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Objective: Pretreatment HIV-drug resistance (PDR, HIVDR) to non-nucleoside reverse transcriptase inhibitors (NNRTIs) is increasing globally. NNRTIs continue to be used as first-line antiretroviral therapy (ART) in some communities due to the cost of dolutegravir-based ART or dolutegravir-associated adverse events. A simplified version of the oligonucleotide ligation assay (OLA) - 'OLA-Simple' - is a low-cost, near point-of-care assay that provides ready-to-use lyophilized reagents and reports HIVDR mutations as colored lines on lateral flow strips. Our objective was to design and validate OLA-Simple for a Mexican cohort., Design: OLA-Simple probes to detect K65R, K103N/S, Y181C, M184V, and G190A were optimized for HIV Mexican sequences. Sixty clinical plasma specimens were analyzed by OLA-Simple by technicians blinded to Illumina-MiSeq sequences, and HIVDR results were compared., Methods: Plasma RNA was tested using OLA-Simple kits. OLA-Simple lateral flow strips were read by in-house software, and were classified as mutant or wild-type at each codon. The comparison of results by OLA-Simple and Miseq was used to generate receiver-operating characteristic curves., Results: OLA-Simple PCR amplified 59 of 60 specimens and successfully genotyped 287 of 295 codons, with eight of 295 (2.7%) indeterminate results. Compared to MiSeq, OLA-Simple gave five of 295 (1.7%) false-positive and four of 295 (1.4%) false-negative results. Excluding indeterminate results, OLA-Simple classified mutant with an accuracy of 97.4 and 98.8% when using thresholds at 10 and 25% mutant within an individual's HIV quasispecies, respectively., Conclusions: Compared to MiSeq, OLA-Simple detected HIVDR with high sensitivity and accuracy. OLA-Simple could expand access to affordable and rapid HIVDR testing to guide appropriate ART choices in populations using NNRTI-based ART.

Objective: Around 20-30% of HIV-infected individuals (HIV+) on successful antiretroviral therapy (ART) fail to normalize their CD4 T-cell counts. Various factors could contribute to the lack of immune reconstitution, one of them being thymic insufficiency. We aimed to explore associations between recent thymic emigrants (RTEs) and CD4 T-cell recovery., Design: ART-naive HIV+ individuals who started ART with advanced AIDS were selected. Good versus poor immune reconstitution was defined by CD4 gains above or below 100 CD4 T cells/μl. The follow-up period was 6 months., Methods: Peripheral blood mononuclear cells were isolated and flow cytometry was used to characterize RTEs as the fraction of naive CD4 T cells expressing CD31, the platelet endothelial cell adhesion molecule. Markers of cellular activation, senescence, exhaustion and cycling were also assessed., Results: After 6 months on ART, HIV+ individuals with good immune reconstitution had higher absolute numbers of RTEs, compared with those with poor immune reconstitution, and these strongly correlated with CD4 gains in those individuals with good immune reconstitution but not with poor immune reconstitution. We also found that CD8 T-cell immune activation decreased as early as 2 months post-ART initiation in individuals with good immune reconstitution, but only at month 6 post-ART in individuals with poor immune reconstitution. Levels of immune activation were inversely correlated with the absolute numbers of RTEs in both groups, but more strongly so in individuals with poor immune reconstitution., Conclusion: We show that RTEs are linked to CD4 T-cell recovery and that the degree of immune reconstitution is not directly linked to persistent immune activation.

Objective: Long-acting rilpivirine is a candidate for preexposure prophylaxis (PrEP) for prevention of HIV-1 infection. However, rilpivirine resistance mutations at reverse transcriptase codon 138 (E138X) occur naturally in a minority of HIV-1-infected persons; in particular those expressing human leukocyte antigen (HLA)-B18 where reverse transcriptase-E138X arises as an immune escape mutation. We investigate the global prevalence, B18-linkage and replicative cost of reverse transcriptase-E138X and its regional implications for rilpivirine PrEP., Methods: We analyzed linked reverse transcriptase-E138X/HLA data from 7772 antiretroviral-naive patients from 16 cohorts spanning five continents and five HIV-1 subtypes, alongside unlinked global reverse transcriptase-E138X and HLA frequencies from public databases. E138X-containing HIV-1 variants were assessed for in-vitro replication as a surrogate of mutation stability following transmission., Results: Reverse transcriptase-E138X variants, where the most common were rilpivirine resistance-associated mutations E138A/G/K, were significantly enriched in HLA-B18-positive individuals globally (P = 3.5 × 10) and in all HIV-1 subtypes except A. Reverse transcriptase-E138X and B18 frequencies correlated positively in 16 cohorts with linked HIV/HLA genotypes (Spearman's R = 0.75; P = 7.6 × 10) and in unlinked HIV/HLA data from 43 countries (Spearman's R = 0.34, P = 0.02). Notably, reverse transcriptase-E138X frequencies approached (or exceeded) 10% in key epidemic regions (e.g. sub-Saharan Africa, Southeastern Europe) where B18 is more common. This, along with the observation that reverse transcriptase-E138X variants do not confer in-vitro replicative costs, supports their persistence, and ongoing accumulation in circulation over time., Conclusions: Results illustrate the potential for a natural immune-driven HIV-1 polymorphism to compromise antiretroviral-based prevention, particularly in key epidemic regions. Regional reverse transcriptase-E138X surveillance should be undertaken before use of rilpivirine PrEP.

Objectives: To investigate the association between Kaposi's sarcoma-associated immune reconstitution inflammatory syndrome (KS-IRIS) and mortality, with the use of glucocorticoids in HIV-infected individuals., Design: Case-control study., Methods: We reviewed the medical records of 145 individuals with HIV-associated Kaposi's sarcoma receiving antiretroviral therapy. The association of different variables with KS-IRIS and Kaposi's sarcoma-related mortality was explored by univariate and multivariate analyses. The main exposure of interest was the use of glucocorticoids. We also compared the time to KS-IRIS and the time to death of individuals treated with glucocorticoids vs. those nontreated with glucocorticoids, and the time to death of individuals with KS-IRIS vs. those without KS-IRIS by hazards regression., Results: Sixty of 145 individuals received glucocorticoids (41.4%) for the management or suspicion of Pneumocystis jirovecii pneumonia. Fifty individuals had KS-IRIS (37%). The use of glucocorticoids was more frequent in individuals with KS-IRIS than in those without KS-IRIS (54.9 vs. 36.47%, P = 0.047). Kaposi's sarcoma-related mortality occurred in 17 cases (11.7%), and glucocorticoid use was more frequent in this group (76.47 vs. 36.7%, P = 0.003). Glucocorticoid use was a risk factor for mortality (adjusted odds ratio = 4.719, 95% confidence interval = 1.383-16.103, P = 0.0132), and was associated with shorter periods to KS-IRIS (P = 0.03) and death (P = 0.0073). KS-IRIS was a risk factor for mortality (P = 0.049)., Conclusion: In HIV-infected individuals, the use of glucocorticoids is a risk factor for KS-IRIS and Kaposi's sarcoma-associated mortality. In addition, KS-IRIS is a risk factor for mortality. Therefore, glucocorticoid administration in this population requires careful consideration based on individualized risk-benefit analysis.

Objective: To describe the clinical course of infection by 2009 (H1N1) influenza virus in different stages of HIV disease., Design: Prospective, observational study., Methods: During the pandemic period, HIV-infected patients presenting respiratory symptoms at a third level referral hospital in Mexico City were tested for 2009 influenza A (H1N1) viral RNA. Clinical files were prospectively analyzed., Results: Infection by H1N1 was confirmed in 30 (23.8%) of the total 126 HIV-infected patients studied. In the group of patients with 2009 H1N1 virus infection, 16 (53.3%) were hospitalized, 12 (40%) had active opportunistic infections and six (20%) died. In the group of 96 patients not infected with 2009 H1N1 virus, 54 (56.25%) were hospitalized with opportunistic infections and 12 (12.5%) died. For all hospitalized patients, being on HAART and having undetectable HIV viral loads at hospitalization was associated with higher survival (P = 0.019). Patients with 2009 H1N1 virus infection had a higher mortality rate, even after adjusting for HAART (P = 0.043). Coinfection by HIV and H1N1 2009 virus was more severe in patients with opportunistic infections, as shown by longer hospital stays (P = 0.0013), higher rates of hospitalization (P < 0.0001), use of mechanical ventilation (P = 0.0086) and death (P = 0.026). Delayed administration of oseltamivir in hospitalized patients was significantly associated with mortality (P = 0.0022)., Conclusion: Our data suggest that infection by 2009 H1N1 is more severe in HIV-infected patients with late and advanced HIV disease than in well controlled patients under HAART.

An analysis of clinical records after the introduction of highly active antiretroviral therapy (HAART) in Mexico showed a lower prevalence and severity of immune recovery uveitis when HIV-infected patients started HAART after completing cytomegalovirus retinitis treatment than when treatments were concomitant. The findings suggest a protective role of delaying HAART until cytomegalovirus retinitis is controlled.

Objective: To evaluate the efficacy of thalidomide in treating wasting syndrome in patients with advanced HIV disease, and to assess the effects of thalidomide on circulating CD4+ T cells, and on HIV viral burden in peripheral blood mononuclear cells (PBMC)., Design: Randomized, double-blind placebo-controlled clinical trial., Setting: Public tertiary care hospital in Mexico City., Patients: Twenty-eight adults with advanced HIV disease being treated with antiretroviral therapy, and who had received antiretrovirals for at least 6 months, who did not have an active opportunistic infection, and who had 10% weight loss in the previous 6 months., Interventions: Patients received thalidomide (100 mg by mouth, four times daily) or a matching placebo for the duration of the study (12 weeks)., Main Outcome Measures: The main clinical endpoint for efficacy of thalidomide was weight gain or no progression of wasting. Secondary endpoints were Karnofsky performance status, CD4+ cell counts, and HIV viral burden in PBMC., Results: Both groups were comparable in their baseline status. Therapeutic failure occurred in 10 out of 14 patients from the placebo group and in three out of 14 from the thalidomide group (P = 0.021). Weight gain occurred in one patient on placebo and in eight given thalidomide. The Karnofsky index was significantly higher by the end of the study in the thalidomide group (P = 0.003). Mild and transient somnolence and erythematous macular skin lesions were significantly more common in the thalidomide group. CD4+ T cell counts and HIV viral burden in PBMC did not change in either group., Conclusions: Results suggest that thalidomide not only impeded but also reverted the wasting syndrome, preserving the Karnofsky index in patients with advanced HIV disease. Thalidomide, at the dosage used in this study, had no effect on peripheral CD4+ T cells nor on HIV viral burden in PBMC.