ART-exposed Patients Research Articles

Applying Next-Generation Sequencing to Track HIV-1 Drug Resistance Mutations Circulating in Portugal.

The global scale-up of antiretroviral treatment (ART) offers significant health benefits by suppressing HIV-1 replication and increasing CD4 cell counts. However, incomplete viral suppression poses a potential threat for the emergence of drug resistance mutations (DRMs), limiting ART options, and increasing HIV transmission. We investigated the patterns of transmitted drug resistance (TDR) and acquired drug resistance (ADR) among HIV-1 patients in Portugal. Data were obtained from 1050 HIV-1 patient samples submitted for HIV drug resistance (HIVDR) testing from January 2022 to June 2023. Evaluation of DRM affecting viral susceptibility to nucleoside/tide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), and integrase strand transfer inhibitors (INSTIs) was performed using an NGS technology, the Vela Diagnostics Sentosa SQ HIV-1 Genotyping Assay. About 71% of patients were ART naïve and 29% were experienced. Overall, 20% presented with any DRM. The prevalence of TDR and ADR was 12.6% and 41.1%, respectively. M184V, T215S, and M41L mutations for NRTI, K103N for NNRTI, and M46I/L for PIs were frequent in naïve and treated patients. E138K and R263K mutations against INSTIs were more frequent in naïve than treated patients. TDR and ADR to INSTIs were 0.3% and 7%, respectively. Patients aged 50 or over (OR: 1.81, p = 0.015), originating from Portuguese-speaking African countries (PALOPs) (OR: 1.55, p = 0.050), HIV-1 subtype G (OR: 1.78, p = 0.010), and with CD4 < 200 cells/mm3 (OR: 1.70, p = 0.043) were more likely to present with DRMs, while the males (OR: 0.63, p = 0.003) with a viral load between 4.1 to 5.0 Log10 (OR: 0.55, p = 0.003) or greater than 5.0 Log10 (OR: 0.52, p < 0.001), had lower chances of presenting with DRMs. We present the first evidence on TDR and ADR to INSTI regimens in followed up patients presenting for healthcare in Portugal. We observed low levels of TDR to INSTIs among ART-naïve and moderate levels in ART-exposed patients. Regimens containing PIs could be an alternative second line in patients with intermediate or high-level drug resistance, especially against second-generation INSTIs (dolutegravir, bictegravir, and cabotegravir).

High Burden of Cryptococcal Meningitis Among Antiretroviral Therapy-Experienced Human Immunodeficiency Virus-Infected Patients in Northern Uganda in the Era of "Test and Treat": Implications for Cryptococcal Screening Programs.

BackgroundThe impact of the “test and treat” program for human immunodeficiency virus (HIV) treatment in rural areas of Uganda on cryptococcal antigen (CrAg) screening or cryptococcal meningitis (CM) is poorly understood.MethodsWe retrospectively evaluated clinical factors in 212 HIV-infected patients diagnosed with CM from February of 2017 to November of 2019 at Lira Regional Referral Hospital in northern Uganda.ResultsAmong 212 patients diagnosed with CM, 58.5% were male. Median age was 35 years; CD4 count and HIV viral load (VL) were 86 cells/μL and 9463 copies/mL, respectively. Only 10% of patients had a previous history of CM. We found that 190 of 209 (90.9%) patients were ART experienced and 19 (9.1%) were ART naive. Overall, 90 of 212 (42.5%) patients died while hospitalized (median time to death, 14 days). Increased risk of death was associated with altered mental status (hazard ratio [HR], 6.6 [95% confidence interval {CI}, 2.411–18.219]; P ≤ .0001) and seizures (HR, 5.23 [95% CI, 1.245–21.991]; P = .024).ConclusionsCurrent guidelines recommend CrAg screening based on low CD4 counts for ART-naive patients and VL or clinical failure for ART-experienced patients. Using current guidelines for CrAg screening, some ART-experienced patients miss CrAg screening in resource-limited settings, when CD4 or VL tests are unavailable. We found that the majority of HIV-infected patients with CM were ART experienced (90.9%) at presentation. The high burden of CM in ART-experienced patients supports a need for improved CrAg screening of ART-exposed patients.

Impact of ARTs on oncological outcomes in young breast cancer survivors.

Impact of ARTs on oncological outcomes in young breast cancer survivors.

Impact of antiretroviral drugs on PD-L1 expression and copy number gains with clinical outcomes in HIV-positive and -negative locally advanced cervical cancers.

Cervical cancer has become a leading cause of death in both HIV-infected and uninfected women. Previous studies have revealed that antiretroviral therapy (ART) possesses anti-human papillomavirus (HPV) and antitumour properties, potentially serving as an anticancer agent and improving functional immunity in HIV-positive individuals. However, to the best of our knowledge, no studies have examined the association between ART and the clinical outcome of patients with pre-existing invasive cervical cancer. The current study analysed 48 HIV-positive and 123 HIV-negative patients with locally advanced stage IB2-IVA cervical cancer between December 2008 and December 2016. Tumours were categorized based on programmed cell death-ligand 1 (PD-L1) immunoreactivity and copy number alterations in the PD-L1 gene, as determined by fluorescence in situ hybridization. The results revealed that ART-treated patients exhibited a lower prevalence of PD-L1 immunopositivity, PD-L1 amplification and polysomy compared with patients that did not receive ART and those that were HIV-negative. Furthermore, ART-treated patients with PD-L1 immunonegativity exhibited an improved recurrence-free survival (RFS) compared with patients that did not receive ART and HIV-negative individuals with PD-L1 immunopositivity (P=0.041 vs. P=0.030). Additionally, ART-exposed patients with PD-L1 disomy demonstrated improved locoregional recurrence-free survival (LRR) when compared with HIV-negative patients with PD-L1 amplification and polysomy (P=0.039 vs. P=0.007), RFS (P<0.001 vs. P=0.006) and cancer-specific survival (CSS) (P=0.021 vs. P=0.025). ART-exposed patients with PD-L1 disomy also exhibited improved RFS (P<0.001) and CSS (P<0.001) compared with HIV-negative patients with PD-L1 amplification. Improved LRRs were demonstrated in ART-exposed patients with PD-L1 disomy (P=0.028) compared with non-HIV patients with polysomy. Following multivariate analysis, International Federation of Gynaecology and Obstetrics stage and PD-L1 amplification were determined to be predictors of poor a RFS [hazard ratio (HR), 2.43; 95% confidence interval (CI), 1.37–4.30; P=0.002 vs. HR, 7.03; 95% CI, 2.79–17.74; P<0.001) and CSS (HR, 11.47; 95% CI, 4.70–27.99; P<0.001 vs. HR, 4.05; 95% CI, 1.64–9.98; P=0.002). However, only PD-L1 polysomy was determined to be a predictor of poor LRR (HR, 2.50; 95% CI, 1.11–5.63; P=0.027). HIV status was not associated with poor outcomes, as determined using Cox models. The results of the current study indicated that ART may be used for the treatment of cervical cancer in both HIV-infected and uninfected patients. However, additional research is required to further elucidate these results.

Prognostic factors in HIV-positive patients with non-Hodgkin lymphoma: a Peruvian experience

BackgroundNon-Hodgkin lymphoma (NHL) is the most common cancer in people with HIV. Although 95% of HIV patients are in developing countries like Peru, the majority of these studies have been conducted in developed countries. In this study we aim to evaluate prognostic factors associated with outcomes in HIV positive patients undergoing systemic therapy for treatment of NHL.MethodsThis retrospective study includes patients with NHL seen in the Instituto Nacional de Enfermedades Neoplasicas (INEN) between 2004 to 2014. Patients were divided into two groups: antiretroviral therapy (ART) -naïve (n = 34) and those previously treated, ART-exposed (n = 13), at the time of diagnosis. All patients received chemotherapy and ART. The medical records were reviewed. Data were analyzed using t-test and chi-square test. Survival curves were estimated by the Kaplan-Meier method and comparison was done by log-rank test. Multivariate analysis for overall survival (OS) was performed with the Cox proportional hazard regression model.ResultsAll ART-exposed patients were from the capital city (p = 0.039); they had significantly lower hemoglobin levels compared to ART-naïve patients (p = 0.026). The median OS was 47.7 months with a 5-yr OS of 36.1%. The median OS for ART naïve patients was significantly higher than that for ART-exposed patients (57.05 and 21.09 months, respectively; p = 0.018). Advanced stage and low serum albumin were associated with lower OS in both groups. Age > 60 was associated with worse outcomes in the ART-naïve cohort.ConclusionsAdvanced stage, low serum albumin and previous ART treatment were the primary prognostic factors associated with poorer outcomes in patients with NHL and HIV infection. In ART-naïve patients, age > 60 was associated with worse outcomes but in this cohort, older patients still had better overall outcomes than ART-exposed patients.

Incidence and Risk Factors for Prediabetes and Diabetes Mellitus Among HIV-infected Adults on Antiretroviral Therapy: A Systematic Review and Meta-analysis.

To summarize evidence on the rates and drivers of progression from normoglycemia to prediabetes and/or diabetes mellitus (hereafter "diabetes") in antiretroviral treatment (ART)-exposed HIV-infected people. We searched EMBASE, PubMed, Web of Science, and Global Index Medicus to identify articles published from 1 January 2000 to 30 April 2017. A random-effects model produced a summary estimate of the incidence across studies and heterogeneity was assessed using Cochrane's Q statistic. We included 44 studies, whose methodologic quality was high with only 10 (30%) medium-quality studies and none of low quality. There was substantial heterogeneity between studies in estimates of the incidence of diabetes and prediabetes. The pooled incidence rate of overt diabetes and prediabetes were 13.7 per 1,000 person-years of follow-up (95% CI = 13, 20; I = 98.1%) among 396,496 person-years and 125 per 1,000 person-years (95% CI = 0, 123; I = 99.4) among 1,532 person-years, respectively. The major risk factors for diabetes and prediabetes were aging, family history of diabetes, Black or Hispanic origin, overweight/obesity, central obesity, lipodystrophy/lipoatrophy, dyslipidemia, metabolic syndrome, increased baseline fasting glycemia, and certain ART regimens. These data highlight the important and fast-increasing burden of diabetes and prediabetes among the ART-exposed HIV-infected population. More research is needed to better capture the interplay between prediabetes/diabetes and ART in HIV-infected patients, considering the increasing number of ART-exposed patients subsequent to the World Health Organization's recommendation of initiating ART at HIV infection diagnosis regardless of CD4 count and age.

Is there sufficient evidence for a causal association between antiretroviral therapy and diabetes in HIV-infected patients? A meta-analysis.

The association of antiretroviral therapy (ART) with diabetes is inconsistent and varies widely across primary epidemiological studies. A comprehensive and more precise estimate of this association is fundamental to establishing a plausible causal link between ART and diabetes. We identified epidemiological studies that compared mean fasting plasma glucose (FPG) concentrations and proportions of diabetes and metabolic syndrome between HIV-infected patients naïve and exposed to ART. Mean difference in FPG concentrations and odds ratios of diabetes and metabolic syndrome were pooled using random-effects meta-analyses. Data on 20178 participants from 41 observational studies were included in the meta-analyses. Mean FPG concentrations (Pooled mean difference: 4.66mg/dL; 95% confidence interval [CI], 2.52 to 6.80; 24 studies) and the odds of diabetes (Pooled odds ratios: 3.85; 95% CI, 2.93 to 5.07; 10 studies) and metabolic syndrome (Pooled odds ratios: 1.45; 95% CI, 1.03 to 2.03; 18 studies) were significantly higher among ART-exposed patients, compared to their naïve counterparts. ART was also associated with significant increases in FPG levels in studies with mean ART duration ≥18months (Pooled mean difference: 4.97mg/dL; 95% CI, 3.10 to 6.84; 14 studies), but not in studies with mean ART duration <18months (Pooled mean difference: 4.40mg/dL, 95% CI, -0.59 to 9.38; 7 studies). ART may potentially be the single most consistent determinant of diabetes in people living with HIV worldwide. However, given the preponderance of cross-sectional studies in the meta-analysis, the association between ART and diabetes cannot be interpreted as cause and effect.

Evidence of increased blood pressure and hypertension risk among people living with HIV on antiretroviral therapy: a systematic review with meta-analysis.

Owing to antiretroviral drug-induced endothelial dysfunction, HIV-infected patients on antiretroviral therapy (ART) may have elevated blood pressure. We conducted a systematic review and meta-analysis to estimate the effects of ART on blood pressure levels and hypertension risk among HIV-infected populations worldwide. We sought articles that compared the mean blood pressure measurements and hypertension prevalence between HIV-infected adults naive and exposed to ART. Thirty-nine studies comprising 44 903 participants met the inclusion criteria. Overall, systolic (mean difference (MD) 4.52 mm Hg, 95% confidence interval (CI) 2.65-6.39, I(2)=68.1%, 19 studies) and diastolic blood pressure levels (MD 3.17 mm Hg, 95% CI 1.71-4.64, I(2)=72.5%, 16 studies) were significantly higher among ART-exposed patients compared with treatment-naive patients. Similarly, the risk of hypertension was significantly higher among ART-exposed patients, such that among 28 908 ART-exposed patients, 4195 (14.5%) had hypertension compared with 950 of 9086 (10.5%) in those who were treatment-naive (odds ratio 1.68, 95% CI 1.35-2.10, I(2)=81.5%, 32 studies). In summary, exposure to ART is significantly associated with increased systolic and diastolic blood pressure levels, and increased risk of hypertension, regardless of study-level sociodemographic differences. This meta-analysis supports the need for population-based strategies to reduce the risk of high blood pressure among people living with HIV on ART.

Impact of antiretroviral therapy on serum lipoprotein levels and dyslipidemias: A systematic review and meta-analysis

BackgroundAntiretroviral drugs increase biosynthesis and reduce hepatic clearance of serum cholesterol. It is thus important to evaluate the impact of antiretroviral treatment on serum lipoprotein levels and the risk of dyslipidemia. MethodsWe searched EMBASE and PubMed for articles comparing lipid profiles between HIV-infected adult patients naïve and exposed to antiretroviral therapy (ART). Eligible studies were pooled by performing random-effects meta-analyses of mean serum lipoprotein levels and prevalence estimates of dyslipidemias. Results51 observational studies comprising 37,110 patients were included in the meta-analyses. ART-exposed patients had significantly higher concentrations of total cholesterol (45 studies, mean difference [MD]=29.4mg/dL, 95% confidence interval [CI] 26.5 to 32.4, I2=82.2%), low density lipoprotein-cholesterol (37 studies, MD=14.9mg/dL, 95% CI 11.2 to 18.5, I2=86.1%), and triglycerides (43 studies, MD=46.8mg/dL, 95% CI 37.8 to 55.8, I2=97.1%), compared with ART-naïve patients. The risks of hypercholesterolemia (25 studies, pooled odds ratio [OR] 3.8, 95% CI 3.1 to 4.7, I2=60.0%) and hypertriglyceridemia (21 studies, OR 2.2, 95% CI 1.7 to 2.9, I2=81.7%) were also significantly higher among ART-exposed patients, compared with ART-naïve patients. ConclusionAntiretroviral therapy is significantly associated with increase in serum lipid levels and increased risk of dyslipidemia. Whether or not these associations are causal should be investigated by future studies.

Performance and logistical challenges of alternative HIV-1 virological monitoring options in a clinical setting of Harare, Zimbabwe.

We evaluated a low-cost virological failure assay (VFA) on plasma and dried blood spot (DBS) specimens from HIV-1 infected patients attending an HIV clinic in Harare. The results were compared to the performance of the ultrasensitive heat-denatured p24 assay (p24). The COBAS AmpliPrep/COBAS TaqMan HIV-1 test, version 2.0, served as the gold standard. Using a cutoff of 5,000 copies/mL, the plasma VFA had a sensitivity of 94.5% and specificity of 92.7% and was largely superior to the VFA on DBS (sensitivity = 61.9%; specificity = 99.0%) or to the p24 (sensitivity = 54.3%; specificity = 82.3%) when tested on 302 HIV treated and untreated patients. However, among the 202 long-term ART-exposed patients, the sensitivity of the VFA decreased to 72.7% and to 35.7% using a threshold of 5,000 and 1,000 RNA copies/mL, respectively. We show that the VFA (either on plasma or on DBS) and the p24 are not reliable to monitor long-term treated, HIV-1 infected patients. Moreover, achieving acceptable assay sensitivity using DBS proved technically difficult in a less-experienced laboratory. Importantly, the high level of virological suppression (93%) indicated that quality care focused on treatment adherence limits virological failure even when PCR-based viral load monitoring is not available.

Infection duration and inflammatory imbalance are associated with atherosclerotic risk in HIV-infected never-smokers independent of antiretroviral therapy

To determine whether the reported increased atherosclerotic risk among HIV-infected individuals is related to antiretroviral therapy (ART) or HIV infection, whether this risk persists in never-smokers, and whether inflammatory profiles are associated with higher risk. Matched cross-sectional study. A total of 100 HIV-infected patients (50 ART-treated >4 years, 50 ART-naive but HIV-infected >2 years) and 50 HIV-negative controls were recruited in age-matched never-smoking male triads (mean age 40.2 years). Carotid intima-media maximal thickness (c-IMT) was measured across 12 sites. Pro-inflammatory [highly sensitive C-reactive protein (hs-CRP), resistin, interleukin-6, interleukin-18, insulin, serum amyloid A, D-dimer) and anti-inflammatory (total and high molecular weight adiponectin, interleukin-27, interleukin-10) markers were dichotomized into high/low scores (based on median values). c-IMT was compared across HIV/treatment groups or inflammatory profiles using linear regression models adjusted for age, diabetes, hypertension, and, for HIV-infected patients, nadir CD4 cell counts. Although adjusted c-IMT initially tended to be thicker in ART-exposed patients (P=0.2), in post-hoc analyses stratifying by median HIV duration we observed significantly higher adjusted c-IMT in patients with longer (>7.9 years: 0.760±0.008 mm) versus shorter prevalent duration of known HIV infection (<7.9 years: 0.731±0.008 mm, P=0.02), which remained significant after additionally adjusting for ART (P=0.04). Individuals with low anti-inflammatory profile (<median versus >median score) had thicker c-IMT (0.754±0.006mm versus 0.722±0.006 mm, P<0.001), with anti-inflammatory markers declining as prevalent duration of HIV infection increased (P for linear trend <0.001). Known HIV duration is related to thicker c-IMT, irrespective of ART, in these carefully selected age-matched never-smoking HIV-treated and ART-naive male individuals. Higher levels of anti-inflammatory markers appeared protective for atherosclerosis.

Phylogenetic Analysis of Near Full-Length HIV Type 1 Genomic Sequences from 21 Korean Individuals

The Korean subclade of subtype B (KSB) is the most prevalent HIV-1 strain found in Korea. To date, only two near full-length HIV-1 sequences from Korean patients have been reported. Here, we analyzed a total of 24 near full-length genomes of HIV-1 strains that were isolated from 17 antiretroviral therapy (ART)-naive patients and four ART-exposed patients. Proviral DNA from peripheral blood mononuclear cells was PCR amplified and directly sequenced. Phylogenetic analyses were used to classify viruses from 19 patients as KSB, from one patient as subtype B, from one patient as subtype D, and three viruses from one patient as CRF02_AG. All KSB viruses demonstrated TAAAA instead of TATAA at the TATA box in the LTR. Of the 19 KSB patients, their sequence identities at the nucleotide level ranged from 89.8% to 97.1% from the lowest env gene to the highest pol gene. Other than the CRF02_AG viruses, no recombination events were noted in any of the 19 KSB patients, which is consistent with our previous studies on the pol, vif, and nef genes. Except for one strain, all of the strains were classified as non-syncytium-inducing strains. This is the first report to describe near full-length KSB.

Long‐Term Trends of HIV Type 1 Drug Resistance Prevalence among Antiretroviral Treatment–Experienced Patients in Switzerland

Accurate quantification of the prevalence of human immunodeficiency virus type 1 (HIV-1) drug resistance in patients who are receiving antiretroviral therapy (ART) is difficult, and results from previous studies vary. We attempted to assess the prevalence and dynamics of resistance in a highly representative patient cohort from Switzerland. On the basis of genotypic resistance test results and clinical data, we grouped patients according to their risk of harboring resistant viruses. Estimates of resistance prevalence were calculated on the basis of either the proportion of individuals with a virologic failure or confirmed drug resistance (lower estimate) or the frequency-weighted average of risk group-specific probabilities for the presence of drug resistance mutations (upper estimate). Lower and upper estimates of drug resistance prevalence in 8064 ART-exposed patients were 50% and 57% in 1999 and 37% and 45% in 2007, respectively. This decrease was driven by 2 mechanisms: loss to follow-up or death of high-risk patients exposed to mono- or dual-nucleoside reverse-transcriptase inhibitor therapy (lower estimates range from 72% to 75%) and continued enrollment of low-risk patients who were taking combination ART containing boosted protease inhibitors or nonnucleoside reverse-transcriptase inhibitors as first-line therapy (lower estimates range from 7% to 12%). A subset of 4184 participants (52%) had >or= 1 study visit per year during 2002-2007. In this subset, lower and upper estimates increased from 45% to 49% and from 52% to 55%, respectively. Yearly increases in prevalence were becoming smaller in later years. Contrary to earlier predictions, in situations of free access to drugs, close monitoring, and rapid introduction of new potent therapies, the emergence of drug-resistant viruses can be minimized at the population level. Moreover, this study demonstrates the necessity of interpreting time trends in the context of evolving cohort populations.