Pretreatment HIV drug resistance spread within transmission clusters in Mexico City

Abstract

Background: Pretreatment HIV drug resistance (HIVDR) to NNRTIs has consistently increased in Mexico City during the last decade.

Objectives: To infer the HIV genetic transmission network in Mexico City to describe the dynamics of the local HIV epidemic and spread of HIVDR.

Patients and methods: HIV pol sequences were obtained by next-generation sequencing from 2447 individuals before initiation of ART at the largest HIV clinic in Mexico City (April 2016 to June 2018). Pretreatment HIVDR was estimated using the Stanford algorithm at a Sanger-like threshold (≥20%). Genetic networks were inferred with HIV-TRACE, establishing putative transmission links with genetic distances <1.5%. We examined demographic associations among linked individuals with shared drug resistance mutations (DRMs) using a ≥ 2% threshold to include low-frequency variants.

Results: Pretreatment HIVDR reached 14.8% (95% CI 13.4%-16.2%) in the cohort overall and 9.6% (8.5%-10.8%) to NNRTIs. Putative links with at least one other sequence were found for 963/2447 (39%) sequences, forming 326 clusters (2-20 individuals). The inferred network was assortative by age and municipality (P < 0.001). Clustering individuals were younger [adjusted OR (aOR) per year = 0.96, 95% CI 0.95-0.97, P < 0.001] and less likely to include women (aOR = 0.46, 95% CI 0.28-0.75, P = 0.002). Among clustering individuals, 175/963 (18%) shared DRMs (involving 66 clusters), of which 66/175 (38%) shared K103N/S (24 clusters). Eight municipalities (out of 75) harboured 65% of persons sharing DRMs. Among all persons sharing DRMs, those sharing K103N were younger (aOR = 0.93, 95% CI 0.88-0.98, P = 0.003).

Conclusions: Our analyses suggest age- and geographically associated transmission of DRMs within the HIV genetic network in Mexico City, warranting continuous monitoring and focused interventions.

Figure 1.

HIV pretreatment drug resistance (PDR) prevalence in the Mexico City metropolitan area, 2016–18. HIV drug resistance was estimated using next-generation sequencing from 2447 persons starting first-line ART, diagnosed at the Condesa Clinic. (a) HIVDR prevalence by drug class. (b) HIVDR prevalence by antiretroviral drug. Lines represent 95% CI. (c) DRM frequency at different sensitivity thresholds; only surveillance mutations are shown (Stanford HIV Drug Resistance Database). EFV, efavirenz; NVP, nevirapine; RPV, rilpivirine; ETR, etravirine; ABC, abacavir; AZT, zidovudine; d4T, stavudine; ddI, didanosine; FTC, emtricitabine; 3TC, lamivudine; TDF, tenofovir disoproxil fumarate; ATV/r, atazanavir boosted with ritonavir; LPV/r, lopinavir boosted with ritonavir; DRV/r, darunavir boosted with ritonavir; FPV/r, fosamprenavir boosted with ritonavir; IDV/r, indinavir boosted with ritonavir; NFV, nelfinavir; SQV/r, saquinavir boosted with ritonavir; TPV/r, tipranavir boosted with ritonavir; DTG, dolutegravir; EVG, elvitegravir; RAL, raltegravir; INSTI, integrase strand-transfer inhibitor. ^aConsidering EFV, NVP, any NRTI, ATV/r, LPV/r, DRV/r, DTG, EVG and RAL.

Figure 2.

Contribution of young persons in Mexico City’s HIV genetic network, 2016–18. Clusters are coloured by age group. (a) All clusters are shown; age at enrolment is included within each node. (b) Only clusters with putative sequence pairs sharing DRMs at ≥2% threshold are shown; shared K103N is identified. Node shapes denote gender. All edges represent a genetic distance of <1.5% separating nodes. Red edges denote putative sequence pairs sharing DRMs. This figure appears in colour in the online version of JAC and in black and white in the print version of JAC.

Figure 3.

Cluster growth and geographic residence of persons sharing DRMs. (a) Clusters with shared DRMs at ≥20% sensitivity threshold. (b) Clusters with shared DRMs at ≥2% threshold. Nodes are coloured by HIV gene. Node shapes denote gender. All edges represent a genetic distance of <1.5% separating nodes. Red edges denote putative sequence pairs sharing DRMs. Sequences sharing K103N are shown. Annual growth of the network is shown from left to right. (c) Geographic residence of individuals sharing DRMs. Maps of Mexico City metropolitan area divided into municipalities are shown. Eight municipalities are shown, which accounted for 65% of persons sharing DRMs. IN, integrase. This figure appears in colour in the online version of JAC and in black and white in the print version of JAC.

Figure 4.

Linked drug resistance and growth of the Mexico City HIV genetic network 2016–18. Clusters are coloured by the presence of shared DRMs at ≥20% and 2%–19% sensitivity thresholds. All edges represent a genetic distance of <1.5% separating nodes. Annual growth of the network is shown from left to right. This figure appears in colour in the online version of JAC and in black and white in the print version of JAC.

Figure 5.

Lineage dispersal events between municipalities in the Mexico City metropolitan area. (a) Sankey plot showing the proportion of transition events from each source municipality (left) toward the recipient municipality (right). Only strongly supported transitions (adjusted BF >20) are shown and are coloured by source. The size of the boxes is proportional to the number of transitions observed. (b) Number of lineage dispersal events between municipalities. The thickness of the arrows corresponds to the average number of strongly supported, inferred migration events between locations (BF >20). This figure appears in colour in the online version of JAC and in black and white in the print version of JAC.