Characterization of HIV variants from paired Cerebrospinal fluid and Plasma samples in primary microglia and CD4+ T-cells.

Despite antiretroviral therapy (ART), HIV persistence in the central nervous system (CNS) continues to cause a range of cognitive impairments in people living with HIV (PLWH). Upon disease progression, transmigrating CCR5-using T-cell tropic viruses are hypothesized to evolve into macrophage-tropic viruses in the CNS that can efficiently infect low CD4-expressing cells, such as microglia. We examined HIV-1 RNA concentration, co-receptor usage, and CSF compartmentalization in paired CSF and blood samples from 19 adults not on treatment. Full-length envelope CSF- and plasma-derived reporter viruses were generated from 3 subjects and phenotypically characterized in human primary CD4+ T-cells and primary microglia. Median HIV RNA levels were higher in plasma than in CSF (5.01 vs. 4.12 log10 cp/mL; p = 0.004), and coreceptor usage was mostly concordant for CCR5 across the paired samples (n = 17). Genetically compartmentalized CSF viral populations were detected in 2 subjects, one with and one without neurological symptoms. All viral clones could replicate in T-cells (R5 T cell-tropic). In addition, 3 CSF and 1 plasma patient-derived viral clones also had the capacity to replicate in microglia/macrophages and, therefore have an intermediate macrophage tropic phenotype. Overall, with this study, we demonstrate that in a subset of PLWH, plasma-derived viruses undergo genetic and phenotypic evolution within the CNS, indicating viral infection and replication in CNS cells. It remains to be studied whether the intermediate macrophage-tropic phenotype observed in primary microglia represents a midpoint in the evolution towards a macrophage-tropic phenotype that can efficiently replicate in microglial cells and propagate viral infection in the CNS.

Integrated analysis of viral blips, residual viremia, and associated factors in people with HIV: Results from a retrospective cohort study.

The etiology of viral blips is not yet fully elucidated. One of the hypotheses is that blips reflect variations in residual viremia (RV) near the detectability threshold. In this study, we evaluated whether RV is associated with viral blips and which factors are associated with RV. All treatment regimens in 2010-2020 consisting of two nucleos(-t)ide reverse transcriptase inhibitors and one anchor (integrase strand transfer inhibitor [INSTI], non-nucleoside reverse transcriptase inhibitor [NNRTI], or protease inhibitor [PI]) in people with HIV (PWH) were evaluated for RV (detectable viremia <50 cp/mL) and blips (isolated viral loads [VLs] 50-499 cp/mL between measurements <50 cp/mL). All medical records were reviewed and regimens in which a VL ≥ 50 cp/mL was deemed to result from non-adherence (based on the documented conclusion by the treating physician) were excluded. Factors associated with blips and RV were identified using generalized linear mixed models. In total, 24 518 VLs from 1658 PWH were analyzed. VLs were measured during INSTI- (n = 5119; 20.9%), PI- (n = 8935; 36.4%), and NNRTI-use (n = 10 464; 42.7%). VLs were categorized as blips in 1.4% (n = 332). The 24,186 non-blip VLs were RNAneg (no RV) (n = 15 326; 63.4%), 1-19 cp/mL (n = 6318; 26.1%), 20-49 cp/mL (n = 1620; 6.7%), or <50 cp/mL with an unknown RV level (n = 922; 3.8%). In 193/1658 PWH (11.6%), the RV level was RNAneg in all VLs assessed. RV 1-19 cp/mL and 20-49 cp/mL (vs. RNAneg ) were significantly associated with subsequent viral blips (respective odds ratio 2.66 and 4.90 [95% confidence intervals: 1.98-3.58 and 3.41-7.04]). Zenith VL and use of PIs (vs. INSTIs/NNRTIs) were associated with higher RV and blip odds. This large cohort study showed that blips were associated with higher preceding RV. Both the anchor type and factors previously linked to the latent viral reservoir were associated with RV, suggesting blips having a multifactorial origin.

The use of corticosteroids does not influence CD4+ lymphocyte recovery in HIV-infected patients with advanced immunodeficiency.

Corticosteroids inhibit HIV-related immune activation and seem to have a mild favorable effect on immunological recovery in patients with CD4+ counts ≥200 cells/mm3. Data in patients with advanced immunodeficiency are lacking. We analyzed whether corticosteroids negatively influence the short-term CD4+ lymphocyte recovery in patients with CD4+ cell counts <200 cells/mm3 started on combination antiretroviral therapy (cART). We performed a retrospective cohort analysis including all HIV-infected patients under follow-up in our hospital with a documented episode of Pneumocystis Jirovecii Pneumonia (PJP) in the cART era. CD4+ lymphocyte recovery was assessed at three months after the episode of PJP and subsequent start of cART, comparing patients that received adjunctive corticosteroids (AC) versus patients that did not receive corticosteroids (standard care (SC)). In total, 66 patients with an episode of PJP were identified with 38 patients in the AC-group versus 28 patients in the SC-group. Almost all baseline characteristics were similar, including mean CD4+ lymphocyte counts. After three months, the mean CD4+ cell count did not differ; 222 cells/mm3 for the SC-group versus 259 cells/mm3 for the AC-group (p = .29). The use of corticosteroids does not alter CD4+ lymphocyte recovery in HIV-infected patients with advanced immunodeficiency in the first months of antiretroviral therapy.

High Rates of Transmission of Drug-resistant HIV in Aruba Resulting in Reduced Susceptibility to the WHO Recommended First-line Regimen in Nearly Half of Newly Diagnosed HIV-infected Patients.

Background: In Western countries emergence of human immunodeficiency virus (HIV) drug resistance has tremendously decreased, and transmission of drug resistance has merely stabilized in recent years. However, in many endemic settings with limited resources rates of emerging and transmitted drug resistance are not regularly assessed. Methods: We performed a survey including all HIV-infected individuals who received resistance testing in 2010-2015 in Aruba, a highly endemic HIV area in the Caribbean. Transmitted HIV drug resistance was determined using World Health Organization (WHO) criteria. Transmission dynamics were investigated using phylogenetic analyses. In a subset, baseline samples were re-analyzed using next generation sequencing (NGS). Results: Baseline resistance testing was performed in 104 newly diagnosed untreated individuals (54% of all newly diagnosed individuals in 2010-2015): 86% were men, 39% were foreign-born, and 22% had AIDS at diagnosis. And 33% (95% CI: 24-42%) was infected with a drug-resistant HIV variant. The prevalence of resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs) reached 45% (95% CI: 27-64%) in 2015, all based on the prevalence of mutation K103N. NGS did not demonstrate additional minority K103N-variants compared to routine resistance testing. K103N-harboring strains were introduced into the therapy-unexposed population via at least 6 independent transmissions epidemiologically linked to the surrounding countries. Virological failure of the WHO-recommended first-line NNRTI-based regimen was higher in the presence of K103N. Conclusions: The prevalence of resistant HIV in Aruba has increased to alarming levels, compromising the WHO-recommended first-line regimen. As adequate surveillance as advocated by the WHO is limited, the Caribbean region could face an unidentified rise of NNRTI-resistant HIV.

Genotypic susceptibility score (GSS) and CD4+ T cell recovery in HIV-1 patients with suppressed viral load.

OBJECTIVES: HIV drug resistance, measured by the genotypic susceptibility score (GSS), has a deleterious effect on the virological outcome of HIV-1-infected patients. However, it is not known if GSS retains any predictive value for CD4 recovery in patients with suppressed viral load. METHODS: Four hundred and six patients on virological failure (>500 copies/mL) with GSS : <6 months prior to switch therapy who achieved undetectable plasma viral load (<50 copies/mL) within 1 year, remained undetectable >1 year on an unchanged regimen and had CD4 data available during entire follow-up were included. Adjusted and unadjusted analyses of all characteristics at switch related to CD4 recovery were made for three time frames: (i) 'switch-suppression'; (ii) 'suppression-1 year'; and (iii) 'switch-1 year'. RESULTS: Higher GSS was associated with a greater CD4 recovery between 'switch' and '1 year' in the unadjusted analysis (P = 0.010); however, the effect of GSS was no longer statistically significant after adjusting for pre-switch clinical (CD4 count and plasma viral load) and demographic variables. Furthermore, only a lower pre-switch CD4 count was associated with increased CD4 recovery in the 'suppression-1 year' period in both unadjusted and adjusted models. The main CD4 recovery occurred in 'switch-suppression' and the variables associated, both unadjusted and adjusted, were CD4 and plasma viral load at switch, maintaining a trend for GSS (P = 0.06). CONCLUSIONS: In individuals who re-suppressed HIV viraemia after switching therapy, regimens having a higher GSS were associated with improved CD4 recovery only during the period from switch to virological suppression, but, once viral load is re-suppressed, the GSS of the new regimen has no further effect on subsequent CD4 recovery.

Infection with the frequently transmitted HIV-1 M41L variant has no influence on selection of tenofovir resistance.

OBJECTIVES: In ∼10% of newly diagnosed HIV-1 patients, drug-resistant viral variants are detected. In such transmitted HIV-1 variants, the thymidine analogue mutation (TAM) M41L is frequently observed as a single resistance mutation and these viral variants often belong to phylogenetic transmission clusters. The presence of at least three TAMs, in particular patterns with M41L/L210W, impairs the efficacy of the extensively used drug tenofovir. We investigated whether the presence of a single M41L mutation at baseline influences the selection of resistance to tenofovir and emtricitabine in vitro and in vivo. METHODS: The impact of M41L on the development of drug resistance to tenofovir and emtricitabine was determined by extensive in vitro selection experiments and investigation of the virological outcome of patients on a first-line regimen. RESULTS: The presence of a single M41L mutation did not influence the selected mutational profile or the genetic barrier to resistance to tenofovir and/or emtricitabine during long-term in vitro selection experiments. In vivo, virological outcome of first-line regimens containing tenofovir and emtricitabine was comparable between patients diagnosed with HIV-1 harbouring M41L (n=17, 16 were part of one transmission cluster) and WT virus (n=248). CONCLUSIONS: Detection of a single M41L reverse transcriptase mutation at baseline did not influence the development of resistance in vitro or virological outcome on tenofovir-containing regimens in patients belonging to a large transmission cluster. Our results indicate that a high genetic barrier regimen may not be required when patients are diagnosed with HIV variants containing a single M41L mutation in reverse transcriptase.

Evolution and viral characteristics of a long-term circulating resistant HIV-1 strain in a cluster of treatment-naive patients.

BACKGROUND: Transmitted resistant HIV may revert to wild-type in the absence of drug pressure due to reduced replication capacity (RC). We observed eight therapy-naive patients infected with HIV harbouring four mutations at nucleoside reverse transcriptase inhibitor (NRTI) resistance-related positions: M41L, T69S, L210E and T215S. If partial reverted resistance patterns like these are detected at baseline, concerns for more extensive resistance in the quasispecies often directs selection of first-line combination antiretroviral therapy (cART) towards more complex regimens. METHODS: Genotypic resistance testing and phylogenetic analysis was performed using pol sequences of 400 therapy-naive patients and 1322 patients with at least one NRTI-related mutation. Reverse transcriptase (RT) genes were cloned into a reference strain and RC was investigated. RESULTS: Phylogenetic analysis showed that all eight patients are part of a transmission cluster (bootstrap value 92%). The patients resided in three distinct geographical regions and were either homosexually or heterosexually infected. Prior negative serology and analysis of base ambiguity demonstrated circulation for at least 7 years. In vivo evolution showed a mixture with wild-type (T215S/T) in only one untreated patient more than 6 years after diagnosis. The reverted resistance pattern did not confer a substantial reduction in RC compared with wild-type, explaining its persistence in vivo and long-term circulation in the population. Four patients started cART; three of them received quadruple cART. All patients showed good virological and immunological response. CONCLUSIONS: Long-term circulation transcending distinct regions and transmission groups suggests reversion occurred in previous hosts in the transmission chain. Identification of clusters using epidemiological data and active-partner tracing may broaden therapeutic options in cases of transmitted resistance.

No long-term effect of past Pneumocystis jirovecii pneumonia on pulmonary function in people with HIV.

OBJECTIVE: To assess the impact of past Pneumocystis jirovecii pneumonia (PJP) on the pulmonary diffusion capacity in people with HIV (PWH) with a history of advanced immunodeficiency. DESIGN: Prospective cross-sectional study. METHODS: Adult PWH with past PJP >1 year ago were included as the study group. The control group consisted of PWH with a nadir CD4 + lymphocyte count <200 cells/mm 3 , matched by age, sex, smoking status and time since HIV diagnosis. All PWH completed a pulmonary function test (PFT) consisting of pre-bronchodilation spirometry, body plethysmography and single-breath carbon monoxide transfer factor (TLCO) measurement. TLCO, diffusion impairment (defined as a TLCO Z -score <-1.645), total lung capacity (TLC) and forced expiratory volume in one second/forced vital capacity (FEV1/FVC) Z -scores were assessed. Multivariable regression analyses were conducted with Z -scores and odds of diffusion impairment as outcomes. RESULTS: PFTs of 102 participants were analyzed, 51 of whom had past PJP with a median of 10 years since PJP. Mean TLCO Z -score and diffusion impairment rate did not differ significantly between groups ( P  = 0.790; P  = 0.650). Past PJP was not independently associated with TLCO Z -score [ ß = 0.14; 95% confidence interval (CI) -0.30-0.57], diffusion impairment (odds ratio 1.00; 95% CI 0.36-2.75) nor TLC or FEV1/FVC Z -scores, whereas current (vs. never) smoking was associated with more diffusion impairment and lower TLCO Z -scores. CONCLUSION: In our study, past PJP was not associated with long-term diffusion impairment. Our findings suggest that smoking plays a more important role in persistent pulmonary function impairment whereas PJP-related changes seem to be reversible.

A randomized controlled study of accelerated versus standard hepatitis B vaccination in HIV-positive patients.

BACKGROUND: In human immunodeficiency virus (HIV)-infected patients, the immunogenicity of hepatitis B vaccines is impaired. The primary and secondary aims of our study were to investigate the effectiveness and compliance of 2 different vaccination regimen in an HIV-infected population. METHODS: A noninferiority trial with a 10% response margin was designed. Included were patients ≥ 18 years old, with negative HBsAg/anti-HBc serology, and not previously vaccinated against hepatitis B. Patients were stratified according to CD4(+) cell count: <200, 200-500, >500. Participants received 10 µg HBvaxPRO intramuscularly according to a 0-1-3 week schedule or the standard 0-4-24 week schedule. Anti-HBs levels were measured at week 28, considered protective ≥ 10 IU/L. RESULTS: Modified intention to treat analysis in 761 patients was performed. Overall response difference was 50%(standard arm) versus 38.7% (accelerated arm) =11.3% (95% confidence interval [CI], [4.3, 18.3]), close to the 10% response margin. In CD4(+) cell count group 200-500 cells/mm(3,) the response difference was 20.8% (95% CI [10.9, 30.7]). However, the response difference in CD4(+)cell count group >500 cells/mm(3) was -1.8% (95% CI [-13.4,+9.7]). Compliance was significantly superior with the accelerated schedule, 91.8% versus 82.7% (P ≤ .001). CONCLUSION: In HIV-infected patients, compliance with an accelerated hepatitis B vaccination schedule is significantly better. The efficacy of an accelerated schedule proved to be non-inferior in CD4(+) cell count group >500 cells/mm(3). CLINICAL TRIALS REGISTRATION: CT00230061.

Lower Incidence of HIV-1 Blips Observed During Integrase Inhibitor-Based Combination Antiretroviral Therapy.

BACKGROUND: As the nature of viral blips remains unclear, their occurrence often leads to uncertainty. This study compares blip incidence rates during treatment with different combination antiretroviral therapy anchors. SETTING: Retrospective cohort study in a tertiary hospital. METHODS: All antiretroviral regimens between 2010 and 2020 containing 2 nucleos(-t)ide reverse transcriptase inhibitors and 1 anchor in virologically suppressed people living with HIV (PLWH) from our center were evaluated for the occurrence of blips [isolated viral loads (VLs) 50-499 copies/mL between measurements <50 copies/mL]. Factors associated with blips were identified using multivariable generalized estimating equation-based negative binomial models. The relationship between blips and either persistent low-level viremia (consecutive VLs ≥ 50 copies/mL not classified as failure) or virologic failure (consecutive VLs ≥ 200 or 1 VL ≥ 500 copies/mL) was also evaluated. RESULTS: In total, 308 blips occurred during 3405 treatment courses in 1661 PLWH. Compared with a non-nucleoside reverse transcriptase inhibitor anchor, blip incidence was higher for protease inhibitors (incidence rate ratio 1.37; 95% confidence interval 1.05 to 1.78) and lower for integrase inhibitors (INSTIs) (incidence rate ratio 0.64; 95% confidence interval: 0.43 to 0.96). In addition, blips were associated with higher zenith VL, higher VL test frequency, and shorter time since antiretroviral therapy initiation. PLWH experiencing blips were more likely to demonstrate persistent low-level viremia but not virologic failure. Blips led to extra consultations and measurements. CONCLUSIONS: INSTI-based regimens display a low number of blips. Although we found no correlation with virologic failure, the occurrence of blips led to an increased clinical burden. Further research is needed to elucidate the implications and underlying mechanisms of these findings.

Long-Term Virological Treatment Outcomes in Adolescents and Young Adults With Perinatally and Non-Perinatally Acquired Human Immunodeficiency Virus.

Background: Long-term viral suppression on antiretroviral therapy (ART) is not established among all people with human immunodeficiency virus (PWH). Young adults (18-24 years) are recognized as a group vulnerable for suboptimal virological treatment outcomes. The aim of this study is to evaluate longitudinal virological treatment outcomes and to identify risk factors for virological failure (VF) among young adults with non-perinatally and perinatally acquired human immunodeficiency virus (HIV) in the Netherlands. Methods: We included individuals registered in the national ATHENA observational cohort from 2000 until 2020 who had entered care before the age of 25 years, who had received ART for at least 6 months with at least 2 available HIV ribonucleic acid measurements between the age of 18 and 24 years. We compared VF between age groups 12-17, 18-24, and 25-30 years. A multivariable generalized linear mixed model was used to evaluate risk factors for VF. Analyses were stratified by HIV acquisition mode. Results: In total, 1174 non-perinatally PWH and 157 perinatally PWH were included. In 2020, VF rate was 7% in non-perinatally PWH young adults and 19% in perinatally PWH young adults. The adjusted risk for VF was significantly higher in those aged 18-24 compared to 25-30 years in both non-perinatally PWH (odds ratio [OR], 1.27; 95% confidence interval [CI], 1.07-1.50) and perinatally PWH (OR, 2.34; 95% CI, 1.48-3.71). Conclusions: Young adulthood is a vulnerable period, with increased risk for VF, especially for perinatally PWH. The probability of VF decreased over time, but less for perinatally PWH compared to non-perinatally PWH.

Presence of occult HBV, but near absence of active HBV and HCV infections in people infected with HIV in rural South Africa.

Human immunodeficiency (HIV), hepatitis B (HBV), and hepatitis C (HCV) viruses are endemic in Sub-Saharan Africa, but data regarding the prevalence of hepatitis co-infections in HIV-positive individuals residing there are limited. The aim of the study was to determine the prevalence of HBV, HCV, and occult HBV (presence of HBV-DNA in the absence of HBsAg) in a rural, South African cohort. The results were compared to various ethnic groups in a Dutch cohort of people infected with HIV. Antiretroviral-naïve individuals with HIV from both a rural South African clinic (n = 258), and a Dutch University hospital (n = 782), were included. Both serological (HBV and HCV) and molecular (occult HBV) assays were performed. Logistic regression analysis was used to define independent predictors of a hepatitis co-infection. HBV and HCV prevalence rates in the South African cohort were exceptionally low (0.4%, 1/242 and 0.8%, 2/242, respectively), compared to those observed in Caucasians (HBV 4.4% and HCV 10.9%) and African immigrants (HBV 8.9% and HCV 4.8%). Conversely, occult HBV was observed in a considerable proportion (10%, 6/60) of South African patients who were anti-HBc-positive but HBsAg-negative. Occult infections were less frequent in Caucasians and Africans in the Dutch cohort (3.2% and 1.4%, respectively). Independent predictors for occult HBV were not identified, but a trend towards more occult HBV at lower CD4 counts was observed. Local HBV/HCV prevalence data are needed to optimize vaccination and antiretroviral treatment strategies. Occult HBV in patients with HIV may be missed regularly when molecular analyses are not available.

Decreased All-Cause and Liver-Related Mortality Risk in HIV/Hepatitis B Virus Coinfection Coinciding With the Introduction of Tenofovir-Containing Combination Antiretroviral Therapy.

BACKGROUND: The development of efficacious combination antiretroviral therapy (cART) has led to a dramatic decrease in mortality in HIV-positive patients. Specific data on the impact in HIV/hepatitis B virus (HBV)-coinfected patients are lacking. In this study, all-cause and cause-specific mortality risks stratified per era of diagnosis are investigated. METHODS: Data were analyzed from HIV/HBV-coinfected patients enrolled in the ATHENA cohort between January 1, 1998, and December 31, 2017. Risk for (cause-specific) mortality was calculated using Cox proportional hazard regression analysis, comparing patients diagnosed before 2003 with those diagnosed ≥2003. Risk factors for all-cause and liver-related mortality were also assessed using Cox proportional hazard regression analysis. RESULTS: A total of 1301 HIV/HBV-coinfected patients were included (14 882 person-years of follow-up). One-hundred ninety-eight patients (15%) died during follow-up. The adjusted hazard ratio (aHR) for all-cause mortality in patients diagnosed in or after 2003 was 0.50 (95% CI, 0.35-0.72) relative to patients diagnosed before 2003. Similar risk reduction was observed for liver-related (aHR, 0.29; 95% CI, 0.11-0.75) and AIDS-related mortality (aHR, 0.44; 95% CI, 0.22-0.87). Use of a tenofovir-containing regimen was independently associated with a reduced risk of all-cause and liver-related mortality. Prior exposure to didanosine/stavudine was strongly associated with liver-related mortality. Ten percent of the population used only lamivudine as treatment for HBV. CONCLUSIONS: All-cause, liver-related, and AIDS-related mortality risk in HIV/HBV-coinfected patients has markedly decreased over the years, coinciding with the introduction of tenofovir. Tenofovir-containing regimens, in absence of major contraindications, should be strongly encouraged in this population.

Brief Report: Low Sensitivity of the Fracture Risk Assessment Tool in Young HIV-Infected Patients: Time to Revise Our Screening Strategy.

OBJECTIVES: The burden of reduced bone mineral density (BMD) is high among HIV-infected patients. As a screening strategy, current guidelines recommend calculating a Fracture Risk Assessment Tool (FRAX) score in patients aged 40-49 years. Patients with a 10-year risk of a major osteoporotic fracture ≥10% should undergo dual-energy x-ray absorptiometry (DXA) to assess BMD. The aim of this study was to establish the sensitivity of this threshold to identify patients with risk of osteoporosis in this age category-as a surrogate marker for high fracture risk. METHODS: The study group consisted of patients aged 50-59 years and living with HIV for at least 10 years who recently underwent dual-energy x-ray absorptiometry (DXA). A clinical risk factor-based FRAX score was calculated using patient characteristics from 10 years earlier. In this way, we assessed which patients would have undergone DXA while they were 40-49 year old. RESULTS: The cohort consisted of 126 patients; 23 patients (18.3%) had osteoporosis. Ten years before the DXA, none of them met the guideline threshold of a 10-year major osteoporotic fracture probability of ≥10%, resulting in a sensitivity of 0% in this cohort. There was no difference between the median FRAX score between patients who developed osteoporosis and those who did not (3.3% vs. 3.4%. P = 0.55). CONCLUSIONS: FRAX lacks sensitivity to determine which HIV-infected patients aged 40-49 years should undergo BMD testing to identify reduced BMD. Its role should be limited to treatment decisions.

Switching tenofovir disoproxil fumarate to tenofovir alafenamide results in a significant decline in parathyroid hormone levels: uncovering the mechanism of tenofovir disoproxil fumarate-related bone loss?

: An increasing number of patients have been switched from tenofovir disoproxil fumarate (TDF) to tenofovir alafenamide because of its improved bone safety profile, although the pathophysiological mechanism is not fully understood. We show that serum parathyroid hormone levels drop significantly after the switch from TDF to tenofovir alafenamide. This observation supports the theories that TDF-related bone loss is parathyroid hormone-driven and that this effect is dose-dependent.

A Review of Non-Alcoholic Fatty Liver Disease in HIV-Infected Patients: The Next Big Thing?

The burden of liver-related morbidity remains high among HIV-infected patients, despite advances in the treatment of HIV and viral hepatitis. Especially, the impact of non-alcoholic fatty liver disease (NAFLD) is significant with a prevalence of up to 50%. The pathogenesis of NAFLD and the reasons for progression to non-alcoholic steatohepatitis (NASH) are still not fully elucidated, but insulin resistance, mitochondrial dysfunction and dyslipidemia seem to be the main drivers. Both HIV-infection itself and combination antiretroviral therapy (cART) can contribute to the development of NAFLD/NASH in various ways. As ongoing HIV-related immune activation is associated with insulin resistance, early initiation of cART is needed to limit its duration. In addition, the use of early-generation nucleoside reverse transcriptase inhibitors and protease inhibitors is also associated with the development of NAFLD/NASH. Patients at risk should therefore receive antiretroviral drugs with a more favorable metabolic profile. Only weight reduction is considered to be an effective therapy for all patients with NAFLD/NASH, although certain drugs are available for specific subgroups. Since patients with NASH are at risk of developing liver cirrhosis and hepatocellular carcinoma, several non-antifibrotic and antifibrotic drugs are under investigation in clinical trials to broaden the therapeutic options. The epidemiology and etiology of NAFLD/NASH in HIV-positive patients is likely to change in the near future. Current guidelines recommend early initiation of cART that is less likely to induce insulin resistance, mitochondrial dysfunction and dyslipidemia. In contrast, as a result of increasing life expectancy in good health, this population will adopt the more traditional risk factors for NAFLD/NASH. HIV-treating physicians should be aware of the etiology, pathogenesis and treatment of NAFLD/NASH in order to identify and treat the patients at risk.

Impact of Aging, Cytomegalovirus Infection, and Long-Term Treatment for Human Immunodeficiency Virus on CD8+ T-Cell Subsets.

Both healthy aging and human immunodeficiency virus (HIV) infection lead to a progressive decline in naive CD8+ T-cell numbers and expansion of the CD8+ T-cell memory and effector compartments. HIV infection is therefore often considered a condition of premature aging. Total CD8+ T-cell numbers of HIV-infected individuals typically stay increased even after long-term (LT) combination antiretroviral treatment (cART), which is associated with an increased risk of non-AIDS morbidity and mortality. The causes of these persistent changes in the CD8+ T-cell pool remain debated. Here, we studied the impact of age, CMV infection, and LT successful cART on absolute cell numbers in different CD8+ T-cell subsets. While naïve CD8+ T-cell numbers in cART-treated individuals (N = 38) increased to healthy levels, central memory (CM), effector memory (EM), and effector CD8+ T-cell numbers remained higher than in (unselected) age-matched healthy controls (N = 107). Longitudinal analysis in a subset of patients showed that cART did result in a loss of memory CD8+ T-cells, mainly during the first year of cART, after which memory cell numbers remained relatively stable. As CMV infection is known to increase CD8+ T-cell numbers in healthy individuals, we studied whether any of the persistent changes in the CD8+ T-cell pools of cART-treated patients could be a direct reflection of the high CMV prevalence among HIV-infected individuals. We found that EM and effector CD8+ T-cell numbers in CMV+ healthy individuals (N = 87) were significantly higher than in CMV- (N = 170) healthy individuals. As a result, EM and effector CD8+ T-cell numbers in successfully cART-treated HIV-infected individuals did not deviate significantly from those of age-matched CMV+ healthy controls (N = 39). By contrast, CM T-cell numbers were quite similar in CMV+ and CMV- healthy individuals across all ages. The LT expansion of the CM CD8+ T-cell pool in cART-treated individuals could thus not be attributed directly to CMV and was also not related to residual HIV RNA or to the presence of HIV-specific CM T-cells. It remains to be investigated why the CM CD8+ T-cell subset shows seemingly irreversible changes despite years of effective treatment.

Continuous intravenous infusion of enfuvirtide in a patient with a multidrug-resistant HIV strain.

Case description To evaluate whether continuous intravenous (i.v.) administration of enfuvirtide (T20) could be a suitable alternative to subcutaneous (s.c.) administration of T20 in a patient with extensively drug-resistant HIV experiencing difficulties administering T20 subcutaneously. T20 was administered to a patient through 100 mL cassettes once daily via a CADD. Plasma samples were drawn and the pharmacokinetic profile compared to that of s.c. twice daily administration of T20. Also, viral replication and CD4+ count were monitored over a period of 9 months for this study. Continuous i.v. administration of T20 resulted in significantly higher T20 plasma levels compared to s.c. administration, continued viral suppression, a rise in CD4+ count and strong patient preference over s.c. administration. Conclusion This method of T20 administration may be a suitable alternative for selected patients who are not able to tolerate it when given subcutaneously. It may even be considered a priori in selected patients with extensive viral resistance who are unable or unwilling to inject T20 subcutaneously.