Submission for the
Doctor of Science
(DSc)
Degree
Graham P Taylor
2011
Contents
List of publications submitted
Statement of contribution to knowledge in the field (Author’s review)
Statement of responsibility for extent of initiation, conduct and direction of the
work
Curriculum vitae
Copy of each publication
List of publications submitted for the award of the Doctor of Science (DSc) Degree
Graham P Taylor
Sole Authorship
1. 1998. The pathogenesis and treatment of HTLV-I associated myelopathy.
(Review) Sexually Transmitted Infections. 1998;74:316-322, G.P. Taylor.
Conjoint Work
HTLV Epidemiology
2. *1996. The sero-epidemiology of the Human T-cell Leukaemia/Lymphoma
viruses in Europe. Journal of Acquired Immune Deficiency Syndromes and
Human Retrovirology 1996;13:68-77. The HTLV European Research Network
(corresponding author).
3. 1999. The Epidemiology and Clinical Impact of HTLV Infection in Europe. AIDS
Reviews 1999;1:195-204. GP Taylor and the HTLV European Research
Network
4. 2000. HTLV-I-associated disease in England and Wales 1993-1997: A
retrospective review of serology requests. British Medical Journal 2000; 320:
611-612. Tosswill JHC, Taylor GP, Tedder RS, Mortimer PP.
5. 2000. HTLV in Pregnant Women in the United Kingdom. British Medical
Journal 2000;320:1497-1501. Ades AE, Parker S, Walker J, Edginton M,
Taylor GP, Weber JN.
6. 2001. Pooling of samples for seroepidemiological surveillance of human Tcell lymphotropic virus (HTLV) types I and II. Virus Research 2001;78:101106. Andersson S, Gessain A, Taylor GP.
7. *2005. The Sero-epidemiology of human T-lymphotropic viruses types I & II in
Europe: A prospective study of pregnant women. J Acquir Immune Defic
Syndr. 2005 Jan 1;38(1):104-109. Taylor GP, Bodeus M, Courtois F, Pauli G,
Del Mistro A, Machuca A, Padua E, Andersson S, Goubau P, Chieco-Bianchi
L, Soriano V, Coste J, Ades AE, Weber JN.
8. 2009.The prevalence of human T-cell lymphotropic virus type 1 in the general
population is unknown AIDS Reviews 2009;11(4) 205 – 214. Hlela C,
Shepherd S, Khumalo NP, Taylor GP.
HTLV Clinical Studies
9. 1998. Quantification of proviral DNA load in human T-cell leukaemia virus
type-I infections. Journal of Virological Methods. 1998;75:21-26. JHC Tosswill,
GP Taylor, JP Clewley, JN Weber.
10. *1999. Prospective Study of HTLV-I infection in an initially asymptomatic UK
cohort. Journal of Acquired Immune Deficiency Syndromes 1999;22(1):92100. GP Taylor, JHC Tosswill, E Matutes, S Daenke, S Hall, B Bain, R Davis,
M Rossor, D Thomas, CRM Bangham, JN Weber
11. 1999. Effect of Lamivudine on human T-cell leukaemia virus type 1 (HTLV-1)
DNA copy number, T-cell phenotype, and anti-Tax cytotoxic T-cell frequency
in patients with HTLV-1 associated myelopathy. Journal of Virology
1999;73(12):10289-10295. GP Taylor, SE Hall, AD Witkover, S Navarette, R
Davis, CA Michie, MA Rossor, MA Nowak, P Rudge, CRM Bangham, JN
Weber.
12. *2006. Zidovudine plus lamivudine in Human T-Lymphotropic Virus type-Iassociated myelopathy: a randomised trial. Retrovirology. 2006 Sep 19;3:63.
Taylor GP, Goon P, Furukawa Y, Green H, Barfield A, Mosley A, Nose H,
Babiker A, Rudge P, Usuku K, Osame M, Bangham CR, Weber JN
13. *2010. A 15 year UK prospective study of disease progression in patients with
HAM. J Neurology, Neurosurgery and Psychiatry 2010 Dec;81(12):1336-40.
Martin F, Fedina A, Youshya S, Taylor GP
14. 2011. Prospects for the management of HAM/TSP AIDS Reviews 2011 July;
13 (3) 161 - 170 Martin F & Taylor GP.
15. *2011. Use of zidovudine and interferon-a with chemotherapy improves
survival in both acute and lymphoma subtypes of adult T-cell
leukaemia/lymphoma. Journal of Clinical Oncology 2011 Oct 31 published
on-line JCO.2011.35.5578Hodson A, Crichton S, Montoto S, Mir N, Matutes
E, Cwynarski K, Kumaran T, Ardeshna KM, Pagliuca A, Taylor GP, Fields PA.
HTLV Pathogenesis
16. 1996. High activated and memory cytotoxic T-cell responses to HTLV-1 in
healthy carriers and patients with tropical spastic paraparesis. Virology
1996;217:139-146. S Daenke, AG Kermode, SE Hall, GP Taylor, JN Weber,
S Nightingale, & CRM Bangham.
17. 1999. HLA alleles determine human T-lymphotropic virus-I (HTLV-I) proviral
load and the risk of HTLV-I-associated myelopathy. Proceedings of the
National Academy of Science USA 1999;96:3848-3853. Katie JM Jeffery,
Nagai M, Hall SE, Taylor GP, Proctor J, Bunce M, Ogg GS, Welsh KI, Weber
JN, Usuku K, Osame M, Bangham CRM.
18. *2000. Abundant tax protein expression in CD4+ T cells infected with human Tcell leukaemia virus type I (HTLV-I) is prevented by cytotoxic T lymphocytes.
Blood 2000;95:1386-1392. Hanon E, Hall S, Taylor GP, Saito M, Davis R,
Tanaka Y, Weber JN & Bangham CRM.
19. 2001. High production of interferon- but not interleukin-2 by human T cell
lymphotropic virus type I (HTLV-I) – infected peripheral blood mononuclear
cells. Blood 2001; 98: 721-726. Hanon E, Goon P, Taylor GP, Hasegawa H,
Tanaka Y, Weber JN, Bangham CRM.
20. 2002. High frequencies of Th1-type CD4+ T cells specific to HTLV-1 Env and
Tax proteins in patients with HTLV-1-associated myelopathy/tropical spastic
paraparesis. Blood 2002; 99: 3335-3341, Goon PKC, Hanon E, Igakura T,
Tanaka Y, Weber JN, Taylor GP, Bangham CRM.
21. *2003. HTLV-I spreads between T lymphocytes by a virus-induced
immunological synapse. Science 2003;299:1713-1716. Igakura T,
Stinchcombe JC, Goon P, Taylor GP, Weber JN, Griffiths GM, Tanaka Y,
Osame M, Bangham CRM.
22. 2003. High circulating frequencies of TNF and IL-2-secreting HTLV-I-specific
CD4+ T-cells in patients with HTLV-I-associated neurological disease.
Journal of Virology 2003;77(17):9716-9722. Goon PKC, Igakura T, Hanon E,
Mosley AJ, Asquith BE, Gould KG, Taylor GP, Weber JN, Bangham CRM.
23. 2004. HTLV-I-specific CD4+ T cells: Immunodominance hierarchy and
preferential infection with HTLV-I. Journal of Immunology 2004;172:17351743. Goon PKC, Igakura T, Hanon E, Mosley AJ, Barfield A, Barnard AL,
Asquith BE, Tanaka Y, Taylor GP, Weber JN, Bangham CRM.
24. 2005. A functional CD8+ cell assay reveals individual variation in CD8+ cell
antiviral efficacy and explains differences in human T-lymphotropic virus type
1 proviral load. J Gen Virol. 2005 May;86(5):1515-23.Asquith B, Mosley AJ,
Barfield A, Marshall SE, Heaps A, Goon P, Hanon E, Tanaka Y, Taylor GP,
Bangham CR.
25. *2007. In vivo lymphocyte dynamics in humans: The impact of human T-cell
lymphotropic virus type I infection Proceedings of the National Academy of
Science 2007;104(19):8035-40. Asquith BE, Zhang Y, Mosley AJ, de Lara
CM, Wallace DL, Worth A, Kaftanzi L, Meekings K, Griffin GE, Tanaka Y,
Tough DF, Beverly PC, Taylor GP, Macallan DC & Bangham CRM.
26. 2008. High frequency of CD4+FoxP3+ cells in HTLV-1 infection: inverse
correlation with HTLV-1-specific CTL response Blood. 2008 May
15;111(10):5047-53 Toulza F, Heaps A, Tanaka Y, Taylor GP, Bangham
CRM.
27. 2011. The host genomic environment of the provirus determines the
abundance of HTLV-1-infected T cell clones Blood 2011; 117 (11):3113-3122
Gillet NA, Malani N, Melamed A, Gormley N, Carter R, Bentley D, Berry C,
Bushman FD, Taylor GP and Bangham CRM.
28. *2011. In vivo expression of HTLV-1 basic leucine -zipper protein generates
specific CD8+ and CD4+ T-lymphocyte responses that correlate with clinical
outcome. Journal of Infectious Diseases. 2011;203(4):529-36. Hilburn S,
Rowan A, MacNamara A, Asquith B, Bangham CRM & Taylor GP.
29. Susceptibility of primary HTLV-1 isolates from patients with HTLV-1associated myelopathy to reverse transcriptase inhibitors pre- and postsustained in vivo therapy Viruses 2011; 3 (5): 469-483. Macchi B, Balestrieri
E, Ascolani A, Youshya S, Martin F, Mastino A, Taylor GP
HIV and Pregnancy
30. 1999. Rapid Development of Genotypic Resistance to Lamivudine when
combined with Zidovudine in Pregnancy. Journal of Medical Virology
1999;59:364-368. JR Clarke, R Braganza, A Mirza, C Stainsby, M Ait-Khaled,
A Wright, H Lyall, D Parker, MO McCLure, JN Weber & G.P. Taylor
31. *2000. Pharmacological implications of prolonged in utero exposure to
nevirapine Lancet 2000;355:2134-2135. G.P. Taylor, E.G.H. Lyall, D. Back,
C. Ward, G. Tudor-Williams.
32. *2002. Pre-eclampsia, antiretroviral therapy and immune reconstitution.
Lancet 2002;360:1152-1154. Wimalasundera RC, Larbalestier N, Smith JH,
de Ruiter A, Thom SA McG, Hughes AD, Poulter N, Regan L, Taylor GP.
33. 2004. Clinical implications of stopping nevirapine-based antiretroviral therapy:
relative pharmacokinetics and avoidance of drug resistance. HIV Medicine
2004;5 (3):180-184. Mackie N, Fidler S, Tamm N, Clarke JR, Back D, Weber
JN, Taylor GP.
34. 2006. Pregnant Women With HIV Infection Can Expect Healthy Survival:
Three-Year Follow-Up. Journal of Acquired Immune Deficiency Syndrome.
2006 Oct 1;43(2):186-192. Martin F, Navaratne L, Khan W, Sarner L, Mercey
D, Anderson J, Noble H, Fakoya. A, Hawkins DA, Ruiter AD, Taylor GP.
35. *2007. Increased rates of pre-term delivery are associated with the initiation
of highly active antiretroviral therapy during pregnancy: a single centre cohort
study. Journal of Infectious Diseases. 2007;196(4):558-61. Martin F and
Taylor GP
36. 2008. New mutations associated with resistance not detected following
zidovudine monotherapy in pregnancy when used in accordance with British
HIV Association guidelines. HIV Medicine 2008; 9: 448–451.P Read, S
Costelloe, J Mullen, S O’Shea, F Lyons, P Hay, J Welch, N Larbalestier, GP
Taylor, A de Ruiter.
37. 2011. Improved oral bioavailability of lopinavir in melt-extruded tablet
formulation reduces impact of third trimester on lopinavir plasma
concentrations. Antimicrobial Agents and Chemotherapy (in press). LJ Else,
M Douglas, L Dickinson, DJ Back, SH Khoo and GP Taylor.
Graham P Taylor
Statement of how the publications have contributed to knowledge in the
field of human retrovirology
(Publications considered most significant are marked with an asterisk)
HTLV-1
Shortly after joining St. Mary’s Hospital Medical School in 1992 I started two
major initiatives: 1) the HTLV European Research Network (HERN) (with
Professors Weiss, de The, Weber, Chieco-Bianchi and Bertazonni); 2) A
research clinic for patients with HTLV-1 infection with an accompanying study
of the Natural History of HTLV-1 infection. In 1995 I established one of the
first multi-disciplinary HIV/ante-natal clinics in the UK. These clinics continue
to underpin my research, selections of which I present below for consideration
of the degree of Doctor of Science. I start with the serological and clinical
epidemiology that I initially conducted with and through HERN.
HTLV-1 Epidemiology
In 1994, our knowledge of European HTLV epidemiology comprised of many
small, seroprevalence studies, spanning a decade or more, that had utilised a
wide range of assays of variable sensitivity and specificity, and had been
conducted amongst populations of differing perceived risk. In recognition of
this we established the HERN criteria for the diagnosis of HTLV infections for
sero-prevalence studies (1996; HERN*) and a panel of sera for quality control.
Prior to initiating the definitive study of HTLV-1 infection among pregnant
women in Western Europe we determined the reliability of the testing of
pooled sera for HTLV-1 and -2 infections (2001; Andersson). I collated
published and previously unpublished data from the network and in
accordance with our criteria reported the seroprevalence of HTLV infections
within the, then, boundaries of the European Union (1996; HERN, 1999;
Taylor). We demonstrated that HTLV-1 and HTLV-2 sero-prevalence varied
widely by geography and risk group. The most widely tested group, blood
donors, had the lowest prevalence (0 < 3/10,000 donors), pregnant women
were at intermediate risk, and injecting drug users and patients with sexually
transmitted infections had the highest seroprevalence (0 < 6.5%). I then
coordinated the HERN International Antenatal Study of 250,000 pregnant
women in Belgium, France, Germany, Italy, Portugal, Spain and UK which
demonstrated a 10 fold higher prevalence of HTLV infections amongst
pregnant women in these countries compared with blood donors in the same
regions, even though the prevalence varied (2005; Taylor*). In the UK arm we
conducted a linked anonymised study and could therefore further characterise
the risk of being HTLV-1 or HTLV-2 positive. As might be expected, pregnant
women born in regions where HTLV-1 is endemic had the highest prevalence
rates (1.7%), however, such selective screening would have only identified
32% of the infected women (2000; Ades). The HTLV antenatal
seroprevalence data remains the defining study of HTLV infections in Western
Europe and the comparator for any future assessment.
In addition in the UK I used the existing reporting system to describe the
incidence of diagnosed HTLV-associated disease in the UK during 1994 1999 and triangulated these data, with census and the ante-natal
seroprevalence data to estimate 20 – 30,000 prevalent HTLV infections in the
UK (2000; Tosswill). In 2009, I revisited the epidemiology of HTLV, examining
the data on which the much-cited estimate of 10 – 20 million persons infected
worldwide was based and then having reviewed all published studies based
on unselected general populations concluded that there are very few robust
data on which to base any current estimate of HTLV seroprevalence (2009;
Hlela).
HTLV Clinical Studies
The establishment of the HTLV Clinic at St. Mary’s Hospital was the natural
forerunner to a number of descriptive and interventional studies. This clinic,
now the National Centre for Human Retrovirology, remains unique in Europe
and probably hosts the largest cohort of patients with HTLV infections outside
the endemic regions.
The development of viral load quantification assays has played a key role in
our understanding of pathogenesis and prognosis. Our first assay was a
nested HTLV-1 specific DNA PCR able to detect a single HTLV DNA
molecule in 100,000 peripheral blood mononuclear cells (PBMCs). With this
we described the viral load in our cohort showing the median viral load of
patients with HTLV-1-associated myelopathy (14 HTLV-1 copies per 100
PBMCs) to be 10-fold higher than asymptomatic carriers (1.4%) but with
overlapping ranges (1998; Tosswill). Our description of incident HTLV-1associated inflammatory disease (1999; Taylor*) remains a rare, albeit
frequently presumed, documentation that high HTLV-1 viral load precedes
initial symptoms, whereas our observation of the relative stability of HTLV-1
viral load over time in both categories has been reproduced. More recently,
incident cases of adult T-cell leukaemia/lymphoma (ATLL) in the cohort have
all occurred in patients with pre-existent high HTLV viral load (2011; Hodson
submitted) and our HTLV integration site analysis studies have demonstrated
shifts from low to high clonality significantly predating clinical disease (2011;
Gillet). Not all clinicians treating patients with ATLL have been convinced by
the small studies reporting the efficacy of the combination of zidovudine with
interferon-. The international meta-analysis of this treatment compared to
chemotherapy provides compelling evidence of benefit with the leukaemic
forms of ATLL1, whilst our latest work based on the UK experience (2011;
Hodson*) confirms this and further demonstrates a survival advantage for
patients presenting with ATLL – lymphoma, when given in addition to
chemotherapy.
It was clear from my review (1998; Taylor) that the treatment of HTLV-1associated inflammatory disease (HAM) was poorly understood and based on
anecdote and small case reports. Observing that clinical improvement, in a
patient with early HAM, with the cytosine analogue reverse transcriptase
inhibitor was associated with a 2 log reduction in HTLV-1 proviral load and
parallel reduction in the frequency of HTLV-1 specific CD8 T-lymphocytes we
further explored this therapeutic modality in patients with chronic disease
where the results were less impressive (1999; Taylor). Other centres
subsequently reported the treatment of patients with HAM with lamivudine.
Since the HTLV-1 viral load reduction was transient, passing through a period
lasting several months during which HTLV viral load and anti-HTLV CTL
frequency fluctuation suggested a predator-prey phenomenon, returning to
baseline we postulated that intensification of the antiretroviral therapy would
further suppress viral load and that sustained reduction of viral load would be
required to modify disease in patients with chronic disease. We therefore
conducted a UK-Japan collaborative randomised controlled trial (RCT) of
zidovudine plus lamivudine. This remains the only placebo-controlled RCT in
HTLV-1 infection. Despite up to 12 months dual therapy, good adherence and
tolerability, none of the clinical, virological or immunological parameters
showed any significant improvement (2006; Taylor*). (By now we had
developed real-time quantitative HTLV DNA PCR (2004; Goon)). We have
since demonstrated not only that reverse transcriptase (RT) from HTLV
primary isolates obtained before and after treatment in this study remain
sensitive to zidovudine but also that the sensitivity of HTLV-1 RT to various
RT inhibitors differs between isolates and between isolates and virus obtained
from cell lines (2011; Maachi). This failure of antiretroviral therapy led us to
focus on the immune response to HTLV-1 in HAM. As briefly described below
our studies indicate the importance of constant viral expression and immune
response in pathogenesis. Almost immediate clinical improvement, lasting at
least 4 weeks, follows treatment with high dose pulsed methyl prednisolone
(2011; Martin submitted). Our open-label 48 week, proof of principle study of
ciclosporin, shows consistent improvement in clinical parameters (pain,
spasticity and ambulation) with parallel reduction in markers of inflammation
(-2 microglobulin), T cell activation (CD4 CD25 expression), in CD4 T-cell
counts and corrected viral load. The viral load reduction is most marked in the
CSF lymphocytes measured after 12 weeks therapy. Improvement occurs
during the first 24 weeks of therapy and is sustained to week 48, but is lost
after week 48, when ciclosporin was discontinued as per study design (2011;
Martin in preparation). This improvement contrasts with the natural history of
HAM in our cohort, in which for the first time we have documented in a
measured way the constant deterioration in gait which deteriorates at a rate of
2 secs/10m/year in a timed walk (2010; Martin). Thirteen years on from the
first review, there is an appalling paucity of new published data, with the
exception of the prospect of reducing HTLV-1 viral load through the
combination of sodium valproate (a histone deacetylase inhibitor) with
zidovudine (to prevent an early increase in de novo HTLV infection), to review
(2011; Martin).
HTLV-1 pathogenesis studies
The establishment of a clinical cohort has been fundamental to our studies of
HTLV-1 pathogenesis, which in turn have lead to therapeutic studies. Over
the last 15 years the collaboration with Professor Bangham has results in the
following key research findings
1. Cytotoxic T-cells responses are found in HTLV-1 infected asymptomatic
carriers as well as patients with HAM (1996; Daenke) in contrast to earlier
studies.
2. The discovery that HLA alleles influence risk of HAM and that HLA A0201
does so through an associated with low viral load – detected in a
Japanese cohort and confirmed in our predominantly Afro-Caribbean
population (1999; Jeffery)
3. Having observed that high concentrations of HTLV-1 gag could be
detected in culture supernatants after 72 hours (Taylor unpublished) we
conducted a detailed time-course study of unstimulated PBMCs and found
that viral protein expression could be detected as early as 6 hours but
peaked after 24 hours. This not only supported the concept that HTLV-1
expression was persistently present in vivo (as evidenced by a persistent
immune response – see 1996 Daenke and 1999 Taylor above) but
enabled us to: demonstrate CTL activity ex vivo (2000; Hanon*); determine
HTLV-1 Tax protein expression as an independent risk factor for HAM;
and develop the novel functional CTL assay (2005; Asquith) that has
informed our clinical studies.
4. The development of CD4 ELIspot assays enabled our demonstration of
the role of HTLV-1 specific CD4 cells in HTLV-1 infection (2002; Goon)
and the association of CD4 TNF- and IL-2 secretion with HAM (2003;
Goon), which in turn has informed our clinical trials of ciclosporin (see
above) and the anti-TNF- monoclonal antibody, Infliximab.
5. The discovery of the ‘virological synapse’ (2003; Igakura*) has profoundly
changed our understanding of HTLV-1 transmission.
6. Our studies of lymphocyte dynamics in vivo have demonstrated an
increased turnover of CD4 and CD8 lymphocytes in patients infected with
HTLV-1 and in particular demonstrated a higher rate of turnover of HTLV-1
infected cells (2007; Asquith*).
7. Whilst the detail of the role of the immune response to the HTLV-1
regulatory protein Tax, in the pathogenesis and control of HTLV-1 infection
has long been debated we have recently demonstrated the importance of
the cellular response to the HTLV basic leucine zipper protein in the
control of HTLV-1 infection (2011, Hilburn*)
Together these studies, which have considerably advanced our understanding
of the host-pathogen interface, point to virus driven cell proliferation and hostdriven cell death, the balance of which will determine outcome in terms of viral
load and hence disease. The HBZ study is indicative of the importance of
even low frequency responses provided their target is key to viral persistence.
HIV & Pregnancy
My research in HIV has focussed on the efficacy and safety of antiretroviral
therapy in pregnancy. During 1996, when I first treated HIV infection in a
pregnant woman with zidovudine monotherapy (ZDVm), there were only
about 200 HIV positive pregnant women in the UK. The results of the sentinel
ACTG 076 study2 showing a 67% reduction in HIV mother-to-child
transmission (MTCT) had been published in November 2004, but dual therapy
for treatment was already showing promise and I introduced combination
therapy (zidovudine and lamivudine) in pregnancy at the end of 1996.
Detection of mutations in HIV-1 reverse transcriptase gene associated with
reduced drug sensitivity was in its infancy but using a line probe assay we
were the first to report the rapid development of the M184V mutation,
associated with a 100 fold reduction in sensitivity of HIV-1 to lamivudine, in
pregnancy and recommend avoidance of this approach (1999; Clarke). Our
findings were later substantiated by a much larger, cohort study from France 3.
Understanding the kinetics of the development of resistance to antiretroviral
therapy has been more important in pregnancy, for reasons of reducing drug
exposure and rolling out inexpensive treatment strategies in resource-poor
settings, than in all other areas of HIV medicine. The long half-life of
nevirapine, a non-nucleoside RT inhibitor studies lead to the development of
the single-dose nevirapine strategy. We were the first to demonstrate that
standard continuous maternal dosing with nevirapine during pregnancy was
sufficient to maintain therapeutic plasma concentrations and that
transplacental transfer of nevirapine led to foetal hepatic enzyme induction
with implications for neonatal dosing. This was the first ever description of this
phenomenon for any therapy (2000; Taylor*). We also were the first to
document the time (up to 14 days) required to clear nevirapine after
antiretroviral therapy was stopped (2004; Mackie) leading us to recommend a
therapeutic NRTI tail with planned treatment discontinuations. Whilst the
efficacy of ZDVm with pre-labour caesarean section to prevent HIV MTCT has
been conclusively demonstrated this approach is no longer favoured. It is
argued that ZDVm will result in the emergence of mutations associated with
resistance. We have shown that the selective use of ZDVm in pregnancy, in
accordance with British HIV Association guidelines, does not result in the
emergence of such mutations, even as a minority specie (2008; Read), nor
adversely affect subsequent response to combination therapy (2006; Martin).
Conversely, whilst understanding the importance of combination therapy in
pregnancy both to prevent HIV MTCT and for maternal health we have been
at the forefront of documenting the impact of these therapies on pregnancy
outcomes. A low rate of pre-eclampsia among untreated HIV positive women
was a documented, but poorly recognised phenomenon. Our report of a
restoration of the risk of pre-eclampsia to expected levels for the community
was the first such observation, since confirmed, and we hypothesised that this
might be due to immune reconstitution even though there was no significant
change in CD4 T-lymphocyte counts amongst those with pre-eclampsia
compared with the controls (2002; Wimalasundera*). We have also
contributed to the controversial literature on pre-term delivery and
combination therapies. First reported in European studies but not apparent in
some N. American studies we have shown that whilst PTD rates are within the
normal range (6 – 8%) for women on ZDVm PTD is more common (16%) in
women on combination (HAART) especially if HAART is initiated during the
pregnancy (22%), regardless of baseline CD4 T-lymphocyte count and HIV
viral load (2007; Martin*). In an update of this study, the odds ratio for PTD in
women eligible for ZDVm but electing to take HAART was 6.7 compared to
women who were managed with ZDVm (2011, Short, submitted). Fiore et al
have shown a disturbance of the normal change in Th1:Th2 ratio in women on
HAART throughout pregnancy4. We are now exploring the association
between class and timing of antiretroviral therapy in pregnancy, pre-term
delivery and changes in the ratio of Th1:Th2 cytokines. Finally, we have
continued to study the pharmacokinetics of antiretroviral therapy in pregnancy
and in a study spanning almost 5 years have demonstrated that the improved
bioavailability of the tablet formulation of Lopinavir/ritonavir together with the
changes in protein binding, compensate for the reduced concentrations of
lopinavir found with the capsule formulation during the third trimester of
pregnancy (Else; 2011).
Reference List
1. Bazarbachi A, Plumelle Y, Ramos JC et al. Meta-analysis on the use of
zidovudine and interferon-alpha in adult T-cell leukaemia/lymphoma
showing improved survival in the leukaemic subtypes. J Clin Oncol 2010.
2. 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 1994;331(18):1173-1180.
3. Mandelbrot L, Landreau-Mascaro A, Rekacewicz C et al. LamivudineZidovudine combination for prevention of maternal-infant transmission of
HIV-1. JAMA 2001;285(16):2083-2093.
4. Fiore S, Newell M-L, Trabattoni D et al. Antiretroviral therapy-associated
modulation of Th1 and Th2 immune responses in HIV-infected pregnant
women. J Reprod Immunol 2006;70:143-150.