high discordance in plasma and genital tract hiv-1 drug resistance in indian women failing...
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High Discordance in Plasma and Genital Tract HIV-1 Drug Resistance in Indian
Women Failing First-line Therapy
MOPDA0106
S. Saravanan, PhD
Session Code: MOPDA01
Molecular Techniques of HIV-1 Analysis
21 July 2014
It is vital to investigate tissues and compartments other than blood for two important reasons (Cu-Uvin S., et al., 2010).
• From a patient perspective, it is important to determine whether antiretroviral therapy can reduce viral load in non-blood compartments.
• From a public health perspective, it is critical to know the factors that contribute to the “infectiousness” of an individual in order to devise strategies to reduce the likelihood of transmission.
Background:
Much less work has been directed at HIV in non-blood compartments and those compartments may be the potential sanctuary sites harboring HIV and impacting both the transmission and pathogenesis of HIV infection.
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Sequences were aligned (ClustalX) to an Indian subtype C reference (C.IN.AFo67155) and examined for HIV-1 subtype (REGA v2), nucleotide diversity (Highlighter HIV LANL, SLAC in HyPHY) and drug resistance associated mutations (IAS-USA and Stanford HIV Resistance Database).
Materials and Methods:
HIV-infected women (n=200) at YRG CARE in Chennai, India, who were adherent on >6 months of first-line antiretroviral therapy were enrolled.
Genital tract (2 Sno-strips in 500uL of NASBA buffer) RNA levels measured using COBAS® AMPLICOR HIV-1 MONITOR Test, v1.5 & Pol genotyping (Saravanan et al., 2009) was conducted in paired detectable samples from both compartments.
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Demographic details of enrolled study subjectsResults:
Patient Characteristics Women on First-line ART (n=200)
Viremic (n=73) Non-Viremic (n=127)
Age(Mean) years 33.8±6.3 33.4±5.2
PVL (Median) log copies/mL 4.6 (3, 5.9) Not Detected
CD4(Median) cells/µL 246 (15, 832) 530 (27, 1182)
Duration on HAART(Median) Months 35 (7, 114) 34 (6, 122)
NVP 44 (60%) 87 (68.5%)
D4T/AZT 55 (75%) 114 (90%)
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STUDY SUBJECTS ENROLLED; n = 200
VIREMIC; n=73 (36.5%) NON-VIREMIC; n=127 (63.5%)
DETECTABLE GVLn=30/42 (71%)
UNDETECTABLE GVL n=12/42 (29%)
GVL >2000 Copies/mLn=21/30 (70%)
GVL <2000 Copies/mLn=9/30 (30%)
PVL >3000 Copies/mL;n=42/73 (57.5%)
PVL <3000 Copies/mL;n=31/73 (42.5%)
Results:
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Genital and Plasma Sequences (n = 21)
Concordant mutation patterns; n = 4/21 (19%)
Discordant mutation patterns; n = 17/21 (81%)
Total patients with additional mutations in genital tract; n=11/21 (52%)
35%
24%
41%
0%
10%
20%
30%
40%
50%P
erc
en
t o
f s
ub
jec
ts
Additional inGenital
Additional inPlasma
Diverse in both
Discordance Pattern
5 NRTI – T215F, M41L, D67DN, K70T, K219E 7 NNRTI- K103E/N, H221Y, V106M, Y188H, E138A, Y181C
Results:
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Results: p = <0.005
r2 = 0.872 (p=ns)
Figure 1a: Pearson’s rank correlation for comparison between PVL and GVL in patients with discordance (n=17). 1b: Fisher’s exact test for comparison of patients with detectable and undetectable viral load in plasma and genital compartments (n=42)
95% have monophyletically clustered with Indian subtype C with one sequence clustered to CRF_02 AE
Figure 4: Phylogenetic analyses of RT
Women with detectable PVL tend to shed virus in genital secretions (p<0.005)
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Results:
Figure 6: Comparison between the presence of intermediate to high-level resistance in plasma and genital secretions in patients with discordant mutations (n=5).
Genital discordant mutations were responsible for an increase to a predicted intermediate or high level drug resistance to at least one drug in 24% of women
Figure 5: Prevalence of various NRTI and NNRTI DRMs in plasma and genital tract.
High prevalence of M184V in both compartments followed by TAMs.
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If confirmed, GVL and resistance monitoring may need to be considered to prevent sexual and perinatal HIV-1 resistance transmission in countries like India where sexual transmission is the major mode of HIV infection.
Conclusion:
High resistance discordance between plasma and the genital tract among South-Indian women failing first-line antiretroviral therapy, suggesting compartmentalization and independent viral evolution.
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Acknowledgement
IAS International scholarship (S12858)
S. Gomathi, M.ScS. Sivamalar, M.ScG. Kausalya, M.ScP. Selvamuthu, MBBSN. Kumarasamy, MBBS, PhD P. Balakrishnan, PhDSuniti Solomon, MD
Susan Cu-Uvin, MD Rami Kantor, MD
Sunil S. Solomon, MPH, PhD
Indian Council of Medical Research (ICMR) under U.S.-India Collaborative Research Supplement # Indo-US/35/2007-ECD-II
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