Exceptional T CD4+ Recovery Post-antiretroviral Is Linked to a Lower HIV Reservoir with a Specific Immune Differentiation Pattern.

We present a cohort of individuals who reached CD4+ T cell counts of greater than 1,000 cells/mm3 (Hypers) after starting antiretroviral treatment (ART) and compared them with those who reached between 350 and 999 CD4+ T cells/mm3 (Concordants). Demographic data, immune recovery kinetics, T CD4+ subset phenotypes, and integrated HIV DNA were analyzed. Data from individuals living with HIV on their first ART regimen and after 48 months of follow-up were obtained. Immune phenotype by Flow Cytometry analysis on whole blood was performed, cytokines were measured, and integrated HIV-1 DNA was measured by polymerase chain reaction. From a total of 424 individuals, 26 Hypers (6.1%), 314 Concordants (74.1%), and 84 (19.8%) discordants were identified. Hypers had a higher proportion of CD4+-naive (Nv) T cells (37.6 vs. 24.8, p < .05), and a low proportion of CD4+ effector memory T cells (27.9 vs. 39.4, p < .05), with similar results found in CD8+ T cells. Hypers demonstrated a higher percentage of CD4+CD45RA+CD31neg cells with a lower response to interleukin-2 stimulation and a lower integrated HIV-1 DNA/CD4 ratio (1.2 vs. 2.89, p < .05). In Hypers, T cell recovery occurs very early after initiation of ART. Following this initial recovery state, their CD4+ T cell level homeostasis seems to be driven by nonthymic-central-Nv cells. This exceptional recovery is associated with a lower HIV reservoir, which may be related to an increase in noninfected CD4+ T cells. These patients could then be eligible candidates for cure trials.

Persistent high levels of immune activation and their correlation with the HIV-1 proviral DNA and 2-LTR circles loads, in a cohort of Mexican individuals following long-term and fully suppressive treatment.

OBJECTIVES: The aim of this study was to investigate the correlation between the HIV-1 reservoir and the levels of immune activation in chronic patients under fully suppressive cART. METHODS: We quantified the HIV proviral DNA and 2-LTR circles loads from PBMCs, the levels of CD38+ and Ki-67+ T-cells, and the levels of IL-7 in a cohort of patients with more than 5 years of ART at enrollment and after 1 year. RESULTS: In 29 participants with a median of 8 years (IQR, 6.9-9.4) under suppressive cART we found higher levels of CD8+ CD38+ T-cells after 1-year (P = .000). There was a non-statistically significant poor correlation between the levels of immune activation and the proviral DNA of CD4+ and CD8+ T-cells. Ki-67+ T-cells declined without significant differences, and there was no significant correlation with the proportion of CD38+. IL-7 decreased at the follow-up observation (P = .094), but there was no correlation with the levels of CD38+ and Ki-67+ T-cells. CONCLUSIONS: We found a weak but non-statistically significant correlation of the levels of T-cell activation with the proviral DNA and 2-LTR circles. This suggests the likely occurrence of further mechanisms driving chronic versus early immune activation other than viral replication by itself in chronic patients.

HIV-1 acquired drug resistance to integrase inhibitors in a cohort of antiretroviral therapy multi-experienced Mexican patients failing to raltegravir: a cross-sectional study.

BACKGROUND: In resource-limited settings, multi-experienced HIV infected patients are often prescribed raltegravir for salvage therapy. Patients failing raltegravir-containing regimens require other drugs including other integrase inhibitors. In this context, real-life data about the resistance and cross-resistance pathways between integrase inhibitors is limited. The aim of this study was to investigate integrase resistance pathways in a cohort of Mexican multi-experienced patients failing of a raltegravir-containing salvage regimen. METHODS: Twenty-five plasma samples from subjects failing antiretroviral regimens which included raltegravir were obtained from various healthcare centres from 2009 to 2017 in Mexico. Antiretroviral history and demographics were collected. Samples were processed for integrase resistance genotyping testing by sequencing. The viral sequences were analysed with the Stanford HIV drug resistance database algorithm. Data was analysed with SPSS Statistics software. RESULTS: We found a mean viral load of 4.17 log10 c/mL (SD 1.11) at the time of virologic failure. Forty-eight percent of the samples were raltegravir resistant. The Y143R/H/C substitutions were the most prevalent, followed by the N155H, and both Q148H/K and G140S/A in the same proportion. The Q148 + G140 combination was found in (12%) of the samples. Cross-resistance to elvitegravir was found in 83.3% and in 18.2% for both dolutegravir and bictegravir. Thirteen samples (52%) were susceptible to the four integrase strand-transfer inhibitors. CONCLUSIONS: Our findings suggest a high occurrence of resistance and cross-resistance to other integrase inhibitors among multi-experienced subjects failing raltegravir. We found a modestly lower proportion of cross-resistance to dolutegravir than data from clinical trials. Likely this drug could be used for salvage therapy. Explanations for the absence of mutations in half of the samples, other than reduced adherence, should be further investigated. Close surveillance is needed.

The successful application of a national peer advisory committee for physicians who provide salvage regimens to heavily antiretroviral-experienced patients in mexican human immunodeficiency virus clinics.

BACKGROUND: Designing optimal antiretroviral (ARV) salvage regimens for multiclass drug-resistant, human immunodeficiency virus (HIV)-infected patients demands specific clinical skills. Our aim was to assess the virologic and immunologic effects of the treatment recommendations drafted by a peer advisory board to physicians caring for heavily ARV-experienced patients. METHODS: We conducted a nationwide, HIV clinic-based, cohort study in Mexico. Adults infected with HIV were assessed for a median of 33 months (interquartile range [IQR] = 22-43 months). These patients had experienced the virologic failure of at least 2 prior ARV regimens and had detectable viremia while currently being treated; their physicians had received therapeutic advice, by a panel of experts, regarding the ARV salvage regimen. The primary endpoint was the incidence of loss of virologic response (plasma HIV-RNA levels of <200 copies per mL, followed by levels above this threshold) during the follow-up assessment using an observed-failure competing risks regression analysis. RESULTS: A total of 611 patients were observed (median ARV therapy exposure = 10.5 years; median prior regimens = 4). The probabilities of virologic failure were 11.9%, 14.4%, 16.9%, and 19.4% at the 12-, 24-, 36-, and 48-month follow-up assessments, respectively. Of the 531 patients who achieved a confirmed plasma HIV-RNA level below 200 copies per mL, the median increase in blood CD4(+) T-cell count was 162 cells per mL (IQR = 45-304 cells per mL). CONCLUSIONS: In routine practice, a high rate of patients with extensive ARV experience, who received an optimized salvage regimen recommended by a peer advisory committee, achieved a long-term sustained virologic response and immune reconstitution.

Transmitted HIV drug resistance among drug-naive subjects recently infected with HIV in Mexico City: a World Health Organization survey to classify resistance and to field test two alternative patient enrollment methods.

In 2004, the World Health Organization performed a survey to assess transmitted drug resistance in Mexico City among drug-naive persons with newly diagnosed human immunodeficiency virus (HIV) infection and likely to be recently infected who were attending 3 voluntary counseling and testing sites. A parallel study comparing 2 alternative methods of enrolling survey participant was conducted in 9 voluntary counseling and testing sites in central Mexico. In study arm 1, subject information, consent and blood specimens were obtained during the HIV diagnostic testing visit. In study arm 2, consent and blood specimens were obtained at the return visit, only from those who were HIV infected. This survey classified nonnucleoside reverse-transcriptase inhibitor and nucleoside reverse-transcriptase inhibitor transmitted drug resistance as <5% and 5%-15%, respectively. Arm 2 yielded major advantages in cost and workload, with no evidence of increased sampling bias.

Effects of progesterone on the content of CCR5 and CXCR4 coreceptors in PBMCs of seropositive and exposed but uninfected Mexican women to HIV-1.

CCR5 and CXCR4 play an important role in the establishment of HIV infection and disease progression. Caucasian people exposed to HIV but uninfected (EU) present a deletion of 32bp in CCR5 that has not been reported in EU Hispanics from Latin America. Therefore, other factors besides mutations should be involved in this phenomenon. Studies in healthy women have shown that sex hormones such as progesterone (P) can modulate CCR5/CXCR4 expression through an unknown mechanism. The aim of this paper was to determine the role of P in the regulation of CCR5 and CXCR4 in peripheral blood mononuclear cells (PBMCs) of HIV-1 infected and EU women. We analyzed HIV-1-infected women with stable highly active antiretroviral therapy (HAART) with CD4+ cell counts <400/mm(3) or diminution of 20%, EU and HIV-1 seronegative healthy controls. 5×10(6) PBMCs, from HIV-1 infected women, EU women and HIV-1 seronegative healthy controls were cultured and incubated with P (10 or 100 nM), RU486 (P antagonist, 1 µM) or P (100 nM)+RU486 (1 µM). CCR5/CXCR4 content was determined by Western blot. Densitometry data were analyzed using Mann-Whitney test. We found that CCR5 content was reduced by P in all groups. In contrast, CXCR4 content was increased by P in healthy controls and in HIV-1 infected women. Interestingly, CXCR4 content was reduced by P in EU. RU486 did not block P effects in any group. These findings suggest that P should participate in the acquisition and progression of HIV-1 infection by modulating CCR5 and CXCR4 expression. P could contribute to the resistance acquisition of HIV by EU through the down-regulation of both coreceptors.

HIV Drug Resistance-Associated Mutations in Antiretroviral Naïve HIV-1-Infected Latin American Children.

Our goal was to describe the presence of HIV drug resistance among HIV-1-infected, antiretroviral (ARV) naïve children and adolescents in Latin America and to examine resistance in these children in relation to drug exposure in the mother. Genotyping was performed on plasma samples obtained at baseline from HIV-1-infected participants in a prospective cohort study in Brazil, Argentina, and Mexico (NISDI Pediatric Study). Of 713 HIV-infected children enrolled, 69 were ARV naïve and eligible for the analysis. At enrollment, mean age was 7.3 years; 81.2% were infected with HIV perinatally. Drug resistance mutations (DRMs) were detected in 6 (8.7%; 95% confidence interval 3.1-18.2%) ARV-naïve subjects; none of the mothers of these 6 received ARVs during their pregnancies and none of the children received ARV prophylaxis. Reverse transcriptase mutations K70R and K70E were detected in 3 and 2 subjects, respectively; protease mutation I50 V was detected in 1 subject. Three of the 6 children with DRMs initiated ARV therapy during followup, with a good response in 2. The overall rate of primary drug resistance in this pediatric HIV-infected population was low, and no subjects had more than 1 DRM. Mutations associated with resistance to nucleoside reverse transcriptase inhibitors were the most prevalent.

Antiretroviral resistance among HIV type 1-infected women first exposed to antiretrovirals during pregnancy: plasma versus PBMCs.

Resistance-associated mutations (RAMs) in plasma samples from HIV-1-infected women who received antiretroviral (ARV) prophylaxis during pregnancy was assessed and correlated with the detection of RAMs in peripheral blood mononuclear cells (PMBCs). The study population was composed of HIV-1-infected women enrolled in a prospective cohort study in Latin America and the Caribbean (NISDI Perinatal Study) as of March 1, 2005, who were diagnosed with HIV-1 infection during the current pregnancy, who received ARVs during pregnancy for prevention of mother-to-child transmission of HIV-1, and who were followed through at least the 6-12 week postpartum visit. Plasma samples collected at enrollment during pregnancy and at 6-12 weeks postpartum were assayed for RAMs. Plasma results were compared to previously described PBMC results from the same study population. Of 819 enrolled subjects, 197 met the eligibility criteria. Nucleic acid amplification was accomplished in 123 plasma samples at enrollment or 6-12 weeks postpartum, and RAMs were detected in 22 (17.9%; 95%CI: 11.7-25.9%). Previous analyses had demonstrated detection of RAMs in PBMCs in 19 (16.1%). There was high concordance between RAMs detected in plasma and PBMC samples, with only eight discordant pairs. The prevalence of RAMs among these pregnant, HIV-1-infected women is high (15%). Rates of detection of RAMs in plasma and PBMC samples were similar.

Improving outcome of human immunodeficiency virus-infected patients in a Mexican intensive care unit.

BACKGROUND: In Latin America, insufficient data are available to improve local admission policies for human immunodeficiency virus (HIV) patients in the intensive care units (ICU). We undertook this study to evaluate the outcome and survival determinants of HIV patients in a Mexican ICU during three time periods. METHODS: From December 1985 through January 2006, a clinical chart-based, retrospective study of all HIV patients admitted to the ICU was conducted. Demographic, clinical and laboratory data; disease severity score (APACHE II) and mortality were evaluated. A comprehensive database was created and data were analyzed using survival and regression models. RESULTS: Ninety HIV patients were admitted to the ICU during the study: 16 (18%) in 1985-1992 (non-antiretroviral [ARV]-period), 21 (23%) in 1993-1996 (ARV-period), and 53 (58%) in 1996-2006 (highly active antiretroviral treatment [HAART] period). Leading reasons for admission were the need for mechanical ventilatory support (MVS, 85.5%), septic shock (23%), and non-HIV/AIDS complications (15.5%). Survival in the ICU increased from 12.5% (non-ARV period) to 57% (HAART period). Mortality during ICU stay was associated with MVS (HR: 3.2; 95% CI 1.0-10.2) and APACHE II > or =13 points (HR: 2.2; 95% CI 1.3-4.0). Use of steroids (HR: 0.4; 95% CI 0.2-0.8) and HAART (HR: 0.25; 95% CI 0.1-0.5) were associated with a lower risk of death. In multivariate analysis, septic shock was the main predictor of death in the ICU (HR: 2.4; 95% CI 1.1-5.2) and after discharge. HAART remained as a significant protective factor. CONCLUSIONS: Overall survival in Mexican HIV patients admitted to an ICU has substantially increased in recent years. These data should encourage policies that consider HIV patients as good candidates for receiving intensive care.

Drug resistance among HIV-infected pregnant women receiving antiretrovirals for prophylaxis.

OBJECTIVE: To quantify primary resistance mutations (PRMs) among HIV-1-infected women receiving antiretroviral therapy (ART) for prevention of mother-to-child transmission (MTCT). METHODS: Peripheral blood mononuclear cell samples from HIV-1-infected women enrolled in a prospective cohort study in Argentina, the Bahamas, Brazil, and Mexico (NISDI Perinatal Study) were assayed for PRMs. Eligible women were those enrolled by March 2005 and diagnosed with HIV-1 infection during the current pregnancy, and who received ART for MTCT prophylaxis and were followed for 6-12 weeks postpartum. RESULTS: Of 819 women, 198 met the eligibility criteria. At enrollment, 98% were asymptomatic, 62% had plasma viral load < 1000 copies/ml, 53% had CD4+ cell count > or = 500 cells/microl, and 78% were ART-exposed (mean duration, 8.0 weeks; 95% confidence interval, 7.1-8.9). The most complex ART regimen during pregnancy was usually (81%) a three-drug regimen [two nucleoside reverse transcriptase inhibitors (NRTIs) + one protease inhibitor or two NRTIs + one non-nucleoside reverse transcriptase inhibitor). PRMs were observed in samples from 19 (16%) of 118 women that were amplifiable at one or both time points [11/76 (14%) at enrollment; 14/97 (14%) at 6-12 weeks]. The occurrence of PRMs was not associated with clinical, immunological, or virological disease stage at either time point, whether ART-naive versus exposed at enrollment, or the most complex or number of antiretroviral drug regimens received during pregnancy (P > 0.1). Of 55 women with amplifiable samples at both time points, PRMs were detected in 11 samples (20%). CONCLUSIONS: PRMs occurred among 16.1% of relatively healthy HIV-1-infected mothers from Latin American and Caribbean countries receiving MTCT prophylaxis.

Hepatobiliary diseases in patients with human immunodeficiency virus (HIV) treated with non highly active anti-retroviral therapy: frequency and clinical manifestations.

OBJECTIVE: To evaluate the frequency of hepatobiliary diseases and the clinical manifestations in patients with HIV treated with non highly active anti-retroviral therapy. METHODS: Seven hundred clinical records of patients with HIV infection who entered the Instituto Nacional de Ciencias Médicas y de la Nutrición Salvador Zubirán from January 1987 to December 1996 were reviewed. All patients with alterations associated to hepatobiliary disease and/or liver function tests derangement throughout the clinical development of their disease were included. Demographic variables, date of diagnosis and clinical stage of the disease, as well as the presentation forms, diagnostic approach and image studies were analyzed. RESULTS: One hundred and sixty-one patients (22.8%) with hepatobiliary manifestations were found. The average time between the HIV diagnosis and the presentation of hepatic manifestations was 2-12 years. The majority of patients 124/161 (77%) did not show clinical signs of liver damage. The diagnostic suspicion was established by the presence of alkaline phosphatase above normal in 29% and alkaline phosphatase plus aminotransferases above normal in 45%. Hepatomegaly and jaundice were present in 18% and 4% of the patients, respectively. The most frequent ultrasonographic diagnosis were hepatomegaly (40%) and steatosis (30%). Liver biopsies were performed in 85 (51%) of the patients. The main histologic diagnoses were granulomatous hepatitis (29%), steatosis plus granulomatous hepatitis (19.5%), and steatosis alone (14.6%). Microorganisms were isolated in 27.9% being the most frequent Mycobacterium tuberculosis (26.6%), Histoplasma capsulatum (20%), Cytomegalovirus (13.3%), and Mycobacterium avium intracellulare (11%). The HBsAg was positive in 21 of the 69 patients (30.4%). CONCLUSIONS: The clinical presentation was asymptomatic in most of cases and the main etiology could be explained by the presence of associated infections, granulomatoses and liver steatosis.

Identification of the infectious source of an unusual outbreak of histoplasmosis, in a hotel in Acapulco, state of Guerrero, Mexico.

Three isolates of Histoplasma capsulatum were identified from mice lung, liver, and spleen inoculated with soil samples of the X hotel's ornamental potted plants that had been fertilized with organic material known as compost. The presence of H. capsulatum in the original compost was detected using the dot-enzyme-linked immunosorbent assay. Nested-PCR, using a specific protein Hcp100 coding gene sequence, confirmed the fungal identification associated with an unusual histoplasmosis outbreak in Acapulco. Although, diversity between the H. capsulatum isolate from the hotel and some clinical isolates from Guerrero (positive controls) was observed using random amplification of polymorphic DNA based-PCR, sequence analyses of H-anti and ole fragment genes revealed a high homology (92-99%) between them.

[Effectiveness of preemptive therapy with ganciclovir in recipients of renal transplants at high risk (R-/D+) for the development of cytomegalovirus disease]. / Efectividad de la terapia anticipada con ganciclovir en receptores de trasplante renal de alto riesgo (R-/D+) para desarrollo de enfermedad por citomegalovirus.

Current management of renal transplant recipients who are CMV seronegative (R-) and receive an organ from a seropositive donor (D+) is controversial. These patients are at high risk for CMV disease and are usually treated with ganciclovir prophylaxis at variable dose and duration. An alternative to this approach is to administer ganciclovir only to those patients who are identified by virological markers to be at the highest risk to develop the disease (preemptive therapy). This prospective trial was conducted to asses the value of preemptive therapy to prevent CMV disease in R-/D+ kidney transplant recipients on triple drug immunosuppression without antilymphocyte induction. Sixteen adults receiving their first kidney transplant were enrolled and followed with pp65 antigenemia assay performed biweekly for the first 16 postransplant weeks, and then monthly to complete 12 months. Ganciclovir (5 mg/kg/day i.v., for 15 days) was administered as preemptive therapy upon detection of one or more antigen-positive cells per 150 x 10(3) peripheral blood leucocytes examined. For those receiving preemptive therapy, pp65 antigenemia was also repeated after completion of the regimen. CMV antigenemia was detected in 7/16 patients. At mean follow-up of 9 months (4-12 m) none of the 16 patients developed CMV disease. CMV serology (IgM) became positive in all patients after the first antigenemia result. The last follow-up mean serum creatinine (SCr) level was similar in both groups (1.35 mg/dL). In CMV R-/D+, the use of preemptive therapy guided by pp65 antigenemia is effective in preventing CMV disease. By using this strategy, 9 of 16 patients were spared ganciclovir prophylaxis with no effect on rejection or CMV disease. The clinical benefit and cost/effectiveness of this strategy should be evaluated against universal prophylaxis in these high-risk patients.

Efectividad de la terapia anticipada con ganciclovir en receptores de trasplante renal de alto riesgo (R-/D+) para desarrollo de enfermedad por citomegalovirus / Effectiveness of preemptive therapy with ganciclovir in recipients of renal transplants at high risk (R-/D+) for the development of cytomegalovirus disease

Current management of renal transplant recipients who are CMV seronegative (R-) and receive an organ from a seropositive donor (D+) is controversial. These patients are at high risk for CMV disease and are usually treated with ganciclovir prophylaxis at variable dose and duration. An alternative to this approach is to administer ganciclovir only to those patients who are identified by virological markers to be at the highest risk to develop the disease (preemptive therapy). This prospective trial was conducted to asses the value of preemptive therapy to prevent CMV disease in R-/D+ kidney transplant recipients on triple drug immunosuppression without antilymphocyte induction. Sixteen adults receiving their first kidney transplant were enrolled and followed with pp65 antigenemia assay performed biweekly for the first 16 postransplant weeks, and then monthly to complete 12 months. Ganciclovir (5 mg/kg/day i.v., for 15 days) was administered as preemptive therapy upon detection of one or more antigen-positive cells per 150 x 10(3) peripheral blood leucocytes examined. For those receiving preemptive therapy, pp65 antigenemia was also repeated after completion of the regimen. CMV antigenemia was detected in 7/16 patients. At mean follow-up of 9 months (4-12 m) none of the 16 patients developed CMV disease. CMV serology (IgM) became positive in all patients after the first antigenemia result. The last follow-up mean serum creatinine (SCr) level was similar in both groups (1.35 mg/dL). In CMV R-/D+, the use of preemptive therapy guided by pp65 antigenemia is effective in preventing CMV disease. By using this strategy, 9 of 16 patients were spared ganciclovir prophylaxis with no effect on rejection or CMV disease. The clinical benefit and cost/effectiveness of this strategy should be evaluated against universal prophylaxis in these high-risk patients.

Conceptos actuales de la endocarditis infecciosa: diagnóstico, tratamiento y profilaxis / Current concepts of infective endocarditis: diagnosis, treatment and prophylaxis

La endocarditis infecciosa, infección del endocardio valvular y/o mural producida por ciertas bacterias, es generalmente mortal si no se trata de manera oportuna. En el presente artículo se revisan la fisiopatogenia, cuadro clínico, diagnóstico, tratamiento, manejo quirúrgico, pronóstico y profilaxis de este padecimiento.