Androgen and gonadotropin patterns differ in HIV-1-infected men who develop lipoatrophy during antiretroviral therapy: a case-control study

OBJECTIVES: We compared androgen and gonadotropin values in HIV-infected men who did and did not develop lipoatrophy on combination antiretroviral therapy (cART). METHODS: From a population of 136 treatment-naïve male Caucasians under successful zidovudine/lamivudine-based cART, the 10 patients developing lipoatrophy (cases) were compared with 87 randomly chosen controls. Plasma levels of free testosterone (fT), dehydroepiandrosterone (DHEA), follicle-stimulating hormone and luteinizing hormone (LH) were measured at baseline and after 2 years of cART. RESULTS: At baseline, 60% of the cases and 71% of the controls showed abnormally low fT values. LH levels were normal or low in 67 and 94% of the patients, respectively, indicating a disturbance of the hypothalamic-pituitary-gonadal axis. fT levels did not significantly change after 2 years of cART. Cases showed a significant increase in LH levels, while controls showed a significant increase in DHEA levels. In a multivariate logistic regression model, lipoatrophy was associated with higher baseline DHEA levels (P=0.04), an increase in LH levels during cART (P=0.001), a lower body mass index and greater age. CONCLUSIONS: Hypogonadism is present in the majority of HIV-infected patients. The development of cART-related lipoatrophy is associated with an increase in LH and a lack of increase in DHEA levels.

Timing of initiation of antiretroviral therapy in AIDS-free HIV-1-infected patients: a collaborative analysis of 18 HIV cohort studies

BACKGROUND: The CD4 cell count at which combination antiretroviral therapy should be started is a central, unresolved issue in the care of HIV-1-infected patients. In the absence of randomised trials, we examined this question in prospective cohort studies. METHODS: We analysed data from 18 cohort studies of patients with HIV. Antiretroviral-naive patients from 15 of these studies were eligible for inclusion if they had started combination antiretroviral therapy (while AIDS-free, with a CD4 cell count less than 550 cells per microL, and with no history of injecting drug use) on or after Jan 1, 1998. We used data from patients followed up in seven of the cohorts in the era before the introduction of combination therapy (1989-95) to estimate distributions of lead times (from the first CD4 cell count measurement in an upper range to the upper threshold of a lower range) and unseen AIDS and death events (occurring before the upper threshold of a lower CD4 cell count range is reached) in the absence of treatment. These estimations were used to impute completed datasets in which lead times and unseen AIDS and death events were added to data for treated patients in deferred therapy groups. We compared the effect of deferred initiation of combination therapy with immediate initiation on rates of AIDS and death, and on death alone, in adjacent CD4 cell count ranges of width 100 cells per microL. FINDINGS: Data were obtained for 21 247 patients who were followed up during the era before the introduction of combination therapy and 24 444 patients who were followed up from the start of treatment. Deferring combination therapy until a CD4 cell count of 251-350 cells per microL was associated with higher rates of AIDS and death than starting therapy in the range 351-450 cells per microL (hazard ratio [HR] 1.28, 95% CI 1.04-1.57). The adverse effect of deferring treatment increased with decreasing CD4 cell count threshold. Deferred initiation of combination therapy was also associated with higher mortality rates, although effects on mortality were less marked than effects on AIDS and death (HR 1.13, 0.80-1.60, for deferred initiation of treatment at CD4 cell count 251-350 cells per microL compared with initiation at 351-450 cells per microL). INTERPRETATION: Our results suggest that 350 cells per microL should be the minimum threshold for initiation of antiretroviral therapy, and should help to guide physicians and patients in deciding when to start treatment.

The Individualized Genetic Barrier Predicts Treatment Response in a Large Cohort of HIV-1 Infected Patients

The success of combination antiretroviral therapy is limited by the evolutionary escape dynamics of HIV-1. We used Isotonic Conjunctive Bayesian Networks (I-CBNs), a class of probabilistic graphical models, to describe this process. We employed partial order constraints among viral resistance mutations, which give rise to a limited set of mutational pathways, and we modeled phenotypic drug resistance as monotonically increasing along any escape pathway. Using this model, the individualized genetic barrier (IGB) to each drug is derived as the probability of the virus not acquiring additional mutations that confer resistance. Drug-specific IGBs were combined to obtain the IGB to an entire regimen, which quantifies the virus' genetic potential for developing drug resistance under combination therapy. The IGB was tested as a predictor of therapeutic outcome using between 2,185 and 2,631 treatment change episodes of subtype B infected patients from the Swiss HIV Cohort Study Database, a large observational cohort. Using logistic regression, significant univariate predictors included most of the 18 drugs and single-drug IGBs, the IGB to the entire regimen, the expert rules-based genotypic susceptibility score (GSS), several individual mutations, and the peak viral load before treatment change. In the multivariate analysis, the only genotype-derived variables that remained significantly associated with virological success were GSS and, with 10-fold stronger association, IGB to regimen. When predicting suppression of viral load below 400 cps/ml, IGB outperformed GSS and also improved GSS-containing predictors significantly, but the difference was not significant for suppression below 50 cps/ml. Thus, the IGB to regimen is a novel data-derived predictor of treatment outcome that has potential to improve the interpretation of genotypic drug resistance tests.

Impact of Switching From Zidovudine to Tenofovir Disoproxil Fumarate on Bone Mineral Density and Markers of Bone Metabolism in Virologically Suppressed HIV-1 Infected Patients; A Substudy of the PREPARE Study

Context: In virologically suppressed, antiretroviral-treated patients, the effect of switching to tenofovir (TDF) on bone biomarkers compared to patients remaining on stable antiretroviral therapy is unknown. Methods: We examined bone biomarkers (osteocalcin [OC], procollagen type 1 amino-terminal propeptide, and C-terminal cross-linking telopeptide of type 1 collagen) and bone mineral density (BMD) over 48 weeks in virologically suppressed patients (HIV RNA < 50 copies/ml) randomized to switch to TDF/emtricitabine (FTC) or remain on first-line zidovudine (AZT)/lamivudine (3TC). PTH was also measured. Between-group differences in bone biomarkers and associations between change in bone biomarkers and BMD measures were assessed by Student's t tests, Pearson correlation, and multivariable linear regression, respectively. All data are expressed as mean (SD), unless otherwise specified. Results: Of 53 subjects (aged 46.0 y; 84.9% male; 75.5% Caucasian), 29 switched to TDF/FTC. There were reductions in total hip and lumbar spine BMD in those switching to TDF/FTC (total hip, TDF/FTC, −1.73 (2.76)% vs AZT/3TC, −0.39 (2.41)%; between-group P = .07; lumbar spine, TDF/FTC, −1.50 (3.49)% vs AZT/3TC, +0.25 (2.82)%; between-group P = .06), but they did not reach statistical significance. Greater declines in lumbar spine BMD correlated with greater increases in OC (r = −0.28; P = .05). The effect of TDF/FTC on bone biomarkers remained significant when adjusted for baseline biomarker levels, gender, and ethnicity. There was no difference in change in PTH levels over 48 weeks between treatment groups (between-group P = .23). All biomarkers increased significantly from weeks 0 to 48 in the switch group, with no significant change in those remaining on AZT/3TC (between-group, all biomarkers, P < .0001). Conclusion: A switch to TDF/FTC compared to remaining on a stable regimen is associated with increases in bone turnover that correlate with reductions in BMD, suggesting that TDF exposure directly affects bone metabolism in vivo.

Pharmacogenetics-based population pharmacokinetic analysis of etravirine in HIV-1 infected individuals

Objectives: Etravirine (ETV) is metabolized by cytochrome P450 (CYP) 3A, 2C9, and 2C19. Metabolites are glucuronidated by uridine diphosphate glucuronosyltransferases (UGT). To identify the potential impact of genetic and non-genetic factors involved in ETV metabolism, we carried out a two-step pharmacogenetics-based population pharmacokinetic study in HIV-1 infected individuals. Materials and methods: The study population included 144 individuals contributing 289 ETV plasma concentrations and four individuals contributing 23 ETV plasma concentrations collected in a rich sampling design. Genetic variants [n=125 single-nucleotide polymorphisms (SNPs)] in 34 genes with a predicted role in ETV metabolism were selected. A first step population pharmacokinetic model included non-genetic and known genetic factors (seven SNPs in CYP2C, one SNP in CYP3A5) as covariates. Post-hoc individual ETV clearance (CL) was used in a second (discovery) step, in which the effect of the remaining 98 SNPs in CYP3A, P450 cytochrome oxidoreductase (POR), nuclear receptor genes, and UGTs was investigated. Results: A one-compartment model with zero-order absorption best characterized ETV pharmacokinetics. The average ETV CL was 41 (l/h) (CV 51.1%), the volume of distribution was 1325 l, and the mean absorption time was 1.2 h. The administration of darunavir/ritonavir or tenofovir was the only non-genetic covariate influencing ETV CL significantly, resulting in a 40% [95% confidence interval (CI): 13–69%] and a 42% (95% CI: 17–68%) increase in ETV CL, respectively. Carriers of rs4244285 (CYP2C19*2) had 23% (8–38%) lower ETV CL. Co-administered antiretroviral agents and genetic factors explained 16% of the variance in ETV concentrations. None of the SNPs in the discovery step influenced ETV CL. Conclusion: ETV concentrations are highly variable, and co-administered antiretroviral agents and genetic factors explained only a modest part of the interindividual variability in ETV elimination. Opposing effects of interacting drugs effectively abrogate genetic influences on ETV CL, and vice-versa.

Virological outcome and management of persistent low-level viraemia in HIV-1-infected patients: 11 years of the Swiss HIV Cohort Study

BACKGROUND Management of persistent low-level viraemia (pLLV) in patients on combined antiretroviral therapy (cART) with previously undetectable HIV viral loads (VLs) is challenging. We examined virological outcome and management among patients enrolled in the Swiss HIV Cohort Study (SHCS). METHODS In this retrospective study (2000-2011), pLLV was defined as a VL of 21-400 copies/mL on ≥3 consecutive plasma samples with ≥8 weeks between first and last analyses, in patients undetectable for ≥24 weeks on cART. Control patients had ≥3 consecutive undetectable VLs over ≥32 weeks. Virological failure (VF), analysed in the pLLV patient group, was defined as a VL>400 copies/mL. RESULTS Among 9972 patients, 179 had pLLV and 5389 were controls. Compared to controls, pLLV patients were more often on unboosted PI-based (adjusted odds ratio, aOR, [95%CI] 3.2 [1.8-5.9]) and NRTI-only combinations (aOR 2.1 [1.1-4.2]) than on NNRTI and boosted PI-based regimens. At 48 weeks, 102/155 pLLV patients (66%) still had pLLV, 19/155 (12%) developed VF, and 34/155 (22%) had undetectable VLs. Predictors of VF were previous VF (aOR 35 [3.8-315]), unboosted PI-based (aOR 12.8 [1.7-96]) or NRTI-only combinations (aOR 115 [6.8-1952]), and VLs>200 during pLLV (aOR 3.7 [1.1-12]). No VF occurred in patients with persistent very LLV (pVLLV, 21-49 copies/mL; N=26). At 48 weeks, 29/39 patients (74%) who changed cART had undetectable VLs, compared to 19/74 (26%) without change (P<0.001). CONCLUSIONS Among patients with pLLV, VF was predicted by previous VF, cART regimen and VL ≥200. Most patients who changed cART had undetectable VLs 48 weeks later. These findings support cART modification for pLLV >200 copies/ml.

Quantifying the turnover of transcriptional subclasses of HIV-1-infected cells

HIV-1-infected cells in peripheral blood can be grouped into different transcriptional subclasses. Quantifying the turnover of these cellular subclasses can provide important insights into the viral life cycle and the generation and maintenance of latently infected cells. We used previously published data from five patients chronically infected with HIV-1 that initiated combination antiretroviral therapy (cART). Patient-matched PCR for unspliced and multiply spliced viral RNAs combined with limiting dilution analysis provided measurements of transcriptional profiles at the single cell level. Furthermore, measurement of intracellular transcripts and extracellular virion-enclosed HIV-1 RNA allowed us to distinguish productive from non-productive cells. We developed a mathematical model describing the dynamics of plasma virus and the transcriptional subclasses of HIV-1-infected cells. Fitting the model to the data allowed us to better understand the phenotype of different transcriptional subclasses and their contribution to the overall turnover of HIV-1 before and during cART. The average number of virus-producing cells in peripheral blood is small during chronic infection. We find that a substantial fraction of cells can become defectively infected. Assuming that the infection is homogenous throughout the body, we estimate an average in vivo viral burst size on the order of 104 virions per cell. Our study provides novel quantitative insights into the turnover and development of different subclasses of HIV-1-infected cells, and indicates that cells containing solely unspliced viral RNA are a good marker for viral latency. The model illustrates how the pool of latently infected cells becomes rapidly established during the first months of acute infection and continues to increase slowly during the first years of chronic infection. Having a detailed understanding of this process will be useful for the evaluation of viral eradication strategies that aim to deplete the latent reservoir of HIV-1.

Ability to Work and Employment Rates in Human Immunodeficiency Virus (HIV)-1-Infected Individuals Receiving Combination Antiretroviral Therapy: The Swiss HIV Cohort Study

Background.  Limited data exist on human immunodeficiency virus (HIV)-infected individuals' ability to work after receiving combination antiretroviral therapy (cART). We aimed to investigate predictors of regaining full ability to work at 1 year after starting cART. Methods.  Antiretroviral-naive HIV-infected individuals <60 years who started cART from January 1998 through December 2012 within the framework of the Swiss HIV Cohort Study were analyzed. Inability to work was defined as a medical judgment of the patient's ability to work as 0%. Results.  Of 5800 subjects, 4382 (75.6%) were fully able to work, 471 (8.1%) able to work part time, and 947 (16.3%) were unable to work at baseline. Of the 947 patients unable to work, 439 (46.3%) were able to work either full time or part time at 1 year of treatment. Predictors of recovering full ability to work were non-white ethnicity (odds ratio [OR], 2.06; 95% confidence interval [CI], 1.20-3.54), higher education (OR, 4.03; 95% CI, 2.47-7.48), and achieving HIV-ribonucleic acid <50 copies/mL (OR, 1.83; 95% CI, 1.20-2.80). Older age (OR, 0.55; 95% CI, .42-.72, per 10 years older) and psychiatric disorders (OR, 0.24; 95% CI, .13-.47) were associated with lower odds of ability to work. Recovering full ability to work at 1 year increased from 24.0% in 1998-2001 to 41.2% in 2009-2012, but the employment rates did not increase. Conclusions.  Regaining full ability to work depends primarily on achieving viral suppression, absence of psychiatric comorbidity, and favorable psychosocial factors. The discrepancy between patients' ability to work and employment rates indicates barriers to reintegration of persons infected with HIV.

Lysis of HIV-1-infected cells and inhibition of viral replication by universal receptor T cells

Increasing evidence suggests that HIV-1-specific cytotoxic T lymphocytes (CTLs) are a key host immune response to HIV-1 infection. Generation of CTL responses for prevention or therapy of HIV-1 infection has several intrinsic technical barriers such as antigen expression and presentation, the varying HLA restrictions between different individuals, and the potential for viral escape by sequence variation or surface molecule alteration on infected cells. A strategy to circumvent these limitations is the construction of a chimeric T cell receptor containing human CD4 or HIV-1-specific Ig sequences linked to the signaling domain of the T cell receptor ζ chain (universal T cell receptor). CD8+ CTLs transduced with this universal receptor can then bind and lyse infected cells that express surface HIV-1 gp120. We evaluated the ability of universal-receptor-bearing CD8+ cells from a seronegative donor to lyse acutely infected cells and inhibit HIV-1 replication in vitro. The kinetics of lysis and efficiency of inhibition were comparable to that of naturally occurring HIV-1-specific CTL clones isolated from infected individuals. Further study will be required to determine the utility of these cells as a therapeutic strategy in vivo.

Identification of inflections in T-cell counts among HIV-1-infected individuals and relationship with progression to clinical AIDS

Studies of circulating T (CD3+) lymphocytes have shown that on a population basis T-cell numbers remain stable for many years after HIV-1 infection (blind T-cell homeostasis), but decline rapidly beginning approximately 1.5–2.5 years before the onset of clinical AIDS. We derived a general method for defining the loss of homeostasis on the individual level and for determining the prevalence of homeostasis loss according to HIV status and the occurrence of AIDS in more than 5,000 men enrolled in the Multicenter AIDS Cohort Study. We used a segmented regression model for log10 CD3+ cell counts that included separate T-cell trajectories before and after a time (the T-cell inflection point) where the loss of T-cell homeostasis was most likely to have occurred. The average slope of CD3+ lymphocyte counts before the inflection point was close to zero for HIV− and HIV+ men, consistent with blind T-cell homeostasis. After the inflection point, the HIV+ individuals who developed AIDS generally showed a dramatic decline in CD3+ cell counts relative to HIV− men and HIV+ men not developing AIDS. A CD3+ cell decline of greater than 10 percent per year was present in 77% of HIV+ men developing AIDS but in only 23% of HIV+ men with no onset of AIDS. Our findings at the individual level support the blind T-cell homeostasis hypothesis and provide strong evidence that the loss of homeostasis is an important mechanism in the pathogenesis of the severe immunodeficiency that characterizes the late stages of HIV infection.

The HIV-1 regulatory proteins Tat and Rev are frequently targeted by cytotoxic T lymphocytes derived from HIV-1-infected individuals

The HIV-1 regulatory proteins Rev and Tat are expressed early in the virus life cycle and thus may be important targets for the immune control of HIV-1-infection and for effective vaccines. However, the extent to which these proteins are targeted in natural HIV-1 infection as well as precise epitopes targeted by human cytotoxic T lymphocytes (CTL) remain to be defined. In the present study, 57 HIV-1-infected individuals were screened for responses against Tat and Rev by using overlapping peptides spanning the entire Tat and Rev proteins. CD8+ T cell responses against Tat and Rev were found in up to 19 and 37% of HIV-1-infected individuals, respectively, indicating that these regulatory proteins are important targets for HIV-1-specific CTL. Despite the small size of these proteins, multiple CTL epitopes were identified in each. These data indicate that Tat and Rev are frequently targeted by CTL in natural HIV-1 infection and may be important targets for HIV vaccines.

Cross-resistance to elvitegravir and dolutegravir in 502 patients failing on raltegravir: a French national study of raltegravir-experienced HIV-1-infected patients

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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 mutations

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Predicted residual activity of rilpivirine in HIV-1 infected patients failing therapy including NNRTIs efavirenz or nevirapine

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Envelope C2-V3-C3-specific antibodies from HIV-1 infected patients from Angola correlate with neutralization activity in plasma

Poster presented at the 2015 Keystone Symposia Conference X5: HIV Vaccines. Banff, Alberta, Canada, 22-27 March 2015