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Transmission of Integrase Strand-Transfer Inhibitor Multi-drug Resistant HIV: Case Report and Natural History of Response to Raltegravir-containing Antiretroviral Therapy
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Reported by Jules Levin
18th Intl AIDS Conf Vienna July 2010
B Young1,2, S Fransen2, K Greenberg1, A Thomas1, S Martens3,
M St Clair4, C Petropoulos3, B Ha4. 1Rocky Mountain CARES/Denver Infectious Disease Consultants, Denver, CO; 2Health Connections International, Amsterdam; 3Monogram Biosciences, South San Francisco, CA; 4GlaxoSmithKline, RTP, NC
ABSTRACT
Background - To our knowledge, there are no reported cases of HIV transmission with integrase strand-transfer inhibitor (INI)-resistance. We describe here the case of a person with acquired four-drug class resistance.
Methods - Genotypic and phenotypic analyses were performed by Monogram Biosciences. Replication capacity (RC) was measured separately for the PRRT and IN coding regions.
Results - A 53 year-old treatment naïve man initiated abacavir/lamivudine + raltegravir therapy. Baseline CD4 T-cell count was 340 cells/mm3, plasma HIV RNA 77,600 copies/mL. HIV RNA declined to 82 copies/mL at Week 8 [W8].
By W48, viral load was 591 copies/mL, CD4 count 377 cells/mm3. Retrospective baseline genotype identified multiple resistance mutations to RT inhibitors
(K70K/R, K103N, V106A), protease inhibitors (L10I, V32I, M46I, A71V, V82A, L90M), and integrase inhibitors (G140S and Q148H). At W48, baseline PR, RT, and IN inhibitor resistance mutations persisted while RT mutations V75I and M184V emerged with other RT and IN substitutions.
Phenotypic susceptibility was determined at baseline and W48. At W48, non-nucleoside reverse transcriptase inhibitor and raltegravir resistance persisted and resistance to lamivudine emerged; abacavir susceptibility was reduced (FC = 3.74), but remained below the clinical cutoff (FC = 4.5).
Replication capacity (RC) based on PRRT vs IN was discordant; baseline and W48 PRRT RC were 1% and 1.5%, respectively; baseline and W48 IN RC was 97% and 146%.
Conclusions- We believe this is the first documented case of transmitted INI resistant HIV-1. Despite receiving ART with raltegravir, reduction in viral replication (-2 log10 copies/mL) persisted. Patients with high-level transmitted RT and PR inhibitor resistance should be considered for INI resistance testing.
BACKGROUND
Transmission of protease (PR) and reverse transcriptase (RT) inhibitor resistant HIV-1 is well described.
To our knowledge, there are no reported cases of transmission of integrase (IN) inhibitor resistant HIV-1.
This report describes the first case of HIV-1 infection involving resistance to PR, RT and IN inhibitors.
RESULTS
Viral load history: The subject is a 53-year-old, HIV-positive, treatment-naïve man who initiated therapy with abacavir (ABC), lamivudine (3TC) and raltegravir (RAL) with a baseline viral load of 77,600 copies/mL (c/mL), which declined to 82 c/mL by W8 and 591 c/mL by W48 (Figure 2).
· Resistance: Retrospective genotypic analysis of the baseline virus identified mutations associated with resistance to PR inhibitors (L10I, V32I, M46I, A71V, V82A, L90M), RT inhibitors (K70K/R, K103N, V106A), and IN inhibitors (G140S and Q148H) (Table 1).
· PR, RT, and IN inhibitor resistance mutations observed at baseline persisted at W48. Additional RT resistance mutations, V75I and M184V, emerged along with other substitutions in RT and IN (Table 1).
Changes in susceptibility: At W48, reductions in susceptibility to PR inhibitors, non-nucleoside reverse transcriptase inhibitors, and raltegravir persisted, and reductions in susceptibility to 3TC and ABC were observed (Table 2).
Resistance Test Vectors (RTVs): PR/RT and RNaseH/IN RTVs did not differ in replication capacity (RC) at W48 compared to baseline. However pol RTVs displayed a 10-fold reduction in RC at W48 compared to baseline (Figure 3).
Molecular clones: Molecular clones isolated from viral populations confirmed no significant difference in infectivity when comparing PR/RT and RNaseH/IN RTVs at baseline and W48. However a significant difference was observed between baseline and W48 pol RTVs (Figure 4).
Site-directed mutant viruses (SDMs): A panel of SDMs was constructed that contained combinations of mutations observed in the baseline and W48 patient virus. RC was severely compromised in mutants containing multiple resistance mutations. The addition of M184V to K103N/V106A with or without IN mutations resulted in virus that was unable to replicate, confirming the low replication capacity exhibited by the patient derived virus in the presence of multiple resistance mutations throughout pol (Figure 5).
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