Search

Objective: To determine the yield of screening for latent tuberculosis infection (LTBI) among people with HIV (PWH) in low tuberculosis (TB) incidence countries (<10 TB cases per 100 000 persons)., Design: A systematic review and meta-analysis were performed to assess prevalence and predictive factors of LTBI, rate of TB progression, effect of TB preventive treatment (TPT), and numbers needed to screen (NNS)., Methods: PubMed and Cochrane Library were searched for studies reporting primary data, excluding studies on active or paediatric TB. We extracted LTBI cases, odds ratios, and TB incidences; pooled estimates using a random-effects model; and used the Newcastle-Ottawa scale for bias., Results: In 51 studies with 65 930 PWH, 12% [95% confidence interval (CI) 10-14] had a positive LTBI test, which was strongly associated with origin from a TB-endemic country [odds ratio (OR) 4.7] and exposure to TB (OR 2.9). Without TPT (10 629 PWH), TB incidence was 28/1000 person-years (PY; 95% CI 12-45) for LTBI-test positive versus 4/1000 PY (95% CI 0-7) for LTBI-test-negative individuals. Among 625 PWH (1644 PY) receiving TPT, 15 developed TB (6/1000 PY). An estimated 20 LTBI-positive individuals would need TPT to prevent one case of TB, and numbers NNS to detect LTBI or prevent active TB varied according to a-priori risk of LTBI., Conclusion: The relatively high prevalence of LTBI among PWH and the strong correlation with origin from a TB-endemic country support risk-stratified LTBI screening strategies for PWH in low-incidence countries and treating those who test positive., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: We aimed to determine the reversibility of at least 7% weight gain within 12 months following tenofovir alafenamide (TAF) and/or integrase strand transfer inhibitor (INSTI) discontinuation in people with HIV (PWH) from the Dutch ATHENA cohort., Design and Methods: PWH with at least 7% weight gain within 24 months after first switch to TAF and/or INSTI whilst being virally suppressed were selected, excluding those with comorbidities/co-medication known to be associated with weight gain. PWH who discontinued only TAF, only INSTI or TAF+INSTI, with available follow-up weight, were included. Mean weight change in the 24 months prior to and 12 months after discontinuation was modelled using mixed-effects linear regression. Factors associated with yearly weight change were assessed using linear regression., Results: In 115 PWH, discontinuing only TAF ( n  = 39), only INSTI ( n  = 53) or TAF+INSTI ( n  = 23), the adjusted mean modelled weight change in the 24 months prior to discontinuation was +4.50 kg [95% confidence interval (CI) 3.04-6.10], +4.80 kg (95% CI 2.43-7.03) and +4.13 kg (95% CI 1.50-7.13), respectively, and -1.89 kg (95% CI -3.40 to -0.37), -1.93 kg (95% CI -3.92 to +0.07) and -2.55 kg (95% CI -5.80 to +0.02) in the 12 months postdiscontinuation. A greater number of years since HIV diagnosis was associated with greater reversibility of weight gain. No associations were found between weight change postdiscontinuation and changes in NRTI backbone or anchor agent at moment of discontinuation., Conclusion: There was no evidence of rapid reversibility of at least 7% TAF-associated and/or INSTI-associated weight gain after discontinuation of these agents. Studies of larger and more diverse populations of PWH are required to more fully understand the degree to which weight gain is reversible when discontinuing TAF and/or INSTI., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Objectives: We investigated occurrence of and risk factors for severe COVID-19 outcomes in people with HIV (PWH) in the Netherlands., Design: An ongoing prospective nationwide HIV cohort study., Methods: COVID-19 diagnoses and outcomes with other relevant medical information were prospectively collected from electronic medical records in all HIV treatment centers in the Netherlands, from the start of the COVID-19 epidemic until December 31, 2021. Risk factors for COVID-19 related hospitalization and death were investigated using multivariable logistic regression, including demographics, HIV-related factors, and comorbidities., Results: The cohort comprises 21 289 adult PWH, median age 51.2 years, 82% male, 70% were of Western origin, 12.0% were of sub-Saharan African and 12.6% Latin American/Caribbean origin, 96.8% had HIV-RNA less than 200 copies/ml, median CD4 + cell count 690 (IQR 510-908) cells/μl. Primary SARS-CoV-2 infections were registered in 2301 individuals, of whom 157 (6.8%) required hospitalization and 27 (1.2%) ICU admission. Mortality rates were 13 and 0.4% among hospitalized and nonhospitalized individuals, respectively. Independent risk factors for severe outcomes (COVID-19-related hospitalization and death) were higher age, having multiple comorbidities, a CD4 + cell count less than 200 cells/μl, uncontrolled HIV replication, and prior AIDS diagnosis. Migrants from sub-Saharan Africa, Latin America, and the Caribbean were at an increased risk of severe outcomes independently of other risk factors., Conclusion: In our national cohort of PWH, risk of severe COVID-19 outcomes was increased in individuals with uncontrolled HIV replication, low CD4 + cell count, and prior AIDS diagnosis, independently of general risk factors such as higher age, comorbidity burden and migrants originating from non-Western countries., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

In two Dutch observational cohorts of people with HIV, the use of TDF, ETR, or INSTIs was not independently associated with either the risk of incident SARS-CoV-2 infection or severe COVID-19 outcomes, as was suggested by previous observational and molecular docking studies. Our findings do not support a strategy of modifying antiretroviral therapy to include these agents to protect against SARS-CoV-2 infection and severe COVID-19 outcomes., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: Cross-sectional studies, including one from our NOVICE cohort [Neurological Visual and Cognitive performance in children with treated perinatally acquired HIV (PHIV) compared with matched HIV-negative controls], have revealed that the brains of children with PHIV have lower white matter and grey matter volumes, more white matter hyperintensities (WMH) and poorer white matter integrity. This longitudinal study investigates whether these differences change over time., Methods: We approached all NOVICE participants to repeat MRI after 4.6 ± 0.3 years, measuring total white matter and grey matter volume, WMH volume and white matter integrity, obtained by T1-weighted, fluid-attenuated inversion recovery (FLAIR) and diffusion tensor imaging (DTI), respectively. We compared rates of change between groups using multivariable linear mixed effects models, adjusted for sex and age at enrolment. We investigated determinants of developmental deviation, and explored associations with cognitive development., Results: Twenty out of 31 (65%) PHIV-positive, and 20 out of 37 (54%) HIV-negative participants underwent follow-up MRI. Groups did not significantly differ in terms of age and sex. Over time, we found no statistically different changes between groups for white matter and WMH volumes, and for white matter integrity (P > 0.1). Total grey matter volume decreased significantly less in PHIV [group∗time 10 ml, 95% confidence interval -1 to 20, P = 0.078], but this difference in rate of change lost statistical significance after additional adjustment for height (group∗time 9 ml, 95% confidence interval -2 to 20, P = 0.112). We found no HIV-associated determinants for potential reduced grey matter pruning, nor associations with cognitive development., Conclusion: While using long-term antiretroviral treatment, structural brain development of adolescents growing up with perinatally acquired HIV appears largely normal., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Whether continued, accelerated liver fibrosis progression occurs following acute hepatitis C virus infection (AHCVI) in HIV-positive MSM is unknown., Design and Methods: HIV-positive MSM from the AIDS Therapy Evaluation in the Netherlands and MSM Observational Study for Acute Infection with Hepatitis C-cohorts with primary AHCVI and at least one fibrosis-4 (FIB-4) measurement less than 2 years before and 1 year after estimated AHCVI were included. Mixed-effect linear models were used to evaluate (time-updated) determinants of FIB-4 levels over time. Determinants of transitioning to and from FIB-4 ≤ 1.45 and > 1.45 were examined using multistate Markov models., Results: Of 313 MSM, median FIB-4 measurements per individual was 12 (interquartile range  = 8-18) and median follow-up following AHCVI was 3.5 years (interquartile range = 1.9-5.6). FIB-4 measurements averaged at 1.00 [95% confidence interval (CI) = 0.95-1.05] before AHCVI, 1.31 (95% CI = 1.25-1.38) during the first year of AHCVI and 1.10 (95% CI = 1.05-1.15) more than 1 year after AHCVI. Mean FIB-4 more than 1 year after AHCVI was higher for chronically infected patients compared with those successfully treated (P = 0.007). Overall FIB-4 scores were significantly higher with older age, lower CD4 cell count, longer duration from HIV-diagnosis or AHCVI, and nonresponse to HCV-treatment. At the end of follow-up, 60 (19.2%) and eight MSM (2.6%) had FIB-4 between 1.45-3.25 and ≥ 3.25, respectively. Older age, lower CD4 cell count and detectable HIV-RNA were significantly associated with higher rates of progression to FIB-4 > 1.45, whereas older age, longer duration from HIV-diagnosis and nonresponse to HCV-treatment were significantly associated with lower rates of regression to FIB-4 ≤ 1.45., Conclusion: In this population of HIV-positive MSM, FIB-4 scores were higher during the first year of AHCVI, but FIB-4 ≥ 3.25 was uncommon by the end of follow-up. Well controlled HIV-infection appears to attenuate FIB-4 progression.

Objective: To assess incidence, determinants and clinical consequences of suboptimal immune recovery in HIV-1 infected adults in sub-Saharan Africa with sustained viral suppression on antiretroviral therapy (ART)., Design: Multicountry prospective cohort., Methods: Suboptimal immune recovery was defined as proportions of participants who failed to attain clinically relevant CD4+ cell count thresholds (>200, >350 and >500 cells/μl) despite sustained viral suppression on continuous first-line ART. Participants were censored at the earliest of death, loss to follow-up, last viral load less than 50 copies/ml, or database closure. Determinants of immune recovery were assessed using multivariable Cox regression. We estimated incidence rates of AIDS, pulmonary tuberculosis and all-cause mortality for CD4+ strata., Results: One thousand, five hundred and ninety-two participants were included; 60% were women, median age was 37 years (IQR 31-43) and median pre-ART CD4+ cell count was 147 cells/μl (IQR 76-215). After 6 years of ART, suboptimal immune recovery at CD4+ cell counts less than 200 cells/μl, less than 350  cells/μl, and less than 500 cells/μl occurred in 7, 27, and 57% of participants, respectively. Compared with participants with CD4+ cell count greater than 500 cells/μl, on-ART incidence rates were 12.5, 4.1, 0.9 times higher for AIDS and 16.9, 3.5, and 2.3 times higher for pulmonary tuberculosis in participants with CD4+ cell count less than 200, 200-349, and 350-499 cells/μl, respectively. All-cause mortality was highest in participants with CD4+ cell count less than 200 cells/μl, and comparable across the higher CD4+ strata. Older age, male sex, and lower pre-ART CD4+ cell count were strongly associated with suboptimal immune recovery., Conclusion: These findings warrant close clinical and laboratory monitoring until adequate immune reconstitution is achieved and support early ART initiation before decline of CD4+ cell count.

Objectives: To investigate the incidence and risk factors of immune reconstitution inflammatory syndrome (IRIS) associated with toxoplasmic encephalitis (TE) in patients starting combination antiretroviral therapy (cART)., Design: A historical multicenter cohort study., Methods: We included all HIV-infected patients diagnosed with toxoplasmic encephalitis in six Dutch hospitals between 1996 and 2016. Diagnosis of TE-IRIS was made using predefined IRIS criteria. We distinguished paradoxical TE-IRIS (worsening of underlying treated infection) from unmasking TE-IRIS (unmasking of subclinical infection after start of cART). We compared CD4 cell count, plasma viral load and timing of cART initiation between patients with and without paradoxical TE-IRIS., Results: A total of 211 toxoplasmic encephalitis cases were included. Among 143 cases at risk for paradoxical TE-IRIS, we identified five cases of paradoxical TE-IRIS (3.5%). In six other cases, we could not differentiate paradoxical TE-IRIS from recurrence of disease due to inadequate secondary Toxoplasma prophylaxis. There was no difference in time between start of toxoplasmic encephalitis treatment and cART initiation for patients who did or did not develop paradoxical TE-IRIS (P = 0.50). Within the group of 2228 patients who started cART while having a CD4 cell count below 200 × 10 cells/l and receiving adequate primary prophylaxis, we identified eight cases of unmasking TE-IRIS (0.36%). Unmasking TE-IRIS could not be differentiated from a newly occurring toxoplasmic encephalitis in six other patients, as they were not receiving adequate primary prophylaxis against Toxoplasma., Conclusion: Unmasking TE-IRIS was rare in this cohort, whereas paradoxical TE-IRIS did occur more often. We found no relationship between the timing of cART initiation and the occurrence of paradoxical TE-IRIS.

Objective: To assess if HIV-infected patients on long-term successful combination antiretroviral therapy show cerebral blood flow (CBF) alterations in comparison with HIV-uninfected, otherwise similar controls. To explore whether such alterations are associated with HIV-associated cognitive impairment and to explore potential determinants of CBF alterations in HIV., Design: Cross-sectional comparison of CBF in an observational cohort study., Methods: Clinical, cognitive and MRI data of 100 middle-aged aviremic HIV-infected men on combination antiretroviral therapy and 69 HIV-uninfected controls were collected and compared. From pseudocontinuous arterial spin labeling MRI data, CBF-maps were calculated. The associations of mean gray matter CBF with clinical and cognitive parameters were explored in regression models, followed by a spatial delineation in a voxel-based analysis., Results: CBF was decreased in HIV-infected patients compared with HIV-uninfected controls (P = 0.02), adjusted for age, ecstasy use and waist circumference. Spatially distinct and independent effects of total gray matter volume and HIV-serostatus on CBF were found. Within the HIV-infected group, decreased CBF was associated with increased triglyceride levels (P = 0.005) and prior clinical AIDS (P = 0.03). No association between CBF and cognitive impairment was found., Conclusion: Decreased CBF was observed among HIV-infected patients, which was associated with both vascular risk factors as well as with measures of past immune deficiency. These results provide support for increased vascular disease in HIV-infected patients as represented by hemodynamic alteration, but without overt cognitive consequences within the current cohort of patients on long-term successful treatment.

Objectives: The objective of this study was to assess whether HIV-infected patients on long-term successful combination antiretroviral therapy (cART) have more extensive white matter hyperintensities (WMH) of presumed vascular origin compared with uninfected controls and whether these intensities are associated with cognitive impairment. Furthermore, we explored potential determinants of increased WMH load long-term suppressed HIV infection., Design: A cross-sectional comparison of WMH in an observational cohort., Methods: Clinical, cognitive, and MRI data were collected from 103 middle-aged, aviremic HIV-infected men on cART, and 70 HIV-uninfected, otherwise similar controls. In the MRI data, WMH load was quantified by automated approaches and qualitatively reviewed by an experienced neuroradiologist using the Fazekas scale., Results: HIV-infected men had an increased WMH load. Among HIV-infected patients, increased WMH load was independently associated with older age, higher DBP, higher D-dimer levels, and longer time spent with a CD4 cell count below 500 cells/μl. HIV-associated cognitive deficits were associated with increased WMH load., Conclusions: WMH are more extensive and associated with cognitive deficits in middle-aged, aviremic cART-treated HIV-infected men. The extent of WMH load was associated with both cardiovascular risk factors and past immune deficiency. As cognitive impairment in these same patients is also associated with these risk factors, this may suggest that in the setting of HIV, WMH, and cognitive deficits share a common cause. This supports the importance of optimizing cardiovascular risk management, and early, effective treatment of HIV infection.

Background: It is unclear whether HIV infection is associated with liver fibrosis in the absence of chronic hepatitis B or C virus (HBV/HCV) coinfection. We compared prevalence of liver fibrosis, noninvasively assessed by the Fibrosis-4 (FIB-4) index, between HIV-infected patients and uninfected controls, and explored determinants of a higher FIB-4 score, indicative of more liver fibrosis., Methods: FIB-4 was assessed in HIV-uninfected and HIV-1-infected, predominantly virologically suppressed participants of the AGEhIV Cohort Study without HBV and/or HCV coinfection, and aged at least 45. Using multivariable regression, we investigated associations between FIB-4 and HIV-status, HIV-disease characteristics, antiretroviral drugs and markers of microbial translocation and immune activation., Results: Prevalence of advanced liver fibrosis (FIB-4 ≥ 3.25) was low: 1.4% in HIV-infected and 1.0% in HIV-uninfected participants. After adjustment for age, sex, ethnicity, detectable anti-hepatitis B core/anti-HCV antibodies and excessive alcohol intake, HIV remained significantly associated with higher FIB-4 (+4.2%, P = 0.05). Prior exposure to didanosine, longer duration of a CD4 cell count below 500 cells/μl and a lower CD4 cell count at enrollment were each associated with a higher FIB-4. Markers of immune activation (soluble CD163, activated CD8 T-lymphocytes and regulatory T-lymphocytes) were associated with a higher FIB-4 in HIV-infected but not HIV-uninfected study participants., Conclusion: HIV infection was independently associated with higher FIB-4 scores, indicating more advanced liver fibrosis, though the difference in FIB-4 scores between HIV-infected and HIV-uninfected was small. Higher levels of immune activation were associated with liver fibrosis in HIV-infected, even in the absence of HBV or HCV infection, but not in HIV-uninfected individuals.

Objective: Cognitive impairment is highly prevalent in HIV-1-infected (HIV+) patients, despite adequate suppression of viral replication by combination antiretroviral therapy (cART). Cerebral white matter structure alterations are often associated with cognitive impairment and have commonly been reported in the natural course of HIV infection. However, the existence of these alterations in adequately treated HIV+ patients remains unknown, as well as its possible association with cognitive impairment., Design: We used diffusion tensor imaging (DTI) to investigate whether white matter structure alterations exist in HIV+ patients with sustained suppressed viral replication on cART, and if such alterations are related to HIV-associated cognitive deficits., Methods: We compared 100 aviraemic HIV+ men on cART with 70 HIV-uninfected, otherwise comparable men. Clinical and neuropsychological assessments were performed. From DTI data, white matter fractional anisotropy and mean diffusion were calculated. Subsequently, tract-based spatial statistics (TBSS) was performed, with and without masking out white matter lesions., Results: HIV+ patients showed diffuse white matter structure alterations as compared with HIV-uninfected controls, observed as widespread decreased fractional anisotropy and an increased mean diffusion. These white matter structure alterations were associated with the number of years spent with a CD4 cell count below 500 cells/μl, but not with HIV-associated cognitive deficits., Conclusion: Cerebral white matter structure alterations are found in middle-aged HIV+ men with sustained suppression of viraemia on cART, and may result from periods with immune deficiency when viral toxicity and host-inflammatory responses were at their peak. These white matter structure alterations were not associated with the observed subtle HIV-associated cognitive deficits., Video Abstract: .

Background: Frailty is an age-related syndrome of decreased physiological reserve and resistance to stressors, associated with increased morbidity and mortality in the general elderly population. An increased prevalence of frailty has been reported amongst HIV-infected individuals., Methods: Fried frailty phenotype was systematically assessed in predominantly virologically suppressed HIV type 1 (HIV-1)-infected and otherwise comparable HIV-uninfected participants aged at least 45 at enrollment into the AGEhIV Cohort Study. Multivariable ordinal logistic regression was used to investigate associations between HIV- and antiretroviral therapy-related covariates, markers of inflammation and body composition and prefrailty/frailty., Results: Data were available for 521 HIV-infected and 513 HIV-uninfected individuals. Prevalence of frailty (10.6 versus 2.7%) and prefrailty (50.7 versus 36.3%) were significantly higher in HIV-infected individuals (Ptrend < 0.001). HIV infection remained statistically significantly associated with prefrailty/frailty after adjustment for age, sex, race/ethnicity, smoking, hepatitis C infection, comorbidities and depression [adjusted odds ratio (ORadj) 2.16, P < 0.001]. A higher waist-to-hip ratio attenuated the coefficient of HIV-infected status (ORadj 1.93, P < 0.001), but not waist- or hip-circumference individually or markers of inflammation. Within the HIV-infected group, parameters related to body composition were most strongly and independently associated with prefrailty/frailty: current BMI less than 20 kg/m2 (OR 2.83, P = 0.01), nadir BMI less than 20 kg/m2 (OR 2.51, P = 0.001) and waist-to-hip ratio (OR 1.79 per 0.1 higher, P < 0.001)., Conclusion: HIV infection was independently associated with prefrailty/frailty in middle-aged HIV-infected patients compared with HIV-uninfected controls. This partly may be mediated by the higher waist- and lower hip-circumference in the HIV-infected individuals, potentially partially caused by lipodystrophy, and in part be a consequence of historic weight loss associated with advanced HIV-disease.

Background: Tenofovir disoproxil fumarate (TDF) has been associated with proximal renal tubulopathy and reduction in estimated glomerular filtration rate (eGFR), without accounting for the tubular secretion of creatinine., Methods: A substudy was performed among 19 participants of a randomized 48-week trial, comparing continuing first-line zidovudine/lamivudine (ZDV/3TC) with switching to TDF/emtricitabine (FTC). GFR was measured with [(125)I]-iothalamate (mGFR) and effective renal plasma flow (ERPF) with [(131)I]-hippuran. eGFR and tubular effects were assessed using plasma and urine samples., Results: Of the 19 patients, 18 were men, 15 whites, mean (SD) age 46.0 (8.9) years, plasma HIV-1 RNA less than 50 copies/ml in all. After 48 weeks, eGFR using Cockcroft-Gault equation and ERPF, but not mGFR, had significantly decreased, and urinary α1-microglobulin/creatinine and microalbumin/creatinine significantly increased in patients on TDF. Although phosphate metabolism on TDF was affected at week 4, differences between groups disappeared during follow-up., Conclusion: Replacing ZDV/3TC with TDF/FTC in this limited sample of virologically suppressed HIV-1-infected adults was associated with mild persistent tubular but not glomerular dysfunction over 48 weeks. The observed persistent decrease in Cockcroft-Gault-based eGFR, but not mGFR, rather than being indicative of glomerular dysfunction may be explained by TDF inhibiting tubular creatinine excretion.

Objective: To assess the bone mineral density (BMD) in a cohort of men with primary HIV-1 infection (PHI)., Methods: Thirty-three men with PHI had a dual-energy X-ray absorptiometry (DXA) of the lumbar spine, femoral neck and total hip. Osteopenia and osteoporosis were defined according to WHO criteria as T-scores between -1 and -2.5 and -2.5 or less, respectively. The association between clinical and laboratory parameters and BMD was investigated using multivariable linear regression analysis., Results: Mean age was 38 (SD 9) years and mean body mass index (BMI) 22.7 (SD 3.3) kg/m. Twenty-four men (73%) had a negative or indeterminate Western blot, 32 men (97%) were combination antiretroviral therapy-naive. Mean plasma HIV-1 RNA was 5.0 (SD 1.2) log10 copies/ml. Mean lumbar spine T (-0.8, SD 1.3, P = 0.001) and Z-scores (-0.7, SD 1.3, P = 0.004) and femoral neck T-score (-0.5, SD 0.9, P = 0.003) were significantly lower compared to the reference population. 15/33 men (45%) had osteopenia and 2/33 (6%) osteoporosis. Markers of bone turnover did not differ between patients with or without osteopenia/osteoporosis. Age was negatively associated with femoral neck (beta-coefficient = -0.05, P < 0.001) and total hip T-scores (beta = -0.03, P = 0.04). BMI was associated with lumbar spine (beta = 0.3), femoral neck (beta = 0.2) and total hip (beta = 0.2) T-scores (P < 0.001) and thyroid-stimulating hormone (TSH) with lumbar spine (beta = 0.5, P = 0.045) and femoral neck T-scores (beta = 0.4, P = 0.005). Increased plasma viral load was associated with lower total hip T-scores (beta = -0.2, P = 0.02)., Conclusions: Reduced BMD was prevalent in PHI men and was associated with increased age, lower BMI and TSH levels, and higher levels of HIV-1 viremia.

Objective: To improve the pharmacokinetics of protease inhibitors, boosting with low-dose ritonavir is performed. However, toxicity, storage conditions and high costs of antiretroviral treatment may necessitate interruption of ritonavir. Ketoconazole was investigated as a potential booster of once-daily (o.d.) saquinavir., Methods: In a single-group, two-period design, 25 virologically and immunologically stable patients on saquinavir/ritonavir 2000/100 mg o.d. were switched to saquinavir/ketoconazole 2000/400 mg o.d. for 2 weeks. Two steady-state pharmacokinetic curves were recorded at both periods., Results: Fourteen females and 11 male patients were included. Median age was 34 years [interquartile range (IQR), 32-42 years], body weight 54 kg (IQR, 47-59 kg) and body mass index 21 kg/m (19-23 kg/m). The mean saquinavir area under the curve (AUC) during boosting with ritonavir was 57.93 +/- 27.96 mg/h/l, maximum observed concentration (Cmax) was 7.50 +/- 3.45 mg/l and concentration at 24 h (Cmin) was 0.35 +/- 0.30 mg/l. When ketoconazole was used, the saquinavir AUC, Cmax, and Cmin were 12.00 +/- 6.97 mg/h/l, 2.43 +/- 1.35 mg/l and 0.03 +/- 0.04 mg/l, respectively., Conclusion: Boosting with ketoconazole resulted in 80% lower exposure to saquinavir. Although saquinavir AUC might still be adequate for treatment, concentrations at 24 h reached levels below the recommended trough concentrations of 0.1 mg/l, which may result in selection of resistant HIV-1 viral strains. Therefore, boosting of saquinavir by ketoconazole is not recommended.

We studied T cell dynamics in four patients who initially responded well to highly active antiretroviral therapy (HAART) but subsequently experienced virological failure. Maintenance of peripheral blood CD4T cell counts was associated with low levels of immune activation. Low reactivity to rebounding virus may preserve normal T lymphocyte distribution over blood and tissues and be associated with stable peripheral blood T cell numbers in virological failures to HAART.

Background: The treatment of HIV-1-infected patients with triple-drug combination therapy results in profound suppression of viral replication. In most therapy-naive patients plasma HIV-1-RNA levels (pVL) drop below the lower limit of quantification (LLQ) of currently used assays. In a large percentage of such patients, more sensitive assays provide evidence of residual viral replication. The question is whether more potent therapy can further suppress this residual replication., Methods: Thirty control patients who, using very strict criteria, had not experienced virological failure during 3 years of standard therapy, were compared with 10 patients treated with a five-drug regimen, consisting of three different classes of antiretroviral drugs (alternative multidrug regimen). A modified ultrasensitive assay with an LLQ of 5 copies/ml was used to re-test plasma obtained at week 48 and at three timepoints at and around week 144., Results: At weeks 48 and 144 pVL could be quantified significantly more frequently in control patients than in patients using the alternative multidrug regimen (week 48: 42 versus 0% with quantifiable pVL, P = 0.017; week 144: 60 versus 14% with at least one quantifiable pVL, P = 0.036, respectively). A low baseline CD4T cell count was predictive of quantifiable pVL in control patients, but not in alternative multidrug patients., Conclusion: This proof-of-principle study demonstrates that the use of an alternative multidrug regimen results in stronger long-term suppression of pVL compared with clinically successful treatment with standard therapy.