; Lyall, H. Collaborative HIV Paediatric Study (CHIPS).Young people in the United Kingdom and Ireland with perinatally acquired HIV: The pediatric legacy for adult services. AIDS Patient Care STDS 2009, 23, 159–166. [Google Scholar] [CrossRef] [PubMed]
  4. Cruz, M.L.S.; Cardoso, C.A.; João, E.C.; Gomes, I.M.; Abreu, T.F.; Oliveira, R.H.; Machado, E.S.; Dias, I.R.; Rubini, N.M.; Succi, R.M. Pregnancy in HIV-1 vertically-infected adolescents and young women: A new generation of HIV-exposed infants. AIDS 2010, 24, 2727–2731. [Google Scholar] [CrossRef] [PubMed]
  5. Dollfus, C.; Le, C.J.; Faye, A.; Blanche, S.; Briand, N.; Rouzioux, C.; Warszawski, J. Long-term outcomes in adolescents perinatally infected with HIV-1 and followed up since birth in the French perinatal cohort (EPF/ANRS CO10). Clin. Infect. Dis. 2010, 51, 214–224. [Google Scholar] [CrossRef] [PubMed]
  6. Zyl, G.U.; Rabie, H.; Nuttall, J.J.; Cotton, M.F. It is time to consider third-line options in antiretroviral-experienced paediatric patients? J. Int. AIDS Soc. 2011, 14, 55. [Google Scholar] [PubMed]
  7. Nglazi, M.D.; Kranzer, K.; Holele, P.; Kaplan, R.; Mark, D.; Jaspan, H.; Lawn, S.D.; Wood, R.; Bekker, L.G. Treatment outcomes in HIV-infected adolescents attending a community-based antiretroviral therapy clinic in South Africa. BMC Infect. Dis. 2012, 12, 21. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  8. Agwu, A.L.; Fairlie, L. Antiretroviral treatment, management challenges and outcomes in perinatally HIV-infected adolescents. J. Int. AIDS Soc. 2013, 16, 18579. [Google Scholar] [CrossRef] [PubMed]
  9. Fair, C.; Wiener, L.; Zadeh, S.; Albright, J.; Mellins, C.A.; Mancilla, M.; Tepper, V.; Trexler, C.; Purdy, J.; Osherow, J.; et al. Reproductive health decision-making in perinatally HIV-infected adolescents and young adults. Matern. Child Health J. 2013, 17, 797–808. [Google Scholar] [CrossRef] [PubMed]
  10. Lowenthal, E.D.; Bakeera-Kitaka, S.; Marukutira, T.; Chapman, J.; Goldrath, K.; Ferrand, R.A. Perinatally Acquired HIV Infection in Adolescents from Sub-Saharan Africa: A Review of Emerging Challenges. Available online: http://repository.upenn.edu/botswana_schol/15 (accessed on 9 March 2016).
  11. Phillips, U.K.; Rosenberg, M.G.; Dobroszycki, J.; Katz, M.; Sansary, J.; Golatt, M.A.; Wiznia, A.A.; Abadi, J. Pregnancy in women with perinatally acquired HIV-infection: Outcomes and challenges. AIDS Care 2011, 23, 1076–1082. [Google Scholar] [CrossRef] [PubMed]
  12. Clavel, F. Mechanisms of HIV drug resistance: A primer. In The PRN Notebook; Markowitz, M., Miller, V., Eds.; Physician Rechearch Network, Inc.: New York, NY, USA, 2004; Volume 9, pp. 3–7. [Google Scholar]
  13. Teixeira, M.L.B.; Nafae, S.; Yeganeh, N.; Santos, E.; Gouvea, M.I.; Joao, E.; Ceci, L.; Cruz, M.L.S.; Bressan, C.; Sidi, L.C.; et al. High rates of baseline antiretroviral resistance among HIV-infected pregnant women in an HIV referral center in Rio de Janeiro, Brazil. Int. J. STD AIDS 2015, 26, 922–928. [Google Scholar] [CrossRef] [PubMed]
  14. Calitri, C.; Gabiano, C.; Galli, L.; Chiappini, E.; Giaquinto, C.; Buffolano, W.; Genovese, O.; Esposito, S.; Bernardi, S.; Martino, M.D.; et al. For the Italian register for HIV infection in children. The second generation of HIV-1 vertically exposed infants: A case series from the Italian Register for paediatric HIV infection. BMC Infect. Dis. 2014, 14, 277. [Google Scholar] [CrossRef] [PubMed]
  15. Kenny, J.; Williams, B.; Prime, K.; Tookey, P.; Foster, C. Pregnancy outcomes in adolescents in the UK and Ireland growing up with HIV. HIV Med. 2012, 13, 304–308. [Google Scholar] [CrossRef] [PubMed]
  16. Sanchez, P.R.; Holguın, A. Drug resistance in the HIV-1-infected paediatric population worldwide: A systematic review. J. Antimicrob. Chemother. 2014, 69, 2032–2042. [Google Scholar] [CrossRef] [PubMed]
  17. Rhee, S.Y.; Liu, T.; Ravela, J.; Gonzales, M.J.; Shafer, R.W. Distribution of human immunodeficiency virus type 1 protease and reverse transcriptase mutation patterns in 4183 persons undergoing genotypic resistance testing. Antimicrob. Agents Chemother. 2004, 4, 3122–3126. [Google Scholar] [CrossRef] [PubMed]
  18. Stanford HIV Drug Resistance Database. Available online: http://hivdb.stanford.edu/pages/drugSummaries.html (accessed on 9 May 2016).
  19. Servais, J.; Plesséria, J.M.; Lambert, C.; Fontaine, E.; Robert, I.; Arendt, V.; Staub, T.; Schneide, F.; Hemme, R.; Schmit, J.C. Genotypic correlates of resistance to HIV-1 protease inhibitors on longitudinal data: The role of secondary mutations. Antivir. Ther. 2001, 6, 239–248. [Google Scholar] [PubMed]
  20. Heinrich, S.; Pia, D.; Heike, M. Effects of the V82A and I54V mutations on the dynamics and ligand binding properties of HIV-1 protease. J. Mol. Model. 2010, 16, 1577–1583. [Google Scholar]
  21. Jao, J.; Sigel, K.; Chen, K.T.; Rodriguez-Caprio, G.; Posada, R.; Shust, G.; Wisnivesky, J.; Abrams, E.J.; Sperling, R.S. Small for Gestational Age Birth Outcomes in Pregnant Women with Perinatally Acquired HIV. AIDS 2012, 26, 855–859. [Google Scholar] [CrossRef] [PubMed]
Table 1. Genotypic resistance mutations identified and antiretroviral resistance profile in pregnant women with perinatally-acquired HIV infection.
Table 1. Genotypic resistance mutations identified and antiretroviral resistance profile in pregnant women with perinatally-acquired HIV infection.
Patient NumberSubtypeProtease Inhibitors (PI)Reverse Transcriptase Inhibitor MutationsResistance Profile
Major MutationsMinor MutationsNRTINNRTILowIntermediateHigh
1NR0L10V00
2B0L10V00
3B0000
4B0K20T A71TM41L M184V T215DK101P K103NS Y188HLTDF
NFV
ABC ZVD D4T DDI3TC FTC
EFV ETR NVP RVP
5F10L10IM184V T215YV90I K103N E138ADDI
RPV
ABC ZVD D4T3TC FTC
EFV NVP
6B00D67N T69D M184V K219QA98G Y181C H221YABC ZVD D4TDDI EFV ETR RPV3TC FTC
NVP
7BV32I M46I I47AL10I A71VM41L D67N V75M M184V L210W T215Y K219NK103N ATZ/r DRV/r IDV/r TPV/rABC ZVD D4T DDI 3TC FTC TDF EFV NVP
FSP/r NFV LPV/r
8F10L10V0K103N EFV NVP
9B0000
10BM46L I54IV V82AV L90LML10F L33F G73AGM41L T215S K219RK103N3TC FTC
DRV/r
ABC DDI TDF
TPV/r
ZVD D4T
EFV NVP
ATZ/r FSP/r IDV/r LPV/r NFV SQV/r
11F1000K103N V106I EFV NVP
12BM46I I54V L76V V82AL10V A71VD67N T69N K70R M184V K219Q0TDF
DRV/r TPV/r
ABC D4T DDI
ATZ/r SQV/r
ZVD 3TC FTC
FSP/r IDV/r LPV/r NFV
13B/F0A71V00
14F100D67N K70R M184V K219QK103N P225HTDFABC AZT D4T DDI3TC FTC
EFV NVP
15B00M184VK103NDDI ABC 3TC FTC
EFV NVP
16B00M184VV179D Y188LABC
ETR
3TC FTC
EFV NVP RPV

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MDPI and ACS Style

Cruz, M.L.; Santos, E.; Benamor Teixeira, M.D.L.; Poletti, M.; Sousa, C.; Gouvea, M.I.; Nielsen-Saines, K.; João, E. Viral Suppression and Resistance in a Cohort of Perinatally-HIV Infected (PHIV+) Pregnant Women. Int. J. Environ. Res. Public Health 2016, 13, 568. https://0-doi-org.brum.beds.ac.uk/10.3390/ijerph13060568

AMA Style

Cruz ML, Santos E, Benamor Teixeira MDL, Poletti M, Sousa C, Gouvea MI, Nielsen-Saines K, João E. Viral Suppression and Resistance in a Cohort of Perinatally-HIV Infected (PHIV+) Pregnant Women. International Journal of Environmental Research and Public Health. 2016; 13(6):568. https://0-doi-org.brum.beds.ac.uk/10.3390/ijerph13060568

Chicago/Turabian Style

Cruz, Maria Letícia, Edwiges Santos, Maria De Lourdes Benamor Teixeira, Monica Poletti, Carolina Sousa, Maria Isabel Gouvea, Karin Nielsen-Saines, and Esaú João. 2016. "Viral Suppression and Resistance in a Cohort of Perinatally-HIV Infected (PHIV+) Pregnant Women" International Journal of Environmental Research and Public Health 13, no. 6: 568. https://0-doi-org.brum.beds.ac.uk/10.3390/ijerph13060568

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