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- Assessing transmissibility of HIV-1 drug resistance mutations from treated and from drug-naive individualsPublication . Winand, Raf; Theys, Kristof; Eusébio, Mónica; Aerts, Jan; Camacho, Ricardo J.; Gomes, Perpétua; Suchard, Marc A.; Vandamme, Anne-Mieke; Abecasis, Ana B.; on behalf of the Portuguese HIV-1 Resistance Study GroupOBJECTIVES: Surveillance drug resistance mutations (SDRMs) in drug-naive patients are typically used to survey HIV-1-transmitted drug resistance (TDR). We test here how SDRMs in patients failing treatment, the original source of TDR, contribute to assessing TDR, transmissibility and transmission source of SDRMs. DESIGN: This is a retrospective observational study analyzing a Portuguese cohort of HIV-1-infected patients. METHODS: The prevalence of SDRMs to protease inhibitors, nucleoside reverse transcriptase inhibitors (NRTIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs) in drug-naive and treatment-failing patients was measured for 3554 HIV-1 subtype B patients. Transmission ratio (prevalence in drug-naive/prevalence in treatment-failing patients), average viral load and robust linear regression with outlier detection (prevalence in drug-naive versus in treatment-failing patients) were analyzed and used to interpret transmissibility. RESULTS: Prevalence of SDRMs in drug-naive and treatment-failing patients were linearly correlated, but some SDRMs were classified as outliers - above (PRO: D30N, N88D/S, L90 M, RT: G190A/S/E) or below (RT: M184I/V) expectations. The normalized regression slope was 0.073 for protease inhibitors, 0.084 for NRTIs and 0.116 for NNRTIs. Differences between SDRMs transmission ratios were not associated with differences in viral loads. CONCLUSION: The significant linear correlation between prevalence of SDRMs in drug-naive and in treatment-failing patients indicates that the prevalence in treatment-failing patients can be useful to predict levels of TDR. The slope is a cohort-dependent estimate of rate of TDR per drug class and outlier detection reveals comparative persistence of SDRMs. Outlier SDRMs with higher transmissibility are more persistent and more likely to have been acquired from drug-naive patients. Those with lower transmissibility have faster reversion dynamics after transmission and are associated with acquisition from treatment-failing patients.
- HIV-1 late diagnosis : strategies to overcome the misclassification of individuals acutely infected with HIV-1 as individuals diagnosed latePublication . Miranda, Mafalda N. S.; Pimentel, Victor; Santos, André; Alemão, André; Gonçalves, Fátima; Cabanas, Joaquim; Costa, Inês; Diogo, Isabel; Fernandes, Sandra; Seabra, Sofia G.; Gomes, Perpétua; Pingarilho, Marta; Abecasis, Ana; on behalf of the Portuguese HIV-1 Resistance Study GroupObjectives: Late HIV diagnosis is associated with a higher impact on treatment outcomes and a potential for prolonged transmissibility of HIV-1 infection. The consensus definition for late HIV diagnosis is problematic. It was updated in 2022; however, this definition relies on information that might not be clinically available. This study aimed to assess late HIV diagnosis using alternative parameters, in addition to the definition of clusters of differentiation (CD4) cell count, namely, sequence ambiguity rate and estimated time of infection inferred through phylogenetic analysis. Methods: Clinical, socio-demographic, and genotypic information from 3668 antiretroviral therapy–naïve individuals living with HIV was retrieved from the REGA database. Individuals were classified according to three approaches: (i) CD4 cell count, (ii) sequence ambiguity rate, and (iii) phylogenetic reconstruction using TreeTime to estimate the time of most recent common ancestor (MRCA) as a proxy for time of infection. Results: Based on CD4 cell count, 53.8% of individuals had a late diagnosis and 46.2% had a non-late diagnosis. Based on sequence ambiguity rate, 57.8% had a chronic and 42.2% had a recent infection, and 86.4% had an estimated time of infection of more than 3 years, whereas 13.6% had less than 3 years. A total of 114 individuals were classified as diagnosed late by CD4 criteria and showed evidence of recent infection based on low ambiguity rates and MRCA estimates under 3 years. These individuals had significantly lower viral loads than those with true late diagnoses (median 61,358 vs 134,730 copies/ml; P <0.001). Overall, 41% of individuals were consistently classified across all three methods. Conclusions: The definition of late diagnosis remains a major challenge. Alternative and complementary methods, such as the use of viral loads, combined with some more clinical information, may improve the lack of baseline data.
- Predicted residual activity of rilpivirine in HIV-1 infected patients failing therapy including NNRTIs efavirenz or nevirapinePublication . Theys, K.; Camacho, R. J.; Gomes, P.; Vandamme, A. M.; Rhee, S. Y.; on behalf of the Portuguese HIV-1 Resistance Study Group"Rilpivirine is a second-generation nonnucleoside reverse-transcriptase inhibitor (NNRTI) currently indicated for first-line therapy, but its clinical benefit for HIV-1 infected patients failing first-generation NNRTIs is largely undefined. This study quantified the extent of genotypic rilpivirine resistance in viral isolates from 1212 patients upon failure of efavirenz- or nevirapine-containing antiretroviral treatment, of whom more than respectively 80% and 90% showed high-level genotypic resistance to the failing NNRTI. Of all study patients, 47% showed a rilpivirine resistance-associated mutation (RPV-RAM), whereas preserved residual rilpivirine activity was predicted in half of the patients by three genotypic drug resistance interpretation algorithms. An NNRTI-dependent impact on rilpivirine resistance was detected. Compared with the use of nevirapine, the use of efavirenz was associated with a 32% lower risk of having a RPV-RAM and a 50% lower risk of predicted reduced rilpivirine susceptibility. Most prevalent RPV-RAMs after nevirapine experience were Y181C and H221Y, whereas L100I+K103N, Y188L and K101E occurred most in efavirenz-experienced patients. Predicted rilpivirine activity was not affected by HIV-1 subtype, although frequency of individual mutations differed across subtypes. In conclusion, this genotypic resistance analysis strongly suggests that the latest NNRTI, rilpivirine, may retain activity in a large proportion of HIV-1 patients in whom resistance failed while they were on an efavirenz- or nevirapine-containing regimen, and may present an attractive option for second-line treatment given its good safety profile and dosing convenience. However, prospective clinical studies assessing the effectiveness of rilpivirine for NNRTI-experienced patients are warranted to validate knowledge derived from genotypic and phenotypic drug resistance studies."
- Sub-epidemics explain localized high prevalence of reduced susceptibility to Rilpivirine in treatment-naive HIV-1-infected patients: subtype and geographic compartmentalization of baseline resistance mutationsPublication . Theys, Kristof; Laethem, Kristel Van; Gomes, Perpétua; Baele, Guy; Pineda-Peña, Andrea-Clemencia; Vandamme, Anne-Mieke; Camacho, Ricardo J.; Abecasis, Ana B.; on behalf of the Portuguese HIV-1 Resistance Study Group"Objective: The latest nonnucleoside reverse transcriptase inhibitor (NNRTI) rilpivirine (RPV) is indicated for human immunodeficiency virus type-1 (HIV-1) patients initiating antiretroviral treatment, but the extent of genotypic RPV resistance in treatment-naive patients outside clinical trials is poorly defined. Study Design: This retrospective observational study of clinical data from Belgium and Portugal evaluates genotypic information from HIV-1 drug-naive patients obtained for the purpose of drug resistance testing. Rilpivirine resistance-associated mutations (RPV-RAMs) were defined based on clinical trials, phenotypic studies, and expert-based resistance algorithms. Viral susceptibility to RPV alone and to the single-tablet regimen was estimated using expert-based resistance algorithms. Results: In 4,631 HIV-1 treatment-naive patients infected with diverse HIV-1 subtypes, major RPV-RAMs were detected in 4.6%, while complete viral susceptibility to RPV was estimated in 95% of patients. Subtype C- and F1-infected patients displayed the highest levels of reduced viral susceptibility at baseline, respectively 13.2% and 9.3%, mainly due to subtype- and geographic-dependent occurrence of RPV-RAMs E138A and A98G as natural polymorphisms. Strikingly, a founder effect in Portugal resulted in a 138A prevalence of 13.2% in local subtype C-infected treatment-naive patients. The presence of transmitted drug resistance did not impact our estimates. Conclusion: RPV is the first HIV-1 inhibitor for which, in the absence of transmitted drug resistance, intermediate or high-level genotypic resistance can be detected in treatment-naive patients. The extent of RPV susceptibility in treatment-naive patients differs depending on the HIV-1 subtype and dynamics of local compartmentalized epidemics. The highest prevalence of reduced susceptibility was found to be 15.7% in Portuguese subtype C-infected treatment-naive patients. In this context, even in the absence of transmitted HIV-1 drug resistance (TDR), drug resistance testing at baseline should be considered extremely important before starting treatment with this NNRTI."